tbuckley/cabot-search huggingface dataset:
Effective and less toxic trimodality approach in muscle invasive urinary bladder cancer.
Authors: Reham Abdel-Wahab, Ahmed M. Eltaher, Hoda H. Essa, Samir-Shehata M. Eid
Journal: Journal of Clinical Oncology (2013)

e15505 Background: Bladder cancer represents a global health problem. Radical cystectomy considered the standard of care for invasive bladder cancer. Because of the potential morbidity with surgery, organ preservation via trimodality approach has been the subject of investigation. The concurrent use of cisplatin with 5-FU or gemcitabin with local radiotherapy has been studied and the results were better than radical cystectomy. However, this was associated with grade 3-4 (G3-4) toxicity. Recently, similarly effective but less toxic regimen by the use of paclitaxel and cisplatin is under investigation. Methods: We proposed a single-center, single arm, phase II prospective cohort study. 30 patients (22 male and 8 female) with T2-T3 bladder cancer according to the AJCC 2010 were included. All patients were &gt;18y with exclusion of those with bladder capacity &lt; 350cc, hydronephrosis, with previous intravesical therapy, systemic chemotherapy or pelvic radiation, those currently receiving nephrotoxic or ototoxic drugs, and those with other malignancies. All patients treated with maximum transurethral resection (TUR) followed by local radiotherapy 64Gy concurrently with weekly 60mg/m2 Paclitaxel and 20mg/m2 Cisplatin. Results: Cystoscopic re-evaluation 6-8 weeks after the end of treatment revealed that 90% of patients achieve complete response (CR), 6.7% achieve partial response (PR) and 3.3% had stable disease (SD). Mild toxicity was infrequent and easily controlled without interruption of treatment except in one patient. Toxicity was in the form of cystitis G1 in 46.7% and G2 in 3.3%. Diarrhea G1 in 33.3% and G2 in 3.3%. Only one patient who has past history of piles, developed G2 proctitis that leads to irregularity of treatment. Other mild toxicities were: G1 dermatitis (80%), G1 bleeding per rectum (3.3%), G1 anemia (13.3%), G1 and G2 nausea and vomiting (50% and 33.3% respectively), while neutropenia and thrompocytopenia were not seen. Conclusions: Our preliminary results revealed that weekly low dose paclitaxel and cisplatin concurrently with local radiotherapy was effective, tolerable and has acceptable toxicity in the treatment of muscle invasive urinary bladder cancer.
A theory of lexical access in speech production
Authors: Willem J. M. Levelt, Ardi Roelofs, Antje S. Meyer
Journal: Behavioral and Brain Sciences (1999)

Preparing words in speech production is normally a fast and accurate process. We generate them two or three per second in fluent conversation; and overtly naming a clear picture of an object can easily be initiated within 600 msec after picture onset. The underlying process, however, is exceedingly complex. The theory reviewed in this target article analyzes this process as staged and feedforward. After a first stage of conceptual preparation, word generation proceeds through lexical selection, morphological and phonological encoding, phonetic encoding, and articulation itself. In addition, the speaker exerts some degree of output control, by monitoring of self-produced internal and overt speech. The core of the theory, ranging from lexical selection to the initiation of phonetic encoding, is captured in a computational model, called weaver++. Both the theory and the computational model have been developed in interaction with reaction time experiments, particularly in picture naming or related word production paradigms, with the aim of accounting for the real-time processing in normal word production. A comprehensive review of theory, model, and experiments is presented. The model can handle some of the main observations in the domain of speech errors (the major empirical domain for most other theories of lexical access), and the theory opens new ways of approaching the cerebral organization of speech production by way of high-temporal-resolution imaging.
Evaluation of haematopoietic stem cell transplantation in patients diagnosed with cutaneous T‐cell lymphoma at a tertiary care centre: should we avoid chemotherapy in conditioning regimes?
Authors: S. Ritchie, I. Qureshi, K. Molloy, J. Yoo, F. Shah, A. Stevens, C. Irwin, S. Chaganti, J.J. Scarisbrick
Journal: British Journal of Dermatology (2019)
Effect of Empagliflozin on Endothelial Function in Patients With Type 2 Diabetes and Cardiovascular Disease: Results from the Multicenter, Randomized, Placebo-Controlled, Double-Blind EMBLEM Trial
Authors: Atsushi Tanaka, Michio Shimabukuro, Noritaka Machii, Hiroki Teragawa, Yosuke Okada, Kosuke R. Shima, Toshinari Takamura, Isao Taguchi, Itaru Hisauchi, Shigeru Toyoda, Yasushi Matsuzawa, Hirofumi Tomiyama, Minako Yamaoka-Tojo, Hisako Yoshida, Yasunori Sato, Yumi Ikehara, Shinichiro Ueda, Yukihito Higashi, Koichi Node, Junya Ako, Hirohisa Amano, Teruo Inoue, Hideaki Jinnouchi, Atsushi Kawaguchi, Yoshiyuki Kawano, Kazuo Kimura, Akira Kurozumi, Takaaki Kusumoto, Tatsuya Maruhashi, Hirofumi Misu, Katsunori Nakamura, Manabu Narisawa, Junya Nishi, Tsuguhito Ota, Jun-ichi Oyama, Masashi Sakuma, Kazuki Shiina, Seigo Sugiyama, Kunihiro Suzuki, Naohiko Takahashi, Yasuhiko Takemoto, Yumie Takeshita, Hiroshi Tamaki, Akira Tamura, Kenichi Tanaka, Takafumi Toita, Keiichi Torimoto, Hiroki Uehara, Fumi Uemura, Ken Yamakawa, Kunio Yufu
Journal: Diabetes Care (2019)

