Showing papers by "Rutgers University published in 2015"
TL;DR: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, and has reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-generation sequencing, deep exome sequencing, and dense microarray genotyping.
Abstract: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
12,661 citations
TL;DR: In this article, the authors present the presentation, nomenclature, and methodology associated with the application of physisorption for surface area assessment and pore size analysis.
Abstract: Gas adsorption is an important tool for the characterisation of porous solids and fine powders. Major advances in recent years have made it necessary to update the 1985 IUPAC manual on Reporting Physisorption Data for Gas/Solid Systems. The aims of the present document are to clarify and standardise the presentation, nomenclature and methodology associated with the application of physisorption for surface area assessment and pore size analysis and to draw attention to remaining problems in the interpretation of physisorption data.
11,019 citations
National Taiwan University1, University of Porto2, University of Tokyo3, Rockefeller University4, Memorial Sloan Kettering Cancer Center5, Karolinska Institutet6, Linköping University7, Lawrence Berkeley National Laboratory8, Cornell University9, Alberta Children's Hospital10, Columbia University11, University of Oslo12, University of Nebraska Medical Center13, University of Hamburg14, University of Pennsylvania15, Princeton University16, Rutgers University17, Fred Hutchinson Cancer Research Center18, Carlos III Health Institute19
TL;DR: It is demonstrated that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells.
Abstract: Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.
3,399 citations
Mayo Clinic1, Cornell University2, Memorial Sloan Kettering Cancer Center3, Johns Hopkins University4, University of Utah5, Oregon Health & Science University6, Rutgers University7, University of Pennsylvania8, Fox Chase Cancer Center9, Harvard University10, Bristol-Myers Squibb11, University of California, Los Angeles12
TL;DR: Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma.
Abstract: BACKGROUND Preclinical studies suggest that Reed–Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin’s lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1–blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin’s lymphoma. METHODS In this ongoing study, 23 patients with relapsed or refractory Hodgkin’s lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression. RESULTS Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed–Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling. CONCLUSIONS Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin’s lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.)
3,008 citations
TL;DR: A solution-based hot-casting technique is demonstrated to grow continuous, pinhole-free thin films of organometallic perovskites with millimeter-scale crystalline grains that are applicable to several other material systems plagued by polydispersity, defects, and grain boundary recombination in solution-processed thin films.
Abstract: State-of-the-art photovoltaics use high-purity, large-area, wafer-scale single-crystalline semiconductors grown by sophisticated, high-temperature crystal growth processes. We demonstrate a solution-based hot-casting technique to grow continuous, pinhole-free thin films of organometallic perovskites with millimeter-scale crystalline grains. We fabricated planar solar cells with efficiencies approaching 18%, with little cell-to-cell variability. The devices show hysteresis-free photovoltaic response, which had been a fundamental bottleneck for the stable operation of perovskite devices. Characterization and modeling attribute the improved performance to reduced bulk defects and improved charge carrier mobility in large-grain devices. We anticipate that this technique will lead the field toward synthesis of wafer-scale crystalline perovskites, necessary for the fabrication of high-efficiency solar cells, and will be applicable to several other material systems plagued by polydispersity, defects, and grain boundary recombination in solution-processed thin films.
2,960 citations
TL;DR: An intelligent collaborative security model to minimize security risk is proposed; how different innovations such as big data, ambient intelligence, and wearables can be leveraged in a health care context is discussed; and various IoT and eHealth policies and regulations are addressed to determine how they can facilitate economies and societies in terms of sustainable development.
Abstract: The Internet of Things (IoT) makes smart objects the ultimate building blocks in the development of cyber-physical smart pervasive frameworks. The IoT has a variety of application domains, including health care. The IoT revolution is redesigning modern health care with promising technological, economic, and social prospects. This paper surveys advances in IoT-based health care technologies and reviews the state-of-the-art network architectures/platforms, applications, and industrial trends in IoT-based health care solutions. In addition, this paper analyzes distinct IoT security and privacy features, including security requirements, threat models, and attack taxonomies from the health care perspective. Further, this paper proposes an intelligent collaborative security model to minimize security risk; discusses how different innovations such as big data, ambient intelligence, and wearables can be leveraged in a health care context; addresses various IoT and eHealth policies and regulations across the world to determine how they can facilitate economies and societies in terms of sustainable development; and provides some avenues for future research on IoT-based health care based on a set of open issues and challenges.
