tbuckley/cabot-search huggingface dataset:
Effect of HER3 dimer feedback upregulation via PI3K-AKT-mTOR pathway inhibition on androgen receptor (AR) stabilization in metastatic prostate cancer.
Authors: Myria Galazi, Mark Salji, Gregory Weitsman, Valentin Gomez, Hing Leung, Tony Ng
Journal: Journal of Clinical Oncology (2018)

226 Background: Metastatic castration resistant prostate cancer (CRPC) is dependent on persistent activation of the AR. In addition, the AR and PI3K-AKT-mTOR pathways have been shown to regulate each other through complex feedback mechanisms. Various early phase clinical studies are currently investigating the role of PI3K-AKT-mTOR pathway inhibitors in improving outcomes in metastatic CRPC. We hypothesise that the formation of a HER3 (human epidermal growth factor receptor) heterodimer, has an important role in regulating the AR and PI3K-AKT-mTOR feedback loop and that its detection can predict response to PI3K-AKT-mTOR pathway inhibition. Methods: LNCAP cells were stably lentiviral transduced with shRNA against HER3. The effect of PI3K-AKT-mTOR inhibition by DS7423, GDC0068, GDC0941 and Everolimus on AR and its direct target gene PSA was evaluated by western blot and real-time quantitative PCR. CWR22 and 22RVI mouse xenograft tumours were stained with fluorescently labelled antibodies for fluorescence lifetime imaging microscopy (FLIM) to assess HER2-HER3 dimerisation by FRET (fluorescence resonance energy transfer) using TRI2 software. Results: We show that there is a statistically significant increase in AR protein levels and PSA gene expression in LNCAP NTC vs HER3kd cells upon treatment with the dual PI3K-mTOR inhibitor DS7423. In addition, there is decreased inhibition of AKT phosphorylation in LNCAP NTC cells, whereas in the absence of HER3 there is complete abrogation of pAKT levels. The use of GDC0941 and Everolimus resulted in similar effect on AR in the LNCAP NTC vs HER3kd cells, however this is less prominent. The AKT inhibitor, GDC0068, has little effect on AR in the presence or absence of HER3. FLIM demonstrated increase in FRET as evidence of HER3 heterodimerisation in 22RVI compared to CWR22 xenograft tissue, showing that HER3 dimerisation emerges in metastatic prostate cancer that has progressed to a castrate resistant phenotype. Conclusions: Our results suggest that HER3 stabilises the AR upon PI3K-AKT- mTOR pathway inhibition and that detection of a HER3 heterodimer can be used as a predictive biomarker of response to these therapies.
Identification of novel lncRNAs regulated by the TAL1 complex in T-cell acute lymphoblastic leukemia
Authors: Phuong Cao Thi Ngoc, Shi Hao Tan, Tze King Tan, Min Min Chan, Zhenhua Li, Allen. E. J. Yeoh, Daniel G Tenen, Takaomi Sanda
Journal: Leukemia (2018)
GP training in the USA
Authors: Christin Gallo
Journal: BMJ (2005)

In the United States, after completing four years of medical school, students apply to various residency programmes. General practice (what we call family practice (FP) or family medicine in the US) is a relatively non-competitive programme. There are many programmes, and each year fewer and fewer graduating medical students choose to take that route. The training lasts three years and consists of rotations in virtually every aspect of medicine, including obstetrics and gynaecology, …
Hyaluronan metabolism enhanced during epidermal differentiation is suppressed by vitamin C
Authors: L. Hämäläinen, E. Kärkkäinen, P. Takabe, L. Rauhala, G. Bart, R. Kärnä, S. Pasonen-Seppänen, S. Oikari, M.I. Tammi, R.H. Tammi
Journal: British Journal of Dermatology (2018)

