tbuckley/cabot-search huggingface dataset:
IRAK1 Augments Cancer Stemness and Drug Resistance via the AP-1/AKR1B10 Signaling Cascade in Hepatocellular Carcinoma
Authors: Bowie Y. Cheng, Eunice Y. Lau, Hoi-Wing Leung, Carmen Oi-Ning Leung, Nicole P. Ho, Shilpa Gurung, Lily K. Cheng, Chi Ho Lin, Regina Cheuk-Lam Lo, Stephanie Ma, Irene Oi-Lin Ng, Terence K. Lee
Journal: Cancer Research (2018)

Abstract Frequent relapse and drug resistance in patients with hepatocellular carcinoma (HCC) can be attributed to the existence of tumor-initiating cells (TIC) within the tumor bulk. Therefore, targeting liver TICs may improve the prognosis of these patients. From transcriptome sequencing of 16 pairs of clinical HCC samples, we report that interleukin-1 receptor-associated kinase 1 (IRAK1) in the TLR/IRAK pathway is significantly upregulated in HCC. IRAK1 overexpression in HCC was further confirmed at the mRNA and protein levels and correlated with advanced tumor stages and poor patient survival. Interestingly, IRAK4, an upstream regulator of IRAK1, was also consistently upregulated. IRAK1 regulated liver TIC properties, including self-renewal, tumorigenicity, and liver TIC marker expression. IRAK1 inhibition sensitized HCC cells to doxorubicin and sorafenib treatment in vitro via suppression of the apoptotic cascade. Pharmacological inhibition of IRAK1 with a specific IRAK1/4 kinase inhibitor consistently suppressed liver TIC populations. We identified aldo-keto reductase family 1 member 10 (AKR1B10) as a novel downstream target of IRAK1, which was found to be overexpressed in HCC and significantly correlated with IRAK1 expression. Knockdown of AKR1B10 negated IRAK1-induced TIC functions via modulation of the AP-1 complex. Inhibition of IRAK1/4 inhibitor in combination with sorafenib synergistically suppressed tumor growth in an HCC xenograft model. In conclusion, targeting the IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway may be a potential therapeutic strategy against HCC. Significance: IRAK4/IRAK1/AP-1/AKR1B10 signaling pathway regulates cancer stemness and drug resistance and may be a novel therapeutic target in HCC. Cancer Res; 78(9); 2332–42. ©2018 AACR.
Allopurinol Dose Escalation and Mortality Among Patients With Gout
Authors: Brian W. Coburn, Kaleb Michaud, Debra A. Bergman, Ted R. Mikuls
Journal: Arthritis & Rheumatology (2018)

