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Category Archives: Gene Medicine

Study Shows Evolution Turns Genes Back On to Regain Function – Stony Brook News

STONY BROOK, NY, November 25, 2019 Genes often mutate and lose their natural or synthetic function over long-term evolution, which could be good if that stops drug resistance of infectious microbes or cancer. A new study by Stony Brook University researchers, published online in PNAS, shows that evolution can exploit positive feedback (PF) within cells to restore gene function. Such repair by evolution may provide a basis for regaining lost gene function, which has implications in medicine and other scientific endeavors.

Based on the idea and experiments of an undergraduate Biomedical Engineering student, Mirna Kheir, and led by Gbor Balzsi, PhD, the Henry Laufer Associate Professor in Stony Brook Universitys Laufer Center for Physical and Quantitative Biology, and Department of Biomedical Engineering, the study included using synthetic PF in yeast cells by way of a chromosomally integrated gene circuit to test the process of regaining lost gene functions.

We showed through these experiments and computational models that many drugs can activate mutant resistance genes through this process, explains Balzsi. Essentially we exposed mutant, drug-sensitive cell populations to conditions where regaining resistance would be beneficial, and we found adaptation scenarios with or without repairing lost gene circuit function.

The results also suggest that inactive, nonfunctional natural drug resistance modules can also regain function upon drug treatment, quickly converting drug-sensitive cancer cells or microbes in drug-resistant ones.

The research is supported in part by a National Institutes of Health (NIH) National Institute of General Medical Sciences grant (R35 GM122561), the Laufer Center, and a Swiss National Science Foundation Ambizione grant.

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About Stony Brook UniversityStony Brook University, widely regarded as a SUNY flagship, is going beyond the expectations of what todays public universities can accomplish. Since its founding in 1957, this young university has grown to become one of only four University Center campuses in the State University of New York (SUNY) system with over 26,000 students, more than 2,700 faculty members and 18 NCAA Division I athletic programs. Our faculty have earned numerous prestigious awards, including the Nobel Prize, Pulitzer Prize, Indianapolis Prize for animal conservation, Abel Prize and the inaugural Breakthrough Prize in Mathematics. The University offers students an elite education with an outstanding return on investment: U.S.News & World Report ranks Stony Brook among the top 40 public universities in the nation. Its membership in the Association of American Universities (AAU) places Stony Brook among the top 62 research institutions in North America. As part of the management team of Brookhaven National Laboratory, the University joins a prestigious group of universities that have a role in running federal R&D labs. Stony Brook University fuels Long islands economic growth. Its impact on the Long island economy amounts to $7.38 billion in increased output. Our state, country and world demand ambitious ideas, imaginative solutions and exceptional leadership to forge a better future for all. The students, alumni, researchers and faculty of Stony Brook University are prepared to meet this challenge.

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Discovery may provide clues for treatment of autism and schizophrenia – News-Medical.net

Researchers at the Case Western Reserve University School of Medicine have identified that a gene critical to clearing up unnecessary proteins plays a role in brain development and contributes to the development of autism spectrum disorders (ASD) and schizophrenia.

The discovery, published today in Neuron, provides important insight into the mechanism of both diseases--a possible step toward finding how to treat the disorders.

Cullin 3 is a core component of an E3 ubiquitin ligase responsible for the cell's clearance of proteins. Mutations of its gene CUL3 have been associated with autism and schizophrenia. However, pathologic mechanisms of CUL3 deficiency have been unclear.

CUL3 is abundant in the brain, yet little is known of its function. Here, we show that CUL3 is critical for brain development and communication between cells in the brain."

Lin Mei, the Allen C. Holmes Professor of Neurological Diseases and chair of the Department of Neurosciences at the Case Western Reserve University School of Medicine

Mei, also director of the Cleveland Brain Health Initiative, is the principal investigator with research assistants Zhaoqi Dong and Wenbing Chen. (The published research is titled "CUL3 deficiency causes social deficits and anxiety-like behaviors by impairing excitation-inhibition balance through the promotion of Cap-dependent translation.")

ASD is a complicated condition that includes difficulty with communication and social interaction, obsessive interests and repetitive behaviors. It affects 1 in 59 children in the United States, according to a recent report by the Centers for Disease Control. Schizophrenia affects about 1 in 100 people worldwide. However, autism and schizophrenia remain among the most mysterious disorders.

