tbuckley/cabot-search huggingface dataset:
Abstract MIP-076: A RECURRENT BCAM-AKT2 FUSION GENE LEADS TO A CONSTITUTIVELY ACTIVATED AKT2 FUSION KINASE IN HIGH-GRADE SEROUS OVARIAN CARCINOMA
Authors: Kalpana Kannan, Cristian Coarfa, Pei-Wen Chao, Liming Luo, Yan Wang, Amy E. Brinegar, Shannon M. Hawkins, Aleksandar Milosavljevic, Martin M. Matzuk, Laising Yen
Journal: Clinical Cancer Research (2017)

Abstract High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. Excessive genomic rearrangements, which are expected to create fusion oncogenes, are the hallmark of this cancer. Using high-throughput RNAseq, we identify a cancer-specific gene fusion between BCAM, a membrane adhesion molecule, and AKT2, a key kinase in the PI3K signaling pathway. This fusion is present in 7% of the 60 patient cancers tested, a significant frequency considering the highly heterogeneous nature of this malignancy. Further, we provide direct evidence that BCAM-AKT2 is translated into an in-frame fusion protein in the patient's tumor. The resulting AKT2 fusion kinase is membrane-associated, constitutively phosphorylated, and activated as a functional kinase in cells. Unlike endogenous AKT2, whose activity is tightly regulated by external stimuli, BCAM-AKT2 escapes the regulation from external stimuli. Moreover, a BCAM-AKT2 fusion gene generated via chromosomal translocation using the CRISPR/Cas9 system leads to focus formation in both OVCAR8 and HEK-293T cell lines, suggesting that BCAM-AKT2 is oncogenic. Together, the results indicate that BCAM-AKT2 expression is a new mechanism of AKT2 kinase activation in HGSC. BCAM-AKT2 is the only fusion gene in HGSC that is proven to translate an aberrant yet functional kinase fusion protein with oncogenic properties. This recurrent genomic alteration is a potential therapeutic target and marker of a clinically relevant subtype for tailored therapy of HGSC. Citation Format: Kalpana Kannan, Cristian Coarfa, Pei-Wen Chao, Liming Luo, Yan Wang, Amy E. Brinegar, Shannon M. Hawkins, Aleksandar Milosavljevic, Martin M. Matzuk, and Laising Yen. A RECURRENT BCAM-AKT2 FUSION GENE LEADS TO A CONSTITUTIVELY ACTIVATED AKT2 FUSION KINASE IN HIGH-GRADE SEROUS OVARIAN CARCINOMA [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-076.
Diving Into Research of Biomedical Engineering in Scuba Diving
Authors: Tobias Cibis, Alistair McEwan, Arne Sieber, Bjoern Eskofier, John Lippmann, Karl Friedl, Michael Bennett
Journal: IEEE Reviews in Biomedical Engineering (2017)

The physiologic response of the human body to different environments is a complex phenomenon to ensure survival. Immersion and compressed gas diving, together, trigger a set of responses. Monitoring those responses in real time may increase our understanding of them and help us to develop safety procedures and equipment. This review outlines diving physiology and diseases and identifies physiological parameters worthy of monitoring. Subsequently, we have investigated technological approaches matched to those in order to evaluated their capability for underwater application. We focused on wearable biomedical monitoring technologies, or those which could be transformed to wearables. We have also reviewed current safety devices, including dive computers and their underlying decompression models and algorithms. The review outlines the necessity for biomedical monitoring in scuba diving and should encourage research and development of new methods to increase diving safety.
Five sentence letter from 1980 helped create US opioid addiction crisis, study concludes
Authors: Michael McCarthy
Journal: BMJ (2017)

Uncritical citation of a five sentence long letter published in the New England Journal of Medicine nearly four decades ago helped create the opioid misuse crisis now facing the US, researchers argue in a new study published in the journal last week.12 Citation of the letter reduced physicians’ concern that long term opioid treatment was associated with a significant risk of addiction, the researchers said.

“Our findings highlight the potential consequences of inaccurate citation and underscore the need for diligence when citing previously published studies,” they wrote.

