tbuckley/cabot-search huggingface dataset:
Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance
Authors: Micol Eleonora Fiori, Simone Di Franco, Lidia Villanova, Paola Bianca, Giorgio Stassi, Ruggero De Maria
Journal: Molecular Cancer (2019)

In the last decades, the role of the microenvironment in tumor progression and therapeutic outcome has gained increasing attention. Cancer-associated fibroblasts (CAFs) have emerged as key players among stromal cells, owing to their abundance in most solid tumors and their diverse tumor-restraining/promoting roles. The interplay between tumor cells and neighboring CAFs takes place by both paracrine signals (cytokines, exosomes and metabolites) or by the multifaceted functions of the surrounding extracellular matrix. Here, we dissect the most recent identified mechanisms underlying CAF-mediated control of tumor progression and therapy resistance, which include induction of the epithelial-to-mesenchymal transition (EMT), activation of survival pathways or stemness-related programs and metabolic reprogramming in tumor cells. Importantly, the recently unveiled heterogeneity in CAFs claims tailored therapeutic efforts aimed at eradicating the specific subset facilitating tumor progression, therapy resistance and relapse. However, despite the large amount of pre-clinical data, much effort is still needed to translate CAF-directed anti-cancer strategies from the bench to the clinic.
Association of Neuropathologically Confirmed Frontotemporal Dementia and Alzheimer Disease With Criminal and Socially Inappropriate Behavior in a Swedish Cohort
Authors: Madeleine Liljegren, Maria Landqvist Waldö, Alexander Frizell Santillo, Susann Ullén, Robert Rydbeck, Bruce Miller, Elisabet Englund
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Criminal and socially inappropriate behavior is encountered among patients with dementia, and it is sometimes the first sign of a dementing disorder. This behavior constitutes a significant burden to society, patients' relatives, and patients themselves. <h3>Objectives</h3> To investigate and compare the prevalence and type of criminal and socially inappropriate behavior, as well as recurrence of criminal behavior, associated with Alzheimer disease (AD) and frontotemporal dementia (FTD) neuropathologically verified post mortem, and to assess whether there is a specific type of protein pathology more closely associated with criminal behavior in patients with FTD. <h3>Design, Setting, and Participants</h3> Cohort study using medical record review of 220 Swedish patients with a postmortem neuropathologic diagnosis of AD (n = 101) or frontotemporal lobar degeneration (n = 119) (hereinafter referred to as FTD) diagnosed between January 1, 1967, and December 31, 2017. <h3>Main Outcomes and Measures</h3> Patient notes containing reports of criminal and socially inappropriate behavior, as well as data on dominant protein pathology for patients with FTD, were duly reviewed and recorded. The Fisher exact test or logistic regression was used to assess possible differences between groups. <h3>Results</h3> Of the 220 patients studied, 128 (58.2%) were female, the median (range) age at disease onset was 63 (30-88) years and at death was 72 (34-96) years, and the median (range) disease duration was 9 (1-28) years. Instances of criminal behavior were found in 65 of the 220 patients (29.5%): in 15 of the 101 patients (14.9%) with AD and 50 of the 119 patients (42.0%) with FTD (<i>P</i> &lt; .001). Recurrence of criminal behavior was significantly higher in the FTD group (89.0%) than in the AD group (53.3%) (<i>P</i> = .04). Instances of socially inappropriate behavior were found in 57 patients (56.4%) with AD and 89 (74.8%) with FTD (<i>P</i> = .004). An expression of non-tau pathology increased the odds for criminal behavior by a factor of 9.0 (95% CI, 3.4-24.0) among patients with FTD. <h3>Conclusions and Relevance</h3> These results suggest that criminal and socially inappropriate behaviors may be more prevalent and criminal behaviors may be more recurrent in patients with FTD than in those with AD. Non-tau pathology, but not tau pathology, appears to be associated with criminal behavior. These findings may help with the clinical diagnostic process.
Immunotherapy of Melanoma: Facts and Hopes
Authors: Sarah A. Weiss, Jedd D. Wolchok, Mario Sznol
Journal: Clinical Cancer Research (2019)

