Category Archives: Cell Medicine

Tong Liu, 13,* Sainan Li, 2,* Liwei Wu, 2 Qiang Yu, 2, 4 Jingjing Li, 1 Jiao Feng, 2 Jie Zhang, 2, 4 Jiaojiao Chen, 2, 4 Yuting Zhou, 2, 4 Jie Ji, 2 Kan Chen, 2 Yuqing Mao, 5 Fan Wang, 6 Weiqi Dai, 7 Xiaoming Fan, 8 Jianye Wu, 1 Chuanyong Guo 1, 2

1Department of Gastroenterology, Putuo Peoples Hospital, Tongji University School of Medicine, Shanghai 200060, Peoples Republic of China; 2Department of Gastroenterology, Shanghai Tenth Peoples Hospital, Tongji University School of Medicine, Shanghai 200072, Peoples Republic of China; 3Department of Gastroenterology, Shandong Provincial Hospital of Shandong University, Jinan 250000, Peoples Republic of China; 4Department of Gastroenterology, Shanghai Tenth Peoples Hospital, School of Clinical Medicine of Nanjing Medical University, Shanghai 200072, Peoples Republic of China; 5Department of Gerontology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, Peoples Republic of China; 6Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, Peoples Republic of China; 7Department of Gastroenterology, Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, Peoples Republic of China; 8Department of Gastroenterology, Jinshan Hospital of Fudan University, Jinshan, Shanghai 201508, Peoples Republic of China

*These authors contributed equally to this work

Correspondence: Jianye WuDepartment of Gastroenterology, Putuo Peoples Hospital, Tongji University School of Medicine, Shanghai 200060, Peoples Republic of ChinaEmail wjymail@163.comChuanyong GuoDepartment of Gastroenterology, Shanghai Tenth Peoples Hospital, Tongji University School of Medicine, Shanghai 200072, Peoples Republic of ChinaEmail guochuanyong@hotmail.com

Objective: Shikonin is a natural product with many activities, including anti-cancer effects. Pyruvate kinase type M2 (PKM2) plays a crucial role in the growth of tumor cells. However, the effect of shikonin on PKM2 in hepatocellular carcinoma (HCC) is unclear.Methods: Cell viability, apoptosis level, glucose uptake, and lactate production were detected in HCC cells. Lentivirus-overexpressed and shRNA of PKM2 were used to verify the key target of shikonin. A xenograft mouse model was used to detect the efficacy of shikonin and its combination with sorafenib in vivo.Results: Shikonin inhibited proliferation and glycolysis and induced apoptosis in HCC cells. Either PKM2-overexpressed or PKM2-shRNA alleviated or enhanced this effect. The results of CCK-8 showed that shikonin significantly inhibited cell viability of HCC cells. The levels of glucose uptake and lactate production were dramatically decreased by shikonin-treated. Results of flow cytometry and Western blot showed that the levels of apoptosis of HCC cells were significantly increased in a dose-dependent manner after shikonin treatment. In addition, shikonin enhanced the anti-cancer effect of sorafenib in vitro and in vivo. Our results showed that SK combined with sorafenib markedly inhibits tumor growth in HCC-transplanted nude mice compared to SK or sorafenib alone.Conclusion: By inhibiting PKM2, shikonin inhibited proliferation and glycolysis and induced cell apoptosis in HCC cells. The effect of shikonin on tumor cell proliferation, apoptosis and glycolsis will make it promising drug for HCC patients.

Keywords: shikonin, PKM2, glycolysis, apoptosis, proliferation, hepatocellular carcinoma

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

See the original post here:
Experimental Study of Hepatocellular Carcinoma Treatment by Shikonin T | JHC - Dove Medical Press

Christopher P Haycook,1 Joseph A Balsamo,2,3 Evan B Glass,1 Charles H Williams,4 Charles C Hong,5 Amy S Major,3,6 Todd D Giorgio1

1Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA; 2Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA; 3Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt Medical Center, Nashville, TN 37232, USA; 4Department of Medicine, Division of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; 5Department of Medicine, Division of Cardiovascular Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA; 6U.S., Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA

Correspondence: Todd D GiorgioDepartment of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USAEmail todd.d.giorgio@vanderbilt.edu