Objective Observational data suggest that hyperuricemia and gout are associated with increased mortality, while allopurinol use is associated with reduced mortality. In addition, the protective effect of allopurinol may be dose dependent. The aim of the current study was to determine whether allopurinol dose escalation is associated with cause‐specific mortality in patients with gout. Methods In this 10‐year observational, active‐comparator study of US Veterans with gout who initiated treatment with allopurinol, propensity score matching, Cox proportional hazards models, and competing risks regression analyses were used to assess differences in cause‐specific mortality between patients whose allopurinol dose was escalated (dose escalators) and those whose allopurinol dose was not escalated or was reduced (non‐escalators) over a 2‐year period. Results Among the 6,428 dose escalators and 6,428 matched non‐escalators, there were 2,867 deaths during the observation period (40.4 deaths per 1,000 person‐years). Dose escalators experienced an increase in all‐cause mortality (hazard ratio [ HR ] 1.08, 95% confidence interval [95% CI ] 1.01–1.17), with the effect sizes being similar for incidence of cardiovascular‐related deaths ( HR 1.08, 95% CI 0.97–1.21) and cancer‐related deaths ( HR 1.06, 95% CI 0.88–1.27), although neither reached statistical significance. Dose escalation to achieve the goal of lowering the serum urate ( SU ) level to &lt;6.0 mg/dl was infrequent. At 2 years, 10% of dose escalators were receiving a final daily dose of &gt;300 mg and 31% had achieved the SU goal. In a sensitivity analysis limited to dose escalators achieving the SU goal, there was a nonsignificant reduction of 7% in the hazard of cardiovascular‐related mortality ( HR 0.93, 95% CI 0.76–1.14). Conclusion This is the largest study to date to investigate the effects of allopurinol use on mortality and is the first to use a rigorous active‐comparator design. Dose escalation was associated with a small (&lt;10%) increase in all‐cause mortality, thus showing that a strategy of allopurinol dose escalation, which in current real‐life practice is characterized by limited dose increases, is unlikely to improve the survival of patients with gout.
SAFETY AND EFFECTIVENESS OF APIXABAN VERSUS WARFARIN IN THE TREATMENT AND PREVENTION OF VENOUS THROMBOEMBOLISM
Authors: Derek Weycker, Xiaoyan Li, Gail Wygant, Theodore Lee, Melissa Hamilton, Xuemei Luo, Lien Vo, Jack Mardekian, Xianying Pan, Leah Burns, Mark Atwood
Journal: Journal of the American College of Cardiology (2018)
Identifying the need for and availability of community rehabilitation for patients in the community with brain and CNS tumours
Authors: Tiffany Treharne, Catharine James
Journal: Neuro-Oncology (2018)

Of the 2.5 million people living with cancer in the UK, 60% have unmet physical or psychological needs following treatment. To provide good person-centred care and enable these people to achieve optimum function and quality of life, “all cancer patients must have access to appropriately skilled Allied Health Professionals, AHPs (including occupational therapists, physiotherapists, speech and language therapists, dietitians and psychologists)” (NHS England, 2016). This Macmillan-funded project is based at the Royal Stoke University Hospital (RSUH), one of the largest hospital trusts in the country. Brain and CNS tumour patients under the care of RSUH come from a large geographical area including Stoke-on Trent, Staffordshire, Central Cheshire, Shropshire and Powys. Brain and CNS tumour patients admitted to the neurosurgery ward at RSUH can access all of the above AHP services. However, when people return home accessing similar services is often difficult; this also applies to non-surgical patients, who are also likely to require AHP support. An analysis of community AHP services showed an inequality in service provision; the larger population of Stoke-on-Trent and North Staffordshire do not have access to community-based, cancer specialist AHPs, which are available in Central Cheshire and Shropshire. Further data was collected from an online survey, with differences between training levels and AHP confidence in working with cancer patients between the counties being analysed. Whilst other projects have demonstrated similar results, in our area we currently find ourselves in an almost unique situation. The four CCGs in the immediate vicinity of the hospital are in the process of ‘tendering out’ Cancer Care and End of Life Care. Consortiums are bidding for the two 10-year contracts with a combined value of £1.2 billion. We are working with all relevant parties to highlight the particular AHP needs of brain and CNS tumour patients.
Prognostic association of FoxP3 regulatory T cells with tumor infiltrating CD8 cytotoxic T cells quantified on resected liver colorectal metastases (LCM).
Authors: Marc Van Den Eynde, Bernhard Mlecnik, Jean-Pascal H. Machiels, Daphne Debetancourt, Gabriela Bindea, Anne Jouret-Mourin, Christine Sempoux, Jean Francois Gigot, Catherine Hubert, Yves Humblet, Nacilla Haicheur, Florence Marliot, Franck Pages, Jerome Galon
Journal: Journal of Clinical Oncology (2015)

