Category Archives: Massachusetts Stem Cells

Research funded by grantsMetals from e-cigarette aerosols accumulate in the brain

Mice exposed to e-cigarette aerosols had a buildup of toxic metals in the brain, according to NIEHS-funded researchers. The exposure also altered brain levels of essential metals, which play a key role in many biological processes. The findings provide clues about the onset of neurodegenerative diseases, which have been linked to toxic metal exposure and the dysregulation of essential metals.

The researchers exposed mice to either the equivalent of secondhand e-cigarette aerosol or a five-fold higher level for two months. They then measured levels of 15 different metals in brain and other central nervous system (CNS) tissues, such as the spinal cord.

Compared with unexposed mice, mice exposed to e-cigarette aerosol had significant buildup of several metals in the brain and CNS. Many of the metals that accumulated in exposed mice were known neurotoxins, including chromium, copper, iron, and lead.

Citation: Re DB, Hilpert M, Saglimbeni B, Strait M, Ilievski V, Coady M, Talayero M, Wilmsen K, Chesnais H, Balac O, Glabonjat RA, Slavkovich V, Yan B, Graziano J, Navas-Acien A, Kleiman NJ. 2021. Exposure to e-cigarette aerosol over two months induces accumulation of neurotoxic metals and alteration of essential metals in mouse brain. Environ Res 202:111557. (Synopsis(https://factor.niehs.nih.gov/2021/9/papers/dert/index.htm#a1))

An NIEHS-funded study in mice showed how chlorine exposure leads to acute chest syndrome, a leading cause of death in patients with sickle cell disease (SCD). The results point to a potential lifesaving therapy for SCD patients exposed to chlorine, which is found in some household cleaning products.

The researchers used genetically engineered mice that resembled SCD in humans (sickle mice) and compared them with healthy control mice with human hemoglobin. They exposed both groups to chlorine gas or normal air.

Within six hours of chlorine exposure, 64% of sickle mice died, whereas none of the controls died. Compared with controls, surviving sickle mice experienced lung injury and hemolysis, or the rupture of red blood cells, which releases hemoglobin into the blood. Hemopexin treatment following exposure significantly improved survival and reduced blood heme levels and lung injury.

Citation: Alishlash AS, Sapkota M, Ahmad I, Maclin K, Ahmed NA, Molyvdas A, Doran S, Albert CJ, Aggarwal S, Ford DA, Ambalavanan N, Jilling T, Matalon S. 2021. Chlorine inhalation induces acute chest syndrome in humanized sickle cell mouse model and ameliorated by postexposure hemopexin. Redox Biol 44:102009. (Synopsis(https://factor.niehs.nih.gov/2021/8/papers/dert/index.htm#a1))

Women exposed to higher temperatures had a lower ovarian reserve, according to NIEHS-funded researchers. Ovarian reserve refers to the number and quality of a womans eggs. A diminished ovarian reserve reduces a womans ability to get pregnant.

The study included 631 women aged 18-45 years enrolled in a reproductive health study in Massachusetts. Using each womans home address, the researchers estimated daily ambient temperature exposures for three months, one month, and two weeks before the ovarian reserve examination. They used ultrasonography to measure antral follicle count (AFC), a measure of ovarian reserve.

Exposure to higher temperatures was associated with a lower AFC. The negative association between temperature and AFC was stronger in November through June compared with the summer months. The finding suggests women may be more susceptible to heat during certain times of the year, potentially because they adapt to heat in the summer.

Citation: Gaskins AJ, Minguez-Alarcon L, VoPham T, Hart JE, Chavarro JE, Schwartz J, Souter I, Laden F. 2021. Impact of ambient temperature on ovarian reserve. Fertil Steril 116(4):10521060. (Synopsis(https://factor.niehs.nih.gov/2021/8/papers/dert/index.htm#a2))

NIEHS grantees developed a gene expression atlas that captures the cellular makeup of the mammary gland across life stages, providing clues on how breast cancer originates. To build the atlas, the researchers used single cell RNA sequencing data, which assesses gene and protein expression of an individual cell. They integrated data from 50,000 mouse mammary cells, covering eight life stages, and 24,000 adult human mammary cells.

Using known genetic markers, team members identified the clusters as three breast epithelial cell types. The scientists compared genetic profiles for each epithelial cell type with known cancer-related genes to infer breast cancer cells of origin. They also examined how reorganization during different life stages altered breast cellular makeup and breast cancer subtype risk. According to the authors, the atlas provides insights into cellular makeup and development of breast cancer subtypes.

Citation: Saeki K, Chang G, Kanaya N, Wu X, Wang J, Bernal L, Ha D, Neuhausen SL, Chen S. 2021. Mammary cell gene expression atlas links epithelial cell remodeling events to breast carcinogenesis. Commun Biol 4(1):660. (Synopsis(https://factor.niehs.nih.gov/2021/8/papers/dert/index.htm#a3))

Children exposed to lead have altered brain structure and poorer cognitive function in midlife, according to NIEHS-funded research. These lead-related brain changes may increase the risk of neurodegenerative disease, like dementia, in later life.

The study included 564 children who were enrolled in a New Zealand birth cohort in the early 1970s and followed to midlife. The researchers measured child blood lead levels at age 11 years. Using magnetic resonance imaging, they examined participants structural brain integrity at age 45 years. They also assessed adult cognitive function and intelligence using a standardized IQ test.

Higher lead exposure in childhood was associated with structural deficits in the middle-aged brain. The results suggest that adults exposed to lead as children may be at increased risk of neurodegenerative diseases in later life and reinforce the need for long-term follow-up of lead-exposed child cohorts.

Citation: Reuben A, Elliott ML, Abraham WC, Broadbent J, Houts RM, Ireland D, Knodt AR, Poulton R, Ramrakha S, Hariri AR, Caspi A, Moffitt TE. 2020. Association of childhood lead exposure with MRI measurements of structural brain integrity in midlife. JAMA 324(19):19701979. (Synopsis(https://factor.niehs.nih.gov/2021/1/papers/dert/index.htm#a2))

Exposure to semi-volatile organic compounds (SVOCs) was linked with changes to young childrens gut microbiome, according to a new NIEHS-funded study. SVOCs are common contaminants of indoor air and dust.

The researchers measured levels of 44 SVOCs, including phthalates and per- and polyfluoroalkyl substances (PFAS), in the blood and urine of 69 children aged 3 to 6 years. Using genetic sequencing techniques, they determined the types and abundance of bacteria and fungi present in child stool samples.

Children with higher levels of PFAS in their blood had a lower number and diversity of bacteria in their gut. Higher phthalate levels were associated with a reduction in gut fungal populations. Surprisingly, children with higher levels of certain SVOCs, including triclosan, had several types of bacteria in their gut known to break down toxic chemicals in the environment.

Citation: Gardner CM, Hoffman K, Stapleton HM, Gunsch CK. 2021. Exposures to semivolatile organic compounds in indoor environments and associations with the gut microbiomes of children. Environ Sci Technol Lett 8(1):7379. (Synopsis(https://factor.niehs.nih.gov/2021/1/papers/dert/index.htm#a4))

A new NIEHS-funded study showed that exposure to nearly 300 common chemicals can cause cells to produce more estrogen or progesterone, which may increase breast cancer risk.

The study included data for more than 650 chemicals tested in the U.S. Environmental Protection Agencys ToxCast program. The researchers examined the data to identify chemicals that increased progesterone or estradiol, a form of estrogen, in a human cancer cell line.

Of the chemicals tested, 296 increased estradiol or progesterone in cells, whereas 71 chemicals increased both hormones. Using data from existing animal studies, the researchers then classified the hormone-increasing chemicals as either likely or unlikely to cause cancer or result in poor reproductive or developmental outcomes. Thirty percent were classified as likely carcinogens or reproductive or developmental toxicants, whereas only 5%-13% were classified as unlikely to cause these health outcomes.

Citation: Cardona B, Rudel RA. 2021. Application of an in vitro assay to identify chemicals that increase estradiol and progesterone synthesis and are potential breast cancer risk factors. Environ Health Perspect 129(7):77003. (Synopsis(https://factor.niehs.nih.gov/2021/9/papers/dert/index.htm#a2))

A study by NIEHS-funded researchers provides insight into how SARS-CoV-2, the virus that causes COVID-19, damages heart cells. The findings may inform treatment strategies to protect heart health in COVID-19 patients.

Using stem cells, the researchers created three types of human heart cells cardiomyocytes, cardiac fibroblasts, and endothelial cells and exposed them to small amounts of the SARS-CoV-2 virus for 48 hours. The virus was only able to infect and replicate in cardiomyocytes, the heart muscle cells. Unlike the other cell types, cardiomyocytes had ACE2 receptors on their surface, which serve as the cellular entry point for the virus.

Infected cardiomyocytes showed structural defects and had decreased expression of genes important in heart contraction. Many cardiomyocytes were missing nuclear DNA. Without this DNA, cells cannot function. Heart tissue samples from deceased COVID-19 patients mirrored the structural and genetic changes observed in cell models.

Citation: Perez-Bermejo JA, Kang S, Rockwood SJ, Simoneau CR, Joy DA, Silva AC, Ramadoss GN, Flanigan WR, Fozouni P, Li H, Chen PY, Nakamura K, Whitman JD, Hanson PJ, McManus BM, Ott M, Conklin BR, McDevitt TC. 2021. SARS-CoV-2 infection of human iPSC-derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19. Sci Transl Med 13(590):eabf7872. (Synopsis(https://factor.niehs.nih.gov/2021/7/papers/dert/index.htm#a2))

Using machine learning, NIEHS-funded researchers identified patterns in maternal autoantibodies, immune proteins that attack a persons own proteins or tissues, that were highly associated with the diagnosis and severity of autism spectrum disorder (ASD).

The team previously identified maternal autoantibodies against eight key proteins related to ASD. In this study, the researchers developed an accurate test for reactivity patterns against those proteins that could predict ASD. They analyzed plasma samples from 450 mothers of children with autism and 342 mothers of typically developing children from the Childhood Autism Risks from Genetics and Environment (CHARGE) study.

The researchers found autoantibody reactivity to a single protein did not correlate with ASD diagnosis. Instead, reactivity to autoantibodies to CRIMP1 combined with any of the top proteins increased the likelihood of a higher ASD severity score. The approach may aid early ASD detection, which can help facilitate early interventions.

Citation: Ramirez-Celis A, Becker M, Nuno M, Schauer J, Aghaeepour N, Van de Water J. 2021. Risk assessment analysis for maternal autoantibody-related autism (MAR-ASD): a subtype of autism. Mol Psychiatry 26(5):15511560. (Synopsis(https://factor.niehs.nih.gov/2021/3/papers/dert/index.htm#a1))

Elevated levels of phthalates during pregnancy may negatively affect executive function in children, according to an NIEHS-funded study. Executive function a set of complex cognitive skills, such as emotional regulation, impulse control, working memory, and attentional flexibility enables people to focus, follow directions, and handle emotions.

Researchers measured 12 phthalate metabolites in urine samples collected at 17 weeks of pregnancy. Among those children sampled, born between 2003 and 2008, the researchers compared 262 children who had attention-deficit hyperactivity disorder symptoms with 78 typically developing children.

Exposure to higher levels of mono-benzyl phthalate (MBzP) in maternal blood during the prenatal period was associated with poorer executive function in both sexes. Also, higher levels of mono-n-butyl phthalate and mono-iso-butyl phthalate affected executive function, but results varied by evaluation method. For example, inhibition reported by parents was most affected by both chemicals, with stronger associations among boys.

Citation: Choi G, Villanger GD, Drover SSM, Sakhi AK, Thomsen C, Nethery RC, Zeiner P, Knudsen GP, Reichborn-Kjennerud T, Overgaard KR, Herring AH, Skogan AH, Biele G, Aase H, Engel SM. 2021. Prenatal phthalate exposures and executive function in preschool children. Environ Int 149:106403. (Synopsis(https://factor.niehs.nih.gov/2021/5/papers/dert/index.htm#a2))

NIEHS-funded researchers observed an increase in respiratory disease and other hospitalizations among older adults following exposure to tropical cyclones, which may help hospitals become better prepared in the future. Tropical cyclone is a generic term used to describe tropical depressions, tropical storms, and hurricanes.

The team used data on 70 million Medicare hospitalizations for individuals 65 years and older and a comprehensive database of county-level local winds to estimate tropical cyclone exposures between 1999 and 2014. Using advanced statistical models, they examined how tropical cyclone exposure related to hospitalizations for 13 different causes.

In the week following tropical cyclone exposure, researchers observed an average increase in hospitalizations from several causes, including respiratory diseases, infectious and parasitic diseases, and injuries. The results demonstrate the need for targeted hospital preparedness strategies before, during, and after tropical cyclones and other extreme weather.

Citation: Parks RM, Anderson GB, Nethery RC, Navas-Acien A, Dominici F, Kioumourtzoglou MA. 2021. Tropical cyclone exposure is associated with increased hospitalization rates in older adults. Nat Commun 12(1):1545. (Synopsis(https://factor.niehs.nih.gov/2021/5/papers/dert/index.htm#a3))

Portable air cleaners may improve respiratory symptoms among former smokers with chronic obstructive pulmonary disease (COPD), according to an NIEHS-funded study. COPD is a progressive disease characterized by lung injury and inflammation and has limited treatment options.

