tbuckley/cabot-search huggingface dataset:
Variant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsy
Authors: Julia N. Bailey, Laurence de Nijs, Dongsheng Bai, Toshimitsu Suzuki, Hiroyuki Miyamoto, Miyabi Tanaka, Christopher Patterson, Yu-Chen Lin, Marco T. Medina, María E. Alonso, José M. Serratosa, Reyna M. Durón, Viet H. Nguyen, Jenny E. Wight, Iris E. Martínez-Juárez, Adriana Ochoa, Aurelio Jara-Prado, Laura Guilhoto, Yolly Molina, Elsa M. Yacubian, Minerva López-Ruiz, Yushi Inoue, Sunao Kaneko, Shinichi Hirose, Makiko Osawa, Hirokazu Oguni, Shinji Fujimoto, Thierry M. Grisar, John M. Stern, Kazuhiro Yamakawa, Bernard Lakaye, Antonio V. Delgado-Escueta
Journal: New England Journal of Medicine (2018)

In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis.Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase ( ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick.A variant, K305T (c.914A→C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic-clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wild-type mice (P=0.02) during light sleep with isoflurane anesthesia.Our data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy. (Funded by the National Institutes of Health and others.).
Targeting hepatic glutaminase activity to ameliorate hyperglycemia
Authors: Russell A Miller, Yuji Shi, Wenyun Lu, David A Pirman, Aditi Jatkar, Matthew Blatnik, Hong Wu, César Cárdenas, Min Wan, J Kevin Foskett, Junyoung O Park, Yiyi Zhang, William L Holland, Joshua D Rabinowitz, Morris J Birnbaum
Journal: Nature Medicine (2018)
Report of the 14th International Conference on Malignant Lymphoma (ICML) Closed Workshop on Future Design of Clinical Trials in Lymphomas
Authors: Anastasios Stathis, Alexia Iasonos, John F. Seymour, Catherine Thieblemont, Vincent Ribrag, Emanuele Zucca, Anas Younes
Journal: Clinical Cancer Research (2018)

The 14th ICML held in Lugano in June 2017 was preceded by a closed workshop (organized in collaboration with the American Association for Cancer Research and the European School of Oncology) where experts in preclinical and clinical research in lymphomas met to discuss the current drug development landscape focusing on critical open questions that need to be addressed in the future to permit a more efficient drug development paradigm in lymphoma. Topics discussed included both preclinical models that can be used to test new drugs and drug combinations, as well as the optimal design of clinical trials and the endpoints that should be used to facilitate accelerated progress. This report represents a summary of the workshop. Clin Cancer Res; 24(13); 2993-8. ©2018 AACR.
Phase I Study of MEDI3617, a Selective Angiopoietin-2 Inhibitor Alone and Combined with Carboplatin/Paclitaxel, Paclitaxel, or Bevacizumab for Advanced Solid Tumors
Authors: David M. Hyman, Naiyer Rizvi, Ronald Natale, Deborah K. Armstrong, Michael Birrer, Lawrence Recht, Efrat Dotan, Vicky Makker, Thomas Kaley, Denison Kuruvilla, Matthew Gribbin, Jennifer McDevitt, Dominic W. Lai, Mohammed Dar
Journal: Clinical Cancer Research (2018)

