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First Patient With B-NHL or CLL Treated With MB-106 in Phase 1/2 Study – Targeted Oncology

Posted: October 13, 2022 at 2:21 am

The phase 1/2 clinical trial of MB-106 is demonstrating high efficacy, durable responses, and a favorable safety profile as the first patient treated did not experience cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome

The first patient has been treated in the phase 1/2 clinical trial (NCT05360238) evaluating the safety and efficacy of MB-106 in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL), according to Mustang Bio, Inc.1

MB-106 is a CD20-targeted, autologous chimeric antigen receptor (CAR) T-cell therapy. The agent, which was developed by researchers at the Fred Hutchinson Cancer Research Center (Fred Hutc), is a third-generation CAR derived from a fully human antibody.

The patient treated with MB-106 did not experience cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS), leading the ongoing clinical trial of MB-106 to continue to elicit high efficacy, durable responses, and a favorable safety profile across wide range of hematologic malignancies.

The first clinical trial under Mustangs investigational new drug application is an important milestone in the ongoing development and evaluation of MB-106. Data presented at several prestigious medical meetings earlier this year from the initial, ongoing phase 1/2 clinical trial at Fred Hutch show that MB-106 continues to demonstrate high efficacy and a favorable safety profile across patients with a wide range of hematologic malignancies, said Manuel Litchman, MD, president and chief executive officer of Mustang Bio, Inc, in the press release, We look forward to providing updates on our multicenter MB-106 clinical trial as it progresses and anticipate reporting efficacy data in the fourth quarter of this year.

The multicenter, open-label, non-randomized, phase 1/2 study aims to evaluate the safety, tolerability, and efficacy of MB-106 in patients with relapsed or refractory B-NHL or CLL.2 However, the study is open to patients with a variety of selected CD20-expressing malignancies, including follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL).

Part 1 of the study will enroll approximately 287 patients with aggressive B-NHL, including DLBCL, and MCL, as well as patients with indolent NHL like FLL. Patients with CLL of small lymphocytic lymphoma (SLL) will also be evaluated in this portion of the trial.

The phase 1 part of the study will administer patients escalating doses of MB-106 in a 3 + 3 study design. The coprimary end points are the incidence of treatment-emergent adverse events (TEAEs) in patients with relapsed or refractory CD20-positive B-NHL or CLL and to determine the recommended phase 2 dose of the agent. Secondary end points for phase 1 are ORR, duration of response (DOR), and minimal residual disease (MRD) in patients with CLL.

In the phase 2 portion of the study, patients with relapsed/refractory DLBCL, including those with MYC, BCL2, BCL6 rearrangement and primary mediastinal large B-cell lymphoma or transformed FL will be enrolled. Patients with B-NHL subtypes that progressed after available therapy, including MCL, marginal zone lymphoma, Waldenstrom macroglobulinemia, Burkitt-like lymphoma, hairy cell leukemia, and CLL/SLL will also be included.

For phase 2, the primary end point of the study is ORR with the secondary end points of DOR, the incidence of TEAEs, and the total number of patients with MRD in CLL.

Patients aged 18 years and older are eligible to enroll in the trial if they have relapsed after treatment with CD19 CAR-T cell therapy, have an ECOG performance status of 0-1, a life expectancy of 16 weeks, meet all laboratory criteria, adequate pulmonary function, and have left ventricular ejection fraction 50%. Further, all patients must be capable of consenting to treatment and be able to follow the visit scheduled and other protocol requirements. Female patients of childbearing potential must provide a negative pregnancy test, and patients of all genders must agree to use contraception for the duration of study.

Interim data from the initial 28 patients treated in the ongoing multicenter, open-label, non-randomized, phase 1/2 clinical trial continue to support the use of MB-106 in B-NHLs and CLL.

Interim data as of September 9, 2022, show the agent to elicit an overall response rate (ORR) of 96% and complete response (CR) rate of 75% in heatologic malignancies, including follicular lymphoma, CLL, diffuse large B-cell lymphoma, and Waldenstrom macroglobulinemia

A total of 12 patients have experienced CR for more than 12 months with 10 ongoing and 4 patients have had a CR for more than 2 years. The longest CR currently seen in a patient in the trial is 33 months. Further, 6 patients had a partial response which improved to a CR. All of these patients remain in ongoing CR. Among the 3 patients previously treated with CD19 CAR T-cell therapy, all have responded to treatment with MB-106.

Regarding safety, MB-106 has shown a favorable safety profile as an outpatient therapy so far with no patients having grade 3 or higher CRS or ICANS. CAR T-cell persistence results in deepening responses following initial 28-day assessments.

Enrollment in this clinical trial of MB-106 is ongoing and data from the study is expected to be released at the end of 2022.

We are excited to broaden the evaluation of MB-106 with this multicenter clinical trial under Mustangs IND. To date, the data from the initial, ongoing clinical trial at Fred Hutch continue to demonstrate a high rate of complete and durable responses, said Mazyar Shadman, MD, MPH, study chair, associate professor and physician at Fred Hutch and University of Washington, in the press release. In addition, MB-106 has shown potential to treat patients in an outpatient setting and provide another immunotherapy option for patients treated previously with CD19-directed CAR T-cell therapy.

