tbuckley/cabot-search huggingface dataset:
Validation of a gene expression-based diagnostic system for malignancy of glioma by multi-institute prospective-retrospective analysis.
Authors: Kikuya Kato, Mitsuaki Shirahata, Yoshitaka Narita, Yoshihiro Muragaki, Motohiko Maruno, Ryo Matoba
Journal: Journal of Clinical Oncology (2013)

2066 Background: Histopathological classification of gliomas is often clinically inadequate due to the diversity of tumors that fall within the same class. Based on the strong correlation between malignancy and gene expression profile in gliomas, we constructed a diagnostic system based on gene expression profiling of 152 glioma samples (Shirahata et al., Cancer Sci, 2009, 100, 165). The diagnostic system was converted to that based on expression value of 27 genes measured with real-time PCR (Kawarazaki et al., BMC Med Genomics, 2010, 3, 52). Methods: First, the diagnostic system was validated with 75 retrospective samples from the National Cancer Center Hospital, and threshold values of the diagnostic score (PC1-score) were determined. Second, the system was evaluated by prospective-retrospective analysis of 127 samples from the four institutions using the threshold. The analysis corresponded to the category C proposed by Simon et al. (JNCI, 2010, 101, 1446). Results: In general, the PC1-score gradually increased with the grade of the glioma from grade II to IV. The prognostic classification by the diagnostic system was compared with that by WHO grade classification using 66 grade IV and 39 grade 3 samples. Harrell’s C-index was 0.673 and 0.573 for the diagnostic system and grade classification, respectively. Hazard Ratio was 5.31 and 4.97, respectively. By the system the 66 grade 4 patients were confirmed to be classified into two prognostic groups (PFS, p = 0.013; OS, p = 0.098). The 39 grade III patients were classified into two prognostic groups (PFS, p = 0.112; OS, p = 0.022).Median observation time is 12 months for PFS and 15.5 months for OS, respectively. As for grade 3 patients, IDH1 mutation had better prognostic ability (PFS, p = 0.007; OS, p = 0.002). Conclusions: Based on two retrospective and one prospective-retrospective analysis, our diagnostic system was demonstrated to be an objective prognostic indicator complementing the grade classification. The prognostic ability within grade 3 or grade 4 may be useful in therapeutic decision making.
OxLDL-derived lysophosphatidic acid promotes the progression of aortic valve stenosis through a LPAR1-RhoA–NF-κB pathway
Authors: Mohamed Jalloul Nsaibia, Marie-Chloé Boulanger, Rihab Bouchareb, Ghada Mkannez, Khai Le Quang, Fayez Hadji, Deborah Argaud, Abdellaziz Dahou, Yohan Bossé, Marlys L. Koschinsky, Philippe Pibarot, Benoit J. Arsenault, André Marette, Patrick Mathieu
Journal: Cardiovascular Research (2017)

Oxidatively modified lipoproteins may promote the development/progression of calcific aortic valve stenosis (CAVS). Oxidative transformation of low-density lipoprotein (OxLDL) generates lysophosphatidic acid (LPA), a lipid mediator that accumulates in mineralized aortic valves. LPA activates at least six different G protein-coupled receptors, which may play a role in the pathophysiology of CAVS. We hypothesized that LPA derived from OxLDL may promote a NF-κB signature that drives osteogenesis in the aortic valve. The role of OxLDL-LPA was examined in isolated valve interstitial cells (VICs) and the molecular pathway was validated in human explanted aortic valves and in a mouse model of CAVS. We found that OxLDL-LPA promoted the mineralization and osteogenic transition of VICs through LPAR1 and the activation of a RhoA-NF-κB pathway. Specifically, we identified that RhoA/ROCK activated IκB kinase alpha, which promoted the phosphorylation of p65 on serine 536 (p65 pS536). p65 pS536 was recruited to the BMP2 promoter and directed an osteogenic program not responsive to the control exerted by the inhibitor of kappa B. In LDLR-/-/ApoB100/100/IGFII transgenic mice (IGFII), which develop CAVS under a high-fat and high-sucrose diet the administration of Ki16425, a Lpar1 blocker, reduced by three-fold the progression rate of CAVS and also decreased the osteogenic activity as measured with a near-infrared fluorescent probe that recognizes hydroxyapatite of calcium. OxLDL-LPA promotes an osteogenic program in the aortic valve through a LPAR1-RhoA/ROCK–p65 pS536 pathway. LPAR1 may represent a suitable target to prevent the progression of CAVS.
Efficacy and safety of lenalidomide and dexamethasone in overtreated multiple myeloma patients.
Authors: Alessandro Moscetti, Federica Resci, Giusy Antolino, Francesca Saltarelli, Bruno Monarca, Maria Paola Bianchi, Virginia Naso, Daniela De Benedittis, Giacinto La Verde
Journal: Journal of Clinical Oncology (2012)