Hyaluronan is a large, linear glycosaminoglycan present throughout the narrow extracellular space of the vital epidermis. Increased hyaluronan metabolism takes place in epidermal hypertrophy, wound healing and cancer. Hyaluronan is produced by hyaluronan synthases and catabolized by hyaluronidases, reactive oxygen species and KIAA1199.To investigate the changes in hyaluronan metabolism during epidermal stratification and maturation, and the impact of vitamin C on these events.Hyaluronan synthesis and expression of the hyaluronan-related genes were analysed during epidermal maturation from a simple epithelium to a fully differentiated epidermis in organotypic cultures of rat epidermal keratinocytes using quantitative reverse transcriptase polymerase chain reaction, immunostaining and Western blotting, in the presence and absence of vitamin C.With epidermal stratification, both the production and the degradation of hyaluronan were enhanced, resulting in an increase of hyaluronan fragments of various sizes. While the mRNA levels of Has3 and KIAA1199 remained stable during the maturation, Has1, Has2 and Hyal2 showed a transient upregulation during stratification, Hyal1 transcription remained permanently increased and transcription of the hyaluronan receptor, Cd44, decreased. At maturation, vitamin C downregulated Has2, Hyal2 and Cd44, whereas it increased high-molecular-mass hyaluronan in the epidermis, and reduced small fragments in the medium, suggesting stabilization of epidermal hyaluronan.Epidermal stratification and maturation is associated with enhanced hyaluronan turnover, and release of large amounts of hyaluronan fragments. The high turnover is suppressed by vitamin C, which is suggested to enhance normal epidermal differentiation in part through its effect on hyaluronan.
GPs in Northern Ireland back formation of practice federations
Authors: Abi Rimmer
Journal: BMJ (2014)

GPs in Northern Ireland are pushing ahead with the formation of practice federations, the chairman of the BMA’s General Practitioners Committee for Northern Ireland has said. 

Tom Black, said GPs at last weekend’s Northern Ireland local medical committees’ conference in Newcastle were “enthused about federations.” He said, “We’re pushing ahead with federations. We’re now going to ensure that every GP, including salaried and sessional GPs, and every practice has the opportunity to be part of a federation.”

Black said federations could help GPs to deal with work that was being transferred from …
RADIATION DOSES TO PHYSICIANS PERFORMING TRANSESOPHAGEAL ECHOCARDIOGRAPHY DURING PERCUTANEOUS LEFT ATRIAL APPENDAGE CLOSURE
Authors: Michael W. McNamara, Jeffrey Decker, Stacie Vanoosterhout, Abbey Mulder, Taylor Ten Brock, Duane Berkompas, Musa Dahu, Jessica Parker, Ryan Madder
Journal: Journal of the American College of Cardiology (2018)
Patient demographic and surgical characteristics in anterior cruciate ligament reconstruction: a description of registries from six countries
Authors: Heather A Prentice, Martin Lind, Caroline Mouton, Andreas Persson, Henrik Magnusson, Ayman Gabr, Romain Seil, Lars Engebretsen, Kristian Samuelsson, Jon Karlsson, Magnus Forssblad, Fares S Haddad, Tim Spalding, Tadashi T Funahashi, Liz W Paxton, Gregory B Maletis
Journal: British Journal of Sports Medicine (2018)

