tbuckley/cabot-search huggingface dataset:
Phosphorylated alpha-Synuclein in Parkinson's Disease
Authors: Yu Wang, Min Shi, Kathryn A. Chung, Cyrus P. Zabetian, James B. Leverenz, Daniela Berg, Karin Srulijes, John Q. Trojanowski, Virginia M. Y. Lee, Andrew D. Siderowf, Howard Hurtig, Irene Litvan, Mya C. Schiess, Elaine R. Peskind, Masami Masuda, Masato Hasegawa, Xiangmin Lin, Catherine Pan, Douglas Galasko, David S. Goldstein, Poul Henning Jensen, Hui Yang, Kevin C. Cain, Jing Zhang
Journal: Science Translational Medicine (2012)
Super-Enhancers Promote Transcriptional Dysregulation in Nasopharyngeal Carcinoma
Authors: Jiang Yuan, Yan-Yi Jiang, Anand Mayakonda, Moli Huang, Ling-Wen Ding, Han Lin, Fenggang Yu, Yanan Lu, Thomas Kwok Seng Loh, Marilynn Chow, Samantha Savage, Jeffrey W. Tyner, De-Chen Lin, H. Phillip Koeffler
Journal: Cancer Research (2017)

Abstract Nasopharyngeal carcinoma (NPC) is an invasive cancer with particularly high incidence in Southeast Asia and Southern China. The pathogenic mechanisms of NPC, particularly those involving epigenetic dysregulation, remain largely elusive, hampering clinical management of this malignancy. To identify novel druggable targets, we carried out an unbiased high-throughput chemical screening and observed that NPC cells were highly sensitive to inhibitors of cyclin-dependent kinases (CDK), especially THZ1, a covalent inhibitor of CDK7. THZ1 demonstrated pronounced antineoplastic activities both in vitro and in vivo. An integrative analysis using both whole-transcriptome sequencing and chromatin immunoprecipitation sequencing pinpointed oncogenic transcriptional amplification mediated by super-enhancers (SE) as a key mechanism underlying the vulnerability of NPC cells to THZ1 treatment. Further characterization of SE-mediated networks identified many novel SE-associated oncogenic transcripts, such as BCAR1, F3, LDLR, TBC1D2, and the long noncoding RNA TP53TG1. These transcripts were highly and specifically expressed in NPC and functionally promoted NPC malignant phenotypes. Moreover, DNA-binding motif analysis within the SE segments suggest that several transcription factors (including ETS2, MAFK, and TEAD1) may help establish and maintain SE activity across the genome. Taken together, our data establish the landscape of SE-associated oncogenic transcriptional network in NPC, which can be exploited for the development of more effective therapeutic regimens for this disease. Cancer Res; 77(23); 6614–26. ©2017 AACR.
The role of adjuvant therapy in the management of resected large cell neuroendocrine carcinoma (LCNEC) of the lung: A National Cancer Database (NCDB) analysis.
Authors: Lara Ann Kujtan, Varsha Muthukumar, Muhammad Toor, Kevin F Kennedy, Ashiq Masood, J Russell Davis, Janakiraman Subramanian
Journal: Journal of Clinical Oncology (2017)

8529 Background: Large cell neuroendocrine carcinoma (LCNEC) is characterized by aggressive behavior and poor outcomes compared with other non-small cell lung cancers (ONSCLC). Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with early stage NSCLC (pathologic stage I, II, IIIA) from 2004-2012 who underwent surgical resection. Patients were divided into two groups: LCNEC and ONSCLC. One-way ANOVA was used to compare continuous variables, and chi-squared testing was used to compare categorical variables. Multivariate logistic regression analyses were used to obtain hazard ratios. Results: We identified 1672 patients with resected LCNEC and 134139 with resected ONSCLC. A higher proportion of patients with ONSCLC had a Charlson-Deyo co-morbidity score of 0 compared to LCNEC patients (50.6% vs. 43.8%; p &lt; 0.001). No other significant differences in clinical and demographic characteristics were identified. Overall survival was lower for LCNEC patients across all stages when compared to patients with resected ONSCLC (46 months versus 74 months; 5-year survival 45% versus 57%; p &lt;0.001). Multivariate analysis confirmed the survival benefit for adjuvant chemotherapy in resected LCNEC across all stages, including stage IA, although it did not reach statistical significance (hazard ratio 0.72 (0.51-1.02), p= 0.64; Table). Conclusions: Adjuvant chemotherapy significantly improves survival for stage IB, II and IIIA LCNEC compared to surgery alone. Patients with stage IA LCNEC appear to benefit from adjuvant chemotherapy although it did not reach statistical significance. The overall magnitude of benefit from adjuvant chemotherapy appears to be higher for patients with LCNEC compared to ONSCLC. [Table: see text]
A Biomarker Ocular
Authors: Mahir Karakas, Tanja Zeller
Journal: Circulation Research (2017)