Abstract Melanoma is among the most sensitive of malignancies to immune modulation. Although multiple trials conducted over decades with vaccines, cytokines, and cell therapies demonstrated meaningful responses in a small subset of patients with metastatic disease, a true increase in overall survival (OS) within a randomized phase III trial was not observed until the development of anti–CTLA-4 (ipilimumab). Further improvements in OS for metastatic disease were observed with the anti–PD-1–based therapies (nivolumab, pembrolizumab) as single agents or combined with ipilimumab. A lower bound for expected 5-year survival for metastatic melanoma is currently approximately 35% and could be as high as 50% for the nivolumab/ipilimumab combination among patients who would meet criteria for clinical trials. Moreover, a substantial fraction of long-term survivors will likely remain progression-free without continued treatment. The hope and major challenge for the future is to understand the immunobiology of tumors with primary or acquired resistance to anti–PD-1 or anti–PD-1/anti–CTLA-4 and to develop effective immune therapies tailored to individual patient subsets not achieving long-term clinical benefit. Additional goals include optimal integration of immune therapy with nonimmune therapies, the development and validation of predictive biomarkers in the metastatic setting, improved prognostic and predictive biomarkers for the adjuvant setting, understanding mechanisms of and decreasing toxicity, and optimizing the duration of therapy.
Porto-sinusoidal vascular disease: proposal and description of a novel entity
Authors: Andrea De Gottardi, Pierre-Emmanuel Rautou, Jeoffrey Schouten, Laura Rubbia-Brandt, Frank Leebeek, Jonel Trebicka, Sarwa Darwish Murad, Valérie Vilgrain, Virginia Hernandez-Gea, Filipe Nery, Aurélie Plessier, Annalisa Berzigotti, Paulette Bioulac-Sage, Massimo Primignani, David Semela, Laure Elkrief, Pierre Bedossa, Dominique Valla, Juan Carlos Garcia-Pagan
Journal: The Lancet. Gastroenterology & hepatology (2019)
Endoscopic ultrasound-guided biliary drainage in a novel radiofrequency ablation-based swine biliary dilatation model
Authors: Dario Ligresti, Stefano Baraldo, Radhika Chavan, Margaret Geri Keane, Yu-Ting Kuo, Shaimaa Saleem, Dong-Wan Seo
Journal: Endoscopy (2019)

Endoscopic ultrasound (EUS)-guided drainage procedures are becoming increasingly widespread in clinical practice, even though they are technically challenging and require a substantial learning curve. In vivo swine biliary dilatation models for training have been described; however, they provide erratic biliary dilatation and can also be technically cumbersome [1 – 5]. We describe EUS-guided gallbladder drainage with a lumen-apposing metal stent (LAMS) in a novel swine biliary dilatation model.
Targeted Inhibition of the Dual Specificity Phosphatases DUSP1 and DUSP6 Suppress MPNST Growth via JNK
Authors: Annmarie Ramkissoon, Katherine E. Chaney, David Milewski, Kyle B. Williams, Rory L. Williams, Kwangmin Choi, Adam Miller, Tanya V. Kalin, Joseph G. Pressey, Sara Szabo, Mohammad Azam, David A. Largaespada, Nancy Ratner
Journal: Clinical Cancer Research (2019)

In neurofibromatosis type 1 (NF1) and in highly aggressive malignant peripheral nerve sheath tumors (MPNSTs), constitutively active RAS-GTP and increased MAPK signaling are important in tumorigenesis. Dual specificity phosphatases (DUSPs) are negative regulators of MAPK signaling that dephosphorylate p38, JNK, and ERK in different settings. Although often acting as tumor suppressors, DUSPs may also act as oncogenes, helping tumor cells adapt to high levels of MAPK signaling. We hypothesized that inhibiting DUSPs might be selectively toxic to cells from NF1-driven tumors.We examined DUSP gene and protein expression in neurofibroma and MPNSTs. We used small hairpin RNA (shRNA) to knock down DUSP1 and DUSP6 to evaluate cell growth, downstream MAPK signaling, and mechanisms of action. We evaluated the DUSP inhibitor, (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI), in MPNST cell lines and in cell-line and patient-derived MPNST xenografts.DUSP1 and DUSP6 are expressed in NF1-deleted tumors. Knockdown of DUSP1 and DUSP6, alone or in combination, reduced MPNST cell growth and led to ERK and JNK hyperactivation increasing downstream TP53 and p-ATM. The DUSP inhibitor, BCI, diminished the survival of NF1-deleted Schwann cells and MPNST cell lines through activation of JNK. In vivo, treatment of an established cell-line xenograft or a novel patient-derived xenograft (PDX) of MPNSTs with BCI increased ERK and JNK activation, caused tumor necrosis and fibrosis, and reduced tumor volume in one model.Targeting DUSP1 and DUSP6 genetically or with BCI effectively inhibits MPNST cell growth and promotes cell death, in vitro and in xenograft models. The data support further investigation of DUSP inhibition in MPNSTs.
International consensus definitions of video signs of concussion in professional sports
Authors: Gavin A Davis, Michael Makdissi, Paul Bloomfield, Patrick Clifton, Ruben J Echemendia, Éanna Cian Falvey, Gordon Ward Fuller, Gary Green, Peter Harcourt, Thomas Hill, Nathan McGuirk, Willem Meeuwisse, John Orchard, Martin Raftery, Allen K Sills, Gary S Solomon, Alex Valadka, Paul McCrory
Journal: British Journal of Sports Medicine (2019)

