tbuckley/cabot-search huggingface dataset:
Why we should focus on the burden of injuries and illnesses, not just their incidence
Authors: Roald Bahr, Benjamin Clarsen, Jan Ekstrand
Journal: British Journal of Sports Medicine (2017)

More and more sports medicine clinicians are taking an active approach to prevent injury and illness within their team.1–3 The first steps in developing a risk management plan is risk estimation and assessment.4–7 In this phase, the main questions are: what injuries can we expect? Or illnesses? And which are the most serious? Another question is: when is injury risk the greatest? The purpose is to identify which problems need to be focused on in a risk management plan in order to mitigate risk.

These questions can be answered by establishing continuous injury surveillance within the team or by reviewing data from epidemiological studies on teams from a similar level.6 7 However, as a practitioner, you need to know how to interpret such data, whether they are your own or from others.

A number of consensus statements have been published to encourage consistency in how injuries are defined and reported in epidemiological studies, initially on cricket (2005, updated in 2016),8 9 followed by football (2006)10 and several other sports such as rugby (2007),11 tennis (2009),12 athletics (2014)13 and aquatic sports (2016).14 In general, these recommend that the rate of injury should be reported as injury incidence, calculated as number of injuries per 1000 hours of exposure. This recommendation has since been followed by the vast majority of surveillance studies, and incidence is typically also the main outcome used to compare sports, genders, age groups and so on. However, we argue that focusing on injury/illness incidence alone may give an incomplete and even erroneous picture of risk.

It should be noted that the consensus statements also recommend that injury severity be reported, generally as the number of days from the date of injury to the date of the player’s return to full participation. …
Alternative splicing induced by ionizing radiation and transcriptional profiling of radiosensitive cancer patients
Authors: Carl Sprung, Deborah Davey, Su Kah Goh, Michael McKay
Journal: Cancer Research (2008)

1460   We are characterizing the transcriptional response to ionizing radiation with particular interest in whole transcriptome alternative splicing. We have used human exon arrays to interrogate the genome for radiation-induced transcriptional expression products in human lymphoblastoid cell lines and primary fibroblasts at both the gene and exon levels. We have identified novel ionizing radiation-regulated gene expression products many of which have been validated by PCR-based techniques. In addition to quantitative changes of full length transcripts, identification of a large number of alternative splicing events were evident, many of which are previously uncharacterised, and that preferentially occur following ionizing radiation exposure. Likewise, we have conducted experiments to explore the transcriptional profile of radiation sensitive patients using these same cell types. We used cell lines from non-radiosensitive cancer patients as controls. We have identified gene expression profiles of radiosensitive patient cell lines and have identified alternative splicing products as well as gene expression differences that are unique to radiosensitive patient cell lines following treatment with ionizing radiation. We also are able to compare the transcriptional responses between these two cell types which will assist in exploring cell-type specific versus global responses. In conclusion, these results could lead to a better understanding of the radiation response and may enable the individualization of radiotherapy to optimize tumor control.
Initial efficacy of anti-lymphocyte activation gene-3 (anti–LAG-3; BMS-986016) in combination with nivolumab (nivo) in pts with melanoma (MEL) previously treated with anti–PD-1/PD-L1 therapy.
Authors: Paolo Antonio Ascierto, Ignacio Melero, Shailender Bhatia, Petri Bono, Rachel E. Sanborn, Evan J. Lipson, Margaret K. Callahan, Thomas Gajewski, Carlos A. Gomez-Roca, F. Stephen Hodi, Giuseppe Curigliano, Marta Nyakas, Matthias Preusser, Yoshinobu Koguchi, Matthew Maurer, Raphael Clynes, Priyam Mitra, Satyendra Suryawanshi, Eva Muñoz-Couselo
Journal: Journal of Clinical Oncology (2017)

