tbuckley/cabot-search huggingface dataset:
Abstract CS1-2: Searching for the optimal duration of adjuvant endocrine therapy in breast cancer
Authors: V Stearns
Journal: Cancer Research (2018)

Abstract Endocrine therapy is an integral part of the adjuvant systemic management of women with early stage hormone receptor-positive breast cancer. Adjuvant endocrine therpay is associated with significant improvements in disease-free and overall survival. Several adjuvant endocrine therapy approaches are available to women based on their menopausal status, disease stage, tumor characteristics, co-morbidities, and individual preferences. The optimal duration of adjuvant endocrine therapy established to date is 5 to 10 years. Extended adjuvant endocrine therpay provides only a modest additional benefit compared to a 5-year treatment duration. Studies reported in recent years offer some guidance to help clinicians provide recommendations regarding the type and duration of adjuvant endocrine therpay. Clinicians must weigh treatment benefits and potential adverse events for individual patients. Models to help individualize treatment recommendations are needed. Several opportunities are available to predict personalized risk of recurrence and likelihood of developing bothersome symptoms or serious adverse events. Women should have a close follow up with their physicians during the first year or therapy to identify emerging symptoms and to provide early interventions to optimize adherence to adjuvant endocrine therpay. Clinicians should engage in continuous discussion with each woman regarding the duration of treatment most appropriate for her and revisit recommendations based on evolving clinical trial results or events in the patient's life. In this presentation I will discuss the available data regarding optimal length of adjuvant endocrine therapy. I will review expected benefits and toxicities. I will also discuss emerging biomarkers and approaches that may help individualize treatment duration for women with hormone receptor-positive breast cancer. Citation Format: Stearns V. Searching for the optimal duration of adjuvant endocrine therapy in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr CS1-2.
Dicer1 Deficiency in the Idiopathic Pulmonary Fibrosis Fibroblastic Focus Promotes Fibrosis by Suppressing MicroRNA Biogenesis
Authors: Jeremy Herrera, Daniel J. Beisang, Mark Peterson, Colleen Forster, Adam Gilbertsen, Alexey Benyumov, Karen Smith, Christopher E. Korenczuk, Victor H. Barocas, Kacey Guenther, Ryan Hite, Lin Zhang, Craig A. Henke, Peter B. Bitterman
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

The lung extracellular matrix (ECM) in idiopathic pulmonary fibrosis (IPF) mediates progression of fibrosis by decreasing fibroblast expression of miR-29 (microRNA-29), a master negative regulator of ECM production. The molecular mechanism is undefined. IPF-ECM is stiffer than normal. Stiffness drives fibroblast ECM production in a YAP (yes-associated protein)-dependent manner, and YAP is a known regulator of miR-29. Therefore, we tested the hypothesis that negative regulation of miR-29 by IPF-ECM was mediated by mechanotransduction of stiffness.To determine how IPF-ECM negatively regulates miR-29.We decellularized lung ECM using detergents and prepared polyacrylamide hydrogels of defined stiffness by varying acrylamide concentrations. Mechanistic studies were guided by immunohistochemistry of IPF lung and used cell culture, RNA-binding protein assays, and xenograft models.Contrary to our hypothesis, we excluded fibroblast mechanotransduction of ECM stiffness as the primary mechanism deregulating miR-29. Instead, systematic examination of miR-29 biogenesis revealed a microRNA processing defect that impeded processing of miR-29 into its mature bioactive forms. Immunohistochemical analysis of the microRNA processing machinery in IPF lung specimens revealed decreased Dicer1 expression in the procollagen-rich myofibroblastic core of fibroblastic foci compared with the focus perimeter and adjacent alveolar walls. Mechanistically, IPF-ECM increased association of the Dicer1 transcript with RNA binding protein AUF1 (AU-binding factor 1), and Dicer1 knockdown conferred primary human lung fibroblasts with cell-autonomous fibrogenicity in zebrafish and mouse lung xenograft models.Our data identify suppression of fibroblast Dicer1 expression in the myofibroblast-rich IPF fibroblastic focus core as a central step in the mechanism by which the ECM sustains fibrosis progression in IPF.
3D tissue engineering, an emerging technique for pharmaceutical research
Authors: Gregory Jensen, Christian Morrill, Yu Huang
Journal: Acta Pharmaceutica Sinica B (2018)

