tbuckley/cabot-search huggingface dataset:
How to fix out of hours care
Authors: Rebecca Coombes
Journal: BMJ (2016)

The BMJ recently held a discussion between experts in general practice, emergency medicine, and paediatrics about the state of out-of-hours care in the UK, and crucially, their vision for a better service. Are children a special case, can urgent care “hubs” be a silver bullet, is NHS 111 up to the job of triaging patients, are there enough clinicians involved in out of hours care, and are other countries doing a better job? <b>Rebecca Coombes</b> reports
Concerted genomic targeting of H3K27 demethylase REF6 and chromatin-remodeling ATPase BRM in Arabidopsis
Authors: Chenlong Li, Lianfeng Gu, Lei Gao, Chen Chen, Chuang-Qi Wei, Qi Qiu, Chih-Wei Chien, Suikang Wang, Lihua Jiang, Lian-Feng Ai, Chia-Yang Chen, Songguang Yang, Vi Nguyen, Yanhua Qi, Michael P Snyder, Alma L Burlingame, Susanne E Kohalmi, Shangzhi Huang, Xiaofeng Cao, Zhi-Yong Wang, Keqiang Wu, Xuemei Chen, Yuhai Cui
Journal: Nature Genetics (2016)
Adoptive Transfer of WT1-Specific TCR Gene-Transduced Lymphocytes in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia
Authors: Isao Tawara, Masahiro Masuya, Shinichi Kageyama, Tetsuya Nishida, Seitaro Terakura, Makoto Murata, Hiroshi Fujiwara, Yoshiki Akatsuka, Hiroaki Ikeda, Yoshihiro Miyahara, Daisuke Tomura, Ikuei Nukaya, Kazutoh Takesako, Nobuhiko Emi, Masaki Yasukawa, Naoyuki Katayama, Hiroshi Shiku
Journal: Blood (2015)
Real‐world effectiveness of ledipasvir/sofosbuvir in 4,365 treatment‐naive, genotype 1 hepatitis C‐infected patients
Authors: Lisa I. Backus, Pamela S. Belperio, Troy A. Shahoumian, Timothy P. Loomis, Larry A. Mole
Journal: Hepatology (2016)

Real‐world effectiveness data are needed to inform hepatitis C virus (HCV) treatment decisions. The uptake of ledipasvir/sofosbuvir (LDV/SOF) regimens across health care settings has been rapid, but variations often occur in clinical practice. The aim of this study was to assess sustained virologic response (SVR) of LDV/SOF±ribavirin (RBV) in routine medical practice. This observational, intent‐to‐treat cohort was comprised of 4,365 genotype 1, treatment‐naive, HCV‐infected veterans treated with LDV/SOF±RBV. SVR rates were 91.3% (3,191/3,495) for LDV/SOF and 92.0% (527/573) for LDV/SOF+RBV ( P = 0.65). African American race (odds ratio 0.70, 95% confidence interval 0.54‐0.90, P = 0.004) and FIB‐4 &gt;3.25 (odds ratio 0.56, 95% confidence interval 0.43‐0.71, P &lt; 0.001) were independently associated with decreased likelihood of SVR; age, sex, body mass index, decompensated liver disease, diabetes, genotype 1 subtype, and regimen did not predict SVR. In models limited to those who completed 12 weeks of treatment, African American race was no longer a significant predictor of SVR but FIB‐4 &gt;3.25 (odds ratio 0.35, 95% confidence interval 0.24‐0.50, P &lt; 0.001) remained. Among those without cirrhosis (defined by FIB‐4 ≤3.25) and with baseline HCV RNA&lt;6,000,000 IU/mL, SVR rates were 93.2% (1,020/1,094) for those who completed 8 weeks of therapy and 96.6% (875/906) for those who completed 12 weeks of therapy ( P = 0.001). Conclusions: In this real‐world cohort, SVR rates with LDV/SOF±RBV nearly matched the rates reported in clinical trials and were consistently high across all subgroups; those without cirrhosis but with HCV RNA&lt;6,000,000 IU/mL were less likely to achieve SVR with 8 weeks compared to 12 weeks of therapy, although the numeric difference in SVR rates was small. (H epatology 2016;64:405‐414)
Comprehensive genomic characterization of squamous cell carcinoma of the lung.
Authors: Ramaswamy Govindan, Peter S. Hammerman, David N. Hayes, Matthew D Wilkerson, Stephen Baylin, Matthew Meyerson
Journal: Journal of Clinical Oncology (2012)