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First Patient With B-NHL or CLL Treated With MB-106 in Phase 1/2 Study - Targeted Oncology

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MaxCyte to Report Third Quarter 2022 Financial Results on November 9, 2022 – Yahoo Finance

Posted: October 13, 2022 at 2:21 am

MaxCyte, Inc

ROCKVILLE, Md., Oct. 12, 2022 (GLOBE NEWSWIRE) -- MaxCyte, Inc., (NASDAQ: MXCT; LSE: MXCT), a leading commercial cell-engineering company focused on providing enabling platform technologies to advance innovative cell-based research as well as next-generation cell therapeutic discovery, development and commercialization, today announced that it will release financial results for the third quarter of 2022 after the U.S. market close on Wednesday, November 9th, 2022. Company management will host a conference call to discuss financial results at 4:30 p.m. Eastern Time.

Conference Call DetailsInvestors interested in listening to the conference call are required to register online. It is recommended to register at least a day in advance. A live and archived webcast of the event will be available on the Events section of the MaxCyte website at https://investors.maxcyte.com/.

About MaxCyteMaxCyte is a leading commercial cell-engineering company focused on providing enabling platform technologies to advance innovative cell-based research as well as next-generation cell therapeutic discovery, development and commercialization. Over the past 20years, we have developed and commercialized our proprietary Flow Electroporation platform, which facilitates complex engineering of a wide variety of cells.Our ExPERT platform, which is based on our Flow Electroporation technology, has been designed to support the rapidly expanding cell therapy market and can be utilized across the continuum of the high-growth cell therapy sector, from discovery and development through commercialization of next-generation, cell-based medicines. The ExPERT family of products includes: four instruments, the ATx, STx GTx and VLx; a portfolio of proprietary related processing assemblies or disposables; and software protocols, all supported by a robust worldwide intellectual property portfolio.

MaxCyte Contacts:

US IR AdviserGilmartin GroupDavid Deuchler, CFA+1 415-937-5400ir@maxcyte.com

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Nominated Adviser and Joint Corporate BrokerPanmure GordonEmma Earl / Freddy CrossleyCorporate BrokingRupert Dearden+44 (0)20 7886 2500

UK IR AdviserConsilium Strategic CommunicationsMary-Jane Elliott / Chris Welsh+44 (0)203 709 5700maxcyte@consilium-comms.com

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Iovance Biotherapeutics Announces First Patient Dosed with PD-1 Inactivated Tumor Infiltrating Lymphocyte (TIL) Therapy – GlobeNewswire

Posted: October 13, 2022 at 2:21 am

First Genetically Modified (TALEN-edited) Iovance TIL Therapy with Inactivated PD-1 Expression

SAN CARLOS, Calif., Oct. 10, 2022 (GLOBE NEWSWIRE) -- Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel T cell-based cancer immunotherapies, announced that the first patient was dosed, and completed the safety observation period, in the IOV-GM1-201 trial of Iovances genetically modified, PD-1 inactivated TIL therapy, IOV-4001. IOV-GM1-201 is a Phase 1/2, first-in-human study investigating the safety and efficacy of IOV-4001 in patients with previously treated metastatic non-small cell lung cancer (NSCLC) or advanced melanoma.

Friedrich Graf Finckenstein, M.D., Chief Medical Officer of Iovance, stated, Dosing the first patient with IOV-4001 is an important first step in providing proof-of-concept for delivering genetically modified TIL therapy to solid tumor patients with significant unmet needs and few treatment options. We look forward to dosing the next patient. This trial may also support our broader platform of genetically modified Iovance TIL therapies to potentially address difficult-to-treat solid tumor cancers.

To inactivate the gene coding for the PD-1 protein, IOV-4001 utilizes the gene-editing TALEN technology licensed from Cellectis (Euronext Growth: ALCLS - NASDAQ: CLLS), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop potentially life-saving cell and gene therapies. This single genetic modification in IOV-4001 may enhance the antitumor activity of the TIL mechanism to directly target and kill tumor cells.

Jason Chesney, M.D., Ph.D.,Director and Endowed Professor, UofL Health Brown Cancer Center, University of Louisville, and an IOV-GM1-201 principal investigator, stated, I am excited about the potential for gene-editing to open new doors for TIL therapy in patients with solid tumor cancers that do not respond well to current treatment options. As the first multicenter clinical trial to investigate a genetically modified TIL therapy, the IOV-GM1-201 trial may pave the way for a promising new treatment approach to cancer.

PD-1 is a checkpoint protein found on T cells that normally acts as an off switch to help to prevent T cells from attacking other cells in the body. It works by binding to PD-L1, a protein found on both normal and cancerous cells, thereby shutting down an attack by a T cell. As a TIL therapy that is genetically modified to remove this important barrier for T cells to attack cancer, IOV-4001 has the potential to become an optimized, next generation TIL therapy for several solid tumor cancers. A poster on preclinical data was presented at the American Association for Cancer Research (AACR) 2022 Annual Meeting.

IOV-GM1-201 is actively enrolling adult participants with advanced NSCLC or unresectable or metastatic melanoma. For more information, eligibility criteria, and trial locations, please visit http://www.clinicaltrials.gov (NCT05361174) or contact clinical.inquiries@iovance.com.

AboutIovance Biotherapeutics, Inc.Iovance Biotherapeutics aims to be the global leader in innovating, developing and delivering tumor infiltrating lymphocyte (TIL) cell therapies for patients with cancer. We are pioneering a transformational approach to cure cancer by harnessing the human immune systems ability to recognize and destroy diverse cancer cells in each patient. Our lead late-stage TIL product candidate, lifileucel for metastatic melanoma, has the potential to become the first approved one-time cell therapy for a solid tumor cancer. The Iovance TIL platform has demonstrated promising clinical data across multiple solid tumors. We are committed to continuous innovation in cell therapy, including gene-edited cell therapy, that may extend and improve life for patients with cancer. For more information, please visit http://www.iovance.com.