Mei and his team studied how CUL3 mutation impacts the brain in mouse models. The researchers were able to demonstrate that altering the gene in mouse models can cause similar social problems that appear in people with these disorders.

Normal mice would spend more time with a mouse over an inanimate object, Mei said. But CUL3-mutant mice couldn't differentiate between a mouse and an inanimate object, showing a problem with social preference.

In another test, normal mice would spend more time with an unfamiliar mouse over a familiar one. But CUL3-mutant mice couldn't remember seeing a familiar mouse, suggesting a problem of social memory. Also, CUL3-mutant mice were more anxious than normal mice.

Researchers at Beijing Normal University and the Louis Stokes Cleveland Veterans Affairs Medical Center contributed to the research.

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A 17-gene expression signature to distinguish patients who are likely to achieve long-term remissions following front-line FCR chemoimmunotherapy from…

In this paper, Carmen D Herling, Department I of Internal Medicine, Center for Integrated Oncology, Aachen-Bonn-Cologne-Duesseldorf, Cologne, Germany, and colleagues hypothesized that the duration of response to FCR chemoimmunotherapy depends on differences in the expression of protein-coding genes. Therefore, they developed and validated a 17-gene expression signature to identify patients that might achieve durable remissions following front-line FCR chemoimmunotherapy.

Study design and patients1

Results1

After the gene expression data analysis for the MDACC cohort, the authors identified 1,136 probes associated with time to progression. Using these probes, patients with similar gene expression patterns were divided into favorable, intermediate, and unfavorable prognosis subsets. The intermediate prognosis and unfavorable prognosis subset had a shorter time to progression compared with patients in the favorable subset.

Genes highly expressed in unfavorable cases (n= 424) were associated with metabolic pathways, including oxidative phosphorylation and ribonucleoside metabolism. Genes highly expressed in favorable or intermediate cases (n= 401) encoded products involved in ATP binding, purine ribonucleoside triphosphate binding, nucleic acid binding, and DNA-template transcription.

The authors developed a prognostic model with 17 genes to distinguish IGHV-unmutated patients that had an intermediate outcome from those with an unfavorable outcome after front-line FCR therapy. The development process included:

These 17 genes were validated in 109 patients with an IGHV-unmutated status from the CLL8 cohort. In this cohort, patients classified as high risk (unfavorable prognosis; median time to progression of 39 months [IQR 2269]) had a hazard ratio of 1.90 (95% CI 1.183.06; P = 0.008) compared with low-risk (intermediate prognosis; median time to progression of 59 months [IQR 2884]) patients. Of the 17 genes, 13 came from the cluster of genes highly expressed in unfavorable cases with shorter time to progression, and increased expression corresponds to increased risk of progression. Three of the 17 genes came from the cluster of genes highly expressed in favorable or intermediate cases with longer time to progression and increased expression corresponds to decreased risk.

Conclusions

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A 17-gene expression signature to distinguish patients who are likely to achieve long-term remissions following front-line FCR chemoimmunotherapy from...

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Transarterial Chemoembolization and Sorafenib Combined with Microwave | CMAR – Dove Medical Press

Jia-Yan Ni,13 Hong-Liang Sun,1,2 Jiang-Hong Luo,1,2 Xiong-Ying Jiang,1,2 Dong Chen,1,2 Wei-Dong Wang,1,2 Yao-Ting Chen,1,2 Jin-Hua Huang,3 Lin-Feng Xu1,2

1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province 510120, Peoples Republic of China; 2Department of Interventional Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province 510120, Peoples Republic of China; 3Department of Minimally Invasive Interventional Radiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Cancer for Cancer Medicine, Guangzhou, Guangdong Province 510060, Peoples Republic of China

Correspondence: Jin-Hua HuangDepartment of Minimally Invasive Interventional Radiology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Cancer for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong Province 510060, Peoples Republic of ChinaTel +86-20-87343447Email huangjh_sysucc@163.comLin-Feng XuGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Interventional Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang Road West, Guangzhou, Guangdong Province 510120, Peoples Republic of ChinaTel +86-20-34078680Email xu_lin_feng@163.com