Findings from individual anterior cruciate ligament reconstruction (ACLR) registry studies are impactful, but how various registries from different countries compare with different patient populations and surgical techniques has not been described. We sought to describe six ACLR registry cohorts to understand variation across countries.Five European registries and one US registry participated. For each registry, all primary ACLR registered between registry establishment through 31December 2014 were identified. Descriptive statistics included frequencies, proportions, medians and IQRs. Revision incidence rates following primary ACLR were computed.101 125 ACLR were included: 21 820 in Denmark, 300 in Luxembourg, 17 556 in Norway, 30 422 in Sweden, 2972 in the UK and 28 055 in the US. In all six cohorts, males (range: 56.8%-72.4%) and soccer injuries (range: 14.1%-42.3%) were most common. European countries mostly used autografts (range: 93.7%-99.7%); allograft was most common in the US (39.9%). Interference screw was the most frequent femoral fixation in Luxembourg and the US (84.8% and 42.9%), and suspensory fixation was more frequent in the other countries (range: 43.9%-75.5%). Interference was the most frequent tibial fixation type in all six cohorts (range: 64.8%-98.2%). Three-year cumulative revision probabilities ranged from 2.8% to 3.7%.Similarities in patient demographics and injury activity were observed between all cohorts of ACLR. However, graft and fixation choices differed. Revision rates were low. This work, including >100 000 ACLR, is the most comprehensive international description of contemporary practice to date.
BRD4 Inhibition Is Synthetic Lethal with PARP Inhibitors through the Induction of Homologous Recombination Deficiency
Authors: Chaoyang Sun, Jun Yin, Yong Fang, Jian Chen, Kang Jin Jeong, Xiaohua Chen, Christopher P. Vellano, Zhenlin Ju, Wei Zhao, Dong Zhang, Yiling Lu, Funda Meric-Bernstam, Timothy A. Yap, Maureen Hattersley, Mark J. O'Connor, Huawei Chen, Stephen Fawell, Shiaw-Yih Lin, Guang Peng, Gordon B. Mills
Journal: Cancer Cell (2018)
ELECTRONIC HEALTH RECORD ALGORITHMS TO DETECT PAD
Authors: William Schuyler Jones, Steven Lippman, Michelle Smerek, Kuntal Shah, Rachael Ward, Adam Brock, Robert Casey Sullivan, Chandler Long, Sreekanth Vemulapalli, Manesh Patel, Melissa Greiner, Chantelle Hardy, Lesley Curtis
Journal: Journal of the American College of Cardiology (2018)
Perfluorooctyl bromide &amp; indocyanine green co-loaded nanoliposomes for enhanced multimodal imaging-guided phototherapy
Authors: Danli Sheng, Tianzhi Liu, Liming Deng, Liang Zhang, Xuelin Li, Jie Xu, Lan Hao, Pan Li, Haitao Ran, Hangrong Chen, Zhigang Wang
Journal: Biomaterials (2018)
Abstract ES7-2: Local regional recurrence
Authors: RC Zellars
Journal: Cancer Research (2018)