Forward-Looking StatementsCertain matters discussed in this press release are forward-looking statements of Iovance Biotherapeutics, Inc. (hereinafter referred to as the Company, we, us, or our) within the meaning of the Private Securities Litigation Reform Act of 1995 (the PSLRA). All such written or oral statements made in this press release, other than statements of historical fact, are forward-looking statements and are intended to be covered by the safe harbor for forward-looking statements provided by the PSLRA. Without limiting the foregoing, we may, in some cases, use terms such as predicts, believes, potential, continue, estimates, anticipates, expects, plans, intends, forecast, guidance, outlook, may, could, might, will, should or other words that convey uncertainty of future events or outcomes and are intended to identify forward-looking statements. Forward-looking statements are based on assumptions and assessments made in light of managements experience and perception of historical trends, current conditions, expected future developments and other factors believed to be appropriate. Forward-looking statements in this press release are made as of the date of this press release, and we undertake no duty to update or revise any such statements, whether as a result of new information, future events or otherwise. Forward-looking statements are not guarantees of future performance and are subject to risks, uncertainties and other factors, many of which are outside of our control, that may cause actual results, levels of activity, performance, achievements and developments to be materially different from those expressed in or implied by these forward-looking statements. Important factors that could cause actual results, developments and business decisions to differ materially from forward-looking statements are described in the sections titled "Risk Factors" in our filings with the Securities and Exchange Commission, including our most recent Annual Report on Form 10-K and Quarterly Reports on Form 10-Q, and include, but are not limited to, the following substantial known and unknown risks and uncertainties inherent in our business: the effects of the COVID-19 pandemic; risks related to the timing of and our ability to successfully develop, submit, obtain and maintain U.S. Food and Drug Administration (FDA) or other regulatory authority approval of, or other action with respect to, our product candidates, and our ability to successfully commercialize any product candidates for which we obtain FDA approval; whether clinical trial results from our pivotal studies and cohorts may support registration and approval by the FDA; preliminary and interim clinical results, which may include efficacy and safety results, from ongoing clinical trials or cohorts may not be reflected in the final analyses of our ongoing clinical trials or subgroups within these trials or in other prior trials or cohorts; the risk that enrollment may need to be adjusted for our trials and cohorts within those trials based on FDA and other regulatory agency input; the changing landscape of care for cervical cancer patients may impact our clinical trials in this indication; the risk that we may be required to conduct additional clinical trials or modify ongoing or future clinical trials based on feedback from the FDA or other regulatory authorities; the risk that our interpretation of the results of our clinical trials or communications with the FDA may differ from the interpretation of such results or communications by the FDA (including from the recent pre-BLA meeting with the FDA); the risk that the rolling BLA submission for lifileucel in metastatic melanoma may take longer than expected; the acceptance by the market of our product candidates and their potential reimbursement by payors, if approved; our ability or inability to manufacture our therapies using third party manufacturers or our own facility may adversely affect our potential commercial launch; the results of clinical trials with collaborators using different manufacturing processes may not be reflected in our sponsored trials; the risk that unanticipated expenses may decrease our estimated cash balances and forecasts and increase our estimated capital requirements; and other factors, including general economic conditions and regulatory developments, not within our control.

CONTACTS

Iovance Biotherapeutics, Inc:Sara Pellegrino, IRCSenior Vice President, Investor Relations & Corporate Communications650-260-7120 ext. 264Sara.Pellegrino@iovance.com

Jen SaundersDirector, Investor Relations & Public Relations267-485-3119Jen.Saunders@iovance.com

TALEN is a trademark owned by Cellectis

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Iovance Biotherapeutics Announces First Patient Dosed with PD-1 Inactivated Tumor Infiltrating Lymphocyte (TIL) Therapy - GlobeNewswire

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Elicera Therapeutics: PhD thesis describing the iTANK-platform awarded best of the year 2021 in Sweden in the field of gene and cell therapy -…

Posted: October 13, 2022 at 2:21 am

Gothenburg, October 12, 2022 - Elicera Therapeutics AB (publ) ("Elicera"), a clinical stage cell and gene therapy company developing next generation immuno-oncological treatments based on enhanced oncolytic viruses and CAR T-cells, today announced that the PhD thesis of the company's co-worker Jing Ma was awarded the best Swedish PhD thesis of the year within the field of gene and cell therapy for 2021 by the Swedish Society for Gene and Cell Therapy (SSGCT).

Jing Ma's PhD thesis describes the development of Elicera's iTANK-platform and the upcoming CAR T-cell study in treatment of B-cell lymphoma. Jing Ma was invited to present her work at the SSGCT board meeting on October 11, 2022.

Jing Ma was supervised by Elicera Therapeutic's co-founder, Associate Professor Di Yu.