Until the 1990s US doctors were generally reluctant to prescribe opioids for non-cancer pain. But after an industry funded effort to promote more liberal use of opioids, particularly for chronic, non-cancer pain, prescriptions for opioids rose sharply, nearly quadrupling between 1999 and 2014. …
PEAK PLANTAR FORCE IN ELITE SOCCER PLAYERS FOLLOWING ACL RECONSTRUCTION: GREATER SYMMETRY AFTER 9 MONTHS WHEN RUNNING
Authors: Athol Thomson, Rod Whiteley, Einar Einarsson, Chris Bleakley
Journal: British Journal of Sports Medicine (2017)

Background Meeting specific objective discharge criteria after ACL reconstruction (ACLR) or delaying return to sport (RTS) until nine months post ACLR decreases the risk of re-injury. Objective Compare plantar forces during running in two groups of soccer players: cases (5–10 months post ACLR) vs controls (no history of ACLR).We also undertook within subjects comparison (injured vs uninjured limb). Players were arbitrarily divided into two groups (≥9 months post ACLR or &lt;9 months post ACLR) and peak plantar forces and symmetry across different running speeds compared. Design Case-control study. Setting Elite male soccer players. Participants Sixteen football players (age 26±4 yrs, weight 74±6 kg, height 178±6 cm) post ACLR on completion of criteria based rehabilitation and 16 uninjured players (28±4 yrs, 77±9 kg, 179±6 cm) were recruited. Interventions In-shoe plantar force measured (Novel PedarX) while running on a treadmill at 12,14, and 16 km/h. Main Outcome Measurements Peak plantar forces of the injured and uninjured limbs in athletes &lt;9 months post-ACLR and those ≥9 months ACLR were compared. Negative vales indicate relatively lower peak forces on the injured leg. Normative data was collected in uninjured players for comparison (N=16). Results Increasing asymmetry for peak plantar force was demonstrated at all running speeds in athletes &lt;9 months post ACLR (n=11) compared to athletes ≥9 months (n=5). Increasing asymmetry was seen with increasing running speed and peaked at 16 km/h −32±11% asymmetry compared to −6±8%; ES=−2.8, p&lt;0.01. Controls showed substantially less asymmetry at each running speed than &lt;9 months ACLR players: 16 km/h (3.8±3% peak plantar force limb asymmetry). Conclusions Relative unloading of the ACLR limb is marked at higher running speeds for athletes &lt;9 months post ACLR despite having completed all functional criteria required to permit return to play. These preliminary findings may help add further objective criteria to guide RTS following ACLR.
Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A.
Authors: Sylvia Adams, Peter Schmid, Hope S. Rugo, Eric P. Winer, Delphine Loirat, Ahmad Awada, David W. Cescon, Hiroji Iwata, Mario Campone, Rita Nanda, Rina Hui, Giuseppe Curigliano, Deborah Toppmeyer, Joyce O'Shaughnessy, Sherene Loi, Shani Paluch-Shimon, Deborah Card, Jing Zhao, Vassiliki Karantza, Javier Cortes
Journal: Journal of Clinical Oncology (2017)