Background: Helper T cell activity is dysregulated in a number of diseases including those associated with rheumatic autoimmunity. Treatment options are limited and usually consist of systemic immune suppression, resulting in undesirable consequences from compromised immunity. Hedgehog (Hh) signaling has been implicated in the activation of T cells and the formation of the immune synapse, but remains understudied in the context of autoimmunity. Modulation of Hh signaling has the potential to enable controlled immunosuppression but a potential therapy has not yet been developed to leverage this opportunity.Methods: In this work, we developed biodegradable nanoparticles to enable targeted delivery of eggmanone (Egm), a specific Hh inhibitor, to CD4+ T cell subsets. We utilized two FDA-approved polymers, poly(lactic-co-glycolic acid) and polyethylene glycol, to generate hydrolytically degradable nanoparticles. Furthermore, we employed maleimide-thiol mediated conjugation chemistry to decorate nanoparticles with anti-CD4 F(ab) antibody fragments to enable targeted delivery of Egm.Results: Our novel delivery system achieved a highly specific association with the majority of CD4+ T cells present among a complex cell population. Additionally, we have demonstrated antigen-specific inhibition of CD4+ T cell responses mediated by nanoparticle-formulated Egm.Conclusion: This work is the first characterization of Egms immunomodulatory potential. Importantly, this study also suggests the potential benefit of a biodegradable delivery vehicle that is rationally designed for preferential interaction with a specific immune cell subtype for targeted modulation of Hh signaling.

Keywords: advanced delivery systems, eggmanone, autoimmunity, controlled release

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Continue reading here:
PEGylated PLGA Nanoparticle Delivery of Eggmanone for T Cell Modulatio | IJN - Dove Medical Press

Researchers from the group of Vlad Cojocaru together with colleagues the Max Planck Institute in Mnster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.A cells identity is driven by which DNA is read or not read at any point in time. Signaling in the cell to start or stop reading DNA happens through proteins called transcription factors. Identity changes happen naturally during development as cells transition from an undesignated cell to a specific cell type. As it turns out, these transitions can also be reversed. In 2012, Japanese researchers were awarded the Nobel prize for being the first to push a regular skin cell backwards to a stem cell.A fuller understanding of molecular processes towards stem cell therapiesUntil now, it is unknown how the conversion of a skin cell into a stem cell happens exactly, on a molecular scale. Fully understanding the processes with atomic details is essential if we want to produce such cells for individual patients in the future in a reliable and efficient manner, says research leader Vlad Cojocaru of the Hubrecht Institute. It is believed that such engineered cell types may in the future be part of the solution to diseases like Alzheimers and Parkinsons, but the production process would have to become more efficient and predictable.Pioneer transcription factorOne of the main proteins involved in the stem cell generation is a transcription factor called Oct4. It induces gene expression, or activity, of the proteins that reset the adult cell into a stem cell. Those genes induced are inactive in the adult cells and reside in tightly packed, closed states of chromatin, the structure that stores the DNA in the cell nucleus. Oct4 contributes to the opening of chromatin to allow for the expression of the genes. For this, Oct4 is known as a pioneer transcription factor.

The data from Cojocaru and his PhD candidate and first author of the publication Jan Huertas show how Oct4 binds to DNA on the so-called nucleosomes, the repetitive nuclear structures in chromatin. Cojocaru: We modelled Oct4 in different configurations. The molecule consists of two domains, only one of which is able to bind to a specific DNA sequence on the nucleosome in this phase of the process. With our simulations, we discovered which of those configurations are stable and how the dynamics of nucleosomes influence Oct4 binding. The models were validated by experiments performed by our colleagues Caitlin MacCarthy and Hans Schler in Mnster.One step closer to engineered factorsThis is the first time computer simulations show how a pioneer transcription factor binds to nucleosomes to open chromatin and regulate gene expression. Our computational approach for obtaining the Oct4 models can also be used to screen other transcription factors and to find out how they bind to nucleosomes, Cojocaru says.

Moreover, Cojocaru wants to refine the current Oct4 models to propose a final structure for the Oct4-nucleosome complex. For already almost 15 years now, we know that Oct4 together with three other pioneer factors transforms adult cells into stem cells. However, we still do not know how they go about. Experimental structure determination for such a system is very costly and time consuming. We aim to obtain one final model for the binding of Oct4 to the nucleosome by combining computer simulations with different lab experiments. Hopefully, our final model will give us the opportunity to engineer pioneer transcription factors for efficient and reliable production of stem cells and other cells needed in regenerative medicine.ReferenceHuertas et al. (2020) Nucleosomal DNA Dynamics Mediate Oct4 Pioneer Factor Binding. Biophysical Journal. DOI: https://doi.org/10.1016/j.bpj.2019.12.038

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

Read the rest here:
Visualizing the Conversion of Adult Cells to Stem Cells - Technology Networks

Houston home to one of the largest medical centers in the world isn't a stranger when it comes to medical innovations and breakthrough research discoveries.

