tbuckley/cabot-search huggingface dataset:
Biogenesis and function of extracellular vesicles in cancer
Authors: Maarten P. Bebelman, Martine J. Smit, D. Michiel Pegtel, S. Rubina Baglio
Journal: Pharmacology & Therapeutics (2018)

Extracellular vesicles (EVs) are heterogeneous multi-signal messengers that support cancer growth and dissemination by mediating the tumor-stroma crosstalk. Exosomes are a subtype of EVs that originate from the limiting membrane of late endosomes, and as such contain information linked to both the intrinsic cell "state" and the extracellular signals cells received from their environment. Resolving the signals affecting exosome biogenesis, cargo sorting and release will increase our understanding of tumorigenesis. In this review we highlight key cell biological processes that couple exosome biogenesis to cargo sorting in cancer cells. Moreover, we discuss how the bidirectional communication between tumor and non-malignant cells affect cancer growth and metastatic behavior.
Costs and of treating Gleason score 9 and 10 prostate cancer vary widely based on need for adjuvant therapy: A critical assessment into the long-term cost implications of additional treatment modalities.
Authors: Aaron Alan Laviana, Christopher Saigal, Matthew J. Resnick, Robert Evan Reiter, Christopher R. King, David Jeffrey Demanes, Michael L. Steinberg, Eric M. Horwitz, Amar Upadhyaya Kishan
Journal: Journal of Clinical Oncology (2018)

53 Background: The costs of treating localized, Gleason score 9 and 10 prostate cancer remain poorly described, especially when the particularly aggressive nature of the disease often requires a multimodal approach. We report the results of time-driven activity-based costing to assess the long-term costs of treating this subset of patients with either RALP, high-dose EBRT, or EBRT with a high-dose rate brachytherapy (BT) boost. Methods: Based on a multi-institutional cohort of 487 patients with Gleason score 9-10 prostate cancer, we generated process maps for each phase of care from the initial urologic visit through a median follow-up of 3.76 years, incorporating all prostate cancer treatment over this horizon. Costs were calculated per unit time, and the proportion of capacity for each step was determined. TDABC was defined as the sum of its resources. Results: Substantial cost variation was demonstrated between treatment modalities with an estimated median cost of $49,681 for EBRT, $35,140 for RALP, and $31,647 for EBRT + BT at 3.76 years. The primary driver in cost variation was the use of ADT. RALP (170 pts) ranged from $18,896 (29.5%) for no postoperative therapy to $63,270 for immediate long-term ADT (5.3%). EBRT (230 pts) had the greatest cost variation [Table 1]. Finally, EBRT + BT (336 pts) ranged from $26,522 for EBRT + BT alone (12.6%) to $37,834 for EBRT + BT + salvage ADT + HIFU (1.2%). Conclusions: Characterizing the costs associated with the distribution of treatments for men with high-risk prostate cancer is essential as we move towards health care accountability. There is substantial long-term cost variation between treatments in this subset of patients, and understanding these differences may affect treatment implications as we shift toward accountable payment models.[Table: see text]
Small Lymph Node Metastasis Detected by 68Ga–Prostate-Specific Membrane Antigen But Not 18F-Fluciclovine PET/CT in Low–Prostate-Specific Antigen Biochemical Recurrence of Prostate Cancer
Authors: Guillaume Chaussé, Gad Abikhzer, Stephan Probst
Journal: Clinical Nuclear Medicine (2018)

A 58-year-old man with Gleason 4+3 prostate cancer was initially treated by radical prostatectomy followed by salvage radiotherapy to the prostate bed for postoperative biochemical failure. One year later, F-fluorocholine PET/CT detected a pelvic lymph node recurrence, which was treated with radiation therapy and 6 months of androgen deprivation. PSA started to rise again 18 months later, but F-fluciclovine PET/CT failed to demonstrate the site of recurrence at a PSA of 0.63 ng/mL. However, Ga-PSMA PET/CT revealed a single positive 4-mm perirectal lymph node (PSA 0.80 ng/mL at time of scan), in retrospect anatomically apparent but negative on F-fluciclovine PET/CT.
Effect of dual PI3K-δ,γ inhibitor duvelisib on immunosuppressive Tregs and myeloid cells to enhance efficacy of checkpoint and co-stimulatory antibodies in a B cell lymphoma model.
Authors: Jonathan A Pachter, David T. Weaver
Journal: Journal of Clinical Oncology (2018)

