tbuckley/cabot-search huggingface dataset:
Endothelial-mesenchymal transition harnesses HSP90α-secreting M2-macrophages to exacerbate pancreatic ductal adenocarcinoma
Authors: Chi-Shuan Fan, Li-Li Chen, Tsu-An Hsu, Chia-Chi Chen, Kee Voon Chua, Chung-Pin Li, Tze-Sing Huang
Journal: Journal of Hematology & Oncology (2019)

Endothelial-to-mesenchymal transition (EndoMT) can provide a source of cancer-associated fibroblasts which contribute to desmoplasia of many malignancies including pancreatic ductal adenocarcinoma (PDAC). We investigated the clinical relevance of EndoMT in PDAC, and explored its underlying mechanism and therapeutic implication.Expression levels of 29 long non-coding RNAs were analyzed from the cells undergoing EndoMT, and an EndoMT index was proposed to survey its clinical associations in the PDAC patients of The Cancer Genome Atlas database. The observed clinical correlation was further confirmed by a mouse model inoculated with EndoMT cells-involved PDAC cell grafts. In vitro co-culture with EndoMT cells or treatment with the conditioned medium were performed to explore the underlying mechanism. Because secreted HSP90α was involved, anti-HSP90α antibody was evaluated for its inhibitory efficacy against the EndoMT-involved PDAC tumor.A combination of low expressions of LOC340340, LOC101927256, and MNX1-AS1 was used as an EndoMT index. The clinical PDAC tissues with positive EndoMT index were significantly correlated with T4-staging and showed positive for M2-macrophage index. Our mouse model and in vitro cell-culture experiments revealed that HSP90α secreted by EndoMT cells could induce macrophage M2-polarization and more HSP90α secretion to promote PDAC tumor growth. Furthermore, anti-HSP90α antibody showed a potent therapeutic efficacy against the EndoMT and M2-macrophages-involved PDAC tumor growth.EndoMT cells can secrete HSP90α to harness HSP90α-overproducing M2-type macrophages to promote PDAC tumor growth, and such effect can be targeted and abolished by anti-HSP90α antibody.
Use of Bone-Modifying Agents Among Medicare Beneficiaries With Multiple Myeloma
Authors: Arjun Gupta, Peiqi Wang, Syed Abbas Ali, S. Vincent Rajkumar, Bishal Gyawali, Heidi N. Overton, Martin A. Makary
Journal: JAMA Oncology (2019)

potentially result in fluorouracil overdosing in women. 1 Conversely, fewer postoperative complications were noted in women, possibly related to the lower rate of abdominoperineal resections.Importantly, we did not detect any sexspecific differences for treatment adherence and long-term clinical outcome.The results are in line with data from the US Intergroup 0114 trial 5 of adjuvant chemoradiotherapy using 4 different fluorouracil drug regimens.Acute toxic effects were significantly increased in women, but no difference occurred for DFS and local control by sex.In a large retrospective Surveillance, Epidemiology, and End Results database analysis with 105 511 patients with stage I to III rectal cancer treated in the United States from 1988 to 2012, 6 better DFS was reported in women.However, these data are limited by their retrospective nature and heterogeneous patient cohorts and treatment schedules.These findings have implications in the clinical setting.Although to our knowledge no data support using different chemotherapy regimens for men and women with rectal cancer, increased awareness of a higher risk of toxic effects among women may facilitate refinement of fluorouracil-based chemoradiotherapy and adjuvant chemotherapy, such as tailored patient education, closer monitoring of adverse effects, and earlier introduction of supportive measures.
Probiotics, including nisin‐based probiotics, improve clinical and microbial outcomes relevant to oral and systemic diseases
Authors: Trang Nguyen, Hanna Brody, Guo‐Hao Lin, Hélène Rangé, Ryutaro Kuraji, Changchang Ye, Pachiyappan Kamarajan, Allan Radaic, Li Gao, Yvonne Kapila
Journal: Periodontology 2000 (2019)

