Phosphatidylinositol 4,5-Bisphosphate Functions as a Second Messenger that Regulates Cytoskeleton–Plasma Membrane Adhesion

Abstract: Binding interactions between the plasma membrane and the cytoskeleton define cell functions such as cell shape, formation of cell processes, cell movement, and endocytosis.

Abstract: Here we use optical tweezers tether force measurements and show that plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP2) acts as a second messenger that regulates the adhesion energy between the cytoskeleton and the plasma membrane.

Abstract: Receptor stimuli that hydrolyze PIP2 lowered adhesion energy, a process that could be mimicked by expressing PH domains that sequester PIP2 or by targeting a 5'-PIP2-phosphatase to the plasma membrane to selectively lower plasma membrane PIP2 concentration.

Abstract: Our study suggests that plasma membrane PIP2 controls dynamic membrane functions and cell shape by locally increasing and decreasing the adhesion between the actin-based cortical cytoskeleton and the plasma membrane.


Tissue-resident memory T cells: local specialists in immune defence

Abstract: T cells have crucial roles in protection against infection and cancer.

Abstract: Although the trafficking of memory T cells around the body is integral to their capacity to provide immune protection, studies have shown that specialization of some memory T cells into unique tissue-resident subsets gives the host enhanced regional immunity.

Abstract: In recent years, there has been considerable progress in our understanding of tissue-resident T cell development and function, revealing mechanisms for enhanced protective immunity that have the potential to influence rational vaccine design.

Abstract: This Review discusses the major advances and the emerging concepts in this field, summarizes what is known about the differentiation and the protective functions of tissue-resident memory T cells in different tissues in the body and highlights key unanswered questions.


Defective replication stress response inhibits lymphomagenesis and impairs lymphocyte reconstitution

Abstract: DNA replication stress promotes genome instability in cancer.

Abstract: However, the contribution of the replication stress response to the development of malignancies remains unresolved.

Abstract: The DNA replication stress response protein SMARCAL1 stabilizes DNA replication forks and prevents replication fork collapse, a cause of DNA breaks and apoptosis.

Abstract: While the fork regression/remodeling functions of SMARCAL1 have been investigated, its in vivo functions in replication stress and cancer are unclear.

Abstract: Using a gamma radiation (IR)-induced replication stress T-cell lymphoma mouse model, we observed a significant inhibition of lymphomagenesis in mice lacking one or both alleles of Smarcal1.

Abstract: Notably, a quarter of the Smarcal1-deficient mice did not develop tumors.

Abstract: Moreover, hematopoietic stem/progenitor cells (HSPCs) and developing thymocytes in Smarcal1-deficient mice showed increased DNA damage and apoptosis during the proliferation burst following IR and an impaired ability to repopulate the thymus after IR.

Abstract: Additionally, mice lacking Smarcal1 showed significant HSPC defects when challenged to respond to other replication stress stimuli.

Abstract: Thus, our data reveal the critical function of the DNA replication stress response and, specifically, Smarcal1 in hematopoietic cell survival and tumor development.

Abstract: Our results also provide important insight into the immunodeficiency observed in individuals with mutations in SMARCAL1 by suggesting that it is an HSPC defect.


Human DNA methylomes at base resolution show widespread epigenomic differences

Abstract: DNA cytosine methylation is a central epigenetic modification that has essential roles in cellular processes including genome regulation, development and disease.

Abstract: Here we present the first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA–protein interaction for several key regulatory factors.

Abstract: Widespread differences were identified in the composition and patterning of cytosine methylation between the two genomes.

Abstract: Nearly one-quarter of all methylation identified in embryonic stem cells was in a non-CG context, suggesting that embryonic stem cells may use different methylation mechanisms to affect gene regulation.

Abstract: Methylation in non-CG contexts showed enrichment in gene bodies and depletion in protein binding sites and enhancers.

Abstract: Non-CG methylation disappeared upon induced differentiation of the embryonic stem cells, and was restored in induced pluripotent stem cells.

Abstract: We identified hundreds of differentially methylated regions proximal to genes involved in pluripotency and differentiation, and widespread reduced methylation levels in fibroblasts associated with lower transcriptional activity.

Abstract: These reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development.


Laparoscopic adhesiolysis in patients with chronic abdominal pain: a blinded randomised controlled multi-centre trial.

Abstract: BACKGROUND Laparoscopic adhesiolysis for chronic abdominal pain is controversial and is not evidence based.

Abstract: We aimed to test our hypothesis that laparoscopic adhesiolysis leads to substantial pain relief and improvement in quality of life in patients with adhesions and chronic abdominal pain.

Abstract: METHODS Patients had diagnostic laparoscopy for chronic abdominal pain attributed to adhesions; other causes for their pain had been excluded.

Abstract: If adhesions were confirmed during diagnostic laparoscopy, patients were randomly assigned either to laparoscopic adhesiolysis or no treatment.

Abstract: Treatment allocation was concealed from patients, and assessors were unaware of patients' treatment and outcome.

Abstract: Pain was assessed for 1 year by visual analogue score (VAS) score (scale 0-100), pain change score, use of analgesics, and quality of life score.

Abstract: Analysis was by intention to treat.

Abstract: FINDINGS Of 116 patients enrolled for diagnostic laparoscopy, 100 were randomly allocated either laparoscopic adhesiolysis (52) or no treatment (48).

Abstract: Both groups reported substantial pain relief and a significantly improved quality of life, but there was no difference between the groups (mean change from baseline of VAS score at 12 months: difference 3 points, p=0.53; 95% CI -7 to 13).

Abstract: INTERPRETATION Although laparoscopic adhesiolysis relieves chronic abdominal pain, it is not more beneficial than diagnostic laparoscopy alone.

Abstract: Therefore, laparoscopic adhesiolysis cannot be recommended as a treatment for adhesions in patients with chronic abdominal pain.


Insulin Signaling and Dietary Restriction Differentially Influence the Decline of Learning and Memory with Age

Abstract: Of all the age-related declines, memory loss is one of the most devastating.

Abstract: While conditions that increase longevity have been identified, the effects of these longevity-promoting factors on learning and memory are unknown.

Abstract: Here we show that the C. elegans Insulin/IGF-1 receptor mutant daf-2 improves memory performance early in adulthood and maintains learning ability better with age but, surprisingly, demonstrates no extension in long-term memory with age.

Abstract: By contrast, eat-2 mutants, a model of Dietary Restriction (DR), exhibit impaired long-term memory in young adulthood but maintain this level of memory longer with age.

Abstract: We find that crh-1, the C. elegans homolog of the CREB transcription factor, is required for long-term associative memory, but not for learning or short-term memory.

Abstract: The expression of crh-1 declines with age and differs in the longevity mutants, and CREB expression and activity correlate with memory performance.

Abstract: Our results suggest that specific longevity treatments have acute and long-term effects on cognitive functions that decline with age through their regulation of rate-limiting genes required for learning and memory.


Unique response pathways are established by allosteric interactions among nuclear hormone receptors

Abstract: Heterodimerization is a common paradigm among eukaryotic transcription factors.

Abstract: The 9-cis retinoic acid receptor (RXR) serves as a common heterodimerization partner for several nuclear receptors, including the thyroid hormone receptor (T3R) and retinoic acid receptor (RAR).

Abstract: This raises the question as to whether these complexes possess dual hormonal responsiveness.

Abstract: We devised a strategy to examine the transcriptional properties of each receptor individually or when tethered to a heterodimeric partner.

Abstract: We find that the intrinsic binding properties of RXR are masked in T3R-RXR and RAR-RXR heterodimers.

Abstract: In contrast, RXR is active as a non-DNA-binding cofactor with the NGFI-B/Nurr1 orphan receptors.

Abstract: Heterodimerization of RXR with constitutively active NGFI-B/Nurr1 creates a novel hormone-dependent complex.

Abstract: These findings suggest that allosteric interactions among heterodimers create complexes with unique properties.

Abstract: We suggest that allostery is a critical feature underlying the generation of diversity in hormone response networks.


Midlife and Late‐Life Vascular Risk Factors and White Matter Microstructural Integrity: The Atherosclerosis Risk in Communities Neurocognitive Study

Abstract: BACKGROUND Diffusion tensor imaging measures of white matter (WM) microstructural integrity appear to provide earlier indication of WM injury than WM hyperintensities; however, risk factors for poor WM microstructural integrity have not been established.

Abstract: Our study quantifies the association between vascular risk factors in midlife and late life with measures of late-life WM microstructural integrity.

Abstract: METHODS AND RESULTS We used data from 1851 participants in ARIC (Atherosclerosis Risk in Communities Study) who completed 3-T magnetic resonance imaging, including diffusion tensor imaging, as part of the ARIC Neurocognitive Study (ARIC-NCS).

Abstract: We quantified the association among lipids, glucose, and blood pressure from the baseline ARIC visit (1987-1989, ages 44-65, midlife) and visit 5 of ARIC (2011-2013, ages 67-90, late life, concurrent with ARIC-NCS) with regional and overall WM mean diffusivity and fractional anisotropy obtained at ARIC visit 5 for ARIC participants.

Abstract: We also considered whether these associations were independent of or modified by WM hyperintensity volumes.

Abstract: We found that elevated blood pressure in midlife and late life and elevated glucose in midlife, but not late life, were associated with worse late-life WM microstructural integrity.

Abstract: These associations were independent of the degree of WM hyperintensity, and the association between glucose and WM microstructural integrity appeared stronger for those with the least WM hyperintensity.

Abstract: There was little support for an adverse association between lipids and WM microstructural integrity.

Abstract: CONCLUSIONS Hypertension in both midlife and late life and elevated glucose in midlife are related to worse WM microstructural integrity in late life.