1008 Background: In KEYNOTE-012, pembro showed durable activity and manageable safety in patients (pts) with PD-L1+ mTNBC. Cohort A of KEYNOTE-086 (NCT02447003) examined the efficacy/safety of pembro in previously treated mTNBC, regardless of PD-L1 expression. Methods: Pts with centrally confirmed mTNBC, ≥1 prior chemotherapy for metastatic disease, and ECOG PS 0-1 had pembro 200 mg Q3W for up to 24 mo; imaging q 9 wk for the first 12 mo, then q 12 wk. Clinically stable pts with PD could remain on pembro until PD confirmed on next assessment. Primary endpoints: ORR (RECIST v1.1, central review) in all pts and pts with PD-L1+ tumors, and safety. Secondary endpoints: DOR, disease control rate (DCR; CR + PR + SD ≥24 wk), PFS, and OS. Planned enrollment was 160 pts; analysis based on data as of Nov 10, 2016. Results: 60% of screened PD-L1-evaluable pts had PD-L1+ tumors (combined positive score ≥1%). Of 170 pts enrolled (100% women; median age 54 y), 44% had ≥3 prior lines of therapy, 51% had elevated LDH, 74% had visceral mets and 62% had PD-L1+ tumors. After a median follow-up of 10.9 mo, 9 (5%) pts remained on pembro. Treatment-related AEs (TRAEs) of any grade and grade 3-4 occurred in 60% and 12% of pts, respectively; 4% discontinued due to TRAEs. There were no deaths due to AE. Overall ORR was 5% regardless of PD-L1 expression (Table). Best overall response was 0.6% CR, 4% PR, 21% SD; not evaluable (3%). DCR was 8% (95% CI 4-13). Median DOR was 6.3 mo (range 1.2+ to 10.3+); 5 (63%) responders w/o PD at data cutoff. Median PFS and OS were 2.0 mo (95% CI 1.9-2.0) and 8.9 mo (95% CI 7.2-11.2), with 6-mo rates of 12% and 69%, respectively. ORR was numerically lower in pts with poor prognostic factors (e.g., high LDH, liver/visceral mets; Table). Conclusions: In KEYNOTE-086 Cohort A, pembro monotherapy showed manageable safety and durable responses in a subset of pts with heavily pretreated mTNBC. Randomized studies of monotherapy and combination therapy are ongoing. Clinical trial information: NCT02447003. [Table: see text]
Primate-Specific Long Non-Coding RNAs and MicroRNAs
Authors: Hassaan Mehboob Awan, Abdullah Shah, Farooq Rashid, Ge Shan
Journal: Genomics Proteomics & Bioinformatics (2017)

Abstract Non-coding RNAs (ncRNAs) are critical regulators of gene expression in essentially all life forms. Long ncRNAs (lncRNAs) and microRNAs (miRNAs) are two important RNA classes possessing regulatory functions. Up to date, many primate-specific ncRNAs have been identified and investigated. Their expression specificity to primate lineage suggests primate-specific roles. It is thus critical to elucidate the biological significance of primate or even human-specific ncRNAs, and to develop potential ncRNA-based therapeutics. Here, we have summarized the studies regarding regulatory roles of some key primate-specific lncRNAs and miRNAs.
Abstract TMEM-017: COLLAGEN TYPE XI ALPHA 1 (COL11A1) IS A NOVEL STROMAL MEDIATOR OF CHEMORESISTANCE
Authors: Miran Rada, Catherine Eldred, Jessica Sage, Sandra Orsulic, Dong-Joo Cheon
Journal: Clinical Cancer Research (2017)