The effects of probiotic supplementation on systemic health and gastrointestinal diseases have been investigated in numerous studies. The aim of this review is to provide an overview of probiotics and their effects on periodontal health. Probiotics show beneficial effects as adjunctive therapeutics and as stand-alone agents in the treatment and prevention of gingivitis as well as specific clinical parameters of periodontitis. This review focuses on the clinical and microbiological aspects of probiotics in the context of health, gingivitis, and periodontitis. In addition, a special focus on nisin-producing probiotics and nisin itself showcase their significant potential for oral and systemic use.
Donor surfactant protein A2 polymorphism and lung transplant survival
Authors: Frank D'Ovidio, Joanna Floros, Beatrice Aramini, David Lederer, Susan L. DiAngelo, Selim Arcasoy, Joshua R. Sonett, Hillary Robbins, Lory Shah, Joseph Costa, Andreacarola Urso
Journal: European Respiratory Journal (2019)

Purpose Gene polymorphisms of surfactant proteins, key players in lung innate immunity, have been associated with various lung diseases. The aim of this study was to investigate the potential association between variations within the surfactant protein (SP)-A gene of the donor lung allograft and recipient post-transplant outcome. Methods Lung-transplant patients (n=192) were prospectively followed-up with pulmonary function tests, bronchoscopies with bronchoalveolar lavage and biopsies. Donor lungs were assayed for SP-A1 (6A n ) and SP-A2 (1A n ) gene polymorphism using the pyrosequencing method. Unadjusted and adjusted stratified Cox survival models are reported. Results SP-A1 and SP-A2 genotype frequency and lung transplant recipient and donor characteristics as well as cause of death are noted. Recipients were grouped per donor SP-A2 variants. Individuals that received lungs from donors with the SP-A2 1A 0 (n=102) versus 1A 1 variant (n=68) or SP-A2 genotype 1A 0 1A 0 (n=54) versus 1A 0 A 1 (n=38) had greater survival at 1 year (log-rank p&lt;0.025). No significant association was noted for SP-A1 variants. Stratified adjusted survival models for 1-year survival and diagnosis showed a reduced survival for 1A 1 variant and the 1A 0 1A 1 genotype. Furthermore, when survival was conditional on 1-year survival no significance was observed, indicating that the survival difference was due to the first year's outcome associated with the 1A 1 variant. Conclusion Donor lung SP-A gene polymorphisms are associated with post-transplant clinical outcome. Lungs from donors with the SP-A2 variant 1A 1 had a reduced survival at 1 year. The observed donor genetic differences, via innate immunity relate to the post-transplant clinical outcome.
Enhanced Loading of Functional miRNA Cargo via pH Gradient Modification of Extracellular Vesicles
Authors: Anjana Jeyaram, Tek N. Lamichhane, Sheng Wang, Lin Zou, Eshan Dahal, Stephanie M. Kronstadt, Daniel Levy, Babita Parajuli, Daphne R. Knudsen, Wei Chao, Steven M. Jay
Journal: Molecular Therapy (2019)

Based on their identification as physiological nucleic acid carriers in humans and other organisms, extracellular vesicles (EVs) have been explored as therapeutic delivery vehicles for DNA, RNA, and other cargo. However, efficient loading and functional delivery of nucleic acids remain a challenge, largely because of potential sources of degradation and aggregation. Here, we report that protonation of EVs to generate a pH gradient across EV membranes can be utilized to enhance vesicle loading of nucleic acid cargo, specifically microRNA (miRNA), small interfering RNA (siRNA), and single-stranded DNA (ssDNA). The loading process did not impair cellular uptake of EVs, nor did it promote any significant EV-induced toxicity response in mice. Cargo functionality was verified by loading HEK293T EVs with either pro- or anti-inflammatory miRNAs and observing the effective regulation of corresponding cellular cytokine levels. Critically, this loading increase is comparable with what can be accomplished by methods such as sonication and electroporation, and is achievable without the introduction of energy associated with these methods that can potentially damage labile nucleic acid cargo. Based on their identification as physiological nucleic acid carriers in humans and other organisms, extracellular vesicles (EVs) have been explored as therapeutic delivery vehicles for DNA, RNA, and other cargo. However, efficient loading and functional delivery of nucleic acids remain a challenge, largely because of potential sources of degradation and aggregation. Here, we report that protonation of EVs to generate a pH gradient across EV membranes can be utilized to enhance vesicle loading of nucleic acid cargo, specifically microRNA (miRNA), small interfering RNA (siRNA), and single-stranded DNA (ssDNA). The loading process did not impair cellular uptake of EVs, nor did it promote any significant EV-induced toxicity response in mice. Cargo functionality was verified by loading HEK293T EVs with either pro- or anti-inflammatory miRNAs and observing the effective regulation of corresponding cellular cytokine levels. Critically, this loading increase is comparable with what can be accomplished by methods such as sonication and electroporation, and is achievable without the introduction of energy associated with these methods that can potentially damage labile nucleic acid cargo.
Shifting blue hue sign: an unusual endoscopic finding in a patient suspected of having gastrointestinal blood loss
Authors: Mark P. Lamberts, Helena T. J. I. de Leest
Journal: Endoscopy (2019)