D espite the routine use of computed tomographic scans and magnetic resonance imaging, the diagnosis of stroke remains challenging because ≈50% of patients with acute ischemic stroke (IS) lack abnormalities in the computed tomographic and magnetic resonance imaging scans.There is an unmet need for new markers that support clinicians in the diagnosis of IS.Moreover, markers of prognosis would be of considerable interest because of the potential to guide secondary preventive therapies enabling personalized treatment.
Long-term outcomes in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in the phase 3 KEYNOTE-006 study who completed pembrolizumab (pembro) treatment.
Authors: Caroline Robert, Georgina V. Long, Jacob Schachter, Ana Arance, Jean Jacques Grob, Laurent Mortier, Adil Daud, Matteo S. Carlino, Catriona M. McNeil, Michal Lotem, James M. G. Larkin, Paul Lorigan, Bart Neyns, Christian U. Blank, Teresa M. Petrella, Omid Hamid, Honghong Zhou, Blanca Homet Moreno, Nageatte Ibrahim, Antoni Ribas
Journal: Journal of Clinical Oncology (2017)

9504 Background: Pembro demonstrated superior PFS and OS vs ipi in ipi-naive pts with advanced melanoma in the phase 3 KEYNOTE-006 study (NCT01866319). Here, we present long-term outcomes for all pts and in those pts who completed pembro therapy. Methods: Eligible pts (N = 834) were randomized 1:1:1 to pembro 10 mg/kg Q2W, pembro 10 mg/kg Q3W, or ipi 3 mg/kg Q3W for 4 doses. Treatment was continued for 2 yr (pembro only) or until disease progression, intolerable toxicity, or pt/investigator decision to discontinue. Per protocol, pts could interrupt pembro for ≤12 wk before discontinuation was required. Tumor imaging was performed at wk 12, then every 6 wk up to wk 48 and every 12 wk thereafter. After the prespecified final analysis, response assessments were per immune-related response criteria (irRC) by investigator review. Results: As of the data cutoff (Nov 3, 2016), median follow-up in the total population was 33.9 mo (range, 32.1-37.6). 33-mo OS rates were 50% in the pooled pembro arms (n = 556) and 39% in the ipi arm (n = 278); 33-mo PFS rates were 31% and 14%. ORR was 42% and 16%. Median duration of response was not reached for pembro (range 1.0+ to 33.8+ mo) or ipi (1.1+ to 34.8+ mo); 46 (68%) pembro-treated pts and 7 (58%) ipi-treated pts had a response lasting ≥30 mo. Among the 104/556 (19%) pts who completed pembro, median exposure to pembro was 24.0 mo (range 22.1-25.9). After a median follow-up of 9.0 mo after completion of pembro, 102 (98%) pts were alive. Responses were durable in pts who completed pembro; 9.7 mo after completion of pembro, estimated PFS (95% CI) was 91% (80-96) in all 104 pts, 95% (69-99) in pts with complete response (n = 24), 91% (74-97) in pts with partial response (n = 68), and 83% (48-96) in pts with stable disease (n = 12). Conclusions: Pembro provides durable efficacy after stopping the protocol-specified duration of treatment in pts with ipi-naive advanced melanoma in KEYNOTE-006. The estimated risk for progression or death nearly 10 mo after completing pembro is 9% and does not appear to differ by best response to pembro. Clinical trial information: NCT01866319.
Differentiation syndrome associated with enasidenib, a selective inhibitor of mutant isocitrate dehydrogenase 2 (mIDH2).
Authors: Amir Tahmasb Fathi, Courtney Denton Dinardo, Irina Kline, Laurie Kenvin, Ira Gupta, Eyal C. Attar, Eytan M. Stein, Stéphane de Botton
Journal: Journal of Clinical Oncology (2017)