In the latest roundup of research innovations, four Houston institutions are working on innovative and in some cases life-saving research projects.

If the germ,group A streptococcus, continues to grow resistant to antibiotics, it can have a profoundly negative affect on the millions who get the illness annually. Photo via houstonmethodist.org

Researchers at Houston Methodist have discovered some troubling information about the strains of group A streptococcus that cause strep throat and a flesh-eating disease are becoming more resistant to beta-lactams antibiotics like penicillin.

James M. Musser is the lead author of the study and chair of Methodist's Department of Pathology and Genomic Medicine. The study which received funding from grants from the Fondren Foundation, Houston Methodist Hospital and Houston Methodist Research Institute, and the National Institutes of Health appeared in the Jan. 29 issue of the Journal of Clinical Microbiology, according to a news release.

"If this germ becomes truly resistant to these antibiotics, it would have a very serious impact on millions of children around the world," Musser says in the release. "That is a very concerning but plausible notion based on our findings. Development of resistance to beta-lactam antibiotics would have a major public health impact globally."

Musser and his team found 7,025 group A streptococcus strains that have been recorded around the world over the past several decades. Of those strains, 2 percent had gene mutations that raised the alarm for the researchers and, upon investigation, Musser's team came to the conclusion that antibiotic treatments can eventually be less effective or even completely ineffective. This, Musser says, calls for an urgent need to develop a vaccine.

"We could be looking at a worldwide public health infectious disease problem," says Musser in the release. "When strep throat doesn't respond to frontline antibiotics such as penicillin, physicians must start prescribing second-line therapies, which may not be as effective against this organism."

University of Houston Professor Mehmet Orman is looking into cells that are able to persist and cause chronic illnesses. Photo via uh.edu

Mehmet Orman, assistant professor of chemical and biomolecular engineering at the University of Houston, is looking into a specific type of persister cells that have been found to be stubborn and drug-resistant.

The research, which is backed by a $1.9 million grant from the National Institute of Allergy and Infectious Diseases, could answer questions about chronic health issues like airway infections in cystic fibrosis patients, urinary tract infections, and tuberculosis, according to a news release.

"If we know how persister cells are formed, we can target their formation mechanisms to eliminate these dangerous cell types," says Orman in a news release.

Orman is looking into cells' self-digestion, or autophagy, process that is found to stimulate persister formation. Per the release, cells can survive periods of starvation by eating their own elements. Specifically, Orman will analyze self-digestion in E. coli.

"By integrating our expertise in bacterial cell biology with advanced current technologies, we aim to decipher the key components of this pathway to provide a clear and much-needed picture of bacterial self-digestion mechanisms," says Orman in the release.

Some patients are predisposed to kidney injury following surgery, this study found. Photo via bcm.edu

Scientists at Baylor College of Medicine are looking into the lead cause of kidney failure in patients who undergo surgery. Individuals who have heightened levels of suPAR protein soluble urokinase-type plasminogen activator receptor have a greater risk of this post-op complication, according to a news release.

"suPAR is a circulating protein that is released by inflammatory cells in the bone marrow and produced by a number of cell/organs in the body," says Dr. David Sheikh-Hamad, professor of medicine nephrology at Baylor College of Medicine and collaborating author of the study, in the release.

The study, which was published in The New England Journal of Medicine, conducted research on mice that were engineered to hive high suPAR levels in their blood. Compared to the control mice, the suPAR mice had more risk of kidney industry. These mice were given suPAR-blocking antibodies, which then helped reduce kidney injury.

"This protective strategy may be used in humans expressing high suPAR levels prior to contrast exposure, or surgery to decrease the likelihood of developing kidney failure," Sheikh-Hamad says in the release.

Christopher Fagundes of Rice University analyzed the emotions of 99 widows and widowers. Jeff Fitlow/Rice University

A new study done by researchers at Rice University finds that spouses that lose their husband or wife and try to suppress their grief are not doing themselves any favors. The study monitored 99 people who had recently lost a spouse, according to a news release.

"There has been work focused on the link between emotion regulation and health after romantic breakups, which shows that distracting oneself from thoughts of the loss may be helpful," says Christopher Fagundes, an associate professor of psychology and the principal investigator, in a news release. "However, the death of a spouse is a very different experience because neither person initiated the separation or can attempt to repair the relationship."

The study included asking participants to respond to how they felt about certain coping strategies, as well as blood tests to measure cytokines levels an inflammatory marker.