9520 Background: Signaling via LAG-3 and other T-cell inhibitory receptors (eg, PD-1) can lead to T-cell dysfunction and tumor immune escape. Simultaneous blockade of LAG-3 + PD-1 may synergistically restore T-cell activation and enhance antitumor immunity. In a phase 1/2a study, BMS-986016 (IgG4 mAb targeting LAG-3) ± nivo (IgG4 mAb targeting PD-1) demonstrated tolerability, peripheral T-cell activation, and preliminary clinical activity (NCT01968109; Lipson E, et al. J Immunother Cancer. 2016;4[s1]:173 [P232]). Here we describe preliminary efficacy of BMS-986016 + nivo in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, along with updated safety from all dose expansion pts. Methods: Pts with MEL must have had prior anti–PD-1/PD-L1 (± anti–CTLA-4 or BRAF/MEK inhibitors) and progressive disease (PD). Pts received BMS-986016 80 mg + nivo 240 mg IV Q2W. Primary objectives were safety and objective response rate (ORR; complete [CR] + partial [PR] response), disease control rate (DCR; CR + uCR + PR + uPR + stable disease [SD] &gt; 12 wk), and duration of response (RECIST v1.1). Results: At data cutoff, 43 pts with MEL had been treated with BMS-986016 + nivo following PD on/after prior anti–PD-1/PD-L1 with known prior best responses of 1 CR, 9 PR, 12 SD, and 16 PD. Of the 43 pts, 30 (70%) also had prior anti–CTLA-4, 20 (47%) had ≥ 3 prior therapies, and 15 (35%) had BRAFmutations .In the 31 efficacy-evaluable pts to date, ORR was 16% (confirmed/unconfirmed) and DCR was 45% with benefit observed even in some pts refractory to prior anti–PD-1. Evaluations are ongoing for most pts, with median treatment duration of 10 wk for all 43 pts. Immunopathologic (eg, PD-1/PD-L1 and LAG-3 expression) and clinical characteristics of responders vs nonresponders will be presented. Any grade and grade 3/4 treatment-related AEs occurred in 46% and 9%, respectively, across all dose expansion pts (n = 129). Conclusion: Addition of BMS-986016 to nivolumab demonstrates encouraging initial efficacy in pts with MEL whose disease progressed on/after prior anti–PD-1/PD-L1 therapy, and a safety profile similar to nivolumab monotherapy. Clinical trial information: NCT01968109.
Abstract 15640: A Digenic Etiology Implicates Alpk3 and Myl2 Variants as Likely Causal Mutations in Familial Hypertrophic Cardiomyopathy
Authors: Lili Li, Yanli Tan, James T Willerson, Ali J Marian
Journal: Circulation (2016)

Introduction:  Familial Hypertrophic Cardiomyopathy (FHCM) is an autosomal dominant single gene disorder, commonly caused by mutations in genes encoding sarcomere proteins. Despite genetic testing by whole exome sequencing (WES), the causal genes in approximately 40% of the FHCM remain unknown.   Hypothesis:  A subset of FHCM is digenic in etiology and hence, the affected individual do not share a single causal variant.   Methods:  WES of FHCM trios, rare variant analysis and sequencing of additional family members.   Results:  We identified 6 FHCM trios in whom WES did not identify a shared causal variant in the known FHCM genes. The WES data were filtered for the heterozygous Loss of Function (LoF), defined as stop gain/loss, splice and frameshift, variants and rare pathogenic missense (MAF ALPK3  gene, implicated in cardiomyopathies, was shared among the affected trios (mother and two offspring). The offspring but not the mother also shared a pathogenic variant (p.A13T) in the  MYL2  gene, a known gene for FHCM. The p.A13T variant was inherited from siblings father, who had cardiac hypertrophy and aortic stenosis. Siblings digenic for the p.A13T and p.T81M variants had severe FHCM, heart failure, and severe left ventricular outflow tract obstruction (mean gradient >100 mmHg). In contrast, family members with the  ALPK3  variant had no or mild cardiac hypertrophy and were asymptomatic. The trio also shared other rare LoF and pathogenic variants, including a p.E2272X variant in  COL6A5  and p.L1228I variant in  PPRC1,  which are expressed at low levels in the heart and were less likely to cause cardiac pathology.   Conclusions:  Rare variant analysis of the WES data in the affected FHCM trios with no shared pathogenic variants in the known FHCM genes led to identification of pathogenic variants in  ALKP3  and  MYL2  as the likely causal variants. The findings suggest that a subset of FHCM might be digenic in etiology. Thus, the “missing causal genes” in the conventionally considered single gene disorders might be in part due to a digenic etiology.
Syphilis and gonorrhoea in the Czech Republic
Authors: H Zákoucká, V Polanecký, V Kaštánková
Journal: Eurosurveillance (2004)