7006 Background: A third of patients with non-small cell lung cancer are diagnosed with squamous cell carcinoma (SCC) histology. This report describes findings from the comprehensive genomic analyses of 178 SCC samples. Methods: The Cancer Genome Atlas (TCGA) is conducting DNA, RNA, and miRNA sequencing along with DNA copy number profiling, quantification of mRNA expression and promoter methylation on surgically resected samples from previously untreated patients with stage I-III SCC of the lung. Results: The demographics of 178 patients enrolled in the study: median age 68 years (range: 40-85); female 47 (26%) and history of tobacco smoking 171 (96%). Over 30 sites of significant somatic copy number alteration (SCNA) were identified. Exome sequencing of 178 lung SCC and matched normal samples revealed 13 significantly mutated genes with a False Discovery Rate (FDR) of &lt;0.01 and high expression levels, including TP53, CDKN2A, PTEN, KEAP1, and NFE2L2. Apart from the near universal loss of TP53 and CDKN2A, alterations in the NFE2L2/KEAP1 and PI3K/AKT pathways were found in 35% and 43% of tumors analyzed. mRNA expression profiling revealed four distinct expression subtypes, each one enriched with distinct mutations and SCNAs - classical (37%): NFE2L2 and KEAP1 mutations, FGFR kinase alterations, increased global methylation and the highest rate of tobacco use; basal (24%): alterations in FGFR kinases; secretory (24%): PDGFRA alterations; primitive (15%): RB1 mutations. Rearrangements involving several known tumor suppressors were detected by whole genome shotgun sequencing of 20 tumor/normal pairs and confirmed by RNA sequencing including PTEN, RB1, NOTCH1, NF1 and CDKN2A. CDKN2A loss by one of several mechanisms (deletion, mutation, rearrangement with loss of function and methylation) was observed in 72% of specimens. Potential therapeutic targets for clinical trials with currently available drugs were identified in 127 patients (75%). Conclusions: SCC of the lung is a distinct molecular subtype of lung cancer potentially amenable to distinct molecularly targeted therapies.
THU0010 Genome-Wide Association Study of Anti-Cyclic Citrullinated Protein-Positive Rheumatoid Arthritis Identifies a New Risk Locus in SLC8A3
Authors: A. Julià, A. Fernandez-Nebro, F. Blanco, I. González, J.D. Cañete, J. Maymό, M. Alperi-Lόpez, B. Fernández-Gutierrez, A. Olivè, H. Corominas, J. Tornero, A. Erra, A. González, V. Martínez Taboada, S. Sánchez, I. Acosta Colmán, A. Alonso, M. Lόpez-Lasanta, R. Tortosa, S. Marsal
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> There is strong evidence that Rheumatoid Arthritis (RA) patients expressing anti-cyclic citrullinated peptide antibodies (ACPA) have a differential genetic background compared to ACPA-negative RA patients. <h3>Objectives</h3> We performed a genome-wide association study (GWAS) on ACPA-positive RA patients to identify additional disease susceptibility genes. <h3>Methods</h3> A total of 924 ACPA-positive RA patients and 1,524 healthy controls were genotyped in 582,591 single-nucleotide polymorphisms (SNPs) in the discovery phase. The most significant SNPs were then analyzed in an independent cohort of 863 ACPA-positive patients and 1,152 healthy controls. <h3>Results</h3> In the discovery phase we found suggestive association (<i>P</i> &lt;5e-4) for 60 novel loci with the risk to develop ACPA-positive RA. In the validation phase, we nominally replicated the association of 12 candidate loci (<i>P</i>&lt;0.05 same direction of effect as in GWAS). Combining the data from the discovery and validation cohorts we found a genome-wide significant association between an intronic SNP in Solute Carrier family 8 gene (<i>SLC8A3</i>) and the risk to develop ACPA-positive RA (OR (95%CI): 1.42 (1.25-1.6), combined <i>P</i>=3.19e-8). <h3>Conclusions</h3> This study identified a new locus associated with ACPA-positive RA. These results support the evidence that RA patients positive for ACPA have a specific genetic background. <h3>Disclosure of Interest</h3> None declared
Soundings: Summer news
Authors: George Dunea
Journal: BMJ (2000)