33 Background: Duvelisib is a dual inhibitor of PI3K-δ and PI3K-γ which has shown clinical activity as monotherapy in CLL/SLL, FL and T cell lymphoma (O’Brien; Flinn; Horwitz, ASH 2014). Recent publications have demonstrated that PI3K-δ inhibition reduces immunosuppressive Tregs (Ali, Nature, 2014) whereas PI3K-γ inhibition reduces immunosuppressive myeloid cells (Kaneda, Nature, 2016; De Henau, Nature, 2016). Hence, we postulated that duvelisib may augment the efficacy of immune checkpoint or co-stimulatory antibodies. Methods: Mice bearing syngeneic A20 B cell lymphoma tumors (60-90 mm 3 ) were treated with vehicle, duvelisib, anti-PD1, anti-PD1 + duvelisib, anti-OX40, or anti-OX40 + duvelisib. Tumor volumes were measured by caliper. Tregs, macrophages and MDSCs were quantified by flow cytometry from mice bearing A20 tumors after 8 days of treatment. Results: In the A20 model, duvelisib, anti-PD-1 and anti-OX40 treatments each induced tumor growth delay. When duvelisib and anti-PD-1 were combined in mice with pre-existing A20 tumors, strong anti-tumor synergy was observed. When anti-OX40 and duvelisib were combined, tumor regression was observed which correlated with strong reduction of tumor Tregs, M2 macrophages and MDSCs. To assess immune memory, tumor-free mice following anti-OX40 alone or anti-OX40 + duvelisib were injected with A20 cells in the contralateral flank with no further treatment. Whereas mice that had received anti-OX40 alone grew new tumors upon A20 re-challenge, all tumor-free mice that had received anti-OX40 + duvelisib did not grow tumors upon re-challenge and showed elevated memory T cells in blood and spleen. These findings indicate that anti-OX40 + duvelisib treatment established immune memory. Conclusions: The dual inhibition of PI3K-δ and PI3K-γ appears to make duvelisib especially effective in reducing both lymphoid and myeloid immuno-suppressive populations, enhancing the anti-tumor efficacy of immune checkpoint and co-stimulatory antibodies. These data support potential clinical exploration of duvelisib in combination with checkpoint or co-stimulatory antibodies.
Extracellular Citrate Affects Critical Elements of Cancer Cell Metabolism and Supports Cancer Development<i>In Vivo</i>
Authors: Maria E. Mycielska, Katja Dettmer, Petra Rümmele, Katharina Schmidt, Cornelia Prehn, Vladimir M. Milenkovic, Wolfgang Jagla, Gregor M. Madej, Margareta Lantow, Moritz Schladt, Alexander Cecil, Gudrun E. Koehl, Elke Eggenhofer, Christian J. Wachsmuth, Vadivel Ganapathy, Hans J. Schlitt, Karl Kunzelmann, Christine Ziegler, Christian H. Wetzel, Andreas Gaumann, Sven A. Lang, Jerzy Adamski, Peter J. Oefner, Edward K. Geissler
Journal: Cancer Research (2018)

Glycolysis and fatty acid synthesis are highly active in cancer cells through cytosolic citrate metabolism, with intracellular citrate primarily derived from either glucose or glutamine via the tricarboxylic acid cycle. We show here that extracellular citrate is supplied to cancer cells through a plasma membrane-specific variant of the mitochondrial citrate transporter (pmCiC). Metabolomic analysis revealed that citrate uptake broadly affected cancer cell metabolism through citrate-dependent metabolic pathways. Treatment with gluconate specifically blocked pmCiC and decreased tumor growth in murine xenografts of human pancreatic cancer. This treatment altered metabolism within tumors, including fatty acid metabolism. High expression of pmCiC was associated with invasion and advanced tumor stage across many human cancers. These findings support the exploration of extracellular citrate transport as a novel potential target for cancer therapy.Significance: Uptake of extracellular citrate through pmCiC can be blocked with gluconate to reduce tumor growth and to alter metabolic characteristics of tumor tissue. Cancer Res; 78(10); 2513-23. ©2018 AACR.
Immunotherapy for biochemically recurrent prostate cancer.
Authors: Ravi Amrit Madan, Fatima Karzai, Marijo Bilusic, Julius Strauss, Susan F. Slovin, Lauren Christine Harshman, Marc Robert Theoret, Philip M. Arlen, Myrna Rauckhorst, Anna Couvillon, Amy Hankin, Monique Williams, Philip W. Kantoff, William L. Dahut, Jeffrey Schlom, James L. Gulley
Journal: Journal of Clinical Oncology (2018)

