tbuckley/cabot-search huggingface dataset:
Prognostic Value and Determinants of CMR-Derived Left Atrial Function Assessed in STEMI
Authors: Jakob Ledwoch, Thomas Stiermaier, Georg Fuernau, Suzanne de Waha, Charlotte Eitel, Janine Pöss, Steffen Desch, Gerhard Schuler, Holger Thiele, Ingo Eitel
Journal: JACC. Cardiovascular imaging (2017)
Abstract 159: Beneficial Cardiac Effects of Caloric Restriction in a Murine Model of Obesity Are Attenuated with Age
Authors: Majd AlGhatrif, Vabren L Watts, Vidhya Sivakumaran, Xiaolin Niu, Marc Halushka, Karen L Miller, Konrad Vandegaer, Djahida Bedja, Karen Fox-Talbot, Alicja Bielawska, Nazareno Paolocci, Susan Aja, Kathleen L Gabrielson, Lili A Barouch
Journal: Circulation Research (2012)

Introduction: Obesity is associated with increased myocardial steatosis, cardiac dysfunction, mitochondrial uncoupling, and increased apoptosis. Caloric restriction (CR) in older leptin deficient ob/obobese micefails to reduce cardiac steatosis and apoptosis but improves mitochondrial function. This discordant response to caloric restriction and the role of aging in this process are not well understood. Methods: We studied 4 month (younger) and 8 month (older) old ob/ob mice and age matched C57BL/6J controls. In each age group, ob/ob mice were assigned to ad lib (AL-ob) or calorie restriction (CR-ob) for 4 weeks. We performed echocardiograms, myocardial triglyceride assays, Oil Red O staining, LC-MS/MS ceramide species measurements, and Western blots. Whole animal metabolism was measured using indirect calorimetry. Results: In younger mice, CR reversed the adverse cardiac effects of obesity by reducing heart weight and ventricular wall thickness, reversing myocardial steatosis measured by myocardial TG assay and Oil red O staining, and upregulating phosphorylation of Akt. This was associated with improvement in diastolic function demonstrated by reduction in isovolumetric relaxation time by echocardiography. In contrast, none of these beneficial changes were observed in the older mice. Whole animal metabolism showed that younger CR-ob mice had decreased respiratory exchange ratio compared to AL-ob, indicating greater reliance on fat as a source of energy. Interestingly, the effect of CR on lipotoxicity measured by the composition of ceramides was similar in both age groups. Conclusion: In this model of obesity, aging attenuates the benefits of CR on myocardial structure and function. This may be due to older animals’ decreased ability to reverse myocardial steatosis and/or accumulation of oxidative damage over time, and the loss of Akt activation with age.
Aerobic exercise promotes executive functions and impacts functional neural activity among older adults with vascular cognitive impairment
Authors: Chun Liang Hsu, John R Best, Jennifer C Davis, Lindsay S Nagamatsu, Shirley Wang, Lara A Boyd, GY Robin Hsiung, Michelle W Voss, Janice Jennifer Eng, Teresa Liu-Ambrose
Journal: British Journal of Sports Medicine (2017)

Background Vascular cognitive impairment (VCI) results from cerebrovascular disease, and worldwide, it is the second most common type of cognitive dysfunction. While targeted aerobic training is a promising approach to delay the progression of VCI by reducing cardiometabolic risk factors, few randomised controlled trials to date have specifically assessed the efficacy of aerobic training on cognitive and brain outcomes in this group at risk for functional decline. Aim To examine the effect of moderate-intensity aerobic training on executive functions and functional neural activity among older adults with mild subcortical ischaemic VCI (SIVCI). Methods Older adults with mild SIVCI were randomly assigned to: (1) 6-month, 3×/week aerobic training (n=10) or (2) usual care (control; n=11). Participants completed functional MRI (fMRI) at baseline and trial completion. During the fMRI sessions, behavioural performance on the Eriksen flanker task and task-evoked neural activity were assessed. Results At trial completion, after adjusting for baseline general cognition, total white matter lesion volume and flanker performance, compared with the control group, the aerobic training group significantly improved flanker task reaction time. Moreover, compared with the controls, the aerobic training group demonstrated reduced activation in the left lateral occipital cortex and right superior temporal gyrus. Reduced activity in these brain regions was significantly associated with improved (ie, faster) flanker task performance at trial completion. Summary Aerobic training among older adults with mild SIVCI can improve executive functions and neural efficiency of associated brain areas. Future studies with greater sample size should be completed to replicate and extend these findings.
Woman With Yellow Palms and Soles
Authors: Zhong-Shuai Wang, Xiao-Ke Liu, Jun Li
Journal: JAMA (2017)