7015 Background: Enasidenib (AG-221), an oral mIDH2 inhibitor, promotes myeloid differentiation of leukemic blasts. Enasidenib treatment (Tx) can result in IDH-inhibitor-associated differentiation syndrome (IDH-DS), with manifestations akin to retinoic acid syndrome seen during acute promyelocytic leukemia Tx. Methods: A phase 1 dose-escalation/expansion study (N = 239) (NCT01915498) included 109 pts with relapsed/refractory AML who received enasidenib 100 mg /day. An independent Differentiation Syndrome Review Committee (DSRC) was formed to review potential IDH-DS cases. The DSRC identified and agreed on signs and symptoms possibly characteristic of IDH-DS, including fever, lung infiltrates, pleural or pericardial effusions, rapid weight gain, edema, and azotemia. Of the 109 pts, the DSRC identified and retrospectively reviewed 27 cases (8 investigator reported IDH-DS cases and 19 cases suggestive of IDH-DS) to determine consistency with IDH-DS. Results: The DSRC found 13 of the 27 cases to be consistent with IDH-DS (11.9% of 109 pts). Median time to onset was 30 days (range 7-116). Manifestations of IDH-DS in &gt; 2 pts were dyspnea (n = 10), pyrexia (9), lung infiltrates (8), pleural effusion (5), and kidney injury (3). IDH-DS was effectively managed with systemic corticosteroids in 12/13 cases. Leukocytosis accompanied 4 cases and hydroxyurea was used for cytoreduction. Enasidenib was interrupted for 9 pts (median 7 days) but dose reductions or discontinuation were not required. Six of 13 pts had clinical responses (2 complete remission [CR], 2 CR with incomplete hematologic recovery, 1 partial remission, 1 morphologic leukemia-free state), 6 had stable disease and 1 had progressive disease. Conclusions: Systemic corticosteroids, close hemodynamic management, and hydroxyurea (in the presence of leukocytosis) are effective management strategies, should be administered promptly when IDH-DS is suspected, and continued until improvement. Enasidenib interruption can be considered if initial intervention is unsuccessful. IDH-DS represents a novel clinical finding in m IDH2 AML treated with enasidenib, and is likely due to its suggested mechanism of action, differentiation. Clinical trial information: NCT01915498.
Who killed Cock Robin?
Authors: T. Delamothe
Journal: BMJ (1998)

After the GMC's decision came the recriminations, followed by the questions that won't go away. Firstly, why weren't surgeons James Wisheart and Janardan Dhasmana stopped from operating on young children once their poor results became widely known? Immediate colleagues, their employer, the Royal College of Surgeons, and the Department of Health all knew—or had been told—how badly they were doing.

The behaviour of each of these came under scrutiny in the days after the judgment. The Guardian said that the GMC had warned several consultant colleagues that their conduct might also be open to question (30 May); the Independent speculated that the forthcoming government inquiry would examine the involvement in the babies' deaths of up to a dozen senior consultants (1 June).

Why was the United Bristol Healthcare NHS Trust so slow to act? The Daily Mail …
Hormonal and reproductive factors and incidence of basal cell carcinoma and squamous cell carcinoma in a large, prospective cohort
Authors: Catherine M. Olsen, Nirmala Pandeya, Bridie S. Thompson, Jean Claude Dusingize, Padmini Subramaniam, Christina M. Nagle, Adele C. Green, Rachel E. Neale, Penelope M. Webb, David C. Whiteman
Journal: Journal of the American Academy of Dermatology (2017)
The Natural History of Rheumatic Heart Disease in the Third, Fourth, and Fifth Decades of Life
Authors: MAY G. WILSON, WAN NGO LIM
Journal: Circulation (1957)

The object of this study is to provide information on the natural course of rheumatic heart disease in the third, fourth, and fifth decades of life. It is concerned with 757 out of 1,042 children under observation during the years 1916 to 1956 who reached the age of 20 or more years. The major manifestations of rheumatic fever experienced by these patients from the onset of the disease is related to the degree of residual cardiac damage. Survival to successive ages was analyzed with respect to sex, type of valvular lesion, and degree of cardiac enlargement.
The Driver Mutational Landscape of Ovarian Squamous Cell Carcinomas Arising in Mature Cystic Teratoma
Authors: Susanna L. Cooke, Darren Ennis, Lisa Evers, Suzanne Dowson, Mei Yen Chan, James Paul, Lynn Hirschowitz, Rosalind M. Glasspool, Naveena Singh, Sarah Bell, Elizabeth Day, Agata Kochman, Nafisa Wilkinson, Philip Beer, Sancha Martin, David Millan, Andrew V. Biankin, Iain A. McNeish
Journal: Clinical Cancer Research (2017)