215 Background: Annually about 30-50,000 men are diagnosed with biochemically recurrent prostate cancer (BCRpc), defined by a rising PSA after radical prostatectomy (RP) or definitive radiation therapy (RT) with negative conventional imaging (CT and bone scan). Standard treatments include salvage therapies, androgen deprivation or surveillance. The role of immunotherapy in BCRpc is undefined. Methods: This study evaluates PROSTVAC, a pox-viral based therapeutic cancer vaccine targeting PSA, in BCRpc. Key eligibility criteria include PSA &gt; 0.8 after RP or &gt; 2.0 after RT with a maximum PSA of 30, PSA doubling time (DT): 5-15 months; testosterone &gt; 100, negative CT and bone scan. Patients (pts) are randomized to vaccine for 6 months or 6 months surveillance followed by 6 months of vaccine. In a post hoc analysis delayed PSA declines were characterized as a confirmed PSA decline after an intra-study apex PSA (ISAP) defined by a peak PSA affirmed by a contiguous PSA within 10% (to exclude lab variations). 80 pts will be enrolled at NCI, Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Results: Of the 26 pts enrolled thus far, 22 have been followed for &gt; 9 months after vaccine and are evaluable. On-study median values were age 66.8 years (54-78), PSA 2.67 ng/ml (0.83-28.5), PSA DT 7.5 months (5.1-14.9). 8 pts (38%) had delayed PSA declines after ISAP (-12% to -99%). Of 13 pts on surveillance for 6 months, only one pt had a similar decline lasting only 56 days. Conclusions: Preliminary data from this study suggests that PROSTVAC may be associated with delayed, but sustained PSA declines in BCRpc which are rarely seen in surveillance alone. Additional data will be acquired from this study, but this provides rationale to develop immunotherapy combinations in BCRpc. Clinical trial information: NCT02649439. [Table: see text]
Pay of most grades of doctor is similar to other professions or higher
Authors: Helen Jaques
Journal: BMJ (2012)

Median total pay of hospital doctors is largely similar to or higher than pay in other professions such as law, insurance, and accounting, says the Review Body on Doctors’ and Dentists’ Remuneration (DDRB).