e14643 Background: The adaptive Th1 immune response (CD3/CD8/CD45RO T-cells) is a strong prognostic factor for the survival of the patients after colorectal primary tumor and metastases resection. The prognostic impact of regulatory T-cells (FoxP3) in metastatic settings is less characterized. Methods: Metastatic colorectal patients undergoing curative liver surgery for all resected LCM were investigated. For this cohort, we previously reported the prognostic role of an immune score based (IS) for T (CD3/CD8/CD45RO) and B (CD20) cells infiltration . The FoxP3 and CD8 cells infiltrating the center (CT ) and the invasive margin (IM) of LCM were immunohistochemically stained and their densities quantified on whole slides with a dedicated image analysis software. The mean value of the 3 most infiltrated areas (0.64 mm²) was calculated. The CT and IM densities of FoxP3 and CD8 were classified into high (Hi) or low (Lo) according to the minimum p-value cut-off. The total number of Hi densities determined the IS : 0-2 Hi (low IS) or 3-4 Hi (high IS). Cumulative DFS/OS analyses were performed using the Kaplan-Meier estimator. The hazard ratio for OS/DFS comparing (IS 0-2 vs 3-4) was determined using univariate Cox regression and the significance by log-rank tests. Results: 294 LCM from 88 patients (Male/Female 1.1, mean 3.3/patient, synchronous/metachronous 5.8) were included. Inter-metastatic heterogeneity for FoxP3 and CD8 (CT/IM) is high and observed among all patients. For the least infiltrated LCM/patient: a high IS is prognostic for DFS (HR:0.31 95%IC 0.18-0.53; p = 0.0006) and OS (HR:0.29 95%IC 0.14-0.64; p = 0.001). Independently of CD8 cells, a high FoxP3 density in both regions (CT/IM) is not prognostic for DFS (HR:0.53 95%IC 0.28-0.97; p = 0.74) but for OS (HR:0.16 95%IC 0.02-1.17; p = 0.04). Conclusions: Regulatory T cells associated with cytotoxic T cells in both tumor regions (CT/IM) of the least infiltrated LCM/patient are highly prognostic after curative resection. These results confirm the important role of tumor regions and FoxP3 for modulating the tumor immune response.
Editor’s Choice: Breeding cynicism
Authors: Tom Moberly
Journal: BMJ (2015)

Completing eight hours of “extraordinarily basic and patronising” learning modules is no one’s idea of fun. But, as Dora Steel highlights this week, newly qualified doctors routinely have to complete hours of basic e-learning modules whenever they start a new job (http://careers.bmj.com/careers/advice/view-article.html?id=20022962).

These modules are mandatory, and trusts do not provide protected study time for their …
Is Patent Foramen Ovale a Risk Factor for Perioperative Stroke?
Authors: Scott E. Kasner, Steven R. Messe
Journal: JAMA (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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
“Scattergun” and stealthy change is undermining medical training, says BMA
Authors: Matthew Limb
Journal: BMJ (2015)

Medical training is being undermined by “scattergun attempts at reform” and moves to make amendments “by stealth,” the BMA has warned.

In its new “vision” document the BMA has outlined the six key principles that it believes should underpin any proposed changes to medical training and organisational change.1 In the document the BMA said that some of these principles were already being “undermined by scattergun attempts at reform” and moves to amend training components “by stealth.” It said that changes to medical training that were based on expediency or short …
Lipid-rich environment: a key role promoting carcinogenesis in obesity-related non-alcoholic fatty liver disease
Authors: Patricia Aspichueta
Journal: Gut (2018)

The epidemic of obesity has led to increased risk of many types of cancer including hepatocellular carcinoma (HCC).1 HCC is the most frequent presentation of liver cancer, the fifth most common cancer in men worldwide and the seventh in women.2 Even though viral and alcohol-related liver diseases are main causes of HCC, non-alcoholic fatty liver disease (NAFLD) has become the most rapidly increasing cause during the last decade.1 Even more, HCC may also develop in the absence of liver cirrhosis, and the incidence in livers without fibrosis is higher in the metabolic syndrome and NAFLD.1 According to data from the Surveillance, Epidemiology and End Results registries (2004–2009), in the USA, NAFLD-driven HCC is associated with shorter survival time and more advanced tumour stage.3 Besides, although numerous drugs have been proposed, there is still no available treatment for most patients with HCC.4 Thus, there is a need to understand the mechanism involved in NAFLD-driven HCC to provide new targets of treatment. A hallmark of NAFLD and HCC is the disrupted lipid metabolism. Fujiwara et al 5 provide a new mechanism that links lipid accumulation with carcinogenesis in …
Perioperative outcomes of aspirin use in radical prostatectomy.
Authors: Matthew D. Ingham, Ross E Krasnow, Matthew Mossanen, Ye Wang, Steven Lee Chang
Journal: Journal of Clinical Oncology (2018)