Purpose: This first-in-human study aimed to determine the MTD and safety of MEDI3617, a selective anti-angiopoietin-2 (Ang2) mAb, alone and combined with bevacizumab or cytotoxic chemotherapy.Patients and Methods: This phase I/Ib, multicenter, open-label, dose-escalation and dose-expansion study evaluated patients with advanced solid tumors. Patients received intravenous MEDI3617 as monotherapy [5-1,500 mg every 3 weeks (Q3W)] or with bevacizumab every 2 weeks (Q2W) or Q3W, weekly paclitaxel, or carboplatin plus paclitaxel Q3W. Dose expansions included a monotherapy cohort in platinum-resistant ovarian cancer and a bevacizumab combination cohort in bevacizumab-refractory malignant glioma. Safety/tolerability, pharmacokinetics, pharmacodynamics, and clinical activity were assessed.Results: We enrolled 116 patients. No formal MTD was identified (monotherapy or combination therapy). MEDI3617 demonstrated linear pharmacokinetics and maximal accumulation of peripheral Ang2 binding at doses above 300 mg Q3W. MEDI3617 monotherapy safety profile was acceptable, except in advanced ovarian cancer [prolonged grade 3 edema-associated adverse events (AE) occurred]. Otherwise, MEDI3617 combined with chemotherapy or bevacizumab was well tolerated. The AE profiles of MEDI3617 and bevacizumab were largely non-overlapping. Overall response rates in ovarian cancer and glioma monotherapy dose-expansion arms were 6% and 0%, respectively.Conclusions: Recommended MEDI3617 monotherapy dosage is 1,500 mg Q3W or 1,000 mg Q2W, except in ovarian cancer. Although peripheral edema has occurred with other Ang2 inhibitors, the severity and duration seen here in ovarian cancer potentially identifies a new, clinically significant safety signal for this class of agents. On the basis of limited clinical activity, MEDI3617 development was discontinued. Clin Cancer Res; 24(12); 2749-57. ©2018 AACR.
A prospective, randomized, blinded, placebo-controlled, phase IIb trial of an autologous tumor lysate + yeast cell wall particles (YCWP) + dendritic cells (DC) vaccine vs unloaded YCWP + DC and embedded phase I/IIa trial with tumor lysate particle only (TLPO) vaccine in stage III and stage IV (resected) melanoma to prevent recurrence.
Authors: John W Myers, Garth S Herbert, Guy T Clifton, Timothy J Vreeland, Tommy A Brown, Kaitlin M. Peace, Julia M Greene, Doreen O Jackson, Diane F Hale, John S Berry, Mark B. Faries, George Earl Peoples
Journal: Journal of Clinical Oncology (2018)

TPS201 Background: Melanoma is a potentially lethal skin malignancy; patients with stage III/IV resected disease have a recurrence rate of 50-90%. Adjuvant checkpoint inhibitor immunotherapy decreases the risk of recurrence but also causes significant immune-related toxicity. Vaccines are a promising strategy for patients with high risk melanoma. The optimal time to intervene may be in the adjuvant setting after attaining a disease-free state through standard of care therapies. Our strategy uses autologous tumor lysate (TL) in a yeast cell wall particle (YCWP) to load dendritic cells (DC) ex vivo. The tumor lysate particle loaded dendritic cell (TLPLDC) vaccine is then given to prevent melanoma recurrences. An alternate vaccine delivery method that we are evaluating utilizes the tumor lysate particle-only (TLPO) technique, in which tumor lysate is loaded into capped YCWP and injected intradermally, allowing an in vivo uptake by the patient’s dendritic cells. Methods: We are performing a prospective, randomized, blinded, placebo-controlled phase IIb trial in patients with resected stage III/IV melanoma who have been rendered disease-free but remain at high risk of recurrence. The study will utilize the TLPLDC strategy vs placebo (2:1) in 120 patients, followed by a bridging study of TLPO vs TLPLDC (2:1) in 60 patients. Both TLPLDC and TLPO inoculations will be monthly x3, followed by boosters at 6, 12, and 18 months. Primary endpoints will be disease free survival (DFS) at 24 months in the TLPLDC arm, and overall safety in the TLPO arm. We have completed enrollment in the phase IIb portion of the study. Clinical trial information: NCT02301611.
Abstract P2-11-21: A prospective phase II study of TARGeted Intraoperative radioTherapy boost plus whole breast irradiation in breast cancer patients undergoing breast-conserving treatment
Authors: HW Lee, C Yoon, SG Ahn, JW Kim, YJ Cha, IJ Lee, J Jeong
Journal: Cancer Research (2018)