e18566 Background: Lenalidomide is a therapeutic option for pretreated patients with multiple myeloma, especially in association with steroids. Methods: Oraldaily lenalidomide (10-25 mg) for 21 days every month (median courses 8.6) and weekly dexamethasone (Dex) were administered until progression in 33 pretreated patients (median age 68.1 yrs) observed between June 2008 and January 2012 at Hematology Department of Sant’Andrea Hospital in Rome. Previous treatment included alkylants, anthracyclines, IFN-α, thalidomide, bortezomib and single or double autograft. Fifteen patients were evaluated after 6 courses of therapy, administered as second to fifth line, and prospectively followed-up; two patients weren’t considered because of early death. Treatment response was assessed according to IMWG uniform response criteria. Results: The overall response rate was 53.3% (8/15 pts) with a median duration of response of 12 months: 8 patients reached a partial response (PR), 6 showed a stable disease (SD) and 1 progressive disease (PD). The median progression free survival was 14 months. Among patients in PR, 5 are alive in continous treatment, 2 died due to PD after 17 courses administered as fifth line therapy and 1 died for unrelated surgical complicancies. The whole responses were achieved indifferently if lenalidomide was administered as second, third or fifth line of therapy (2, 3 and 3 patients respectively). Out of patients in SD, all experienced progressive disease after a median of 12 courses: 3 are still alive in salvage therapy, 3 died during treatment. The only patient in PD died 9 months after the end of Len-Dex treatment during salvage chemotherapy. The reported side effects included pneumonia, neutropenia, diarrhea, peripheral sensitive polyneuropathy, transient liver failure, lower urinary tract infection, skin rash, transient aphasia, conjunctival hemorrhage and deep vein thrombosis, all resolved with brief discontinuance and specific support therapy without hospitalization. Conclusions: Len-Dex association is a completely oral effective salvage therapy with good response rate and manageable side effects also for overtreated relapsed and refractory multiple myeloma patients.
Methotrexate Clearance in Adult Patients with B-Precursor Acute Lymphoblastic Leukemia Treated with the Mini-Hyper-CVD Regimen
Authors: Yogin B Patel, Kelsey N Voit, Koji Sasaki, Farhad Ravandi, Deborah A Thomas, Susan M. O'Brien, Gautam Borthakur, Guillermo Garcia-Manero, Jorge E. Cortes, Marina Konopleva, Nitin Jain, Maro Ohanian, Rebecca Garris, Jovitta Jacob, Hagop M. Kantarjian, Elias J. Jabbour
Journal: Blood (2016)
Acetyl‐coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double‐blind, crossover study
Authors: Kathryn Stiede, Wenyan Miao, Heather S. Blanchette, Carine Beysen, Geraldine Harriman, H. James Harwood, Heather Kelley, Rosana Kapeller, Tess Schmalbach, William F. Westlin
Journal: Hepatology (2017)