KRAS gene amplification and overexpression but not mutation associates with aggressive and metastatic endometrial cancer

Abstract: BACKGROUND Three quarter of endometrial carcinomas are treated at early stage.

Abstract: Still, 15 to 20% of these patients experience recurrence, with little effect from systemic therapies.

Abstract: Homo sapiens v-Ki-ras2 Kirsten rat sarcoma viral oncogenes homologue (KRAS) mutations have been reported to have an important role in tumorigenesis for human cancers, but there is limited knowledge regarding clinical relevance of KRAS status in endometrial carcinomas.

Abstract: METHODS We have performed a comprehensive and integrated characterisation of genome-wide expression related to KRAS mutations and copy-number alterations in primary- and metastatic endometrial carcinoma lesions in relation to clinical and histopathological data.

Abstract: A primary investigation set and clinical validation set was applied, consisting of 414 primary tumours and 61 metastatic lesions totally.

Abstract: RESULTS Amplification and gain of KRAS present in 3% of the primary lesions and 18% of metastatic lesions correlated significantly with poor outcome, high International Federation of Gynaecology and Obstetrics stage, non-endometrioid subtype, high grade, aneuploidy, receptor loss and high KRAS mRNA levels, also found to be associated with aggressive phenotype.

Abstract: In contrast, KRAS mutations were present in 14.7% of primary lesions with no increase in metastatic lesions, and did not influence outcome, but was significantly associated with endometrioid subtype, low grade and obesity.

Abstract: CONCLUSION These results support that KRAS amplification and KRAS mRNA expression, both increasing from primary to metastatic lesions, are relevant for endometrial carcinoma disease progression.


Hyperhomocysteinemia and atherosclerotic vascular disease: pathophysiology, screening, and treatment. off.

Abstract: Hyperhomocysteinemia has recently been identified as an important risk factor for atherosclerotic vascular disease.

Abstract: This article reviews homocysteine metabolism, causes of hyperhomocysteinemia, the pathophysiological findings of this disorder, and epidemiological studies of homocysteine and vascular disease.

Abstract: Screening for hyperhomocysteinemia should be considered for patients at high risk for vascular disease or abnormalities of homocysteine metabolism.

Abstract: For primary prevention of vascular disease, treatment of patients with homocysteine levels of 14 micromol/L or higher should be considered.

Abstract: For secondary prevention, treatment of patients with homocysteine levels of 11 micromol/L or higher should be considered.

Abstract: Treatment is most conveniently administered as a folic acid supplement (400-1000 microg) and a high-potency multivitamin that contains at least 400 microg of folate.

Abstract: Higher doses of folic acid and cyanocobalamin supplements may be required in some patients.

Abstract: Until prospective clinical trial data become available, these conservative recommendations provide a safe, effective, and evidence-based approach to the diagnosis, evaluation, and management of patients with hyperhomocysteinemia.


Best--worst scaling: What it can do for health care research and how to do it.

Abstract: Statements like "quality of care is more highly valued than waiting time" can neither be supported nor refuted by comparisons of utility parameters from a traditional discrete choice experiment (DCE).

Abstract: Best--worst scaling can overcome this problem because it asks respondents to perform a different choice task.

Abstract: However, whilst the nature of the best--worst task is generally understood, there are a number of issues relating to the design and analysis of a best--worst choice experiment that require further exposition.

Abstract: This paper illustrates how to aggregate and analyse such data and using a quality of life pilot study demonstrates how richer insights can be drawn by the use of best--worst tasks.


Genetic variants and non-genetic factors predict circulating vitamin D levels in Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study.

Abstract: Genome-wide association studies (GWAS) have identified common polymorphisms in or near GC, CYP2R1, CYP24A1, and NADSYN1/DHCR7 genes to be associated with circulating levels of 25-hydroxyvitamin D [25(OH)D] in European populations.

Abstract: To replicate these GWAS findings, we examined six selected polymorphisms from these regions and their relation with circulating 25(OH)D levels in 1,605 Hispanic women (629 U.S. Hispanics and 976 Mexicans) and 354 non-Hispanic White (NHW) women.

Abstract: We also assessed the potential interactions between these variants and known non-genetic predictors of 25(OH)D levels, including body mass index (BMI), sunlight exposure and vitamin D intake from diet and supplements.

Abstract: The minor alleles of the two GC polymorphisms (rs7041 and rs2282679) were significantly associated with lower 25(OH)D levels in both Hispanic and NHW women.

Abstract: The CYP2R1 polymorphism, rs2060793, also was significantly associated with 25(OH)D levels in both groups.

Abstract: We found no significant associations for the polymorphisms in the CYP24A1.

Abstract: In Hispanic controls, 25(OH)D levels were significantly associated with the rs12785878T and rs1790349G haplotype in the NADSYN1/DHCR7 region.

Abstract: Significant interactions between GC rs2282679 and BMI and between rs12785878 and time spent in outdoor activities were observed.

Abstract: These results provide further support for the contribution of common genetic variants to individual variability in circulating 25(OH)D levels.

Abstract: The observed interactions between SNPs and non-genetic factors warrant confirmation.


Generation and characterization of methyl-lysine histone antibodies.

Abstract: Publisher Summary This chapter summarizes the development and characterization of rabbit polyclonal antibodies named histone that are directed against the methylated H3-K9 position.

Abstract: It provides protocols for peptide design, rabbit immunizations, and quality controls of methyl-lysine histone antibodies, followed by their in vivo characterization using indirect IF of inter-and metaphase chromatin in wild-type (wt) and mutant mouse cells that are deficient for the Suv39h histone methyltransferases (HMTases).

Abstract: Histone amino-termini (tails) protrude from the nucleosome core and are subject to a variety of post-translational modifications, including acetylation (on lysine residues), phosphorylation (on serine and threonine residues), methylation (on lysine and arginine residues), ubiquitination (on lysine residues), and ADP-ribosylation (on glutamic acid residues).

Abstract: In addition to their structural roles, histones play important functions in the control of gene expression by regulating access to the underlying nucleosomal template.

Abstract: It is without doubt that the development of high-quality, position-specific methyl-lysine histone antibodies can provide important tools for the further decoding of the epigenetic information, which is in part, indexed by distinct methylation states of selective lysine residues in the histone amino-termini.

Abstract: A comparative analysis indicates significant discrepancies in the specificity and avidity of the available methyl-lysine histone antibodies and highlights the need for extensive quality controls, such that experimental data can be correctly interpreted despite the exquisite complexity of histone lysine methylation.


The Hallmarks of Aging

Abstract: Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death.

Abstract: This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases.

Abstract: Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution.

Abstract: This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging.

Abstract: These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.

Abstract: A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects.


A sensitive mass spectrometry platform identifies metabolic changes of life history traits in C. elegans

Abstract: Abnormal nutrient metabolism is a hallmark of aging, and the underlying genetic and nutritional framework is rapidly being uncovered, particularly using C. elegans as a model.

Abstract: However, the direct metabolic consequences of perturbations in life history of C. elegans remain to be clarified.

Abstract: Based on recent advances in the metabolomics field, we optimized and validated a sensitive mass spectrometry (MS) platform for identification of major metabolite classes in worms and applied it to study age and diet related changes.

Abstract: Using this platform that allowed detection of over 600 metabolites in a sample of 2500 worms, we observed marked changes in fatty acids, amino acids and phospholipids during worm life history, which were independent from the germ-line.

Abstract: Worms underwent a striking shift in lipid metabolism after early adulthood that was at least partly controlled by the metabolic regulator AAK-2/AMPK.

Abstract: Most amino acids peaked during development, except aspartic acid and glycine, which accumulated in aged worms.

Abstract: Dietary intervention also influenced worm metabolite profiles and the regulation was highly specific depending on the metabolite class.

Abstract: Altogether, these MS-based methods are powerful tools to perform worm metabolomics for aging and metabolism-oriented studies.


Characterisation of antibiotic prescriptions for acute respiratory tract infections in Danish general practice: a retrospective registry based cohort study

Abstract: Inappropriate use of antibiotics is contributing to the increasing rates of antimicrobial resistance.

Abstract: Several Danish guidelines on antibiotic prescribing for acute respiratory tract infections in general practice have been issued to promote rational prescribing of antibiotics, however it is unclear if these recommendations are followed.

Abstract: We aimed to characterise the pattern of antibiotic prescriptions for patients diagnosed with acute respiratory tract infections, by means of electronic prescriptions, labeled with clinical indications, from Danish general practice.

Abstract: Acute respiratory tract infections accounted for 456,532 antibiotic prescriptions issued between July 2012 and June 2013.

Abstract: Pneumonia was the most common indication with 178,354 prescriptions (39%), followed by acute tonsillitis (21%) and acute otitis media (19%).

Abstract: In total, penicillin V accounted for 58% of all prescriptions, followed by macrolides (18%) and amoxicillin (15%).

Abstract: The use of second-line agents increased with age for all indications, and comprised more than 40% of the prescriptions in patients aged >75 years.

Abstract: Women were more often prescribed antibiotics regardless of clinical indication.

Abstract: This is the first Danish study to characterise antibiotic prescription patterns for acute respiratory tract infections by data linkage of clinical indications.

Abstract: The findings confirm that penicillin V is the most commonly prescribed antibiotic agent for treatment of patients with an acute respiratory tract infection in Danish general practice.

Abstract: However, second-line agents like macrolides and amoxicillin with or without clavulanic acid are overused.

Abstract: Strategies to improve the quality of antibiotic prescribing especially for pneumonia, acute otitis media and acute rhinosinusitis are warranted.

Abstract: RESPIRATORY TRACT INFECTIONS TRACKING THE OVERUSE OF ANTIBIOTICS: Better adherence to guidelines for prescribing antibiotics for different respiratory tract infections are warranted in Danish general practice.