Smoking cessation can slow the advancement of COPD, but former smokers continue to be affected by the disease, which can be worsened by exposure to air pollutants, such as particulate matter and nitrogen dioxide. The team conducted a blinded, randomized controlled trial of 116 former smokers with moderate to severe COPD. Participants received active or sham portable HEPA air cleaners for their homes and were followed for six months.

The active HEPA filter group experienced reduced respiratory symptoms and fewer urgent health care visits compared with the sham group. They also had lower rates of systemic steroid, antibiotic, or rescue medication use.

Citation: Hansel NN, Putcha N, Woo H, Peng R, Diette GB, Fawzy A, Wise RA, Romero K, Davis MF, Rule AM, Eakin MN, Breysse PN, McCormack MC, Koehler K. 2021. Randomized clinical trial of air cleaners to improve indoor air quality and COPD health: results of the CLEAN AIR STUDY. Am J Respir Crit Care Med; doi:10.1164/rccm.202103-0604OC [Online 27 August 2021]. (Synopsis(https://factor.niehs.nih.gov/2021/11/papers/dert/index.htm#a1))

An international team of researchers, funded in part by NIEHS, identified promising new targets for treatment and early diagnosis of pancreatic ductal adenocarcinoma (PDAC), a highly aggressive condition with poor patient survival.

Using samples from 140 pancreatic cancers and more than 70 normal pancreatic tissues, the scientists carried out genomic, RNA, and microRNA sequencing, combined with detailed analyses of protein modifications. Focusing on 222 proteins that were at least twice as abundant in cancerous cells than in normal cells, they identified 12 proteins that they say could aid early detection in blood samples.

They also found nearly 5,000 sites within these proteins with increased phosphate groups and more than 1,700 sites with increased carbohydrate chains. The team said several of these patterns offered clues for treatment, such as blocking the enzymes involved in specific protein modifications associated with PDAC.

Citation: Cao L, Huang C, Cui Zhou D, Hu Y, Lih TM, Savage SR, Krug K, Clark DJ, Schnaubelt M, Chen L, da Veiga Leprevost F, Eguez RV, Yang W, Pan J, Wen B, Dou Y, Jiang W, Liao Y, Shi Z, Terekhanova NV, Cao S, Lu RJ, Li Y, Liu R, Zhu H, Ronning P, Wu Y, Wyczalkowski MA, Easwaran H, Danilova L, Mer AS, Yoo S, Wang JM, Liu W, Haibe-Kains B, Thiagarajan M, Jewell SD, Hostetter G, Newton CJ, Li QK, Roehrl MH, Feny D, Wang P, Nesvizhskii AI, Mani DR, Omenn GS, Boja ES, Mesri M, Robles AI, Rodriguez H, Bathe OF, Chan DW, Hruban RH, Ding L, Zhang B, Zhang H; Clinical Proteomic Tumor Analysis Consortium. 2021. Proteogenomic characterization of pancreatic ductal adenocarcinoma. Cell 184(19):50315052.e26. (Synopsis(https://factor.niehs.nih.gov/2021/11/papers/dert/index.htm#a3))

Working with citizen-scientists, NIEHS-funded researchers demonstrated that leaves can be used as a low-cost, reliable method to assess the level of metals in airborne dust. The method can help assess exposure from former mine sites that emit heavy metals that can be distributed by wind to nearby communities.

Twenty participants from Superior, Arizona, placed a potted peppermint plant and disc sampler in a self-selected area, usually outside of their home. After one month, they submitted two leaves and the disc for analysis of seven different metals arsenic, lead, cadmium, copper, aluminum, nickel, and zinc.

On both the leaves and discs, levels of all metals decreased as distance from the mine increased. The results suggest that plant leaves can serve as a reliable monitor of metal-laden aerosols and that the low-cost technique is applicable to sites where resources are limited.

Citation: Zeider K, Van Overmeiren N, Rine KP, Sandhaus S, Eduardo Saez A, Sorooshian A, Munoz HC Sr, Ramirez-Andreotta MD. 2021. Foliar surfaces as dust and aerosol pollution monitors: an assessment by a mining site. Sci Total Environ 790:148164. (Synopsis(https://factor.niehs.nih.gov/2021/10/papers/dert/index.htm#a2))

Thousands of COVID-19 cases and deaths in the western U.S. may be attributable to increases in fine particulate matter air pollution (PM2.5) from wildfires, according to NIEHS-funded research. Exposure to wildfire smoke can increase the risk of lung infections, including COVID-19.

The researchers linked publicly available data on daily PM2.5 levels and the number of COVID-19 cases and deaths that occurred between March and December 2020 in 92 counties across California, Oregon, and Washington. They developed a model to estimate the association between daily changes in PM2.5 and percentage increase in COVID-19 cases and deaths up to 28 days after exposure.

From August to October 2020, when fire activity was greatest, daily levels of PM2.5 during wildfire days were significantly higher than on non-wildfire days. The total number of COVID-19 cases and deaths attributable to daily increases in PM2.5 from wildfires were 19,742 and 748, respectively.

Citation: Zhou X, Josey K, Kamareddine L, Caine MC, Liu T, Mickley LJ, Cooper M, Dominici F. 2021. Excess of COVID-19 cases and deaths due to fine particulate matter exposure during the 2020 wildfires in the United States. Sci Adv 7(33):eabi8789. (Synopsis(https://factor.niehs.nih.gov/2021/10/papers/dert/index.htm#a4))

Male hormones can protect from inflammation and pre-cancerous conditions in the stomach, according to a study by NIEHS scientists. The study offers novel mechanistic insight into how male hormones regulate stomach inflammation by restraining specialized immune cells.

The authors observed that glucocorticoids, a type of steroid hormone produced by adrenal glands, is required to protect female mice from stomach inflammation. However, in male mice, they found that in addition to glucocorticoids, male sex hormones provide an additional layer of protection against stomach inflammation. The researchers found that the inflammatory response from specific immune cells called type 2 innate-lymphoid cells (ILC2) drives the development of gastric inflammation. Importantly, the study showed that male sex hormones directly repress the proinflammatory state of ILC2, thereby preventing harmful inflammation.

Citation: Busada JT, Peterson KN, Khadka S, Xu X, Oakley RH, Cook DN, Cidlowski JA. 2021. Glucocorticoids and androgens protect from gastric metaplasia by suppressing group 2 innate lymphoid cell activation. Gastroenterology 161(2):637652.e4. (Synopsis(https://factor.niehs.nih.gov/2021/7/papers/dir/index.htm#a3)) (Story)

NIEHS scientists have identified five clusters of conventional dendritic cells (cDC2s) in the lungs of mice following their inhalation of house dust extract. As a result, the team is closer to understanding the cellular and molecular mechanisms involved in pulmonary diseases, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), and asthma.

The researchers used mass cytometry, single cell RNA sequencing, and a mouse model of asthma to assess how the developmental progression of cDC2s affects their ability to promote differentiation of the distinct T-helper (Th) cell lineages, Th2 and Th17. The researchers found that Ly6C, a cell-surface marker of immature dendritic cells, is associated with those cells ability to promote the differentiation of Th17 cells. This finding is important because cDC2s in the lung direct immune responses to inhaled agents in the environmental bioaerosol.

Citation: Izumi G, Nakano H, Nakano K, Whitehead GS, Grimm SA, Fessler MB, Karmaus PW, Cook DN. 2021. CD11b+ lung dendritic cells at different stages of maturation induce Th17 or Th2 differentiation. Nat Commun 12(1):5029. (Synopsis(https://factor.niehs.nih.gov/2021/10/papers/dir/index.htm#a2))

NIEHS researchers discovered that removal of perineuronal nets (PNNs) a specialized form of extracellular matrix in a Mecp2-null mouse model of Rett syndrome (RTT) salvages synaptic plasticity in the hippocampal area CA2 of the brain early in postnatal development. Synaptic plasticity refers to the brains ability to respond to environmental stimuli. RTT is a neurodevelopmental disorder characterized by normal development in the first year of life, followed by rapid, significant decline in cognitive, motor, and social function. The condition affects 1 in 10,000 girls worldwide.

The authors previously found that PNNs limit synaptic plasticity in CA2, a region associated with social learning in mice and an area that is atypically resistant to long-term potentiation. The scientists observed increased PNNs in the CA2 region of postmortem human tissue from an individual with RTT and found that PNNs develop precociously in the murine model of RTT.

Citation: Carstens KE, Lustberg DJ, Shaughnessy EK, McCann KE, Alexander GM, Dudek SM. 2021. Perineuronal net degradation rescues CA2 plasticity in a mouse model of Rett syndrome. J Clin Invest 131(16):e137221. (Synopsis(https://factor.niehs.nih.gov/2021/9/papers/dir/index.htm#a5))

NIEHS researchers and their collaborators found an association between exposure to consumer product chemicals and oxylipins during pregnancy. Oxylipins are lipids that play important roles in inflammation, tissue repair, and blood clotting.

The researchers looked at biomarkers of exposure to three classes of consumer product chemicals, including phenols, phthalates, and organophosphate esters (OPEs) in the urine of 90 mothers during multiple points of pregnancy. These biomarkers were simultaneously examined alongside a panel of oxylipins found in serum.

The scientists demonstrated that several oxylipins involved in inflammatory responses were higher in pregnant women with elevated concentrations of urinary phenol, phthalate, and OPE biomarkers. These associations varied by the class of consumer product chemical and the pathway by which oxylipin was produced. Taken together, this study provides insight into how exposure to environmental chemicals during pregnancy affects specific processes of inflammation.

Citation: Welch BM, Keil AP, Bommarito PA, van T' Erve TJ, Deterding LJ, Williams JG, Lih FB, Cantonwine DE, McElrath TF, Ferguson KK. 2021. Longitudinal exposure to consumer product chemicals and changes in plasma oxylipins in pregnant women. Environ Int 157:106787. (Synopsis(https://factor.niehs.nih.gov/2021/11/papers/dir/index.htm#a2))

Using a mouse model that lacked the gene IRGM1, a research team led by NIEHS researchers determined that a buildup of defective mitochondria led to an autoimmune condition that resembled Sjogrens syndrome. In humans, Sjogrens is characterized by dryness in the mouth, eyes, and other parts of the body. The research suggests a possible mechanism for how autoimmunity develops in people.

IRGM1 is the mouse version of a human gene called IRGM. These genes are responsible for autophagy, a process that removes malfunctioning organelles from the cell. In addition to displaying symptoms of autoimmunity, the scientists determined that IRGM1 knockout mice also had evidence for increased signaling by an inflammatory protein called type 1 interferon. The scientists also provided evidence that the DNA and RNA that spills out of faulty mitochondria elicit an immune response that causes an overproduction of type 1 interferon.

Citation: Rai P, Janardhan KS, Meacham J, Madenspacher JH, Lin WC, Karmaus PWF, Martinez J, Li QZ, Yan M, Zeng J, Grinstaff MW, Shirihai OS, Taylor GA, Fessler MB. 2021. IRGM1 links mitochondrial quality control to autoimmunity. Nat Immunol 22(3):312321. (Synopsis(https://factor.niehs.nih.gov/2021/3/papers/dir/index.htm#a4)) (Story)

NIEHS researchers have revealed how a protein called INO80 controls the fate of pluripotent stem cells, which can give rise to all cell types in the body.

INO80 is involved in many cellular and developmental processes, as well as neurological diseases and cancer. As a chromatin remodeler, INO80 can regulate gene activity by altering the structure of chromatin, which consists of DNA and proteins such as histones.

The researchers inactivated the INO80 gene in mouse stem cells at different developmental stages and found that INO80 enhanced the binding of a histone variant called H2A.Z to key DNA sequences at the later developmental stage. This event triggered the addition of certain chemical groups to histones, thereby decreasing the activity of nearby genes that play important roles in development. The findings revealed unexpected functions of INO80 in regulating the genomic positioning of H2A.Z and gene activity.

Citation: Yu H, Wang J, Lackford B, Bennett B, Li JL, Hu G. 2021. INO80 promotes H2A.Z occupancy to regulate cell fate transition in pluripotent stem cells. Nucleic Acids Res 49(12):67396755. (Synopsis(https://factor.niehs.nih.gov/2021/8/papers/dir/index.htm#a2))

Researchers at NIEHS led a team that reported that short sleep and apnea-specific hypoxia, which is the lack of adequate oxygen because of apnea, are associated with chronic kidney disease (CKD) in a multi-ethnic population. The findings indicate that sleep disturbance was twice as prevalent among African American participants with CKD compared with white participants. The research incorporated novel, more sensitive assessments of sleep apnea and evaluated these associations in a racially and ethnically diverse population. Such data are lacking in the literature.

The scientists found that very short sleep, five or fewer hours per night, and sleep apnea-specific hypoxia were associated with moderate-to-severe CKD. These sleep deficiencies may contribute to CKD by worsening known risk factors, such as dyslipidemia, hypertension, and type 2 diabetes. The association between sleep deficiencies and CKD could be studied by clinicians and public health professionals to address health disparities.