NDI‐010976, an allosteric inhibitor of acetyl‐coenzyme A carboxylases (ACC) ACC1 and ACC2, reduces hepatic de novo lipogenesis (DNL) and favorably affects steatosis, inflammation, and fibrosis in animal models of fatty liver disease. This study was a randomized, double‐blind, placebo‐controlled, crossover trial evaluating the pharmacodynamic effects of a single oral dose of NDI‐010976 on hepatic DNL in overweight and/or obese but otherwise healthy adult male subjects. Subjects were randomized to receive either NDI‐010976 (20, 50, or 200 mg) or matching placebo in period 1, followed by the alternate treatment in period 2; and hepatic lipogenesis was stimulated with oral fructose administration. Fractional DNL was quantified by infusing a stable isotope tracer, [1‐ 13 C]acetate, and monitoring 13 C incorporation into palmitate of circulating very low‐density lipoprotein triglyceride. Single‐dose administration of NDI‐010976 was well tolerated at doses up to and including 200 mg. Fructose administration over a 10‐hour period stimulated hepatic fractional DNL an average of 30.9 ± 6.7% (mean ± standard deviation) above fasting DNL values in placebo‐treated subjects. Subjects administered single doses of NDI‐010976 at 20, 50, or 200 mg had significant inhibition of DNL compared to placebo (mean inhibition relative to placebo was 70%, 85%, and 104%, respectively). An inverse relationship between fractional DNL and NDI‐010976 exposure was observed with &gt;90% inhibition of fractional DNL associated with plasma concentrations of NDI‐010976 &gt;4 ng/mL. Conclusion : ACC inhibition with a single dose of NDI‐010976 is well tolerated and results in a profound dose‐dependent inhibition of hepatic DNL in overweight adult male subjects. Therefore, NDI‐010976 could contribute considerable value to the treatment algorithm of metabolic disorders characterized by dysregulated fatty acid metabolism, including nonalcoholic steatohepatitis. (H epatology 2017;66:324–334).
T-cell lymphomas in murine in vitro and in vivo models are associated with translocations involving chromosomal band 15D3 or trisomy 15
Authors: Cornelia Rudolph, Braig Melanie, Bittner Cordula, Schmitt Clemens, Merz Hartmut, Schlegelberger Brigitte
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

256 

Introduction: Activation of the oncogene C-MYC has been described in various diseases, e.g. in Burkitt's lymphoma. It can result from different mechanisms, e.g. translocations involving the C-MYC locus on human chromosome 8q24 or the murine chromosome 15D3 or from an increase in the gene dosage. We cytogenetically analyzed two different murine T-cell lymphomas, a N-RAS transgenic mice with and without methyltransferase Suv39h1-deficiency and a cell line resembling the human anaplastic large cell lymphoma (ALCL). T-cell lymphomas of both models analyzed showed different alterations of the c-myc locus on mouse chromosome 15D3. Methods: Chromosome spreads were prepared from T-cells according to standard protocols. Spectral karyotyping (SKY) was carried out according to the manufacturer‘s instructions (Applied Spectral Imaging, Ltd., Migdal HaEmek, Israel). Briefly, metaphase chromosomes were denatured in 70% formamide, 2x SSC for 1.5 min and dehydrated. The mouse SKY probe mixture was denatured at 80°C for 7 min and preannealed at 37°C for 1h. Hybridization took place for 48-72h in a humidified chamber. Image acquisition was performed with the SpectraCube system and the SKY View™ software was utilized for analysis. For fluorescence in situ hybridization (FISH), a probe hybridizing to the c-myc locus on 15D3 was generated from BAC clone RP24-488H15. Results: Nearly all T-cell lymphomas from N-RAS transgenic mice and transgenics with Suv39h1 deficiency showed numerical as well as structural chromosomal alterations. 3 of 4 clones from N-RAS transgenic mice with Suv39h1-deficiency and both clones from N-RAS transgenic mice without Suv39h1-deficiency showed translocations with breakpoints in 15D3. Different regions on chromosomes 6, 11, and 14 were involved as translocation partners, but the genes involved remain unclear. Thus, the methyltransferase deficiency does not seem to result in an enhanced chromosomal instability. SKY analysis of the ALCL cell line TS1G6 showed a complex karyotype with numerical as well as structural chromosomal alterations. Trisomy 15 was found in all 20 metaphases of the ALCL cell line. Conclusion: The numerical and structural alterations of murine chromosome 15 described in both models may induce an activation of the c-myc oncogene. The detailed molecular cytogenetic characterization of these alterations may help to clarify the mechanisms of c-myc activation.
Enhancing the implementation of injury prevention exercise programmes in professional football
Authors: James O’Brien
Journal: British Journal of Sports Medicine (2017)

I investigated the use of injury prevention exercise programmes (IPEPs) in professional football teams. The primary aim was to identify barriers and facilitators to successfully implementing these programmes under real-world conditions.

