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Journal of Clinical Investigation
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Cancer Immunotherapy Series overview
Exploring the cancer/immune system relationship
In the early 1900s, Paul Ehrlich postulated that the immune system both recognizes and protects against cancer. Since then, researchers have been trying to elucidate the relationship between cancer, inflammation, and the innate and adaptive immune systems, starting with the theory of immunosurveillance introduced by Lewis Thomas and Sir MacFarlane Burnet. We now know that tumor cells display antigens that are recognized by immune cells, but that tumor cells can circumvent anti-tumor immunity through a variety of escape mechanisms, including alterations in antigen presentation, recruitment of immunosuppressive immune cells, and expression of negative regulatory signals. The goal of cancer immunotherapy is to mount an effective anti-tumor immune response by repairing, stimulating or, enhancing the immune system’s response to cancer cells. Reviews in this series detail progress in cancer immunoediting, immunosuppressive cells in the tumor microenvironment, cancer-associated inflammation, therapeutic cancer vaccines, genomic approaches in immunotherapy, adoptive transfer of genetically engineered T cells, and checkpoint blockade therapy.
http://buff.ly/1KgXIq5
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September 2015 issue published:
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A new batch of articles is now available online at
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Too little vs. too late in retinal gene therapy
Gene therapy is a promising approach for treating retinal degeneration. However, this strategy is likely to be hampered by insufficient gene transduction efficiency and/or the disease being too advanced at diagnosis (the so-called “point of no return”). Susanne Koch and colleagues developed a mouse model of retinitis pigmentosa (RP) in which the mutant gene, cGMP phosphodiesterase 6b (Pde6b), can be inducibly repaired in all diseased photoreceptor cells. With gene transduction optimized, they were able to determine the therapeutic window for rescue. Gene restoration in these mice halted photoreceptor degeneration at early, mid or late stage disease (see the accompanying image). These findings indicate that RP is treatable using gene therapy even at advanced disease stages and suggest that efforts in this area should focus on improved gene delivery. In the accompanying commentary, James Hurley and Jennifer Chao discuss how this study establishes a predictive model for gene therapy response in neurodegenerative diseases.
Read the article: http://buff.ly/1I0cTMJ
Read the accompanying commentary: http://buff.ly/1I0cTMK #ResearchArticle #Neuroscience #Commentary
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Acute lymphoblastic leukemia model elucidates step-wise pathogenesis
Acute lymphoblastic leukemia (ALL) primarily results from acquired genomic aberrations. Recent genomic studies have revealed that leukemias are genetically complex and a three-step model of leukemogenesis has been proposed to account for pathogenesis. To test this model, Jesús Duque-Afonso and colleagues engineered mice that conditionally express E2A-PBX1, a fusion oncogene that is present in 5-7% of pediatric ALL cases. Leukemia incidence was dependent on the Cre driver promoter and ranged from 5-50%. Activation of E2A-PBX1 in B cell precursors resulted in enhanced self–renewal, impaired differentiation of B cell progenitors, and the acquisition of secondary genomic aberrations, including mutations in JAK/STAT signaling pathway components and spontaneous loss of the transcription factor PAX5. Pax5 haploinsufficiency in E2A-PBX1-expressing mice blocked B cell progenitor differentiation, shortened latency, and increased penetrance of leukemias. In the accompanying commentary, Peter Aplan and Terry Fry discuss how these studies establish a murine model of B cell precursor ALL.
Read the article: http://buff.ly/1JaJBwG
Read the accompanying commentary: http://buff.ly/1JaJBwI #ResearchArticle #Oncology #Commentary
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Murine induced pluripotent stem cell-derived neural precursors generate functional myelin
Neural precursors derived from induced pluripotent stem cells (iPSCs) could potentially serve as an autologous source for cell-based therapeutics. Sabah Mozafari and colleagues compared the behavior of iPSC-derived neural precursors to neural precursors isolated from the central nervous system (CNS) both in vitro and in a murine model of adult spinal cord demyelination. They found that iPSC-derived neural precursors differentiated into mature oligodendrocytes and migrated into the demyelinated regions of the adult spinal cord. Importantly, iPSC-derived cells remyelinated host axons (see the accompanying image), restored nodes of Ranvier, and improved conduction velocity as efficiently as CNS-derived neural precursors. These results indicate that patient-specific iPSCs could be used as a personalized source of neural precursor cells for myelin replacement therapy.
Read the article: http://buff.ly/1NrblU9 #ResearchArticle #Neuroscience
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Noninvasive prenatal diagnosis of recessive monogenic disease

Noninvasive prenatal genetic testing (NIPGT) is a blood test that examines cell-free fetal DNA in the maternal bloodstream and is currently used for the diagnosis of chromosomal abnormalities. David Zeevi and colleagues developed an NIPGT method to diagnose monogenic disorders caused by autosomal recessive mutations. Zeevi and colleagues collected blood samples from eight couples of Ashkenazi Jewish heritage that were at risk of passing on type I Gaucher disease-causing alleles of acid β-glucosidase (GBA), as well as from mutation-carrier family members and unrelated individuals who were homozygous for disease-causing mutations. The samples were subjected to high throughput sequencing of GBA-flanking SNPs and fine-mapped to establish a consensus disease-associated haplotype. Zeevi and colleagues then used this haplotype to diagnose six unrelated fetuses. This study establishes a method for the rapid, prenatal diagnosis of recessive disease-causing mutations.
Read the article: http://buff.ly/1VjqIiN #ClinicalMedicine #Genetics
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CWGM

