tbuckley/cabot-search huggingface dataset:
Long-term graft function following autologous hematopoietic cell transplantation and the impact of preemptive plerixafor in predicted poor mobilizers
Authors: Alissa Visram, Christopher Bredeson, David Allan, Mitchell Sabloff, Lothar Huebsch, Jason Tay, Natasha Kekre, Sheryl McDiarmid, Ranjeeta Mallick, Alan Tinmouth, Lisa Martin, Linda Hamelin, Dawn Maze
Journal: Blood Cancer Journal (2018)
Interim safety and clinical activity in patients (pts) with locally advanced and unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma from a multicohort phase I study of ramucirumab (R) plus durvalumab (D).
Authors: Yung-Jue Bang, Talia Golan, Chia-Chi Lin, Yoon-Koo Kang, Zev A. Wainberg, Heather Wasserstrom, Jin Jin, Gu Mi, Samuel McNeely, Naomi Laing, Laura Williams Goff, Siqing Fu
Journal: Journal of Clinical Oncology (2018)

92 Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This global phase 1 trial evaluates the combination of R (anti-VEGFR2) and D (anti-PD-L1) in pts with G/GEJ by simultaneously targeting these two processes. Methods: This ongoing, multi-cohort, phase 1a/b trial (NCT02572687) enrolled pts with confirmed G/GEJ adenocarcinoma with prior progression on 1 or 2 lines of systemic therapy, measurable disease, ECOG PS 0-1, and baseline tumor tissue. PD-L1 expression was assessed using the SP-263 IHC; MSI status was determined using PCR. Enrolled pts received R (8 mg/kg IV) and D (750 mg IV) every two weeks on a 28-day cycle. Primary objective was to assess safety and tolerability of R+D; preliminary efficacy was also examined. Results: As of 26-May-2017, 29 G/GEJ adenocarcinoma pts were treated. The median age was 55 y; 69% were male; 66% had ECOG PS of 1; 48% had PD-L1 ≥25% expression in tumor or immune cells, 3.5% were MSI-high; and 72% received study treatment as second line for advanced disease. Median duration of treatment was 2.5 mo for R and 3.0 mo for D. Treatment-emergent adverse events (TEAEs) occurred in 29 (100%) pts and 21 (72%) pts experienced grade 3/4 TEAEs, while treatment-related AEs (TRAE) occurred in 24 (83%) pts; none resulted in treatment discontinuation. Ten (35%) pts had grade 3 TRAEs, and no grade 4 or 5. All grade TRAEs occurring in ≥10% of pts were hypertension (34%), fatigue (31%), headache (24%), diarrhea (21%), pyrexia (10%) and decreased appetite (10%). Five pts (17%) reported a serious adverse event related to study treatment. Preliminary efficacy data (RECIST v1.1) showed 5 of 29 pts (17%) achieved a confirmed PR. Only 1 responding pt was MSI high. The overall response rate for pts with PD-L1 ≥25% was 36%. Median PFS was 2.6 mo (95% CI, 1.45 to 6.28). As of data cut-off, 6 pts (21%) remain on treatment. Conclusions: R+D generated no unexpected toxicity, and demonstrated antitumor activity in pts with previously treated advanced G/GEJ adenocarcinoma. Clinical trial information: NCT02572687.
Mismatch repair deficiency in cholangiocarcinoma.
Authors: Paul Raymond Kunk, Joseph Mounir Obeid, Kevin Winters, Patcharin Pramoonjago, Dirk G. Brockstedt, Anita Giobbie-Hurder, Edward B Stelow, Todd W. Bauer, Craig L. Slingluff, Osama E. Rahma
Journal: Journal of Clinical Oncology (2018)