"Bodily inflammation is linked to a host of negative health conditions, including serious cardiovascular issues like stroke and heart attack," Fagundes says in the release.

The research, which was funded by a grant from the National Heart, Lung, and Blood Institute, found that the participants who avoided their emotions suffered more of this bodily inflammation.

"The research also suggests that not all coping strategies are created equal, and that some strategies can backfire and have harmful effects, especially in populations experiencing particularly intense emotions in the face of significant life stressors, such as losing a loved one," adss Richard Lopez, an assistant professor of psychology at Bard College and lead author of the study, in the release.

View post:
Photos: Houston Methodist opens new hub to showcase health tech of the future - InnovationMap

Researchers from Childrens Hospital of Philadelphia (CHOP) have led a multi-institutional group to study the link between a strong cancer driver gene that impacts changes in proteins related to alternative splicing regulation. The scientists developed new computational tools and biological model systems for the study, led by Yi Xing, Ph.D., at CHOP and Owen Witte, M.D., at the University of California, Los Angeles (UCLA).

Alternative splicing is the process in which exons and introns are separated in a pre-mRNA strand, and various combinations of exons in the mRNA can be used to translate into proteins.Through this mechanism, a single gene can code for multiple (usually closely related) proteins.

Alternative splicing is an essential process, and it is the RNA that is cut, or spliced, before being translated into proteins, meaning regulation happens at the transcription level. Cancer cells often take advantage of this process to produce proteins that promote growth and survival, allowing them to replicate uncontrollably and metastasize. This happens in many cancers, including prostate cancer, which is associated with shifts in splicing patterns. Yet scientists do not fully understand the process that leads to this change.

Our study provides insight into the relationship between an important cancer driver genes and alternative splicing changes that could be used to guide the development of splicing-targeted cancer therapy, said Xing, director of the Center for Computational and Genomic Medicine at CHOP and senior author of the study.

To better understand the causes and consequences of alternative splicing changes during cancer progression, the team examined RNA sequences from nearly 900 prostate tissue samples, ranging from healthy prostate tissue to localized or aggressive metastatic tumor tissue. To efficiently analyze such a large sequencing dataset, the team created a computational program called rMATS-turbo. This program allowed the researchers to identify more than 13,000 alternative splicing events that occurred across these 900 prostate samples.

The collaborative effort involved researchers at CHOP, UCLA, and the Roswell Park Comprehensive Cancer Center. John Phillips, M.D., Ph.D., a researcher at UCLA, and Yang Pan, a visiting scholar at CHOP and graduate student at UCLA, were first authors of the study.

After the team identified alternative splicing events and rate of occurrence, they developed an analytic tool, dubbed PEGASAS (Pathway Enrichment-Guided Activity Study of Alternative Splicing), to identify which splicing patterns led to the creation of proteins that may help drive cancer genes and pathways. They were searching for alternative splicing patterns that correlated to cancer development.

The scientists found that Myc, a gene normally involved in cell functions but amplified in many cancers, was linked to alternative splicing changes in genes that themselves regulate alternative splicing. Using human prostate cells that were engineered to turn on or off Myc activity, researchers further confirmed that these alternative splicing changes were indeed driven by Myc.

The team of researchers then applied the same PEGASAS strategy to breast cancer and lung cancer datasets and found the same association between Myc activity and alternative splicing, suggesting Myc activation and thus disruptions in splicing occur in many cancer types.

Of course, the MYC family of oncogenes is known to be deregulated in over half of all known human cancers, and this deregulation is frequently associated with poor prognosis and unfavorable patient survival. Myc has a central role in almost every aspect of the oncogenic process, orchestrating proliferation, apoptosis, differentiation, and metabolism,meaning that it may be possible that alternative splicing is just one downstream effect this gene has during the cancer development process.

The successful application of PEGASAS to prostate, breast, and lung cancer datasets suggests that this strategy could be useful in analyzing pathway-driven alternative splicing in many cancer types, said Xing. Given the involvement of oncogenic pathways such as the Myc pathway in pediatric cancers, these tools could reveal pathways and targets for treating pediatric cancers as well.

While this research is in its early stages, linking protein changes to cancer development is an important step in understanding cancer development. If individual spicing patterns for particular proteins can be identified as cancer causing, it would open the door for precision medicine to step in and block those particular proteins from being translated.

It would be of great interest to see if alternative splicing was involved in cancer types that did not involve Myc, and if alternative splicing could be linked to cancers that involved different genetic mutation pathways.

Link:
Alternative Splicing Identified as a Potential Driver of Aggressive Cancers - Clinical OMICs News

Houston home to one of the largest medical centers in the world isn't a stranger when it comes to medical innovations and breakthrough research discoveries.