Abstract: The over-use of antibiotics, particularly so-called 'second-line' agents such as amoxicillin, increases resistance and may lead to a potentially catastrophic scenario where antibiotics are no longer effective.

Abstract: Exactly how widespread the over-use of antibiotics is for different infections, however, is not clear.

Abstract: Rune Aabenhus at the University of Copenhagen and co-workers analyzed primary care data regarding antibiotic prescriptions for acute respiratory tract infections including pneumonia and ear infections in Denmark.

Abstract: They found that penicillin V-the current recommended first-line drug in Scandinavian countries-accounted for 58 per cent of prescriptions, a figure which should be improved.

Abstract: Amoxicillin and macrolides were over-prescribed, particularly in elderly patients.

Abstract: The team also call for further analysis of prescriptions given by out-of-hours clinics.


Lack of Skeletal Muscle IL-6 Affects Pyruvate Dehydrogenase Activity at Rest and during Prolonged Exercise

Abstract: Pyruvate dehydrogenase (PDH) plays a key role in the regulation of skeletal muscle substrate utilization.

Abstract: IL-6 is produced in skeletal muscle during exercise in a duration dependent manner and has been reported to increase whole body fatty acid oxidation, muscle glucose uptake and decrease PDHa activity in skeletal muscle of fed mice.

Abstract: The aim of the present study was to examine whether muscle IL-6 contributes to exercise-induced PDH regulation in skeletal muscle.

Abstract: Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice and floxed littermate controls (control) completed a single bout of treadmill exercise for 10, 60 or 120 min, with rested mice of each genotype serving as basal controls.

Abstract: The respiratory exchange ratio (RER) was overall higher (P<0.05) in IL-6 MKO than control mice during the 120 min of treadmill exercise, while RER decreased during exercise independent of genotype.

Abstract: AMPK and ACC phosphorylation also increased with exercise independent of genotype.

Abstract: PDHa activity was in control mice higher (P<0.05) at 10 and 60 min of exercise than at rest but remained unchanged in IL-6 MKO mice.

Abstract: In addition, PDHa activity was higher (P<0.05) in IL-6 MKO than control mice at rest and 60 min of exercise.

Abstract: Neither PDH phosphorylation nor acetylation could explain the genotype differences in PDHa activity.

Abstract: Together, this provides evidence that skeletal muscle IL-6 contributes to the regulation of PDH at rest and during prolonged exercise and suggests that muscle IL-6 normally dampens carbohydrate utilization during prolonged exercise via effects on PDH.


Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer.

Abstract: PURPOSE Mutations in the BRCA1 and BRCA2 genes confer greater risk of developing breast cancer.

Abstract: We determined whether tumor pathologic features and clinical features differ in patients with and without BRCA mutations.

Abstract: PATIENTS AND METHODS Tumor pathologic features and clinical characteristics were examined in 491 women with breast cancer who underwent genetic testing for BRCA mutations between 1997 and 2006.

Abstract: A retrospective review of medical records was conducted to determine clinical characteristics including ethnicity, age and clinical stage at diagnosis, age at parity, number of full-term pregnancies, use of oral contraceptives and hormone replacement therapy, and BRCA mutation status.

Abstract: Tumor pathology was reviewed to determine histologic type, tumor grade, and estrogen receptor, progesterone receptor, and HER-2/neu status.

Abstract: RESULTS Of the 491 patients with identified breast cancers, 391 patients were BRCA negative, and 86 patients were BRCA positive.

Abstract: Triple-negative breast cancer (ie, those with negative estrogen receptor, progesterone receptor, and HER-2/neu status) was diagnosed in 57.1% of the BRCA1-positive patients, 23.3% of the BRCA2-positive patients, and 13.8% of the BRCA-negative patients.

Abstract: BRCA1 mutation carriers had higher nuclear grade tumors than the other two groups (P < .001).

Abstract: Of the triple-negative cancer patients, BRCA2 mutation carriers were older when diagnosed than BRCA1 mutation carriers and noncarriers (P < .01).

Abstract: CONCLUSION These results suggest that tumors associated with BRCA1 mutations may be divided into two distinct groups, triple-negative and non-triple-negative groups.

Abstract: Future studies should seek to determine whether patients with BRCA1 mutations and triple-negative breast cancer respond to treatment better than BRCA-negative patients with similar tumor pathology.


Interferons: Success in anti-viral immunotherapy.

Abstract: The interferons (IFNs) are glycoproteins with strong antiviral activities that represent one of the first lines of host defense against invading pathogens.

Abstract: These proteins are classified into three groups, Type I, II and III IFNs, based on the structure of their receptors on the cell surface.

Abstract: Due to their ability to modulate immune responses, they have become attractive therapeutic options to control chronic virus infections.

Abstract: In combination with other drugs, Type I IFNs are considered as "standard of care" in suppressing Hepatitis C (HCV) and Hepatitis B (HBV) infections, while Type III IFN has generated encouraging results as a treatment for HCV infection in phase III clinical trials.

Abstract: However, though effective, using IFNs as a treatment is not without the need for caution.

Abstract: IFNs are such powerful cytokines that affect a wide array of cell types; as a result, patients usually experience unpleasant symptoms, with a percentage of patients suffering system wide effects.

Abstract: Thus, constant monitoring is required for patients treated with IFN in order to reach the treatment goals of suppressing virus infection and maintaining quality of life.


Genetic analysis of human obesity in an Italian sample.

Abstract: An analysis of the genetic factors in obesity has been carried out on a sample of nuclear families from Aosta (N. Italy).

Abstract: The families consisted of the parents and sibs of all elementary school children considered to be obese during a preliminary screening and a similar sample of non-obese children and their nuclear families.

Abstract: The numbers of such families were 67 and 112, respectively.

Abstract: Several tests were applied in order to examine the genetic contribution to obesity, and in particular to investigate the presence of a dominant major gene.

Abstract: Our conclusions are that genetic factors are certainly present.

Abstract: Several analyses suggest the presence of a dominant major gene with weak effect.


The non-coding RNA landscape of human hematopoiesis and leukemia

Abstract: Non-coding RNAs have emerged as crucial regulators of gene expression and cell fate decisions.

Abstract: However, their expression patterns and regulatory functions during normal and malignant human hematopoiesis are incompletely understood.

Abstract: Here we present a comprehensive resource defining the non-coding RNA landscape of the human hematopoietic system.

Abstract: Based on highly specific non-coding RNA expression portraits per blood cell population, we identify unique fingerprint non-coding RNAs-such as LINC00173 in granulocytes-and assign these to critical regulatory circuits involved in blood homeostasis.

Abstract: Following the incorporation of acute myeloid leukemia samples into the landscape, we further uncover prognostically relevant non-coding RNA stem cell signatures shared between acute myeloid leukemia blasts and healthy hematopoietic stem cells.

Abstract: Our findings highlight the importance of the non-coding transcriptome in the formation and maintenance of the human blood hierarchy.

Abstract: While micro-RNAs are known regulators of haematopoiesis and leukemogenesis, the role of long non-coding RNAs is less clear.

Abstract: Here the authors provide a non-coding RNA expression landscape of the human hematopoietic system, highlighting their role in the formation and maintenance of the human blood hierarchy.


Incidence and risk of central nervous system metastases as site of first recurrence in patients with HER2-positive breast cancer treated with adjuvant trastuzumab.

Abstract: BACKGROUND Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported.

Abstract: We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab.

Abstract: METHODS Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence.

Abstract: Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models.

Abstract: RESULTS A total of 9020 patients were included.

Abstract: The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab.

Abstract: The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02-1.78, P = 0.038) compared with control arms without trastuzumab therapy.

Abstract: The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively.

Abstract: No statistically significant differences were found based on trastuzumab schedule or median follow-up time.

Abstract: No evidence of publication bias was observed.

Abstract: CONCLUSIONS Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients.


Neutrophils in the activation and regulation of innate and adaptive immunity

Abstract: Neutrophils have long been viewed as the final effector cells of an acute inflammatory response, with a primary role in the clearance of extracellular pathogens.

Abstract: However, more recent evidence has extended the functions of these cells.

Abstract: The newly discovered repertoire of effector molecules in the neutrophil armamentarium includes a broad array of cytokines, extracellular traps and effector molecules of the humoral arm of the innate immune system.

Abstract: In addition, neutrophils are involved in the activation, regulation and effector functions of innate and adaptive immune cells.

Abstract: Accordingly, neutrophils have a crucial role in the pathogenesis of a broad range of diseases, including infections caused by intracellular pathogens, autoimmunity, chronic inflammation and cancer.


Functions of DNA methylation: islands, start sites, gene bodies and beyond

Abstract: DNA methylation is frequently described as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originally proposed in the 1970s.

Abstract: Now, thanks to improved genome-scale mapping of methylation, we can evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences.

Abstract: The emerging picture is that the function of DNA methylation seems to vary with context, and the relationship between DNA methylation and transcription is more nuanced than we realized at first.

Abstract: Improving our understanding of the functions of DNA methylation is necessary for interpreting changes in this mark that are observed in diseases such as cancer.


Metaplasia and transdifferentiation: from pure biology to the clinic

Abstract: Transformations from one tissue type to another make up a well established set of phenomena that can be explained by the principles of developmental biology.

Abstract: Although these phenomena might be rare in nature, we can now imagine the possibility of deliberately reprogramming cells from one tissue type to another by manipulating the expression of transcription factors.

Abstract: This approach could generate new therapies for many human diseases.


Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes.

Abstract: IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers.

Abstract: OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers.

Abstract: DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes.

Abstract: A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders.

Abstract: A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012.