269 Background: Cholangiocarcinoma (CC) is a fatal malignancy with an unmet treatment need. With the approval of immunotherapy for solid tumors with mismatch repair (MMR) deficiency, there is a renewed interest in MMR testing. Little is known about the incidence of MMR deficiency in CC or its correlation to survival, immune cell infiltration, PD-L1 and other proteins expressed in CC such as mesothelin. Methods: CC tumors were identified from patients treated at the University of Virginia from 2000-2014. Tissue microarrays (TMAs) were constructed of 3-4 cores from each tumor and were stained by immunohistochemistry for MMR genes (MLH1, PMS2, MSH2, MSH6), mesothelin, PD-L1 and immune cells. TMAs were scanned using the Leica SCN400 and analyzed using the Digital Image Hub software. Stain intensity thresholds for defining positive cells were determined by two users and recorded as an average of all cores from each tumor. Mesothelin and PD-L1 expression were measured as a percentage of positive tumor cells. Correlation with overall survival was assessed using log-rank tests and classification and regression trees, with p values &lt; 0.05 considered significant. Results: Ninety-one tumors were analyzed: 24 intrahepatic, 33 hilar, and 34 distal. MMR deficiency was found in 20 tumors (22%). None of the MMR deficient tumors co-expressed PD-L1 (&gt;1%), which was found in 15% of the remaining tumors. T cell infiltration (CD4, CD8 and FoxP3) did not differ between MMR deficient or proficient tumors. Patients with MMR deficiency had a trend towards worse survival compared to those with proficiency (median OS: 19.2 vs. 28.1 months, p = 0.07). MMR deficient tumors showed a lower mesothelin expression compared to MMR proficient tumors, median 8 vs. 129 positive cells per TMA (p = 0.08). Patients with MMR deficiency and low mesothelin expression had a worse outcome compared to patients with MMR proficiency and high mesothelin expression (median OS: 14.5 vs. 30.0 months, p = 0.05). Conclusions: Given the high rate of MMR deficiency, all CC tumors should be tested and may benefit from anti-PD-1 therapy. The poor prognosis of MMR deficient CC may be independent of T-cell infiltration and additional studies are needed to better characterize the genetic and molecular landscape of this subset of tumors.
Temporal Trends and Clinical Consequences of Wait Times for Transcatheter Aortic Valve Replacement
Authors: Gabby Elbaz-Greener, Shannon Masih, Jiming Fang, Dennis T. Ko, Sandra B. Lauck, John G. Webb, Brahmajee K. Nallamothu, Harindra C. Wijeysundera
Journal: Circulation (2018)

Transcatheter aortic valve replacement (TAVR) represents a paradigm shift in the therapeutic options for patients with severe aortic stenosis. However, rapid and exponential growth in TAVR demand may overwhelm capacity, translating to inadequate access and prolonged wait times. Our objective was to evaluate temporal trends in TAVR wait times and the associated clinical consequences.In this population-based study in Ontario, Canada, we identified all TAVR referrals from April 1, 2010, to March 31, 2016. The primary outcome was the median total wait time from referral to procedure. Piecewise regression analyses were performed to assess temporal trends in TAVR wait times, before and after provincial reimbursement in September 2012. Clinical outcomes included all-cause death and heart failure hospitalizations while on the wait list.The study cohort included 4461 referrals, of which 50% led to a TAVR, 39% were off-listed for other reasons, and 11% remained on the wait list at the conclusion of the study. For patients who underwent a TAVR, the estimated median wait time in the postreimbursement period stabilized at 80 days and has remained unchanged. The cumulative probability of wait-list mortality and heart failure hospitalization at 80 days was ≈2% and 12%, respectively, with a relatively constant increase in events with increased wait times.Postreimbursement wait time has remained unchanged for patients undergoing a TAVR procedure, suggesting the increase in capacity has kept pace with the increase in demand. The current wait time of almost 3 months is associated with important morbidity and mortality, suggesting a need for greater capacity and access.
Cytosolic DNA Sensing Promotes Macrophage Transformation and Governs Myocardial Ischemic Injury
Authors: Dian J. Cao, Gabriele G. Schiattarella, Elisa Villalobos, Nan Jiang, Herman I. May, Tuo Li, Zhijian J. Chen, Thomas G. Gillette, Joseph A. Hill
Journal: Circulation (2018)

Myocardium irreversibly injured by ischemic stress must be efficiently repaired to maintain tissue integrity and contractile performance. Macrophages play critical roles in this process. These cells transform across a spectrum of phenotypes to accomplish diverse functions ranging from mediating the initial inflammatory responses that clear damaged tissue to subsequent reparative functions that help rebuild replacement tissue. Although macrophage transformation is crucial to myocardial repair, events governing this transformation are poorly understood.Here, we set out to determine whether innate immune responses triggered by cytoplasmic DNA play a role.We report that ischemic myocardial injury, along with the resulting release of nucleic acids, activates the recently described cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Animals lacking cyclic GMP-AMP synthase display significantly improved early survival after myocardial infarction and diminished pathological remodeling, including ventricular rupture, enhanced angiogenesis, and preserved ventricular contractile function. Furthermore, cyclic GMP-AMP synthase loss of function abolishes the induction of key inflammatory programs such as inducible nitric oxide synthase and promotes the transformation of macrophages to a reparative phenotype, which results in enhanced repair and improved hemodynamic performance.These results reveal, for the first time, that the cytosolic DNA receptor cyclic GMP-AMP synthase functions during cardiac ischemia as a pattern recognition receptor in the sterile immune response. Furthermore, we report that this pathway governs macrophage transformation, thereby regulating postinjury cardiac repair. Because modulators of this pathway are currently in clinical use, our findings raise the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure.
Cybermedics—a virtual reality
Authors: Rita Pal
Journal: BMJ (2005)

