tbuckley/cabot-search huggingface dataset:
3′-epi-12β-hydroxyfroside, a new cardenolide, induces cytoprotective autophagy via blocking the Hsp90/Akt/mTOR axis in lung cancer cells
Authors: Yan Sun, Yong-Hao Huang, Feng-Ying Huang, Wen-Li Mei, Quan Liu, Cai-Chun Wang, Ying-Ying Lin, Canhua Huang, Yue-Nan Li, Hao-Fu Dai, Guang-Hong Tan
Journal: Theranostics (2018)

Rationale: Cardenolides have potential as anticancer drugs. 3'-epi-12β-hydroxyfroside (HyFS) is a new cardenolide structure isolated by our research group, but its molecular mechanisms remain poorly understood. This study investigates the relationship between its antitumor activities and autophagy in lung cancer cells. Methods: Cell growth and proliferation were detected by MTT, lactate dehydrogenase (LDH) release, 5-ethynyl-20-deoxyuridine (EDU) and colony formation assays. Cell apoptosis was detected by flow cytometry. Autophagic and signal proteins were detected by Western blotting. Markers of autophagy and autophagy flux were also detected by immunofluorescence, transmission electron microscopy and acridine orange staining. Real time RT-PCR was used to analyze the gene expression of Hsp90. Hsp90 ubiquitination was detected by coimmunoprecipitation. The antitumore activities of HyFS were observed in nude mice. Results: HyFS treatment inhibited cell proliferation and induced autophagy in A549 and H460 lung cancer cells, but stronger inhibition of cell proliferation and induction of cell apoptosis were shown when HyFS-mediated autophagy was blocked. The Hsp90/Akt/mTOR axis was found to be involved in the activation of HyFS-mediated autophagy. Evidence of direct interaction between Hsp90 and Akt was observed. HyFS treatment resulted in decreased levels of heat shock protein 90 (Hsp90) and phosphorylated Akt, overexpression of Hsp90 increased activation of autophagy, and inhibition of Hsp90 expression decreased autophagy. In addition, ubiquitin-mediated degradation of Hsp90 and subsequent dephosphorylation of its client protein Akt were also found in HyFS-treated lung cancer cells. Moreover, combination treatment with HyFS and chloroquine showed remarkably increased tumor inhibition in both A549- and H460-bearing mice. Conclusion: Our results demonstrate that HyFS induced cytoprotective autophagy through ubiquitin-mediated degradation of Hsp90, which further blocked the Akt/mTOR pathway in lung cancer cells. Thus, a combination of a HyFS-like cardenolide and an autophagic inhibitor is a potential alternative approach for the treatment of lung cancer.
Royal colleges welcome renewed junior contract talks
Authors: Abi Rimmer
Journal: BMJ (2016)

Medical royal colleges have welcomed the renewal of talks between the BMA and the government on a new contract for junior doctors in England.

The BMA announced on Saturday 7 May that it would re-enter talks with the government on a new contract, after the government said that it would pause the introduction of the contract for five days.1

The talks, which are scheduled to take place over …
Prostate 8 study: A pilot randomized controlled trial (RCT) of a web-based lifestyle intervention versus control group among men with prostate cancer.
Authors: Stacey A. Kenfield, Erin Van Blarigan, Niloufar Ameli, Emil Lavaki, Cynthia Monroy, Lucy K. Tantum, Robert Usher Newton, Li Zhang, Matthew R. Cooperberg, Peter Carroll, June M. Chan
Journal: Journal of Clinical Oncology (2018)