Recent large trials on sodium–glucose cotransporter 2 (SGLT2) inhibitors showed that these agents improved cardiovascular outcomes in patients with type 2 diabetes (T2D) with a high risk of cardiovascular events (1). However, the underlying mechanisms of these clinical benefits and vascular effect of SGLT2 inhibitors in that patient group remain uncertain. Endothelial dysfunction is exacerbated by metabolic disorders, such as diabetes, and involved in the pathophysiology of diabetes-related cardiovascular complications (2,3). We therefore investigated whether empagliflozin added to standard therapy, compared with placebo, affected endothelial function in patients with T2D and established cardiovascular disease (CVD). This was a prospective, multicenter, randomized, placebo-controlled, double-blind clinical trial undertaken in 16 centers in Japan (clinical trial reg. no. UMI24502, www.umin.ac.jp/ctr/index.htm) (4). A total of 117 adults with T2D and established CVD were randomized (1:1) to receive either empagliflozin 10 mg daily or placebo for 24 weeks. Randomization was performed by using the web-based minimization dynamic allocation method stratified according to HbA1c, age, systolic blood pressure (BP), and smoking status. The placebo was indistinguishable from empagliflozin, and both study drugs were sequentially numbered and concealed. The participants and investigators remained masked to group assignments until the database lock (an action taken to prevent further changes to a clinical trial database). The effects of treatment on endothelial function were assessed by the reactive hyperemia peripheral arterial tonometry index (RHI) (5), with the primary efficacy end point being the change in RHI from baseline to 24 weeks. Ethics approval and informed patient consent were obtained.

Of the 117 patients, 105 were included in the full analysis set. Ten patients dropped out prior to initiation of the study drug, and two patients in the placebo group were excluded due to a serious protocol deviation (lack of data …
Over-the-scope tissue retraction system (TRS)-facilitated endoscopic submucosal dissection of a large rectal polyp
Authors: Rathan Reddy, Sheila Rastegari, Paul Tarnasky, Prashant Kedia
Journal: Endoscopy (2019)