A woman presented with 6 months of yellowing skin on her palms and soles 6 months after beginning to take beta carotene supplements. She had no scleral icterus; liver enzyme and bilirubin values were normal, as were results of thyroid function tests. What would you do next?
Consensus Statement of the European Urology Association and the European Urogynaecological Association on the Use of Implanted Materials for Treating Pelvic Organ Prolapse and Stress Urinary Incontinence
Authors: Christopher R. Chapple, Francisco Cruz, Xavier Deffieux, Alfredo L. Milani, Salvador Arlandis, Walter Artibani, Ricarda M. Bauer, Fiona Burkhard, Linda Cardozo, David Castro-Diaz, Jean Nicolas Cornu, Jan Deprest, Alfons Gunnemann, Maria Gyhagen, John Heesakkers, Heinz Koelbl, Sheila MacNeil, Gert Naumann, Jan-Paul W.R. Roovers, Stefano Salvatore, Karl-Dietrich Sievert, Tufan Tarcan, Frank Van der Aa, Francesco Montorsi, Manfred Wirth, Mohamed Abdel-Fattah
Journal: European Urology (2017)
A phase I study of twice weekly pulse dose and daily low dose erlotinib as initial treatment for patients (pts) with EGFR-mutant lung cancers.
Authors: Helena Alexandra Yu, Camelia S. Sima, Dalicia Reales, Shomari Jordan, Charles M. Rudin, Mark G. Kris, Franziska Michor, William Pao, Gregory J. Riely
Journal: Journal of Clinical Oncology (2015)