Syphilis remains a public health problem in the Czech Republic and worldwide. The Czech Republic--until 1993 a part of Czechoslovakia--has a long tradition in public health activities, and STI surveillance is mainly focused on the infections traditionally called venereal diseases--syphilis, gonorrhoea, chancroid, and lymphogranuloma venereum. Campaigns from the early 1950s, were successful in controlling syphilis and gonorrhoea; and chancroid and lymphogranuloma venereum infections are extremely rare. In late 1980s, a low incidence of newly reported syphilis cases was achieved (100-200 cases annually), while around 6500 cases of gonorrhoea were recorded annually during the same period. Health care and prevention of STI diseases in the Czech Republic are based on close cooperation between clinical departments and laboratory and epidemiological services of Environmental Health Offices. Annual statistics showing data on reported cases of 'venereal diseases', based on ICD-10 codes, are available from 1959. Separate statistical data on other STIs are not available, and aggregated numbers only for Chlamydia trachomatis infections have been presented annually since 2000. Following the political and social changes in the Czech community in 1989, a distinct increase of syphilis was recorded. Between 50% and 60% of notified cases were classified as late latent or of unknown duration. The continuing annual occurrence of congenital syphilis (7-18 cases per year) reported during the 1990s has also been a very serious phenomenon. Cases have been concentrated in large urban areas with a high level of commercial sex activity, and a high proportion of cases is also noted in refugees. While the annual incidence of gonorrhoea gradually decreased from 1994 to 2001 (from 28.5 to 8.9 per 100,000 population), the incidence of syphilis increased in this period from 3.6 to 9.6 per 100,000 population (the highest value was 13.4 in 2001) and in 2000, for the first time in many years, it exceeded the incidence of gonorrhoea.
Phase II clinical and molecular trial of oral ENMD-2076 in clear cell ovarian cancer (CCOC): A study of the Princess Margaret phase II consortium.
Authors: Stephanie Lheureux, Julia V. Burnier, Qian Tan, Yada Kanjanapan, Blaise Clarke, Anna Tinker, Prafull Ghatage, Neesha C. Dhani, Marcus O. Butler, Stephen Welch, Johanne Ingrid Weberpals, David Shao Peng Tan, Kelly Brooks, Janelle Ramsahai, Lisa Wang, Patricia Ann Shaw, Ming Sound Tsao, Swati Garg, Tracy Stockley, Amit M. Oza
Journal: Journal of Clinical Oncology (2017)