Abstract Purpose: We sought to identify the genomic abnormalities in squamous cell carcinomas (SCC) arising in ovarian mature cystic teratoma (MCT), a rare gynecological malignancy of poor prognosis. Experimental design: We performed copy number, mutational state, and zygosity analysis of 151 genes in SCC arising in MCT (n = 25) using next-generation sequencing. The presence of high-/intermediate-risk HPV genotypes was assessed by quantitative PCR. Genomic events were correlated with clinical features and outcome. Results: MCT had a low mutation burden with a mean of only one mutation per case. Zygosity analyses of MCT indicated four separate patterns, suggesting that MCT can arise from errors at various stages of oogenesis. A total of 244 abnormalities were identified in 79 genes in MCT-associated SCC, and the overall mutational burden was high (mean 10.2 mutations per megabase). No SCC was positive for HPV. The most frequently altered genes in SCC were TP53 (20/25 cases, 80%), PIK3CA (13/25 cases, 52%), and CDKN2A (11/25 cases, 44%). Mutation in TP53 was associated with improved overall survival. In 8 of 20 cases with TP53 mutations, two or more variants were identified, which were bi-allelic. Conclusions: Ovarian SCC arising in MCT has a high mutational burden, with TP53 mutation the most common abnormality. The presence of TP53 mutation is a good prognostic factor. SCC arising in MCT share similar mutation profiles to other SCC. Given their rarity, they should be included in basket studies that recruit patients with SCC of other organs. Clin Cancer Res; 23(24); 7633–40. ©2017 AACR.
Abstract 18836: Differences in Cardiopulmonary Exercise Test Data and Prognosis in Black and White Men with Heart Failure: the Henry Ford HospITal CardioPulmonary EXercise Testing (FIT-CPX) Project
Authors: Matthew A Saval, Clinton A Brawner, Ali Shafiq, Heather E Aldred, Raakesh Hassan, Stephanie Vasko, Jonathan K Ehrman, Yelena Selektor, Christina Tita, Mauricio Velez, Celeste T Williams, David E Lanfear, Steven J Keteyian
Journal: Circulation (2014)

Introduction: Numerous metrics from the cardiopulmonary exercise test (CPX) are associated with outcomes among patients with heart failure with reduced ejection fraction (HFrEF). Among patients with HFrEF, mortality rates differ by race; however, the influence of race on the association between common measures obtained during CPX and mortality has not been fully described. Purpose: Retrospective analysis to describe the relationship between key CPX measures and the composite endpoint of mortality, left ventricular assist device (LVAD), or cardiac transplant (CT) in white and black men with HFrEF. Methods: Self-identified white and black male patients (n= 761; age= 55 ± 12 y; BMI= 30.6±6.6) with a CPX between 1997 and 2010 and confirmed HFrEF (ejection fraction [EF] ≤ 40%) were identified. Endpoint data was obtained through 2011. The association with the composite endpoint was evaluated separately for 7 key CPX measures with adjustment for age, hypertension, beta-blocker therapy, EF, and ischemic etiology using Cox regression stratified by race. Results: During a median follow-up of 3.5 y there were 195 (54%) and 193 (48%) events for white and black patients, respectively. All CPX variables were associated (p&lt;0.05) with the composite endpoint in both white and black patients (Table). The greatest Wald statistic among white patients was % predicted peak oxygen uptake (ppVO 2 ) at 76.2, and among black patients it was ventilatory efficiency (V E -VCO 2 slope) at 90.8. Conclusion: Among white and black male patients, % predicted peak VO 2 and V E -VCO 2 slope, respectively, were most strongly associated with the combined end point of mortality, LVAD or CT. These data suggest that risk stratification using CPX variables may differ by race. Further research is needed to determine if race-specific methods of CPX-based risk stratification are needed.
Mortality prediction in stable hemodialysis patients is refined by YKL-40, a 40-kDa glycoprotein associated with inflammation
Authors: Georg Lorenz, Michael Schmalenberg, Stephan Kemmner, Bernhard Haller, Dominik Steubl, Dang Pham, Anita Schreiegg, Quirin Bachmann, Alina Schmidt, Sandra Haderer, Monika Huber, Susanne Angermann, Roman Günthner, Matthias Braunisch, Christine Hauser, Anna-Lena Reichelt, Julia Matschkal, Yana Suttmann, Philipp Moog, Konrad Stock, Claudius Küchle, Klaus Thürmel, Lutz Renders, Axel Bauer, Marcus Baumann, Uwe Heemann, Peter B. Luppa, Christoph Schmaderer
Journal: Kidney International (2017)
Radiation Studies of Women Treated for Benign Gynecologic Disease
Authors: John D. Boice, Jr, Sc.D., Ruth A. Kleinerman, M.P.H.
Journal: JNCI Journal of the National Cancer Institute (1986)