8017 Background: Pts with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKI) develop clinical resistance, most frequently due to acquisition of EGFR T790M. Modeling suggests that a twice weekly pulse dose, and daily low dose erlotinib schedule may delay the emergence of EGFR T790M. Pulse dose erlotinib may have superior central nervous system (CNS) penetration. Methods: We evaluated toxicity, pharmacokinetics, and efficacy of twice weekly pulse-dose and daily low dose erlotinib in pts with EGFR-mutant lung cancers (NCT01967095). Using a 3+3 dose escalation, we assessed escalating pulse doses of erlotinib on days 1 -2 (D1-2), and 50mg low-dose erlotinib on days 3-7 (D3-7) weekly. Six pulse dose levels of erlotinib were tested: 600, 750, 900, 1050, 1200, and 1350 mg. Response was evaluated by RECIST 1.1. After the maximum tolerated dose (MTD) was determined, we treated an additional 10 pts at the MTD. Results: From Nov 2013 to January 2015, 34 pts were enrolled. Median age: 60; Women: 20 (59%); never-smoker: 23 (68%); EGFR L858R: 11 (24%) and Ex19del: 22 (65%). Three DLTs were seen: transaminitis (1050mg), mucositis (1350mg) and rash (1350mg) during the dose-escalation period. The MTD was determined to be erlotinib 1200mg D1, D2 and 50mg D3-7 weekly. In total, 16 pts were treated at the MTD. Treatment-related AEs were all grade 1-3. The most frequent treatment-emergent AEs (any grade) were rash (85%), diarrhea (79%), elevated AST (50%) and nausea (41%). Of the 16 pts treated at the MTD, 3 (19%) required a dose reduction of the pulse dose. Of 27 evaluable patients, 22 partial responses were seen (81%). Median-progression free survival is 11 months. 17 pts remain on study. 8 (24%) pts came off for progression, 7 (21%) for toxicity and 2 (6%) for non-adherence. Of those who progressed, 5/8 (62%) had EGFR T790M identified upon rebiopsy (none at MTD). Twelve pts (35%) had CNS disease at diagnosis; no pts came off study due to progressive or new CNS metastases. Conclusions: This kinetics-based EGFR TKI dosing schedule of pulse-continuous erlotinib was well-tolerated. TKI dose optimization may enhance efficacy. Further studies are planned in pts with brain metastases. Clinical trial information: NCT01967095.
Targetable kinase gene fusions in high-risk B-ALL: a study from the Children’s Oncology Group
Authors: Shalini C. Reshmi, Richard C. Harvey, Kathryn G. Roberts, Eileen Stonerock, Amy Smith, Heather Jenkins, I-Ming Chen, Marc Valentine, Yu Liu, Yongjin Li, Ying Shao, John Easton, Debbie Payne-Turner, Zhaohui Gu, Thai Hoa Tran, Jonathan V. Nguyen, Meenakshi Devidas, Yunfeng Dai, Nyla A. Heerema, Andrew J. Carroll, Elizabeth A. Raetz, Michael J. Borowitz, Brent L. Wood, Anne L. Angiolillo, Michael J. Burke, Wanda L. Salzer, Patrick A. Zweidler-McKay, Karen R. Rabin, William L. Carroll, Jinghui Zhang, Mignon L. Loh, Charles G. Mullighan, Cheryl L. Willman, Julie M. Gastier-Foster, Stephen P. Hunger
Journal: Blood (2017)
Comparable survival for nonablative and ablative allogeneic transplantation for chronic lymphocytic leukemia (CLL): The case for early intervention
Authors: Issa F Khouri, Mark Munsell, Salim Yajzi, Susan O'Brien, Sergio Giralt, Martin Korbling, Cindy Ippoliti, Michèle Donato, Michael Keating, Richard E Champlin
Journal: Blood (2000)
PEGylation rate influences peptide-based nanoparticles mediated siRNA delivery in vitro and in vivo
Authors: Gudrun Aldrian, Anaïs Vaissière, Karidia Konate, Quentin Seisel, Eric Vivès, Frédéric Fernandez, Véronique Viguier, Coralie Genevois, Franck Couillaud, Héléne Démèné, Dina Aggad, Aurélie Covinhes, Stéphanie Barrère-Lemaire, Sébastien Deshayes, Prisca Boisguerin
Journal: Journal of Controlled Release (2017)
Whole-Exome Sequencing of Metaplastic Breast Carcinoma Indicates Monoclonality with Associated Ductal Carcinoma Component
Authors: Bracha Erlanger Avigdor, Katie Beierl, Christopher D. Gocke, Daniel J. Zabransky, Karen Cravero, Kelly Kyker-Snowman, Berry Button, David Chu, Sarah Croessmann, Rory L. Cochran, Roisin M. Connolly, Ben H. Park, Sarah J. Wheelan, Ashley Cimino-Mathews
Journal: Clinical Cancer Research (2017)

Although most human cancers display a single histology, there are unusual cases where two or more distinct tissue types present within a primary tumor. One such example is metaplastic breast carcinoma, a rare but aggressive cancer with a heterogeneous histology, including squamous, chondroid, and spindle cells. Metaplastic carcinomas often contain an admixed conventional ductal invasive or
Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined non-small cell lung cancer (NSCLC) patients.
Authors: Jacques De Greve, Teresa Moran, Marie-Pascale Graas, Daniella Galdermans, Peter Vuylsteke, Jean-Luc Canon, Vikram K. Chand, Yali Fu, Dan Massey, Johan Vansteenkiste
Journal: Journal of Clinical Oncology (2013)