For further information please contact:

Jamal El-Mosleh, CEO, Elicera Therapeutics AB

Phone: +46 (0) 703 31 90 51 jamal.elmosleh@elicera.com

About the iTANK platform

The iTANK- (immunoTherapies Activated with NAP for efficient Killing) platform is the company's own fully developed technology platform for arming and enhancing CAR T-cells to meet two of the major challenges CAR T-cell therapies face in the treatment of solid tumors: tumor antigen heterogeneity and a hostile tumor microenivornment. The technology is used to incorporate a transgene into CAR T-cells encoding a neutrophil activating protein (NAP) from the bacterium Helicobacter pylori. Upon activation, NAP secreted from the CAR(NAP) T-cells has been shown to be able to enhance the function of the CAR T-cell in addition to activating a parallel immune response via CD8+ killer T-cells. This is expected to lead to a broad attack against most antigen targets on cancer cells. The iTANK-platform is used to enhance the company's own CAR T-cells but can also be universally applied to other CAR T-cell therapies under development. More information about iTANK-platform is available here: https://www.elicera.com/technology

About Elicera Therapeutics AB

Elicera Therapeutics AB is a clinical stage cell and gene therapy company that develops next generation immuno-oncology treatments based on enhanced oncolytic viruses and CAR T-cells. The work is based on high-profile long-standing research conducted by Professor Magnus Essand's research group at Uppsala University and has resulted in the development of four drug candidates, including two CAR T-cells and two oncolytic viruses. In addition, Elicera has developed a technology platform called iTANK that can be used to optimize all CAR T-cells in development and activate killer T-cells against cancer. The company's share (ELIC) is traded on Nasdaq First North Growth Market. G&W Fondkommission has been appointed the Company's Certified Adviser. E-mail: ca@gwkapital.se, tel: +468-503 000 50.

For more information, please visit http://www.elicera.com

https://news.cision.com/elicera-therapeutics/r/elicera-therapeutics--phd-thesis-describing-the-itank-platform-awarded-best-of-the-year-2021-in-swed,c3646903

https://mb.cision.com/Main/20218/3646903/1637620.pdf

(c) 2022 Cision. All rights reserved., source Press Releases - English

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Glowing embryonic gecko hand and otherworldly slime mold amaze in winning microscope photos – Livescience.com

Posted: October 13, 2022 at 2:19 am

Shots of a stunningly detailed embryonic gecko hand, an otherworldly slime mold and a psychedelically stained segment of dinosaur bone are among some of the intricate and awe-inspiring entries in a recent microscopic photography contest.

The Nikon Small World Photomicrography Competition, which has been running for almost 50 years, is a specialist event that blends "science and artistry under the microscope," organizers said in a statement (opens in new tab). The contest, which highlights the beauty of incredibly small things, is open to anyone as long as the images are captured using a light microscope. This year's top 20 images were revealed by event organizers on Oct. 11.

Grigorii Timin, a doctoral student at the University of Geneva in Switzerland, won first prize at this year's competition with a painstakingly curated shot of a developing gecko hand stained with fluorescent dyes. Captured under the supervision of Michel Milinkovitch, an evolutionary geneticist at the University of Geneva, the winning picture is a composite of thousands of individual images that have been stitched together.

"The scan consists of 300 tiles, each containing about 250 optical sections, resulting in more than two days of acquisition and approximately 200 GB of data," Timin said in the statement. The developing lizard's hand is around 0.12 inch (3 millimeters) long, which is a massive subject to capture with microscopic detail, he added.

Related: Hidden secrets revealed in microscopic images of ancient artifacts

Researchers stained the gecko's nerves with a cyan-tinted dye and colored the reptile's bones, tendons, ligaments, skin and blood cells in warmer colors like yellow and orange. Zooming in on particular regions of the image reveals how "structures [within the hand] are organized at a cellular level," Timin said.

However, the multi-colored gecko hand was not the only image that stole the show at this year's competition.

Alison Pollack, a California-based photographer who specializes in macro and extreme macro photography, won 5th place with a stunning shot of a slime mold from the genus Lamproderma. The iridescent blue structure, which looks like some sort of alien tree, is the organism's reproductive fruiting body. However, like all slime molds, the strange specimen is one individual cell with no internal membranes and multiple nucleuses dotted throughout its body. The image is also a composite, this time of more than 100 images stitched together.

"Despite the rather unflattering common name, slime molds are astonishingly beautiful organisms," Pollack told Live Science in an email. "While they grow in almost any kind of environment all over the world, they are little known because they are so tiny."

This particular slime mold was collected by Pollack from a leaf just outside her home after heavy rainfall. The best place to look for slime molds is in woodland areas after it has rained, Pollock said. Anyone can go hunting for the bizarre creatures, but "unless you have very good eyes, they are best found with the aid of a light and a good magnifying lens," she added.

Randy Fullbright, a photographer based near the Dinosaur National Monument in Utah, took 13th place with a boldly colored shot of a dinosaur bone fragment stained yellow and blue. The bone likely belonged to a sauropod a group of large dinosaurs with long tails and necks, such as Brachiosaurus and Diplodocus and was uncovered at a ranch at the Morrison Formation in northwest Colorado, which dates back to around 150 million years ago toward the end of the Jurassic period, Fullbright told Live Science in an email. The specimen was cut using a diamond saw, and the minerals within the bone were stained different colors, he added.

"I feel very blessed for the opportunity to show a world that most will never see," Fullbright said.

Tenth place in the competition went to Murat ztrk, a Turkish photographer based in Ankara, with a breathtaking shot of a fly trapped under the chin of a tiger beetle. The fly appears to be struggling to escape the beetle's death grip the beetle is sticking its mandibles, or serrated mouthparts, into its prey's eyes.

Tiger beetles, which are a subfamily of ground beetles known as Cicindelinae, are the fastest-running insects on Earth. The fastest tiger beetle species, Rivacindela hudsoni, can run at around 5.6 mph (9km/h), which is around 120 times its own body length per second. In 2014, a study published in the journal Proceedings of the Royal Society B (opens in new tab), showed that, at this speed, R. hudsoni becomes functionally blind while running and relies on its antennae to see its prey instead of using its eyes.