Tissue engineering and the tissue engineering model have shown promise in improving methods of drug delivery, drug action, and drug discovery in pharmaceutical research for the attenuation of the central nervous system inflammatory response. Such inflammation contributes to the lack of regenerative ability of neural cells, as well as the temporary and permanent loss of function associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and traumatic brain injury. This review is focused specifically on the recent advances in the tissue engineering model made by altering scaffold biophysical and biochemical properties for use in the treatment of neurodegenerative diseases. A portion of this article will also be spent on the review of recent progress made in extracellular matrix decellularization as a new and innovative scaffold for disease treatment.
Association of preoperative monocyte-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio with overall survival after resection of pancreatic neuroendocrine tumors.
Authors: Roheena Z. Panni, Jesse T Davidson, Bradley A. Krasnick, Martha McGilvray, Jorge Zarate Rodriguez, Alexandra G Lopez-Aguiar, Mary Dillhoff, George A. Poultsides, Emily Winslow, Flavio G. Rocha, Kamran Idrees, Chet Hammill, Clifford Cho, Maria Majella Doyle, William C. Chapman, William G. Hawkins, Steven M. Strasberg, Nikolaos A Trikalinos, Shishir Maithel, Ryan Fields
Journal: Journal of Clinical Oncology (2018)

216 Background: Neutrophil, monocyte and lymphocyte counts are important biomarkers of the tumor-induced systemic inflammatory response. A lower monocyte-to-lymphocyte ratio (MLR) and neutrophil-to-lymphocyte ratio (NLR) is associated with a favorable prognosis for certain tumors. However, this association has not yet been demonstrated in resected pancreatic neuroendocrine tumors (PNETs). The aim of this study was to investigate the prognostic significance of MLR and NLR in patients with resectable PNETs with regards to overall survival (OS). Methods: Eligible patients undergoing surgery for PNETs between 2000 and 2016 were identified using a national multi-center cohort dataset. Their pre-operative neutrophil, monocyte and lymphocyte counts were imported and NLR and MLR were calculated. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut offs for NLR and MLR. Univariate analyses were used to compare patient factors and tumor characteristics in different groups. The difference in OS between high and low groups was explored with the use of Kaplan Meier curves and compared using log-rank tests. Results: A total of 635 patients were analyzed. Univariate analysis revealed that higher lymphocyte, low monocyte and low neutrophil counts were associated with improved OS (P = 0.0002, 0.014 and 0.011 respectively). The mean NLR and MLR level was 4.11 ± 0.219 and 0.4295 ± 0.0196, respectively. Lower NLR ( &lt; 4) and lower MLR ( &lt; 0.25) were significantly associated with improved OS (p &lt; 0.001 &amp; p &lt; 0.0001). Median survival was 141 months in the low NLR group (n = 474) and 119 months in the high NLR group (n = 161). The median survival in the high MLR group (n = 464) was 120 months and has not been reached in the low MLR group (n = 171). On multivariate analysis, low MLR was independent predictor of improved OS when controlling for age, race and comorbidities (p &lt; 0.001). Conclusions: For resectable PNETs, low pre-operative NLR and MLR levels are significantly associated with improved survival. NLRs and MLRs may serve as valuable markers to stratify PNET patients for subsequent therapies and clinical trial enrollment.
Screening for infectious diseases among newly arrived asylum seekers, Bavaria, Germany, 2015
Authors: Nikolaus Ackermann, Durdica Marosevic, Stefan Hörmansdorfer, Ute Eberle, Gabriele Rieder, Bianca Treis, Anja Berger, Heribert Bischoff, Katja Bengs, Regina Konrad, Wolfgang Hautmann, Katharina Schönberger, Anne Belting, Gisela Schlenk, Gabriele Margos, Martin Hoch, Friedrich Pürner, Volker Fingerle, Bernhard Liebl, Andreas Sing
Journal: Eurosurveillance (2018)