News travels fast nowadays, but not everybody may know (or care) that in mid-July Chicago's 18 year old Mauyak gave birth to a five foot long beluga baby whale weighing 125 lbs, her previous breech birth having been unsuccessful. Paternity tests are underway, as there were two male whales present when she became pregnant.

Meanwhile animal advocates are trying to find homes for 47 cats abandoned in cages in a one car garage. Wizards are everywhere, and quidditch is threatening to replace football as teeneagers are crowding into bookstores to read about Harry Potter and his muggle family. Akhenaten has moved in at the Art Institute and will interview 125 000 visitors this summer.

Tobacco companies are still reeling from the shock of the $145bn (£97bn) punitive damages awarded to their innocent smoking victims, and dental associations are warning teenagers against tongue piercing—a fashionable trend that may cause infections, damaged teeth, dysphagia, dysphonia, or suffocation from dislodged tongue rings.

In Illinois the governor has declared a moratorium on executions until the legal system is fixed to avoid mistakes. Several Chicago beaches had to be closed because of high E coli counts. A judge has banned fishing in parts of Hawaii to save endangered turtles, to the great indignation of the fishing industry and sashimi gourmets. Everybody here is complaining about the high cost of drugs, and presidential candidates are promising free drug schemes for senior citizens. The latter will need to stay alive longer because of various proposals to gradually eliminate the death tax over 10 years. In Africa 19 million people have died of AIDS and 34 million are infected in an epidemic reminiscent of the bubonic plague.

There is some excitement about statins possibly preventing fractures; disappointment about the platelet inhibitor clopidogrel causing thrombotic thrombocytopenic purpura; hope that the new antibiotic linezolid will eliminate vancomycin resistant enterococci; lingering uncertainty about how to treat most prostate cancers; questions on whether sildenafil should be given away free in public hospitals; continuing debate about whether angiotensin receptor blockers are as good or better than ACE inhibitors; and doubts about how effective oseltamivir will really be in preventing inluenza.
TCTAP A-049 Coronary Computed Tomography Angiography Guided Percutaneous Coronary Intervention Using Bioresorbable Scaffolds in Calcified Coronary Stenoses
Authors: Michael Chun-Leng Lim, Hima Bindu Ragoori, Wei Hu, Jose Sandoval Poblete, Ralph Anthony Daray
Journal: Journal of the American College of Cardiology (2016)
A bridge to silencing: Co-assembling anionic nanoparticles of siRNA and hyaluronan sulfate via calcium ion bridges
Authors: Efrat Forti, Olga Kryukov, Edan Elovic, Matan Goldshtein, Efrat Korin, Gal Margolis, Shani Felder, Emil Ruvinov, Smadar Cohen
Journal: Journal of Controlled Release (2016)
Case 43-1989
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, Peter P. Anas, Daniel I. Rosenthal
Journal: New England Journal of Medicine (1989)