The use of video to assist professional sporting bodies with the diagnosis of sport-related concussion (SRC) has been well established; however, there has been little consistency across sporting codes with regards to which video signs should be used, and the definitions of each of these signs.The aims of this study were to develop a consensus for the video signs considered to be most useful in the identification of a possible SRC and to develop a consensus definition for each of these video signs across the sporting codes.A brief questionnaire was used to assess which video signs were considered to be most useful in the identification of a possible concussion. Consensus was defined as >90% agreement by respondents. Existing definitions of these video signs from individual sports were collated, and individual components of the definitions were assessed and ranked. A modified Delphi approach was then used to create a consensus definition for each of the video signs.Respondents representing seven sporting bodies (Australian Football League, Cricket Australia, Major League Baseball, NFL, NHL, National Rugby League, World Rugby) reached consensus on eight video signs of concussion. Thirteen representatives from the seven professional sports ranked the definition components. Consolidation and refinement of the video signs and their definitions resulted in consensus definitions for six video signs of possible concussion: lying motionless, motor incoordination, impact seizure, tonic posturing, no protective action-floppy and blank/vacant look.These video signs and definitions have reached international consensus, are indicated for use by professional sporting bodies and will form the basis for further collaborative research.
USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cells
Authors: Zhengxin Chen, Hong-Wei Wang, Shuai Wang, Ligang Fan, Shuang Feng, Xiaomin Cai, Chenghao Peng, Xiaoting Wu, Jiacheng Lu, Dan Chen, Yuanyuan Chen, Wenting Wu, Daru Lu, Ning Liu, Yongping You, Huibo Wang
Journal: Journal of Clinical Investigation (2019)

The mesenchymal (MES) subtype of glioblastoma (GBM) stem cells (GSCs) represents a subpopulation of cancer cells that are notorious for their highly aggressive nature and resistance to conventional therapy. Aldehyde dehydrogenase 1A3 (ALDH1A3) has been recently suggested as a key determinant for the maintenance of MES features of GSCs. However, the mechanisms underpinning aberrant ALDH1A3 expression remain elusive. Here, we identified ubiquitin-specific protease 9X (USP9X) as a bona fide deubiquitinase of ALDH1A3 in MES GSCs. USP9X interacted with, depolyubiquitylated, and stabilized ALDH1A3. Moreover, we showed that FACS-sorted USP9Xhi cells were enriched for MES GSCs with high ALDH1A3 activity and potent tumorigenic capacity. Depletion of USP9X markedly downregulated ALDH1A3, resulting in a loss of self-renewal and tumorigenic capacity of MES GSCs, which could be largely rescued by ectopic expression of ALDH1A3. Furthermore, we demonstrated that the USP9X inhibitor WP1130 induced ALDH1A3 degradation and showed marked therapeutic efficacy in MES GSC–derived orthotopic xenograft models. Additionally, USP9X strongly correlated with ALDH1A3 expression in primary human GBM samples and had a prognostic value for patients with the MES subgroup. Collectively, our findings unveil USP9X as a key deubiquitinase for ALDH1A3 protein stabilization and a potential target for GSC-directed therapy.
Common Premutations in the General Population
Authors: Monia B. Hammer, Andrew B. Singleton
Journal: JAMA Neurology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Wishing on a CAR: Understanding the Scope of Intrinsic T-cell Deficits in Patients with Cancer
Authors: Mark Leick, Marcela V. Maus
Journal: Cancer Discovery (2019)