Citation: Jackson CL, Umesi C, Gaston SA, Azarbarzin A, Lunyera J, McGrath JA, Jackson WB, Diamantidis CJ, Boulware E, Lutsey PL, Redline S. 2020. Multiple, objectively measured sleep dimensions including hypoxic burden and chronic kidney disease: findings from the Multi-Ethnic Study of Atherosclerosis. Thorax 76(7):704713. (Synopsis(https://factor.niehs.nih.gov/2021/2/papers/dir/index.htm#a3))

The gene regulatory protein GLIS1 is associated with glaucoma in humans and the regulation of intraocular pressure inside the eyes of mice, according to NIEHS researchers and their collaborators. This study sheds light on the cellular and molecular causes of the second most common cause of blindness in the U.S. and may lead to the development of new therapies.

In most cases, glaucoma is caused by an increase in intraocular pressure, which is largely regulated by an eye tissue known as the trabecular meshwork. The researchers found that mice lacking GLIS1 developed enlarged eyes and a long-lasting increase in intraocular pressure,

The study revealed that low levels of GLIS1 induce the degeneration of the trabecular meshwork, leading to inefficient drainage of the ocular fluid called the aqueous humor. The research also showed that GLIS1 regulates the expression of several glaucoma-associated genes in trabecular meshwork cells.

Citation: Nair KS, Srivastava C, Brown RV, Koli S, Choquet H, Kang HS, Kuo YM, Grimm SA, Sutherland C, Badea A, Johnson GA, Zhao Y, Yin J, Okamoto K, Clark G, Borras T, Zode G, Kizhatil K, Chakrabarti S, John SWM, Jorgenson E, Jetten AM. 2021. GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans. Nat Commun 12(1):4877. (Synopsis(https://factor.niehs.nih.gov/2021/10/papers/dir/index.htm#a3))

NIEHS researchers and their collaborators reported that an epigenetic modification known as histone crotonylation (Kcr) is necessary for the differentiation of human embryonic stem cells (hESCs) during early embryonic development. Epigenetics, the study of how genes are read and expressed, is known to be important in regulation of pluripotency and differentiation of hESCs in response to metabolic alterations, but the specific mechanisms were unclear.

Using immunofluorescence and quantitative proteomic analyses, the authors showed that histone Kcr, a specific epigenetic modification to the proteins that package DNA inside chromosomes, increases during a metabolic switch from glycolysis to oxidative phosphorylation early in the process by which hESCs differentiate into mesoendodermal cells. This increase induces mesoendodermal gene expression and promotes mesoendoderm differentiation in vitro and in vivo. The data directly link metabolic programming to histone Kcr and further demonstrate that Kcr plays a role in promoting mesoendodermal gene expression.

Citation: Fang Y, Xu X, Ding J, Yang L, Doan MT, Karmaus PWF, Snyder NW, Zhao Y, Li JL, Li X. 2021. Histone crotonylation promotes mesoendodermal commitment of human embryonic stem cells. Cell Stem Cell 28(4):748763.e7. (Synopsis(https://factor.niehs.nih.gov/2021/3/papers/dir/index.htm#a5))

The mosquito protein AEG12 disrupts the lipid envelope that covers some viruses, according to NIEHS researchers and their collaborators. Flaviviruses a class that includes dengue, yellow fever, and zika virus are mainly transmitted by mosquitos and typically covered by a protective coating of lipids. Mosquitos produce AEG12 in response to a blood meal or flavivirus infection.

After solving the three-dimensional structure of AEG12 by X-ray crystallography, the researchers identified AEG12 as a lipid-binding protein. They further demonstrated that AEG12 was capable of rupturing membranes of red blood cells and inhibiting the replication of flaviviruses and other enveloped viruses, including human coronaviruses.

AEG12 breaks open the cells or virus by swapping the lipid it carries with those in the cell membrane or virus envelop. By doing so, AEG12 contributes to both insect digestion and the antiviral immune response.

Citation: Foo ACY, Thompson PM, Chen SH, Jadi R, Lupo B, DeRose EF, Arora S, Placentra VC, Premkumar L, Perera L, Pedersen LC, Martin N, Mueller GA. 2021. The mosquito protein AEG12 displays both cytolytic and antiviral properties via a common lipid transfer mechanism. Proc Natl Acad Sci U S A 118(11):e2019251118. (Synopsis(https://factor.niehs.nih.gov/2021/5/papers/dir/index.htm#a2)) (Story)

Although women with type 2 diabetes (T2D) may have increased breast cancer risk, use of the antidiabetic drug metformin may reduce that risk. A team led by NIEHS researchers found women with T2D and long-term metformin use were 38% less likely to develop estrogen receptor-positive (ER-positive) breast cancer compared with women without T2D. However, women with T2D and metformin use were at increased risk of ER-negative breast cancer and triple-negative breast cancer (TNBC).

The scientists used data from 44,541 women in the Sister Study, a prospective study of risk factors for breast cancer and other diseases. Participants were aged 35-74 years and breast-cancer free at enrollment. Although the researchers did not find an association between T2D and breast cancer overall, 74% of those with T2D used metformin, and long-term metformin treatment was associated with reduced risk of ER-positive breast cancer.

Citation: Park Y-MM, Bookwalter DB, O'Brien KM, Jackson CL, Weinberg CR, Sandler DP. 2021. A prospective study of type 2 diabetes, metformin use, and risk of breast cancer. Ann Oncol 32(3):351359. (Synopsis(https://factor.niehs.nih.gov/2021/4/papers/dir/index.htm#a5))

NIEHS researchers and their colleagues used structural biology to study the endoribonuclease nonstructural protein 15 (Nsp15), an enzyme that cuts single- and double-strand viral RNA. Nsp15 is found in all coronaviruses and, through a complex process, helps the virus evade a hosts immune system. These findings may allow researchers to design therapeutics that bind to the Nsp15 active site of SARS-CoV-2, which could help treat COVID-19 cases.

Researchers used cryogenic electron microscopy, or cryo-EM, to visualize the structure of Nsp15. In addition to creating structural images, they performed molecular dynamics simulations to assess the biological function of the protein. They found that Nsp15 is stable and active when bound with RNA, but when it is not bound with RNA, Nsp15 constantly shifts and creates a wobble effect. Although the significance of the wobble is not completely understood, it may present a previously unexplored function.

Citation: Pillon MC, Frazier MN, Dillard LB, Williams JG, Kocaman S, Krahn JM, Perera L, Hayne CK, Gordon J, Stewart ZD, Sobhany M, Deterding LJ, Hsu AL, Dandey VP, Borgnia MJ, Stanley RE. 2021. Cryo-EM structures of the SARS-CoV-2 endoribonuclease Nsp15 reveal insight into nuclease specificity and dynamics. Nat Commun 12(1):636. (Synopsis(https://factor.niehs.nih.gov/2021/3/papers/dir/index.htm#a3))

Read the original:
January 2022: 2021 Papers of the year - Environmental Factor Newsletter

Lisocabtagene maraleucel (liso-cel; Breyanzi) fostered a better quality of life (QoL) in patients with relapsed/refractory large B-cell lymphoma (LBCL) compared with current standard of care (SOC), according to data from a comparative analysis of the phase 3 TRANSFORM trial (NCT03575351) presented during the 2021 ASH Annual Meeting.1

Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30 items (EORTC QLQ-C30), a linear mixed model for repeated measures (MMRM) group analysis found that those in the liso-cel arm had more favorable overall least square (LS) mean changes from baseline to day 126 vs the SOC arm in most of the domains analyzed.

Evaluable patients who received the CAR T-cell therapy (n = 47) experienced a mean change in cognitive functioning of 2.21 (range, -1.48 to 5.90) vs -2.09 (range, -6.00 to 1.83) in those who received SOC (n = 43); this translated to a difference of 4.30 (range, -0.76 to 9.36) on day 126 from baseline.

Those in the liso-cel arm also experienced a mean change in fatigue of -1.95 (range, -7.40 to 3.51) compared with 3.75 (range, -2.17 to 9.68) in the SOC arm, equating to a difference of -5.70 (range, -13.24 to 1.84) on day 126 from baseline. In these domains, the liso-cel group improved, as the SOC group deteriorated.

Additionally, the liso-cel arm had a mean change in global health status/QoL (GH/QoL) of 3.08 (range, -1.83 to 7.99) from baseline to day 126; the SOC arm experienced a mean change of 0.04 (range, -5.24 to 5.31), resulting in a difference of 3.04 (range, -3.62 to 9.70) between the 2 arms.

The liso-cel group also experienced mean changes in physical functioning and pain of -2.75 (range, -6.76 to 1.25) and -11.14 (range, -16.37 to -5.92), respectively, compared with -2.17 (range, -6.64 to 2.30) and -15.56 (range, -21.25 to -9.88), respectively, for the SOC group. The differences between the 2 arms in physical functioning and pain were -0.58 (range, -6.17 to 5.01) and 4.42 (range, -2.72 to 11.56), respectively.

Individual-level analyses demonstrated that the proportion of patients with meaningful improvement was higher for GH/QoL, and deterioration was lower with liso-cel vs SOC from day 126 to month 6.

At the 6-month mark, 53% of patients in the liso-cel arm reported improvement in GH/QoL, compared with 14% of those in the SOC arm. Eighteen percent of patients in the liso-cel arm reported deterioration of GH/QoL at this time point vs 57% of those on the SOC arm. Furthermore, 47% of patients in the liso-cel group experienced improvement in fatigue at 6 months vs 29% of those in the SOC group. Eighteen percent of patients in the liso-cel arm experienced deterioration regarding fatigue at this time point vs 71% of those in the SOC arm.

It is important to emphasize that higher scores on functionality domains and lower scores on symptom domains indicate a better QoL, presenting study author Jeremy Abramson, MD, of Massachusetts General Hospital Cancer Center, said during the poster presentation of the data.

TRANSFORM enrolled patients between the ages of 18 and 75 years who had aggressive non-Hodgkin lymphoma and who were refractory or relapsed 12 months or less following first-line treatment containing an anthracycline and a CD20-targeted agent. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1, be eligible for hematopoietic stem cell transplantation and have a left ventricular ejection fraction of over 40%. Patients with secondary central nervous system lymphoma were permitted. There was no minimum lymphocyte count.

Participants were randomized 1:1 to receive either SOC comprised of 3 cycles of salvage chemotherapy and BEAM (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem cell transplantation for responding patients, or liso-cel following lymphodepletion treatment. Crossover to the liso-cel arm was permitted for patients who failed SOC treatment. Patients received the CAR T-cell therapy at a dose of 100 x 106CAR-positive T cells.

The primary end point of the trial was event-free survival (EFS), and key secondary end points comprised complete response (CR) rate, progression-free survival (PFS), and overall survival. Other end points of interest included duration of response, objective response rate, PFS on the next line of treatment, safety, and patient-reported outcomes (PROs).

In a prespecified interim analysis of data from TRANSFORM, liso-cel demonstrated highly statistically relevant and clinically meaningful improvement vs SOC regarding the primary end point of EFS, plus secondary end points of CR and PFS.2In the analysis presented during the 2021 ASH Annual Meeting, Abramson reported findings pertaining to QoL.

Investigators evaluated QoL by leveraging the EORTC QLQ-C30 and FACT-LymS tools. The former evaluated cancer-associated symptoms and functioning and is comprised of 30 items that address 15 domains. Primary functional domains of interest that were evaluated in TRANSFORM were GH/QoL, physical functioning, and cognitive functioning. Primary symptom domains of interest were fatigue and pain. The FACT-LymS tool evaluated symptoms that were specific to lymphoma and was comprised of 15 items. With this assessment, higher scores are representative of better QoL.

To assess the between-treatment differences in overall LS mean change from baseline for each primary domain, a MMRM analysis was conducted, and this leveraged data collected up to day 126 for visits with a sample size per are of 10 or more. All analyses were prospectively defined, and the findings reported during the 2021 ASH Annual Meeting are descriptive.

To be eligible for PRO analyses, patients needed to complete a baseline assessment and at least 1 post-baseline assessment. Notably, a similar proportion of patients were included in the EORTC QLQ-C30 analyses sets for liso-cel (51%) and SOC (47%).

In the liso-cel group of 92 patients, 47 were evaluable for the EORTC QLQ-C30 analysis, and 45 were evaluable for the FACT LymS analysis. Notably, 45 patients were not included in the EORTC QLQ-C30 analysis because they did not complete a baseline assessment (n = 28), a post-baseline assessment (n = 1), or both (n = 16).

In the SOC group, 43 and 40 out of 92 patients were evaluable for the EORTC QLQ-C30 and FACT Lym-S analyses, respectively. Patients from this group were excluded from the EORTC QLQ-C30 analysis due to lack of baseline assessment (n = 20), lack of post-baseline assessment (n = 6), or lack of both (n = 23).

Additional data presented during the 2021 ASH Annual Meeting showed that with regard to the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS), the difference in mean change between the 2 arms was -0.16 (range, -2.71 to 2.40). On the 126-day mark, the liso-cel group had a FACT-LymS mean change of 1.48 (range, -0.30 to 3.26), compared with 1.63 (range, -0.41 to 3.68) in the SOC group. Notably, for FACT-LymS, similar proportions of patients between the investigative and control arms experienced deterioration (24% and 29%, respectively) and improvement (47% and 43%) at month 6.