105 Background: Lifestyle behaviors may reduce risk of prostate cancer progression. Guidelines and tools to support lifestyle modification are needed to improve prostate cancer care. Methods: We conducted a 12-week RCT among 73 men with clinical stage T1-T3a prostate cancer to determine if a lifestyle intervention that included a responsive website, Fitbits, and text messaging helps men adopt 8 healthy lifestyle behaviors (vigorous activity, not smoking, and 6 diet factors) compared to a control group. Eligible men had no contra-indications to aerobic exercise, Internet access, and engaged in ≤4 of the targeted 8 habits at baseline. We explored the efficacy of the intervention (n = 32) vs. control (n = 32) on behavior change via a lifestyle survey, 7 days of ActiGraph GT3X+ accelerometer data, and the Prostate 8 (P8) score (8 self-reported behaviors assigned 0 or 1 point, range 0-8). Results: Baseline characteristics were similar between arms. The median baseline P8 score was 3 in each arm. 12-week assessments were 88% complete (intervention, 94%; control, 82%). Intervention arm participants’ wore their Fitbits a median of 82 days (98%, IQR: 72-83), replied to a median of 71% of texts (N = 60, IQR: 57-89%), and visited the website a median of 3 days [IQR: 2-5] and over 3 visits [IQR: 2-5]. Baseline moderate and vigorous activity were self-reported as 3.7 hrs/wk and 12 min/wk (intervention) and 5.3 hrs/wk and 18 min/wk (control). 1 person was a smoker at baseline. Median [IQR] absolute change in the P8 score from baseline to 12 wks was 2.0 [1.0, 3.0] (intervention) and 0.0 [-1.0, 1.0] (control) (p = 0.0005); and the change between groups was statistically significant for cooked tomatoes, cruciferous vegetables, fish, processed meat, but not significant for healthy sources of vegetable fat (high at baseline) or vigorous activity. Accelerometer data indicated no significant differences in change in physical activity between arms. Conclusions: This novel intervention was feasible and acceptable. These data suggest that the intervention was effective for promoting healthier dietary changes; further research is warranted to examine how to facilitate improvements in physical activity. Clinical trial information: NCT02470936.
Immune Biomarkers Predictive for Disease-Free Survival with Adjuvant Sunitinib in High-Risk Locoregional Renal Cell Carcinoma: From Randomized Phase III S-TRAC Study
Authors: Daniel J. George, Jean-François Martini, Michael Staehler, Robert J. Motzer, Ahmed Magheli, Bernard Escudier, Paola Gerletti, Sherry Li, Michelle Casey, Brigitte Laguerre, Hardev S. Pandha, Allan J. Pantuck, Anup Patel, Maria J. Lechuga, Alain Ravaud
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov number NCT00375674). A prospectively designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit. Experimental Design: Tissue blocks were used for immunohistochemistry (IHC) staining of programmed cell death ligand 1 (PD-L1), CD4, CD8, and CD68. DFS was compared between &amp;lt; versus ≥ median IHC parameter using the Kaplan–Meier method. For biomarkers with predictive potential, receiver operating characteristics curves were generated. Results: Baseline characteristics were similar in patients with (n = 191) and without (n = 419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8+ T-cell density ≥ versus &amp;lt; median [median (95% CI), not reached (6.83–not reached) versus 3.47 years (1.73–not reached); hazard ratio (HR) 0.40 (95% CI, 0.20–0.81); P = 0.009] treated with sunitinib (n = 101), but not with placebo (n = 90). The sensitivity and specificity for CD8+ T-cell density in predicting DFS were 0.604 and 0.658, respectively. Shorter DFS was observed in placebo-treated patients with PD-L1+ versus PD-L1− tumors (HR 1.75; P = 0.103). Among all patients with PD-L1+ tumors, DFS was numerically longer with sunitinib versus placebo (HR 0.58; P = 0.175). Conclusions: Greater CD8+ T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk nonmetastatic RCC should also be further explored. Clin Cancer Res; 24(7); 1554–61. ©2018 AACR.
Limited weekend cover has led to concerns over junior doctors’ training, says NHS chief
Authors: Abi Rimmer
Journal: BMJ (2014)

A lack of consultant supervision at weekends has led to concerns about junior doctors’ training, the national medical director of NHS England has said.

Addressing junior doctors at an Agents for Change event in London on Friday, Bruce Keogh said that he was concerned about the way the NHS ran at weekends. He said, “Many of you will know that I have raised a debate over the last couple of …
GMC is given time to respond to allegations it failed doctor who stole fentanyl
Authors: Clare Dyer
Journal: BMJ (2018)

An inquest into the death of a junior doctor who died after injecting himself with the opioid fentanyl has been adjourned so that the General Medical Council can obtain legal representation to respond to allegations made against it.

Julien Warshafsky, 31, was found dead by his wife at his flat in Woking, Surrey, while he was on sick leave in June 2016.

Warshafsky, a trainee anaesthetist at Royal Surrey County Hospital in Guildford, had been stealing fentanyl left over after operations to treat himself for depression. He had also illegally looked up the medical records of celebrities.