Abstract Background: TARGIT-A trial showed that intraoperative radiotherapy (IORT) using Intrabeam® concurrent with lumpectomy within a risk-adapted approach could be considered as an option for eligible patients with early breast cancer. To introduce IORT in clinical practice for Korean breast cancer patients, safety profiles for this new technique from clinical trial with Korean are required due to ethnic (anatomical) difference. Acute toxicity is a key hurdle for patients receiving IORT, because IORT may affect wound healing and increase wound complications. We conducted a phase II study as a feasibility test of IORT at the dose of 20 Gy for the replacement of boost-EBRT in Korean women who are candidates for breast-conserving treatment. Methods: This single-arm trial aimed to investigate acute toxicity occurred within 6 months after IORT. In 1,119 patients receiving EBRT from TARGIT-A trial, the incidence of acute toxicity within 6 months is 15%. Compared with WBRT, we aim to prove a non-inferiority of IORT with 20 Gy. A sample size of 195 achieves 80% power to detect a non-inferiority proportion (P0) of 0.2300 using a one-sided binomial test for non-inferiority. These results assume that the actual proportion (P1) is 0.1500. Considering a drop-out rate of 10%, the trial would need to enroll 215 patients in total. This trial is registered with ClinicalTrials.gov, number NCT02213991. Results: From August 2014 to November 2016, 233 women with early breast cancer were screened, and 215 undergoing IORT were enrolled. In 36 women, clinically significant complications during acute period are noted. The rate of patients experiencing acute toxicity was 16.7% (95% CI, 11.8-21.7%). The actual non-inferiority margin of our trial was 21.7% under the pre-specified margin as 23.0%. In details, There are 31 with seroma collection (more than 3 times when aspiration volume is over 10cc), 2 with wound infection, and 5 with skin break down. At a median follow-up of 17.8 months, there is no local recurrence. Conclusions: Targeted intraoperative radiotherapy using Intrabeam® is a safe procedure for Korean breast cancer patients with acceptable toxicity profile in acute period. Citation Format: Lee HW, Yoon C, Ahn SG, Kim JW, Cha YJ, Lee IJ, Jeong J. A prospective phase II study of TARGeted Intraoperative radioTherapy boost plus whole breast irradiation in breast cancer patients undergoing breast-conserving treatment [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 P2-11-21.
Over half of GPs say they will leave NHS before age of 60, survey finds
Authors: Abi Rimmer
Journal: BMJ (2015)

Over half of GPs say they want to retire or leave the NHS before they reach the age of 60, a survey commissioned by the BBC has found.

A survey carried out by ComRes for a special GP edition of the BBC’s Inside Out programme asked 1004 UK GPs under 60 years of age whether they expected to retire or leave general practice before they reached the age of 60.1 Of the 935 GPs who responded …
Integrative Genomic Analysis Predicts Causative <i>Cis</i>-Regulatory Mechanisms of the Breast Cancer–Associated Genetic Variant rs4415084
Authors: Yi Zhang, Mohith Manjunath, Shilu Zhang, Deborah Chasman, Sushmita Roy, Jun S. Song
Journal: Cancer Research (2018)

Previous genome-wide association studies (GWAS) have identified several common genetic variants that may significantly modulate cancer susceptibility. However, the precise molecular mechanisms behind these associations remain largely unknown; it is often not clear whether discovered variants are themselves functional or merely genetically linked to other functional variants. Here, we provide an integrated method for identifying functional regulatory variants associated with cancer and their target genes by combining analyses of expression quantitative trait loci, a modified version of allele-specific expression that systematically utilizes haplotype information, transcription factor (TF)-binding preference, and epigenetic information. Application of our method to a breast cancer susceptibility region in 5p12 demonstrates that the risk allele rs4415084-T correlates with higher expression levels of the protein-coding gene mitochondrial ribosomal protein S30 (MRPS30) and lncRNA RP11-53O19.1 We propose an intergenic SNP rs4321755, in linkage disequilibrium (LD) with the GWAS SNP rs4415084 (r2 = 0.988), to be the predicted functional SNP. The risk allele rs4321755-T, in phase with the GWAS rs4415084-T, created a GATA3-binding motif within an enhancer, resulting in differential GATA3 binding and chromatin accessibility, thereby promoting transcription of MRPS30 and RP11-53O19.1. MRPS30 encodes a member of the mitochondrial ribosomal proteins, implicating the role of risk SNP in modulating mitochondrial activities in breast cancer. Our computational framework provides an effective means to integrate GWAS results with high-throughput genomic and epigenomic data and can be extended to facilitate rapid functional characterization of other genetic variants modulating cancer susceptibility.Significance: Unification of GWAS results with information from high-throughput genomic and epigenomic profiles provides a direct link between common genetic variants and measurable molecular perturbations. Cancer Res; 78(7); 1579-91. ©2018 AACR.
GP leaders rule out strike on contract imposition but hint at other forms of protest
Authors: Caroline White
Journal: BMJ (2012)