Image 1 of 3

Other noteworthy images include a multi-colored mural of human neurons derived from stem cells, a neatly stacked tower of moth eggs and the luminous network of nerve cells inside a zebrafish embryo's tail.

Past winners of Nikon's Small World competition include a helix-shaped plankton, a mosquito's heart and a fluorescent, rainbow-colored turtle embryo.

On Sept. 13, the winners of Nikon's Small World in Motion competition the sister competition that focuses on the very best microscopic videos produced by scientists and photographers announced its winners. The standout video was a "completely hypnotic" donut of swirling cell microtubules.

Editor's note: This article was updated Oct.12 at 4:35 a.m. ET to correct the age of the dinosaur bone fragment following new information received from the photographer.

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Researchers develop method to study brain connectivity, functionality – Florida Hospital News and Healthcare Report – South Florida Hospital News

Posted: October 13, 2022 at 2:16 am

Research method integrates human cortical organoids into developing rat brains, allowing for study of brain processes associated with disease.

This work provides a significant advance in the ability of scientists to study the cellular and circuit underpinnings of complex human brain disorders. It allows organoids to get wired in a more biologically relevant context and function in ways they cant do in a petri dish, said David Panchision, Ph.D., chief of the Developmental and Genomic Neuroscience Research Branch in the Division of Neuroscience and Basic Behavioral Science at NIMH.

ResearcherSergiu Pasca, M.D.(link is external), and colleagues at Stanford University, Stanford, California, demonstrated that a cortical organoid cultured from human stem cells can be transplanted ontoand integrated intothe developing rat brain to study certain developmental and functional processes. The findings suggest that transplanted organoids may offer a powerful tool for investigating the processes associated with disease development.

Researchers sometimes use cortical organoidsthree-dimensional cultures of human stem cells that can mirror some of the developmental processes seen in typical brainsas a model for investigating how some aspects of the human brain develops and functions. However, cortical organoids lack the connectivity seen in typical human brains, limiting their usefulness for understanding complex brain processes. Researchers have been trying to overcome some of these limitations by transplanting individual human neurons into adult rodent brains. While these transplanted neurons connect with rodent brain cells, they do not become fully integrated due to the developmental limitations of the adult rat brain.

In this study, the team of researchers advanced the use of brain organoids for research by transplanting an intact human cortical organoid into a developing rat brain. This technique creates a unit of human tissue that can be examined and manipulated. The researchers used methods previously pioneered in the Pasca lab to create cortical organoids using human-induced pluripotent stem cellscells derived from adult skin cells that have been reprogrammed into an immature stem-cell-like state. They then implanted these organoids onto the rat primary somatosensory cortex, a part of the brain involved in processing sensation.

The researchers did not detect any motor or memory abnormalities or abnormalities in brain activity in the rats that received the transplanted organoid. Blood vessels from the rat brain successfully supported the implanted tissue, which grew over time.

To understand the extent to which the organoids could integrate into the rat somatosensory cortex, the researchers infected a cortical organoid with a viral tracer that spreads through brain cells as an indicator of functional connections. After transplanting the marked organoid onto the rats primary somatosensory cortex, researchers detected the viral tracer in multiple brain areas, such as the ventrobasal nucleus and the somatosensory cortex. In addition, the researchers observed new connections between the thalamus and the transplanted area. These connections were activated using electrical stimulation and stimulation of the rats whiskers, indicating that they were receiving meaningful sensory input. Moreover, the researchers were able to activate human neurons in the transplanted organoid to modulate the rats reward-seeking behavior. The findings suggest functional integration of the transplanted organoid into specific brain pathways.

Structurally and functionally, after seven to eight months of growth, the transplanted brain organoid resembled neurons from human brain tissue more than human organoids maintained in cell culture. The fact that the transplanted organoids mirrored the structural and functional features of human cortical neurons led the researchers to wonder if they could use transplanted organoids to examine aspects of human disease processes.

The promise of this platform is not only in identifying what molecular processes underlie the advanced maturation of human neurons in living circuits and leveraging it to improve conventionalin vitromodels, but also in providing behavioral readouts for human neurons, said Dr. Pasca.

To examine this, the researchers generated cortical organoids with cells from three participants with a rare genetic disorder associated with autism and epilepsy calledTimothy syndromeand three participants without any known diseases and implanted them onto the rat brain. Both types of organoids integrated into the rat somatosensory cortex, but organoids derived from Timothy Syndrome patients displayed structural differences. These structural differences did not appear in organoids that were created from the cells of patients with Timothy Syndrome and maintained in cell culture.

These experiments suggest that this novel approach can capture processes that go beyond what we can detect with currentin vitromodels, said Dr. Pasca. This is important because many of the changes that cause psychiatric disease are likely subtle differences at the circuit level.

Grant:MH115012,DA050662,RR026917,OD030452

About the National Institute of Mental Health (NIMH):The mission of theNIMHis to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure. For more information, visit theNIMH website.

About the National Institutes of Health (NIH):NIH, the nations medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visitwww.nih.gov.