Presentation of CaseA 79-year-old woman was admitted to the hospital because of back pain, an osteolytic lesion, and increasing paraparesis after a fall.The patient was in a stable state of health until 13 days earlier, when she tripped and fell at home and was unable to walk because of severe back pain. She was admitted to another hospital.There was a history of mild arthritis of the spine in recent times, of osteoporosis, and of 30 years of diabetes mellitus that was treated in the past seven months with NPH insulin and diet. She used hydrochlorothiazide for hypertension . . .
A comparison of medical resource use for 4 chemotherapy regimens as first-line treatment for metastatic colorectal cancer (MCRC): XELOX vs. FOLFOX4 ± bevacizumab (A)
Authors: W. Scheithauer, J. Cassidy, A. Figer, R. Wong, S. Koski, M. Lichinitser, T. Yang, S. Clarke, E. Diaz-Rubio, L. Garrison
Journal: Journal of Clinical Oncology (2007)

4098 Background: A recent randomized phase III trial with a 2x2 factorial design compared 4 chemotherapy regimens as first-line treatment for MCRC: oral capecitabine + i.v. oxaliplatin q3w (XELOX); 5-FU/LV + i.v. oxaliplatin (FOLFOX4); XELOX+A; and FOLFOX4+A. The XELOX regimens were found to be non-inferior to FOLFOX4 in terms of progression-free survival (the primary endpoint), and the A regimens were superior to the placebo arms. The attractiveness of these regimens to providers, patients, and payers will also depend on the medical resources involved. The purpose of this analysis was to compare the expected resource use across the 4 groups. Methods: A resource use model was constructed based on trial data and projections from trial protocols. Both medical resources and patient time were considered. The medical resources included visits for chemotherapy administration, central venous access (CVA), treatment of adverse events (AEs), and hospital use for common treatment-related AEs. Patient time for chemotherapy administration, ambulatory visits, and hospital stays was estimated. Results: FOLFOX and FOLFOX4+A required more administration visits due to the q2w cycle (22–27 visits in total for the FOLFOX arms vs. 7–9 visits for the XELOX arms). With FOLFOX regimens, patients spend 60–200 additional hours receiving i.v. drug administration, and 22–27 additional hours traveling and waiting to receive chemotherapy. The rate of hospital admissions for common AEs did not differ among the arms, but mean hospital days for common AEs were slightly higher in the XELOX arms. Ambulatory encounters to treat AEs added only about 1 hour of encounter time per patient on average in all 4 arms. The 2 FOLFOX4 arms had twice as many placements for CVA. Conclusion: In the first-line setting, the 2 FOLFOX4 chemotherapy regimens involve substantially more i.v. drug administration visits and time - the equivalent of more than two 40-hour workweeks. The 4 regimens were similar in terms of the amount of resource use needed to treat AEs. No significant financial relationships to disclose.
P0981 : Adaptation of hepatic mitochondrial function in obese humans with or without non-alcoholic steatohepatitis
Authors: C. Koliaki, J. Szendroedi, K. Kaul, T. Jelenik, P. Nowotny, F. Jankowiak, C. Herder, M. Carstensen, M. Krausch, W. Trudo Knoefel, M. Schlensak, M. Roden
Journal: Journal of Hepatology (2015)
Adjuvant sequential docetaxel and cyclophosphamide-doxorubicin combination in operable breast cancer patients
Authors: H. S. Coskun, O. Er, M. Ozkan, B. Eser, M. Altinbas
Journal: Journal of Clinical Oncology (2004)