Abstract Through careful study, we are certain of the management necessary to achieve excellent local regional control rates in early stage breast cancer (ESBC). Due to less study, there is some uncertainty on how to best manage the small percentage of women with ESBC who have local regional recurrences (LRR). Classically, the management of LRR requires some form of salvage surgery. The surgery could be limited, as in wide local excision after initial mastectomy, or more radical, as in mastectomy after initial breast conserving therapy. Often after salvage surgery, radiation, or in some cases re-irradiation, is added. Today there is information which calls into question whether these common treatments for LRR are required, sufficient or the sole options. During this session, we will review the data supporting these common treatments for LRR, as well as alternatives such as surgery alone, partial breast re-irradiation, photodynamic therapy and hyperthermia. After the presentation, the attendee will have a greater understanding of the various local therapy options for treating LRR of breast cancer and the need for prospective study of this small but significant group of patients. Citation Format: Zellars RC. Local regional recurrence [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 ES7-2.
PREDICTION OF ALL CAUSE DEATH IN PATIENTS WITH ACUTE DECOMPENSATED HEART FAILURE USING THE COMBINATION OF THE FIBROSIS-4 INDEX AND GERIATRIC NUTRITIONAL RISK INDEX
Authors: Yoshihiro Sato, Masahiro Kumada, Takuma Iida, Yukinori Okazaki, Tsutomu Nakagawa
Journal: Journal of the American College of Cardiology (2018)
P122 Treatment with rituximab to demand in rheumatoid arthritis. effectiveness analysis
Authors: U Julia, MJ Fobelo, M Guzman
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody that has been shown to be effective in the treatment of rheumatoid arthritis (RA). At present we have different treatment regimens in terms of the time of administration, every 6 months or on demand and with respect to the dose used: cycles of 1000 mg x 2 or 500 mg x 2. <h3>Objectives</h3> Our objetive was to analyse the effectiveness on- demand tratment regimen of RTX in RA <h3>Methods</h3> Retrospective observational study on RA with RTX treatment between January 2006 and February 2015 was carried out. Administration was performed if DAS28 &gt;3.2. The median time of retreatment and the number of patients portrayed at 8, 12, 16, 20 and 24 months were calculated <h3>Results</h3> 57 patients were included, mean age 55 years, 70% women; 93% FR+, 31.6% ACPA +and 63.2% with erosive disease. The median time of evolution of RA at the start of RTX 8.1 years. All patients had high activity at the start of RTX [median DAS28=5.6; HAQ=1.75]. Prior to RTX, all patients were treated with another biological (24.5% with two or more). 56% of patients were receiving DMARDs. The median time of retreat was 7 months. The number of patients portrayed was: at 8 months 55.8%, at 12 months 69.4%, at 16 months 80%, at 20 months 81.3% and at 24 months at 88.6%. Those not evaluated in each quarter are those who are discontinued RTX before two years of follow-up (four due to inefficacy and one due to adverse reaction) or, at the time of completing the study, have not completed two years of treatment. The effectiveness considered as the median number of cycles received at two years was 2. <h3>Conclusions</h3> Although the median time to retreatment was seven months, there are some patients who remain unplastered for about two years. 80% of the patients had been portrayed at 16 months, half with 1 cycle of RTX and the other half with 2. The pattern on demand even allowed to decrease the doses of concomitant DMARDs. A subsequent individualised analysis of patients will allow us to evaluate the possible characteristics that can affect the effectiveness of the pattern on demand <h3>Disclosure of interest</h3> None declared
Future of GP partnership model is uncertain, as “forces” against it mount, says RCGP president
Authors: Abi Rimmer
Journal: BMJ (2015)

The future of the GP partnership is in doubt, as the disadvantages of the system begin to outweigh the positives, the president of the Royal College of General Practitioners has said.

Speaking at the college’s annual conference in Glasgow on 1 October, Mike Pringle said that future GPs may require a more flexible career path than that provided by the partnership model.

Responding to a question on the future of general practice from a junior doctor in the third year of specialty training, Pringle said, “Firstly, the idea of partnership for life is almost certainly not going to work.” He added, “For your generation and the generations coming up …
Vortical features for myocardial rotation assessment in hypertrophic cardiomyopathy using cardiac tagged magnetic resonance
Authors: Santiago Sanz-Estébanez, Lucilio Cordero-Grande, Teresa Sevilla, Ana Revilla-Orodea, Rodrigo de Luis-García, Marcos Martín-Fernández, Carlos Alberola-López
Journal: Medical Image Analysis (2018)
IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC)
Authors: Robert J. Motzer, Thomas Powles, Michael B. Atkins, Bernard Escudier, David F. McDermott, Cristina Suarez, Sergio Bracarda, Walter Michael Stadler, Frede Donskov, Jae-Lyun Lee, Robert E. Hawkins, Alain Ravaud, Boris Y. Alekseev, Michael D. Staehler, Motohide Uemura, Francis Donaldson, Shi Li, Mahrukh A. Huseni, Christina Schiff, Brian I. Rini
Journal: Journal of Clinical Oncology (2018)