In the latest roundup of research innovations, four Houston institutions are working on innovative and in some cases life-saving research projects.

If the germ,group A streptococcus, continues to grow resistant to antibiotics, it can have a profoundly negative affect on the millions who get the illness annually. Photo via houstonmethodist.org

Researchers at Houston Methodist have discovered some troubling information about the strains of group A streptococcus that cause strep throat and a flesh-eating disease are becoming more resistant to beta-lactams antibiotics like penicillin.

James M. Musser is the lead author of the study and chair of Methodist's Department of Pathology and Genomic Medicine. The study which received funding from grants from the Fondren Foundation, Houston Methodist Hospital and Houston Methodist Research Institute, and the National Institutes of Health appeared in the Jan. 29 issue of the Journal of Clinical Microbiology, according to a news release.

"If this germ becomes truly resistant to these antibiotics, it would have a very serious impact on millions of children around the world," Musser says in the release. "That is a very concerning but plausible notion based on our findings. Development of resistance to beta-lactam antibiotics would have a major public health impact globally."

Musser and his team found 7,025 group A streptococcus strains that have been recorded around the world over the past several decades. Of those strains, 2 percent had gene mutations that raised the alarm for the researchers and, upon investigation, Musser's team came to the conclusion that antibiotic treatments can eventually be less effective or even completely ineffective. This, Musser says, calls for an urgent need to develop a vaccine.

"We could be looking at a worldwide public health infectious disease problem," says Musser in the release. "When strep throat doesn't respond to frontline antibiotics such as penicillin, physicians must start prescribing second-line therapies, which may not be as effective against this organism."

University of Houston Professor Mehmet Orman is looking into cells that are able to persist and cause chronic illnesses. Photo via uh.edu

Mehmet Orman, assistant professor of chemical and biomolecular engineering at the University of Houston, is looking into a specific type of persister cells that have been found to be stubborn and drug-resistant.

The research, which is backed by a $1.9 million grant from the National Institute of Allergy and Infectious Diseases, could answer questions about chronic health issues like airway infections in cystic fibrosis patients, urinary tract infections, and tuberculosis, according to a news release.

"If we know how persister cells are formed, we can target their formation mechanisms to eliminate these dangerous cell types," says Orman in a news release.

Orman is looking into cells' self-digestion, or autophagy, process that is found to stimulate persister formation. Per the release, cells can survive periods of starvation by eating their own elements. Specifically, Orman will analyze self-digestion in E. coli.

"By integrating our expertise in bacterial cell biology with advanced current technologies, we aim to decipher the key components of this pathway to provide a clear and much-needed picture of bacterial self-digestion mechanisms," says Orman in the release.

Some patients are predisposed to kidney injury following surgery, this study found. Photo via bcm.edu

Scientists at Baylor College of Medicine are looking into the lead cause of kidney failure in patients who undergo surgery. Individuals who have heightened levels of suPAR protein soluble urokinase-type plasminogen activator receptor have a greater risk of this post-op complication, according to a news release.

"suPAR is a circulating protein that is released by inflammatory cells in the bone marrow and produced by a number of cell/organs in the body," says Dr. David Sheikh-Hamad, professor of medicine nephrology at Baylor College of Medicine and collaborating author of the study, in the release.

The study, which was published in The New England Journal of Medicine, conducted research on mice that were engineered to hive high suPAR levels in their blood. Compared to the control mice, the suPAR mice had more risk of kidney industry. These mice were given suPAR-blocking antibodies, which then helped reduce kidney injury.

"This protective strategy may be used in humans expressing high suPAR levels prior to contrast exposure, or surgery to decrease the likelihood of developing kidney failure," Sheikh-Hamad says in the release.

Christopher Fagundes of Rice University analyzed the emotions of 99 widows and widowers. Jeff Fitlow/Rice University

A new study done by researchers at Rice University finds that spouses that lose their husband or wife and try to suppress their grief are not doing themselves any favors. The study monitored 99 people who had recently lost a spouse, according to a news release.

"There has been work focused on the link between emotion regulation and health after romantic breakups, which shows that distracting oneself from thoughts of the loss may be helpful," says Christopher Fagundes, an associate professor of psychology and the principal investigator, in a news release. "However, the death of a spouse is a very different experience because neither person initiated the separation or can attempt to repair the relationship."

The study included asking participants to respond to how they felt about certain coping strategies, as well as blood tests to measure cytokines levels an inflammatory marker.