GPs’ leaders have ruled out a strike in protest at the government’s attempts to force through proposed changes to their contracts, the full details of which are likely to be known shortly. But they have hinted that industrial action of some kind might be on the cards, depending on what the final deal looks like.

Laurence Buckman, who chairs the BMA’s General Practitioners Committee, said that as yet the government had not given the BMA the full details of the deal it wanted for GPs, although this was expected within the next week …
Abstract P2-04-07: Triple negative breast cancer-specific chromatin conformation links Notch signal to tumor-specific transcriptional program
Authors: J Petrovic, Y Zhou, G Georgakilas, G Vahedi, WS Pear, RB Faryabi
Journal: Cancer Research (2018)

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is currently incurable with conventional chemotherapy. Some TNBC patients harbor either recurrent somatic gain-of-function mutations or focal amplification in genes coding for Notch receptors. Recent findings suggest that Notch signals, in the absence of Notch mutations are also important to maintain chemotherapy-resistant circulating tumor cells. Importantly, elevated Notch signaling is specifically enriched in the TNBC and is associated with worse survival in this subtype. These findings underscore the importance of Notch signaling in pathogenesis of TNBC and suggest potential new avenue for therapeutic approaches. Despite this, the target genes and oncogenic mechanisms downstream of aberrant Notch signaling are poorly understood. To create a high confidence map of the oncogenic Notch-driven regulome in TNBC, we performed an integrative, comprehensive and functional genome-wide analysis of Notch-driven targets in Notch-mutated TNBC cell lines by combining high-resolution genome-wide chromatin topology data (HiChIP), dynamic mapping of Notch transcriptional complex members and active and repressive chromatin marks (ChIP-seq), as well as evaluation of dynamic transcription (RNAseq) in presence and absence of Notch signals. One important oncogene and critical Notch target in TNBC is MYC. Our integrative analysis identified detailed map of Notch-dependent MYC regulatory network. The TNBC-specific MYC regulatory region, located 5' of MYC, is much more complex compared to other known Notch-driven malignancies and constitutes of a broad domain of active enhancers marked by H3K27ac that are not present in Notch-driven lymphoma and leukemia. Integrative analysis of ChIP-seq and HiChIP revealed multiple enhancers within this broad domain of regulatory elements that are directly bound by the members of Notch transcriptional complex, sensitive to acute changes in Notch activation and that contact MYC promoter via tumor specific chromatin loops. We showed that genetic perturbation of MYC by CRISPR/Cas9 approach was sufficient to kill TNBC cells. Since, MYC is difficult to target pharmacologically an alternative strategy is to use drugs that inhibit factors regulating MYC expression. To this end, elucidating the Notch regulatory landscape, and in particular, the mechanism by which Notch regulates MYC expression in TNBC may reveal new therapeutic strategies to precisely target MYC in Notch-dependent breast cancer. Citation Format: Petrovic J, Zhou Y, Georgakilas G, Vahedi G, Pear WS, Faryabi RB. Triple negative breast cancer-specific chromatin conformation links Notch signal to tumor-specific transcriptional program [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 P2-04-07.
A career in the City is becoming tempting with all the changes causing havoc with medical training. I have been advised that an MBA at a good school is a good start. Is this the best way?
Authors: Adam Poole
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. <b>www.bmjcareers.com/advicezone</b>
Female Reproductive and Hormonal Factors and Incidence of Primary Total Knee Arthroplasty Due to Osteoarthritis
Authors: Sultana Monira Hussain, Yuanyuan Wang, Graham G. Giles, Stephen Graves, Anita E. Wluka, Flavia M. Cicuttini
Journal: Arthritis & Rheumatology (2018)