Abstract Summary: Treatment with chimeric antigen receptor T cells has led to impressive and durable responses in adult and pediatric malignancies refractory to conventional therapy; however, only patients with a handful of cancers have responded thus far and significant disparities exist between the response rates of pediatric and adult patients. A new extensive analysis of pediatric patient T-cell subsets at diagnosis and throughout the patients' chemotherapy courses in a variety of solid and hematologic malignancies sheds new light on the intrinsic T-cell deficits that may be partly to blame. See related article by Das et al., p. 492.
Ndufs2, a Core Subunit of Mitochondrial Complex I, Is Essential for Acute Oxygen-Sensing and Hypoxic Pulmonary Vasoconstriction
Authors: Kimberly J. Dunham-Snary, Danchen Wu, François Potus, Edward A. Sykes, Jeffrey D. Mewburn, Rebecca L. Charles, Philip Eaton, Richard A. Sultanian, Stephen L. Archer
Journal: Circulation Research (2019)

Hypoxic pulmonary vasoconstriction (HPV) optimizes systemic oxygen delivery by matching ventilation to perfusion. HPV is intrinsic to pulmonary artery smooth muscle cells (PASMCs). Hypoxia dilates systemic arteries, including renal arteries. Hypoxia is sensed by changes in mitochondrial-derived reactive oxygen species, notably hydrogen peroxide (H2O2) ([H2O2]mito). Decreases in [H2O2]mito elevate pulmonary vascular tone by increasing intracellular calcium ([Ca2+]i) through reduction-oxidation regulation of ion channels. Although HPV is mimicked by the Complex I inhibitor, rotenone, the molecular identity of the O2 sensor is unknown.To determine the role of Ndufs2 (NADH [nicotinamide adenine dinucleotide] dehydrogenase [ubiquinone] iron-sulfur protein 2), Complex I's rotenone binding site, in pulmonary vascular oxygen-sensing.Mitochondria-conditioned media from pulmonary and renal mitochondria isolated from normoxic and chronically hypoxic rats were infused into an isolated lung bioassay. Mitochondria-conditioned media from normoxic lungs contained more H2O2 than mitochondria-conditioned media from chronic hypoxic lungs or kidneys and uniquely attenuated HPV via a catalase-dependent mechanism. In PASMC, acute hypoxia decreased H2O2 within 112±7 seconds, followed, within 205±34 seconds, by increased intracellular calcium concentration, [Ca2+]i. Hypoxia had no effects on [Ca2+]i in renal artery SMC. Hypoxia decreases both cytosolic and mitochondrial H2O2 in PASMC while increasing cytosolic H2O2 in renal artery SMC. Ndufs2 expression was greater in PASMC versus renal artery SMC. Lung Ndufs2 cysteine residues became reduced during acute hypoxia and both hypoxia and reducing agents caused functional inhibition of Complex I. In PASMC, siNdufs2 (cells/tissue treated with Ndufs2 siRNA) decreased normoxic H2O2, prevented hypoxic increases in [Ca2+]i, and mimicked aspects of chronic hypoxia, including decreasing Complex I activity, elevating the nicotinamide adenine dinucleotide (NADH/NAD+) ratio and decreasing expression of the O2-sensitive ion channel, Kv1.5. Knocking down another Fe-S center within Complex I (Ndufs1, NADH [nicotinamide adenine dinucleotide] dehydrogenase [ubiquinone] iron-sulfur protein 1) or other mitochondrial subunits proposed as putative oxygen sensors (Complex III's Rieske Fe-S center and COX4i2 [cytochrome c oxidase subunit 4 isoform 2] in Complex IV) had no effect on hypoxic increases in [Ca2+]i. In vivo, siNdufs2 significantly decreased hypoxia- and rotenone-induced constriction while enhancing phenylephrine-induced constriction.Ndufs2 is essential for oxygen-sensing and HPV.
Book: Diseases of Globalization: Socioeconomic Transitions and Health
Authors: L. Morrison
Journal: BMJ (2001)

Diseases of Globalization: Socioeconomic Transitions and Health by Christine McMurray, Roy Smith. Earthscan, £16.95, pp 200. ISBN 18538 3 711 3. Rating: ★★★


Since 11 September, we have all become acutely aware of what a small world we live in, of how vulnerable we all are to one of the worst diseases of globalisation—terrorism. The extent to which our lifestyles in the affluent North contribute to the poverty and alienation that breed terrorists has been hotly debated. This book, published before 11 September, sets out to examine the impact of modernisation and globalisation on health. It explores the manner in which a global political economy has developed and the role of global capitalism. 