He had reported himself to the GMC after being caught by colleagues. But evidence about the regulator’s response to the notification led the Surrey assistant …
NHS Commissioning Board to be responsible for general practice contracts
Authors: Helen Jaques
Journal: BMJ (2012)

The NHS Commissioning Board will hold contracts and make contract payments for general practices and will manage performers lists from April 2013, latest guidance from the organisation says.

The board will hold and negotiate all general medical services (GMS), personal medical services (PMS), and alternative provider medical services (APMS) contracts, with a view to developing “greater consistency” in the different forms of contract.

The board and its 27 local area teams will also be responsible for contract monitoring and performance management of …
What fixes PSA screening guidelines gone wrong?
Authors: James Austin Talcott, Maureen Bezuhly, Michael P. Osborne
Journal: Journal of Clinical Oncology (2018)

TPS159 Background: Guidelines provide guidance but patient (PT) factors alter recommendations. We studied PT factors that alter the correct recommendation (CR) and physician (MD) advice in real-time cancer screening discussions in a 2x2 cluster-randomized trial of MD educational supports. Methods: We enrolled an age-(30-89 years) and sex-stratified sample of 18 patients (PTs) who underwent a physical examination at 2 urban hospitals by each of 12 primary care MDs. We assigned screening guideline formatting (color-coding [CC]) and academic detailing (AD) to MDs randomly. Immediate post-encounter surveys recorded PT and MD recall of screening discussions. Because PSA screening, the focus here, is controversial, we defined correct recommendations (CR) only when against screening, for men too old ( &gt; 75 yrs) or too young (African American [AA] &lt; 40 or non-AA &lt; 50). For other men, either recommendation was considered correct. MD-reported serious comorbidity or PT choice against screening were also valid reasons against. Results: Of the first 174 participants, 92 were male. They were diverse (69% white) and highly educated (87% attended, 61% graduated college). Using age and race alone, 49% should not be screened, but increased to 65% by adding comorbidity (1%) and PT choice (15%). By these criteria, MDs advised correctly in 91% of encounters. In univariate analysis, CC (p = 0.08) but not AD, PT education, shared decision making and age tended to increase CR. Conclusions: In a highly educated, diverse patient population, including comorbidity and PT choice increased CR against screening to 16% more men. An educational support (CC) tended to increase CR. General guidelines can produce incorrect recommendations. Simple supports may improve them. Clinical trial information: NCT02430948.
Automated scoring of vitiligo using superpixel-generated computerized digital image analysis of clinical photographs: a novel and consistent way to score vitiligo
Authors: J. J. H. Toh, S. Bhoi, V. W. D. Tan, S.Y. Chuah, A. Jhingan, A. W. K. Kong, S. T. G. Thng
Journal: British Journal of Dermatology (2018)
Novel<i>in vivo</i>observations of scrotal<i>Nannizzia gypsea</i>infection
Authors: X.-J. Xia, Y. Zhang, Y. Zhong, B. Sang, Q.-P. Li, M. Wang, W.-W. Lv, H.-L. Zhi, X.-D. Wang, H. Shen, Z.-H. Liu
Journal: British Journal of Dermatology (2018)
HEE to roll out scheme to improve medical training
Authors: Abi Rimmer
Journal: BMJ (2014)

Health Education England plans to implement a scheme it has piloted that is aimed at improving medical training.

A paper presented to the organisation’s board, written by HEE’s stakeholder engagement manager, Renee Knopp, and director of national programme, Patrick Mitchell, has recommended the national adoption of the Better Training, Better Care Programme.1 The programme was designed to deliver recommendations made by John Temple’s review …
Role of core location in targeted MRI-ultrasound fusion biopsy of prostate lesions.
Authors: Amanda Lu, Kamyar Ghabili, Kevin Nguyen, Preston Sprenkle
Journal: Journal of Clinical Oncology (2018)