"Bodily inflammation is linked to a host of negative health conditions, including serious cardiovascular issues like stroke and heart attack," Fagundes says in the release.

The research, which was funded by a grant from the National Heart, Lung, and Blood Institute, found that the participants who avoided their emotions suffered more of this bodily inflammation.

"The research also suggests that not all coping strategies are created equal, and that some strategies can backfire and have harmful effects, especially in populations experiencing particularly intense emotions in the face of significant life stressors, such as losing a loved one," adss Richard Lopez, an assistant professor of psychology at Bard College and lead author of the study, in the release.

More:
These are 4 medical innovations coming out of Houston institutions - InnovationMap

Treatment of patients suffering from bile duct cancer could be improved by tailoring medication to the levels of a key protein in people with the disease, according to new research.

Cholangiocarcinoma (CCA) is a deadly disease with few treatments, but researchers in the UK and Thailand have discovered that the PRH/HHEX protein is a key driver in the disease, with increased levels affecting the response of cancer cells to therapeutic drugs.

Formation of CCA is driven by alterations in the levels of the PRH protein which controls genes and signaling pathways in the body - a discovery which could allow doctors to use specific drugs to treat the cancer.

Researchers from the Universities of Birmingham and Nottingham worked with partners at the Chulabhorn Research Institute, in Bangkok. The study, funded by the Medical Research Council (Newton Fund) and Thailand Research Fund, is published in Cancer Research and featured on front cover of Cancer Research 15 February 2020 issue.

Dr Padma Sheela Jayaraman, from the Institute of Cancer and Genomic Sciences at the University of Birmingham, commented: "Clinical efficacy of chemotherapeutic strategies is likely to depend on PRH expression level. Tailoring patient medication according to the individual level of PRH expression could improve clinical usefulness of several compounds, recently suggested as potential novel treatments for bile duct cancer."

Aberrant Notch and Wnt signalling are known drivers of CCA, but the underlying factors controlling these pathways were not previously known.

The researchers found that hyper-activation of Notch and Wnt signalling is connected to dysregulation of PRH. Moreover, they suggest new therapeutic options based on the dependence of specific Wnt, Notch, and CDK4/6 inhibitors on PRH activity.

They demonstrate that expression of PPH is elevated in cases of CCA and that reduction in PRH levels reduced CCA tumour growth in a model of cancer. They showed that high PRH expression in primary human biliary epithelial cells isolated from human liver, by Dr Simon Afford from the University of Birmingham's Centre for Liver and Gastrointestinal Research, tended to increase cancer cell properties such as invasion and anchorage-independent growth.

Professor Kevin Gaston, from the University of Nottingham School of Medicine and Biodiscovery Institute, commented: "We are excited by the outcomes of this international collaborative study and we are working towards translating these findings into new ways of treating individual patients in the UK and in Thailand, where there is a particularly high incidence of CCA."

For more information, interviews and an embargoed copy of the research paper, please contact Tony Moran, International Communications Manager, University of Birmingham on +44 (0)121 414 8254 or +44 (0)7827 832 312. For out-of-hours enquiries, please call +44 (0)7789 921 165.

The University of Birmingham is ranked amongst the world's top 100 institutions, its work brings people from across the world to Birmingham, including researchers and teachers and more than 6,500 international students from over 150 countries.

'A runaway PRH/HHEX-Notch3 positive feedback loop drives cholangiocarcinoma and determines response to CDK4/6 inhibition' - Philip Kitchen, Ka Ying Lee, Danielle Clark, Nikki Lau, Jomnarong Lertsuwan, Anyaporn Sawasdichai, Jutamaad Satayavivad, Sebastian Oltean, Simon Afford, Kevin Gaston and Padma-Sheela Jayaraman is published in Cancer Research and featured on the front cover of the 15 February 2020 issue.

Excerpt from:
Bile duct cancer treatment potential boost from tailored medication - study - University of Birmingham

Taisuke Kaiho,1 Takahiro Nakajima,1 Shunichiro Iwasawa,2 Yoko Yonemori,3 Ichiro Yoshino1

1Department of General Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan; 2Department of Respirology, Chiba University Graduate School of Medicine, Chiba, Japan; 3Department of Pathology, Chiba Rosai Hospital, Chiba, Japan

Correspondence: Takahiro NakajimaDepartment of General Thoracic Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, JapanTel +81-43-222-7171Fax +81-43-226-2172Email takahiro_nakajima@med.miyazaki-u.ac.jp

Abstract: Specific tyrosine-kinase inhibitors (TKIs) are widely used for the treatment of non-small-cell lung cancers with anaplastic lymphoma kinase (ALK) translocations. However, most treated patients eventually develop resistance to the TKIs. The histological transformation into small cell carcinoma is well known to be the underlying mechanism for acquired resistance; however, transformation to squamous cell carcinoma is extremely rare. We, herein, report a case of ALK rearrangement-positive adenocarcinoma that transformed to squamous cell carcinoma after administration of alectinib, and was found to be resistant to ceritinib.