822 Background: Docetaxel is one of the most active drugs for breast cancer. Impact of the Docetaxel in the adjuvant setting of breast cancer is being actively studied. Methods: We investigated that effect of sequential docetaxel and cyclophospahamide-doxorubicin combination. Patients with four and more positive axillary lymph node (ALN) were included to study. Patients with 1–3 positive ALN and negative endocrine receptors were also accepted to study. Fifty-seven patients who had undergone modified radical mastectomy were treated cyclophosphamide (600 mg/m) and doxorubicin (60 mg/m) combination 4 cycles every 3 weeks and docetaxel (100 mg/m) 4 cycles every 3 weeks sequentially. Median number of positive ALN was 7 (1–25). Percent of 1–3, and 4 or more positive ALN were 17.5%, 82.5% respectively. Results: Median age was 42 (23–68). Fifty-four patients were treated by adjuvant radiotherapy and 16 patients received endocrine treatment (7 tamoxifen and 9 tamoxifen and goserelin). Relapse was detected in 12 (21%) patients. The most frequently metastatic side was bone. Estimated median progression free survival (PFS) was 40 months (95% CI 36.9–44.9) and overall survival (OS) was 46.4 months (95% CI 43.9–44.9). PFS and OS rate at 24 and 48 months were 84.6%, 68.8% and 95.5%, 83.0%, respectively. There was no difference on survival parameters according to age, primary tumor size, endocrine receptors, grade, and histopathology. Patients with ten or more positive ALN had worst survival than low positive ALN but differences have limited statistical power. Nonhematologic grade 3 and 4 toxicity was not detected in this protocol. Conclusions: Cyclophosphamide-doxorubicin combination plus sequentially docetaxel on adjuvant treatment in axillary positive breast cancer may improve to survival. No significant financial relationships to disclose.
Philip Henry Connell Allan Urquhart Downie Christopher Chilcot Evans John Bonham Carter Evelegh Gustav ("Gus") Julius Fraenkel Desmond Robert Gamble Alexander ("Sanyi") Gellert Beryl Jennie Goff Henry Russell
Authors: T. Bewley, S. Lock, T. Ashmore, A. Harden, A G Huff, D. Pyke, E. I Tanner, V. Somen, A. Gellert, B. Grimmett, K J Waters, T S Waters
Journal: BMJ (1998)

Philip was a child
Abstract 3479: CPX-351 (cytarabine:daunorubicin liposome for injection) anti-leukemia activity is potentiated by Chk1 inhibition
Authors: Nicole D. Vincelette, Larry M. Karnitz, Judith E. Karp, Douglas B. Smith, Allan D. Hess, Lawrence D. Mayer, Scott H. Kaufmann
Journal: Cancer Research (2015)

Abstract Background: Cytarabine and an anthracycline, the mainstay of AML therapy, affords a five-year survival below 30%. Accordingly, there is a continuing need for improved AML therapies. CPX-351 encapsulates within liposomes a fixed 5:1 molar ratio of cytarabine and daunorubicin that is synergistic (in vitro) and markedly improved in anti-leukemic activity (in vivo). Promising evidence of improved remission and survival rates with CPX-351 compared to standard of care treatments has also been observed clinically and a pivotal Phase 3 trial is currently ongoing. Because Chk1 inhibition has been shown to enhance the actions of both cytarabine and anthracyclines, there has been interest in assessing the effect of CPX-351 when combined with Chk1 inhibitors. Here we describe the evaluation of CPX-351 alone and in combination with the Chk1 inhibitors MK-8776 and LY2603618 in AML cell lines and in clinical AML samples ex vivo. Methods: Effects of CPX-351 on Chk1 phosphorylation and cell cycle distribution in the human AML lines U937 and HL-60 were analyzed by immunoblotting and flow cytometry. Effects of Chk1 inhibitors on CPX-351-induced apoptosis were assessed by flow cytometry after propidium iodide staining (DNA cleavage), Hoechst staining (nuclear fragmentation) and colony formation in soft agar (long-term survival). Effects CPX-351 ± MK-8776 on clinical AML samples were assayed using clonogenic assays. Results: Treatment of U937 cells with CPX-351 resulted in phosphorylation of Chk1 on Ser317 and Ser296 (sites of ATR-mediated phosphorylation and autophosphorylation, respectively) as well as S phase slowing consistent with Chk1 activation. Co-treatment of AML cell lines with Chk1 inhibitors + CPX-351 resulted in increased apoptotic morphological changes and DNA fragmentation as well as diminished clonogenic survival compared to CPX-351 alone. The CPX-351/MK-8776 combination displayed enhanced antiproliferative effects against some clinical AML isolates ex vivo compared to CPX-351 alone, with additional assays ongoing. Conclusions: Collectively, these results show that Chk1 inhibition enhances the cytotoxicity of CPX-351 in AML cell lines and some clinical AML samples, offering the possibility that CPX-351 may be well suited for combining with such molecularly targeted agents. Citation Format: Nicole D. Vincelette, Larry M. Karnitz, Judith E. Karp, Douglas B. Smith, Allan D. Hess, Lawrence D. Mayer, Scott H. Kaufmann. CPX-351 (cytarabine:daunorubicin liposome for injection) anti-leukemia activity is potentiated by Chk1 inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3479. doi:10.1158/1538-7445.AM2015-3479
Constitutive Vs. Stroma-Induced Kinase Dependencies in Myeloma Cells: Functional Mapping Using Small Molecule Inhibitors As Chemical Probes
Authors: Eugen Dhimolea, Emily King, Michal Sheffer, Yiguo Hu, Pallavi P. Awate, Subhashis Sarkar, Geoffrey M. Matthews, Megan Murnane, Megan A. Bariteau, Blake T. Aftab, Constantine S Mitsiades
Journal: Blood (2015)
Abstract 235: Molecular Signature Of Cardiomyogenic c-kit-positive Bone Marrow Cells
Authors: Junghyun Kim, Fumihiro Sanada, João D Pereira, Anna Czarna, Jared Churko, Joseph C Wu, Marcello Rota, Piero Anversa, Annarosa Leri
Journal: Circulation Research (2014)