A 50-year-old woman with no significant past medical history was referred to our clinic for evaluation and management of a large rectal tubulovillous adenoma with high grade dysplasia that had been noted on routine screening colonoscopy.
Immunome perturbation is present in patients with juvenile idiopathic arthritis who are in remission and will relapse upon anti-TNFα withdrawal
Authors: Jing Yao Leong, Phyllis Chen, Joo Guan Yeo, Fauziah Ally, Camillus Chua, Sharifah Nur Hazirah, Su Li Poh, Lu Pan, Liyun Lai, Elene Seck Choon Lee, Loshinidevi D/O Thana Bathi, Thaschawee Arkachaisri, Daniel Lovell, Salvatore Albani
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Biologics treatment with antitumour necrosis factor alpha (TNFα) is efficacious in patients with juvenile idiopathic arthritis (JIA). Despite displaying clinical inactivity during treatment, many patients will flare on cessation of therapy. The inability to definitively discriminate patients who will relapse or continue to remain in remission after therapy withdrawal is currently a major unmet medical need. CD4 T cells have been implicated in active disease, yet how they contribute to disease persistence despite treatment is unknown. Methods We interrogated the circulatory reservoir of CD4 + immune subsets at the single-cell resolution with mass cytometry (cytometry by time of flight) of patients with JIA (n=20) who displayed continuous clinical inactivity for at least 6 months with anti-TNFα and were subsequently withdrawn from therapy for 8 months, and scored as relapse or remission. These patients were examined prior to therapy withdrawal for putative subsets that could discriminate relapse from remission. We verified on a separate JIA cohort (n=16) the dysregulation of these circulatory subsets 8 months into therapy withdrawal. The immunological transcriptomic signature of CD4 memory in relapse/remission patients was examined with NanoString. Results An inflammatory memory subset of CD3 + CD4 + CD45RA − TNFα + T cells deficient in immune checkpoints (PD1 − CD152 − ) was present in relapse patients prior to therapy withdrawal. Transcriptomic profiling reveals divergence between relapse and remission patients in disease-centric pathways involving (1) T-cell receptor activation, (2) apoptosis, (3) TNFα, (4) nuclear factor-kappa B and (5) mitogen-activated protein kinase signalling. Conclusions A unique discriminatory immunomic and transcriptomic signature is associated with relapse patients and may explain how relapse occurs.
γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming
Authors: Alejandro Torres‐Hernandez, Wei Wang, Yuri Nikiforov, Karla Tejada, Luisana Torres, Aleksandr Kalabin, Salma Adam, Jingjing Wu, Lu Lu, Ruonan Chen, Aaron Lemmer, Jimmy Camargo, Mautin Hundeyin, Brian Diskin, Berk Aykut, Emma Kurz, Juan A. Kochen Rossi, Mohammed Khan, Miguel Liria, Gustavo Sanchez, Nan Wu, Wenyu Su, Steven Adams, Muhammad Israr Ul Haq, Mohammad Saad Farooq, Varshini Vasudevaraja, Joshua Leinwand, George Miller
Journal: Hepatology (2019)

Background and Aims The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis (SH). Approach and Results We found that in SH, γδT cells are recruited to the liver by C‐C chemokine receptor (CCR) 2, CCR5, and nucleotide‐binding oligomerization domain‐containing protein 2 signaling and are skewed toward an interleukin (IL)‐17A + phenotype in an inducible costimulator (ICOS)/ICOS ligand–dependent manner. γδT cells exhibit a distinct Vγ4 + , PD1 + , Ly6C + CD44 + phenotype in SH. Moreover, γδT cells up‐regulate both CD1d, which is necessary for lipid‐based antigens presentation, and the free fatty acid receptor, CD36. γδT cells are stimulated to express IL‐17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet‐induced SH and accelerates disease resolution. Conclusions We demonstrate that hepatic γδT cells exacerbate SH, independent of IL‐17 expression, by mitigating conventional CD4 + T‐cell expansion and modulating their inflammatory program by CD1d‐dependent vascular endothelial growth factor expression.
G Protein–Coupled Receptor Pharmacology at the Single-Molecule Level
Authors: Davide Calebiro, Jak Grimes
Journal: The Annual Review of Pharmacology and Toxicology (2019)

G protein-coupled receptors (GPCRs) mediate the effects of numerous hormones and neurotransmitters and are major pharmacological targets. Classical studies with crude cell lysates or membrane preparations have identified the main biochemical steps involved in GPCR signaling. Moreover, recent studies on purified proteins have provided astounding details at the atomic level of the 3-D structures of receptors in multiple conformations, including in complex with G proteins and β-arrestins. However, several fundamental questions remain regarding the highly specific effects and rapid nature of GPCR signaling. Recent developments in single-molecule microscopy are providing important contributions to answering these questions. Overall, single-molecule studies have revealed unexpected levels of complexity, with receptors existing in different conformations and dynamically interacting among themselves, their signaling partners, and structural elements of the plasma membrane to produce highly localized signals in space and time. These findings may provide a new basis to develop innovative strategies to modulate GPCR function for pharmacological purposes.
Analysis of Hohn (HC) and porth-a-cath (PAC) central venous catheters (CVC) adverse events (AEs) and related costs in advanced soft tissue sarcomas (STS) treated with trabectedin (TR) 24-hour (24-h) infusion therapy.
Authors: Erica Palesandro, Paola Boccone, Lorenzo D'Ambrosio, Danilo Galizia, Sandra Aliberti, Felicino Debernardi, Francesco Bona, Antonio Manca, Giovanni Carlo Anselmetti, Filippo Russo, Delia Campanella, Massimo Aglietta, Giovanni Grignani
Journal: Journal of Clinical Oncology (2012)