Abstract: Cohorts were from Kaiser Permanente Northern California.

Abstract: EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent.

Abstract: MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma.

Abstract: RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer.

Abstract: Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively.

Abstract: Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26).

Abstract: Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80).

Abstract: In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71).

Abstract: Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively.

Abstract: No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose.

Abstract: CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded.

Abstract: The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality.


Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro

Abstract: We describe the derivation of pluripotent embryonic stem (ES) cells from human blastocysts.

Abstract: Two diploid ES cell lines have been cultivated in vitro for extended periods while maintaining expression of markers characteristic of pluripotent primate cells.

Abstract: Human ES cells express the transcription factor Oct-4, essential for development of pluripotential cells in the mouse.

Abstract: When grafted into SCID mice, both lines give rise to teratomas containing derivatives of all three embryonic germ layers.

Abstract: Both cell lines differentiate in vitro into extraembryonic and somatic cell lineages.

Abstract: Neural progenitor cells may be isolated from differentiating ES cell cultures and induced to form mature neurons.

Abstract: Embryonic stem cells provide a model to study early human embryology, an investigational tool for discovery of novel growth factors and medicines, and a potential source of cells for use in transplantation therapy.


Multipoint Kras oncogene mutations potentially indicate mucinous carcinoma on the entire spectrum of mucinous ovarian neoplasms

Abstract: Kras mutation is a common phenomenon in many human neoplasms.

Abstract: We aimed to assess the Kras mutational status along the histological continuum from normal ovaries to the development of benign, borderline and malignant ovarian mucinous neoplasms.

Abstract: We analyzed 41 cases of malignant, 10 cases of borderline, 7 cases of benign mucinous ovarian tumors and 7 cases of normal ovarian tissue.

Abstract: The prevalence of Kras mutations in the normal ovary was 0.00% (n=0/7), while the prevalence in benign, borderline and malignant mucinous neoplasms was 57.14% (n=4/7), 90.00% (n=9/10) and 75.61% (n=31/41), respectively.

Abstract: Multiple Kras mutations were detected in 6 cases of mucinous carcinoma, including 5 double mutations with G13D/V14I (n=1), G12V/G13S (n=1), G12D/G13S (n=3) and one triple mutation with A11V/G13N/V14I (n=1).

Abstract: We identified six cases with 3 novel Kras mutations not previously described in the COSMIC database, which included A11V (n=3) and V14I (n=2) in mucinous carcinomas, and A11T (n=1) in a mucinous borderline tumor.

Abstract: In conclusion, Kras mutation appears to be one of the imperative events in the ovarian mucinous adenoma-borderline tumor-carcinoma sequence, as increased numbers of Kras mutations have been shown to be the strongest predictor of unequivocal malignancy in ovarian mucinous neoplasms.


Identification and distinct regulation of yeast TATA box-containing genes.

Abstract: Despite being one of the first eukaryotic transcriptional regulatory elements identified, the sequence of a native TATA box and its significance remain elusive.

Abstract: Applying criteria associated with TATA boxes we queried several Saccharomyces genomes and arrived at the consensus TATA(A/T)A(A/T)(A/G).

Abstract: Approximately 20% of yeast genes contain a TATA box.

Abstract: Strikingly, TATA box-containing genes are associated with responses to stress, are highly regulated, and preferentially utilize SAGA rather than TFIID when compared to TATA-less promoters.

Abstract: Transcriptional regulation in yeast appears to be mechanistically bipolar, possibly reflecting a need to balance inducible stress-related responses with constitutive housekeeping functions.


IL6 derived from cancer-associated fibroblasts promotes chemoresistance via CXCR7 in esophageal squamous cell carcinoma

Abstract: Various factors and cellular components in the tumor microenvironment are key drivers associated with drug resistance in many cancers.

Abstract: Here, we analyzed the factors and molecular mechanisms involved in chemoresistance in patients with esophageal squamous cell carcinoma (ESCC).

Abstract: We found that interleukin 6 (IL6) derived mainly from cancer-associated fibroblasts played the most important role in chemoresistance by upregulating C-X-C motif chemokine receptor 7 (CXCR7) expression through signal transducer and activator of transcription 3/nuclear factor-κB pathway.

Abstract: CXCR7 knockdown resulted in the inhibition of IL6-induced proliferation and chemoresistance.

Abstract: In addition, CXCR7 silencing significantly decreased gene expression associated with stemness, chemoresistance and epithelial–mesenchymal transition and suppressed the proliferation ability of ESCC cells in three-dimensional culture systems and angiogenesis assay.

Abstract: In clinical samples, ESCC patients with high expression of CXCR7 and IL6 presented a significantly worse overall survival and progression-free survival upon receiving cisplatin after operation.

Abstract: These results suggest that the IL6–CXCR7 axis may provide a promising target for the treatment of ESCC.


Myelodysplastic syndromes: revisiting the role of the bone marrow microenvironment in disease pathogenesis

Abstract: Myelodysplastic syndromes are a heterogeneous group of diseases characterized by ineffective hematopoiesis and the propensity to leukemic transformation.

Abstract: Their pathogenesis is complex and likely depends on interplay between aberrant hematopoietic cells and their microenvironment.

Abstract: How niche cells play a role in disease evolution is poorly defined, but the delineation of the hematopoietic stem cell niche and the ability to interrogate its role in hematopoietic disease in animal models have furthered our insights in recent years.

Abstract: The data support a view in which the microenvironment can play an active role in the evolution of myelodysplasia and myeloproliferative disorders, thus providing further rationale to explore therapeutic targeting of mesenchymal–hematopoietic interactions in these diseases.


SMC complexes differentially compact mitotic chromosomes according to genomic context

Abstract: Structural maintenance of chromosomes (SMC) protein complexes are key determinants of chromosome conformation.

Abstract: Using Hi-C and polymer modelling, we study how cohesin and condensin, two deeply conserved SMC complexes, organize chromosomes in the budding yeast Saccharomyces cerevisiae.

Abstract: The canonical role of cohesin is to co-align sister chromatids, while condensin generally compacts mitotic chromosomes.

Abstract: We find strikingly different roles for the two complexes in budding yeast mitosis.

Abstract: First, cohesin is responsible for compacting mitotic chromosome arms, independently of sister chromatid cohesion.

Abstract: Polymer simulations demonstrate that this role can be fully accounted for through cis-looping of chromatin.

Abstract: Second, condensin is generally dispensable for compaction along chromosome arms.

Abstract: Instead, it plays a targeted role compacting the rDNA proximal regions and promoting resolution of peri-centromeric regions.

Abstract: Our results argue that the conserved mechanism of SMC complexes is to form chromatin loops and that distinct SMC-dependent looping activities are selectively deployed to appropriately compact chromosomes.


Patterns of chlamydia testing in different settings and implications for wider STI diagnosis and care: a probability sample survey of the British population

Abstract: BACKGROUND Following widespread rollout of chlamydia testing to non-specialist and community settings in the UK, many individuals receive a chlamydia test without being offered comprehensive STI and HIV testing.

Abstract: We assess sexual behaviour among testers in different settings with a view to understanding their need for other STI diagnostic services.

Abstract: METHODS A probability sample survey of the British population undertaken 2010-2012 (the third National Survey of Sexual Attitudes and Lifestyles).

Abstract: We analysed weighted data on chlamydia testing (past year), including location of most recent test, and diagnoses (past 5 years) from individuals aged 16-44 years reporting at least one sexual partner in the past year (4992 women, 3406 men).

Abstract: RESULTS Of the 26.8% (95% CI 25.4% to 28.2%) of women and 16.7% (15.5% to 18.1%) of men reporting a chlamydia test in the past year, 28.4% of women and 41.2% of men had tested in genitourinary medicine (GUM), 41.1% and 20.7% of women and men respectively tested in general practice (GP) and the remainder tested in other non-GUM settings.

Abstract: Women tested outside GUM were more likely to be older, in a relationship and to live in rural areas.

Abstract: Individuals tested outside GUM reported fewer risk behaviours; nevertheless, 11.0% (8.6% to 14.1%) of women and 6.8% (3.9% to 11.6%) of men tested in GP and 13.2% (10.2% to 16.8%) and 9.6% (6.5% to 13.8%) of women and men tested in other non-GUM settings reported 'unsafe sex', defined as two or more partners and no condom use with any partner in the past year.

Abstract: Individuals treated for chlamydia outside GUM in the past 5 years were less likely to report an HIV test in that time frame (women: 54.5% (42.7% to 65.7%) vs 74.1% (65.9% to 80.9%) in GUM; men: 23.9% (12.7% to 40.5%) vs 65.8% (56.2% to 74.3%)).

Abstract: CONCLUSIONS Most chlamydia testing occurred in non-GUM settings, among populations reporting fewer risk behaviours.

Abstract: However, there is a need to provide pathways to comprehensive STI care to the sizeable minority at higher risk.


Treatment of nonalcoholic fatty liver disease: role of AMPK.

Abstract: Nonalcoholic fatty liver disease (NAFLD) is a growing worldwide epidemic and an important risk factor for the development of insulin resistance, type 2 diabetes, nonalcoholic steatohepatitis (NASH), and hepatic cellular carcinoma (HCC).

Abstract: Despite the prevalence of NAFLD, lifestyle interventions involving exercise and weight loss are the only accepted treatments for this disease.

Abstract: Over the last decade, numerous experimental compounds have been shown to improve NAFLD in preclinical animal models, and many of these therapeutics have been shown to increase the activity of the cellular energy sensor AMP-activated protein kinase (AMPK).

Abstract: Because AMPK activity is reduced by inflammation, obesity, and diabetes, increasing AMPK activity has been viewed as a viable therapeutic strategy to improve NAFLD.