136 Background: Targeted mpMRI fusion biopsy has gained adoption with superior clinically significant cancer detection rates and accuracy over template biopsy. We sought to establish the role of biopsy location within a prostate lesion to detect clinically significant prostate cancer. Methods: From Nov 2016-Aug 2017, 110 patients with positive multiparametric-MRI (mpMRI) underwent targeted and systematic MRI-US fusion biopsy at our institution for clinical suspicion or known history of prostate cancer. Lesions were scored by Prostate imaging reporting and data system (PI-RADS) classification schema by experienced genitourinary radiologists. Biopsy was performed by an oncology-trained urologist (PS) performing a high volume of fusion biopsies. 5 cores were taken from each lesion, each corresponding to a predetermined location (central, medial, lateral, apex, and base of the lesion). Cancer detection rates (CDR) were calculated on a per lesion basis from biopsy histology. Results: 154 prostate lesions were identified and biopsied with an average volume of 1.31 mL. Detection of clinically significant cancer (G&gt;3+4) did not differ significantly among the 5 locations (Table 1). The central core detected slightly more G≥3+4 cancers than the apex core. No concordance of pathology grade was found between the central core and location of the peripheral core (medial, lateral, apex, or base). In 32% (50/154) of lesions, the peripheral cores had a higher Gleason score than the central core. Biopsy of only the central core missed 40% (21/52) of G≥3+4 cancers and 17% (4/24) of G&gt;3+4 cancers. Lesions with higher PIRADs score were more likely to detect cancer in both the central and peripheral cores, but lesion volume was not a significant predictor. Conclusions: Location of biopsy cores within mpMRI-identified prostate lesions has little correlation with detection of clinically significant cancer. However, targeted biopsy of only the center of a lesion can miss 17% of Gleason &gt;3+4 cancers. [Table: see text]
Association of Schizophrenia With the Risk of Breast Cancer Incidence
Authors: Chuanjun Zhuo, Patrick Todd Triplett
Journal: JAMA Psychiatry (2018)

Importance Patients with schizophrenia are considered to have many risk factors for the development of cancer. However, the incidence of breast cancer in women with schizophrenia compared with the general population remains uncertain. Objective To perform an updated meta-analysis to evaluate the association between schizophrenia and the risk of breast cancer. Data Sources A systematic search of the PubMed and EMBASE databases was conducted using the search terms schizophrenia , schizophrenic , psychosis , combined with breast and cancer , tumor , neoplasm , or carcinoma . The final literature search was performed on August 15, 2017. Study Selection Cohort studies reporting the standardized incidence ratio (SIR) for the risk of breast cancer in women with schizophrenia compared with the general population. Data Extraction and Synthesis The meta-analysis adhered to Meta-analysis of Observational Studies in Epidemiology and the Cochrane Handbook for Systematic Reviews of Interventions . Data extraction was performed independently. A random-effects model was used to pool the results, and a recently proposed prediction interval was calculated to describe the heterogeneity. Main Outcomes and Measures The SIR for the risk of breast cancer in women with schizophrenia compared with the general population or those without schizophrenia. Results Twelve cohorts were included in this meta-analysis. The results of the meta-analysis showed that schizophrenia was associated with a significantly increased risk of breast cancer incidence in women (SIR, 1.32; 95% CI, 1.15-1.51; P &amp;amp;lt; .001), with significant heterogeneity ( P &amp;amp;lt; .001; I 2 = 90%). Substantial between-study variance was also suggested by the wide prediction interval (0.82-2.11), which indicated that it is possible that a future study will show a decreased breast cancer risk in women with schizophrenia compared with the general population. The subgroup analysis results showed that the association was not significantly affected by whether breast cancer cases were excluded at baseline or the sample size of the included studies. Conclusions and Relevance The incidence of breast cancer in women with schizophrenia is higher than that of the general female population. However, significant heterogeneity exists among the included studies. Women with schizophrenia deserve intensive prevention and treatment of breast cancer.
Thirteenth Stanmore basic fracture management course
Authors: Aadil Mumith
Journal: BMJ (2011)

According to the website this course is aimed at foundation year 2 doctors (FY2), specialty trainees (ST) 1-3, accident and emergency staff, and casting staff. The delegates during my time on the course included FY1 trainees through to core trainee (CT)/ST2 surgical trainees, nurse practitioners, and associate specialists in accident and emergency.

February 2010, core surgical training year 1.