In its annual report on doctors’ and dentists’ pay, the review body also notes that median total earnings for all grades of hospital doctor are higher than the median earnings of public sector and private employees across the UK, with median earnings of all hospital doctors except foundation year 1 trainees being above the top decile of earnings of full time employees …
CLINICAL BENEFIT OF TRANSCATHETER CLOSURE FOR NEWLY DEVELOPED ATRIAL FIBRILLATION IN ADULT PATIENTS WITH ATRIAL SEPTAL DEFECT
Authors: Teiji Akagi, Yasuhiro Fujii, Yoichi Takaya, Sho Takahashi, Koji Nakagawa, Shingo Kasahara, Hiroshi Ito
Journal: Journal of the American College of Cardiology (2018)
Mountain Climbing, Motherhood, and Surgical Practice
Authors: Kelly L. McCoy, Linwah Yip, Sally E. Carty
Journal: JAMA Surgery (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
P050 High cholesterol levels by apoe deficiency reduce bone destruction in antigen-induced arthritis via reduction of the number of osteoclasts
Authors: G Ascone, I Di Ceglie, M van den Bosch, A Sloetjes, P van der Kraan, E Lindhout, A Blom, P van Lent
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by immune complex (IC) deposition in the synovium, leading to increased bone destruction. In RA, joint destruction has been associated with high levels of low density lipoproteins (LDL) and enhanced LDL oxidation (oxLDL). Apolipoprotein E (Apoe) is an important regulator of LDL transportation and its absence strongly elevates circulating LDL levels, which may lead to increased oxLDL levels during inflammation. <h3>Objectives</h3> In this study, we investigated the effects of high LDL levels on bone destruction during antigen-induced arthritis (AIA) and how increased LDL/oxLDL levels affect osteoclast formation. <h3>Methods</h3> AIA was induced by injection of methylated BSA (mBSA) into the right knee joint of <i>Apoe<sup>-/-</sup></i> and wild type (WT) control mice previously immunised with mBSA and complete Freund's adjuvant (CFA). WT and <i>Apoe<sup>-/-</sup></i> Hoxb8 myeloid precursor cells were differentiated into osteoclasts using 20 ng/mL RANKL and 30 ng/mL M-CSF, then stimulated for 24 hour with 10 µg/mL LDL/oxLDL. Oil Red O staining was performed to assess lipid uptake by osteoclasts. mRNA levels of c-Fos, RANK, NFATc1, DC-STAMP, TRAP, CTR, ClC-7 and Cat K were measured by qPCR. Bone erosion was quantified by histological analysis using an arbitrary scale from 0 to 3 and TRAP<sup>+</sup> cells were determined using immunohistochemistry. <h3>Results</h3> <i>Apoe<sup>-/-</sup></i> mice showed significantly higher LDL serum levels than WT controls. At day 21 after AIA induction, bone erosion was significantly decreased in <i>Apoe<sup>-/-</sup></i> mice (25% reduction from 1.5±0.2 to 1.1±0.1). In line with that, the number of osteoclasts within the knee joints was 36% lower in <i>Apoe<sup>-/-</sup></i> mice, as determined by image analysis of TRAP staining. To study the role of Apoe and high LDL levels on osteoclastogenesis in more detail, we differentiated WT and <i>Apoe<sup>-/-</sup></i> myeloid precursor cells (Hoxb8) into osteoclasts and found similar mRNA levels of osteoclast markers. Whereas LDL stimulation did not affect osteoclast formation, oxLDL strongly impaired cell fusion keeping them in a mononuclear state. mRNA levels of DC-STAMP were significantly down-regulated in both WT and <i>Apoe<sup>-/-</sup></i> osteoclasts (1.4 and 2.3 fold decrease, respectively) as well as TRAP activity (49% and 58% reduction in WT and <i>Apoe<sup>-/-</sup></i> osteoclasts), underlining a major role of oxLDL in inhibiting osteoclastogenesis. <h3>Conclusions</h3> High LDL/oxLDL levels by <i>Apoe</i> deficiency affect bone destruction during AIA by reducing the number of osteoclasts in the synovium, probably by interfering with osteoclastogenesis. <h3>Disclosure of interest</h3> None declared
A phase I study to evaluate the safety of trigriluzole (BHV-4157) in combination with PD-1 blocking antibodies.
Authors: Ann W. Silk, Robert Berman, Vlad Coric, Laura Ruggiero, Allen B. Reitz, Weichung Shih, Michael P. Kane, Janice M. Mehnert, Jeffrey C Pelletier, Andrew Zloza, James Steven Goydos
Journal: Journal of Clinical Oncology (2018)

TPS80 Background: The Metabotropic Glutamate Receptor 1 (GRM1) is expressed in 60-100% of human melanomas, breast cancers, and other solid tumors. Riluzole, an FDA-approved drug for ALS, inhibits GRM1 signal transduction. A phase 0 trial in melanoma patients demonstrated that riluzole suppressed signaling through the MAPK and PI3K/AKT pathways but no objective responses were seen in a phase 2 study.The clinical use of riluzole outside of ALS has been limited by: (i) poor oral bioavailability, (ii) extensive first-pass hepatic metabolism, (iii) high variability in PK parameters, (iv) food-related decrease in bioavailability, and (v) dose-related hepatotoxicity. Trigriluzole (BHV-4157) is a third generation prodrug of riluzole with improved PK/PD properties. In our MASS20 in vivo murine model of melanoma, GRM1 signal transduction appears to suppress tumor immunity through up-regulation of M-CSF and CCL2 expression with a subsequent increase in the percentage of M2 macrophages in the tumor microenvironment. In an immunocompetent mouse model, treatment with trigriluzole and anti-PD-1 antibody was more effective than either drug alone. Methods: Subjects with advanced or refractory solid cancers or lymphoma will be treated with increasing doses of trigriluzole in this phase 1b study. The dosing cohorts of trigriluzole will be using a semi-Bayesian modified toxicity probability interval dose escalation procedure. Trigriluzole monotherapy will be given for a 14-day lead in period and then patients will receive trigriluzole in combination with nivolumab 240mg IV every 2 weeks. After the maximum tolerated dose (MTD) of trigriluzole is identified, it will be checked in a cohort of 6 patients in combination with pembrolizumab. Total sample size will be 12 – 27 subjects. PD-1-directed therapy prior to entry is allowed. Blood samples and optional biopsies will be collected for correlative analysis. PBMCs and fresh tumor tissue will be grafted into NSG mice to create a patient-derived autologous double-humanized murine model for each participant. Clinical trial information: NCT03229278.
Information and education provision in bronchiectasis: co-development and evaluation of a novel patient-driven resource in a digital era
Authors: Katy L.M. Hester, Julia Newton, Tim Rapley, Vicky Ryan, Anthony De Soyza
Journal: European Respiratory Journal (2018)