Star rating of websites 

Health care in the 21st century is a frenetic business, with doctors now so busy that they have little time to socialise or interact with colleagues outside their immediate vicinity. Fortunately, the internet offers some impressive (and some not so impressive) solutions to this problem in the form of doctors only online communities.

The oldest, and best known, is probably Doctors Net UK (www.doctors.net.uk). However, a wave …
Impact of Interferon Lambda 4 Genotype on Interferon‐Stimulated Gene Expression During Direct‐Acting Antiviral Therapy for Hepatitis C
Authors: Narayan Ramamurthy, Emanuele Marchi, M. Azim Ansari, Vincent Pedergnana, Angela Mclean, Emma Hudson, Rory Bowden, Chris C.A. Spencer, Eleanor Barnes, Paul Klenerman
Journal: Hepatology (2018)

New directly acting antivirals (DAAs) provide very high cure rates in most patients infected by hepatitis C virus (HCV). However, some patient groups have been relatively harder to treat, including those with cirrhosis or infected with HCV genotype 3. In the recent BOSON trial, genotype 3, patients with cirrhosis receiving a 16-week course of sofosbuvir and ribavirin had a sustained virological response (SVR) rate of around 50%. In patients with cirrhosis, interferon lambda 4 (IFNL4) CC genotype was significantly associated with SVR. This genotype was also associated with a lower interferon-stimulated gene (ISG) signature in peripheral blood and in liver at baseline. Unexpectedly, patients with the CC genotype showed a dynamic increase in ISG expression between weeks 4 and 16 of DAA therapy, whereas the reverse was true for non-CC patients. Conclusion: These data provide an important dynamic link between host genotype and phenotype in HCV therapy also potentially relevant to naturally acquired infection. (Hepatology 2018; 00:000-000).
Newcastle course on orbital and neuroimaging for ophthalmology
Authors: Anshuman Sengupta
Journal: BMJ (2009)

The Newcastle course on orbital and neuroimaging for ophthalmology is a new one day course that is run jointly by consultant ophthalmologists and specialist neuroradiologists. It revises the basic principles of neuroimaging techniques such as computed tomography, magnetic resonance imaging, and contrast angiography, as well as relevant neuroanatomy, with a focus on a variety of conditions affecting the orbits and the central nervous system. The course is lecture based and provides exposure to a large number of images.

The course is advertised for trainees at any level in ophthalmology, radiology, and neurology, although doctors from other disciplines are also encouraged to attend. Although it is targeted at orbital imaging, the general principles and anatomy are relevant to a wider audience of doctors, …
General practice wins over hospital medicine in doctors’ future career choice
Authors: Caroline White
Journal: BMJ (2016)

Over half of UK doctors consider general practice a more attractive future option than a career in hospital medicine, show the results of a survey by the UK Medical Careers Research Group at Oxford University.1

When survey respondents were asked whether general practice was currently a more attractive career prospect than hospital medicine, over half (56.2%) agreed or strongly agreed that it was, with just under a quarter taking the opposite view.

The survey has been tracking the current and intended career paths of 6795 doctors who qualified from UK medical schools in 2008. The results of the third survey, which had a response rate of 59% (2369 of 4031 who could be traced) in 2013-14, showed that most doctors had high levels of job satisfaction and intended to stay in medicine, working in the UK.