Injuries in football are common and have multiple negative impacts. The efficacy of IPEPs for football has been established in large-scale randomised controlled trials. Despite this, many teams choose not to adopt these programmes, or do not comply with them fully.1 2 Unfortunately, the reasons for low adoption and compliance are poorly understood and have received very little research attention. My PhD aimed to address this gap by evaluating barriers and facilitators to IPEP implementation under real-world conditions.

Firstly, I conducted two systematic reviews of published IPEPs trials, in both football and …
Platelets subvert T cell immunity against cancer via GARP-TGFβ axis
Authors: Saleh Rachidi, Alessandra Metelli, Brian Riesenberg, Bill X. Wu, Michelle H. Nelson, Caroline Wallace, Chrystal M. Paulos, Mark P. Rubinstein, Elizabeth Garrett-Mayer, Mirko Hennig, Daniel W. Bearden, Yi Yang, Bei Liu, Zihai Li
Journal: Science Immunology (2017)

Cancer-associated thrombocytosis has long been linked to poor clinical outcome, but the underlying mechanism is enigmatic. We hypothesized that platelets promote malignancy and resistance to therapy by dampening host immunity. We show that genetic targeting of platelets enhances adoptive T cell therapy of cancer. An unbiased biochemical and structural biology approach established transforming growth factor β (TGFβ) and lactate as major platelet-derived soluble factors to obliterate CD4+ and CD8+ T cell functions. Moreover, we found that platelets are the dominant source of functional TGFβ systemically as well as in the tumor microenvironment through constitutive expression of the TGFβ-docking receptor glycoprotein A repetitions predominant (GARP) rather than secretion of TGFβ per se. Platelet-specific deletion of the GARP-encoding gene Lrrc32 blunted TGFβ activity at the tumor site and potentiated protective immunity against both melanoma and colon cancer. Last, this study shows that T cell therapy of cancer can be substantially improved by concurrent treatment with readily available antiplatelet agents. We conclude that platelets constrain T cell immunity through a GARP-TGFβ axis and suggest a combination of immunotherapy and platelet inhibitors as a therapeutic strategy against cancer.
Balance of Anti-CD123 Chimeric Antigen Receptor Binding Affinity and Density for the Targeting of Acute Myeloid Leukemia
Authors: Silvia Arcangeli, Maria Caterina Rotiroti, Marco Bardelli, Luca Simonelli, Chiara Francesca Magnani, Andrea Biondi, Ettore Biagi, Sarah Tettamanti, Luca Varani
Journal: Molecular Therapy (2017)

Chimeric antigen receptor (CAR)-redirected T lymphocytes are a promising immunotherapeutic approach and object of pre-clinical evaluation for the treatment of acute myeloid leukemia (AML). We developed a CAR against CD123, overexpressed on AML blasts and leukemic stem cells. However, potential recognition of low CD123-positive healthy tissues, through the on-target, off-tumor effect, limits safe clinical employment of CAR-redirected T cells. Therefore, we evaluated the effect of context-dependent variables capable of modulating CAR T cell functional profiles, such as CAR binding affinity, CAR expression, and target antigen density. Computational structural biology tools allowed for the design of rational mutations in the anti-CD123 CAR antigen binding domain that altered CAR expression and CAR binding affinity without affecting the overall CAR design. We defined both lytic and activation antigen thresholds, with early cytotoxic activity unaffected by either CAR expression or CAR affinity tuning but later effector functions impaired by low CAR expression. Moreover, the anti-CD123 CAR safety profile was confirmed by lowering CAR binding affinity, corroborating CD123 is a good therapeutic target antigen. Overall, full dissection of these variables offers suitable anti-CD123 CAR design optimization for the treatment of AML.
Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models
Authors: Teeru Bihani, Hitisha K. Patel, Heike Arlt, Nianjun Tao, Hai Jiang, Jeffrey L. Brown, Dinesh M. Purandare, Gary Hattersley, Fiona Garner
Journal: Clinical Cancer Research (2017)