Bronchiectasis presents a significant burden of disease for patients, their families and healthcare services, with recurrent hospital admissions and poorer health-related quality of life, in addition to higher rates of fatigue, depression and cardiovascular disease [1–3]. The increasing prevalence and burden of bronchiectasis is recognised worldwide [3–6]. Patient education is a fundamental part of long-term management planning, as highlighted in the new European Respiratory Society guidelines, yet there is a lack of information available to patients in comparison to other chronic respiratory conditions. Improvements in information for those living with bronchiectasis should use patient-driven co-development processes <http://ow.ly/vWCB30iCn2M> We would like to acknowledge Holly Ainsworth for assistance with using statistical software for the analysis of the BRIEF study data, and the staff of the William Leech Centre for Lung Research at the Freeman Hospital in the recruitment and study visit conduct in the BRIEF study. We also thank the participants. Author contributions: KH is the first and corresponding author of this article. TR, JN, VR and ADS were contributors to the manuscript and all authors read and approved the final manuscript.
The Federal Right to Try Act of 2017—A Wrong Turn for Access to Investigational Drugs and the Path Forward
Authors: Alison Bateman-House, Christopher T. Robertson
Journal: JAMA Internal Medicine (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Use Brexit to strengthen language tests and increase time for training, surgeons’ college says
Authors: Tom Moberly
Journal: BMJ (2016)

Ministers should use the UK’s departure from the EU to strengthen language testing for overseas doctors and increase the time allocated to medical training, the Royal College of Surgeons (RCS) has said.

In a position statement issued in December 2016, the college urged the government to give the same language tests to doctors who have qualified in the EU as those from the rest of the world. These tests should include assessing doctors’ English language abilities in medical settings, …
Postincarceration Fatal Overdoses After Implementing Medications for Addiction Treatment in a Statewide Correctional System
Authors: Traci C. Green, Jennifer Clarke, Lauren Brinkley-Rubinstein, Brandon D. L. Marshall, Nicole Alexander-Scott, Rebecca Boss, Josiah D. Rich
Journal: JAMA Psychiatry (2018)

This analysis examines the association of death from overdose among individuals released from the Rhode Island correctional system after implementation of a comprehensive program of medications for addiction therapy.
INFLAMMATORY AND CARDIAC BIOMARKERS ARE ASSOCIATED WITH RENAL OUTCOMES IN PATIENTS WITH TYPE 2 DIABETES MELLITUS: INSIGHTS FROM SAVOR-TIMI 53
Authors: Thomas Zelniker, David A. Morrow, Ofri Mosenzon, Yared Gurmu, Kyungah Im, Avivit Cahn, Itamar Raz, Eugene Braunwald, Deepak Bhatt, Benjamin Scirica
Journal: Journal of the American College of Cardiology (2018)
GPs condemn GMC’s lack of leadership over revalidation
Authors: Helen Jaques
Journal: BMJ (2012)

GP leaders have slammed the General Medical Council for failing to spell out how GPs in need of remediation should be supported in the process of revalidation and for “opening the door” to local variation in appraisal.

But a GMC council member, Malcolm Lewis, told the conference of local medical committees this week that the lack of guidance on remediation shouldn’t delay the introduction of revalidation.

“I know a concern about remediation is the patchy approach to delivery across the UK and across specialties,” he said. “I think revalidation has brought attention to that issue, but don’t let it stop revalidation, because otherwise …
Leukotriene E4 induces airflow obstruction and mast cell activation through the cysteinyl leukotriene type 1 receptor
Authors: Nikolaos Lazarinis, Johan Bood, Cristina Gomez, Johan Kolmert, Ann-Sofie Lantz, Pär Gyllfors, Andy Davis, Craig E. Wheelock, Sven-Erik Dahlén, Barbro Dahlén
Journal: Journal of Allergy and Clinical Immunology (2018)