5522 Background: CCOC is a rare chemoresistant subtype of OC. ENMD-2076 is an oral multi-target kinase inhibitor with antiangiogenic/antiproliferative profile; selective activity against the mitotic kinase Aurora A and VEGFRs, FGFRs. Methods: This is a multi-center Phase II study of ENMD-2076 in pts with recurrent CCOC and prior platinum. Primary endpoints were ORR and 6-m PFS rate. Correlative analyses include ARID1A, PTEN expression by IHC and genome sequencing by custom capture library of 555 genes. Results: Completed study enrolled 40 pts – 37 evaluable, median age of 54 (39-78). 12 pts (31%) received prior radiation and 24 (62%), 11 (28%), 4 (10%) had 1, 2 or 3 lines of chemotherapy. Archival tissue was available for 36/37 pts. Best response was PR for 2 pts (1 unconfirmed), SD for 25 (68%) and PD for 10 (26%) pts. Median PFS was 3.7 months (m) (95%CI: 3.4-4.4). ENMD was well tolerated with main related AE: hypertension (21 pts - 8 G3), nausea (18 pts -1 G3) and diarrhea (17 pts - 4 G3). By IHC, median PFS (95%CI) in ARID1A loss (19 pts) was 4.1m (3.5-10.3) vs 3.6m (1.7-3.9) in ARID1A positive (17 pts) (p = 0.024). Whilst, by IHC, PTEN was loss in 20 pts; intact in 10 and heterogeneous in 6 pts; no difference in PFS was observed. By PI3KCA mutation status, median PFS (95%CI) in wild-type (WT) (12 pts) was 5m (3.4-19.3) vs 3.7m (167-4.4) in mutated group (20 pts) (p = 0.038). Molecular profiling showed variants in PI3KCA (27%), ARID1A (26%), TP53 (7%), BRIP1 (7%), ATM (11%), BRCA1 (5%), BRCA2 (3%), RAD50 (3%), PABL2 (1%), RAD51C (1%), FANCA (1%), CTNNB1 (3%).The patient with the longest treatment duration (22m) was PTEN WT, diploid PTEN, putative bi-allelic inactivation of ARID1A. Conclusions: The PFS at 6 months was 20% for the evaluable patients, 31% in ARID1A loss and 12% in ARID1A positive patients. Loss of ARID1A, a known negative prognostic factor, was correlated with better PFS on ENMD-2076. Additional molecular profiling of the baseline biopsy material is underway. Clinical trial information: NCT01914510.
Massive A-to-I RNA editing is common across the Metazoa and correlates with dsRNA abundance
Authors: Hagit T. Porath, Binyamin A. Knisbacher, Eli Eisenberg, Erez Y. Levanon
Journal: Genome biology (2017)

Adenosine to inosine (A-to-I) RNA editing is a post-transcriptional modification catalyzed by the ADAR (adenosine deaminase that acts on RNA) enzymes, which are ubiquitously expressed among metazoans. Technical requirements have limited systematic mapping of editing sites to a small number of organisms. Thus, the extent of editing across the metazoan lineage is largely unknown. Here, we apply a computational procedure to search for RNA-sequencing reads containing clusters of editing sites in 21 diverse organisms. Clusters of editing sites are abundant in repetitive genomic regions that putatively form double-stranded RNA (dsRNA) structures and are rarely seen in coding regions. The method reveals a considerable variation in hyper-editing levels across species, which is partly explained by differences in the potential of sequences to form dsRNA structures and the variability of ADAR proteins. Several commonly used model animals exhibit low editing levels and editing levels in primates is not exceptionally high, as previously suggested. Editing by ADARs is highly prevalent across the Metazoa, mostly targeting dsRNA structures formed by genomic repeats. The degree to which the transcriptome of a given species undergoes hyper-editing is governed by the repertoire of repeats in the underlying genome. The strong association of RNA editing with the long dsRNA regions originating from non-coding repetitive elements is contrasted by the almost non-existing signal seen in coding regions. Hyper-edited regions are rarely expressed in a non-edited form. These results support the notion that the main role of ADAR is to suppress the cellular response to endogenous dsRNA structures.
Downregulation of BRCA1 protein in clear cell renal cellular carcinoma
Authors: E. Sarnowska, N. Rusetska, M. Szymanski, I. Jancewicz, M. Chmielarczyk, R. Konopinski, M. Leszczynski, A. Chrzan, M. Ligaj, A. Maassen, T. Sarnowski, J. Siedlecki
Journal: Annals of Oncology (2017)
Double-blind, randomized phase 3 study to compare efficacy and safety of the biosimilar CT-P10 to rituximab combined with CVP therapy in patients with previously untreated advanced-stage follicular lymphoma.
Authors: Won Seog Kim, Wojciech Jurczak, Juan-Manuel Sancho, Edvard Javrid, Jin Seok Kim, Jose Angel Hernandez Rivas, Aliaksandr Prokharau, Mariana Vasilica, Rajnish Nagarkar, Dzhelil Osmanov, Christian Buske, Larry Kwak, Michinori Ogura, Sang Joon Lee, Sung Young Lee, Yunju Bae, Bertrand Coiffier
Journal: Journal of Clinical Oncology (2017)