578 Background: Atezolizumab (atezo; anti–PD-L1) + bevacizumab (bev; anti-VEGF) showed first-line (1L) anti-tumor activity with a manageable safety profile in PD-L1+ mRCC pts in a Phase II study (McDermott ASCO-GU 2017). Here we describe the first randomized Phase III trial of a PD-L1/PD-1 pathway inhibitor combined with an anti-VEGF agent in 1L mRCC. Methods: IMmotion151 (NCT02420821) enrolled treatment-naïve pts regardless of prognostic risk group randomized 1:1 to receive atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sunitinib (sun) 50 mg PO QD 4 wk on/2 wk off. Pts were stratified by PD-L1 status (&lt; 1% vs ≥ 1% PD-L1 expression on tumor-infiltrating immune cells [IC]; SP142 IHC assay). Coprimary endpoints: progression-free survival (PFS; by investigator per RECIST v1.1) in PD-L1+ pts (≥ 1% IC) and overall survival (OS) in intent-to-treat (ITT) pts. Secondary endpoints included PFS in ITT pts, ORR and DOR. Results: Baseline characteristics were comparable between arms within PD-L1+ (40% of ITT) and ITT pts. Median survival follow-up was 15 mo. PFS HR for atezo + bev vs sun was 0.74 (95% CI 0.57, 0.96) in PD-L1+ pts and 0.83 (95% CI 0.70, 0.97) in ITT pts. OS was immature at first interim analysis. PFS benefit was consistent across analyzed subgroups, including MSKCC risk, liver metastases and sarcomatoid histology. In PD-L1+ pts, ORR was 43% and DOR was not reached for atezo + bev vs 35% and 12.9 mo for sun. 40% of atezo + bev–treated pts and 54% of sun-treated pts had treatment-related Gr 3-4 AEs; 12% and 8% of treatment-related all-Gr AEs led to discontinuation, respectively. Conclusions: The study showed longer PFS for atezo + bev vs sun in PD-L1+ pts. Improved PFS was also observed in ITT pts. Safety was consistent with that of the individual agents. These results support the use of atezo + bev as a 1L treatment option in mRCC. Clinical trial information: NCT02420821. [Table: see text]
Leptin Replacement Reestablishes Brain Insulin Action in the Hypothalamus in Congenital Leptin Deficiency
Authors: Sabine Frank-Podlech, Julia von Schnurbein, Ralf Veit, Martin Heni, Jürgen Machann, Jaana M. Heinze, Stephanie Kullmann, Jaida Manzoor, Saqib Mahmood, Hans-Ulrich Häring, Hubert Preissl, Martin Wabitsch, Andreas Fritsche
Journal: Diabetes Care (2018)

OBJECTIVE Human obesity is associated with impaired central insulin signaling, and in very rare cases, severe obesity can be caused by congenital leptin deficiency. In such patients, leptin replacement results in substantial weight loss and improvement in peripheral metabolism. RESEARCH DESIGN AND METHODS In a leptin-deficient patient, we investigated the impact of leptin substitution on central insulin action, as quantified by changes in neuronal activity after intranasal insulin application. This was assessed before and during the first year of metreleptin substitution. RESULTS After only 1 year, treatment with metreleptin reestablishes brain insulin sensitivity, particularly in the hypothalamus and, to a lesser degree, in the prefrontal cortex. Results are depicted in comparison with a control group. In our patient, brain activation changes were accompanied by substantial weight loss, reduced visceral adipose tissue, reduced intrahepatic lipid content, and improved whole-body insulin sensitivity. CONCLUSIONS Leptin replacement and weight loss improved homeostatic insulin action in the patient in question.
Risk of Breast, Prostate, and Colorectal Cancer Diagnoses Among HIV-Infected Individuals in the United States
Authors: Anna E Coghill, Eric A Engels, Maria J Schymura, Parag Mahale, Meredith S Shiels
Journal: JNCI Journal of the National Cancer Institute (2018)