Background and aim As a consequence of socioeconomic and political crises in many parts of the world, many European Union/European Economic Area (EU/EEA) countries have faced an increasing number of migrants. In the German federal state of Bavaria, a mandatory health screening approach is implemented, where individuals applying for asylum have to undergo a medical examination that includes serological testing for HIV and hepatitis B, screening for tuberculosis, and until September 2015, stool examination for Salmonella spp. and Shigella spp.. Methods : Data from mandatory screening of all first-time asylum seekers in Bavaria in 2015 was extracted from the mandatory notification and laboratory information system and evaluated. Results : The HIV positivity and hepatitis B surface antigen (HBsAg) positivity rate of tested samples from asylum seekers were 0.3% and 3.3%, respectively, while detection rate of active tuberculosis was between 0.22% and 0.38%. The rates for HIV, hepatitis B, and tuberculosis among asylum seekers were similar to the corresponding prevalence rates in most of their respective countries of birth. Only 47 Salmonella spp. (0.1%) were isolated from stool samples: 45 enteric and two typhoid serovars. Beyond mandatory screening, louse-borne relapsing fever was found in 40 individuals. Conclusions : These results show that mandatory screening during 2015 in Bavaria yielded overall low positivity rates for all tested infectious diseases in asylum seekers. A focus of mandatory screening on specific diseases in asylum seekers originating from countries with higher prevalence of those diseases could facilitate early diagnosis and provision of treatment to affected individuals while saving resources.
Antiphospholipid Antibodies Inhibit Trophoblast Toll‐Like Receptor and Inflammasome Negative Regulators
Authors: Melissa J. Mulla, Ingrid C. Weel, Julie A. Potter, Stefan M. Gysler, Jane E. Salmon, Maria T. S. Peraçoli, Carla V. Rothlin, Lawrence W. Chamley, Vikki M. Abrahams
Journal: Arthritis & Rheumatology (2018)

Objective Women with antiphospholipid antibodies (aPL) are at risk for pregnancy complications associated with poor placentation and placental inflammation. Although these antibodies are heterogeneous, some anti–β 2 ‐glycoprotein I (anti‐β 2 GPI) antibodies can activate Toll‐like receptor 4 (TLR‐4) and NLRP3 in human first‐trimester trophoblasts. The objective of this study was to determine the role of negative regulators of TLR and inflammasome function in aPL‐induced trophoblast inflammation. Methods Human trophoblasts were not treated or were treated with anti‐β 2 GPI aPL or control IgG in the presence or absence of the common TAM (TYRO3, AXL, and Mer tyrosine kinase [MERTK]) receptor ligand growth arrest–specific protein 6 (GAS6) or the autophagy‐inducer rapamycin. The expression and function of the TAM receptor pathway and autophagy were measured by quantitative reverse transcription–polymerase chain reaction (qRT‐PCR), Western blotting, and enzyme‐linked immunosorbent assay (ELISA). Antiphospholipid antibody–induced trophoblast inflammation was measured by qRT‐PCR, activity assays, and ELISA. Results Anti‐β 2 GPI aPL inhibited trophoblast TAM receptor function by reducing cellular expression of the receptor tyrosine kinases AXL and MERTK and the ligand GAS6. The addition of GAS6 blocked the effects of aPL on the TLR‐4–mediated interleukin‐8 (IL‐8) response. However, the NLRP3 inflammasome‐mediated IL‐1β response was not affected by GAS6, suggesting that another regulatory pathway was involved. Indeed, anti‐β 2 GPI aPL inhibited basal trophoblast autophagy, and reversing this with rapamycin inhibited aPL‐induced inflammasome function and IL‐1β secretion. Conclusion Basal TAM receptor function and autophagy may serve to inhibit trophoblast TLR and inflammasome function, respectively. Impairment of TAM receptor signaling and autophagy by anti‐β 2 GPI aPL may allow subsequent TLR and inflammasome activity, leading to a robust inflammatory response.
World Medical Association fundamentals of medical ethics course
Authors: David Warriner
Journal: BMJ (2009)

The functions of the World Medical Association fundamentals of medical ethics e-learning course are manifold: the course acts as an excellent platform for further study; gentle revision for the morally rusty; or as a comprehensive beginners’ guide. If you are a busy doctor, a medical student, a health professional, or any other interested party, I would recommend this course as a firm foundation on which to build your knowledge of medical ethics.

I did the course at the start of my core training year 1 placement in respiratory medicine in autumn 2008.

I disliked medical ethics intensely as a medical student; I found the principles difficult to understand and could not see its relevance. Medical ethics is a notoriously difficult subject to teach, and although the overarching principles are clear, putting these into practice is another matter. With the hindsight of maturity and …
COMPUTED TOMOGRAPHY MYOCARDIAL PERFUSION ADDS DIAGNOSTIC POWER TO CORONARY COMPUTED TOMOGRAPHY ANGIOGRAPHY IN RENAL TRANSPLANT CANDIDATES: PRELIMINARY RESULTS
Authors: Eduardo Leal Adam, Carlos Rochitte, Pedro Lemos, Luiz Machado Cesar, Jose Jayme de Lima, Luis Henrique Gowdak
Journal: Journal of the American College of Cardiology (2018)
Bacterial growth, flow, and mixing shape human gut microbiota density and composition
Authors: Markus Arnoldini, Jonas Cremer, Terence Hwa
Journal: Gut Microbes (2018)