8063 Background: EGFR mutation+ (M+) NSCLC pts have an improved response to EGFR TKIs vs non-M+ pts. Data on EGFR FISH+ (gene amplified) and HER2 M+ pts are, however, limited. Afatinib is an irreversible ErbB Family Blocker with efficacy in Ph II/III trials in EGFR M+ NSCLC. This exploratory, open-label trial assessed afatinib in 3 genotypically and demographically defined NSCLC groups. Methods: Never/ex-smokers with stage IIIB/IV lung adenocarcinoma with EGFR M+ tumors who had failed prior EGFR TKIs, HER2 M+ tumors independent of prior therapy, or EGFR FISH+ tumors who received ≤3 prior chemotherapies were enrolled. Afatinib 50 mg qd was administered until disease progression or intolerable adverse events. Tumor assessments (RECIST 1.0) were performed every 8 wks. Pts who progressed on afatinib but experienced clinical benefit could continue treatment with afatinib 40 mg qd + paclitaxel 80 mg/m² qw on days 1, 8 and 15 every 28-day cycle. Primary endpoint: Confirmed objective response. Results: 41 pts were treated: 63% female; median age 63 yrs; 68% never smokers; 32% ex-smokers. 33 pts received afatinib monotherapy only; 8 pts received afatinib followed by afatinib/paclitaxel combination therapy. 78% (n=32) of pts were EGFR M+, 5% (n=2) were EGFR FISH+ and 17% (n=7) were HER2 M+. For afatinib monotherapy, 1 confirmed partial response (PR) was observed (EGFR FISH+), stable disease (SD) was seen in 5/7 HER2 M+, 2/2 EGFR FISH+ and 17/32 EGFR M+ pts, and overall disease control (DC) rate was 59% (n=24); mean duration of DC was 26 wks.Median PFS was 16 wks (17 wks in HER2 M+ pts). Of 8 afatinib/paclitaxel-treated pts, 1 had a confirmed PR and 2 had SD; median PFS was 7 wks. Most frequently reported drug-related AEs in afatinib monotherapy pts were diarrhea (n=39; grade ≥3 n=13), rash/acne (n=33; grade ≥3 n=4) and stomatitis (n=19; grade ≥3 n=2). In the combination arm these were diarrhea (n=4; grade ≥3 n=1) and nausea (n=3; grade ≥3 n=0). Conclusions: Efficacy of afatinib in EGFR M+ NSCLC pts has been established in previous trials. Novel activity of afatinib in HER2 M+ and EGFR FISH+ NSCLC pts has been demonstrated here, with a manageable safety profile of afatinib in the overall population. Clinical trial information: NCT00730925.
SSRP1 Cooperates with PARP and XRCC1 to Facilitate Single-Strand DNA Break Repair by Chromatin Priming
Authors: Ying Gao, Changling Li, Leizhen Wei, Yaqun Teng, Satoshi Nakajima, Xiukai Chen, Jianquan Xu, Brittany Leger, Hongqiang Ma, Stephen T. Spagnol, Yong Wan, Kris Noel Dahl, Yang Liu, Arthur S. Levine, Li Lan
Journal: Cancer Research (2017)

Abstract DNA single-strand breaks (SSB) are the most common form of DNA damage, requiring repair processes that to initiate must overcome chromatin barriers. The FACT complex comprised of the SSRP1 and SPT16 proteins is important for maintaining chromatin integrity, with SSRP1 acting as an histone H2A/H2B chaperone in chromatin disassembly during DNA transcription, replication, and repair. In this study, we show that SSRP1, but not SPT16, is critical for cell survival after ionizing radiation or methyl methanesulfonate–induced single-strand DNA damage. SSRP1 is recruited to SSB in a PARP-dependent manner and retained at DNA damage sites by N-terminal interactions with the DNA repair protein XRCC1. Mutational analyses showed how SSRP1 function is essential for chromatin decondensation and histone H2B exchange at sites of DNA strand breaks, which are both critical to prime chromatin for efficient SSB repair and cell survival. By establishing how SSRP1 facilitates SSB repair, our findings provide a mechanistic rationale to target SSRP1 as a general approach to selectively attack cancer cells. Cancer Res; 77(10); 2674–85. ©2017 AACR.
Mario Bizzini #TranslatingInjuryPrevention #SuperMario
Authors: Johann Windt
Journal: British Journal of Sports Medicine (2017)

Academically, finishing my PhD back in 2010 in Oslo, Norway. Sharing the moment with my family, friends and colleagues.