2,190 citations
Harvard University1, Boston University2, Johns Hopkins University3, University of Wisconsin-Madison4, Temple University5, Cleveland Clinic6, Mayo Clinic7, Case Western Reserve University8, University of Virginia9, Washington University in St. Louis10, University of Chicago11, University of Michigan12, Rutgers University13
TL;DR: Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone.
Abstract: BACKGROUND Androgen-deprivation therapy (ADT) has been the backbone of treatment for metastatic prostate cancer since the 1940s. We assessed whether concomitant treatment with ADT plus docetaxel would result in longer overall survival than that with ADT alone. METHODS We assigned men with metastatic, hormone-sensitive prostate cancer to receive either ADT plus docetaxel (at a dose of 75 mg per square meter of body-surface area every 3 weeks for six cycles) or ADT alone. The primary objective was to test the hypothesis that the median overall survival would be 33.3% longer among patients receiving docetaxel added to ADT early during therapy than among patients receiving ADT alone. RESULTS A total of 790 patients (median age, 63 years) underwent randomization. After a median follow-up of 28.9 months, the median overall survival was 13.6 months longer with ADT plus docetaxel (combination therapy) than with ADT alone (57.6 months vs. 44.0 months; hazard ratio for death in the combination group, 0.61; 95% confidence interval [CI], 0.47 to 0.80; P<0.001). The median time to biochemical, symptomatic, or radiographic progression was 20.2 months in the combination group, as compared with 11.7 months in the ADT-alone group (hazard ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). The rate of a prostate-specific antigen level of less than 0.2 ng per milliliter at 12 months was 27.7% in the combination group versus 16.8% in the ADT-alone group (P<0.001). In the combination group, the rate of grade 3 or 4 febrile neutropenia was 6.2%, the rate of grade 3 or 4 infection with neutropenia was 2.3%, and the rate of grade 3 sensory neuropathy and of grade 3 motor neuropathy was 0.5%. CONCLUSIONS Six cycles of docetaxel at the beginning of ADT for metastatic prostate cancer resulted in significantly longer overall survival than that with ADT alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00309985.)
2,009 citations
Huntsman Cancer Institute1, Rutgers University2, University of North Carolina at Chapel Hill3, University of Texas MD Anderson Cancer Center4, University of Louisville5, Emory University6, Lynn University7, University of California, San Diego8, Amgen9, Vanderbilt University10, Temple University11, University of Iowa Hospitals and Clinics12, University of Arizona13, University of Colorado Boulder14, Washington University in St. Louis15, The Royal Marsden NHS Foundation Trust16, National Institute for Health Research17, McGill University18
TL;DR: T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III clinical trial and represents a novel potential therapy for patients with metastatic melanoma.
Abstract: Purpose Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1‐derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. T-VEC was compared with GM-CSF in patients with unresected stage IIIB to IV melanoma in a randomized open-label phase III trial. Patients and Methods Patients with injectable melanoma that was not surgically resectable were randomly assigned at a two-to-one ratio to intralesional T-VEC or subcutaneous GM-CSF. The primary end point was durable response rate (DRR; objective response lasting continuously 6 months) per independent assessment. Key secondary end points included overall survival (OS) and overall response rate. Results Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3%; 95% CI, 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%]; odds ratio, 8.9; P .001). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P .051). T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. The most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. The only grade 3 or 4 AE occurring in 2% of T-VEC‐treated patients was cellulitis (2.1%). No fatal treatment-related AEs occurred.
1,815 citations
University of Massachusetts Amherst1, National Oceanic and Atmospheric Administration2, Université du Québec à Montréal3, Newcastle University4, University of Bern5, Chinese Academy of Sciences6, Rutgers University7, École Polytechnique Fédérale de Lausanne8, University of Graz9, University of Reading10, Shanxi University11, University of Alberta12, Environment Canada13
TL;DR: In this paper, the authors review important mechanisms that contribute towards elevation-dependent warming, such as snow albedo and surface-based feedbacks, water vapour changes and latent heat release, surface water vapours and radiative flux changes, surface heat loss and temperature change; and aerosols.
Abstract: There is growing evidence that the rate of warming is amplified with elevation, such that high-mountain environments experience more rapid changes in temperature than environments at lower elevations. Elevation-dependent warming (EDW) can accelerate the rate of change in mountain ecosystems, cryospheric systems, hydrological regimes and biodiversity. Here we review important mechanisms that contribute towards EDW: snow albedo and surface-based feedbacks; water vapour changes and latent heat release; surface water vapour and radiative flux changes; surface heat loss and temperature change; and aerosols. All lead to enhanced warming with elevation (or at a critical elevation), and it is believed that combinations of these mechanisms may account for contrasting regional patterns of EDW. We discuss future needs to increase knowledge of mountain temperature trends and their controlling mechanisms through improved observations, satellite-based remote sensing and model simulations.