References

Revah, O., Gore, F., Kelley, K. W., Andersen, J., Sakai, N., Chen, X., Li, M., Birey, F., Yang, X., Saw, N. L., Baker, S. W., Amin, N. D., Kulkarni, S., Mudipalli, R., Cui, B., Nishino, S., Grant, G. A., Knowles, J. K., Shamloo, M. Paca S. P. (2022).Maturation and circuit integration of transplanted human cortical organoids(link is external).Nature

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Organoids: science fiction or the future of pre-clinical studies? – Lexology

Posted: October 13, 2022 at 2:16 am

New technologies based on human cells are increasingly seen as key to reducing the time and cost in bringing drugs to market. This is an evolving area of study, though the field itself, which developed out of study into 3D cell architecture, is not new. These approaches replicate human physiology to study diseases, treatments, and for drug-development purposes. In parallel to major advances made from a medical and scientific standpoint, novel legal and ethical questions arise.

The definition of organoid is problematic and covers a range of cell culture techniques. Scientists have developed ways of culturing organ-specific tissue from human stem cells or progenitor cells to re-create important aspects of the 3D anatomy e.g. the pancreas, kidney, liver, thyroid, retina, and brain, to recapitulate key organ features. A list of definitions can be found at the end of this article.

A potential game-changer

Breakthroughs in stem cell technology and tissue engineering are driving the change. In addition to this, trends in other areas, like cell and gene therapy and personalised medicine have acted as catalysts. By simulating organ function, specific disease states can be modelled and studied. This is especially useful when looking at rare diseases, how tissue and microbiota interact, or how drugs interact with each other.

The use of organoids holds great promise in several medical-scientific areas like disease modelling, precision medicine, and transplantation. One of the most notable possibilities is to supplement or to a certain extent replace animal models during pre-clinical studies in drug development.

The field is at an early stage, but the trend is an upward one. Companies involved are seeing increasing demand for their services from pharma, biotech, research and academic institutes as well as the cosmetics industry. According to a recent market report the annual growth rate is set to increase by 37.4% during 2022-2028. Cambridge-based CN Bio recently doubled the size of its laboratory facilities due to demand. In the US, Hesperos Inc., a contract research organisation (CRO) provides a multi-organ chip platform (Human-on-a-Chip) based in Florida filed for a USD 20 million IPO. Another fascinating company is Labskin, who make full thickness human skin models, providing reproduceable results for microbiome research. Labskin just announced the first ever commercially available pigmented skin-equivalent in a joint project with Bradford University. These new models incorporate melanocytes, the cells that give skin its colour and present a huge opportunity to study melanomas.

The need for new and/or updated regulatory frameworks

For the use of these new models to be considered by regulatory authorities across the globe in the evaluation of safety and efficacy of drugs (subject to valid scientific demonstrations), regulatory frameworks will have to be adapted on a jurisdiction-by-jurisdiction basis.

In the US, the FDA Modernization Act of 2021 has been introduced to amend the Federal Food, Drug, and Cosmetic Act. The amendment strikes animal and inserts nonclinical tests or studies to be used in the evaluation of safety and efficacy of drugs, such as MPS, cell-based assays and computer models. In addition, the FDA recently approved the first clinical trial using efficacy data collected from a microphysiological system. More data may be needed to convince regulators, but the impetus - and interest - is there.

In the EU, is a 3-year Science With and For Society (SwafS) project, funded under HORIZON2020. The project is being coordinated by the University of Oslo, Norway and involves major research institutions across the EU. It is currently being carried out with the objective of developing a comprehensive regulatory framework for organoid research and organoid-related technologies. In the meantime, the European Parliament is working on legislation aimed at reducing the number of animal studies. The European Medicines Agency already recognized that organoids and organ-on-chip may become suitable alternatives to animal models during medicines development, in its wider effort to promote the 3R principles (replace, reduce and refine).

Further legal and ethical challenges to be addressed

The use of organoids and other MPS raises critical legal and ethical issues, which must be urgently addressed to allow their wide-spread utilization as part of pre-clinical studies within an acceptable framework.

In particular, since organoids are grown from human cells, initial donors rights must be respected and efficiently enforced. The original cells may come from foetal or adult tissues they may be pluripotent stem cells (PSCs), adult stem cells taken from specific tissues and reengineered somatic cells. Key challenges notably relate to the donors informed consent, (which issue has already been addressed by many scholars), research on human embryos and data protection issues. Complete anonymity of human tissue has been shown to be neither possible (due to the identifiable nature of DNA) nor desirable (as the data is necessary to validate prediction models). The donor must be able to control, to some extent, the subsequent use of his/her samples; in practice, consent may not be easily withdrawn (or with very limited effect) once organoids have been successfully developed and used in a pre-clinical study.

Strong quality standards should further be developed and complied with when it comes to producing organoids for pre-clinical purposes. Indeed, a set of specifications for the production of human 3D organoids used as medicines has been proposed. One could imagine specific guidelines applicable to the production of organoids for drug development purposes, to ensure consistent production methods as well as reliability as pre-clinical models. This calls for a wider systemic approach as to the regulation of human tissue and cells intended for human versus research application. On this point, it is interesting to note that a proposal for a regulation on standards of quality and safety for substances of human origin intended for human application is currently being examined in the EU, which expressly excludes their use in research that does not involve application to the human body.

Moreover, specific issues are triggered depending on the type of laboratory-cultivated model. For instance, the development of human cerebral organoids raises questions in terms of moral status and legal protection. Indeed, studies suggest that developed neuronal models show complex electrical activity the human cerebral organoids (sometimes referred to as mini-brains) can command a muscle connected thereto, be receptive to stimuli and may even exhibit a rudimentary form of consciousness. This raises questions as to the core definition of human being and, from a legal standpoint, personhood, the beginning and end of life, as well as the legal protection that should be awarded to such in vitro models (how they can be engineered, used, destroyed etc). In addition, the existence of sophisticated sentient models creates uncertainty regarding what moral status should be awarded to them. These issues are particularly complex as legal, ethical, philosophical, societal and political aspects are necessarily intertwined, and the way they are addressed may greatly vary from one jurisdiction to another.