Keywords: lung adenocarcinoma, anaplastic lymphoma kinase, transformation, squamous cell carcinoma, acquired resistance

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Read more:
ALK Rearrangement Adenocarcinoma with Histological Transformation to S | OTT - Dove Medical Press

Bringing new medicines to patients struggling with serious illness is the driving force behind drug discovery and development. Originating as small molecules, drugs have shifted to large molecule therapies and will continue to shift as precision medicine is adopted. In spite of these different types of drugs, the development time to create them has not changed dramatically. It still takes 10 to 15 years to bring a drug to market. For this reason, there is tremendous interest when it comes to finding ways to develop drugs with higher throughput methods. This article highlights advances in three technology areas that show great promise to speed the drug discovery and development process.Automation and roboticsThe need for automation and robotics is not a new topic in drug discovery but an area where great progress has been and continues to be made. Automation is essential to implementing high-throughput strategies. What started out as a solution to achieve higher throughput has extra benefits. An automated process provides better data quality due to process consistency. Human error is minimized, and the presence of an audit trail allows traceability if questions arise. Automation also provides walk away freedom for the scientist to pursue other tasks.

To witness an automated set up, one may find that each automation step may not be fast in and of itself. But consider the shift away from an 8-hour employee workday to one of continuous 24-hour operation. Screening projects are now reduced by at least a factor of 3, thus yielding higher throughput.

Automation can be categorized into three general modes defined as (1) batch, (2) semi-automated, and (3) integrated. The three modes range from limited to extensive on key automation criteria which include things like flexibility, walk away capabilities, number and complexity of tasks. Batch mode, for example still requires a scientist to load stacks of plates that then are subjected to a limited step in the process. Integrated automation, the most sophisticated, is capable of carrying out multiple scheduled steps facilitated by a robotic mover. This allows unmanned operation for extended periods providing walk away or overnight convenience.1An important consideration in any automated solution is the skill requirement of the operator. More sophisticated systems will require automation programming skills often leveraging automation engineers. Specialized training from the equipment vendor may also be required. Batch automation can often be accomplished with little specialized training. Compared to ten years ago, automation today has evolved and become more democratized. This continued trend will reduce the need for specialized training in the future with more turn-key and intuitive solutions becoming commercially available.

David Ebner, Principal investigator at the Target Discovery Institute in Oxford, UK explains: There are two key limiting factors for any group trying to do high-throughput screening today. The first is the expertise to translate a benchtop assay to a high-throughput platform and the second factor is the expense. Centralized core facilities are one way to address the expense factor. And as automation becomes more turn-key, the need for specialized engineers is reduced, allowing future resources to be more research scientist driven.

The discovery and development of small molecules and antibodies targeting T cell function, as well as T cell-based cell therapies and cell manufacturing, require assays to rapidly and reliably profile T cell activation and cell health. In this app note, discover how phenotypic screening addresses these needs, using a single assay to provide rapid, optimized monitoring of cell proliferation, activation markers and cytokines.