A 75-year-old man presented to the emergency department with lower abdominal pain for 4 days. He had a history of atrial fibrillation for which he used rivaroxaban. He did not report any trauma. He mentioned that he had black tarry stools. His vital signs were normal. Physical examination showed some tenderness in the lower abdomen. Rectal examination was not performed. His hemoglobin had dropped to 10.6 g/dL.
Radiotherapy as an Immunological Booster in Patients with Metastatic Melanoma or Renal Cell Carcinoma Treated with High-Dose Interleukin-2: Final Data
Authors: L. Ridolfi, J. Bulgarelli, E. Petracci, E. Pancisi, C. Piccinini, A. Granato, M. Petrini, M. Tazzari, V. Ancarani, L. Turci, G. Gentili, L. Valmorri, A. Romeo, U.F.F. De Giorgi, S.L. Burgio, C. Casadei, P. Cortesi, C. Lolli, F. De Rosa, M. Guidoboni
Journal: Annals of Oncology (2019)
Working as a doctor in Australia
Authors: Helen Jones
Journal: BMJ (2019)

With its promise of sun and a laidback lifestyle, Australia has long been a popular destination for UK trained doctors looking for a temporary or permanent move overseas. Getting a job there, however, has just become more difficult.

In its 2019 budget, the Australian government outlined plans to cut the number of overseas trained doctors entering Australia to work in primary healthcare by about 10%—around 200 people annually—over the next four years. The government says it is a gradual process and will provide opportunities for the growing number of Australian trained medical graduates. Overseas trained doctors will be directed to “areas of workforce need,” which means rural and remote communities.

That said, there are still plenty of opportunities available and, while more junior hospital positions may be filled within Australia, senior and specialised staff are in particular demand.

GPs are in demand in rural areas although you may have …
Stimuli-responsive polymeric prodrug-based nanomedicine delivering nifuroxazide and doxorubicin against primary breast cancer and pulmonary metastasis
Authors: Lei Luo, Fanshu Xu, Huilan Peng, Yonghuang Luo, Xiaohe Tian, Giuseppe Battaglia, Hu Zhang, Qiyong Gong, Zhongwei Gu, Kui Luo
Journal: Journal of Controlled Release (2019)
Long-term Outcome of Implantable Cardioverter/Defibrillator Lead Failure
Authors: Gustav Arnar Davidsson, Gudlaug M. Jonsdottir, Hjortur Oddsson, Sigrun H. Lund, David O. Arnar
Journal: JAMA Internal Medicine (2019)

Jay Sengupta, MD; Katelyn Storey, BA; Susan Casey, RN; Lena Trager, BA; Melissa Buescher, MPH; Mark Horning, RN; Charles Gornick, MD; Raed Abdelhadi, MD; Chuen Tang, MD; Suzanne Brill, RN; Laura Ashbach, RN; Robert G. Hauser, MD
Endoscopic suturing for refractory bilious reflux after gastroduodenostomy and gastrojejunostomy
Authors: Nitin Jagtap, Rakesh Kalapala, G. Venkat Rao, D. Nageshwar Reddy
Journal: Endoscopy (2019)

A 35-year-old woman who had undergone previous multiple abdominal surgeries, including Billroth I gastrectomy with gastrojejunostomy and gastroduodenostomy, presented with a 6-month history of regurgitation and bilious vomiting. These symptoms were refractory to proton pump inhibitors, prokinetics, and lifestyle modification. Contrast study ([Fig. 1 a]) revealed a patent gastrojejunostomy with flow of contrast into the duodenal loop and no distal obstruction. Endoscopy revealed significant bilious secretions in the stomach with a patent gastrojejunostomy and gastroduodenostomy.
Abstract 11912: Glycocalyx Shedding is Markedly Increased During Acute Phase of Takotsubo Cardiomyopathy
Authors: Thanh H Nguyen, Saifei Liu, Gao Ong, Irene Stafford, Michael Frenneaux, John D Horowitz
Journal: Circulation (2016)

