tbuckley/cabot-search huggingface dataset:
Is radical radiotherapy effective for elderly patients with muscle invasive bladder cancer?
Authors: James Price, Mayuran Sivanandan, Rania Elmusharaf, Prabir R Chakraborti, Mike Smith-Howell, Prantik Das
Journal: Journal of Clinical Oncology (2018)

506 Background: Radical radiotherapy (RT) is a curative option for muscle-invasive bladder cancer (MIBC), and offers the chance of bladder preservation. RT and radical cystectomy have not been compared in an RCT, but landmark trials of RT +/- concurrent systemic therapy have demonstrated outcomes comparable to surgery. In clinical practice, patients are often older and less fit compared to trials, and consequently may not be fit for concurrent chemotherapy which may impact treatment outcomes. Methods: A retrospective review of all patients aged 70 years or older treated with radical RT for MIBC from January 2010 – October 2016. Minimum 12 months follow-up. iSOFT manager for used for clinical data and MOSAIQ for radiotherapy parameters. Statistical analysis performed using Stata version 11.2. Results: 71 patients were identified. Male: female ratio 3:1 and median age 79 (range 71 – 93). Median performance status (PS) 1. 81.7% of patients had pT2 disease or greater, 77.5% of patients underwent TURBT prior to RT and 97.2% had transitional cell-carcinoma histology. 38 patients were treated to 60-64Gy/30-32 fractions and 33 patients to 52.5-55Gy/20 fractions. 6 patients (8.5%) received neoadjuvant chemotherapy and 15 (21.1%) received concurrent chemotherapy. Of the 53 patients who did not receive chemotherapy, all were deemed not suitable. 23 of 71 patients (32.4%) developed a loco-regional relapse, either in the bladder (n = 18), pelvic lymph nodes (n = 4), or on cytology alone (n = 1). 24 patients (33.8%) developed distant metastases, only 7 of these were fit for palliative chemotherapy. The median progression-free survival (PFS) was 17 months (95% C.I. 10 – 34 months). Neoadjuvant and concurrent chemotherapy use was not associated with an increased PFS (p = 0.99 and p = 0.97, log rank). The median overall survival was 18 months (95% C.I. 14 – 27 months). Conclusions: Our data demonstrate RT produces favourable outcomes for elderly patients and reasonably well tolerated without significant toxicities. Use of concurrent systemic therapy did not significantly improve outcomes, but numbers were small.
AMPLATZER VASCULAR PLUGS AND AMPLATZER DUCT OCCLUDER II ADDITIONAL SIZES FOR OCCLUSION OF PATENT DUCTUS ARTERIOSUS: A MULTI-INSTITUTIONAL STUDY
Authors: Dennis Vanloozen, Juan Pablo Sandoval, Jeffrey Delaney, Carlos Pedra, Zahid Amin
Journal: Journal of the American College of Cardiology (2018)
Rab6-dependent retrograde traffic of LAT controls immune synapse formation and T cell activation
Authors: Jean-Marie Carpier, Andres E. Zucchetti, Laurence Bataille, Stéphanie Dogniaux, Massiullah Shafaq-Zadah, Sabine Bardin, Marco Lucchino, Mathieu Maurin, Leonel D. Joannas, Joao Gamelas Magalhaes, Ludger Johannes, Thierry Galli, Bruno Goud, Claire Hivroz
Journal: The Journal of Experimental Medicine (2018)

The adapter molecule linker for activation of T cells (LAT) orchestrates the formation of signalosomes upon T cell receptor (TCR) stimulation. LAT is present in different intracellular pools and is dynamically recruited to the immune synapse upon stimulation. However, the intracellular traffic of LAT and its function in T lymphocyte activation are ill defined. We show herein that LAT, once internalized, transits through the Golgi–trans-Golgi network (TGN), where it is repolarized to the immune synapse. This retrograde transport of LAT depends on the small GTPase Rab6 and the target soluble N-ethylmaleimide-sensitive factor attachment protein receptor (t-SNARE) Syntaxin-16, two regulators of the endosome-to-Golgi/TGN retrograde transport. We also show in vitro in Syntaxin-16– or Rab6-silenced human cells and in vivo in CD4+ T lymphocytes of the Rab6 knockout mouse that this retrograde traffic controls TCR stimulation. These results establish that the retrograde traffic of LAT from the plasma membrane to the Golgi-TGN controls the polarized delivery of LAT at the immune synapse and T lymphocyte activation.
SALINE INDUCED PD/PA RATIO CAN PREDICT FUNCTIONAL SIGNIFICANCE OF CORONARY STENOSIS ASSESSED BY FRACTIONAL FLOW RESERVE
Authors: Satoshi Hashimoto, Yoshiharu Fujimori, Kyohei Yamazaki, Kazuto Kurihara, Kenichiro Ebisuda, Yuya Terasawa, Tomoko Baba, Tadamasa Wakabayashi, Taku Imai
Journal: Journal of the American College of Cardiology (2018)
Poor workforce planning has “destroyed” productivity, HEE says
Authors: Matthew Limb
Journal: BMJ (2014)