Overall QoL was either improved or maintained from baseline in patients with relapsed/refractory LBCL who received liso-cel as second-line treatment, Abramson concluded. These results were achieved despite only responders to salvage chemotherapy remaining in the SOC arm past day 64. These findings corroborated with previously reported HRQoL associated with liso-cel treatment.

References

Read more from the original source:
Liso-Cel Outperforms Standard Therapy in Improving QoL in Relapsed/Refractory LBCL - http://www.oncnursingnews.com/

Cells in the body have specific purposes, but stem cells are cells that do not yet have a specific role and can become almost any cell that is required.

Stem cells are undifferentiated cells that can turn into specific cells, as the body needs them.

Scientists and doctors are interested in stem cells as they help to explain how some functions of the body work, and how they sometimes go wrong.

Stem cells also show promise for treating some diseases that currently have no cure.

Stem cells originate from two main sources: adult body tissues and embryos. Scientists are also working on ways to develop stem cells from other cells, using genetic reprogramming techniques.

A persons body contains stem cells throughout their life. The body can use these stem cells whenever it needs them.

Also called tissue-specific or somatic stem cells, adult stem cells exist throughout the body from the time an embryo develops.

The cells are in a non-specific state, but they are more specialized than embryonic stem cells. They remain in this state until the body needs them for a specific purpose, say, as skin or muscle cells.

Day-to-day living means the body is constantly renewing its tissues. In some parts of the body, such as the gut and bone marrow, stem cells regularly divide to produce new body tissues for maintenance and repair.

Stem cells are present inside different types of tissue. Scientists have found stem cells in tissues, including:

However, stem cells can be difficult to find. They can stay non-dividing and non-specific for years until the body summons them to repair or grow new tissue.

Adult stem cells can divide or self-renew indefinitely. This means they can generate various cell types from the originating organ or even regenerate the original organ, entirely.

This division and regeneration are how a skin wound heals, or how an organ such as the liver, for example, can repair itself after damage.

In the past, scientists believed adult stem cells could only differentiate based on their tissue of origin. However, some evidence now suggests that they can differentiate to become other cell types, as well.

From the very earliest stage of pregnancy, after the sperm fertilizes the egg, an embryo forms.

Around 35 days after a sperm fertilizes an egg, the embryo takes the form of a blastocyst or ball of cells.

The blastocyst contains stem cells and will later implant in the womb. Embryonic stem cells come from a blastocyst that is 45 days old.

When scientists take stem cells from embryos, these are usually extra embryos that result from in vitro fertilization (IVF).

In IVF clinics, the doctors fertilize several eggs in a test tube, to ensure that at least one survives. They will then implant a limited number of eggs to start a pregnancy.

When a sperm fertilizes an egg, these cells combine to form a single cell called a zygote.

This single-celled zygote then starts to divide, forming 2, 4, 8, 16 cells, and so on. Now it is an embryo.

Soon, and before the embryo implants in the uterus, this mass of around 150200 cells is the blastocyst. The blastocyst consists of two parts:

The inner cell mass is where embryonic stem cells are found. Scientists call these totipotent cells. The term totipotent refer to the fact that they have total potential to develop into any cell in the body.

With the right stimulation, the cells can become blood cells, skin cells, and all the other cell types that a body needs.

In early pregnancy, the blastocyst stage continues for about 5 days before the embryo implants in the uterus, or womb. At this stage, stem cells begin to differentiate.

Embryonic stem cells can differentiate into more cell types than adult stem cells.

MSCs come from the connective tissue or stroma that surrounds the bodys organs and other tissues.

Scientists have used MSCs to create new body tissues, such as bone, cartilage, and fat cells. They may one day play a role in solving a wide range of health problems.

Scientists create these in a lab, using skin cells and other tissue-specific cells. These cells behave in a similar way to embryonic stem cells, so they could be useful for developing a range of therapies.

However, more research and development is necessary.

To grow stem cells, scientists first extract samples from adult tissue or an embryo. They then place these cells in a controlled culture where they will divide and reproduce but not specialize further.

Stem cells that are dividing and reproducing in a controlled culture are called a stem-cell line.

Researchers manage and share stem-cell lines for different purposes. They can stimulate the stem cells to specialize in a particular way. This process is known as directed differentiation.

Until now, it has been easier to grow large numbers of embryonic stem cells than adult stem cells. However, scientists are making progress with both cell types.

Researchers categorize stem cells, according to their potential to differentiate into other types of cells.

Embryonic stem cells are the most potent, as their job is to become every type of cell in the body.

The full classification includes:

Totipotent: These stem cells can differentiate into all possible cell types. The first few cells that appear as the zygote starts to divide are totipotent.

Pluripotent: These cells can turn into almost any cell. Cells from the early embryo are pluripotent.

Multipotent: These cells can differentiate into a closely related family of cells. Adult hematopoietic stem cells, for example, can become red and white blood cells or platelets.

Oligopotent: These can differentiate into a few different cell types. Adult lymphoid or myeloid stem cells can do this.

Unipotent: These can only produce cells of one kind, which is their own type. However, they are still stem cells because they can renew themselves. Examples include adult muscle stem cells.

Embryonic stem cells are considered pluripotent instead of totipotent because they cannot become part of the extra-embryonic membranes or the placenta.

Stem cells themselves do not serve any single purpose but are important for several reasons.

First, with the right stimulation, many stem cells can take on the role of any type of cell, and they can regenerate damaged tissue, under the right conditions.

This potential could save lives or repair wounds and tissue damage in people after an illness or injury. Scientists see many possible uses for stem cells.

Tissue regeneration is probably the most important use of stem cells.

Until now, a person who needed a new kidney, for example, had to wait for a donor and then undergo a transplant.

There is a shortage of donor organs but, by instructing stem cells to differentiate in a certain way, scientists could use them to grow a specific tissue type or organ.

As an example, doctors have already used stem cells from just beneath the skins surface to make new skin tissue. They can then repair a severe burn or another injury by grafting this tissue onto the damaged skin, and new skin will grow back.

In 2013, a team of researchers from Massachusetts General Hospital reported in PNAS Early Edition that they had created blood vessels in laboratory mice, using human stem cells.

Within 2 weeks of implanting the stem cells, networks of blood-perfused vessels had formed. The quality of these new blood vessels was as good as the nearby natural ones.

The authors hoped that this type of technique could eventually help to treat people with cardiovascular and vascular diseases.

Doctors may one day be able to use replacement cells and tissues to treat brain diseases, such as Parkinsons and Alzheimers.

In Parkinsons, for example, damage to brain cells leads to uncontrolled muscle movements. Scientists could use stem cells to replenish the damaged brain tissue. This could bring back the specialized brain cells that stop the uncontrolled muscle movements.

Researchers have already tried differentiating embryonic stem cells into these types of cells, so treatments are promising.

Scientists hope one day to be able to develop healthy heart cells in a laboratory that they can transplant into people with heart disease.

These new cells could repair heart damage by repopulating the heart with healthy tissue.

Similarly, people with type I diabetes could receive pancreatic cells to replace the insulin-producing cells that their own immune systems have lost or destroyed.

The only current therapy is a pancreatic transplant, and very few pancreases are available for transplant.

Doctors now routinely use adult hematopoietic stem cells to treat diseases, such as leukemia, sickle cell anemia, and other immunodeficiency problems.

Hematopoietic stem cells occur in blood and bone marrow and can produce all blood cell types, including red blood cells that carry oxygen and white blood cells that fight disease.

People can donate stem cells to help a loved one, or possibly for their own use in the future.

Donations can come from the following sources:

Bone marrow: These cells are taken under a general anesthetic, usually from the hip or pelvic bone. Technicians then isolate the stem cells from the bone marrow for storage or donation.

Peripheral stem cells: A person receives several injections that cause their bone marrow to release stem cells into the blood. Next, blood is removed from the body, a machine separates out the stem cells, and doctors return the blood to the body.

Umbilical cord blood: Stem cells can be harvested from the umbilical cord after delivery, with no harm to the baby. Some people donate the cord blood, and others store it.

This harvesting of stem cells can be expensive, but the advantages for future needs include:

Stem cells are useful not only as potential therapies but also for research purposes.

For example, scientists have found that switching a particular gene on or off can cause it to differentiate. Knowing this is helping them to investigate which genes and mutations cause which effects.

Armed with this knowledge, they may be able to discover what causes a wide range of illnesses and conditions, some of which do not yet have a cure.

Abnormal cell division and differentiation are responsible for conditions that include cancer and congenital disabilities that stem from birth. Knowing what causes the cells to divide in the wrong way could lead to a cure.

Stem cells can also help in the development of new drugs. Instead of testing drugs on human volunteers, scientists can assess how a drug affects normal, healthy tissue by testing it on tissue grown from stem cells.

Watch the video to find out more about stem cells.

There has been some controversy about stem cell research. This mainly relates to work on embryonic stem cells.

The argument against using embryonic stem cells is that it destroys a human blastocyst, and the fertilized egg cannot develop into a person.

Nowadays, researchers are looking for ways to create or use stem cells that do not involve embryos.

Stem cell research often involves inserting human cells into animals, such as mice or rats. Some people argue that this could create an organism that is part human.

In some countries, it is illegal to produce embryonic stem cell lines. In the United States, scientists can create or work with embryonic stem cell lines, but it is illegal to use federal funds to research stem cell lines that were created after August 2001.

Some people are already offering stem-cells therapies for a range of purposes, such as anti-aging treatments.

However, most of these uses do not have approval from the U.S. Food and Drug Administration (FDA). Some of them may be illegal, and some can be dangerous.

Anyone who is considering stem-cell treatment should check with the provider or with the FDA that the product has approval, and that it was made in a way that meets with FDA standards for safety and effectiveness.

Original post:
Stem cells: Sources, types, and uses - Medical News Today

Yi-Bin Chen, MD, discusses the nuances of diagnosing patients with cGVHD, the need for biomarkers to inform who is likely to develop the disease, the introduction of ruxolitinib and belumosudil to the paradigm, and future directions with novel strategies in the space.

The approvals of ruxolitinib (Jakafi) and belumosudil (Rezurock) have shaken up the second- and third-line treatment of patients with chronic graft-vs-host disease (cGVHD), said Yi-Bin Chen, MD, who added that real-world data with these agents could further inform their utility in clinical practice and whether there is a place for frontline use in combination or in place of systemic steroids.

Enough time has passed where we will see more real-world data for ruxolitinib in cGVHD to get a better handle on what is actually happening, said Chen, director of the BMT Program and the Cara J. Rogers Endowed Scholar at Massachusetts General Hospital, and an associate professor of medicine at Harvard Medical School. We all trust randomized trials, such as REACH3 [NCT03112603], but we do appreciate real-world experiences as we apply it because the majority of our patients dont fit the eligibility [criteria] for how these trials are designed.

Its too early to get any data on the real-world experience of belumosudil, but in the next couple of years that should be coming, Chen added.

In an interview with OncLive, Chen discussed the nuances of diagnosing patients with cGVHD, the need for biomarkers to inform who is likely to develop the disease, the introduction of ruxolitinib and belumosudil to the paradigm, and future directions with novel strategies in the space.

Chen: The diagnosis of GVHD, be it acute or chronic, is still a clinical diagnosis that requires the [patients] entire history, their symptoms, exam findings, and laboratory diagnostics. Although we can biopsy affected tissueand those histological findings can help support a diagnosis of GVHD or rule out other thingsthe diagnosis remains the entire clinical picture.

There are times when its a bit difficult to know what is causing something for a patient. Of anything that happens to our patients in at least the first 2 years after transplant, cGVHD is always in the differential; we have to think about it. The disease is unbelievably heterogenous from patient to patient, so we cant read a textbook to understand what we are going to see.

The manifestations are protean; it can affect almost any organ in the body. Its interesting because cGVHD is not only a disease of the immune system and direct attack of that immune system on the patient, but it reflects a state of immunological disarray and probably causes that as well. [Patients] lose their normal regulatory mechanisms.

Therefore, we see some manifestations that are classical cGVHD where the donor immune system attacks recipients, but there are other manifestations that are just a reflection of immunological disarray. Those manifestations arent necessarily GVHD in the classical sense but are things such as immune-mediated thrombocytopenia or nephrotic syndrome. Those arent thought of as classical manifestations of the donor attacking the host, but they are evidence that the immune system has gone awry.

We pay attention to everyone who gets an allogeneic transplant. However, we must think about certain patients who are more at risk than others. Thats based on certain clinical risk factors that are inherent to the patient, the disease, the transplant platform used, GVHD prevention, and the events that happen afterward.

To take that in order, we know that certain characteristics of a patient make them more at risk for cGVHD. Specifically, the older in age someone is, if they are male and receive a graft from a female donor, and the actual transplant platform [are all risks]. If we use myeloablative conditioning vs reduced-intensity or nonmyeloablative therapy, which is certainly much more borne out for acute GVHD [aGVHD], it is a signal for cGVHD, especially [regarding] the use of high-dose total body irradiation.

Certainly, the type of donor matters in terms of donor and host [human leukocyte antigen] matching. That by far predicts for the most GVHD relationship. The graft source [also matters]. We know from randomized studies that peripheral blood stem cells have a much higher incidence of cGVHD vs bone marrow or cord blood if we can get [patients] past the early complications.