1,628 citations
Heidelberg University1, University of Marburg2, Queen Mary University of London3, University of Leeds4, Rutgers University5, University of New South Wales6, University of Münster7, Aarhus University8, Columbia University9, University of Chieti-Pescara10, Norwegian University of Science and Technology11, Karolinska Institutet12, Université catholique de Louvain13, University of Sydney14, University of Western Australia15, University of Dundee16, Katholieke Universiteit Leuven17, Maastricht University18, National Yang-Ming University19
TL;DR: The IASP Task Force, which comprises pain experts from across the globe, has developed a new and pragmatic classification of chronic pain for the upcoming 11th revision of the International Classification of Diseases, termed “multiple parenting.”
Abstract: Chronic pain has been recognized as pain that persists past normal healing time5 and hence lacks the acute warning function of physiological nociception.35 Usually pain is regarded as chronic when it lasts or recurs for more than 3 to 6 months.29 Chronic pain is a frequent condition, affecting an estimated 20% of people worldwide6,13,14,18 and accounting for 15% to 20% of physician visits.25,28 Chronic pain should receive greater attention as a global health priority because adequate pain treatment is a human right, and it is the duty of any health care system to provide it.4,13
The current version of the International Classification of Diseases (ICD) of the World Health Organization (WHO) includes some diagnostic codes for chronic pain conditions, but these diagnoses do not reflect the actual epidemiology of chronic pain, nor are they categorized in a systematic manner. The ICD is the preeminent tool for coding diagnoses and documenting investigations or therapeutic measures within the health care systems of many countries. In addition, ICD codes are commonly used to report target diseases and comorbidities of participants in clinical research. Consequently, the current lack of adequate coding in the ICD makes the acquisition of accurate epidemiological data related to chronic pain difficult, prevents adequate billing for health care expenses related to pain treatment, and hinders the development and implementation of new therapies.10,11,16,23,27,31,37
Responding to these shortcomings, the International Association for the Study of Pain (IASP) contacted the WHO and established a Task Force for the Classification of Chronic Pain. The IASP Task Force, which comprises pain experts from across the globe,19 has developed a new and pragmatic classification of chronic pain for the upcoming 11th revision of the ICD. The goal is to create a classification system that is applicable in primary care and in clinical settings for specialized pain management.
A major challenge in this process was finding a rational principle of classification that suits the different types of chronic pain and fits into the general ICD-11 framework. Pain categories are variably defined based on the perceived location (headache), etiology (cancer pain), or the primarily affected anatomical system (neuropathic pain). Some diagnoses of pain defy these classification principles (fibromyalgia).
This problem is not unique to the classification of pain, but exists throughout the ICD. The IASP Task Force decided to give first priority to pain etiology, followed by underlying pathophysiological mechanisms, and finally the body site. Developing this multilayered classification was greatly facilitated by a novel principle of assigning diagnostic codes in ICD-11, termed “multiple parenting.” Multiple parenting allows the same diagnosis to be subsumed under more than 1 category (for a glossary of ICD terms refer to Table Table1).1). Each diagnosis retains 1 category as primary parent, but is cross-referenced to other categories that function as secondary parents.
Table 1
Glossary of ICD-11 terms.
The new ICD category for “Chronic Pain” comprises the most common clinically relevant disorders. These disorders were divided into 7 groups (Fig. (Fig.1):1): (1) chronic primary pain, (2) chronic cancer pain, (3) chronic posttraumatic and postsurgical pain, (4) chronic neuropathic pain, (5) chronic headache and orofacial pain, (6) chronic visceral pain, and (7) chronic musculoskeletal pain. Experts assigned to each group are responsible for the definition of diagnostic criteria and the selection of the diagnoses to be included under these subcategories of chronic pain. Thanks to Bedirhan Ustun and Robert Jakob of the WHO, these pain diagnoses are now integrated in the beta version of ICD-11 (http://id.who.int/icd/entity/1581976053). The Task Force is generating content models for single entities to describe their clinical characteristics. After peer review overseen by the WHO Steering Committee,39 the classification of chronic pain will be voted into action by the World Health Assembly in 2017.