7532 Background: CT-P10 is a biosimilar candidate to the innovator rituximab (RTX). In patients with rheumatoid arthritis, CT-P10 has demonstrated equivalence in pharmacokinetics (PK) and efficacy (Yoo, ACR 2016). This study aimed to demonstrate non-inferiority of efficacy and PK equivalence between CT-P10 and RTX in patients with newly diagnosed advanced follicular lymphoma (AFL) (NCT02162771). PK equivalence was confirmed (Coiffier, ASH 2016). Methods: A total of 140 patients were randomized in a 1:1 ratio to receive CT-P10 or RTX (375 mg/m 2 i.v) plus CVP (cyclophosphamide, vincristine, and prednisone) every 3 weeks over 8 cycles. Overall response rate (ORR) according to the 1999 IWG criteria over 24 weeks was assessed by the independent review committee. Results: Noninferiority of CT-P10 to RTX was shown for the primary efficacy endpoint of ORR. The ORR difference was 4.3% (Table) and the lower bound of the 95% confidence interval was -4.25%. B-cell depleted after the 1st infusion and remained as depleted over 8 cycles in both groups. Overall safety profile of CT-P10 was consistent with that of RTX and the proportion of patients with positive anti-drug antibody was similar in both groups (4.3% and 2.9%) for 24 weeks. Neither progressive multifocal leukoencephalopathy nor Hepatitis B virus reactivation was reported in each group. Conclusions: This study demonstrates noninferiority of efficacy of CT-P10 to RTX combined with CVP in previously untreated AFL. CT-P10 was well-tolerated and the safety profile including immunogenicity of CT-P10 was comparable to that of RTX over 8 cycles of induction period. Clinical trial information: NCT02162771. [Table: see text]
Adherence to International ESO-ESMO (ABC) guide-lines in HER2-ve metastatic breast cancer (MBC) patients (pts): Preliminary results of the GIM 13 - AMBRA Study
Authors: M. Cazzaniga, G. Mustacchi, M. Giordano, O. Garrone, M. Donadio, L. del mastro, L. Livi, C. Natoli, A. Michelotti, A. Turletti, R. Ferdinando, M. De Laurentiis, P. Marchetti, M. Montemurro, E. Romagnoli, S. De Placido, P. Pronzato, L. Biganzoli, G. Bisagni, E. Bria
Journal: Annals of Oncology (2017)
MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia
Authors: Nakhle S. Saba, Deanna H. Wong, Georges Tanios, Jessica R. Iyer, Patricia Lobelle-Rich, Eman L. Dadashian, Delong Liu, Lorena Fontan, Erik K. Flemington, Cydney M. Nichols, Chingiz Underbayev, Hana Safah, Ari Melnick, Adrian Wiestner, Sarah E. M. Herman
Journal: Cancer Research (2017)