Abstract Despite an initial satisfactory response to platinum and taxane-based regimens, approximately 80% of ovarian cancer patients will succumb to chemoresistant recurrent disease. Thus, there is a dire need to understand the mechanism by which tumor cells develop resistance to subsequent therapies after first-line cisplatin treatment. We previously identified that collagen type XI, alpha 1 (COL11A1) is a novel biomarker associated with poor survival, metastasis, and chemoresistance in ovarian cancer. COL11A1 is expressed in a subset of α-SMA-positive cancer-associated fibroblasts (CAFs) adjacent to tumor cells. COL11A1 expression in peritumoral CAFs increases during ovarian cancer progression, with the highest expression in recurrent tumors. However, the functional significance of stromal COL11A1 in ovarian cancer progression and chemoresistance is largely unknown. To determine the role of stromal COL11A1 in chemoresistance, we generated COL11A1-overexpressing TRS3 ovarian fibroblasts, co-cultured them with A2780 and OVCAR3 ovarian cancer cells, and measured cancer cell sensitivity to cisplatin. Our data showed that ovarian cancer cells become resistant to cisplatin when cultured in direct contact with COL11A1-overexpressing fibroblasts as well as in fibroblast conditioned media. Furthermore, full-length COL11A1 protein, extracted from A204 cell line, increased cisplatin resistance in ovarian cancer cells, suggesting that COL11A1 is sufficient to induce chemoresistance. Interestingly, culture of cancer cells on full-length COL11A1 protein resulted in increased number of ALDHhigh cancer stem-like cells and activation of Akt, the principal mediator of pro-survival signaling. To further dissect the mechanism by which COL11A1 leads to cisplatin resistance in tumor cells, we performed RNA-seq analysis of tumor cells after COL11A1 overexpression. Our data showed that COL11A1 did not change the levels of genes involved in cisplatin transport and DNA repair pathway in cancer cells, which are well-established mechanisms to confer cisplatin resistance. Rather, COL11A1 increased the expression of pro-inflammatory genes, some of which are known to confer chemoresistance in ovarian cancer. Consistently, our Western data showed that COL11A1 activates NF-kB signaling in cancer cells, a central pathway regulating pro-inflammatory genes. Collectively, our data suggest that COL11A1 contributes to chemoresistance possibly due to an increased survival of ALDHhigh cancer stem-like cells through activation of pro-inflammatory signaling. Citation Format: Miran Rada, Catherine Eldred, Jessica Sage, Sandra Orsulic and Dong-Joo Cheon. COLLAGEN TYPE XI ALPHA 1 (COL11A1) IS A NOVEL STROMAL MEDIATOR OF CHEMORESISTANCE [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr TMEM-017.
The efficacy of motivational counselling and SMS reminders on daily sitting time in patients with rheumatoid arthritis: a randomised controlled trial
Authors: Tanja Thomsen, Mette Aadahl, Nina Beyer, Merete Lund Hetland, Katrine Løppenthin, Julie Midtgaard, Robin Christensen, Mikkel Østergaard, Poul Jørgen Jennum, Bente Appel Esbensen
Journal: Annals of the Rheumatic Diseases (2017)

The aim of this report is to investigate the efficacy of an individually tailored, theory-based behavioural intervention for reducing daily sitting time, pain and fatigue, as well as improving health-related quality of life, general self-efficacy, physical function and cardiometabolic biomarkers in patients with rheumatoid arthritis (RA).In this randomised controlled trial 150 patients with RA were randomised to an intervention or a no-intervention control group. The intervention group received three individual motivational counselling sessions and short message service or text messages aimed at reduction of sedentary behaviour during the 16-week intervention period. Primary outcome was change in daily sitting time measured objectively by ActivPAL. Secondary outcomes included change in pain, fatigue, physical function, general self-efficacy, quality of life, blood pressure, blood lipids, haemoglobin A1c, body weight, body mass index, waist circumference and waist-hip ratio.75 patients were allocated to each group. Mean reduction in daily sitting time was -1.61 hours/day in the intervention versus 0.59 hours/day increase in the control group between-group difference -2.20 (95% CI -2.72 to -1.69; p<0.0001) hours/day in favour of the intervention group. Most of the secondary outcomes were also in favour of the intervention.An individually tailored, behavioural intervention reduced daily sitting time in patients with RA and improved patient-reported outcomes and cholesterol levels.NCT01969604; Results.
Evaluation of antiangiogenic therapy with bevacizumab in addition to neoadjuvant chemotherapy in the treatment of locally advanced breast cancer.
Authors: Erin McCammack, Reumu Birhiray
Journal: Journal of Clinical Oncology (2017)