As a sports physio, reaching the playoff finals of the Swiss Pro ice hockey championship with ‘my’ team (despite losing the Cup in game 7).

My cousin Lucio (almost a brother for me), who played professional football (FC Servette) and studied at the University of Geneva with me.

Wake up at 05:30–06:00, go to the clinic (office) and drink coffee while checking emails. At 7:30 I’ll have a small breakfast with some clinic colleagues, then start working on projects for the day.

Working at the 2010 FIFA World Cup in South Africa (the first World Cup in the African continent).

I don’t think it’s up to me to say this, but I hope to have contributed a bit to the promotion of injury prevention and sports physiotherapy internationally.

Staying humble (and working hard).

Mobilising the upper limbs of …
Response rates in the PIAMA-project: a study on the prevalence and incidence of asthma and mite allergy in the Netherlands.
Authors: R. van Strien, B. Brunekreef, A. Wijga, H.A. Smit, L.P. Koopman, I. Praet, H.J. Neijens, J.C. de Jongste, M. Kerkhof, J. Gerritsen
Journal: European Respiratory Journal (1998)
Irish MP calls for key documents on Pandemrix to be handed to lawyers representing children with narcolepsy
Authors: Clare Dyer
Journal: BMJ (2017)

A member of Dail Eireann, the Irish parliament, has accused the Irish state body responsible for buying vaccines of choosing GlaxoSmithKline’s Pandemrix for its swine flu programme when it knew it had a higher risk of side effects than other vaccines.

Clare Daly made the allegation in a debate in the Dail, when she told the taoiseach, Enda Kenny, “The Health Service Executive (HSE) decided to purchase Pandemrix and continued to distribute it even after they knew it was dangerous and untested, and before most of the public in Ireland received it.” The executive knew that there was a seven to eightfold risk of side effects in comparison with a different vaccine, she said.

Around 80 Irish …
The Immunogenicity of a Human Lymphoid Cell-Restricted Minor Histocompatibility Antigen Results from Differential Protein Translation.
Authors: Anthony G. Brickner, Anne M. Evans, Jeffrey K. Mito, Suzanne M. Xuereb, Xin Feng, Donald F. Hunt, Jeffrey Shabanowitz, Victor H. Engelhard, Stanley R. Riddell, Edus H. Warren
Journal: Blood (2004)
NPR1 over expression reduces the proliferation of rhybdomyosarcoma (RMS) cells by inhibiting MAPK/ERK1,2 signaling in vitro
Authors: Yimin Wang, Bikul Das, David Malkin
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3478 