Introduction: Acute myocardial infarction (AMI) and other forms of myocardial acute oxidative stress are associated with variable “shedding” of vascular and other glycocalyx. This glycocalyx shedding (GCS) can be quantitated by release into plasma of glycocalyx components such as Syndecan-1 (SD1), which is the most prevalent proteoglycan. Previous in vitro studies have implicated both catecholamines and BNP release as potential accentuating factors in GCS: since these are prominent aspects of the pathogenesis of Takotsubo cardiomyopathy (TTC), we hypothesised that TTC (i) would be associated with increased GCS both acutely and during subsequent 3 months of continued myocardial inflammation and (ii) extent of GCS would be predictable on the basis of NT-proBNP and catecholamine releases. Methods: SD1 concentrations were measured in 49 TTC patients acutely and after 3 months in comparison with 12 normal age-matched controls and 10 myocardial infarct patients. Correlations between SD1 and (i) acute LV function, (ii) lowest BP on admission, (iii) peak catecholamine release, and (iv) extent of systemic and myocardial inflammatory activation [measured by high sensitive C-reactive protein (hsCRP), NT-proBNP concentrations, and myocardial T2 signal intensity on cardiac MRI] were sought. Results: Acute SD1 concentrations in TTC patients were significantly elevated compared to 3 month and control values (2-way ANOVA) (Figure). However, there was no significant difference between acute TTC and MI levels. In addition, there were no correlations between SD1 concentrations and extent of severity of acute episode. Conclusions: 1. TTC, despite minimal associated myocardial necrosis, is associated with marked increase in GCS. 2. Extent of GCS in TTC is not closely related to either release of NT-proBNP or normetanephrine. We postulate that GCS may contribute to some of the clinical features of TTC, such as development of pulmonary oedema without marked increases in PCWP.
Human tau pathology transmits glial tau aggregates in the absence of neuronal tau
Authors: Sneha Narasimhan, Lakshmi Changolkar, Dawn M. Riddle, Alexandra Kats, Anna Stieber, Sarah A. Weitzman, Bin Zhang, Zhiyong Li, Erik D. Roberson, John Q. Trojanowski, Virginia M.Y. Lee
Journal: The Journal of Experimental Medicine (2019)

Tauopathies are characterized by abnormal accumulation of tau protein in neurons and glia. In Alzheimer’s disease (AD), tau aggregates in neurons, while in corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), tau also aggregates in astrocytes and oligodendrocytes. We previously demonstrated that human CBD and PSP tauopathy lysates (CBD-tau and PSP-tau) contain distinct tau strains that propagate neuronal and glial tau aggregates in nontransgenic (nonTg) mouse brain. Yet the mechanism of glial tau transmission is unknown. Here, we developed a novel mouse model to knock down tau in neurons to test for glial tau transmission. While oligodendroglial tau pathology propagated across the mouse brain in the absence of neuronal tau pathology, astrocytic tau pathology did not. Oligodendroglial tau aggregates propagated along white matter tracts independently of neuronal axons, and resulted in oligodendrocyte cell loss. Thus, glial tau pathology has significant functional consequences independent of neuronal tau pathology.
Thelma M Phelps
Authors: Rachel Angus, Christine Hopton
Journal: BMJ (2019)