The authors make clear that the correlation between health and wealth is only partial, demonstrated, for instance, by the economic ability of people to buy imported junk food rather than nutritious, but low status, local produce. The book claims to differ from previous studies of health and lifestyles in that it considers factors at individual and community levels as well as at a global level. Specifically, it examines three case studies of marginalised communities: Mongolia, Uzbekistan, and the Marshall Islands. Comparing these three communities, it describes the demographic and health transitions that have occurred. Much of the information in this section is fascinating but, unfortunately, also often repetitive. It reads as a composite of two academic publications and, while providing a rich supply of references, would have benefited from more aggressive editing.

The authors are clearly experts in their field. Christine McMurray is the demographer at the Secretariat of the Pacific Community and Roy Smith is codirector of the Centre for Asia-Pacific Studies at Nottingham Trent University. However, there are places where they seem to be merely stating the obvious. For example, in describing the lifestyle of young people in the urban areas of the Marshall Islands, they say, “A favourite activity of adolescent boys is to establish gangs with their own rituals and signs, which contribute to the close bonding of sibling groups.” Surely this is not specific to the Marshall Islands? A few questionable medical statements have also crept in. The traditional Mongolian lifestyle, with lack of toilet facilities, is said to be associated with “genitourinary tract conditions including gallstones.” Somewhat frustrating is the lack of acknowledgement of the responsibility that we, in the North, must take for the effects of putting multinational profits ahead of health and wellbeing.

The book, however, makes for stimulating reading and might help to make sense of the lives of some of the people and patients we see in our surgeries, outpatient clinics, and, perhaps particularly, teaching sessions.
IL-10-producing regulatory B cells restrain the T follicular helper cell response in primary Sjögren’s syndrome
Authors: Xiang Lin, Xiaohui Wang, Fan Xiao, Kongyang Ma, Lixiong Liu, Xiaoqi Wang, Dong Xu, Fei Wang, Xiaofei Shi, Dongzhou Liu, Yan Zhao, Liwei Lu
Journal: Cellular and Molecular Immunology (2019)
Abstract P004: Shift-working Firefighters Have Poorer Heart Health Than They Think: An Intervention Opportunity
Authors: Freda Patterson, Richard Suminski, Susan K Malone, Alicia Lozano, Sara A Jahnke, Walter S Poston
Journal: Circulation (2017)

Background: As an occupational sub-group, career firefighters experience a disproportionately higher prevalence of cardiac events and risk factors than the general population. The pervasive nature of poor cardiovascular health (CVH) in this population might belie an occupational norm. Underestimation of poor health could be a barrier to the adoption of health-enhancing behaviors. Methods: Baseline data from a sample of 478 male firefighters from five different fire houses were used to examine the relationship between objective and perceived health. Objective CVH was defined as meeting the American Heart Association ideal recommendations for the following six, CVH metrics: tobacco use (non-smoker), body mass index (≤24.9 kg/m 2 ), physical activity (≥75 min/wk vigorous or ≥150 min/wk moderate activity), fruit and vegetable intake (≥4.5 cups/d), blood pressure (&lt;120/80 mm Hg) and total lipids (&lt;200 mg/dL). Firefighters rated their perceived health as excellent, average, fair or poor. The proportion of firefighters meeting the ideal status for each CVH metric, and total CVH metrics achieved, was generated. A chi-square test of independence examined differences between the binary ideal CVH metrics (0-3 versus 4-6 ideal CVH metrics) and perceived excellent/average health. Results: The mean age of the sample was 38.2 years (SD=9.9), 89% (413/478) were Caucasian, 73% (334/478) were married, 67% (290/478) had an annual income of at least $75,000, and 90% (410/478) had attended college. Three-quarters (76%; 225/478) of the sample met the ideal recommendations for tobacco use, 20% (93/478) for body mass index, 0% for physical activity, 36% (174/478) for fruit and vegetable intake, 39% (184/478) for blood pressure, and 88% (345/478) for lipids. Overall, none of the firefighters sampled had ideal status on all 6 CVH metrics considered. Ninety-two percent (426/478) of the sample rated their health as average to excellent, although only 10% (47/478) of the sample had ideal status for 4-6 of the CVH metrics; 90% (431/478) had ideal status for 0-3 metrics (X 2 = 4.54; p=.03). Conclusion: The CVH status of firefighters is poor, but firefighters with poor heart health inaccurately perceive their health as average or better. Addressing this misperception gap will be necessary to optimize responses to CVH interventions delivered to this population.