Figure 1
Organizational chart of Task Force, IASP, and WHO interactions. The IASP Task Force was created by the IASP council and its scope defined in direct consultation of the chairs (R.D.T. and W.R.) with WHO representatives in 2012. The Task Force reports to ...
2. Classification of chronic pain
Chronic pain was defined as persistent or recurrent pain lasting longer than 3 months. This definition according to pain duration has the advantage that it is clear and operationalized.
Optional specifiers for each diagnosis record evidence of psychosocial factors and the severity of the pain. Pain severity can be graded based on pain intensity, pain-related distress, and functional impairment.
2.1. Chronic primary pain
Chronic primary pain is pain in 1 or more anatomic regions that persists or recurs for longer than 3 months and is associated with significant emotional distress or significant functional disability (interference with activities of daily life and participation in social roles) and that cannot be better explained by another chronic pain condition. This is a new phenomenological definition, created because the etiology is unknown for many forms of chronic pain. Common conditions such as, eg, back pain that is neither identified as musculoskeletal or neuropathic pain, chronic widespread pain, fibromyalgia, and irritable bowel syndrome will be found in this section and biological findings contributing to the pain problem may or may not be present. The term “primary pain” was chosen in close liaison with the ICD-11 revision committee, who felt this was the most widely acceptable term, in particular, from a nonspecialist perspective.
1,627 citations
TL;DR: A measurement of the Higgs boson mass is presented based on the combined data samples of the ATLAS and CMS experiments at the CERN LHC in the H→γγ and H→ZZ→4ℓ decay channels.
Abstract: A measurement of the Higgs boson mass is presented based on the combined data samples of the ATLAS and CMS experiments at the CERN LHC in the H→γγ and H→ZZ→4l decay channels. The results are obtained from a simultaneous fit to the reconstructed invariant mass peaks in the two channels and for the two experiments. The measured masses from the individual channels and the two experiments are found to be consistent among themselves. The combined measured mass of the Higgs boson is mH=125.09±0.21 (stat)±0.11 (syst) GeV.
TL;DR: MDTraj is a modern, lightweight, and fast software package for analyzing MD simulations that simplifies the analysis of MD data and connects these datasets with the modern interactive data science software ecosystem in Python.
TL;DR: Experimental results and theoretical calculations indicate that Ni3S2/NF's excellent catalytic activity is mainly due to the synergistic catalytic effects produced in it by its nanosheet arrays and exposed {2̅10} high-index facets.
Abstract: Elaborate design of highly active and stable catalysts from Earth-abundant elements has great potential to produce materials that can replace the noble-metal-based catalysts commonly used in a range of useful (electro)chemical processes. Here we report, for the first time, a synthetic method that leads to in situ growth of {210} high-index faceted Ni3S2 nanosheet arrays on nickel foam (NF). We show that the resulting material, denoted Ni3S2/NF, can serve as a highly active, binder-free, bifunctional electrocatalyst for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER). Ni3S2/NF is found to give ∼100% Faradaic yield toward both HER and OER and to show remarkable catalytic stability (for >200 h). Experimental results and theoretical calculations indicate that Ni3S2/NF’s excellent catalytic activity is mainly due to the synergistic catalytic effects produced in it by its nanosheet arrays and exposed {210} high-index facets.
University of Lausanne1, Memorial Sloan Kettering Cancer Center2, Rutgers University3, University of North Carolina at Chapel Hill4, Harvard University5, University of Southern California6, Broad Institute7, Washington University in St. Louis8, Buck Institute for Research on Aging9, University of British Columbia10, Van Andel Institute11, The Chinese University of Hong Kong12, University of Utah13, Stanford University14, University of California, San Francisco15, United States Department of Veterans Affairs16, University of Pittsburgh17, University of Texas MD Anderson Cancer Center18, BC Cancer Agency19
TL;DR: This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options, suggesting differential modulation of ER activity in I LC and IDC.
TL;DR: The results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells and provide strong support for further development of this approach.
Abstract: Purpose T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19 B-cell malignancies. Patients and Methods We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells. Results Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/L.
TL;DR: Associations between inherited cellular transport gene variants and risk of EOC histologic subtypes are revealed on a large cohort of women.
Abstract: BACKGROUND: Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS: In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. RESULTS: The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). CONCLUSION: These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.