Purpose: Estrogen receptor-positive (ER+) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER+ breast cancer.Experimental Design: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER+ breast cancer models, including several patient-derived xenograft models.Results: Elacestrant induces the degradation of ER, inhibits ER-mediated signaling and growth of ER+ breast cancer cell lines in vitro and in vivo, and significantly inhibits tumor growth of multiple PDX models. Furthermore, we demonstrate that elacestrant in combination with palbociclib or everolimus can lead to greater efficacy in certain contexts. Finally, elacestrant exhibits significant antitumor activity both as a single agent and in combination with palbociclib in two patient-derived breast cancer xenograft models harboring ESR1 mutations.Conclusions: These data underscore the potential clinical utility of elacestrant as a single agent and as a combination therapy, for both early- and late-stage ER+ disease. Clin Cancer Res; 23(16); 4793-804. ©2017 AACR.
Epidemiology of competition injuries in youth karate athletes: a prospective cohort study
Authors: Dušana Čierna, Reidar P Lystad
Journal: British Journal of Sports Medicine (2017)

To determine the injury incidence rate and injury pattern among youth karate athletes competing in national tournaments in Slovakia, and to identify risk factors for injury.Data were collected at nine national youth karate tournaments in Slovakia in 2015 and 2016. Injury incidence rates were calculated per 1000 athlete-exposures (IIRAE) and per 1000 min of exposure (IIRME) with 95% CIs. Subgroups were compared by calculating their rate ratios (RR) with 95% CIs.The overall IIRAE and IIRME were 45.3 (95% CI 38.7 to 52.6) and 35.9 (95% CI 30.7 to 41.7), respectively. The most frequently injured anatomical region was the head/neck (57%), while the most common type of injury was contusion (85%). The risk of injury for the 12-17-year-old age group was almost twice that of the 6-12-year-old age group, after accounting for exposure time (RRME 1.92 (95% CI 1.39 to 2.65)), and the difference was more pronounced for girls than boys (RRME 2.47 (95% CI 1.52 to 4.00) vs RRME 1.62 (95% CI 1.06 to 2.49), respectively).Youth karate has a relatively large proportion of head injuries. Adolescent and female youth karate athletes are at higher risk of injury compared with their child and male counterparts.
Are We on the Same Page? Patient and Provider Perceptions About Exercise in Cancer Care: A Focus Group Study
Authors: Agnes Smaradottir, Angela L. Smith, Andrew J. Borgert, Kurt R. Oettel
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: Physical activity (PA) during and after cancer treatment can help with symptom management and reduce the risk of cancer recurrence. However, it is unclear what constitutes an optimal exercise program. In addition, provider and patient barriers exist to the recommendation and adoption of exercise as part of a cancer treatment plan. The goal of this study was to determine how providers and patients feel about exercise during cancer treatment and explore what the barriers to implementing such a program might be. Patients and Methods: Focus groups and interviews were held with patients with malignancy, both metastatic and nonmetastatic, and oncology providers. In total, 20 patients participated in either a focus group or an individual interview and 9 providers contributed to the focus group. An equal number of patients (n=10) were interviewed as attended a focus group. Audiotaped sessions were transcribed verbatim. Theme identification was independently coded by 4 coders and synthesized as a group. Results: Neither patient group recalled PA instruction from oncology providers during their cancer treatment. Most participants (95%) felt exercise is important during cancer treatment, citing overall well-being benefits versus improved disease outcome. Most patients (80%) preferred a home-based exercise program provided by the oncologist. Fatigue was the most cited barrier to regular exercise during treatment (50%). All providers acknowledged benefits of PA to patients, but not universally for all. More than half of providers (55%) preferred a referral system for exercise programs. Clinic visit time constraints and a perceived lack of expertise in the area of PA were common barriers to making exercise recommendations a routine part of the treatment plan. Conclusions: Patients with cancer and oncologists recognize the benefits of PA during treatment. Disagreement exists between to whom, how, and where exercise plans should be disseminated and implemented.
A 12 month weight loss programme would be cost effective for NHS, study finds
Authors: Gareth Iacobucci
Journal: BMJ (2017)

GPs should refer overweight or obese adults to weight loss programmes for 12 months rather than the standard three months, researchers have recommended.1

A study published in the Lancet reported that people referred to 52 week weight loss programmes lost more weight and experienced more clinical benefits than people who followed a 12 week programme or used self help materials.

Although a 52 week behavioural programme would be more expensive than the standard three months offered through the NHS, the study found that improvements in quality of life would be cost effective in the long term. …