Further legal and ethical challenges should be addressed in connection with the production and use of organoids beyond pre-clinical studies such as their potential patentability, their commercialization (while certain countries like France forbids the commercialization of human products and elements), their use for transplantation, the articulation with regulations on genome editing, chimeras and human cloning etc.

Conclusion

The rapid progress of scientific research around organoids and other MPS bears the potential to revolutionize many aspects of medical and pharmaceutical research. In particular, they hold great promise in the pursuit of a suitable (and potentially more reliable) alternative to the use of animal models in pre-clinical studies. Beyond this, legal and ethical challenges should be addressed in connection with the production and use of organoids in other applications such as their potential patentability, their commercialization (while certain countries like France forbids the commercialization of human products and elements), their use for transplantation, and the articulation with the regulations on genome editing, the creation of chimeras and human cloning.

Definitions:

Microphysiological systems (MPS): an umbrella term for organ-on-chip (OOC), organoids or tumoroids (stem cells grown in a dish).

Organ-on-a-chip (OOC): from the field of microfluidics, a multi-channel 3-D cell culture. An integrated circuit that simulates the activities, mechanics and physiological response of an entire organ or an organ system.

Organoid: means resembling an organ. Organoids are defined by three characteristics. The cells arrange themselves in vitro into three-dimensional organization that is characteristic for the organ in vivo, the resulting structure consists of multiple cells found in that particular organ and the cells execute at least some of the functions that they normally carry out in that organ.

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Resilience may improve health among older adults with type 2 diabetes – Medical News Today

Posted: October 13, 2022 at 2:15 am

As the population ages, experts are working to understand factors that influence healthy aging and encourage a better quality of life. Type 2 diabetes (T2D) is a chronic metabolic disorder that can impact long-term health outcomes.

A new study published in the Journal of the American Geriatrics Society found that older adults diagnosed with T2D who had high levels of psychological resilience were more likely to have better physical functioning, higher quality of life, and a lower likelihood of frailty and self-reported disability.

Psychological resilience, or just resilience, depends on peoples ability to respond and adapt to complex events like stress or trauma. It has to do with bouncing back after experiencing hardship.

Anamara Ritt-Olson, Ph.D., an associate professor of health, society, and behavior at the School of Public Health at the University of California, Irvine, not involved in the study, explained resilience to MNT in this way:

Resilience is the incredibly common ability to both withstand and bounce back from adversity. It is the armor that we wear to weather the difficulties of life. We are often put in the spin cycle of life, but resiliency allows us to come out relatively unharmed.

Both internal and external factors impact resilience. People are different, so their levels of resilience are also different. For example, adults with greater levels of social support are more likely to have more robust levels of resilience.

Resilience can impact many aspects of peoples lives, including how they cope with chronic conditions. T2D is a chronic metabolic disorder that affects the bodys ability to use glucose for energy.

It requires careful long-term management. If left unmanaged, it can lead to severe health complications like diabetic nephropathy and heart disease. Experts are still researching the best disease management methods and factors influencing long-term health outcomes.

Experts in this current study wanted to examine how psychological resilience impacted health in older adults with T2D.

The study included over 3,000 older adult participants with T2D. These participants were originally enrolled in a clinical trial that compared different diabetes management interventions. Current study authors followed up with these participants on average fourteen and a half years later. They measured a few different components among the participants:

Overall, researchers found that higher levels of psychological resilience were associated with better health outcomes, including lower numbers of hospitalizations, better physical functioning and quality of life, and fewer symptoms of depression.

Study author KayLoni Olson, Ph.D., noted the following study highlights to MNT:

In this study, we found that among older adults with Type 2 diabetes, individuals who reported a greater degree of psychological resilience (being able to bounce back after stress) also reported better overall aging-related health. This includes metrics like fewer hospitalizations in the previous year, lower likelihood of meeting criteria for frailty, and greater mental well-being.

However, researchers also found some variation between the association of resilience with some metrics. They note that this indicates that some associations may differ based on race [or] ethnicity.

This particular study had a few limitations indicating the need for more in-depth research.

First, the study cannot determine causality. It was also a cross-sectional study, which means that the authors could not determine the directional relationship of the variables.

Other limitations are related to particular study and analysis methods. For example, they did not look at all of the sociocultural factors that may impact resilience. They also didnt examine specific aspects of aging, like cognitive function. The majority of participants were white and female, which can limit the generalization of the studys findings.

Dr. Ritt-Olson offered the following insights and words of caution:

Their findings suggest that when older adults build their resiliency, they will find benefits it both their mental and physical strength. They may even be able to avoid hospitalizations. There are challenges with the study that the authors also acknowledge, for example, their measure of resiliency is about your general perception of how quickly you bounce back. We can overestimate our abilities to bounce back, and it isnt tied to an actual event that one needed to adapt to.

Regardless, the study offers insight into the important relationship between the mind and the body. Further research can confirm the impact of psychological resilience and provide longer-term follow-up.

The current study cant tell us if psychological resilience causes better overall health or vice versa, which means that additional research is important for teasing these relationships apart, Dr. Ritt-Olson noted.