Almost eight in 10 (78%) said that they would “definitely” or “probably” pursue a medical career in the …
Abstract P5-08-03: Poly-ligand profiling and target identification from formalin-fixed-paraffin embedded HER2+ breast cancer specimens
Authors: HA O'Neill, TT Tinder, V Maher, M Rosenow, M Richards, R Santhanam, X Wei, V Domenyuk, MR Miglarese, D Spetzler
Journal: Cancer Research (2018)

Abstract We have previously described the ADAPT Biotargeting System™as a novel platform for highly multiplexed poly-ligand profiling of complex phenotypes such as drug response. Here we report extended capabilities of the this platform for target identification directly from formalin-fixed-paraffin embedded (FFPE) tissues using aptamer libraries enriched toward HER2+ breast cancer. Standard mass spectrometry-based biomarker and drug target discovery from FFPE tissues can be challenging due to limited amounts of tissue, harsh conditions of fixation and extraction and the general problem of masking by highly abundant proteins. A single stranded-oligodeoxynucleotide aptamer library was enriched on HER2+ FFPE breast cancer specimens and conjugated with biotin as well as a label transfer reagent, Sulfo-NHS-SS-Diazirine (Sulfo-SDAD). The biotinylated-SDAD conjugated library (B-SDAD-EL) was applied to HER2+ FFPE tissues and photocrosslinked to cognate binding partners within the FFPE sample in order to preserve aptamer-protein interactions under harsh denaturing conditions required for protein extraction and sample preparation. Aptamer-protein complexes were affinity purified and the label was transferred from bound aptamers to their binding partners under reducing conditions that enable proteomic digestion and high resolution mass spectrometry detection. An open database search was performed where the precursor ion tolerance was set to ± 500 Da for database searching, which enabled identification of peptides containing the transferred label as well as additional unknown variable modifications induced by the tissue fixation process. We identified proteins with known roles in HER2+ breast cancer along with several potentially drugable targets not previously associated with HER2 positivity. Differential expression of candidate targets was orthogonally confirmed by immunohistochemistry. By nature of its extreme molecular complexity and its ability to be enriched or “trained,” toward phenotypes of interest, the ADAPT Biotargeting SystemTM can be deployed to advance precision medicine by identifying predictive biomarkers and drug targets with novel associations to complex interactomes. Citation Format: O'Neill HA, Tinder TT, Maher V, Rosenow M, Richards M, Santhanam R, Wei X, Domenyuk V, Miglarese MR, Spetzler D. Poly-ligand profiling and target identification from formalin-fixed-paraffin embedded HER2+ breast cancer specimens [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 P5-08-03.
Mechanistic Exploration of Cancer Stem Cell Marker Voltage-Dependent Calcium Channel α2δ1 Subunit-mediated Chemotherapy Resistance in Small-Cell Lung Cancer
Authors: Jiangyong Yu, Shuhang Wang, Wei Zhao, Jianchun Duan, Zhijie Wang, Hanxiao Chen, Yanhua Tian, Di Wang, Jun Zhao, Tongtong An, Hua Bai, Meina Wu, Jie Wang
Journal: Clinical Cancer Research (2018)

Purpose: Chemoresistance in small-cell lung cancer (SCLC) is reportedly attributed to the existence of resistant cancer stem cells (CSC). Studies involving CSC-specific markers and related mechanisms in SCLC remain limited. This study explored the role of the voltage-dependent calcium channel α2δ1 subunit as a CSC marker in chemoresistance of SCLC, and explored the potential mechanisms of α2δ1-mediated chemoresistance and strategies of overcoming the resistance.Experimental Design: α2δ1-positive cells were identified and isolated from SCLC cell lines and patient-derived xenograft (PDX) models, and CSC-like properties were subsequently verified. Transcriptome sequencing and Western blotting were carried out to identify pathways involved in α2δ1-mediated chemoresistance in SCLC. In addition, possible interventions to overcome α2δ1-mediated chemoresistance were examined.Results: Different proportions of α2δ1+ cells were identified in SCLC cell lines and PDX models. α2δ1+ cells exhibited CSC-like properties (self-renewal, tumorigenic, differentiation potential, and high expression of genes related to CSCs and drug resistance). Chemotherapy induced the enrichment of α2δ1+ cells instead of CD133+ cells in PDXs, and an increased proportion of α2δ1+ cells corresponded to increased chemoresistance. Activation and overexpression of ERK in the α2δ1-positive H1048 cell line was identified at the protein level. mAb 1B50-1 was observed to improve the efficacy of chemotherapy and delay relapse as maintenance therapy in PDX models.Conclusions: SCLC cells expressing α2δ1 demonstrated CSC-like properties, and may contribute to chemoresistance. ERK may play a key role in α2δ1-mediated chemoresistance. mAb 1B50-1 may serve as a potential anti-SCLC drug. Clin Cancer Res; 24(9); 2148-58. ©2018 AACR.
A Circuit for Integration of Head- and Visual-Motion Signals in Layer 6 of Mouse Primary Visual Cortex
Authors: Mateo Vélez-Fort, Edward F. Bracey, Sepiedeh Keshavarzi, Charly V. Rousseau, Lee Cossell, Stephen C. Lenzi, Molly Strom, Troy W. Margrie
Journal: Neuron (2018)