GVHD prevention [is critical]. We know that the inclusion of polyclonal antiT-cell globulins, such as ATG products reduce the incidence of cGVHD. Ex vivo manipulations, such as T-cell depletion, do that as well. If we use the newly emergent, posttransplant, high-dose cyclophosphamide-based GVHD prevention [strategy], that appears to reduce the incidence of cGVHD as well.

By far, if we play all this out, the biggest risk factor along the way would be the development of aGVHD. Thats just a biological reflection of allogeneic reactivity. That is how we think of patients and what we have done. For a patient with a benign disease, such as aplastic anemia, I would design a transplant platform that would maximize GVHD prevention. I would know that patient is at a much lower risk [of developing GVHD] compared with someone with a high-grade hematologic malignancy who has a higher rate of relapse.

[In that situation], I would at least tolerate some GVHD to bring about better graft-vs-leukemia. That is how we think about patients as we go forward. We make conscious decisions about how we manage their immunosuppression in terms of rapidity of taper [of steroids] and things like that.

Going forward, it behooves us to invest in studies to try to define better ways to [make those decisions], not just with the diagnosis, but in real time along the way. That would [mean identifying] cGVHD biomarkers. That could help risk-stratify patients in real time to high or low risk for developing cGVHD. That would be a huge step forward and ongoing research is already trying to figure this out. Its much more along for aGVHD vs cGVHD for a lot of reasons, but [ultimately] the key is to have biomarkers that can predict for certain manifestations. We could then either design preemptive approaches to prevent [cGVHD] or predict for differential responses to therapies. That way we could tailor our therapies based on those biomarkers.

In patients who present with localized cGVHD, which is very common, we tend to try to maximize local therapy. That includes eye drops to the eyes, topical mouth rinses for mouth involvement, and topical skin cream for limited skin involvement. At some point, if the manifestation becomes so severe or there is clear multi-organ involvement, [treatment] becomes much more of a systemic process than initially appreciated. There comes a time when we must decide to initiate systemic therapy.

Unfortunately, systemic therapy at this point remains the reinitiation of systemic steroids, such as prednisone. Most of these patients are outpatients [and receive] prednisone in oral tablets. We tend to give [prednisone] in a dose somewhere between 0.5 mg/kg and 1 mg/kg of the recipients body weight per day. That has been the same for the past couple of decades.

It is heartbreaking to add steroids back to a patients treatment because many patients have already been through a lot of complications like aGVHD or infections. Certainly, we need to treat the cGVHD, but we also know the patient is accruing some morbidity and risk [with additional steroids].

I worry about infections, causing or worsening diabetes, bone health and osteoporosis, worsening hypertension, and mood effects from long-term prednisone. [We also worry about] the effects on body habitus in terms of fat distribution and cushingoid appearance. All of those [risks] make steroids not an ideal choice.

We dont have any data to say whether we should use a different agent for first-line therapy or combine steroids with something else; however, those trials are ongoing, and we are awaiting the results. More than half of patients will have an unsatisfying response to steroids, be it no response or a plateaued response that is not good enough for their quality of life. In more than half of patients, we need to add something [to steroids].

Its sobering that recent data from the cGVHD Consortium would suggest that in anybody who we start on systemic steroids for cGVHD, only about a third of them ever get off steroids for a durable time. That is a reality that makes us think about how to frame [treatment] for patients in terms of long-term expectations.

In terms of second-line therapy, we view GVHD in general as an immunological disease, which it is. The historical therapies were immunosuppressive to treat the GVHD. Although that works to a certain extent, it comes with a high costthat being certain opportunistic infections.

However, just as in aGVHD, the evolution in cGVHD [treatment] is toward more pathway-specific inhibitors that we think are especially active. Those [agents] also have less off-target toxicities, thus they yield less risk and morbidity to our patients who are a bit fragile.

We have some more options, excitingly. A few years back the BTK inhibitor ibrutinib [Imbruvica] was approved in steroid-refractory cGVHD. That [approval] was built on the foundation that there is some B-cell activity in cGVHD. For a subset of patients, that is why ibrutinib does work to a certain extent.

Other agents, such as rituximab [Rituxan], have had some efficacy. However, the real-world experience with ibrutinib has not mirrored what we saw in the clinical trial that led to its approval. That trial was somewhat restrictive in its eligibility criteria, so [the lack of consistency with the real-world experience] makes sense. That real-world experience has been a bit difficult not only in efficacy but just in the inherent toxicities [associated with ibrutinib].

More recently, ruxolitinib was approved for second-line therapy. This was based on the findings from the REACH3 study, which was one of the only large, randomized phase 3 studies in steroid-refractory cGVHD. [The results] showed a significant benefit with ruxolitinib vs best available therapy. The primary end points were overall response rate at 24 weeks and failure-free survival. Ruxolitinib had a significant benefit [in those end points] compared with best available therapy.

Weve been using [ruxolitinib] at Massachusetts General Hospital as our standard second-line therapy for the past 4 years for cGVHD. This was partly because of the anecdotes that had been published, partly from our own experience, and partly because we have a lot of experience using ruxolitinib in aGVHD and other indications in which it is approved for. We had found it to be a very satisfying drug, although it is not a home run. We dont have a home run if we look at all the trials to date for cGVHD. Of responses reported, complete remissions are the extreme minority. Thats how we know we dont have a home run.

There is more work to be done in diagnosing cGVHD earlier and designing better therapies. Anecdotally, we have found that ruxolitinib benefits at least three-quarters of patients started on it. It is a well-tolerated agent, but we must watch for cytopenias. If a patient develops [adverse effects (AEs)], they can be managed with dose adjustments or dose interruptions. I hope one day to be able to see how [ruxolitinib] functions as first-line therapy or even in prevention [of cGVHD].

[In July 2021], belumosudil, an oral ROCK-2 inhibitor, was approved for third-line therapy of cGVHD. That [approval] was based on the momentum of the ROCKstar study [NCT03640481], which showed a response rate of over 70% with 2 different dosing strategies. Belumosudil is interesting in terms of its mechanism of action, in that it targets the fibrosis cascade. It certainly appears to help most patients without a significant amount of concern over toxicity. I want to see more data on the real-world experience with belumosudil in patients.

A couple of agents are being studied. We shouldnt forget about extracorporeal photopheresis [ECP]. That is a modality that has been around for a long time and certainly has efficacy in cGVHD without much in the way of immunosuppression. The reason why it is not as attractive as the other agents is the logistics it takes for patients to receive the therapy in terms of proximity, time spent at the center, and [the need to insert] an indwelling catheter. Learning how to sequence ECP with [systemic] therapies is a must going forward.

A monoclonal antibody against CSF1R is being developed by a company called Syndax. That agent is being [tested] as an every-other-week infusion and targets activating macrophages that are thought to be very active in the fibrotic process, which is the histological hallmark of GVHD. Large expansion trials are ongoing right now [with that agent, called axatilimab]. We are all eagerly awaiting the results.

Outside of that, other agents are very early in development and are not yet ready for prime time. We saw an interesting abstract from Europe using a form of arsenic as frontline therapy that showed a very high response rate when combined with steroids. That goes along with what the next step is in cGVHD, which is to move approved therapies up to study them with systemic steroids in the frontline setting. This could not only improve response rates but allow more rapid steroid tapers to spare patients [from AEs] during response.

We also want to think about designing trials where we can parse out a subset of patients that dont need steroids because they are low risk or [we] dont think that that phenotype or biological sign of patients will respond to steroids. [In these populations], we can try these newer agents as frontline therapy without steroids. A goal is to replace steroids in the frontline setting, so these are trial designs being talked about in the community going forward. Now, one big step is already out of the way because these novel agents are approved in later-line settings.

Im always interested in the newer agents being studied. These are small trials out of single centers, but those start the whole process. I am keeping my eye out for those types of studies.

As we move forward, it will be less about designing more therapies for third-, fourth-, or fifth-line treatment and more about how we can better prevent cGVHD either by doing so preemptively or by adding to the prevention backbone without sacrificing other factors. That has been much of the discussion in the community to try to glean whether there are any data we are going to see that will inform us to design those steps going forward.

Now that ruxolitinib is approved and a lot of us are using it as our standard second-line agent, we are going to see a lot of different formulations of ruxolitinib or other JAK inhibitors. In the community, we have been asking for about 3 years for some form of JAK inhibitor eye drops, skin creams, and mouth rinses. Right now, we use steroids for those topical formulations. Not only do we think that some sort of localized ruxolitinib application would be more effective, but certainly less toxic [vs steroids]. We will be watching out for that as adjunct treatment for the populations that have limited disease and dont need systemic therapy.

Continue reading here:
cGVHD Paradigm Gains Systemic Options Beyond Steroids, But Real-World Data Are Required - OncLive

Potency tests assure doctors that a medicine has good quality and will be effective for treatment. Although potency tests are common for drug medicines, developing them for stem cell treatments has been difficult. For stem cell treatments, no reliable potency tests have been available.

At the June 21-26, 2021 Annual Meeting of the International Society for Stem Cell Research, stem cell biotechnology company Asymmetrex will present data and examples for a new test for evaluation of the potency of tissue stem cell treatments. The technology, called kinetic stem cell (KSC) counting, can tell doctors the number of live tissue-renewing stem cells in a treatment sample.

The President & CEO of Asymmetrex, James L. Sherley, M.D., Ph.D., explains, "Stem cell medicine has needed a quality and effectiveness index like drug specific activity for pharmaceuticals. What could work better than knowing the number of live tissue stem cells that can restore other tissue cells? That's what our KSC counting TORTOISE TestTM platform can tell doctors: the number of live stem cells in a treatment that can renew an organ or tissue."

Asymmetrex is currently focused on conducting preclinical and clinical evaluations of how well its tissue stem cell-specific data indicate the effectiveness of stem cell treatments in different patients. In his company's presentations at ISSCR 2021, Sherley says that he will also introduce the immediate benefits of KSC counting to stem cell scientists for their tissue stem cell research. "It's a no brainer that now knowing how many tissue stem cells are in experiments will greatly improve stem cell researchand, as a consequence, stem cell medicine."

About Asymmetrex

Asymmetrex, LLC is a Massachusetts life sciences company with a focus on developing technologies to advance stem cell medicine. Asymmetrex is a member company of the Advanced Regenerative Manufacturing Institute BioFabUSA (ARMI)and the Massachusetts Biotechnology Council (MassBio).

Media Contact: James L Sherley, [emailprotected]

SOURCE Asymmetrex, LLC

asymmetrex.com

See more here:
Asymmetrex Will Present a New Test for Therapeutic Stem Cell Potency at the ISSCR 2021 Annual Meeting - PRNewswire

Male scientists have long waxed poetic on the contents of their testes. Sperm is a drop of brain, wrote the ancient Greek writer Diogenes Laertius. Leonardo da Vinci drew the penis with a sperm duct that connected directly to the spinal cord. The 17th-century microscopist Antonie van Leeuwenhoek claimed that each sperm cell contained within it a folded-up human being waiting patiently to unfurl.

For nearly as long, scientists have fretted about sperms seemingly inevitable decline. Most recently, a series of alarming headlines as well as a new book by a public health researcher at Mount Sinai Medical Center in New York warned that falling sperm counts might threaten the future of the human race. Its a global existential crisis, saysShanna H Swan, author of the book Count Down.

Most of these headlines can be traced to an influential 2017 meta-analysis by Swan and others, which found that sperm counts in Europe, North America, Australia and New Zealand had plummeted by nearly 60 per cent since 1973. The authors screened 7,500 sperm-count studies from around the world, weeded out most of them and ultimately analysed 185 studies on 43,000 men worldwide.

They called the decline a canary in the coal mine for waning male reproductive health worldwide. Today, the authors would revise that statement. There is clear and present alarm now, says Dr Hagai Levine, a public-health researcher at Hebrew University-Hadassah School of Public Health and an author of the 2017 review. The canary is in trouble now. Swan agrees.

Now a group of interdisciplinary researchers from Harvard and Massachusetts Institute of Technology contend that fears of an impending Spermageddon have been vastly overstated. In a study published in May in the journal Human Fertility, they re-evaluated the 2017 review and found that it relied on flawed assumptions and failed to consider alternate explanations for the apparent decline of sperm.

Sarah Richardson, a Harvard scholar on gender and science and the senior author ofthe new study, calls the conclusion of the 2017 review an astonishing and terrifying claim that, were it to be true, would justify the apocalyptic tenor of some of the writing. Fortunately, she and her coauthors argue, there is little evidence that this is the case.

The 2017 authors were methodologically rigorous in screening sperm-count studies for quality and consistency, Richardson and her colleagues write. But even the data that passed muster was geographically sparse and uneven and often lacked basic criteria such as the age of the men. Moreover, its authors took for granted that a single metric sperm count was an accurate predictor of male fertility and overall health.

No one knows what an optimal sperm count is. The World Health Organisation sets a range of normal sperm count as from 15 million to 250 million sperm per millilitre. (Men produce about 2ml to 5ml per ejaculation.) But it isnt clear that more is better. Above a certain threshold 40 million per millilitre, according to the WHO a higher count does not mean a man is more fertile.

Doubling your sperm count from 25 million to 50 million doesnt double your chances, says Allan Pacey, an andrologist at the University of Sheffield, in England, and the editor of Human Fertility. Doubling it from 100 million to 200 million doesnt double your chances in fact it flattens off, if anything.