The course runs over three days at the Royal National Orthopaedic Hospital. Each day is split into morning and afternoon sessions, and there are frequent coffee breaks. The morning sessions are lecture based and can be quite didactic, but active discussion of the topics covered is encouraged, and there are question and answer sessions after most lectures. The afternoon sessions are practical workshops, which are the most enjoyable part …
Clinical experience with PSMA-Actinium-225 (Ac-225) radioligand therapy (RLT) in end-stage metastatic castration-resistant prostate cancer (mCRPC) patients.
Authors: Maarten Johannes van der Doelen, Niven Mehra, Minke Smits, Inge M. van Oort, Marcel J.R. Janssen, Uwe Haberkorn, Clemens Kratochwil, Winald Gerritsen
Journal: Journal of Clinical Oncology (2018)

344 Background: Prostate-specific membrane antigen (PSMA) is an ideal target for RLT in mCRPC patients (pts). Alpha-emitting radioisotope Actinium-225 (Ac-225) may be more efficacious than beta-emitting Lutetium-177, due to higher rates of double-strand DNA breaks in prostate cancer cells, with less tissue penetration and minimal bystander effects in PSMA-negative cells. Limited data is available on the clinical efficacy and side effects of PSMA-Ac-225 RLT in mCRPC pts. Here we describe our clinical experience so far. Methods: Between February 2016 and October 2017, 11 pts underwent PSMA-Ac-225 RLT in Heidelberg, Germany. Prostate-specific antigen (PSA) responses were measured every two weeks. Pts underwent PSMA PET/CT prior to and after RLT. Consenting pts had tissue and blood collected for translational biomarker studies, including targeted-next generation sequencing and whole genome sequencing to discover biomarkers and mechanisms of RLT resistance. In addition, pts received structured questionnaires on quality of life and xerostomia evaluation. Results: All pts were heavily pre-treated, with a median of four therapies prior to PSMA-Ac-225 RLT. Pts underwent a median of three RLT cycles (range 1-4 cycles) of median 8 MBq (range 6-10 MBq). Five pts (45%) had died at time of analysis. Median overall survival since start of RLT was 12.6 months (95% CI 5.0-20.1). Median baseline PSA was 878 µg/L (range 6-2249). Eight of eleven pts had &gt; 50% PSA response, with median change in PSA reduction of 87%. Six pts were evaluable according to PCWG3 criteria with 5/6 (83%) pts showing partial responses, and one patient with stable disease following RLT. No grade 3-4 hematologic toxicity occurred. Grade 2-3 xerostomia was mentioned by all pts. Pts with features of neuro-endocrine prostate cancer (NEPC) showed less response to RLT, with blood-based NEPC biomarkers increasing during RLT. Conclusions: PSMA-Ac-225 RLT resulted in remarkable clinical, biochemical and radiological responses in end-stage mCRPC pts, and may be considered a promising therapy for mCRPC pts.
David's new haircut⇓
Authors: Nicola Sharp
Journal: BMJ (2004)

“I will not see a counsellor.” Martha slammed the car door.

“I think it would be good for you to talk.” David Millstone turned the key in the ignition; the car spluttered and heaved.

“That Veronica Dove woman you saw tried to seduce you,” said Martha.

“She did not; we just talked,” said David. His face reddened.

“Don't talk, act,” said Martha.

“I feel you need to face your problems, dear,” said David.

“I'm looking at mine now,” said Martha. She watched David stroke his head with his right hand. The car swerved and scraped along a stone wall.

“David, it's all gone,” said Martha.

“I didn't knock the wall over,” said David.

“Not that. Your hair's all gone. Not that you had much in the first place.”

“Do you like it, dear?” David looked at himself in the rear view mirror and smiled.

“There's nothing there,” said Martha. “You look like a mushroom.”

“I use special oils every day after I've shaved it,” said David.

“You mean you've gone completely bald on purpose?”

“Does it make me look younger, dear?”

“No.”

\* * *|

“You don't seem very interested,” said Justin Peters.

“Sorry, what were you talking …
GROWTH DIFFERENTIATION FACTOR 15 AS A NOVEL BIOMARKER OF HEART FAILURE AND PULMONARY HYPERTENSION IN CONGENITAL HEART DISEASE WITH LEFT TO RIGHT SHUNT IN YOUNG PATIENTS
Authors: Yoshiyuki Kagiyama, Yuusuke Koteda, Yasuto Maeda, Shintarou Kishimoto, Kenji Suda
Journal: Journal of the American College of Cardiology (2018)