150 Background: Increasing cardiovascular disease has led to increases in the patient population on anti-platelet therapy who require urologic surgery. We sought to study perioperative outcomes for those undergoing radical prostatectomy (RP) while taking or not taking perioperative aspirin (pASA). Methods: A retrospective review of patients undergoing RP was performed on the Premier Hospital Database from 2003 to 2015, with survey projection weighting resulting in a cohort of 157,674 patients. Two groups were formed – those continued on pASA (group 1, n = 4400) and those with no pASA (group 2, n = 153,274). In-hospital complication rates were studied: major bleeding, overall transfusion, day-of-surgery transfusion, prolonged ( &gt; 4 days) length of stay (LOS), and prolonged ( &gt; 285 minutes) operative time. We also assessed 90-day rates of: cardiovascular catastrophe, readmission, major complication, and DVT/PE. Unadjusted rates were calculated for all RP patients and further subdivided into open and minimally invasive RP. Adjusted odds ratios (OR) were then calculated between groups 1 and 2. Results: Group 1 was older (51.5% vs 41.8% ≥65 years, p = 0.002) and less healthy (13.8% vs 5.3% with a CCI score ≥2, p &lt; 0.0001) vs those in group 2. Group 1 patients were more likely to receive an open RP (42.3% vs 28.1%, p &lt; 0.0001). For in-hospital outcomes for all RPs, no significant differences were noted regardless of surgical approach. For 90-day outcomes, those in group 1 were more likely to suffer a MI (OR 5.88, CI [3.4-10.18], p &lt; 0.001), major complication (OR2.95, CI [1.58-5.5], p &lt; 0.001), or be readmitted (OR 1.63, CI [1.18-2.26], p &lt; 0.05). The disparity in both MI and major complication rates appeared to be largely driven by those undergoing minimally invasive RPs, with an OR of 7.92 and 4.02 noted, respectively. Conclusions: This large, retrospective, database review of both academic and community hospitals provides an important assessment of the impact pASA has on RP outcomes. In-hospital outcomes were equivalent between groups but those on pASA saw increased rates of MI, major complication, and readmission. Despite this, this study lends support to the belief that pASA should likely not be considered an absolute contraindication to RP.
Seven day opening and 5000 new GPs will be undeliverable after latest recruitment figures, says BMA
Authors: Abi Rimmer
Journal: BMJ (2015)

The government’s plans to recruit 5000 new GPs and introduce seven day opening in practices are undeliverable, the BMA has said, after figures showed that a sixth of GP training posts remain unfilled. 

Figures released by the GP National Recruitment Office show that, after two rounds of recruitment, 611 (17%) posts remain unfilled. The number of vacancies varies widely across geographical areas. While some areas …
A High-risk Haplotype for Premature Menopause in Childhood Cancer Survivors Exposed to Gonadotoxic Therapy
Authors: Russell J Brooke, Cindy Im, Carmen L Wilson, Matthew J Krasin, Qi Liu, Zhenghong Li, Yadav Sapkota, WonJong Moon, Lindsay M Morton, Gang Wu, Zhaoming Wang, Wenan Chen, Rebecca M Howell, Gregory T Armstrong, Smita Bhatia, Sogol Mostoufi-Moab, Kristy Seidel, Stephen J Chanock, Jinghui Zhang, Daniel M Green, Charles A Sklar, Melissa M Hudson, Leslie L Robison, Wassim Chemaitilly, Yutaka Yasui
Journal: JNCI Journal of the National Cancer Institute (2017)