To interpret visual-motion events, the underlying computation must involve internal reference to the motion status of the observer's head. We show here that layer 6 (L6) principal neurons in mouse primary visual cortex (V1) receive a diffuse, vestibular-mediated synaptic input that signals the angular velocity of horizontal rotation. Behavioral and theoretical experiments indicate that these inputs, distributed over a network of 100 L6 neurons, provide both a reliable estimate and, therefore, physiological separation of head-velocity signals. During head rotation in the presence of visual stimuli, L6 neurons exhibit postsynaptic responses that approximate the arithmetic sum of the vestibular and visual-motion response. Functional input mapping reveals that these internal motion signals arrive into L6 via a direct projection from the retrosplenial cortex. We therefore propose that visual-motion processing in V1 L6 is multisensory and contextually dependent on the motion status of the animal's head.
Validation of a MEK/MET-specific NGS panel for early phase trial interrogation
Authors: P Maxwell, Favero J Del, MA Fuchs, J Tabernero, T Maughan, M Middleton, R Addams, C Rolfo, B Hennessey, P Laurent-Puig, A Bardelli, T Andre, Vlad Popovici, P Johnstone, R Wilson, M Lawler, Schaeybroeck S Van, Tellez
Journal: Cancer Research (2016)
Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice
Authors: Miguel A. Lanaspa, Ana Andres-Hernando, David J. Orlicky, Christina Cicerchi, Cholsoon Jang, Nanxing Li, Tamara Milagres, Masanari Kuwabara, Michael F. Wempe, Joshua D. Rabinowitz, Richard J. Johnson, Dean R. Tolan
Journal: Journal of Clinical Investigation (2018)

Increasing evidence suggests a role for excessive intake of fructose in the Western diet as a contributor to the current epidemics of metabolic syndrome and obesity. Hereditary fructose intolerance (HFI) is a difficult and potentially lethal orphan disease associated with impaired fructose metabolism. In HFI, the deficiency of aldolase B results in the accumulation of intracellular phosphorylated fructose, leading to phosphate sequestration and depletion, increased adenosine triphosphate (ATP) turnover, and a plethora of conditions that lead to clinical manifestations such as fatty liver, hyperuricemia, Fanconi syndrome, and severe hypoglycemia. Unfortunately, there is currently no treatment for HFI, and avoiding sugar and fructose has become challenging in our society. In this report, through use of genetically modified mice and pharmacological inhibitors, we demonstrate that the absence or inhibition of ketohexokinase (Khk), an enzyme upstream of aldolase B, is sufficient to prevent hypoglycemia and liver and intestinal injury associated with HFI. Herein we provide evidence for the first time to our knowledge of a potential therapeutic approach for HFI. Mechanistically, our studies suggest that it is the inhibition of the Khk C isoform, not the A isoform, that protects animals from HFI.
Getting an internet address
Authors: Mohammad Al-Ubaydli
Journal: BMJ (2005)

An internet address is called a domain; an example is “doctors.net.uk” or “bmj.com”. Different prefixes give different functions. An example of a web address is “www.bmj.com”, and an email address is “mohammad@doctors.net.uk”. Web addresses allow others to find you on the internet and are great for providing information for …
We need a review of all sepsis deaths, not the conviction of health professionals
Authors: Azeem Majeed, Paul Morgan
Journal: BMJ (2018)

NHS England estimates that approximately 37 000 deaths a year are caused by sepsis.1 This means that in the seven year period between 2011 and 2017, around 259 000 people died from sepsis in England. Only one of these deaths, that of Jack Adcock in Leicester in 2011, has resulted in the conviction of health professionals for manslaughter (Hadiza Bawa-Garba and Isabel Amaro).2

Sepsis can …
Long-term results of CT-guided percutaneous radiofrequency ablation of inoperable patients with stage Ia non-small cell lung cancer: A retrospective cohort study
Authors: Bing-Yang Huang, Xin-Min Li, Xiao-Yong Song, Jun-Jun Zhou, Zhuang Shao, Zhi-Qi Yu, Yi Lin, Xin-yu Guo, Da-Jiang Liu, Lu Li
Journal: International Journal of Surgery (2018)