e20512 Background: TR is registered as second line in STS. The 24-h infusion schedule showed a better activity profile but a CVC is mandatory to administer TR with related costs and possible complications. The HC (Bard Access System, USA) is a silicone, open-ended, non-tunneled CVC characterized by low cost and easy placement and removal. We performed a retrospective analysis of STS patients (pts) treated with TR through a CVC to evaluate the incidence of CVC AEs (malfunctioning, thrombosis, infection or extravasation) in pts carrying HC or PAC. Methods: Eligible criteria were: at least 1 course of TR via CVC, adequate premedication (steroid and 4000 units/die of low molecular weight heparin), absence of previous CVC alterations or any underlying coagulation disorder. All CVC were placed in our Institution under radiological control and full medical history was available for all pts included into the study. Average total costs (placement, hospital admission, device, and medications) are 255 and 560 $ for HC and PAC, respectively. Results: Between March 2008 and October 2011 42 pts, median age 58 (20-74) yrs, received TR after placement of a CVC: 14 (33%) HC and 28 (67%) PAC. At the time of TR administration, pts had received a median of 2 (range 1-4) chemotherapeutic lines. A total of 185 courses of TR (44 via HC / 141 via PAC) were administered at a median dose of 1.3 mg/m2 with a median of 3 (1-22) courses per pts. AEs occurred after a median of 2 (range 1-6) TR courses. We recorded 13 CVC-related AEs: 7 infection (2 HC / 5 PAC), 4 thrombosis (2 HC / 2 PAC), 2 malfunctioning (1 HC / 1 PAC,) no extravasation. CVC had to be removed and substituted in 10 pts (5 HC/5 PAC) with an estimated total cost of 280 and 680 $ for HC and PAC, respectively. In PAC pts, AEs determined 5 dose delays, only. Conclusions: CVC AEs should be considered in the management of pts treated with TR. HC showed a favorable safety profile and its AEs management is easier compared to implanted CVC. If disease does not progress after 2 cycles, HC can be converted in an implanted CVC. However, HC is also an adequate and cheaper device when best supportive care is the only useful therapy left.
Concomitant endoscopic fundoplication – can it reduce the risk of gastroesophageal reflux following peroral endoscopic myotomy?
Authors: Amol Bapaye, Siddharth Dharamsi, Rishabh Jain, Guru Basava, Jay A. Bapaye, Rajendra Pujari, Harshal Gadhikar
Journal: Endoscopy (2019)

Gastroesophageal reflux is an emerging concern after peroral endoscopic myotomy (POEM) with a reported incidence of up to 50 % [1]. Recently, a novel natural orifice transluminal endoscopic surgery (NOTES) procedure that creates an endoscopic anterior partial fundoplication (POEM + F) was reported [2]. We report on four patients with achalasia cardia treated using POEM + F.
MPs call for inquiry into troubled urology unit after whistleblower publishes book
Authors: Clare Dyer
Journal: BMJ (2019)

MPs are pressing England’s health secretary, Matt Hancock, for an inquiry into urology services at University Hospitals of Morecambe Bay NHS Foundation Trust after a whistleblowing urologist lifted the lid on a catalogue of clinical failings in a hard hitting book.

At a meeting on 10 September the trust’s board of governors discussed a possible referral to the police after Peter Duffy’s book, Whistle in the Wind , accused colleagues of disobeying instructions from a coroner who concluded that failures in care had contributed to a patient’s death.

Duffy was forced out of the trust after raising concerns about three colleagues and was awarded compensation of £102 000 (€115 000; $129 000) for unfair constructive dismissal last year after a bitter legal battle.1 He accused the trust of being willing to “financially annihilate” him and his family.