Germaine M Buck Louis, a reproductive-public-health researcher at George Mason University, in the United States, agrees that sperm count is a poor indicator of fertility. We dont see it predicting much of anything, especially in the context of a partner with a healthy female pelvis, says Buck Louis, who was not involved in the sperm-count studies.

The authors of the 2017 study inferred that lower sperm counts equated to lower fertility even though the sperm-count declines they documented all took place within the normal range, Richardson notes. Its similar to the whole conversation around testosterone more is better, and more is manlier, she says. Thats really a point we make, that there is no known normal or baseline for average population sperm counts.

Sperm count has other limitations as a metric. It takes about two months for stem cells in the testes to develop into new sperm, meaning that any single count is merely a snapshot of an evolving landscape.

Something thats going on in a mans body one month may be totally different from whats happening the next month, and the effects on sperm count might be changing also, says Meredith Reiches, an author ofthe 2021 paper and a biological anthropologist at the University of Massachusetts,Boston.

It also overlooks a vital piece of the infertility puzzle: women. Focusing only on the male metric leaves out key interactions between sperm, the female reproductive tract and the egg. Its very important, actually, to look at the couple, says Dr Bradley D Anawalt, a reproductive endocrinologist at the University of Washington school of medicine.

In her book, Swan suggests that sperm counts have plummeted largely because of the rise of endocrine disrupters, a class of hormone-mimicking chemicals found in everything from shampoo to TV-dinner packaging. (She also cites lifestyle factors such as obesity, alcoholand smoking.)

Richardson and her coauthors suggested an alternative: perhaps sperm levels naturally rise and fall over time and within populations. The question has not been explored by reproductive researchers and cannot be answered easily, as global sperm counts before 1970 are largely unknown.

There are other possible explanations, as well. Sperm-counting is a tricky business and notoriously prone to human error, Pacey says. (I say it from the point of view of someone who spent 30 years counting sperm and knows how difficult it is, he adds.) In a 2013 review article, he notes that as methodologies for counting had improved and been standardised since the 1980s, sperm counts had appeared to fall. In other words, it may simply be that earlier scientists were overcounting sperm.

Swan and Levine agree that exploring these alternative hypotheses was important, so that threats to reproductive health could be prevented. We showed evidence for decline, and raised alarm, Levine writes in an email. We need to study the causes, including the unlikely possibility of non-pathological decline.

There is one point that every author agrees on: mens reproductive health matters. And until nowit has been surprisingly neglected.

Male infertility contributes to at least half of all cases of infertility worldwide. Yet, historically, women have shouldered most of the blame for the inability to conceive. And with the rise of reproductive technologies such as in-vitro fertilisation, womens bodies are the ones that have been meticulously measured and tracked by reproductive medicine.

As a result, science still lacks basic knowledge when it comes to sperm, says Rene Almeling, a sociologist of medicine and author of GUYnecology: The Missing Science of Mens Reproductive Health.

We have built up such a medical infrastructure around the fertility and reproductivity of womens bodies that we havent asked some of the basic questions about mens reproductive health, Almeling says. There is just so, so much basic research still to be done about sperm.

The main qualities of sperm that infertility specialists look at nowadays how many, what shape and how they swim have not changed in the past 40 years, says Dr Abraham Morgentaler, a urologist and founder of Mens Health Boston.

Morgentaler, who worked at a semen-analysis lab at Beth Israel Deaconess Medical Center, in Boston, in the 1980s, attributes this stagnation to the rise of IVF and other technologies, which have become frontline treatments for almost any male-factor fertility problem. It almost doesnt even matter whats wrong with the sperm, he says.

These knowledge gaps radiate out to all bodies. Swan says part of her motivation for writing the book was that she wanted to see men and women become more proactive about their reproductive health.

Its invisible, she says. People dont talk about it. You talk about, Oh, Ive got a high cholesterol measure, or My blood pressures up. But you never would say, My egg count is down, or My sperm count is down.

Richardson agrees that the effect of reproductive toxins on fertility deserved further investigation. To say that we think these are alarmist and apocalyptic claims, and theyre not well founded, is not to say that we think it isnt an important research agenda, she says. There is a need to centre on mens reproductive health and understand their bodies as reproductive and as porous to the environment as anyones bodies. New York Times

View original post here:
Infertility: Men account for at least half of cases. So why have women shouldered the blame? - The Irish Times

A powerful series of speakers at the Picower Institute for Learning and Memorys biennial Spring Symposium, Early Life Stress and Mental Health, blended personal stories and rigorous research to demonstrate that while remedying the lifelong toxic stress and disadvantage many people incur during childhood can be difficult, it is by no means intractable.

Picower Institute Director Li-Huei Tsai opened the symposium, co-produced with the JPB Foundation led by Barbara Picower, with the observation that while problems such as poverty, racism, injustice, and child abuse have been around for a long time, finding and implementing ways to fight the health problems that can result has become increasingly urgent.

This feels especially so right now, as we grapple with a time in which many of us have seen young people endure historic stresses, she said. The many tragedies and disruptions of the Covid-19 pandemic and stark examples of racial and social injustice have made this a particularly difficult time to grow up.

Stories of systemic stress

Educator Geoffrey Canada, founder and president of the Harlem Childrens Zone, emphasized that the current moment is especially crucial in the Black community.

If I am right about what I suspect is going to happen in this country, I can just say for those of us who care about toxic stress we haven't seen nothing yet, he said. What's coming, in my opinion, is sort of unprecedented.

Early Life Stress and Mental Health - Geoffrey Canada

Canada, who grew up in the impoverished South Bronx, New York, recounted several episodes in which generations of his family encountered racism, sometimes at the hands of police and health care providers. Many Black people have come to regard such stresses as the price of living in America, he said. But after observing the disproportionately terrible impacts of Covid-19 in his and other communities of color, his concern is heightened further.

I think it's very clear in this country, your race determines largely whether you lived or died, whether you got sick, whether you ended up working at home or being on the front lines, he said, whether your children got an education, and whether or not you're going to have anything that looks like a recovery from this experience.

Moreover, the murder of George Floyd and other police killings were seared into the psyche, adding even more to the stresses black children now face.

Lawyer Bryan Stevenson, founder of the Equal Justice Initiative, called out other harms the justice system has inflicted, particularly on women and children. But he also recommended a prescription for the nation to reconsider policies that have led to mass incarceration and prosecution of children as adults.

Over the last 25 years, the percentage of women going to jails and prisons has increased 800 percent, he said. Eighty percent of the women that we put in our jails and prisons are single parents with minor children, which means that the lives of a generation of children are being disrupted by these carceral policies.

Moreover, in a country where one-in-three Black and one-in-six Latino boys are projected to be in prison during their lives, Stevenson said that when he sits down with preteens in poor communities, theyll say things that break my heart. Ive talked to too many children who tell me that they expect to be in jail.

He called for more people to get proximate to families struggling with poverty, addiction, and other difficulties because proximity promotes understanding and empathy and provides an opportunity to provide the affirmation, care, safety, and opportunity that children growing up among violence need. Proximity, for instance, can help undo the discredited but persistent narrative that juveniles accused of crimes are somehow super predators and not still children. It can combat the politics of fear and anger, he said, that led the country to treat addiction disorders through the legal system rather than as a health care problem. And it can dispel, he said, a sense in America, lingering since slavery and the genocide of Indigenous Americans, of a racial hierarchy.

Jose Antonio Vargas put a similar emphasis on inspiring empathy through storytelling. The organization he founded, Define American, is a culture change organization that uses the power of narrative to humanize conversations about immigrants. Vargas, who came to the United States from the Philippines as a child, discovered his undocumented status when he was a teenager. As difficult as living undocumented can be under typical circumstances he drew a parallel between limitations on travel many felt during the Covid pandemic with the restrictions undocumented people consistently face becoming a public advocate amid intense policy debate can add to that stress.

Early Life Stress and Mental Health - Jose Antonio Vargas

Define American has therefore spearheaded research with the University of Massachusetts at Amherst, funded by the National Geographic Society, to survey immigration advocates for signs of post-traumatic stress disorder, stress, depression, and other signs of mental health troubles, as well as resilience. Full results, he said, will be published this summer, but reflect high rates of both trauma and resilience.

Science begets solutions

Several symposium speakers emphasized that much as personal stories and proximity can aid reveal the roots of toxic stress, scientific data and research can also lead to remedies by discovering the mechanisms that underlie health problems.

Picower Institute neuroscientist Gloria Choi, associate professor in the MIT Department of Brain and Cognitive Sciences (BCS), for example, shared her research tracing a long-observed but never explained link between pregnant women getting sick from infection and the emergence of autism-like symptoms in their children. Her research in mouse models showed that when specific bacteria are in the gut microbiome of pregnant dams, infection during a specific time of pregnancy stimulates the release of cytokine molecules from immune cells. Those cytokines reach neurons in the S1DZ region of the cortex of the fetus, disrupting the development of inhibitory neurons. That in turn leads to hyperactivity of circuits governing social behaviors, causing the autism-like neurodevelopmental disorder.

By achieving this kind of detailed, causal understanding, Choi said, scientists pinpoint targets for therapeutic interventions.

We scientists, to be able to help children, I think we need to understand at mechanistic levels as to how mother's health can shape that of her child, she said.

At a population level, as well, extracting cause and effect from data can help guide public health and policy remedies, said social epidemiologist Mariana Arcaya, associate professor in MITs Department of Urban Studies and Planning. She made the case that while many researchers have shown that neighborhood characteristics such as poverty and violence can undermine health, fewer have studied what may be an equally important link existing health conditions can make it harder for families to move. Appreciating this bidirectional relationship between health and geography should not be overlooked in devising interventions, she said. Her research has helped to document it.

If poor health is a factor that is going to limit socioeconomic and geographic mobility, and we know that there's huge baseline disparities in health in the United States, Arcaya said, then we really need to be concerned about the co-production of health and neighborhood and housing conditions and how some families may be in a kind of cyclical disadvantage for both health outcomes and socioeconomic and neighborhood outcomes.

As the first surgeon general of the State of California, physician Nadine Burke Harris has galvanized a science-based statewide response to the public health crisis of adverse childhood experiences (ACEs), such as abuse, neglect, or disruptions in home life. More than 60 percent of adults have experienced at least one ACE and 15.8 percent have experienced four or more. Research shows that ACEs accumulate to raise the risk of serious health problems, including Alzheimers disease and suicide. In all, ACE-related health problems, she said, add $112.5 billion to annual health-care costs in California and more than $1 trillion across North America and Europe as a whole. On top of those, poverty and racism are also risk factors for future health difficulties.

Early Life Stress and Mental Health - Nadine Burke Harris

Over the last several decades weve begun to explore the biological mechanisms for how this happens, she said. Weve heard that trauma, especially in childhood, is damaging to our physical health, our mental health, but now we want to understand why, because when we understand the mechanism, that gives us tools to be able to unpack this.

In affected people, she said, ACEs trigger toxic stress an abnormally sustained stress hormone and immune system response as well as epigenetic changes that alter expression of genes. These factors, many of which act directly on the brain, lead to health risks. They can be mitigated, however, by providing safe, stable, and nurturing relationships and environments, as well as with stress management and medication.

So California has launched programs that have trained more than 17,000 primary care providers to screen more than 300,000 patients for ACEs and toxic stress risk. From there, doctors can help families with strategies to better manage the response. Moreover, the state has invested more than $30 million this year in grants covering 27 counties to link medical, social, educational, and community service providers together in trauma-informed networks of care that support families more broadly.

Extending opportunities

In a panel discussion moderated by Laura Schulz, a professor in BCS and the departments associate head for Diversity, Equity Inclusion and Justice Initiatives, the symposium also highlighted another dimension of harmful inequity that prevents people from reaching their full potential: the lack of diversity in science, technology, engineering, and mathematics, or STEM. Mirroring the focus other speakers put on seeking solutions, the panel featured people at MIT who are working to improve diversity in STEM, and participants in some of those programs who described what involvement has meant for them.

Picower Institute postdoc Hctor De Jess-Corts, a member of Picower Professor Mark Bears lab, for example, described how his participation as a student in Puerto Rico in the NIH-funded Minority Access for Research Careers program enabled him to do full-time research and to launch his scientific career. That and other opportunities inspired him to co-found the Sagrado MIT Neuroscience Pre-College Program, which helps high school students all over Puerto Rico to gain more exposure to science and knowledge about science careers. Of the 11 juniors who participated last year, many are now headed for colleges such as Stanford University, Yale University, Emory University, Cornell University, and Georgia Tech, he said.

Early Life Stress and Mental Health - Panel

The MIT Office of Engineering Outreachs three programs are currently serving about 365 high-achieving pre-college students from underrepresented groups and disadvantaged backgrounds. In all, OEOP has served more than 5,000 students, said Executive Director Eboney Hearn. About 80 percent have gone on to earn at least bachelors degrees in STEM fields, she said, including many at MIT.

Our alumni tell us that our programs have helped to level the playing field and helped them to get to places in their academic and personal journeys that didnt seem possible, she said.

Schulzs lab has been an active locus within BCS for inspiring and mentoring students at various stages. Graduate student Junyi Chu, for instance, described how last year she helped to launch the labs high school internship program, in partnership with Somerville High School and Black Girls Code. The lab has already engaged 17 students in the labs work studying cognition in babies. Interns also learn about science careers and publishing.