Poor workforce planning has created additional workload pressure on doctors and has “destroyed” productivity in the NHS, Health Education England has warned.

Ian Cumming, its chief executive, said that NHS workforce planning had gone badly wrong because staffing decisions were being made in response to short term financial pressures rather than to the needs of patients. He said that employers had cut back on some groups of staff when facing difficult financial situations. This had led to a crisis in acute care hospitals, because the numbers of nursing and support staff had not kept pace with rising numbers of consultants, he said.

Speaking at a King’s Fund in conference in London, Cumming said it appeared as if organisations believed that “nobody will notice,” when in fact such action created additional workload pressure on doctors that “destroyed” productivity.

“There is no point in having highly trained, highly competent, expensive clinicians if they are spending their time doing jobs that other members of …
Carry on camping⇓
Authors: Nicola Sharp
Journal: BMJ (2004)

“This did not happen,” Martha Millstone sat on Hubert's desk and did up her bra strap.

“Martha, it has happened every day this week.” Hubert slid his hairy hand around Martha's waist.

“We must forget about it.” Martha pulled away from Hubert and picked up her skirt.

“It happened three times on Thursday.” Hubert looked longingly at Martha's legs.

“A bad day. A complete lack of judgment.” Martha's bleep went off. She picked it up.

“Really? Can you honestly say that Thursday was a complete lack of judgment? Did you not enjoy yourself at all? You sounded as though you did.”

“Don't be so vulgar.” Martha clipped her bleep on to the waistband of her skirt. “All right, I did enjoy myself.”

“I know you did,” said Hubert. “So there is something going on between us.”

“All right, yes there is.” Martha picked up her jacket.

“Hooray. We're back together again.” Hubert sprang off his desk and leaped around the room, completely naked.

“People will see you,” said Martha.

“You don't usually care what people think.”

“There are journalists out there, with cameras.”

Hubert moved away from the window. “But will you divorce David?”

“I must go to …
LONG-TERM PROGNOSTIC VALUE OF THE COMBINATION OF THE GET WITH THE GUIDELINES-HEART FAILURE RISK SCORE AND ACUTE KIDNEY INJURY IN PATIENTS WITH ADMITTED FOR ACUTE DECOMPENSATED HEART FAILURE
Authors: Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Tsutomu Kawai, Masahiro Seo, Iyo Ikeda, Eiji Fukuhara, Jun Nakamura, Makoto Abe, Kazuya Tanabe, Kiyomi Kayama, Masatsugu Kawahira, Masatake Fukunami
Journal: Journal of the American College of Cardiology (2018)
SAFETY OF THORACIC MAGNETIC RESONANCE IMAGING IN PATIENTS WITH PACEMAKERS AND DEFIBRILLATORS
Authors: Deepak Padmanabhan, Danesh Kella, Niyada Naksuk, Abhishek Deshmukh, Siva Mulpuru, Suraj Kapa, Ramila Mehta, Connie Dalzell, Nora Olson, Joel Felmlee, Mary Lou Jondal, Samuel Asirvatham, Robert Watson, Yong-Mei Cha, Paul Friedman
Journal: Journal of the American College of Cardiology (2018)
INSUFFICIENT MITRAL LEAFLET REMODELING CONTRIBUTES TO MITRAL REGURGITATION IN PATIENTS WITH ATRIAL FIBRILLATION: A QUANTITATIVE THREE-DIMENSIONAL TRANSESOPHAGEAL ECHOCARDIOGRAPHIC STUDY
Authors: Holmann Tang, Zhe Tang, Yiting Fan, Steven Fan, Josie Chow, Alex Pui-Wai Lee
Journal: Journal of the American College of Cardiology (2018)
Cosegregation of cfDNA AR amplifications and mutations in relation to BRAF and MYC in CRPC.
Authors: Bryce Raymon Christensen, Elisa Ledet, Marcus Marie Moses, Lynne Chapman, Peter Steinwald, Ashkan Shahbandi, Patrick Cotogno, Joshua Schiff, Jodi Lyn Layton, Brian E. Lewis, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2018)