Purpose: The aim of this study was to investigate the safety and efficacy of transarterial chemoembolization and sorafenib (TACE-S) combined with microwave ablation (TACE-S-MWA) for the treatment of patients with advanced primary hepatocellular carcinoma (HCC).Methods: Between January 2015 and December 2018, 152 consecutive advanced HCC patients, who underwent TACE-S-MWA (MWA group, n=77) or TACE-S (Non-MWA group, n=75), were investigated. Overall survival (OS), time to progression (TTP) and safety were compared between the two groups. Prognostic factors were analyzed using the Cox proportional hazard regression model.Results: Baseline patient characteristics were balanced between the two groups. MWA group was associated with a higher OS (median, 19.0 vs 13.0 months; P<0.001) and a longer TTP (median, 6.0 vs 3.0 months; P<0.001) compared with non-MWA group. Multivariate analyses showed that portal vein tumor thrombosis (PVTT) (P=0.002), duration of sorafenib (P<0.001), and MWA treatment (P=0.011) were independently associated with OS. MWA treatment strategy (P<0.001) was a significant predictor of TTP. There were no treatment-related mortalities in either group. The rates of minor complications (42.9% vs 38.7%, P=0.599) and major complications (1.29% vs 1.33%, P=0.985) in the MWA group were similar to those in the non-MWA group.Conclusion: TACE-S-MWA was safe and effective for advanced primary HCC. TACE-S-MWA resulted in better OS and TTP than did TACE-S for treatment of patients with advanced primary HCC.

Keywords: hepatocellular carcinoma, transarterial chemoembolization, microwave ablation, sorafenib, survival

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.

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Dual Role For A MEK Inhibitor As A Modulator Of Inflammation And Host | COPD – Dove Medical Press

Nisha Kurian,1 Taylor S Cohen,2 Lisa berg,3 Erica De Zan,3 Gabriel Skogberg,4 Stefan Vollmer,3 Engin Baturcam,3 Petter Svanberg,5 Britta Bonn,5 Paul D Smith,6 Outi Vaarala,3 Danen M Cunoosamy3

1Respiratory Inflammation and Autoimmune (RIA) Precision Medicine Unit, Precision Medicine, Oncology R&D, AstraZeneca, Gothenburg, Sweden; 2Microbial Sciences, Medimmune, Gaithersburg, MD, USA; 3Translational Science and Experimental Medicine, Research and Early Development, RIA, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 4Bioscience, Research and Early Development, RIA, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 5Drug Metabolism and Pharmacokinetics, Research and Early Development, RIA, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 6Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK

Correspondence: Nisha KurianRespiratory Inflammation and Autoimmune (RIA) Precision Medicine Unit, Precision Medicine, Oncology R&D, AstraZeneca, Gothenburg, SwedenTel +46 72 197 9662Email Nisha.e.kurian@astrazeneca.com

Background: Unlike p38 mitogen-activated protein Kinases (MAPK) that has been extensively studied in the context of lung-associated pathologies in COPD, the role of the dual-specificity mitogen-activated protein kinase kinase (MEK1/2) or its downstream signaling molecule extracellular signal-regulated kinases 1/2 (ERK1/2) in COPD is poorly understood.Objectives: The aim of this study was to address whether MEK1/2 pathway activation is linked to COPD and that targeting this pathway can improve lung inflammation through decreased immune-mediated inflammatory responses without compromising bacterial clearance.Methods: Association of MEK1/2 pathway activation to COPD was investigated by immunohistochemistry using lung tissue biopsies from COPD and healthy individuals and through analysis of sputum gene expression data from COPD patients. The anti-inflammatory effect of MEK1/2 inhibition was assessed on cytokine release from lipopolysaccharide-stimulated alveolar macrophages. The effect of MEK1/2 inhibition on bacterial clearance was assessed using Staphylococcus aureus killing assays with RAW 264.7 macrophage cell line and human neutrophils.Results: We report here MEK1/2 pathway activation demonstrated by increased pERK1/2 staining in bronchial epithelium and by the presence of MEK gene activation signature in sputum samples from COPD patients. Inhibition of MEK1/2 resulted in a superior anti-inflammatory effect in human alveolar macrophages in comparison to a p38 inhibitor. Furthermore, MEK1/2 inhibition led to an increase in bacterial killing in human neutrophils and RAW 264.7 cells that was not observed with the p38 inhibitor.Conclusion: Our data demonstrate the activation of MEK1/2 pathway in COPD and highlight a dual function of MEK1/2 inhibition in improving host defense responses whilst also controlling inflammation.

Keywords: exacerbation, infection, alveolar macrophage, p38 MAPK, steroid, transcriptomics, sputum

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.