Childhood cancer survivors are at increased risk of therapy-related premature menopause (PM), with a cumulative incidence of 8.0%, but the contribution of genetic factors is unknown. Genome-wide association analyses were conducted to identify single nucleotide polymorphisms (SNPs) associated with clinically diagnosed PM (menopause < 40 years) among 799 female survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study (SJLIFE). Analyses were adjusted for cyclophosphamide equivalent dose of alkylating agents and ovarian radiotherapy (RT) dose (all P values two-sided). Replication was performed using self-reported PM in 1624 survivors participating in the Childhood Cancer Survivor Study (CCSS). PM was clinically diagnosed in 30 (3.8%) SJLIFE participants. Thirteen SNPs (70 kb region of chromosome 4q32.1) upstream of the Neuropeptide Receptor 2 gene (NPY2R) were associated with PM prevalence (minimum P = 3.3 × 10-7 for rs9999820, all P < 10-5). Being a homozygous carrier of a haplotype formed by four of the 13 SNPs (seen in one in seven in the general population but more than 50% of SJLIFE clinically diagnosed PM) was associated with markedly elevated PM prevalence among survivors exposed to ovarian RT (odds ratio [OR] = 25.89, 95% confidence interval [CI] = 6.18 to 138.31, P = 8.2 × 10-6); this finding was replicated in an independent second cohort of CCSS in spite of its use of self-reported PM (OR = 3.97, 95% CI = 1.67 to 9.41, P = .002). Evidence from bioinformatics data suggests that the haplotype alters the regulation of NPY2R transcription, possibly affecting PM risk through neuroendocrine pathways. The haplotype captures the majority of clinically diagnosed PM cases and, with further validation, may have clinical application in identifying the highest-risk survivors for PM for possible intervention by cryopreservation.
The founder of Operation Smile
Authors: Negin Shamsian
Journal: BMJ (2005)

W illiam P Magee Jr is a leading US plastic and craniofacial surgeon who set up the global children's charity Operation Smile with his wife Kathleen in 1982.

When I was six, my mom used to kick us out of the house at weekends and we used to go on rounds with my dad, who was a physician. He would sit at his patient's bedside and talk to them about their hopes, their dreams, and their fears. I remember how gentle he was with them, and I enjoyed watching that relationship of him being able to help them and them respecting him. It seemed so human to me and so I always thought about becoming a physician.

I was very close to going into construction because I enjoyed working with my hands. I wasn't sure if I wanted to work as hard as I had seen my father work. Then a good friend of mine suggested dentistry because the lifestyle was better. So I went to dental school and became a dentist. In my last year of dental school a number of crazy things happened which redirected me towards medicine. I decided to go to George Washington University …
Ensartinib (X-396) in ALK-Positive Non–Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study
Authors: Leora Horn, Jeffrey R. Infante, Karen L. Reckamp, George R. Blumenschein, Ticiana A. Leal, Saiama N. Waqar, Barbara J. Gitlitz, Rachel E. Sanborn, Jennifer G. Whisenant, Liping Du, Joel W. Neal, Jon P. Gockerman, Gary Dukart, Kimberly Harrow, Chris Liang, James J. Gibbons, Allison Holzhausen, Christine M. Lovly, Heather A. Wakelee
Journal: Clinical Cancer Research (2018)

Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC).Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible.Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%.Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771-9. ©2018 AACR.
Ambient Temperature and Screening for Nasopharyngeal Cancer
Authors: K C Allen Chan, Sam W I Chu, Y M Dennis Lo
Journal: New England Journal of Medicine (2018)

False Positive Epstein–Barr Virus Screening Screening for EBV was previously found to improve survival in nasopharyngeal cancer. The authors now report that false positive results were more common among older people and people in colder climates. Screening may yield fewer false positive results if conducted in summer.