The human gut microbiota is highly dynamic, and host physiology and diet exert major influences on its composition. In our recent study, we integrated new quantitative measurements on bacterial growth physiology with a reanalysis of published data on human physiology to build a comprehensive modeling framework. This can generate predictions of how changes in different host factors influence microbiota composition. For instance, hydrodynamic forces in the colon, along with colonic water absorption that manifests as transit time, exert a major impact on microbiota density and composition. This can be mechanistically explained by their effect on colonic pH which directly affects microbiota competition for food. In this addendum, we describe the underlying analysis in more detail. In particular, we discuss the mixing dynamics of luminal content by wall contractions and its implications for bacterial growth and density, as well as the broader implications of our insights for the field of gut microbiota research.
Adiposity Impacts Intrarenal Hemodynamic Function in Adults With Long-standing Type 1 Diabetes With and Without Diabetic Nephropathy: Results From the Canadian Study of Longevity in Type 1 Diabetes
Authors: Petter Bjornstad, Julie A. Lovshin, Yuliya Lytvyn, Genevieve Boulet, Leif E. Lovblom, Omar N. Alhuzaim, Mohammed A. Farooqi, Vesta Lai, Josephine Tse, Leslie Cham, Andrej Orszag, Daniel Scarr, Alanna Weisman, Hillary A. Keenan, Michael H. Brent, Narinder Paul, Vera Bril, Bruce A. Perkins, David Z.I. Cherney
Journal: Diabetes Care (2018)

OBJECTIVE Central adiposity is considered to be an important cardiorenal risk factor in the general population and in type 1 diabetes. We sought to determine the relationship between central adiposity and intrarenal hemodynamic function in adults with long-standing type 1 diabetes with and without diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS Patients with type 1 diabetes (n = 66, duration ≥50 years) and age-/sex-matched control subjects (n = 73) were studied. The cohort was stratified into 44 DN Resistors (estimated glomerular filtration rate [eGFR] &amp;gt;60 mL/min/1.73 m2 and &amp;lt;30 mg/day urine albumin) and 22 patients with DN (eGFR ≤60 mL/min/1.73 m2 or ≥30 mg/day urine albumin). Intrarenal hemodynamic function (glomerular filtration rate for inulin [GFRINULIN], effective renal plasma flow for p-aminohippuric acid [ERPFPAH]) was measured. Afferent arteriolar resistance, efferent arteriolar resistance, renal blood flow, renal vascular resistance [RVR], filtration fraction, and glomerular pressure were derived from the Gomez equations. Fat and lean mass were quantified by DXA. RESULTS Whereas measures of adiposity did not associate with GFRINULIN or ERPFPAH in healthy control subjects, trunk fat mass inversely correlated with GFRINULIN (r = −0.46, P &amp;lt; 0.0001) and ERPFPAH (r = −0.31, P = 0.01) and positively correlated with RVR (r = 0.53, P = 0.0003) in type 1 diabetes. In analyses stratified by DN status, greater central adiposity related to lower GFRINULIN values in DN and DN Resistors, but the relationships between central adiposity and ERPFPAH and RVR were attenuated and/or reversed in patients with DN compared with DN Resistors. CONCLUSIONS The adiposity-intrarenal hemodynamic function relationship may be modified by the presence of type 1 diabetes and DN, requiring further study of the mechanisms by which adiposity influences renal hemodynamic function.
Peter Pritchard: general practitioner with “legendary” improvisation skills
Authors: Iona Heath
Journal: BMJ (2018)

Peter Pritchard, who died just a few months short of his centenary, had an extraordinary ability to improvise pragmatic solutions to practical problems, whether physical or organisational. This made him well prepared for 37 years in NHS general practice.

Perhaps in some way the unusual circumstances of his birth and childhood fostered his particular skills. He was born in London on 19 May 1918 during a German Zeppelin raid. His father had joined the Royal Naval Air Service in 1916 and had trained as an airship pilot. Unlike so many of his contemporaries, Peter’s father survived the war and in July 1919 he was a member of crew of the R34 airship which was the first aircraft to cross the Atlantic from east to west and back again. On arrival in New York after the four day crossing, he parachuted to the ground to supervise the landing of the airship, so becoming the first person to arrive in America by air. After this triumph, he was then killed in 1921, when the R38 airship exploded and plunged into the Humber estuary. Peter was only 3 years old, his sister 6, and his brother 5.