Radiation Studies of Women Treated for Benign Gynecologic Disease Get access John D. Boice, Jr, Sc.D., John D. Boice, Jr, Sc.D. Radiation Epidemiology Branch, Epidemiology and Biostatistics Program, Division of Cancer Etiology, National Cancer Institute, National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, Bethesda, Maryland 20892 Search for other works by this author on: Oxford Academic PubMed Google Scholar Ruth A. Kleinerman, M.P.H. Ruth A. Kleinerman, M.P.H. Radiation Epidemiology Branch, Epidemiology and Biostatistics Program, Division of Cancer Etiology, National Cancer Institute, National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, Bethesda, Maryland 20892 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 76, Issue 3, March 1986, Pages 4549, https://doi.org/10.1093/jnci/76.3.549 Published: 01 March 1986
The interaction of hip and foot biomechanics in the presentation and management of patellofemoral pain
Authors: Simon Lack
Journal: British Journal of Sports Medicine (2017)

My thesis, consisting of six independent studies, investigated whether the interaction of hip and foot biomechanics better explains patellofemoral pain (PFP) presentation and management and could be used to inform feasibility studies delivering biomechancially tailored interventions for individuals with this recalcitrant condition.

PFP remains one of the most common conditions within sports medicine, orthopaedic and general practice settings.1 Long-term treatment outcomes are poor and emerging evidence indicates PFP may be on a continuum with patellofemoral osteoarthritis.2 Delivering tailored interventions, directed at the hip and foot, that reflected mine and others clinical practice has been proposed as an approach that improves patient outcome.3 To achieve patient-specific intervention, a greater understanding of effective treatments and the mechanisms of these effects was required.

I conducted two systematic reviews with meta-analysis to (Study 1) identify predictors of conservative management outcomes …
Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma
Authors: M. Schlumberger, R. Elisei, S. Müller, P. Schöffski, M. Brose, M. Shah, L. Licitra, J. Krajewska, M.C. Kreissl, B. Niederle, E.E.W. Cohen, L. Wirth, H. Ali, D.O. Clary, Y. Yaron, M. Mangeshkar, D. Ball, B. Nelkin, S. Sherman
Journal: Annals of Oncology (2017)

Primary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up.
Mobilizing Transit-Amplifying Cell-Derived Ectopic Progenitors Prevents Hair Loss from Chemotherapy or Radiation Therapy
Authors: Wen-Yen Huang, Shih-Fan Lai, Hsien-Yi Chiu, Michael Chang, Maksim V. Plikus, Chih-Chieh Chan, You-Tzung Chen, Po-Nien Tsao, Tsung-Lin Yang, Hsuan-Shu Lee, Peter Chi, Sung-Jan Lin
Journal: Cancer Research (2017)

Abstract Genotoxicity-induced hair loss from chemotherapy and radiotherapy is often encountered in cancer treatment, and there is a lack of effective treatment. In growing hair follicles (HF), quiescent stem cells (SC) are maintained in the bulge region, and hair bulbs at the base contain rapidly dividing, yet genotoxicity-sensitive transit-amplifying cells (TAC) that maintain hair growth. How genotoxicity-induced HF injury is repaired remains unclear. We report here that HFs mobilize ectopic progenitors from distinct TAC compartments for regeneration in adaptation to the severity of dystrophy induced by ionizing radiation (IR). Specifically, after low-dose IR, keratin 5+ basal hair bulb progenitors, rather than bulge SCs, were quickly activated to replenish matrix cells and regenerated all concentric layers of HFs, demonstrating their plasticity. After high-dose IR, when both matrix and hair bulb cells were depleted, the surviving outer root sheath cells rapidly acquired an SC-like state and fueled HF regeneration. Their progeny then homed back to SC niche and supported new cycles of HF growth. We also revealed that IR induced HF dystrophy and hair loss and suppressed WNT signaling in a p53- and dose-dependent manner. Augmenting WNT signaling attenuated the suppressive effect of p53 and enhanced ectopic progenitor proliferation after genotoxic injury, thereby preventing both IR- and cyclophosphamide-induced alopecia. Hence, targeted activation of TAC-derived progenitor cells, rather than quiescent bulge SCs, for anagen HF repair can be a potential approach to prevent hair loss from chemotherapy and radiotherapy. Cancer Res; 77(22); 6083–96. ©2017 AACR.