Yeshiva University1, Harvard University2, Hamilton Health Sciences3, Sunnybrook Research Institute4, Loyola University Chicago5, University of Michigan6, Virginia Commonwealth University7, University of North Carolina at Chapel Hill8, Mayo Clinic9, Duke University10, University of Maryland, Baltimore11, Wake Forest University12, National Institutes of Health13, Indiana University14, Northwestern University15, Baylor College of Medicine16, Washington University in St. Louis17, Yonsei University18, Allegheny General Hospital19, Emory University20, University of Texas at San Antonio21, Vanderbilt University22, University of Pittsburgh23, Rutgers University24, Indiana University – Purdue University Indianapolis25, Stanford University26
TL;DR: In this article, a prospective trial involving women with hormone-receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0cm in the intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features.
Abstract: BackgroundPrior studies with the use of a prospective–retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker. MethodsWe performed a prospective trial involving women with hormone-receptor–positive, human epidermal growth factor receptor type 2 (HER2)–negative, axillary node–negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase–polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-...
TL;DR: In this article, three distinct Class 2 CRISPR-Cas systems are described, two of which contain RuvC-like endonuclease domains distantly related to Cpf1.
TL;DR: The umbrella review methodology described here is the first to consider reviews that report other than quantitative evidence derived from randomized controlled trials, and provides a ready means for decision makers in healthcare to gain a clear understanding of a broad topic area.
Abstract: Aims:With the increase in the number of systematic reviews available, a logical next step to provide decision makers in healthcare with the evidence they require has been the conduct of reviews of existing systematic reviews Syntheses of existing systematic reviews are referred to by many d
TL;DR: The concept of translanguaging is clarified, establishing it as a particular conception of the mental grammars and linguistic practices of bilinguals and of special relevance to schools interested in the linguistic and intellectual growth of bilingual students as well as to minoritized communities involved in language maintenance and revitalization efforts.
Abstract: The concept of translanguaging is clarified, establishing it as a particular conception of the mental grammars and linguistic practices of bilinguals. Translanguaging is different from code switching. Under translanguaging, the mental grammars of bilinguals are structured but unitary collections of features, and the practices of bilinguals are acts of feature selection, not of grammar switch. A proper understanding of translanguaging requires a return to the well known but often forgotten idea that named languages are social, not linguistic, objects. Whereas the idiolect of a particular individual is a linguistic object defined in terms of lexical and structural features, the named language of a nation or social group is not; its boundaries and membership cannot be established on the basis of lexical and structural features. The two named languages of the bilingual exist only in the outsider's view. From the insider's perspective of the speaker, there is only his or her full idiolect or repertoire, which belongs only to the speaker, not to any named language. Translanguaging is the deployment of a speaker' sf ull linguistic repertoire without regard for watchful adherence to the socially and politically defined boundaries of named (and usually national and state) languages. In schools, the translanguaging of bilinguals tends to be severely restricted. In addition, schools confuse the assessment of general linguistic proficiency, which is best manifested in bilinguals while translanguaging, with the testing of profi- ciency in a named language, which insists on inhibiting translanguaging. The concept of translanguaging is of special relevance to schools interested in the linguistic and intellectual growth of bilingual students as well as to minoritized communities involved in language maintenance and revitalization efforts.
TL;DR: This Review provides a comprehensive overview of the basic biology supporting oncolytic viruses as cancer therapeutic agents, describes oncoleytic viruses in advanced clinical trials and discusses the unique challenges in the development of on colytic virus as a new class of drugs for the treatment of cancer.
Abstract: Oncolytic viruses can kill tumour cells through a dual mechanism of action; the direct lysis of cells, and the induction of an immune response. The first oncolytic virus has been approved in China, and another has been recommended for approval in the United States. This Review discusses the biology of oncolytic viruses as well as key oncolytic viruses in clinical development, and investigates the challenges associated with developing oncolytic viruses as a new therapeutic modality for cancer.
TL;DR: Today’s low rates of marine extinction may be the prelude to a major extinction pulse, similar to that observed on land during the industrial revolution, as the footprint of human ocean use widens.