Objective To examine the associations of female reproductive and hormonal factors with incidence of total knee arthroplasty ( TKA ) for osteoarthritis ( OA ), and to determine whether the associations differ according to overweight/obesity status. Methods This study included 22,289 women in the Melbourne Collaborative Cohort Study. Data on age at menarche, pregnancy, parity, years of menstruation, oral contraceptive ( OC ) use, menopausal status, and hormone replacement therapy ( HRT ) were collected in 1990–1994. Incidence of TKA during 2001–2013 was determined by linking cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. All analyses were adjusted for age, body mass index ( BMI ) at midlife, change in BMI (from early reproductive age to midlife), country of birth, physical activity, smoking, and education level. Results Over the course of 12.7 years, 1,208 TKA s for OA were identified. Ever being pregnant was associated with increased risk of TKA (hazard ratio [ HR ] 1.32 [95% confidence interval (95% CI ) 1.06–1.63]). Parity was positively associated with risk of TKA ( P for trend = 0.003). OC users had increased risk of TKA compared with non‐users (for OC use of &lt;5 years, HR 1.25 [95% CI 1.08–1.45]; for OC use of ≥5 years, HR 1.17 [95% CI 1.00–1.37]). A 1‐year increase in menstruation was associated with a 1% decrease in risk of TKA ( HR 0.99 [95% CI 0.97–0.99]). These associations remained significant only in women of normal weight at early reproductive age. Current HRT users had increased risk of TKA compared with non‐users ( HR 1.37 [95% CI 1.14–1.64]); the association was significant only in non‐obese women at midlife. Conclusion Reproductive and hormonal factors were associated with risk of knee OA . These associations remained significant in women of normal weight at early reproductive age and in non‐obese women at midlife. Further work is needed to understand the complex effect of these factors on knee OA .
WEIGHT LOSS FOLLOWING CORONARY ARTERY CALCIUM TESTING IN OBESE PATIENTS
Authors: Sadeer G. Al-Kindi, Robert Gilkeson, Les Ciancebello, Nataly Johnson, John Shanahan, Michelle Bryant-Hodges, Stan Pokras, Mirela Dobre, Daniel Simon, Sanjay Rajagopalan, David Zidar
Journal: Journal of the American College of Cardiology (2018)
CAN WE PREDICT THE ANGIOGRAPHIC SEVERITY OF CORONARY ARTERY DISEASE IN PATIENTS WITH ACUTE CORONARY SYNDROME USING NT-PROBNP?
Authors: Khanh P.N. Pham, Hoang H.N. Duong, Van N. Truong, Tam M.N. Ngo, Ha T. Ngo, Quynh T. Dinh, Sang T. Tran, Tram B. Nguyen, Huy D. Dinh, Thien M. Thai, Dat V. Nguyen, Nhut L. Nguyen, Wojciech Mazur, Eugene Chung, Thach Nguyen, Vinh N. Pham, Vien T. Truong
Journal: Journal of the American College of Cardiology (2018)
Is it possible for a person with a PhD in genetics to work as a geneticist in an NHS hospital?
Authors: Fiona Lalloo
Journal: BMJ (2004)

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 (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.
Professor Patrick Sissons, Regius professor of physic, University of Cambridge, and head of the School of Clinical Medicine, University of Cambridge
Authors: Hannah Peters
Journal: BMJ (2008)

“When I told my school house master about my career plans he said to me, ‘Sissons, are you sure you want to do that? There is an awful lot of blood in medicine.’ But he did not put me off and my stepmother arranged for me to shadow the family general practitioner in Hull. The GP said, ‘If you want to be a doctor, come and live with me.’ So I lived in his house as a sixth former and had to get up and go out with him whenever he was called out in the night. He also arranged for me to shadow a local pathologist, who asked me on my first day if I wanted to watch a postmortem, which took me aback. However, this experience made me realise that I definitely wanted to become a doctor. It would probably be difficult to do something like that today.

“In 1964 I started medical school at St Mary’s, London. Despite its reputation as a rugby playing medical school, I had a very good preclinical education from some of the leading biomedical scientists of the day (including Rodney Porter, who went on to win the Nobel prize). …