e12115 Background: Anti-angiogenic therapy improves outcomes in cancer therapy; we hypothesized an improved outcome with the addition of bevacizumab to dose dense neoadjuvant chemotherapy (ddNAC) in the treatment of locally advanced breast cancer (LABC). Methods: We added bevacizumab to ddNAC in the pre-operative management of LABC. Eligible subjects signed an informed consent, had biopsy and radiographically confirmed stage II-III LABC and absence of major organ malfunction. ddNAC was comprised of docetaxel 35mg/M 2 intravenous (IV) on days 1 and 8, capecitabine 800mg/M 2 by mouth two times a day on days 1-14 and bevacizumab 15mg/kg IV repeated every 21 days for 4 cycles, followed with doxorubicin 60 mg/M 2 and cyclophosphamide 600mg/M 2 IV with peg-filgrastim 6mg given subcutaneously on day 1, every 14 days for 4 cycles (TX/ddAC). Subsequently, subjects underwent surgery and adjuvant radiation and/or hormonal therapy as clinically indicated. The primary objective was the pathologic complete response rate (pCR). As a secondary end point, we compared the rates of pCR with our prior study of the same chemotherapy regimen without bevacizumab (n = 52). Lastly, we evaluated the safety and tolerability of the regimen. Results: 34 subjects were enrolled and 31 completed the study. Using a modified intent to treat analysis, pCR with residual in-situ carcinoma (pCR inv ) was 3/31 (9.7%), total pCR 8/31 (25.8%), and residual invasive carcinoma 20/31 (64.5%). In comparison, our prior study results, presented at the 2006 San Antonio Breast Cancer Symposium, showed a pCR inv 7/52 (13.5%), total pCR 27/52 (52%), and rate of residual invasive carcinoma of 25/52 (48%). Observed toxicities included hand/foot syndrome, alopecia, nausea/vomiting, mucositis, neutropenia, febrile neutropenia, nail changes and hyperlacrimation. There was one treatment related death. Conclusions: The addition of bevacizumab to chemotherapy (TX/ddAC) did not improve the observed rates of pCR. However, the role of capecitabine in the neoadjuvant setting needs to be explored further. Moreover a post hoc analysis of the efficacy of the regimen in LABC subtypes is ongoing, with biologic correlates.
Race/Ethnicity and Cardiovascular Events Among Patients With Systemic Lupus Erythematosus
Authors: Medha Barbhaiya, Candace H. Feldman, Hongshu Guan, Jose A. Gómez‐Puerta, Michael A. Fischer, Daniel H. Solomon, Brendan Everett, Karen H. Costenbader
Journal: Arthritis & Rheumatology (2017)