Abstract: In this review, we propose three primary mechanisms by which AMPK activation may improve NAFLD.

Abstract: In addition, we examine the mechanisms by which AMPK is activated.

Abstract: Finally, we identify 27 studies that have used AMPK activators to reduce NAFLD.

Abstract: Future considerations for studies examining the relationship between AMPK and NAFLD are highlighted.


Microenvironment-dependent growth of pre-neoplastic and malignant plasma cells in humanized mice

Abstract: Most human cancers, including myeloma, are preceded by a precursor state.

Abstract: There is an unmet need for in vivo models to study the interaction of human preneoplastic cells in the bone marrow microenvironment with non-malignant cells.

Abstract: Here, we genetically humanized mice to permit the growth of primary human preneoplastic and malignant plasma cells together with non-malignant cells in vivo.

Abstract: Growth was largely restricted to the bone marrow, mirroring the pattern in patients with myeloma.

Abstract: Xenografts captured the genomic complexity of parental tumors and revealed additional somatic changes.

Abstract: Moreover, xenografts from patients with preneoplastic gammopathy showed progressive growth, suggesting that the clinical stability of these lesions may in part be due to growth controls extrinsic to tumor cells.

Abstract: These data demonstrate a new approach to investigate the entire spectrum of human plasma cell neoplasia and illustrate the utility of humanized models for understanding the functional diversity of human tumors.


Effect of activated charcoal hemoperfusion on renal function in patients with paraquat poisoning.

Abstract: The present study retrospectively analyzed 19 patients diagnosed with paraquat (PQ) poisoning with the aim to investigate the effect of activated charcoal hemoperfusion on renal function and PQ elimination.

Abstract: The results indicated that 7 patients died and 12 survived.

Abstract: Non-oliguric renal failure occurred in all of the 7 patients who died.

Abstract: Among the 12 surviving patients, 10 had normal renal function and 2 developed non-oliguric renal failure.

Abstract: There was a linear correlation between plasma and urine paraquat concentration prior to and during activated charcoal hemoperfusion.

Abstract: The equation parameters together with the correlation coefficient on admission were as follows: Y=0.5820+1.7348X (R2=0.678; F=35.768; P<0.0001).

Abstract: The equation parameters together with the correlation coefficient were as follows during activated charcoal hemoperfusion: Y=0.6827+1.2649X (R2=0.626; F=50.308; P<0.0001).

Abstract: Therefore, it was concluded that in patients with normal renal function, the elimination kinetics of PQ by the kidneys were only associated with the plasma PQ concentration.

Abstract: Activated charcoal hemoperfusion had little effect on avoiding acute kidney injury in patients with severe PQ poisoning.


Diabetes-induced effects on cardiomyocytes in chick embryonic heart micromass and mouse embryonic D3 differentiated stem cells.

Abstract: Diabetes mellitus during pregnancy is a considerable medical challenge, since it is related to augmented morbidity and mortality concerns for both the fetus and the pregnant woman.

Abstract: Records show that the etiology of diabetic embryopathy is complicated, as many teratological factors might be involved in the mechanisms of diabetes mellitus-induced congenital malformation.

Abstract: In this study, the potential cardiotoxic effect of hyperglycemia with hyperketonemia was investigated by using two in vitro models; primary chick embryonic cardiomyocytes and stem cell derived cardiomyocytes, where adverse effects were recorded in both systems.

Abstract: The cells were evaluated by changes in beating activity, cell activity, protein content, ROS production, DNA damage and differentiating stem cell migration.

Abstract: The diabetic formulae used produced an increase in DNA damage and a decline in cell migration in mouse embryonic stem cells.

Abstract: These results provide an additional insight into adverse effects during gestational diabetes mellitus and a recommendation for expectant mothers and maternity staff to monitor glycaemic levels months ahead of conception.

Abstract: This study also supports the recommendation of using antioxidants during pregnancy to prevent DNA damage by the production of ROS, which might result in heart defects as well as other developmental anomalies.


Motion magnification

Abstract: We present motion magnification, a technique that acts like a microscope for visual motion.

Abstract: It can amplify subtle motions in a video sequence, allowing for visualization of deformations that would otherwise be invisible.

Abstract: To achieve motion magnification, we need to accurately measure visual motions, and group the pixels to be modified.

Abstract: After an initial image registration step, we measure motion by a robust analysis of feature point trajectories, and segment pixels based on similarity of position, color, and motion.

Abstract: A novel measure of motion similarity groups even very small motions according to correlation over time, which often relates to physical cause.

Abstract: An outlier mask marks observations not explained by our layered motion model, and those pixels are simply reproduced on the output from the original registered observations.

Abstract: The motion of any selected layer may be magnified by a user-specified amount; texture synthesis fills-in unseen "holes" revealed by the amplified motions.

Abstract: The resulting motion-magnified images can reveal or emphasize small motions in the original sequence, as we demonstrate with deformations in load-bearing structures, subtle motions or balancing corrections of people, and "rigid" structures bending under hand pressure.


Human TRPML1 channel structures in open and closed conformations

Abstract: Transient receptor potential mucolipin 1 (TRPML1) is a Ca2+-releasing cation channel that mediates the calcium signalling and homeostasis of lysosomes.

Abstract: Mutations in TRPML1 lead to mucolipidosis type IV, a severe lysosomal storage disorder.

Abstract: Here we report two electron cryo-microscopy structures of full-length human TRPML1: a 3.72-Å apo structure at pH 7.0 in the closed state, and a 3.49-Å agonist-bound structure at pH 6.0 in an open state.

Abstract: Several aromatic and hydrophobic residues in pore helix 1, helices S5 and S6, and helix S6 of a neighbouring subunit, form a hydrophobic cavity to house the agonist, suggesting a distinct agonist-binding site from that found in TRPV1, a TRP channel from a different subfamily.

Abstract: The opening of TRPML1 is associated with distinct dilations of its lower gate together with a slight structural movement of pore helix 1.

Abstract: Our work reveals the regulatory mechanism of TRPML channels, facilitates better understanding of TRP channel activation, and provides insights into the molecular basis of mucolipidosis type IV pathogenesis.


Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration

Abstract: Data visualization is an essential component of genomic data analysis.

Abstract: However, the size and diversity of the data sets produced by today's sequencing and array-based profiling methods present major challenges to visualization tools.

Abstract: The Integrative Genomics Viewer (IGV) is a high-performance viewer that efficiently handles large heterogeneous data sets, while providing a smooth and intuitive user experience at all levels of genome resolution.

Abstract: A key characteristic of IGV is its focus on the integrative nature of genomic studies, with support for both array-based and next-generation sequencing data, and the integration of clinical and phenotypic data.

Abstract: Although IGV is often used to view genomic data from public sources, its primary emphasis is to support researchers who wish to visualize and explore their own data sets or those from colleagues.

Abstract: To that end, IGV supports flexible loading of local and remote data sets, and is optimized to provide high-performance data visualization and exploration on standard desktop systems.

Abstract: IGV is freely available for download from http://www.broadinstitute.org/igv, under a GNU LGPL open-source license.


Can genome engineering be used to target cancer-associated enhancers?

Abstract: Transcriptional misregulation is involved in the development of many diseases, especially neoplastic transformation.

Abstract: Distal regulatory elements, such as enhancers, play a major role in specifying cell-specific transcription patterns in both normal and diseased tissues, suggesting that enhancers may be prime targets for therapeutic intervention.

Abstract: By focusing on modulating gene regulation mediated by cell type-specific enhancers, there is hope that normal epigenetic patterning in an affected tissue could be restored with fewer side effects than observed with treatments employing relatively nonspecific inhibitors such as epigenetic drugs.

Abstract: New methods employing genomic nucleases and site-specific epigenetic regulators targeted to specific genomic regions, using either artificial DNA-binding proteins or RNA-DNA interactions, may allow precise genome engineering at enhancers.

Abstract: However, this field is still in its infancy and further refinements that increase specificity and efficiency are clearly required.


Long‐Term Follow‐up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia

Abstract: Background CD19‐specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B‐cell acute lymphoblastic leukemia (ALL) and long‐term remissions in a subgroup of patients.

Abstract: Methods We conducted a phase 1 trial involving adults with relapsed B‐cell ALL who received an infusion of autologous T cells expressing the 19‐28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC).

Abstract: Safety and long‐term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics.

Abstract: Results A total of 53 adults received 19‐28z CAR T cells that were manufactured at MSKCC.

Abstract: After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died.

Abstract: Complete remission was observed in 83% of the patients.

Abstract: At a median follow‐up of 29 months (range, 1 to 65), the median event‐free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4).

Abstract: Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event‐free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached).

Abstract: Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long‐term survival than did patients with a low disease burden.

Abstract: Conclusions In the entire cohort, the median overall survival was 12.9 months.

Abstract: Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19‐28z CAR T‐cell infusion than was observed among patients with a higher disease burden.

Abstract: (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069.)


Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin

Abstract: Bone regeneration relies on the activation of skeletal stem cells (SSCs) that still remain poorly characterized.

Abstract: Here, we show that periosteum contains SSCs with high bone regenerative potential compared to bone marrow stromal cells/skeletal stem cells (BMSCs) in mice.

Abstract: Although periosteal cells (PCs) and BMSCs are derived from a common embryonic mesenchymal lineage, postnatally PCs exhibit greater clonogenicity, growth and differentiation capacity than BMSCs.

Abstract: During bone repair, PCs can efficiently contribute to cartilage and bone, and integrate long-term after transplantation.

Abstract: Molecular profiling uncovers genes encoding Periostin and other extracellular matrix molecules associated with the enhanced response to injury of PCs.

Abstract: Periostin gene deletion impairs PC functions and fracture consolidation.