Thelma M Phelps was born in south London. She attended the Mary Datchelor School and the Royal Free Hospital School of Medicine for Women. Her father believed that money spent on education was never wasted. Shortly after the start of the first year of the course, the second world war broke out and the students were evacuated to St Andrews. In the …
Determining Levers of Cost-effectiveness for Screening Infants at High Risk for Peanut Sensitization Before Early Peanut Introduction
Authors: Matthew Greenhawt, Marcus Shaker
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Early peanut introduction reduces the risk of developing peanut allergy, especially in high-risk infants. Current US recommendations endorse screening but are not cost-effective relative to other international strategies. <h3>Objective</h3> To identify scenarios in which current early peanut introduction guidelines would be cost-effective. <h3>Design, Setting, and Participants</h3> This simulation/cohort economic evaluation used microsimulations and cohort analyses in a Markov model to evaluate the cost-effectiveness of early peanut introduction with and without peanut skin prick test (SPT) screening in high-risk infants during an 80-year horizon from a societal perspective. Data were analyzed from April to May 2019. <h3>Exposures</h3> High-risk infants with early-onset eczema and/or egg allergy underwent early peanut introduction with and without peanut SPT screening (100 000 infants per treatment strategy) using a dichotomous 8-mm SPT cutoff value (stipulated in the current US guideline). <h3>Main Outcomes and Measures</h3> Cost, quality-adjusted life-years (QALYs), net monetary benefit, peanut allergic reactions, severe allergic reactions, and deaths due to peanut allergy. <h3>Results</h3> In the simulated cohort of 200 000 infants and using the base case during the model horizon, a no-screening approach had lower mean (SD) costs ($13 449 [$38 163] vs $15 279 [$38 995]) and higher mean (SD) gain in QALYs (29.25 [3.28] vs 29.23 [3.30]) vs screening but resulted in more allergic reactions (mean [SD], 1.07 [3.15] vs 1.01 [3.02]), severe allergic reactions (mean [SD], 0.53 [1.66] vs 0.52 [1.62]), and anaphylaxis involving cardiorespiratory compromise (mean [SD], 0.50 [1.59] vs 0.49 [1.47]) per individual. In deterministic SPT sensitivity analyses at base-case sensitivity and specificity rates, screening could be cost-effective at a high disutility rate (the negative effect of a food allergic reaction) (76-148 days of life traded) for an at-home vs in-clinic reaction in combination with high baseline peanut allergy prevalence among infants at high risk for peanut allergy and not yet exposed to peanuts. If an equivalent rate and disutility of accidental and index anaphylaxis was assumed and the 8-mm SPT cutoff had 0.85 sensitivity and 0.98 specificity, screening was cost-effective at a peanut allergy prevalence of 36%. <h3>Conclusions and Relevance</h3> The results of this study suggest that the current screening approach to early peanut introduction could be cost-effective at a particular health utility for an in-clinic reaction, SPT sensitivity and specificity, and high baseline peanut allergy prevalence among high-risk infants. However, such conditions are unlikely to be plausible to realistically achieve. Further research is needed to define the health state utility associated with reaction location.
Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure
Authors: Timothy P. Hughes, Michael J. Mauro, Jorge E. Cortes, Hironobu Minami, Delphine Rea, Daniel J. DeAngelo, Massimo Breccia, Yeow-Tee Goh, Moshe Talpaz, Andreas Hochhaus, Philipp le Coutre, Oliver Ottmann, Michael C. Heinrich, Juan L. Steegmann, Michael W.N. Deininger, Jeroen J.W.M. Janssen, Francois-Xavier Mahon, Yosuke Minami, David Yeung, David M. Ross, Martin S. Tallman, Jae H. Park, Brian J. Druker, David Hynds, Yuyan Duan, Christophe Meille, Florence Hourcade-Potelleret, K. Gary Vanasse, Fabian Lang, Dong-Wook Kim
Journal: New England Journal of Medicine (2019)

Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown.
NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2+
Authors: Louis Fehrenbacher, Reena S. Cecchini, Charles E. Geyer Jr, Priya Rastogi, Joseph P. Costantino, James N. Atkins, John P. Crown, Jonathan Polikoff, Jean-Francois Boileau, Louise Provencher, Christopher Stokoe, Timothy D. Moore, André Robidoux, Patrick J. Flynn, Virginia F. Borges, Kathy S. Albain, Sandra M. Swain, Soonmyung Paik, Eleftherios P. Mamounas, Norman Wolmark
Journal: Journal of Clinical Oncology (2019)

PURPOSE Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer. PATIENTS AND METHODS A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) &lt; 2.0 or, if ratio was not performed, HER2 gene copy number &lt; 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks. RESULTS At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab [CRxT] v 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; P = .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50; P = .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95; P = .15). There were no unexpected toxicities from the addition of trastuzumab to CRx. CONCLUSION The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2–overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.
Heterozygous Mutations of Clpb As a Newly Identified and Frequent Cause of Severe Congenital Neutropenia
Authors: Julia T Warren, Peeradol Wattanasirakul, David H Spencer, Adam Locke, Vahagn Makaryan, Audrey Anna Bolyard, Karl Welte, Julia Skokowa, David C. Dale, Daniel C. Link
Journal: Blood (2019)
The dynamics between neo-adjuvant treatment and immune responses in human breast cancer
Authors: N. Thomas, S. Garaud, A. De Wind, A. Pabois, P. De Silva, L. Craciun, A. Boisson, C. Naveaux, H. Duvillier, D. Larsimont, A. Awada, K. Willard-Gallo
Journal: Annals of Oncology (2019)