Objective Systemic lupus erythematosus (SLE) is more prevalent and results in more severe outcomes among blacks, Asians, and Hispanics than among whites. Cardiovascular disease (CVD) is the leading cause of death among SLE patients. We undertook this study to examine racial/ethnic variations in risk of CVD events among SLE patients. Methods Within the Medicaid Analytic eXtract from 2000 to 2010, we identified patients ages 18–65 years with SLE (≥3 International Classification of Diseases, Ninth Revision 710.0 codes, ≥30 days apart) and with ≥12 months of continuous enrollment. Subjects were followed up from the index date to the first CVD event (myocardial infarction [MI] or stroke), death, disenrollment, loss to follow‐up, or end of follow‐up period. Race/ethnicity‐specific annual CVD event rates were calculated. Cox regression models estimated hazard ratios (HRs) with 95% confidence intervals (95% CIs), accounting for competing risk of death and adjusting for baseline demographics and comorbidities. Results Of 65,788 SLE patients, 93.1% were women and ∼42% were black, 38% were white, 16% were Hispanic, 3% were Asian, and 1% were American Indian/Alaska Native. Mean ± SD follow‐up was 3.8 ± 3.1 years. CVD event rates were highest among blacks (incidence rate [IR] 10.57 [95% CI 9.96–11.22]) and lowest among Asians (IR 6.63 [95% CI 4.97–8.85]). After multivariable adjustment, risk of CVD events was increased among blacks (HR 1.14 [95% CI 1.03–1.26]) compared to whites. Hispanics and Asians had a lower risk of MI (HR 0.61 [95% CI 0.48–0.77] and HR 0.57 [95% CI 0.34–0.96], respectively), while blacks and Hispanics had a higher risk of stroke (HR 1.31 [95% CI 1.15–1.49] and HR 1.22 [95% CI 1.03–1.44], respectively). Conclusion Among SLE patients enrolled in Medicaid, the risk of MI was lower among Hispanics and Asians compared to whites, while the risk of stroke was elevated among blacks and Hispanics compared to whites.
Italian Real Life Experience with Brentuximab Vedotin: Results of a National Observational Study on Relapsed/Refractory Hodgkin's Lymphoma
Authors: Alessandro Broccoli, Alessandro Pulsoni, Luigi Rigacci, Caterina Patti, Guido Gini, Donato Mannina, Monica Tani, Chiara Rusconi, Alessandra Romano, Anna Vanazzi, Barbara Botto, Armando Santoro, Stefan Hohaus, Gian Matteo Rigolin, Pellegrino Musto, Patrizio Mazza, Stefano Molica, Paolo Corradini, Angelo Fama, Francesco Gaudio, Michele Merli, Fioravante Ronconi, Giuseppe Gritti, Daniele Vallisa, Patrizia Tosi, Anna Marina Liberati, Antonello Pinto, Vincenzo Pavone, Filippo Gherlinzoni, Elena Cavalieri, Stefano Volpetti, Andrea Visentin, Maria Cecilia Goldaniga, Maurizio Bonfichi, Amalia De Renzo, Corrado Schiavotto, Michele Spina, Angelo Michele Carella, Lisa Argnani, Pier Luigi Zinzani
Journal: Blood (2016)
Outcome of acute Myeloid Leukemia in Adults Patients Treated According to Morocco National AML-MA-2011 Protocol in Casablanca, Morocco
Authors: Romaric Massi, Mouna Lamchahab, Hanaa Bencharef, Bienvenu Houssou, Nisrine Khoubila, Siham Cherkoui, Meryem Qachouh, Mohamed Rachid, Abdallah Madani, Uma H. Athale, Asmaa AQ Quessar
Journal: Blood (2016)
Diagnostic accuracy of a rapid E1-antigen test for chikungunya virus infection in a reference setting
Authors: R. Huits, T. Okabayashi, L. Cnops, B. Barbé, R. Van Den Berg, K. Bartholomeeusen, K.K. Ariën, J. Jacobs, E. Bottieau, E.E. Nakayama, T. Shioda, M. Van Esbroeck
Journal: Clinical Microbiology and Infection (2017)
Phase Ib study to assess the safety, tolerability, and clinical activity of gedatolisib in combination with palbociclib and either letrozole or fulvestrant in women with metastatic or locally advanced/recurrent breast cancer (B2151009; NCT02684032).
Authors: Andres Forero-Torres, Robert Wesolowski, Aditya Bardia, Haresh S. Jhangiani, Peter Kabos, Elizabeth Claire Dees, Kenneth Alan Kern, Rachelle Perea, Kristen J. Pierce, Hope S. Rugo
Journal: Journal of Clinical Oncology (2017)

TPS1113 Background: Hormone receptor positive (HR+) disease is the most common subset of both early and late stage breast cancer (BC). The majority of women with HR+ metastatic BC (MBC) ultimately develop resistance to endocrine therapy, with a median survival of ~2-3 years. A new standard-of-care strategy to treat HR+ metastatic disease involves the combination of hormone therapy and cyclin-dependent kinase (CDK) 4/6 inhibition, which has demonstrated improved progression-free survival (PFS) in both the first- and later-line metastatic setting. More recently, preclinical data with the dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor gedatolisib (PF-05212384) suggest synergy with the combination of hormone therapy, CDK 4/6 inhibition, and inhibition of the PI3K/mTOR pathway. Methods: This phase Ib study includes a dose escalation portion to evaluate dose-limiting toxicities (primary endpoint) and determine the recommended phase II dose for triplet therapy with gedatolisib combined with palbociclib/letrozole or palbociclib/fulvestrant in women with HR+ HER2-negative MBC or locally advanced/recurrent BC, in the first- and later-line setting. Thereafter, a 3-arm expansion for early signals of efficacy will investigate objective response rates (primary endpoint) with gedatolisib combined with palbociclib/letrozole (n = 26), palbociclib/fulvestrant in patients without prior CDK 4/6 inhibition (n = 28), and palbociclib/fulvestrant in patients who have previously received palbociclib (n = 27). The rates of objective response will be compared to historical controls. Secondary endpoints include safety, tumor response, PFS (expansion portion only), pharmacokinetics, and biomarker correlations associated with the PI3K/mTOR pathway. This trial is now recruiting. Clinical trial information: NCT02684032.