He now …
In Vivo Imaging of Translocator Protein in Long-term Cannabis Users
Authors: Tania Da Silva, Sina Hafizi, Jeremy J. Watts, Cynthia Shannon Weickert, Jeffrey H. Meyer, Sylvain Houle, Pablo Rusjan, Romina Mizrahi
Journal: JAMA Psychiatry (2019)

Cannabis is the most commonly used illicit drug in the world. Cannabinoids have been shown to modulate immune responses; however, the association of cannabis with neuroimmune function has never been investigated in vivo in the human brain.To investigate neuroimmune activation or 18-kDa translocator protein (TSPO) levels in long-term cannabis users, and to evaluate the association of brain TSPO levels with behavioral measures and inflammatory blood biomarkers.This cross-sectional study based in Toronto, Ontario, recruited individuals from January 1, 2015, to October 30, 2018. Participants included long-term cannabis users (n = 24) and non-cannabis-using controls (n = 27). Cannabis users were included if they had a positive urine drug screen for only cannabis and if they used cannabis at least 4 times per week for the past 12 months and/or met the criteria for cannabis use disorder. All participants underwent a positron emission tomography scan with [18F]FEPPA, or fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide.Total distribution volume was quantified across regions of interest. Stress and anxiety as well as peripheral measures of inflammatory cytokines and C-reactive protein levels were also measured.In total, 24 long-term cannabis users (mean [SD] age, 23.1 [3.8] years; 15 men [63%]) and 27 non-cannabis-using controls (mean [SD] age, 23.6 [4.2] years; 18 women [67%]) were included and completed all study procedures. Compared with the controls, cannabis users had higher [18F]FEPPA total distribution volume (main group effect: F1,48 = 6.5 [P = .01]; ROI effect: F1,200 = 28.4 [P < .001]; Cohen d = 0.6; 23.3% higher), with a more prominent implication for the cannabis use disorder subgroup (n = 15; main group effect: F1,39 = 8.5 [P = .006]; ROI effect: F1,164 = 19.3 [P < .001]; Cohen d = 0.8; 31.5% higher). Greater TSPO levels in the brain were associated with stress and anxiety and with higher circulating C-reactive protein levels in cannabis users.The results of this study suggest that TSPO levels in cannabis users, particularly in those with cannabis use disorder, are higher than those in non-cannabis-using controls. The findings emphasize the need for more complementary preclinical systems for a better understanding of the role of cannabinoids and TSPO in neuroimmune signaling.
An examination of the relationship between shame, guilt and self-harm: A systematic review and meta-analysis
Authors: Kate Sheehy, Amna Noureen, Ayesha Khaliq, Katie Dhingra, Nusrat Husain, Eleanor E. Pontin, Rosanne Cawley, Peter J. Taylor
Journal: Clinical Psychology Review (2019)

Self-harm is a major public health concern associated with suicide risk and significant psychological distress. Theories suggest that aversive emotional states are an important process that drives self-harm. Shame and guilt may, in particular, be important emotions in self-harm. This review therefore sought to provide a systematic review and meta-analysis of the relationship between shame, guilt, and self-harm. A systematic search of electronic databases (PsycINFO; Medline; CINAHL Plus; Web of Science and ProQuest) was undertaken to identify studies measuring shame, guilt and self-harm (including suicidal and non-suicidal behaviour). Meta-analysis was undertaken where papers focused on the same subtype of shame or guilt and shared a common outcome. Thirty studies were identified for inclusion. Most forms of shame were associated with non-suicidal self-injury (NSSI), but research was sparse concerning suicidal behaviour. Fewer studies examined guilt and findings were more varied. Methodological issues included a paucity of longitudinal designs and lack of justification for sample sizes. Results of this review support the link between shame and self-harm, particularly NSSI. The direction of this relationship is yet to be established. Clinically, consideration should be given to the role of shame amongst individuals who present with NSSI. This review was pre-registered on PROSPERO (CRD42017056165).
Systematic Identification of Host Cell Regulators of Legionella pneumophila Pathogenesis Using a Genome-wide CRISPR Screen
Authors: Edwin E. Jeng, Varun Bhadkamkar, Nnejiuwa U. Ibe, Haley Gause, Lihua Jiang, Joanne Chan, Ruiqi Jian, David Jimenez-Morales, Erica Stevenson, Nevan J. Krogan, Danielle L. Swaney, Michael P. Snyder, Shaeri Mukherjee, Michael C. Bassik
Journal: Cell Host & Microbe (2019)