Abstract: Periostin-deficient periosteum cannot reconstitute a pool of PCs after injury demonstrating the presence of SSCs within periosteum and the requirement of Periostin in maintaining this pool.

Abstract: Overall our results highlight the importance of analyzing periosteum and PCs to understand bone phenotypes.


Metabolism strikes back: metabolic flux regulates cell signaling.

Abstract: Mammalian cells depend on growth factor signaling to take up nutrients; however, coordination of glucose and glutamine uptake has been a mystery.

Abstract: In this issue of Genes & Development, Wellen and colleagues (pp.

Abstract: 2784-2799) show that glucose flux through the hexosamine biosynthesis pathway regulates growth factor receptor glycosylation and enables glutamine consumption.

Abstract: This mechanism ensures that cells do not engage in anabolic metabolism when nutrients are limiting, and highlights how substrate availability for protein modifications can modulate cell signaling.


Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma.

Abstract: IMPORTANCE The programmed death 1 (PD-1) pathway limits immune responses to melanoma and can be blocked with the humanized anti-PD-1 monoclonal antibody pembrolizumab.

Abstract: OBJECTIVE To characterize the association of pembrolizumab with tumor response and overall survival among patients with advanced melanoma.

Abstract: DESIGN, SETTINGS, AND PARTICIPANTS Open-label, multicohort, phase 1b clinical trials (enrollment, December 2011-September 2013).

Abstract: Median duration of follow-up was 21 months.

Abstract: The study was performed in academic medical centers in Australia, Canada, France, and the United States.

Abstract: Eligible patients were aged 18 years and older and had advanced or metastatic melanoma.

Abstract: Data were pooled from 655 enrolled patients (135 from a nonrandomized cohort [n = 87 ipilimumab naive; n = 48 ipilimumab treated] and 520 from randomized cohorts [n = 226 ipilimumab naive; n = 294 ipilimumab treated]).

Abstract: Cutoff dates were April 18, 2014, for safety analyses and October 18, 2014, for efficacy analyses.

Abstract: EXPOSURES Pembrolizumab 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks continued until disease progression, intolerable toxicity, or investigator decision.

Abstract: MAIN OUTCOMES AND MEASURES The primary end point was confirmed objective response rate (best overall response of complete response or partial response) in patients with measurable disease at baseline per independent central review.

Abstract: Secondary end points included toxicity, duration of response, progression-free survival, and overall survival.

Abstract: RESULTS Among the 655 patients (median [range] age, 61 [18-94] years; 405 [62%] men), 581 had measurable disease at baseline.

Abstract: An objective response was reported in 194 of 581 patients (33% [95% CI, 30%-37%]) and in 60 of 133 treatment-naive patients (45% [95% CI, 36% to 54%]).

Abstract: Overall, 74% (152/205) of responses were ongoing at the time of data cutoff; 44% (90/205) of patients had response duration for at least 1 year and 79% (162/205) had response duration for at least 6 months.

Abstract: Twelve-month progression-free survival rates were 35% (95% CI, 31%-39%) in the total population and 52% (95% CI, 43%-60%) among treatment-naive patients.

Abstract: Median overall survival in the total population was 23 months (95% CI, 20-29) with a 12-month survival rate of 66% (95% CI, 62%-69%) and a 24-month survival rate of 49% (95% CI, 44%-53%).

Abstract: In treatment-naive patients, median overall survival was 31 months (95% CI, 24 to not reached) with a 12-month survival rate of 73% (95% CI, 65%-79%) and a 24-month survival rate of 60% (95% CI, 51%-68%).

Abstract: Ninety-two of 655 patients (14%) experienced at least 1 treatment-related grade 3 or 4 adverse event (AE) and 27 of 655 (4%) patients discontinued treatment because of a treatment-related AE.

Abstract: Treatment-related serious AEs were reported in 59 patients (9%).

Abstract: There were no drug-related deaths.

Abstract: CONCLUSIONS AND RELEVANCE Among patients with advanced melanoma, pembrolizumab administration was associated with an overall objective response rate of 33%, 12-month progression-free survival rate of 35%, and median overall survival of 23 months; grade 3 or 4 treatment-related AEs occurred in 14%.

Abstract: TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01295827.


Inflammatory signaling in human Tuberculosis granulomas is spatially organized

Abstract: Granulomas are the pathological hallmark of tuberculosis (TB).

Abstract: However, their function and mechanisms of formation remain poorly understood.

Abstract: To understand the role of granulomas in TB, we analyzed the proteomes of granulomas from subjects with tuberculosis in an unbiased manner.

Abstract: Using laser-capture microdissection, mass spectrometry and confocal microscopy, we generated detailed molecular maps of human granulomas.

Abstract: We found that the centers of granulomas have a pro-inflammatory environment that is characterized by the presence of antimicrobial peptides, reactive oxygen species and pro-inflammatory eicosanoids.

Abstract: Conversely, the tissue surrounding the caseum has a comparatively anti-inflammatory signature.

Abstract: These findings are consistent across a set of six human subjects and in rabbits.

Abstract: Although the balance between systemic pro- and anti-inflammatory signals is crucial to TB disease outcome, here we find that these signals are physically segregated within each granuloma.

Abstract: From the protein and lipid snapshots of human and rabbit lesions analyzed here, we hypothesize that the pathologic response to TB is shaped by the precise anatomical localization of these inflammatory pathways during the development of the granuloma.


Suppression of interferon-mediated anti-HBV response by single CpG methylation in the 5′-UTR of TRIM22

Abstract: Objective Interferons (IFNs) mediate direct antiviral activity.

Abstract: They play a crucial role in the early host immune response against viral infections.

Abstract: However, IFN therapy for HBV infection is less effective than for other viral infections.

Abstract: Design We explored the cellular targets of HBV in response to IFNs using proteome-wide screening.

Abstract: Results Using LC-MS/MS, we identified proteins downregulated and upregulated by IFN treatment in HBV X protein (HBx)-stable and control cells.

Abstract: We found several IFN-stimulated genes downregulated by HBx, including TRIM22, which is known as an antiretroviral protein.

Abstract: We demonstrated that HBx suppresses the transcription of TRIM22 through a single CpG methylation in its 5′-UTR, which further reduces the IFN regulatory factor-1 binding affinity, thereby suppressing the IFN-stimulated induction of TRIM22.

Abstract: Conclusions We verified our findings using a mouse model, primary human hepatocytes and human liver tissues.

Abstract: Our data elucidate a mechanism by which HBV evades the host innate immune system.


Developmental Analysis of Bone Marrow Neutrophils Reveals Populations Specialized in Expansion, Trafficking, and Effector Functions

Abstract: Summary Neutrophils are specialized innate cells that require constant replenishment from proliferative bone marrow (BM) precursors as a result of their short half‐life.

Abstract: Although it is established that neutrophils are derived from the granulocyte‐macrophage progenitor (GMP), the differentiation pathways from GMP to functional mature neutrophils are poorly defined.

Abstract: Using mass cytometry (CyTOF) and cell‐cycle‐based analysis, we identified three neutrophil subsets within the BM: a committed proliferative neutrophil precursor (preNeu) which differentiates into non‐proliferating immature neutrophils and mature neutrophils.

Abstract: Transcriptomic profiling and functional analysis revealed that preNeu require the C/EBP&egr; transcription factor for their generation from the GMP, and their proliferative program is substituted by a gain of migratory and effector function as they mature.

Abstract: preNeus expand under microbial and tumoral stress, and immature neutrophils are recruited to the periphery of tumor‐bearing mice.

Abstract: In summary, our study identifies specialized BM granulocytic populations that ensure supply under homeostasis and stress responses.

Abstract: Graphical Abstract Figure.

Abstract: No Caption available.

Abstract: HighlightsProliferation activity identifies committed neutrophil precursor in mice and humansNeutrophil subsets possess distinct transcriptomic and functional signaturesDefect in neutrophil development leads to impaired neutrophil‐mediated responsesIncreased circulating immature neutrophils are associated with cancer progression &NA; The neutrophil differentiation pathway is poorly defined.

Abstract: Evrard et.

Abstract: al. demonstrate a workflow of characterizing bone marrow neutrophil subsets on the basis of their proliferative capacity and molecular signatures and thereby define the developmental trajectory and functional properties of neutrophils.


TAK1-mediated autophagy and fatty acid oxidation prevent hepatosteatosis and tumorigenesis.

Abstract: The MAP kinase kinase kinase TGFβ-activated kinase 1 (TAK1) is activated by TLRs, IL-1, TNF, and TGFβ and in turn activates IKK-NF-κB and JNK, which regulate cell survival, growth, tumorigenesis, and metabolism.

Abstract: TAK1 signaling also upregulates AMPK activity and autophagy.

Abstract: Here, we investigated TAK1-dependent regulation of autophagy, lipid metabolism, and tumorigenesis in the liver.

Abstract: Fasted mice with hepatocyte-specific deletion of Tak1 exhibited severe hepatosteatosis with increased mTORC1 activity and suppression of autophagy compared with their WT counterparts.

Abstract: TAK1-deficient hepatocytes exhibited suppressed AMPK activity and autophagy in response to starvation or metformin treatment; however, ectopic activation of AMPK restored autophagy in these cells.

Abstract: Peroxisome proliferator-activated receptor α (PPARα) target genes and β-oxidation, which regulate hepatic lipid degradation, were also suppressed in hepatocytes lacking TAK1.

Abstract: Due to suppression of autophagy and β-oxidation, a high-fat diet challenge aggravated steatohepatitis in mice with hepatocyte-specific deletion of Tak1.

Abstract: Notably, inhibition of mTORC1 restored autophagy and PPARα target gene expression in TAK1-deficient livers, indicating that TAK1 acts upstream of mTORC1.