Abstract: BACKGROUND: Comparing patterns of ter- restrial and marine defaunation helps to place human impacts on marine fauna in context and to navigate toward recovery. De- faunation began in ear- nest tens of thousands of years later in the oceans than it did on land. Al- though defaunation has been less severe in the oceans than on land, our effects on marine animals are increasing in pace and impact. Humans have caused few complete extinctions in the sea, but we are responsible for many ecological, commercial, and local extinctions. Despite our late start, humans have already powerfully changed virtually all major marine ecosystems. ADVANCES: Humans have profoundly de- creased the abundance of both large (e.g., whales) and small (e.g., anchovies) marine fauna. Such declines can generate waves of ecological change that travel both up and down marine food webs and can alter ocean ecosystem functioning. Human harvesters have also been a major force of evolutionary change in the oceans and have reshaped the genetic structure of marine animal popula- tions. Climate change threatens toaccelerate marine defaunation over the next century. The high mobility of many marine animals offers some increased, though limited, ca- pacity for marine species to respond to cli- mate stress, but it also exposes many species to increased risk from other stressors. Be- cause humans are intensely reliant on ocean ecosystems for food and other ecosystem ser- vices, we are deeply affected by all of these forecasted changes. Three lessons emerge when comparing the marine and terrestrial defaunation ex-
National Institutes of Health1, Cornell University2, Memorial Sloan Kettering Cancer Center3, University of California, Los Angeles4, Rutgers University5, University of Wisconsin-Madison6, University of Rochester7, Ohio State University8, University of Washington9, Stanford University10, University of Texas MD Anderson Cancer Center11, Genentech12, Mayo Clinic13, Hofstra University14
TL;DR: The selective development of ibrutinib for the treatment of ABC DLBCL is supported, with the highest number of responses occurred in ABC tumors that lacked BCR mutations, suggesting that oncogenic BCR signaling in ABC does not require B CR mutations and might be initiated by non-genetic mechanisms.
Abstract: The two major subtypes of diffuse large B cell lymphoma (DLBCL)--activated B cell-like (ABC) and germinal center B cell-like (GCB)--arise by distinct mechanisms, with ABC selectively acquiring mutations that target the B cell receptor (BCR), fostering chronic active BCR signaling. The ABC subtype has a ∼40% cure rate with currently available therapies, which is worse than the rate for GCB DLBCL, and highlights the need for ABC subtype-specific treatment strategies. We hypothesized that ABC, but not GCB, DLBCL tumors would respond to ibrutinib, an inhibitor of BCR signaling. In a phase 1/2 clinical trial that involved 80 subjects with relapsed or refractory DLBCL, ibrutinib produced complete or partial responses in 37% (14/38) of those with ABC DLBCL, but in only 5% (1/20) of subjects with GCB DLBCL (P = 0.0106). ABC tumors with BCR mutations responded to ibrutinib frequently (5/9; 55.5%), especially those with concomitant myeloid differentiation primary response 88 (MYD88) mutations (4/5; 80%), a result that is consistent with in vitro cooperation between the BCR and MYD88 pathways. However, the highest number of responses occurred in ABC tumors that lacked BCR mutations (9/29; 31%), suggesting that oncogenic BCR signaling in ABC does not require BCR mutations and might be initiated by non-genetic mechanisms. These results support the selective development of ibrutinib for the treatment of ABC DLBCL.
TL;DR: The formulation of SHs is an important advancement for future multi-omics studies and for better understanding the mechanisms of fermentation inhibition in lignocellulosic hydrolysates, which was instrumental for defining the most important inhibitors in the ACH.
Abstract: The fermentation inhibition of yeast or bacteria by lignocellulose-derived degradation products, during hexose/pentose co-fermentation, is a major bottleneck for cost-effective lignocellulosic biorefineries. To engineer microbial strains for improved performance, it is critical to understand the mechanisms of inhibition that affect fermentative organisms in the presence of major components of a lignocellulosic hydrolysate. The development of a synthetic lignocellulosic hydrolysate (SH) media with a composition similar to the actual biomass hydrolysate will be an important advancement to facilitate these studies. In this work, we characterized the nutrients and plant-derived decomposition products present in AFEX™ pretreated corn stover hydrolysate (ACH). The SH was formulated based on the ACH composition and was further used to evaluate the inhibitory effects of various families of decomposition products during Saccharomyces cerevisiae 424A (LNH-ST) fermentation. The ACH contained high levels of nitrogenous compounds, notably amides, pyrazines, and imidazoles. In contrast, a relatively low content of furans and aromatic and aliphatic acids were found in the ACH. Though most of the families of decomposition products were inhibitory to xylose fermentation, due to their abundance, the nitrogenous compounds showed the most inhibition. From these compounds, amides (products of the ammonolysis reaction) contributed the most to the reduction of the fermentation performance. However, this result is associated to a concentration effect, as the corresponding carboxylic acids (products of hydrolysis) promoted greater inhibition when present at the same molar concentration as the amides. Due to its complexity, the formulated SH did not perfectly match the fermentation profile of the actual hydrolysate, especially the growth curve. However, the SH formulation was effective for studying the inhibitory effect of various compounds on yeast fermentation. The formulation of SHs is an important advancement for future multi-omics studies and for better understanding the mechanisms of fermentation inhibition in lignocellulosic hydrolysates. The SH formulated in this work was instrumental for defining the most important inhibitors in the ACH. Major AFEX decomposition products are less inhibitory to yeast fermentation than the products of dilute acid or steam explosion pretreatments; thus, ACH is readily fermentable by yeast without any detoxification.