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Partnership aims to accelerate cell and gene therapy – Harvard Gazette

MIT Provost Martin A. Schmidt said sharing the risk among several institutions will not only make possible work that would be difficult for a single institution to tackle, it will also encourage collaboration that accelerates the process of moving discoveries from lab to patient.

MIT researchers are developing innovative approaches to cell and gene therapy, designing new concepts for such biopharmaceutical medicines as well as new processes to manufacture these products and qualify them for clinical use, Schmidt said. A shared facility to de-risk this innovation, including production, will facilitate even stronger collaborations among local universities, hospitals, and companies and ultimately, such a facility can help speed impact and access for patients. MIT appreciates Harvards lead in convening exploration of this opportunity for the Commonwealth.

Richard McCullough, Harvards vice provost for research and professor of materials science and engineering, who also helped lead the project, said although the centers activity will revolve around science and manufacturing, its true focus will be on patients.

The centers overarching goal will be improving patient care, McCullough said. This would occur both by speeding access to the essential, modified cells that patients in clinical trials await, and by fostering discoveries through collaborations within the centers innovation space. The aim is that discoveries result in whole new treatments or improved application of existing treatments to provide relief to a wider universe of patients.

Organized as a private nonprofit, the center will be supported by more than $50 million pledged by its partners. It will be staffed by a team of at least 40, experienced in the latest cell-manufacturing techniques and trained in the use of the latest equipment. Among its goals is disseminating badly needed skills into the Boston life-sciences workforce.

We have to be sure that we are constantly feeding the industry with talented people who know the right things, so personally, I am very excited about education programs, Ligner said. Initiatives like [this center] are essential to advancing the industry because they help organizations build on one anothers advances. For example, the full potential of cell and gene therapies will only be realized if we collaborate to address challenges, such as manufacturing, improving access, accelerating innovation, tackling cost issues, and then sharing our learnings.

The new center emerged from conversations with state officials, including Gov. Charlie Baker and Attorney General Maura Healey, and industry sector leaders about ways to bolster Massachusetts preeminence in life science research and medical innovation. Those conversations sparked a two-year consultation process at the invitation of Garber and Harvard Corporation Senior Fellow Bill Lee, that was coordinated with state officials and included representatives from industry, academia, venture capital, area hospitals, and government.

Cell and gene therapies have the potential to revolutionize the global health system. Recently, in Sweden, the first patient received cell therapy outside of a clinical trial. Its the start of an incredible time in the industry and in human health.

Emmanuel Ligner, president and chief executive of GE Healthcare Life Sciences

Called the Massachusetts Life Sciences Strategies Group, members reached out to regional experts beginning in 2017to discover what fields they considered most important and how best to support them. Cell and gene therapy rose to the top because of the considerable excitement generated by activity already going on, its potential to help patients, and its high potential for future growth and innovation. Also important were the opportunities to spread the high cost of these technologies across multiple institutions and, while so doing, capture the collaborative power of housing each player in the development chain within a single facility.

The centers board of directors will be comprised of Harvard, MIT, and industry partners Fujifilm, Alexandria Real Estate Equities, and GE Healthcare Life Sciences. Other members will include Harvard-affiliated teaching hospitals Massachusetts General Hospital, Brigham and Womens Hospital, Beth Israel Deaconess Medical Center, Boston Childrens Hospital, and the Dana-Farber Cancer Institute; as well as the Commonwealth of Massachusetts and life-sciences company MilliporeSigma.

When you look at the constellation of players coming together, you really have the best universities and the best teaching hospitals and the best corporate players all supporting it, McGuire said, which I think is a great opportunity.

The facility intends to provide researchers and emerging companies outside the consortium with access to excess material, though organizers said they expect it to be in high demand by center partners.

The centers boost to the areas cell and gene therapy endeavors comes early enough that it should help maintain leadership over places like California and China, which have made clear their interest in life-science research, McGuire said.

I think getting this early mover advantage is going to be huge [in] developing the technology and the know-how and, ultimately, the intellectual property around it, McGuire said.

For Sharpe, the ultimate payoff will come from using cancer immunotherapys checkpoint blockade and other cell and gene therapies to save and improve lives.

We are seeing long-term benefits in some patients whove received checkpoint blockade, Sharpe said. There are patients who are more than a decade out and are melanoma-free. I think that it really has transformed patient care, quality of life, and longevity. So Im optimistic that the more we learn, the more were going to be able to do to help patients.

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Partnership aims to accelerate cell and gene therapy - Harvard Gazette

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