In the short term, incorporating concepts like resilience into the study of aging may not only contribute to a more holistic understanding of the aging experience but may also help expand the narrative around aging so that individuals feel empowered as opposed to passive participants. This intersects with efforts within the aging research community to define healthy aging not just by the absence of health-related issues but also by the quality of later years of life.

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Years of Diabetes Could Speed Onset of Menopause | Health | derbyinformer.com – The Derby Informer

Posted: October 13, 2022 at 2:15 am

WEDNESDAY, Oct. 12, 2022 (HealthDay News) -- The earlier a woman is diagnosed with diabetes, the sooner she may enter menopause, new research shows.

Rates of diabetes have grown steadily, so researchers wanted to understand the long-term implications of premenopausal diabetes on women's reproductive health.

Their study of more than 11,000 women found that being diagnosed with type 1 diabetes before age 30 or type 2 diabetes between 30 and 39 were both linked to earlier onset of menopause.

A diagnosis of type 2 diabetes after age 40, however, was associated with later menopause, compared to women without diabetes.

The researchers found no significant association between diabetes during pregnancy (gestational diabetes) and age at menopause.

"Even after adjusting for covariates associated with age at natural menopause, we still find an association between early diagnosis of diabetes and earlier menopause and a later diabetes diagnosis with a later age at menopause as compared to those who did not have diabetes," said lead study author Vrati Mehra, of the University of Toronto.

"We hope our work lays the foundation for more research in this area so we can better understand and prevent the long-term impacts of diabetes on the human body and the reproductive system," she added.

The findings are scheduled to be presented in Atlanta Thursday at a meeting of the North American Menopause Society (NAMS). Findings presented at medical meetings should be considered preliminary until published in a peer-reviewed journal.

NAMS medical director Dr. Stephanie Faubion said the research adds to growing evidence about the collective toll diabetes takes on the human body.

"In this case, it shows that young women living with a diagnosis of diabetes are more susceptible to accelerated ovarian aging and early menopause," Faubion said in a society news release.

More information

The U.S. Centers for Disease Control and Prevention has more on diabetes.

SOURCE: North American Menopause Society, news release, Oct. 12, 2022

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Insulin Use May Predict the Development of Diabetic Retinopathy – MD Magazine

Posted: October 13, 2022 at 2:15 am

Among people with type 2 diabetes (T2D) attending diabetic retinopathy (DR) screening in Denmark, markers including insulin use were important predictors for the development of present, incident, and progressive DR.

A multivariable model indicated that patients who used insulin were 2.3 times more likely to have DR and they had a 1.92.4 times higher risk for DR-development or progression, while the use of cholesterol-lowering medicine was associated with a lower presence of DR.

However, through the follow-up period in 2013 2018, the nationwide cohort reported a considerably lower prevalence, incidence, and progression of DR, when compared with earlier reports.

Potential explanations for this might include that the recent years have led to better treatment and optimized risk factor control in diabetes, which might decrease the onset and progression of DR, said Jakob Grauslund, MD, PhD, Department of Ophthalmology, Odense University Hospital.

Duration of diabetes was reported as a leading indicator of DR and proliferative DR (PDR), being 2.45 and 9.79 times more frequent in patients with a duration of more than 20 years than those who were diagnosed within 10 years.

The team of investigators evaluated the prevalence and incidence of DR along with associated markers in patients with type 2 diabetes in the Danish DR-screening program between 2013 and 2018. Stages of DR were defined according to the International Clinical Diabetic Retinopathy Disease Severity Scale as levels 0 (no DR), 13 (mild, moderate, and severe non-PDR), or 4 (PDR).

Investigators linked data from the national Danish Registry of Diabetic Retinopathy (DiaBase) to various national health registries in order to retrieve information on diabetes duration, marital status, comorbidity, insulin use, and systemic medication.

The study included all 153,238 people with T2D (56.4% male) from the study period, with a mean age of 66.9 years and duration of diabetes at 5.3 years.

The rates of use of insulin, non-insulin glucose lowering drugs, blood pressure lowering therapy and cholesterol lowering therapy at the first screening episode were reported as 15.8%, 86.5%, 77.8%, and 77.3%, respectively. Most patients did not have DR at their first screening (91.2%).

The prevalence and 5-year incidences of DR, 2-step-or-more progression of DR and progression to PDR were 8.6%, 2.8%, 0.7%, and 0.2%, respectively.

Multivariable regression models indicate the prevalence of DR was associated with male sex (odds ratio [OR], 1.30; 95% CI, 1.25 1.36), age (OR, 0.77; 95% CI, 0.74 - 0.81 per 10 years of age), duration of diabetes (OR, 3.07; 95% CI, 2.96 3.18 per 10 years), and the use of insulin (OR, 2.34; 95% CI, 2.24 - 2.44).

The prospective part of the study determined the leading marker of incident DR and progression to PDR were duration of diabetes (hazard ratio [HR], 1.98; 95% CI, 1.87 - 2.09; HR, 2.89, 95% CI, 2.34 - 3.58 per 10 years of duration) and use of insulin (HR, 1.88; 95% CI, 1.76 - 2.01; HR, 2.40, 95% CI, 1.84 - 3.13).

Meanwhile, the use of cholesterol-lowering medication was considered a protective marker (HR, 0.87; 95% CI, 0.81 0.93; HR, 0.70; 95% CI, 0.52 - 0.93).

The study, Presence and development of diabetic retinopathy in 153,238 patients with type 2 diabetes in the Danish Registry of Diabetic Retinopathy, was published in Acta Ophthalmologica.

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