Panelist Liora Jones, from Torrington, Connecticut, was a Schulz lab intern. She just graduated high school and will study cognitive science at Wellesley College in the fall. Inspired by the fields of human-computer interaction, psychology, and artificial intelligence, she said she saw the internship as a way to learn more about cognition and to gain research skills. She did, and in the process met a mentor, new friends, and attended her first research conference.

Chu has also mentored college students in the MIT Summer Research Program. Among them is Kailande Cassamajor, who just graduated from Howard University with a degree in biology and psychology, and will attend a masters program in data science at Columbia University in the fall. Cassamajor said she enjoyed the chance to meet fellow MSRP students from other schools as well as to work with graduate students, like Junyi, who exposed her to cognitive and computational neuroscience. She greatly expanded her experience using a new programming language, for example.

In his remarks, panelist Tyler Bonnen provided vivid, personal representation of many of the themes of the day. Now a fifth-year neuroscience graduate student at Stanford, he described his adolescence in Miami Dade County, Florida, as mired within the criminal justice system: rehabs, hospitals, jail cells, psych wards, detention centers. But he had a good judge and was lucky enough to be picked for a study in which he and his family were helped. He got out of the institutions in which he was being harmed, he said, did social justice work, and then found his way to community college, where he encountered a program that would finance his education if he would study science.

After earning a degree at Columbia, he studied at MIT as a BCS postbaccalaureate scholar with Schulz and Professor Rebecca Saxe. Now hes dedicating his multidisciplinary research to studying how memory works, with the goal of better understanding trauma and helping people overcome it. Hes bringing his stories and science together to help others overcome acute stresses of their own.

Read the original post:
On systemic sources of early life stress, and empathetic responses - MIT News

Human lung cells (blue) infected with SARS-CoV-2 (red). Courtesy of Hekman, et al. Credit: Courtesy of Hekman, et al.

Multipronged BU research team finds 18 FDA-approved drugs that could halt coronavirus infection earlier.

What if scientists knew exactly what impact the SARS-CoV-2 virus had inside our lung cells, within the first few hours of being infected? Could they use that information to find drugs that would disrupt the virus replication process before it ever gets fully underway? The discovery that several existing FDA-approved drugsincluding some originally designed to fight cancercan stop coronavirus in its tracks indicates the answer is a resounding yes.

A team of Boston University researchershailing from BUs National Emerging Infectious Diseases Laboratories (NEIDL), the Center for Regenerative Medicine (CReM) at BUs Medical Campus, and BUs Center for Network Systems Biology (CNSB)embarked on a months-long, collaborative and interdisciplinary quest, combining multiple areas of expertise in virology, stem cellderived lung tissue engineering, and deep molecular sequencing to begin answering those questions. They simultaneously infected tens of thousands of human lung cells with the SARS-CoV-2 virus, and then tracked precisely what happens in all of those cells during the first few moments after infection. As if that was not complicated enough, the team had to cool their entire high-containment research facility inside the NEIDL to a brisk 61 degrees Fahrenheit.

The result of that challenging and massive undertaking? The BU team has revealed the most comprehensive map to date of all the molecular activities that are triggered inside lung cells at the onset of coronavirus infection. They also discovered there are at least 18 existing, FDA-approved drugs that could potentially be repurposed to combat COVID-19 infections shortly after a person becomes infected. Experimentally, five of those drugs reduced coronavirus spread in human lung cells by more than 90 percent. Their findings were recently published in Molecular Cell.

Now, academic and industry collaborators from around the world are in contact with the team about next steps to move their findings from bench to bedside, the researchers say. (Although COVID-19 vaccines are starting to be rolled out, its expected to take the better part of a year for enough people to be vaccinated to create herd immunity. And there are no guarantees that the current vaccine formulations will be as effective against future SARS-CoV-2 strains that could emerge over time.) More effective and well-timed therapeutic interventions could help reduce the overall number of deaths related to COVID-19 infections.

What makes this research unusual is that we looked at very early time points [of infection], at just one hour after the virus infects lung cells. It was scary to see that the virus already starts to damage the cells so early during infection, says Elke Mhlberger, one of the studys senior investigators and a virologist at BUs NEIDL. She typically works with some of the worlds most lethal viruses like Ebola and Marburg.

The most striking aspect is how many molecular pathways are impacted by the virus, says Andrew Emili, another of the studys senior investigators, and the director of BUs CNSB, which specializes in proteomics and deep sequencing of molecular interactions. The virus does wholesale remodeling of the lung cellsits amazing the degree to which the virus commandeers the cells it infects.

Viruses cant replicate themselves because they lack the molecular machinery for manufacturing proteinsthats why they rely on infecting cells to hijack the cells internal machinery and use it to spread their own genetic material. When SARS-CoV-2 takes over, it completely changes the cells metabolic processes, Emili says, and even damages the cells nuclear membranes within three to six hours after infection, which the team found surprising. In contrast, cells infected with the deadly Ebola virus dont show any obvious structural changes at these early time points of infection, and even at late stages of infection, the nuclear membrane is still intact, Mhlberger says.

The nuclear membrane surrounds the nucleus, which holds the majority of a cells genetic information and controls and regulates normal cellular functions. With the cell nucleus compromised by SARS-CoV-2, things rapidly take a bad turn for the entire cell. Under siege, the cellswhich normally play a role in maintaining the essential gas exchange of oxygen and carbon dioxide that occurs when we breathedie. As the cells die, they also emit distress signals that boost inflammation, triggering a cascade of biological activity that speeds up cell death and can eventually lead to pneumonia, acute respiratory distress, and lung failure.

I couldnt have predicted a lot of these pathways, most of them were news to me, says Andrew Wilson, one of the studys senior authors, a CReM scientist, and a pulmonologist at Boston Medical Center (BMC), BUs teaching hospital. At BMC, Bostons safety net hospital, Wilson has been on the front lines of the COVID-19 pandemic since March 2020, trying to treat and save the sickest patients in the hospitals ICU. Thats why our [experimental] model is so valuable.

Science is the answerif we use science to ask the lung cells what goes wrong when they are infected with coronavirus, the cells will tell us. Darrell Kotton

The team leveraged the CReMs organoid expertise to grow human lung air sac cells, the type of cell that lines the inside of lungs. Air sac cells are usually difficult to grow and maintain in traditional culture and difficult to extract directly from patients for research purposes. Thats why much coronavirus research to date by other labs has relied on the use of more readily available cell types, like kidney cells from monkeys. The problem with that is kidney cells from monkeys dont react the same way to coronavirus infection as lung cells from humans do, making them a poor model for studying the viruswhatever is learned from them doesnt easily translate into clinically relevant findings for treating human patients.

Our organoids, developed by our CReM faculty, are engineered from stem cellstheyre not identical to the living, breathing cells inside our bodies, but they are the closest thing to it, says Darrell Kotton, one of the studys senior authors. He is a director of the CReM and a pulmonologist at BMC, where he has worked alongside Wilson in the ICU treating COVID-19 patients. The two of them often collaborated with Mhlberger, Emili, and other members of their research team via Zoom calls that they managed to join during brief moments of calm in the ICU.

In another recent study using the CReMs engineered human lung cells, the research team confirmed that existing drugs remdesivir and camostat are effective in combating the virus, though neither is a perfect fix for controlling the inflammation that COVID-19 causes. Remdesivir, a broad-use antiviral, has already been used clinically in coronavirus patients. But based on the new studys findings that the virus does serious damage to cells within hours, setting off inflammation, the researchers say theres likely not much that antiviral drugs like remdesivir can do once an infection has advanced to the point where someone would need to be put on a ventilator in the ICU. [Giving remdesivir] cant save lives if the disease has already progressed, Emili says.

Seeing how masterfully SARS-CoV-2 commandeers human cells and subverts them to do the manufacturing work of replicating the viral genome, it reminded the researchers of another deadly invader.

I was surprised that there are so many similarities between cancer cells and SARS-CoV-2-infected cells, Mhlberger says. The team screened a number of cancer drugs as part of their study and found that several of them are able to block SARS-CoV-2 from multiplying. Like viruses, cancer cells want to replicate their own genomes, dividing over and over again. To do that, they need to produce a lot of pyrimidine, a basic building block for genetic material. Interrupting the production of pyrimidineusing a cancer drug designed for that purposealso blocks the SARS-CoV-2 genome from being built. But Mhlberger cautions that cancer drugs typically have a lot of side effects. Do we really want to use that heavy stuff against a virus? she says. More studies will be needed to weigh the pros and cons of such an approach.

The findings of their latest study took the four senior investigators and scientists, postdoctoral fellows, and graduate students from their laboratories almost four months, working nearly around the clock, to complete the research. Of critical importance to the teams leaders was making sure that the experimental setup had rock-solid foundations in mimicking whats actually happening when the SARS-CoV-2 virus infects people.

Science is the answerif we use science to ask the lung cells what goes wrong when they are infected with coronavirus, the cells will tell us, Kotton says. Objective scientific data gives us hints at what to do and has lessons to teach us. It can reveal a path out of this pandemic.

Hes particularly excited about the outreach the team has received from collaborators around the world. People with expertise in supercomputers and machine learning are excited about using those tools and the datasets from our publication to identify the most promising drug targets [for treating COVID-19], he says.

Kotton says the theme thats become obvious among COVID-19 clinicians and scientists is understanding that timing is key. Once a patient is on a ventilator in the ICU, we feel limited in what we can do for their body, he says. Timing is everything, its crucial to identify early windows of opportunity for intervention. You can keep guessing and hope we get luckyor you [do the research] to actually understand the infection from its inception, and take the guesswork out of drug development.

Reference: Actionable Cytopathogenic Host Responses of Human Alveolar Type 2 Cells to SARS-CoV-2 by Ryan M. Hekman, Adam J. Hume, Raghuveera Kumar Goel, Kristine M. Abo, Jessie Huang, Benjamin C. Blum, Rhiannon B. Werder, Ellen L. Suder, Indranil Paul, Sadhna Phanse, Ahmed Youssef, Konstantinos D. Alysandratos, Dzmitry Padhorny, Sandeep Ojha, Alexandra Mora-Martin, Dmitry Kretov, Peter E.A. Ash, Mamta Verma, Jian Zhao, J.J. Patten, Carlos Villacorta-Martin, Dante Bolzan, Carlos Perea-Resa, Esther Bullitt, Anne Hinds, Andrew Tilston-Lunel, Xaralabos Varelas, Shaghayegh Farhangmehr Ulrich Braunschweig, Julian H. Kwan, Mark McComb, Avik Basu, Mohsan Saeed, Valentina Perissi, Eric J. Burks, Matthew D. Layne, John H. Connor, Robert Davey, Ji-Xin Cheng, Benjamin L. Wolozin, Benjamin J. Blencowe, Stefan Wuchty, Shawn M. Lyons, Dima Kozakov, Daniel Cifuentes, Michael Blower, Darrell N. Kotton, Andrew A. Wilson, Elke Mhlberger and Andrew Emili, 18 November 2020, Molecular Cell.DOI: 10.1016/j.molcel.2020.11.028

This research was funded by the National Institutes of Health, the Australian National Health and Medical Research Council, the Pulmonary Fibrosis Foundation, the Massachusetts Consortium on Pathogen Readiness, the C3.ai Digital Transformation Institute, the Canadian Institutes of Health Research, and Fast Grants.

The rest is here:
How Coronavirus Damages Lung Cells Within Mere Hours And What Drugs Could Halt COVID-19 Infection - SciTechDaily

Nine abstracts accepted demonstrating potential of HSC gene therapy to treat multiple neurodegenerative disorders

New clinical data from all eight patients treated with OTL-203 for Mucopolysaccharidosis type I (MPS I)

Biomarker data from first three patients treated with OTL-201 for Mucopolysaccharidosis type IIIA (MPS-IIIA or Sanfilippo Syndrome Type A)

Multiple abstracts highlighting clinical and real-world data for OTL-200 and Metachromatic Leukodystrophy (MLD)

Company to host virtual investor webinar to review symposium data on Tuesday, February 9, 2021 at 4:30 p.m. ET

BOSTON and LONDON, Jan. 28, 2021 (GLOBE NEWSWIRE) -- Orchard Therapeutics(Nasdaq: ORTX), a global gene therapy leader, today outlined nine upcoming presentations from its neurodegenerative portfolio to be featured at the 17th Annual WORLDSymposium being held on February 8-12, 2021. Accepted abstracts include clinical data from three of its hematopoietic stem cell (HSC) gene therapy programs OTL-200 for MLD, OTL-203 for MPS-I and OTL-201 for MPS-IIIA as well as data supporting Orchards multi-pronged patient identification and market access strategies for eligible MLD patients in Europe.

Together with our clinical partners, were proud of our presence at the upcoming WORLDSymposium, which for the first time features clinical data on cognitive function and growth in all eight MPS-I patients treated with gene therapy, said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard. Alongside emerging data in MPS-IIIA and our extensive body of clinical and real-world data in MLD, our programs are establishing a clear picture of the transformative potential of HSC gene therapy across multiple fatal neurodegenerative conditions.