Introduction: Neuropilins (NRP) are membrane receptors capable of binding two disparate ligands, vascular endothelial growth factors (VEGF) and class 3 semaphorins (SEMA), and regulating two diverse systems, angiogenesis and neuronal guidance. It has been reported that most tumor cells express NRP1 while VEGFR1 and 2 are less commonly expressed. Our studies on rhabdomyosarcoma (RMS) showed that NRP1 is expressed in several tumor cell lines, however, the functional activities including tumor growth and angiogenesis remain unclear. Hence, here we investigated the role of NPR1 over expression in RMS. Methods: 7 RMS cell lines (RD, Rh6, A204, Rh4, Rh18, Rh28, and Rh30) were analyzed for VEGF and VEGF receptor expression by qPCR and western blot analysis. Results: All 7 subtypes of VEGF and NRP1 were found to be highly expressed by q PCR and western blot analysis. Rh30 and A204 cells were selected for further NRP1 study since they express low Flt1 and no KDR or VEGFR3. We generated stable transfectant clones expressing NRP1 in Rh30 and A204 cells. These clones showed more than 5 times higher NRP1 expression than their vector control. Interestingly, the proliferation of NRP1 over-expressing clones in Rh30 was significantly reduced compared to the vector control. MTT assay showed a 32% reduction (n =4; p = 0.0022) in proliferation while Trypan Blue analysis showed a 47% decrease in cell number (p=0.0113). Furthermore, clonogenic assays showed significant decrease of colony growth of NRP1 over-expressing clones. We also report a similar degree of reduction in proliferation and growth in A204 cell derived NRP1 over-expressing clones. We hypothesized that NRP1 over expression may inhibit VEGF mediated proliferative signaling. To investigate this possibility, we performed qPCR analysis and found that NRP1 over expression was associated with up-regulation of all 7 VEGF subtypes and all VEGF receptors including Flt1 sFlt1, sNRP1 sNRP2, KDR and VEGFR3 while signal pathway genes AKT, ERK, JUN, JNK and mTOR were dramatically down regulated. Since the MAPK pathway is associated with cell proliferation and survival, down regulation of these genes might explain the reduction in RMS cell proliferation. Hence, we performed MAPK/ERK1,2 phosphorylation studies and found that MAPK/ERK1,2 phosphorylation was induced in Rh30 and A204 cells following treatment with recombinant human VEGF165 administration. This phosphorylation was not affected by siRNA Flt1 knockdown. Conclusion: Our results indicate that NRP1 may reduce cell proliferation and growth in RMS by down regulating MAPK/ERK1,2 signaling. This mechanism may be relevant in other non-mesenchymal tumors as well.
New ARCHITECT plasma pro-gastrin-releasing peptide assay and lung cancer: Implications for diagnosis, follow-up, and prognosis.
Authors: Benjamin Nisman, Hovav Nechushtan, Haim Biran, Nir Peled, Hadas Gantz-Sorotsky, Victoria Doviner, Marina Perelman, Jair Bar, Beatrice Uziely, Tamar Peretz-Yablonski
Journal: Journal of Clinical Oncology (2015)

7570 Background: Pro-gastrin-releasing peptide (proGRP) is a precursor of the neuropeptide hormone produced by small cell lung cancer (SCLC) and considered as a potential serum marker for this disease. However, proGRP was shown to be more stable in plasma compared to serum. In this prospective study we evaluated the new proGRP assay in plasma format. Methods: Plasma proGRP was determined using the ARCHITECT i System (Abbott Diagnostics, Wiesbaden, Germany) in four cohorts: healthy individuals (n = 100) and patients with benign lung diseases (BLD, n = 102), non-small cell lung carcinoma (NSCLC, n = 241), and SCLC (n = 90). Results: The median (95 percentile) concentrations of plasma proGRP in healthy, BLD, NSCLC and SCLC were: 38 (64), 39 (64), 40 (121) and 680 (17695) pg/ml, respectively. There was no association with age, gender or smoking. The proGRP assay proved to be effective in distinguishing SCLC from NSCLC with area under the curve 0.941, 95%CI 0.906-0.975, 84.4% sensitivity, 95% specificity, at a cut-off 121 pg/ml. False-negative results in SCLC were associated with lack of thyroid transcription factor-1 (Fisher's Exact Test, P = 0.0006). False-positive results in NSCLC were associated with large cell neuroendocrine carcinoma (LCNEC) (Fisher's Exact Test, P < 0.0001). The elevated proGRP was found in 44.5% (5 of 11) patients with LCNEC. Fifty patients with SCLC were followed by plasma proGRP during chemotherapy. The decline of proGRP during chemotherapy below a cut-off (121 pg/ml) was associated with objective image based response (Fisher's Exact Test, P = 0.0003). In multivariate Cox regression analysis the proGRP response adjusted for imaging response and ECOG performance status independently affected progression free survival (PFS, hazard ratio [HR] = 0.38, 95%CI 0.20-0.74, P = 0.009) and overall survival (OS, HR = 0.32, 95%CI 0.16-0.63, P = 0.003). Conclusions: Plasma proGRP is a highly specific and sensitive marker supporting diagnosis of high grade neuroendocrine lung tumors, mainly SCLC. Elevation of proGRP in NSCLC is associated with LCNEC. The changes in the plasma proGRP during SCLC chemotherapy showed a significant association with imaging assessments of response, PFS and OS.