Abstract: mTORC1 inhibition also suppressed spontaneous liver fibrosis and hepatocarcinogenesis in animals with hepatocyte-specific deletion of Tak1.

Abstract: These data indicate that TAK1 regulates hepatic lipid metabolism and tumorigenesis via the AMPK/mTORC1 axis, affecting both autophagy and PPARα activity.


Formins at the Junction.

Abstract: The actin cytoskeleton and adhesion junctions are physically and functionally coupled at the cell-cell interface between epithelial cells.

Abstract: The actin regulatory complex Arp2/3 has an established role in the turnover of junctional actin; however, the role of formins, the largest group of actin regulators, is less clear.

Abstract: Formins dynamically shape the actin cytoskeleton and have various functions within cells.

Abstract: In this review we describe recent progress on how formins regulate actin dynamics at cell-cell contacts and highlight formin functions during polarized protein traffic necessary for epithelialization.


CRISPR adaptation biases explain preference for acquisition of foreign DNA

Abstract: CRISPR-Cas (clustered, regularly interspaced short palindromic repeats coupled with CRISPR-associated proteins) is a bacterial immunity system that protects against invading phages or plasmids.

Abstract: In the process of CRISPR adaptation, short pieces of DNA ('spacers') are acquired from foreign elements and integrated into the CRISPR array.

Abstract: So far, it has remained a mystery how spacers are preferentially acquired from the foreign DNA while the self chromosome is avoided.

Abstract: Here we show that spacer acquisition is replication-dependent, and that DNA breaks formed at stalled replication forks promote spacer acquisition.

Abstract: Chromosomal hotspots of spacer acquisition were confined by Chi sites, which are sequence octamers highly enriched on the bacterial chromosome, suggesting that these sites limit spacer acquisition from self DNA.

Abstract: We further show that the avoidance of self is mediated by the RecBCD double-stranded DNA break repair complex.

Abstract: Our results suggest that, in Escherichia coli, acquisition of new spacers largely depends on RecBCD-mediated processing of double-stranded DNA breaks occurring primarily at replication forks, and that the preference for foreign DNA is achieved through the higher density of Chi sites on the self chromosome, in combination with the higher number of forks on the foreign DNA.

Abstract: This model explains the strong preference to acquire spacers both from high copy plasmids and from phages.


High-resolution mapping of open chromatin in the rice genome.

Abstract: Gene expression is controlled by the complex interaction of transcription factors binding to promoters and other regulatory DNA elements.

Abstract: One common characteristic of the genomic regions associated with regulatory proteins is a pronounced sensitivity to DNase I digestion.

Abstract: We generated genome-wide high-resolution maps of DNase I hypersensitive (DH) sites from both seedling and callus tissues of rice (Oryza sativa).

Abstract: Approximately 25% of the DH sites from both tissues were found in putative promoters, indicating that the vast majority of the gene regulatory elements in rice are not located in promoter regions.

Abstract: We found 58% more DH sites in the callus than in the seedling.

Abstract: For DH sites detected in both the seedling and callus, 31% displayed significantly different levels of DNase I sensitivity within the two tissues.

Abstract: Genes that are differentially expressed in the seedling and callus were frequently associated with DH sites in both tissues.

Abstract: The DNA sequences contained within the DH sites were hypomethylated, consistent with what is known about active gene regulatory elements.

Abstract: Interestingly, tissue-specific DH sites located in the promoters showed a higher level of DNA methylation than the average DNA methylation level of all the DH sites located in the promoters.

Abstract: A distinct elevation of H3K27me3 was associated with intergenic DH sites.

Abstract: These results suggest that epigenetic modifications play a role in the dynamic changes of the numbers and DNase I sensitivity of DH sites during development.


Prospective study of body fat distribution and the risk of endometrial cancer.

Abstract: BACKGROUND Epidemiologic studies have found that overall obesity is positively related to endometrial cancer (EC) risk.

Abstract: However, data assessing the association between body fat distribution and risk of EC are still limited.

Abstract: METHODS We followed 51,948 women who first reported waist circumference (WC) and hip circumference in 1986 in the Nurses' Health Study.

Abstract: Waist-to-hip ratio (WHR) was calculated.

Abstract: RESULTS During 24 years of follow-up, 449 incident invasive EC cases were diagnosed.

Abstract: In a multivariate analysis without adjusting for body mass index (BMI), the relative risks (RRs) for EC comparing extreme categories were 2.44 (95% confidence interval [CI] 1.72-3.45) for WC and 1.69 (95% CI=1.20-2.40) for WHR.

Abstract: However, after adjustment of BMI, those positive associations were substantially attenuated and no longer significant; RR=1.08 (95% CI=0.69-1.67) for WC and 1.15 (95% CI=0.81-1.64) for WHR, respectively.

Abstract: CONCLUSION In our prospective cohort study, we found no independent association between body fat distribution and the risk of EC after adjustment for BMI.


Breast cancer clusters in the northeast United States: a geographic analysis.

Abstract: High breast cancer mortality rates have been reported in the northeastern part of the United States, with recent attention focused on Long Island, New York.

Abstract: In this study, the authors investigate whether the high breast cancer mortality is evenly spread over the Northeast, in the sense that any observed clusters of deaths can be explained by chance alone, or whether there are clusters of statistical significance.

Abstract: Demographic data and age-specific breast cancer mortality rates for women were obtained for all 244 counties in 11 northeastern states and for the District of Columbia for 1988-1992.

Abstract: A recently developed spatial scan statistic is used, which searches for clusters of cases without specifying their size or location ahead of time, and which tests for their statistical significance while adjusting for the multiple testing inherent in such a procedure.

Abstract: The basic analysis is adjusted for age, with further analyses examining how the results are affected by incorporating race, urbanicity, and parity as confounding variables.

Abstract: There is a statistically significant and geographically broad cluster of breast cancer deaths in the New York City-Philadelphia, Pennsylvania, metropolitan area (p = 0.0001), which has a 7.4% higher mortality rate than the rest of the Northeast.

Abstract: The cluster remains significant when race, urbanicity, and/or parity are included as confounding variables.

Abstract: Four smaller subclusters within this area are also significant on their own strength: Philadelphia with suburbs (p = 0.0001), Long Island (p = 0.0001), central New Jersey (p = 0.0001), and northeastern New Jersey (p = 0.0001).

Abstract: The elevated breast cancer mortality on Long Island might be viewed less as a unique local phenomenon and more as part of a more general situation involving large parts of the New York City-Philadelphia metropolitan area.

Abstract: The several known and hypothesized risk factors for which we could not adjust and that may explain the detected cluster are most notably age at first birth, age at menarche, age at menopause, breastfeeding, genetic mutations, and environmental factors.


CD200R/CD200 Inhibits Osteoclastogenesis: New Mechanism of Osteoclast Control by Mesenchymal Stem Cells in Human

Abstract: Bone homeostasis is maintained by the balance between bone-forming osteoblasts and bone-degrading osteoclasts.

Abstract: Osteoblasts have a mesenchymal origin whereas osteoclasts belong to the myeloid lineage.

Abstract: Osteoclast and osteoblast communication occurs through soluble factors secretion, cell-bone interaction and cell-cell contact, which modulate their activities.

Abstract: CD200 is an immunoglobulin superfamilly member expressed on various types of cells including mesenchymal stem cells (MSCs).

Abstract: CD200 receptor (CD200R) is expressed on myeloid cells such as monocytes/macrophages.

Abstract: We assume that CD200 could be a new molecule involved in the control of osteoclastogenesis and could play a role in MSC-osteoclast communication in humans.

Abstract: In this study, we demonstrated that soluble CD200 inhibited the differentiation of osteoclast precursors as well as their maturation in bone-resorbing cells in vitro.

Abstract: Soluble CD200 did not modify the monocyte phenotype but inhibited the receptor activator of nuclear factor kappa-B ligand (RANKL) signaling pathway as well as the gene expression of osteoclast markers such as osteoclast-associated receptor (OSCAR) and nuclear factor of activated T cells cytoplasmic 1 (NFATc1).

Abstract: Moreover, MSCs inhibited osteoclast formation, which depended on cell-cell contact and was associated with CD200 expression on the MSC surface.

Abstract: Our results clearly demonstrate that MSCs, through the expression of CD200, play a major role in the regulation of bone resorption and bone physiology and that the CD200-CD200R couple could be a new target to control bone diseases.


Tumor-specific Th17-polarized cells eradicate large established melanoma.

Abstract: CD4+ T cells can differentiate into multiple effector subsets, but the potential roles of these subsets in anti-tumor immunity have not been fully explored.

Abstract: Seeking to study the impact of CD4+ T cell polarization on tumor rejection in a model mimicking human disease, we generated a new MHC class II-restricted, T-cell receptor (TCR) transgenic mouse model in which CD4+ T cells recognize a novel epitope in tyrosinase-related protein 1 (TRP-1), an antigen expressed by normal melanocytes and B16 murine melanoma.

Abstract: Cells could be robustly polarized into Th0, Th1, and Th17 subtypes in vitro, as evidenced by cytokine, chemokine, and adhesion molecule profiles and by surface markers, suggesting the potential for differential effector function in vivo.

Abstract: Contrary to the current view that Th1 cells are most important in tumor rejection, we found that Th17-polarized cells better mediated destruction of advanced B16 melanoma.

Abstract: Their therapeutic effect was critically dependent on interferon-gamma (IFN-gamma) production, whereas depletion of interleukin (IL)-17A and IL-23 had little impact.

Abstract: Taken together, these data indicate that the appropriate in vitro polarization of effector CD4+ T cells is decisive for successful tumor eradication.