A conversation with Rudolf Jaenisch

In this month’s issue, Editor-at-large Ushma Neill interviews Rudolf Jaenisch of MIT’s Whitehead Institute. Dr. Jaenisch created the first transgenic mice and conducted the first experiment demonstrating that therapeutic cloning could correct a genetic defect. Additionally, Jaenisch has been at the forefront of research on induced pluripotent stem cells and has shown that these cells can correct sickle cell anemia and Parkinson’s disease in rodents. In this interview, Jaenisch discusses his work as a postdoctoral fellow in Arnold Levine’s lab studying DNA replication with the tumor virus SV40, which led to his collaboration with developmental geneticist Beatrice Mintz. Additionally, Jaenisch discusses adoption of new methods and technologies to address interesting questions in genetics, as well as the application of these technologies to humans.
Watch the interview: http://buff.ly/1PXQvKy
Read the article: http://buff.ly/1PXQxC3 #CWGMA
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Addressing the point of no return for gene therapy
Retinitis pigmentosa (RP) is hereditary retinal degenerative disease that is characterized by progressive loss of photoreceptor function. In human trials, gene therapy has been shown to improve vision; however, this benefit has not been sustainable. It is not clear if the lack of long-term benefit is due to the advanced stage of the disease at the time of therapy or due to inefficient delivery of the functional gene. In this episode of JCI's Author's Take, Stephen Chang and Susanne Koch discuss the development of a murine RP model that allows induction of the corrected gene at various stages of disease.
Watch the Author's Take video: http://buff.ly/1KrrTcK
Read the article: http://buff.ly/1KrrS8x #AuthorsTake #Neuroscience
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DNA replication stress linked to ciliopathies
Ciliopathy syndromes result from primary cilium dysfunction and are often associated with premature renal failure due to nephronophthisis. While the genetic mutations that underlie a range of ciliopathies have been identified, the link between these genes and disease phenotypes remain elusive. Mutations in the gene encoding the large centrosomal protein CEP290 are associated with several ciliopathies, including Joubert syndrome (JS). CEP290 localizes to the centrosome and the base of the primary cilium; however, it is also found within the nucleus, where its function is largely unknown. Gisela Slaats and colleagues at the University Medical Center Utrecht have demonstrated that loss of CEP290 induces DNA damage response signaling, DNA breaks, and replication stress in the kidney.
Read the Scientific Show Stopper: http://buff.ly/1LAvZOh
Read the article: http://buff.ly/1LAvZOm #ScientificShowStopper #Nephrology
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HIV-1 infection sensitizes innate lymphoid cells to Fas-mediated apoptosis
Group 3 innate lymphoid cells (ILC3s) support survival and expansion of mature B cells and direct immune cell migration into the gut. Because ILC3s are depleted in HIV-1 patients, Zheng Zhang, Liang Cheng, and colleagues used a humanized mouse model to study ILC3s in the setting of persistent HIV-1 infection. They found that, as in humans, ILC3s were depleted in this model and that ILC3 loss was reversed by anti-retroviral therapy, depletion of plasmacytoid dendritic cells (pDCs), or blockade of IFN-I or the Fas/FasL pathway. Notably, HIV-1 infection upregulated the expression of Fas on ILC3s in a pDC- and IFN-I-dependent manner. Based on these findings, Zhang and colleagues proposed a model in which HIV-1 infection activates pDCs, thereby inducing IFN-I production, which upregulates Fas expression on ILC3s, sensitizing them to FasL-mediated apoptosis (see the accompanying image). In the accompanying commentary, Xiaohuan Guo and Yang-Xin Fu discuss the role of chronic inflammation in HIV-1 pathogenesis.
Read the article: http://buff.ly/1NrbZB4
Read the accompanying commentary: http://buff.ly/1NrbWVO #ResearchArticle #AIDS/HIV #Commentary
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Examining the iron/appetite relationship
Iron deficiency is associated with appetite loss and can be reversed with iron supplementation; however, the underlying mechanisms are poorly understood. Yan Gao and colleagues examined the effect of iron on leptin, which regulates food intake and energy homeostasis. In both mice and in a cohort of humans with metabolic syndrome, serum ferritin levels were inversely correlated with serum leptin, independently of inflammation and BMI. Mice fed a high iron diet exhibited increased food intake and decreased serum leptin. The effects on leptin were recapitulated in mice with adipocyte-specific deletion of the iron exporter ferroportin. Mechanistically, elevated adipocyte iron levels decrease leptin promoter activity by increasing cAMP response element-binding protein (CREB) occupancy of the leptin promoter. In the accompanying commentary, Nancy Andrews discusses how these findings raise additional questions about the relationship between iron, leptin, and food intake.
Read the article: http://buff.ly/1NrbOWa
Read the accompanying commentary: http://buff.ly/1NrbOWd #ResearchArticle #Endocrinology #Commentary
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In their circles
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Have them in circles
68 people
Joslin Diabetes's profile photo
Chris Christodoulou's profile photo
Ginger Tissier's profile photo
Fumihiko Urano's profile photo
Nathaniel L. Stewart-Brown's profile photo
Cure Brain Cancer Foundation's profile photo
Dr Rakesh Chaurasiya's profile photo
ΕΥΑΓΓΕΛΟΣ ΔΗΜΗΤΡΙΟΥ's profile photo
Louise Abeita's profile photo
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Premiere venue for discoveries in basic and clinical biomedical science.
Introduction
The Journal of Clinical Investigation (JCI) is a top-tier venue for discoveries in basic and clinical biomedical research that will advance the practice of medicine. Founded in 1924, the journal is published by the American Society for Clinical Investigation (ASCI) and has a 2013 Impact Factor of 13.765. Since 2012, the JCI has been headed by Dr. Howard A. Rockman, Editor, with an Editorial Board of peer scientists at Duke University Medical Center, the University of North Carolina, Duke-NUS, and the Sanford-Burnham Medical Research Institute. The JCI provides free access to all of its research articles.