Abstract The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway–dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV. Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease. Cancer Res; 77(24); 7038–48. ©2017 AACR.
Targeting anti-PD1-resistant tumors via indoleamine 2,3-dioxygenase 1 (IDO1) inhibition.
Authors: Ailin Li, Jonathan E. Schoenhals, Hampartsoum B. Barsoumian, Xiaohong Wang, David R. Valdecanas, Sharareh Niknam, Ann Klopp, Ahmed I. A. Younes, Daniel Richard Gomez, Joe Y. Chang, Ritsuko Komaki, Guang Li, Maria Angelica Cortez, James William Welsh
Journal: Journal of Clinical Oncology (2017)

e14103 Background: Anti-PD1 inhibitors are effective in only a subset of lung cancers, and many that respond later develop resistance. We recently found in a mouse model of anti-PD1 resistance that tumor-infiltrating lymphocytes (TILs) overexpressed indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting step in the catabolism of tryptophan (Trp) to kynurenine (Kyn) often implicated in immunosuppression. We tested whether inhibiting IDO would affect anti-PD1 mediated resistance. Methods: We used our anti-PD1-resistant lung cancer model (344SQ_R), which involved treating the parental 344SQ cells (344SQ_P) with anti-PD1 antibody followed by passage in 129SV/ev mice. We treated 344SQ_P and 344SQ_R mice with or without a selective IDO1 inhibitor (INCB023843) and measured tumor growth and lung metastasis. Plasma Trp and Kyn levels were tested by liquid chromatography–tandem mass spectrometry. TILs from blood and tumor-draining lymph nodes were isolated, analyzed by flow cytometry, and RNA was extracted for qPCR. Plasma C-C motif chemokine 22 (CCL22) levels were tested by ELISA. Data were analyzed with Prism 5.0 (GraphPad Software) and Flowjo V-10. Results: In untreated mice, IDO1 expression was 12 times higher in TILs from 344SQ_R mice than 344SQ_P mice, and mean plasma Kyn and Kyn/Trp levels were 3 times higher in 344SQ_R than in 344SQ_P. IDO inhibition was effective only in the PD1-resistant mice, reducing both tumor growth and lung metastasis. A subpopulation of myeloid-derived suppressor cells (Gr1 int/lo CD11b + F4/80 + ) showed the greatest increase in IDO1 expression when comparing 344SQ_R to 344SQ_P and decreased after INCB023843 treatment only in 344SQ_R. INCB023843 also increased infiltrating CD8 + T cells, decreased CCL22 and regulatory T cells only in 344SQ_R tumors. Conclusions: Our results suggest that IDO1 is overexpressed in TILs from tumors resistant to anti-PD1 therapy; that a high plasma Kyn/Try ratio may be a marker of anti-PD1 resistance; and that IDO1 inhibition could be a promising approach for treating lung cancer that does not respond to anti-PD1 therapy.
Abstract 17731: Persistence With Non-vitamin K Oral Anticoagulants And Vitamin K Antagonists Treatment: A Nationwide Study Of Danish Patients With Non-Valvular Atrial Fibrillation
Authors: Rikke Sørensen, Jannik L Pallisgaard, Berit J Nielsen, Kevin Bowrin, Christian Torp-Pedersen
Journal: Circulation (2016)

Introduction: Treatment with oral anticoagulation (OAC) in patients with atrial fibrillation (AF) has changed substantially since approval of Non-vitamin K oral anticoagulants (NOAC), but little is...
Mixed adeno-neuroendocrine carcinoma (MANEC) of the gastroenteropancreatic (GEP) tract: A multicentre retrospective study
Authors: M. Frizziero, X. Wang, B. Chakrabarty, A. Childs, T.V. Luong, T. Walter, M. Elshafie, T. Shah, P. Fulford, A. Minicozzi, W. Mansoor, T. Meyer, R.A. Hubner, J.W. Valle, M.G. McNamara
Journal: Annals of Oncology (2017)
Overall survival and quality of life in patients with metastatic breast cancer treated with nab-paclitaxel: Final results of the non-interventional study NABUCCO
Authors: K. Potthoff, A. Nusch, U. Söling, R. Hansen, C. Salat, S. Grebhardt, J. Harde, N. Marschner
Journal: Annals of Oncology (2017)