The presentations are listed below and the full preliminary program is available online on the WORLDSymposium website. The ePosters will open at 2:30 p.m. ET on Monday, February 8, 2021 and will remain open throughout WORLDSymposium 2021.

Orchard is planning to host a virtual investor webinar on Tuesday, February 9th, 2021 at 4:30 p.m. ET to review the data from its neurodegenerative programs presented at the WORLDSymposium. A live webcast will be available under Events in the Investors & Media section of the companys website at http://www.orchard-tx.com and a replay of the webcast will be archived following the event.

Platform Oral Presentation Details:

Ex-vivo autologous stem cell gene therapy clinical trial for mucopolysaccharidosis type IIIA: Update on phase I/II clinical trialPresenting Author: Jane Kinsella, Royal Manchester Childrens Hospital 2021 Young Investigator Award RecipientDate/Time: Tuesday, February 9, 2021, 11:12 a.m. ET

Ex vivo hematopoietic stem cell gene therapy for mucopolysaccharidosis type I (Hurler syndrome)Presenting Author: Bernhard Gentner, San Raffaele Telethon Institute for Gene TherapyDate/Time: Tuesday, February 9, 2021, 11:24 a.m. ET

Lentiviral hematopoietic stem and progenitor cell gene therapy provides durable clinical benefit in early-symptomatic early juvenile metachromatic leukodystrophyPresenting Author: Francesca Fumagalli, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific InstituteDate/Time: Wednesday, February 10, 2021, 11:36 a.m. ET

ePoster Presentation Details:

Lentiviral haematopoietic stem cell gene therapy for metachromatic leukodystrophy: Results in nine patients treated with a cryopreserved formulation of OTL-200Abstract Number: 25Presenting Author: Valeria Calbi, San Raffaele Telethon Institute for Gene TherapyDate/Time: Wednesday, February 10, 2021, 2:30 3:30 p.m. ET

Initial signs and symptoms of metachromatic leukodystrophy: A caregiver perspectiveAbstract Number: 64Presenting Author: Florian Eichler, Massachusetts General HospitalDate/Time: Thursday, February 11, 2021, 2:30 3:30 p.m. ET

Demographic and clinical characteristics of patients with metachromatic leukodystrophy in the United Kingdom: Interim results from an observational real-world studyAbstract Number: 110Presenting Author: Simon Jones, Manchester Centre for Genomic Medicine Date/Time: Thursday, February 11, 2021, 2:30 3:30 p.m. ET

Quality of life of patients with metachromatic leukodystrophy and their caregivers in the US, UK, Germany and FranceAbstract Number: 186Presenting Author: Francis Pang, Orchard TherapeuticsDate/Time: Thursday, February 11, 2021, 2:30 3:30 p.m. ET

Health-related quality of life in metachromatic leukodystrophy based on a societal utility study in the UKAbstract Number: 187Presenting Author: Francis Pang, Orchard TherapeuticsDate/Time: Thursday, February 11, 2021, 2:30 3:30 p.m. ET

Newborn screening for metachromatic leukodystrophy in Northern Germany - a prospective studyAbstract Number: 269Presenting Author: Thomas Wiesinger, ARCHIMEDlifeDate/Time: Thursday, February 11, 2021, 2:30 3:30 p.m. ET

About Libmeldy / OTL-200Libmeldy (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase-A (ARSA) gene), also known as OTL-200, has been approved by the European Commission for the treatment of MLD in eligible early-onset patients characterized by biallelic mutations in the ARSA gene leading to a reduction of the ARSA enzymatic activity in children with i) late infantile or early juvenile forms, without clinical manifestations of the disease, or ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline. Libmeldy is the first therapy approved for eligible patients with early-onset MLD.

The most common adverse reaction attributed to treatment with Libmeldy was the occurrence of anti-ARSA antibodies. In addition to the risks associated with the gene therapy, treatment with Libmeldy is preceded by other medical interventions, namely bone marrow harvest or peripheral blood mobilization and apheresis, followed by myeloablative conditioning, which carry their own risks. During the clinical studies, the safety profiles of these interventions were consistent with their known safety and tolerability.

For more information about Libmeldy, please see the Summary of Product Characteristics (SmPC) available on the EMA website.

Libmeldy is not approved outside of the European Union, UK, Iceland, Liechtenstein and Norway. OTL-200 is an investigational therapy in the US.

Libmeldy was developed in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy.

About OrchardOrchard Therapeutics is a global gene therapy leader dedicated to transforming the lives of people affected by rare diseases through the development of innovative, potentially curative gene therapies. Our ex vivo autologous gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of disease in a single administration. In 2018, Orchard acquired GSKs rare disease gene therapy portfolio, which originated from a pioneering collaboration between GSK and theSan Raffaele Telethon Institute for Gene Therapy in Milan, Italy. Orchard now has one of the deepest and most advanced gene therapy product candidate pipelines in the industry spanning multiple therapeutic areas where the disease burden on children, families and caregivers is immense and current treatment options are limited or do not exist.

Orchard has its global headquarters in London and U.S. headquarters in Boston. For more information, please visit http://www.orchard-tx.com, and follow us on Twitter and LinkedIn.

Availability of Other Information About OrchardInvestors and others should note that Orchard communicates with its investors and the public using the company website (www.orchard-tx.com), the investor relations website (ir.orchard-tx.com), and on social media (Twitter andLinkedIn), including but not limited to investor presentations and investor fact sheets,U.S. Securities and Exchange Commissionfilings, press releases, public conference calls and webcasts. The information that Orchard posts on these channels and websites could be deemed to be material information. As a result, Orchard encourages investors, the media, and others interested in Orchard to review the information that is posted on these channels, including the investor relations website, on a regular basis. This list of channels may be updated from time to time on Orchards investor relations website and may include additional social media channels. The contents of Orchards website or these channels, or any other website that may be accessed from its website or these channels, shall not be deemed incorporated by reference in any filing under the Securities Act of 1933.

Forward-Looking StatementsThis press release contains certain forward-looking statements about Orchards strategy, future plans and prospects, which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include express or implied statements relating to, among other things, Orchards business strategy and goals, and the therapeutic potential of Orchards product candidates, including the product candidate or candidates referred to in this release. These statements are neither promises nor guarantees and are subject to a variety of risks and uncertainties, many of which are beyond Orchards control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, these risks and uncertainties include, without limitation: the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchards product candidates, will be insufficient to support regulatory submissions or marketing approval in the US or EU, as applicable, or that long-term adverse safety findings may be discovered; the risk that any one or more of Orchards product candidates, including the product candidates referred to in this release, will not be approved, successfully developed or commercialized; the risk of cessation or delay of any of Orchards ongoing or planned clinical trials; the risk that Orchard may not successfully recruit or enroll a sufficient number of patients for its clinical trials; the delay of any of Orchards regulatory submissions; the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchards product candidates or the receipt of restricted marketing approvals; the inability or risk of delays in Orchards ability to commercialize its product candidates, if approved, or Libmeldy in the EU; the risk that the market opportunity for Libmeldy, or any of Orchards product candidates, may be lower than estimated; and the severity of the impact of the COVID-19 pandemic on Orchards business, including on clinical development, its supply chain and commercial programs. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.

Other risks and uncertainties faced by Orchard include those identified under the heading "Risk Factors" in Orchards quarterly report on Form 10-Q for the quarter endedSeptember 30, 2020, as filed with theU.S. Securities and Exchange Commission(SEC), as well as subsequent filings and reports filed with theSEC. The forward-looking statements contained in this press release reflect Orchards views as of the date hereof, and Orchard does not assume and specifically disclaims any obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law.

Contacts

InvestorsRenee LeckDirector, Investor Relations+1 862-242-0764Renee.Leck@orchard-tx.com

MediaChristine HarrisonVice President, Corporate Affairs+1 202-415-0137media@orchard-tx.com

See more here:
Orchard Therapeutics Outlines Comprehensive Presence at 2021 WORLDSymposium - GlobeNewswire

BrainStorm Cell Therapeutics has opened an expanded access program (EAP) in the U.S. to allow certain amyotrophic lateral sclerosis (ALS) patients to gain access to its investigational cell-based therapy NurOwn.

EAPs, also known as compassionate use programs, are intended to make investigational therapies available outside of a clinical trial to people whose serious or life-threatening conditions have few or no adequate treatments, when the therapys benefits are thought to outweigh potential risks.

Developed in partnership with the U.S. Food and Drug Administration (FDA), the program will allow clinicians to prescribe NurOwn, at no cost, to ALS patients who completed the therapys pivotal, placebo-controlled Phase 3 trial (NCT03280056) and who meet specific eligibility criteria.

Those with less advanced disease as measured by the ALS Functional Rating Scale(ALSFRS-R) will be the first to receive the treatment. This decision was based on the trials top-line data, which showed a superior treatment response in people in earlier stages of ALS.

Detailed, full data are expected to be presented at upcoming scientific conferences, and published in a peer-reviewed scientific journal.

We are pleased to have the opportunity to treat additional patients with NurOwn through this Expanded Access Program, which was strongly advocated for by members of the ALS advocacy community, Chaim Lebovits, BrainStorms CEO, said in a press release.

We recognize the urgency with which people with ALS want and need access to new potential treatments. This EAP is an important next step to providing an immediate option for some patients, Lebovits added.

Fred Fisher, president and CEO of The ALS Associations Golden West Chapter, said that enabling early access, while the data review continues, is an extraordinary gesture of support and compassion for those living with ALS, and reflects an understanding of the ALS communitys urgent need for an effective therapy. The Golden West Chapter represents the largest ALS community in the U.S.

I applaud Brainstorm for taking this important step, and I look forward to learning the results of their full data analysis, Fisher added.

Lebovits emphasized that BrainStorm remains committed to rapidly advancing NurOwn through clinical development and regulatory review in the hope that the greatest number of people living with ALS may benefit. The EAP will not interfere with data or regulatory timelines.

NurOwn involves collecting mesenchymal stem cells(MSCs) from a patientsown bone marrow, and expanding and maturating them into cells that produce high levels of neurotrophic factors molecules that promote nervous tissue growth and survival. MSCs are stem cells that can generate a variety of other cell types.

The mature cells called MSC-NTF cells are then injected into the patients spinal canal to promote and support nerve cell repair. Using a patients own cells minimizes the risk of an immune reaction, as might occur with cells from a donor.

NurOwn has been designated an orphan drug in both the U.S. and European Union, and given to fast track designation in the U.S.; all help to speed its clinical development and review.

Afterpromising Phase 2 resultsin people with fast-progressing ALS, BrainStorm launched a Phase 3 trial to confirm NurOwns benefits in a larger patient population.

The Phase 3 study evaluated the therapys safety and effectiveness in 189 people with rapidly progressing ALS, who wererandomly assigned to a total of three injections of either NurOwn or a placebo, given directly into the spinal canal, every other month.

Patients were recruited at six clinical sites in the U.S.: three in California, two in Massachusetts, and one in Minnesota. NurOwn will be available under the EAP at these six centers.

Top-line data showed that a greater proportion of NurOwn-treated patients (34.7%) had a slower disease progression as assessed with the ALSFRS-R compared with those given a placebo (27.7%).

However, this difference did not reach statistical significance. This was mainly due to unexpectedly good placebo group responses, exceeding those reported in other ALS trials, the company reported.

Also, no significant group differences were observed in ALSFRS-R score mean changes over the seven months of treatment (-5.52 in the NurOwn group vs. -5.88 in the placebo group), meaning that the trial failed to meet both its main and secondary effectiveness goals.

However, greater treatment responses were seen in a pre-specified group of participants with less advanced disease.

In this group, 34.6% of those given NurOwn showed a slower disease progression, compared with 15.6% of those in the placebo group. In addition, the mean decline in the ALSFRS-R total score was 1.77 with NurOwn and 3.78 with a placebo reflecting a 2.01-point improvement with the cell-based therapy.

Differences between these groups were also not statistically significant, but they were considered clinically meaningful. Based on these positive findings, BrainStorm is actively working with the FDA to identify regulatory pathways that may support NurOwn approval as an ALS treatment.

Biomarker analyses also confirmed that NurOwn was driving its intended biological effects. Its use significantly increased the levels of neurotrophic factors, and dropped those of neurodegenerative and neuroinflammatory biomarkers, in patients cerebrospinal fluid a finding not observed among placebo patients. (The cerebrospinal fluid is the liquid that surrounds the brain and spinal cord.)

This expanded access program is an appropriate and welcome next step in following up the exciting results of the Phase 3 study; it is widely anticipated and deeply appreciated by our ALS patients, said Robert Brown, MD, PhD, one of the trials principal investigators.

Brown is also the Leo P. and Theresa M. LaChance chair in medical research, and chair of the neurology department atUniversity of Massachusetts Medical Schooland UMass Memorial Medical Center.

NurOwn will initially be manufactured by the Dana Farber Cancer Institute, assisted by on-site BrainStorm personnel.

BrainStorm also is evaluating NurOwn as a potential therapy for other neurodegenerative diseases, such as multiple sclerosis, Parkinsons disease, Huntingtons disease, as well as for autism spectrum disorder.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.

Total Posts: 45

Ins holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Cincias e Tecnologias and Instituto Gulbenkian de Cincia. Ins currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.

Read this article:
NurOwn May Be Given to Early ALS Patients in US Who Finished Phase... - ALS News Today