Microfluidic technology, a more extreme form of miniaturization, addresses some of these known fluid handling challenges.4 Microfluidic chips provide the benefits of reduced volumes while replacing liquid handling mechanics with channels connected to liquid reservoirs. In some cases, the device has integrated tools such as electrodes built-in and can combine multiple operational steps. 5Microfluidic devices are also able to isolate single cells, which can be further cultured on the chip. This ability removes cellular heterogeneity on cancer cell populations as an example. Traditional drug screening methods see response information from an average of all cells. The microfluidic solution allows analysis of a single cell's antidrug response.4 In addition to this cell-on-chip model, recent advances have led to tissue-on-chip and organ-on-chip models which are still early in development. These kind of chip models may someday provide a powerful alternative to animal models.6 Because they are early in development, they are not high- throughput solutions today. But they show great promise to speed determination of drug activity, optimal combinatorial drug screening and toxicity testing in the future.4Artificial intelligenceApplied to drug discovery, artificial intelligence (AI) has been used in medicinal chemistry for designing compounds since the 1960s. 7 Machine-learning tools like quantitative structure-activity relationship (QSAR) modeling have identified potential target molecules from millions of candidate compounds. 8 Today, AI has expanded its application in drug discovery to a range of tasks from robotics control to image analysis and logistics. AI has also been applied throughout the drug discovery process from target selection, hit identification, lead optimization through to preclinical studies and clinical trials. 7, 8Dr Mohammad HamediRad and colleagues at the University of Illinois explain that with new uses of AI, "the role of researcher changes from drivers of the experiments to supervisors of the system." AI, integrated with robotic systems enables automation of the design, build, test, and learn (DBTL) cycle. This results in a platform that designs experiments, executes them, analyzes the data then optimizes and executes subsequent experiments iteratively. This closed loop discovery reduces the total number of experiments and generates the best possible optimization. The concept was demonstrated by HamediRad and colleagues in 2019. Their fully-automated platform evaluated less than 1% of possible variants and outperformed traditional screening methods by 77%.9AI platforms can cut down the development time from lead molecule to a candidate by more than half. AI predicted molecules are more likely to be correct and allow a focused effort. Time isnt wasted testing irrelevant molecules which would have been worked on otherwise and make up 90% of the molecules tested by traditional methods.10 Currently, AI can help find novel compounds which are more potent and selective using high quality screening data sets much faster and at less expense than screening alone, explains Ebner.

Personalized or precision medicine is another area where AI plays an important role. Precision medicines are a growing proportion of drugs in the industry pipeline. 11 Extensive collections of human samples (diseased and healthy) are required for biomarker identification in developing a personalized medicine. 12 Typically, all samples are sequenced using next-generation sequencing which generates massive amounts of data. AI methods of deep-learning make analysis of these big data sets possible. 8Automation Journey Guide: How To Automate Simple to Complex Workflows To Achieve Results Beyond High-throughput

Laboratory automation is playing a key role in advancing scientific research, from pharmaceutical development to diagnostics. Whether it is to automate a simple or sophisticated workflow, automation is now used in labs throughout the world to increase their capacity and throughput. In this eBook, discover a detailed guide to introducing automation to your lab.

Original post:
High-throughput Technologies in Drug Discovery - Technology Networks

Sanaz Mansouri,1,* Behzad Khansarinejad,2,* Ghasem Mosayebi,2 Aziz Eghbali,3 Mahdieh Mondanizadeh1,4

1Department of Biotechnology and Molecular Medicine, Arak University of Medical Sciences, Arak, Iran; 2Department of Microbiology and Immunology, Arak University of Medical Sciences, Arak, Iran; 3Department of Pediatrics, School of Medicine, Arak University of Medical Sciences, Arak, Iran; 4Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran

*These authors contributed equally to this work

Correspondence: Mahdieh MondanizadehDepartment of Biotechnology and Molecular Medicine, Arak University of Medical Sciences, Arak, IranTel/Fax +98-8634173526Email m_mondanizadeh@yahoo.com

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and malignant neoplasm that arises from the hematopoietic T-cell precursors. Inactivation of FBXW7 gene is frequently observed in T-cell acute lymphoblastic leukemia, suggesting a significant tumor-suppressive role for FBXW7 in the pathobiology of this leukemia. Considering the role of microRNAs in cell proliferation and regulation of apoptosis, the aim of this study was to identify novel oncogenic microRNAs that suppress FBXW7 in patients with T-ALL.Patients and Methods: The expression levels of two bioinformatically predicted microRNAs miR-32 and miR-107 were compared in patients with T-ALL and a control group. A total of 80 plasma samples were subjected to RNA extraction, and the microRNA expression profiles were assessed by the RT-qPCR. The expression level of miR-103 was used as the endogenous reference for normalization of quantitative data.Results: The plasma levels of miR-32 and miR-107 in patients with T-ALL were significantly higher (5.65, P< 0.001) and lower (0.432, P= 0.002), respectively. On the other hand, the expression levels of FBXW7 gene were significantly downregulated by 76.9 fold in T-ALL patients (P< 0.001). The results of the ROC curve analysis indicated that overexpression of miR-32 might be used to distinguish T-ALL patients with reasonable sensitivity and specificity.Conclusion: miR-32 is considered as a novel oncomir that targets FBXW7 and might have a role in the etiology or progression of T-ALL. Furthermore, miR-32 can potentially serve as a non-invasive biomarker for detection of T-ALL.

Keywords: biomarker, FBXW7, T-ALL, microRNA

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Read more:
Alteration in Expression of miR-32 and FBXW7 Tumor Suppressor in Plasm | CMAR - Dove Medical Press