TL;DR: Synthetic methods for preparing different classes of CSNs, including the Stöber method, solvothermal method, one-pot synthetic method involving surfactants, etc., are briefly mentioned here.
Abstract: Core–shell nanoparticles (CSNs) are a class of nanostructured materials that have recently received increased attention owing to their interesting properties and broad range of applications in catalysis, biology, materials chemistry and sensors. By rationally tuning the cores as well as the shells of such materials, a range of core–shell nanoparticles can be produced with tailorable properties that can play important roles in various catalytic processes and offer sustainable solutions to current energy problems. Various synthetic methods for preparing different classes of CSNs, including the Stober method, solvothermal method, one-pot synthetic method involving surfactants, etc., are briefly mentioned here. The roles of various classes of CSNs are exemplified for both catalytic and electrocatalytic applications, including oxidation, reduction, coupling reactions, etc.
TL;DR: The ability to tune the chemistry by choosing a unique combination of transition metals and chalcogen atoms along with controlling their properties by phase engineering allows new functionalities to be realized with TMDs.
Abstract: Transition metal dichalcogenides (TMDs) represent a family of materials with versatile electronic, optical, and chemical properties. Most TMD bulk crystals are van der Waals solids with strong bonding within the plane but weak interlayer bonding. The individual layers can be readily isolated. Single layer TMDs possess intriguing properties that are ideal for both fundamental and technologically relevant research studies. We review the structure and phases of single and few layered TMDs. We also describe recent progress in phase engineering in TMDs. The ability to tune the chemistry by choosing a unique combination of transition metals and chalcogen atoms along with controlling their properties by phase engineering allows new functionalities to be realized with TMDs.
Paris Descartes University1, Institut Gustave Roussy2, Mount Sinai Hospital3, University of Texas Southwestern Medical Center4, University of Kiel5, Thomas Jefferson University6, Seconda Università degli Studi di Napoli7, University of Toronto8, University of Massachusetts Medical School9, Louisiana State University10, Ghent University11, Flanders Institute for Biotechnology12, Queen Mary University of London13, Cancer Research UK14, Roswell Park Cancer Institute15, Karolinska Institutet16, University of Freiburg17, Buck Institute for Research on Aging18, University of California, San Francisco19, French Institute of Health and Medical Research20, Université Paris-Saclay21, University College London22, University of Rome Tor Vergata23, Northwestern University24, Memorial Sloan Kettering Cancer Center25, National Institutes of Health26, Technion – Israel Institute of Technology27, Johns Hopkins University28, University of Chieti-Pescara29, University of Ulm30, Genentech31, New York University32, Pennsylvania State University33, University of Salento34, Yale University35, Goethe University Frankfurt36, University of Burgundy37, Pasteur Institute38, University of Strasbourg39, University of Zurich40, University of Tokyo41, Technische Universität München42, University of Bern43, University of Michigan44, Medical Research Council45, University of South Australia46, University of Adelaide47, Medical University of South Carolina48, Howard Hughes Medical Institute49, University of Texas at Dallas50, St. John's University51, University of Oviedo52, University of Graz53, Istituto Superiore di Sanità54, Katholieke Universiteit Leuven55, Trinity College, Dublin56, University of Geneva57, University of Amsterdam58, Stony Brook University59, University of Washington60, University of Ferrara61, Royal College of Surgeons in Ireland62, La Trobe University63, University of Buenos Aires64, University of Virginia65, University of Padua66, University of Lisbon67, University of Cambridge68, University of Würzburg69, Soochow University (Suzhou)70, Columbia University71, University of Glasgow72, Foundation for Research & Technology – Hellas73, University of Crete74, Innsbruck Medical University75, Carlos III Health Institute76, Rutgers University77, University of Minnesota78, Harvard University79, City University of New York80, Moscow State University81
TL;DR: The Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
Abstract: Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
TL;DR: The current status of models that employ two leading techniques to simulate the physics of galaxy formation: semianalytic models and numerical hydrodynamic simulations is reviewed in this paper, where the authors focus on a set of observational targets that describe the evolution of the global and structural properties of galaxies from roughly cosmic high noon (z ∼ 2 − 3) to the present.