261 Background: cfDNA can be utilized to evaluate androgen receptor (AR) alterations in metastatic castrate resistant prostate cancer (mCRPC) patients. Given the role of androgen receptors in the pathophysiology of PC, mutations in the AR gene can have important implications regarding prognosis and treatment. The goal of this research was to evaluate associations between certain PC treatments and AR mutations. Methods: Treatment and demographic data from 121 patients diagnosed with PC was collected including genetic data derived from the Guardant360 test (Guardant Health, Redwood City, CA). AR alterations were compared among race, treatment history, and other somatic alterations. Results: 52.9% (n = 64) of the mCRPC pts evaluated had an AR alteration. Of the pts with AR alterations, 43.8% (n = 28) had AR amplification (amps), 37.5% (n = 24) had AR mutations (muts), and 18.8% (n = 12) had both. AR muts included: T878A (n = 15), H875Y (n = 8), W742C (n = 11), AR L702H (n = 7), and others. AR alterations comprised on average about 7% of tumoral cfDNA. To better understand the relationship between AR alterations and other commonly detected cfDNA aberrations, associations between BRAF (27.3%), TP53 (44.6%), and MYC (19.0%) and AR were assessed. Among these genes, P53 alterations were all Muts. MYC (n = 21) and BRAF (n = 27) alterations were predominantly amps though muts were also detected in MYC (n = 3) and BRAF (n = 9). P53 muts were not significantly associated with AR alterations. BRAF and MYC alterations significantly associated with AR alterations (p = 0.0012 and p = 0.0223). Pts were re-tested upon disease progression; among these patients, 52.2% (n = 24) had an increase in overall mut burden. Conclusions: AR alterations in cfDNA impact both disease progression and response to therapy. Co-segregation of AR, BRAF, and MYC alterations may also have significant prognostic and therapeutic implications. Further research, a larger sample size, and longitudinal assessment are needed to further elucidate associations between disease progression and treatment response to the development of somatic alterations over time in mCRPC.
Wide skin markings pattern: melanoma descriptor or patient-related factor?: reply from the authors
Authors: C. Longo, A. Lallas, A. Kyrgidis, S. Bassoli, E. Moscarella, G. Pellacani, G. Argenziano
Journal: British Journal of Dermatology (2018)

Linked Articles:Bassoli S et al. Br J Dermatol 2018; 178:e217–e218. Rishpon A et al. Br J Dermatol 2018; 178:1224–1225.
Acute Oral Administration of Single‐Walled Carbon Nanotubes Increases Intestinal Permeability and Inflammatory Responses: Association with the Changes in Gut Microbiota in Mice
Authors: Hanqing Chen, Ruifang Zhao, Bing Wang, Lingna Zheng, Hong Ouyang, Hailong Wang, Xiaoyan Zhou, Dan Zhang, Zhifang Chai, Yuliang Zhao, Weiyue Feng
Journal: Advanced Healthcare Materials (2018)

With the increasing production and widespread potential applications of single-walled carbon nanotubes (SWCNTs), the possible impacts of oral administration of SWCNTs on gastrointestinal tract at currently occupational exposure limits and potential biomedical applications should be concerned. To address the concerns, mice are orally administrated of SWCNTs at doses of 0.05, 0.5, and 2.5 mg kg-1 body weight per day for 7 d. The investigation shows that SWCNT treatment had promoted intestinal injuries at the acute dose of 2.5 mg kg-1 per day, including increase of histological lesion scores, intestinal permeability, and proinflammatory cytokine (IL-1β, IL-6, and TNF-α) secretion. Analysis of gut microbiota composition using 16S rRNA gene sequencing approach reveals that acute oral administration of SWCNTs induces significant shifts of the predominant microbe phyla from Firmicutes to Bacteroidetes and increases abundance of proinflammatory bacteria Alitipes_uncultured_bacterium and Lachnospiraceae bacterium A4. These notable findings suggest that SWCNT-induced intestinal injury is linked to SWCNT interaction with intestinal tract and gut bacteria and the consequent triggering of "metabolic inflammation" responses. Furthermore, the study has shown that oral administration of carbon nanomaterials, including SWCNTs, multiwalled CNTs, and graphene oxide, can lead to different inflammatory responses and specific alteration in gut microbiota in mice.
I am having difficulty finding jobs in obstetrics and gynaecology and in paediatrics that are suitable for general practitioner trainees. Any tips?
Authors: Anne Hastie
Journal: BMJ (2004)