Ten years later Peter started at Woodbridge School …
The impact of prostate cancer (PC) margin extent (ME) at radical prostatectomy (RP) on biochemical relapse-free survival (bRFS).
Authors: Steven Neema Seyedin, Sarah L Mott, Anthony N Snow, James Kyle Russo, John Watkins
Journal: Journal of Clinical Oncology (2018)

83 Background: Surgical margin involvement (M+) by PC at RP is associated with suboptimal bRFS; however, the interaction of M+ with coincident high-risk clinicopathologic and treatment factors obscures accurate estimation of recurrence risk. The objective of this study is to determine whether ME permits risk stratification. Methods: Retrospective analysis of clinicopathologic factor association with bRFS. Eligible patients underwent RP alone for clinically localized PC. Patients with metastatic disease, PSA &gt; 30 at diagnosis, pathologic involvement of seminal vesicles or lymph nodes at RP, insufficient follow-up, or receipt of pre-RP or adjuvant therapy were excluded. Slides from RP specimens with close or positive margins were re-reviewed by study pathologists blinded to outcome. Results: From 2002-2010, 667 patients were eligible for analysis. The median age was 61 yrs (range, 43-76), and all had cT1-2 disease (83% T1c), with median PSA 5.6 (0.9-28.0; 85% ≤10). Robot-assisted RP was employed in 141 cases (21%). Two hundred ten patients (31%) had M+, with single maximal ME 3mm (0.1-23), and cumulative ME 4mm (0.1-34). At median follow-up of 102 months (13-184), 149 patients (22%) had recurrence, with estimated 8-year bRFS rates of 85%/56% for M-/+ patients (p &lt; 0.01). Multivariable analysis identified PSA, Gleason score (GS), extraprostatic extension, and M+ as associated with bRFS. Specific to patients with involved margins, the combination of ME and GS permitted recurrence risk stratification, with a low-risk subset identified (GS≤6 and ME &lt; 3mm; Table). Conclusions: The current investigation suggests that GS6 patients with maximal or cumulative ME &lt; 3mm appear to have favorable early 8-year bRFS following RP. GS6 patients with wider ME and GS ≥7 with any extent M+ appear to have suboptimal bRFS. RP pathology reports should include ME details, in order to more precisely estimate risk of subsequent disease recurrence. [Table: see text]
Response and adverse events to chemotherapy after prior checkpoint inhibition in lung cancer.
Authors: Julia Judd, Chethan Ramamurthy, Elizabeth Handorf, Hossein Borghaei, Matthew R. Zibelman, Daniel M. Geynisman, Jessica Ruth Bauman
Journal: Journal of Clinical Oncology (2018)

170 Background: Historically, responses to chemotherapy beyond the first line for lung cancer range from 5-10%. The effect of antecedent immunotherapy on the response and reaction to chemotherapy is not well-established, but the immunomodulatory effects of many chemotherapy agents may lead to synergistic effects including both improved responses and unique toxicities. Methods: We reviewed the charts of patients at our institution who received at least one dose of an anti-PD-1 agent (aPD-1) as monotherapy prior to June 1, 2017. Patients with a diagnosis of non-small cell lung cancer or small cell lung cancer who received subsequent chemotherapy were included for analysis. Charts were assessed for response to aPD-1, occurrence of immune-related adverse event (irAE) on aPD1, type of post-aPD-1 (PaPD-1) chemotherapy, PaPD-1 best response to chemotherapy, and occurrence of irAE during PaPD-1 chemotherapy. irAEs were assessed based on treating physician diagnoses. We tested the association between response and treatment characteristics using Fisher’s exact and Wilcoxon rank-sum tests. Results: A total of 40 patients met criteria for inclusion. Histology was NSCLC in 38 (95%) and SCLC in 2 (5%). Median age was 68 and mean number of lines of therapy prior to aPD-1 was 2.00 (95% CI, 1.72-2.28). PaPD-1 chemotherapies included paclitaxel (15%), docetaxel (28%), gemcitabine (23%), docetaxel-ramucirumab (7.5%), pemetrexed (2.5%) and platinum doublet (15%). The disease control rate to PaPD-1 chemotherapy was 35% and the ORR was 15% (0 complete responses, 6 partial responses). The response to PaPD-1 was not higher in taxane-containing regimens than in non-taxane-containing regimens (16% v. 13%, p = 0.99). Four (10%) patients were diagnosed with an irAE during their receipt of PaPD-1 chemotherapy. These PaPD-1 irAEs included dermatitis, colitis, and pneumonitis that responded to steroid therapy and occurred on various chemotherapy agents (gemcitabine, paclitaxel, docetaxel). Conclusions: In lung cancer, the response to chemotherapy beyond first line may be modestly higher when administered after aPD-1 therapy. Immune-related adverse events can occur during chemotherapy administered after aPD-1 therapy has been stopped.