Abstract: Modeling galaxy formation in a cosmological context presents one of the greatest challenges in astrophysics today due to the vast range of scales and numerous physical processes involved. Here we review the current status of models that employ two leading techniques to simulate the physics of galaxy formation: semianalytic models and numerical hydrodynamic simulations. We focus on a set of observational targets that describe the evolution of the global and structural properties of galaxies from roughly cosmic high noon (z ∼ 2–3) to the present. Although minor discrepancies remain, overall, models show remarkable convergence among different methods and make predictions that are in qualitative agreement with observations. Modelers have converged on a core set of physical processes that are critical for shaping galaxy properties. This core set includes cosmological accretion, strong stellar-driven winds that are more efficient at low masses, black hole feedback that preferentially suppresses star formation a...
TL;DR: In this article, the authors discuss how and why social media platforms have become powerful sites for documenting and challenging episodes of police brutality and the misrepresentation of racialized bodies in mainstream media.
Abstract: As thousands of demonstrators took to the streets of Ferguson, Missouri, to protest the fatal police shooting of unarmed African American teenager Michael Brown in the summer of 2014, news and commentary on the shooting, the protests, and the militarized response that followed circulated widely through social media networks. Through a theorization of hashtag usage, we discuss how and why social media platforms have become powerful sites for documenting and challenging episodes of police brutality and the misrepresentation of racialized bodies in mainstream media. We show how engaging in “hashtag activism” can forge a shared political temporality, and, additionally, we examine how social media platforms can provide strategic outlets for contesting and reimagining the materiality of racialized bodies. Our analysis combines approaches from linguistic anthropology and social movements research to investigate the semiotics of digital protest and to interrogate both the possibilities and the pitfalls of engaging in “hashtag ethnography.”
TL;DR: In a US national cohort of adults with schizophrenia, excess deaths from cardiovascular and respiratory diseases implicate modifiable cardiovascular risk factors, including especially tobacco use, which highlight threats posed by substance abuse.
Abstract: Importance Although adults with schizophrenia have a significantly increased risk of premature mortality, sample size limitations of previous research have hindered the identification of the underlying causes. Objective To describe overall and cause-specific mortality rates and standardized mortality ratios (SMRs) for adults with schizophrenia compared with the US general population. Design, Setting, and Participants We identified a national retrospective longitudinal cohort of patients with schizophrenia 20 to 64 years old in the Medicaid program (January 1, 2001, to December 31, 2007). The cohort included 1 138 853 individuals, 4 807 121 years of follow-up, and 74 003 deaths, of which 65 553 had a known cause. Main Outcomes and Measures Mortality ratios for the schizophrenia cohort standardized to the general population with respect to age, sex, race/ethnicity, and geographic region were estimated for all-cause and cause-specific mortality. Mortality rates per 100 000 person-years and the mean years of potential life lost per death were also determined. Death record information was obtained from the National Death Index. Results Adults with schizophrenia were more than 3.5 times (all-cause SMR, 3.7; 95% CI, 3.7-3.7) as likely to die in the follow-up period as were adults in the general population. Cardiovascular disease had the highest mortality rate (403.2 per 100 000 person-years) and an SMR of 3.6 (95% CI, 3.5-3.6). Among 6 selected cancers, lung cancer had the highest mortality rate (74.8 per 100 000 person-years) and an SMR of 2.4 (95% CI, 2.4-2.5). Particularly elevated SMRs were observed for chronic obstructive pulmonary disease (9.9; 95% CI, 9.6-10.2) and influenza and pneumonia (7.0; 95% CI, 6.7-7.4). Accidental deaths (119.7 per 100 000 person-years) accounted for more than twice as many deaths as suicide (52.0 per 100 000 person-years). Nonsuicidal substance-induced death, mostly from alcohol or other drugs, was also a leading cause of death (95.2 per 100 000 person-years). Conclusions and Relevance In a US national cohort of adults with schizophrenia, excess deaths from cardiovascular and respiratory diseases implicate modifiable cardiovascular risk factors, including especially tobacco use. Excess deaths directly attributable to alcohol or other drugs highlight threats posed by substance abuse. More aggressive identification and management of cardiovascular risk factors, as well as reducing tobacco use and substance abuse, should be leading priorities in the medical care of adults with schizophrenia.