<i>Got a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site.</i>
Abstract ES10-1: Genetic dissection of cancer development, therapy response, and resistance in mouse models of breast cancer
Authors: J Jonkers
Journal: Cancer Research (2018)

Abstract Genetically engineered mouse models (GEMMs) and patient-derived xenograft (PDX) models of breast cancer have proven invaluable for basic and translational cancer research. These preclinical models have been useful for in vivo analysis of breast cancer initiation and progression, as well as for investigating anti-tumor efficacy of targeted drugs and immunotherapeutics. However, the establishment of GEMMs and PDX models involves cost and time limitations that represent serious bottlenecks. To keep pace with the growing number of hypotheses that warrant preclinical in vivo testing, continuous refinement of current breast cancer models is crucial. Novel technologies, such as CRISPR/Cas9-based in vivo gene editing, non-germline mouse models of breast cancer, and breast cancer-derived organoids enable accelerated and more refined in vivo and ex vivo modeling of human breast cancer. The resulting preclinical models can be used to identify and validate breast cancer driver genes and candidate drug targets, evaluate anticancer drug efficacy, and identify novel mechanisms of drug resistance. Citation Format: Jonkers J. Genetic dissection of cancer development, therapy response, and resistance in mouse models of 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 ES10-1.
Identification of novel recurrent CPSF6-RARG fusions in acute myeloid leukemia resembling acute promyelocytic leukemia
Authors: Tianhui Liu, Lijun Wen, Hongjian Yuan, Yi Wang, Li Yao, Yang Xu, Jiannong Cen, Changgeng Ruan, Depei Wu, Suning Chen
Journal: Blood (2018)
The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer Invasion
Authors: Swadesh K. Das, Anjan K. Pradhan, Praveen Bhoopathi, Sarmistha Talukdar, Xue-Ning Shen, Devanand Sarkar, Luni Emdad, Paul B. Fisher
Journal: Cancer Research (2018)

Abstract Although prostate cancer is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation-associated gene-9 [syntenin, or syndecan binding protein (SDCBP)] in prostate cancer progression. Using tissue samples from various Gleason stage prostate cancer patients with adjacent normal tissue, a series of normal prostate and prostate cancer cell lines (with differing tumorigenic/metastatic properties), mda-9/syntenin-manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/Syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/syntenin in prostate cancer invasion. MDA-9/Syntenin physically interacted with insulin-like growth factor-1 receptor following treatment with insulin-like growth factor binding protein-2 (IGFBP2), regulating downstream signaling processes that enabled STAT3 phosphorylation. This activation enhanced expression of MMP2 and MMP9, two established enzymes that positively regulate invasion. In addition, MDA-9/syntenin-mediated upregulation of proangiogenic factors including IGFBP2, IL6, IL8, and VEGFA also facilitated migration of prostate cancer cells. Collectively, our results draw attention to MDA-9/Syntenin as a positive regulator of prostate cancer metastasis, and the potential application of targeting this molecule to inhibit invasion and metastasis in prostate cancer and potentially other cancers. Significance: This study provides new mechanistic insight into the proinvasive role of MDA-9/Syntenin in prostate cancer and has potential for therapeutic application to prevent prostate cancer metastasis. Cancer Res; 78(11); 2852–63. ©2018 AACR.
Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability
Authors: Andrew J. King, Matthew Siegel, Ying He, Baoming Nie, Ji Wang, Samantha Koo-McCoy, Natali A. Minassian, Qumber Jafri, Deng Pan, Jill Kohler, Padmapriya Kumaraswamy, Kenji Kozuka, Jason G. Lewis, Dean Dragoli, David P. Rosenbaum, Debbie O’Neill, Allein Plain, Peter J. Greasley, Ann-Cathrine Jönsson-Rylander, Daniel Karlsson, Margareta Behrendt, Maria Strömstedt, Tina Ryden-Bergsten, Thomas Knöpfel, Eva M. Pastor Arroyo, Nati Hernando, Joanne Marks, Mark Donowitz, Carsten A. Wagner, R. Todd Alexander, Jeremy S. Caldwell
Journal: Science Translational Medicine (2018)