Abstract: This principle should be considered in designing clinical trials involving adoptive transfer-based immunotherapy of human malignancies.


Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study.

Abstract: BACKGROUND In the assessment of severity in community acquired pneumonia (CAP), the modified British Thoracic Society (mBTS) rule identifies patients with severe pneumonia but not patients who might be suitable for home management.

Abstract: A multicentre study was conducted to derive and validate a practical severity assessment model for stratifying adults hospitalised with CAP into different management groups.

Abstract: METHODS Data from three prospective studies of CAP conducted in the UK, New Zealand, and the Netherlands were combined.

Abstract: A derivation cohort comprising 80% of the data was used to develop the model.

Abstract: Prognostic variables were identified using multiple logistic regression with 30 day mortality as the outcome measure.

Abstract: The final model was tested against the validation cohort.

Abstract: RESULTS 1068 patients were studied (mean age 64 years, 51.5% male, 30 day mortality 9%).

Abstract: Age >/=65 years (OR 3.5, 95% CI 1.6 to 8.0) and albumin <30 g/dl (OR 4.7, 95% CI 2.5 to 8.7) were independently associated with mortality over and above the mBTS rule (OR 5.2, 95% CI 2.7 to 10).

Abstract: A six point score, one point for each of Confusion, Urea >7 mmol/l, Respiratory rate >/=30/min, low systolic(<90 mm Hg) or diastolic (</=60 mm Hg) Blood pressure), age >/=65 years (CURB-65 score) based on information available at initial hospital assessment, enabled patients to be stratified according to increasing risk of mortality: score 0, 0.7%; score 1, 3.2%; score 2, 3%; score 3, 17%; score 4, 41.5% and score 5, 57%.

Abstract: The validation cohort confirmed a similar pattern.

Abstract: CONCLUSIONS A simple six point score based on confusion, urea, respiratory rate, blood pressure, and age can be used to stratify patients with CAP into different management groups.


Mitochondrial iron chelation ameliorates cigarette-smoke induced bronchitis and emphysema in mice

Abstract: Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants.

Abstract: We have previously identified iron-responsive element-binding protein 2 (IRP2) as an important COPD susceptibility gene and have shown that IRP2 protein is increased in the lungs of individuals with COPD.

Abstract: Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD.

Abstract: By integrating RNA immunoprecipitation followed by sequencing (RIP-seq), RNA sequencing (RNA-seq), and gene expression and functional enrichment clustering analysis, we identified Irp2 as a regulator of mitochondrial function in the lungs of mice.

Abstract: Irp2 increased mitochondrial iron loading and levels of cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD.

Abstract: Frataxin-deficient mice, which had higher mitochondrial iron loading, showed impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas mice deficient in the synthesis of cytochrome c oxidase, which have reduced COX, were protected from CS-induced pulmonary inflammation and impairment of MCC.

Abstract: Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD.

Abstract: Mitochondrial iron chelation also alleviated CS-induced impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.


Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.

Abstract: Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression.

Abstract: Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects.

Abstract: Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy.

Abstract: We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors.

Abstract: CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors.

Abstract: Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors.

Abstract: Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.


Phenotypic deficits in the HIV-1 envelope are associated with the maturation of a V2-directed broadly neutralizing antibody lineage

Abstract: Broadly neutralizing antibodies (bnAbs) to HIV-1 can evolve after years of an iterative process of virus escape and antibody adaptation that HIV-1 vaccine design seeks to mimic.

Abstract: To enable this, properties that render HIV-1 envelopes (Env) capable of eliciting bnAb responses need to be defined.

Abstract: Here, we followed the evolution of the V2 apex directed bnAb lineage VRC26 in the HIV-1 subtype C superinfected donor CAP256 to investigate the phenotypic changes of the virus populations circulating before and during the early phases of bnAb induction.

Abstract: Longitudinal viruses that evolved from the VRC26-resistant primary infecting (PI) virus, the VRC26-sensitive superinfecting (SU) virus and ensuing PI-SU recombinants revealed substantial phenotypic changes in Env, with a switch in Env properties coinciding with early resistance to VRC26.

Abstract: Decreased sensitivity of SU-like viruses to VRC26 was linked with reduced infectivity, altered entry kinetics and lower sensitivity to neutralization after CD4 attachment.

Abstract: VRC26 maintained neutralization activity against cell-associated CAP256 virus, indicating that escape through the cell-cell transmission route is not a dominant escape pathway.

Abstract: Reduced fitness of the early escape variants and sustained sensitivity in cell-cell transmission are both features that limit virus replication, thereby impeding rapid escape.

Abstract: This supports a scenario where VRC26 allowed only partial viral escape for a prolonged period, possibly increasing the time window for bnAb maturation.

Abstract: Collectively, our data highlight the phenotypic plasticity of the HIV-1 Env in evading bnAb pressure and the need to consider phenotypic traits when selecting and designing Env immunogens.

Abstract: Combinations of Env variants with differential phenotypic patterns and bnAb sensitivity, as we describe here for CAP256, may maximize the potential for inducing bnAb responses by vaccination.


High somatic mutation and neoantigen burden are correlated with decreased progression-free survival in multiple myeloma

Abstract: Tumor-specific mutations can result in immunogenic neoantigens, both of which have been correlated with responsiveness to immune checkpoint inhibitors in highly mutagenic cancers.

Abstract: However, early results of single-agent checkpoint inhibitors in multiple myeloma (MM) have been underwhelming.

Abstract: Therefore, we sought to understand the relationship between mutation and neoantigen landscape of MM patients and responsiveness to therapies.

Abstract: Somatic mutation burden, neoantigen load, and response to therapy were determined using interim data from the MMRF CoMMpass study (NCT01454297) on 664 MM patients.

Abstract: In this population, the mean somatic and missense mutation loads were 405.84(s=608.55) and 63.90(s=95.88) mutations per patient, respectively.

Abstract: There was a positive linear relationship between mutation and neoantigen burdens (R2=0.862).

Abstract: The average predicted neoantigen load was 23.52(s=52.14) neoantigens with an average of 9.40(s=26.97) expressed neoantigens.

Abstract: Survival analysis revealed significantly shorter progression-free survival (PFS) in patients with greater than average somatic missense mutation load (N=163, 0.493 vs 0.726 2-year PFS, P=0.0023) and predicted expressed neoantigen load (N=214, 0.555 vs 0.729 2-year PFS, P=0.0028).

Abstract: This pattern is maintained when stratified by disease stage and cytogenetic abnormalities.

Abstract: Therefore, high mutation and neoantigen load are clinically relevant risk factors that negatively impact survival of MM patients under current standards of care.


Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010

Abstract: Importance Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics.

Abstract: These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making.

Abstract: Objectives To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk.

Abstract: Design and Setting Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017.

Abstract: Exposures Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near–regulatory deadline approval, and regulatory review time.

Abstract: Main Outcomes and Measures A composite of (1) withdrawals due to safety concerns, (2) FDA issuance of incremental boxed warnings added in the postmarket period, and (3) FDA issuance of safety communications.

Abstract: Results From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics).

Abstract: There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics.

Abstract: The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%).

Abstract: In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P < .001), those receiving accelerated approval (IRR = 2.20; 95% CI, 1.15-4.21; P = .02), and those with near–regulatory deadline approval (IRR = 1.90; 95% CI, 1.19-3.05; P = .008); events were statistically significantly less frequent among those with regulatory review times less than 200 days (IRR = 0.46; 95% CI, 0.24-0.87; P = .02).

Abstract: Conclusions and Relevance Among 222 novel therapeutics approved by the FDA from 2001 through 2010, 32% were affected by a postmarket safety event.

Abstract: Biologics, psychiatric therapeutics, and accelerated and near–regulatory deadline approval were statistically significantly associated with higher rates of events, highlighting the need for continuous monitoring of the safety of novel therapeutics throughout their life cycle.


Who is where at risk for Chronic Obstructive Pulmonary Disease? A spatial epidemiological analysis of health insurance claims for COPD in Northeastern Germany

Abstract: BACKGROUND Chronic obstructive pulmonary disease (COPD) has a high prevalence rate in Germany and a further increase is expected within the next years.

Abstract: Although risk factors on an individual level are widely understood, only little is known about the spatial heterogeneity and population-based risk factors of COPD.

Abstract: Background knowledge about broader, population-based processes could help to plan the future provision of healthcare and prevention strategies more aligned to the expected demand.

Abstract: The aim of this study is to analyze how the prevalence of COPD varies across northeastern Germany on the smallest spatial-scale possible and to identify the location-specific population-based risk factors using health insurance claims of the AOK Nordost.

Abstract: METHODS To visualize the spatial distribution of COPD prevalence at the level of municipalities and urban districts, we used the conditional autoregressive Besag-York-Mollié (BYM) model.

Abstract: Geographically weighted regression modelling (GWR) was applied to analyze the location-specific ecological risk factors for COPD.

Abstract: RESULTS The sex- and age-adjusted prevalence of COPD was 6.5% in 2012 and varied widely across northeastern Germany.

Abstract: Population-based risk factors consist of the proportions of insurants aged 65 and older, insurants with migration background, household size and area deprivation.

Abstract: The results of the GWR model revealed that the population at risk for COPD varies considerably across northeastern Germany.

Abstract: CONCLUSION Area deprivation has a direct and an indirect influence on the prevalence of COPD.

Abstract: Persons ageing in socially disadvantaged areas have a higher chance of developing COPD, even when they are not necessarily directly affected by deprivation on an individual level.

Abstract: This underlines the importance of considering the impact of area deprivation on health for planning of healthcare.

Abstract: Additionally, our results reveal that in some parts of the study area, insurants with migration background and persons living in multi-persons households are at elevated risk of COPD.