Conflicting results have been reported concerning the ability of c-kit-positive bone marrow cells (c-kit-BMCs) to transdifferentiate into cardiomyocytes in vivo. We have raised the possibility that c-kit-BMCs may constitute a functionally heterogeneous pool, containing cells with different cardiomyogenic potential. To test this hypothesis, clonal analysis of individual c-kit-BMCs was introduced to track in vivo the progeny derived from a single founder cell. By employing viral gene-tagging, only a limited fraction of clonal c-kit-BMC was found to be able to generate cardiomyocytes in the acutely infarcted heart. On this basis, c-kit-BMC-derived clones were classified as myogenic or non-myogenic. The gene profile of these two categories of cells was studied by RNA-sequencing to determine whether myogenic c-kit-BMCs had a distinct molecular signature. Genes that showed a significant (p&lt;0.05) expression difference of at least 2-fold among cell groups were included in the analysis; 1243 genes were upregulated and 493 genes were downregulated in myogenic c-kit-BMCs when compared with non-myogenic c-kit-BMCs. An additional comparison involved freshly isolated c-kit-BMCs. 2512 genes were upregulated in myogenic c-kit-BMCs and 1844 genes were downregulated in this cell group. These results were subjected to functional annotation using gene ontology for the identification of molecular pathways showing different state of activation or repression in myogenic BMCs. The affected transcripts in myogenic c-kit-BMCs involved mostly signal transduction and muscle development including cardiac muscle. Similarly, a set of genes implicated in the regulation of angiogenesis were more represented in myogenic c-kit-BMCs, possibly reflecting the proficiency of this cell class to form vessels in the microenvironment of the infarcted heart. Our findings document that myogenic clonal c-kit-BMCs have a distinct molecular signature that differs from that of non-moygenic and non-expanded c-kit-BMCs. On this basis, c-kit-BMCs with high cardiomyogenic ability can be prospectively isolated and employed clinically for the treatment of patients with cardiac diseases.
Atrial Fibrillation Revisited
Authors: Arthur Selzer
Journal: New England Journal of Medicine (1982)

Atrial fibrillation is the grandfather of cardiac arrhythmias. Known in the 19th century as "arrhythmia perpetua," it was clearly defined clinically by MacKenzie and electrocardiographically by Lewis at the beginning of this century. Except for the development of direct-current shock therapy some two decades ago, the management of atrial fibrillation has changed little from that well described by Mackenzie in 1925.1 In the present era of sophisticated approaches to arrhythmias, atrial fibrillation has attracted little interest among electrophysiologists; its management still depends largely on the use of two of the oldest cardiac drugs: digitalis and quinidine.Yet atrial fibrillation remains . . .