Tenapanor inhibits sodium/hydrogen exchanger isoform 3 to reduce intestinal phosphate absorption via reduction of passive paracellular phosphate flux.
I start my medical degree in a few months. Will the fact that I am a nurse hinder or help me through my medical career?
Authors: Jim Bolton
Journal: BMJ (2005)

Have a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site. www.bmjcareers.com/advicezone
DIFFERENT CONTRIBUTION OF SARCOMERE AND MITOCHONDRIA RELATED GENE MUTATIONS TO HYPERTROPHIC CARDIOMYOPATHY
Authors: Hyemoon Chung, Jong-Youn Kim, Pil-Ki Min, Young Won Yoon, Byoung Kwon Lee, Bum-Kee Hong, Se-Joong Rim, Hyuck Moon Kwon, Eui-Young Choi
Journal: Journal of the American College of Cardiology (2018)
A Model for Sustained Collaboration to Address the Unmet Global Burden of Bladder Exstrophy-Epispadias Complex and Penopubic Epispadias
Authors: Rakesh S. Joshi, Dhirendra Shrivastava, Richard Grady, Anjana Kundu, Jaishri Ramji, Pramod P. Reddy, Joao Luiz Pippi-Salle, Jennifer R. Frazier, Douglas A. Canning, Aseem R. Shukla
Journal: JAMA Surgery (2018)

<h3>Importance</h3> International collaboration to alleviate the massive burden of surgical disease is recognized by World Health Organization as an urgent need, yet the surgical mission model to treat reconstructive surgical challenges is often constrained in ensuring adequate patient follow-up, optimal outcomes, and sustainability. <h3>Objective</h3> To determine whether a collaboration predicated on long-term commitment by surgeons returning to the same institution annually combined with an experienced host surgical team and infrastructure to ensure sustained patient follow-up could provide surgical care with acceptable outcomes to treat bladder exstrophy-epispadias complex (BE) and penopubic epispadias (PE). <h3>Design, Setting, and Participants</h3> In this prospective, observational study, long-term collaboration was created and based at a public hospital in Ahmedabad, India, between January 2009 and January 2015. The entire postoperative cohort was recalled in January 2016 for comprehensive examination, measurement of continence outcomes, and assessment of surgical complications. Seventy-six percent of patients (n = 57) who underwent complete primary repair of exstrophy during the study interval returned for annual follow-up in 2016 and formed the study cohort: 23 patients with primary BE, 19 patients with redo BE, and 11 patients with PE repair. <h3>Main Outcomes and Measures</h3> Demographics, operative techniques, and perioperative complications were recorded. A postoperative protocol outlining procedures to ensure monitoring of study participants was followed including removal of ureteral stents, urethral catheter, external fixators, imaging, and patient discharge. <h3>Results</h3> Of the 57 patients, 4 were excluded because they underwent ureterosigmoidostomy. Median age at time of surgery was 3 years (primary BE), 7 years (redo BE), and 10 years (PE), with median follow-up of 3 years, 5 years and 3 years, respectively; boys made up more than 70% of each cohort (n = 17 for primary BE, n = 15 for redo BE, and n = 9 for PE). All BE and 3 PE repairs (27%) were completed with concurrent anterior pubic osteotomies. Seventeen of 53 patients (32%) experienced complications. Only 1 patient with BE (4%) had a bladder dehiscence and was repaired the following year. <h3>Conclusions and Relevance</h3> A unique surgical mission model consisting of an international collaborative focused on treating the complex diagnoses of BE and PE offers outcomes comparable with those in high-income countries, demonstrating a significant patient retention rate and an opportunity to rigorously study outcomes over an accelerated interval owing to the high burden of disease in India. Postoperative care following a systematized algorithm and rigorous follow-up is mandatory to ensure safety and optimal outcomes.