Although people living with HIV or AIDS (PLWHA) are at higher risk for many cancers, breast, prostate, and colorectal cancer rates are lower in this patient population. Because these tumors are often screen-detected, these inverse associations could be driven by HIV-related differences in utilization of cancer screening. We ascertained incident breast, prostate, and colorectal cancer in PLWHA using data from the HIV/AIDS Cancer Match Study (1996–2012). Comparisons with general population cancer rates were made using standardized incidence ratios (SIRs), overall and stratified by tumor stage/size, breast cancer estrogen receptor status, and colorectal site. We also examined the potential effect of study design and unmeasured confounding on inverse standardized incidence ratios. Compared with the general population, PLWHA had lower rates of invasive breast (SIR = 0.63, 95% confidence interval [CI] = 0.58 to 0.68), prostate (SIR = 0.48, 95% CI = 0.46 to 0.51), proximal colon (SIR = 0.67, 95% CI = 0.59 to 0.75), distal colon (SIR = 0.51, 95% CI = 0.43 to 0.59), and rectal cancers (SIR = 0.69, 95% CI = 0.61 to 0.77). Reduced risk persisted across tumor stage/size for prostate and colorectal cancers. Although distant-stage breast cancer rates were not reduced (SIR = 0.94, 95% CI = 0.73 to 1.20), HIV-infected women had lower rates of large (>5 cm) breast tumors (SIR = 0.65, 95% CI = 0.50 to 0.83). The magnitude of these inverse standardized incidence ratios could not plausibly be attributed to case underascertainment, out-migration, or unmeasured confounding. Breast, prostate, and colorectal cancer rates are markedly lower among PLWHA, including rates of distant-stage/large tumors that are not generally screen-detected. This set of inverse HIV-cancer associations is therefore unlikely to be due primarily to differential screening and may instead represent biological relationships requiring future investigation.
Caspase-1 self-cleavage is an intrinsic mechanism to terminate inflammasome activity
Authors: Dave Boucher, Mercedes Monteleone, Rebecca C. Coll, Kaiwen W. Chen, Connie M. Ross, Jessica L. Teo, Guillermo A. Gomez, Caroline L. Holley, Damien Bierschenk, Katryn J. Stacey, Alpha S. Yap, Jelena S. Bezbradica, Kate Schroder
Journal: The Journal of Experimental Medicine (2018)

Host-protective caspase-1 activity must be tightly regulated to prevent pathology, but mechanisms controlling the duration of cellular caspase-1 activity are unknown. Caspase-1 is activated on inflammasomes, signaling platforms that facilitate caspase-1 dimerization and autoprocessing. Previous studies with recombinant protein identified a caspase-1 tetramer composed of two p20 and two p10 subunits (p20/p10) as an active species. In this study, we report that in the cell, the dominant species of active caspase-1 dimers elicited by inflammasomes are in fact full-length p46 and a transient species, p33/p10. Further p33/p10 autoprocessing occurs with kinetics specified by inflammasome size and cell type, and this releases p20/p10 from the inflammasome, whereupon the tetramer becomes unstable in cells and protease activity is terminated. The inflammasome–caspase-1 complex thus functions as a holoenzyme that directs the location of caspase-1 activity but also incorporates an intrinsic self-limiting mechanism that ensures timely caspase-1 deactivation. This intrinsic mechanism of inflammasome signal shutdown offers a molecular basis for the transient nature, and coordinated timing, of inflammasome-dependent inflammatory responses.
Moving out of the comfort zone
Authors: Rhona MacDonald
Journal: BMJ (2004)

Some of the articles in this week's issue may make you feel very uncomfortable. We are dealing with a subject that most people don't like to think about, let alone talk or read about-sexual assault.

According to 2002 statistics, about 1 in 20 women in the United Kingdom said that they had been raped, and 5% of those seen at a London based service for managing victims …
Ixekizumab treatment shows a neutral impact on cardiovascular parameters in patients with moderate-to-severe plaque psoriasis: Results from UNCOVER-1, UNCOVER-2, and UNCOVER-3
Authors: Alexander Egeberg, Jashin J. Wu, Neil Korman, James A. Solomon, Orin Goldblum, Fangyi Zhao, Lotus Mallbris
Journal: Journal of the American Academy of Dermatology (2018)