tbuckley/cabot-search huggingface dataset:
Randomised controlled trial of prolonged treatment in the remission phase of ANCA-associated vasculitis
Authors: Alexandre Karras, Christian Pagnoux, Marion Haubitz, Kirsten de Groot, Xavier Puechal, Jan Willem Cohen Tervaert, Mårten Segelmark, Loic Guillevin, David Jayne
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> A prospective randomised trial to compare two different durations of maintenance immunosuppressive therapy for the prevention of relapse in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). <h3>Methods</h3> Patients with AAV were recruited 18–24 months after diagnosis if they were in stable remission after cyclophosphamide/prednisolone-based induction followed by azathioprine/prednisolone maintenance therapy. They were randomised (1:1) to receive continued azathioprine/prednisolone to 48 months from diagnosis (continuation group) or to withdraw azathioprine/prednisolone by 24 months (withdrawal group). The primary endpoint was the relapse risk, from randomisation to 48 months from diagnosis. <h3>Results</h3> One hundred and seventeen patients were randomised and 110 remained to the trial end. At entry, median serum creatinine was 116 μmol/L (range 58–372), 53% were ANCA positive. The percentage of patients presenting with relapse was higher in the withdrawal than in the continuation treatment group (63% vs 22%, p&lt;0.0001, OR 5.96, 95% CI 2.58 to 13.77). ANCA positivity at randomisation was associated with relapse risk (51% vs 29%, p=0.017, OR 2.57, 95% CI 1.16 to 5.68). Renal function, ANCA specificity, vasculitis type and age were not predictive of relapse. Severe adverse events were more frequent in the continuation than withdrawal groups (nine vs three events), but the continuation group had better renal outcome (0 vs 4 cases of end-stage renal disease), with no difference in patient survival. <h3>Conclusions</h3> Prolonged remission maintenance therapy with azathioprine/prednisolone, beyond 24 months after diagnosis reduces relapse risk out to 48 months and improves renal survival in AAV. <h3>Trial registration number</h3> ISRCTN13739474
Regulator-watching: a typology of regulatory methods adopted by sports governing bodies in concussion management
Authors: Annette Greenhow
Journal: British Journal of Sports Medicine (2017)

Objective Responses to the harm caused by sports-related concussion constitute a new interdisciplinary field of research (Doherty, 2012). Regulatory theory and principles of what constitutes ‘good’ regulation can contribute to the discussion. The aim of this research is to present a typology of regulatory responses adopted by sports governing bodies in those sports with published injury surveillance data, and to classify the responses according to the regulatory methods used by the organisations.Sports governing bodies are voluntary self-regulated associations and custodians of their sport. As the dominant regulator responsible for the development of rules and standards, the organisation carries the responsibility to provide a safe system for participants within its regulatory field, focussing on precautionary-based approaches and risk reduction strategies to preserve the health, safety and welfare of participants. The expectation is that these interventions are based on well-defined objectives and an understanding of the variety of regulatory methods available to achieve the objectives. Design This presentation provides the results of a review of the regulatory activities of the sports governing bodies across contact and collision sport. By adopting a qualitative research method, the regulatory actions of the organisations are classified according to the four response areas of concussion management, concussion prevention, concussion research and concussion education. Main results A variety of regulatory methods were employed by the organisations across each of the four categories. Early interventions focus on concussion management and concussion prevention with more recent interventions focussed on concussion education and concussion research strategies. Conclusions Those organisations with clearly defined objectives and comprehensive injury surveillance data reporting systems adopted regulatory methods across each of the four categories. Competing interests None
Seeing the Forest through the Phylogenetic Tree
Authors: Ana I. Robles, Jean C. Zenklusen
Journal: New England Journal of Medicine (2017)

Cancer is generally considered to be a genetic disease. Tumors arise as a result of cumulative genetic alterations (gene mutations, copy-number changes, gene fusions, or RNA overexpression or underexpression) that affect the properties of single cells and endow them with a growth advantage. Early on, this stepwise path was depicted as a linear model of sequential acquisition of mutations leading to tumor progression.1 It has now become clear that evolution to increasingly malignant phenotypes is a complex, multilayered process, in which various competing subclones that arise from the stochastic accumulation of genomic alterations are selected for fitness by environmental pressures, . . .
MEDU-06. NOVEL MOLECULAR SUBGROUPS IMPROVE CLINICAL CLASSIFICATION AND OUTCOME PREDICTION FOR CHILDHOOD MEDULLOBLASTOMA
Authors: Edward Schwalbe, Janet Lindsey, Sirintra Nakjang, Stephen Crosier, Amanda Smith, Debbie Hicks, Gholamreza Rafiee, Rebecca Hill, Alice Iliasova, Thomas Stone, Barry Pizer, Anthony Michalski, Abhijit Joshi, Keith Robson, Stephen Wharton, Thomas Jacques, Simon Bailey, Daniel Williamson, Steven Clifford
Journal: Neuro-Oncology (2017)

BACKGROUND: International consensus recognises four medulloblastoma molecular subgroups - WNT (MBWNT), SHH (MBSHH), Group 3 (MBGrp3) and Group 4 (MBGrp4) - each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. Subgroups harbor distinct clinico-pathological and molecular features, underpin current disease sub-classification and initial subgroup-directed therapies are underway in clinical trials (i.e. reduced risk-adapted treatments for favorable-risk MBWNT patients; SMO inhibitors for MBSHH patients). However, significant biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. METHODS: We undertook comprehensive molecular profiling and unsupervised class discovery (non-negative matrix factorization, t-SNE) of test and validation cohorts (n=704 in total), to identify consensus primary molecular subgroups within childhood medulloblastoma (<16.0 years), and characterize their clinical and biological significance. Survival modeling was performed in clinically-annotated centrally-reviewed patients (>3.0 years). FINDINGS: Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified, characterized by distinct biological/clinical features. For instance, MBSHH comprised two age-dependent subgroups, while MBGrp3 and MBGrp4 each split into two subgroups with significantly different survival rates. Survival analysis identified secondary features predictive of outcome. Cross-validated subgroup-dependent models incorporating these novel subgroups along with secondary features and established disease risk-factors, outperformed current disease risk-stratification schemes. These schema stratified patients into four clinical risk-groups - favorable-risk (91% 5-year survival, 25% of patients), standard-risk (81%, 23%), high-risk (42%, 38%) and very high-risk (28%, 13%) - to be considered for treatment reduction, intensification or novel therapies respectively. INTERPRETATION: The discovery of seven novel, clinically-significant, subgroups significantly improves disease risk-stratification and provides a new foundation for future research and clinical investigations.
A New AAV10-U7-Mediated Gene Therapy Prolongs Survival and Restores Function in an ALS Mouse Model
Authors: Maria Grazia Biferi, Mathilde Cohen-Tannoudji, Ambra Cappelletto, Benoit Giroux, Marianne Roda, Stéphanie Astord, Thibaut Marais, Corinne Bos, Thomas Voit, Arnaud Ferry, Martine Barkats
Journal: Molecular Therapy (2017)

One of the most promising therapeutic approaches for familial amyotrophic lateral sclerosis linked to superoxide dismutase 1 (SOD1) is the suppression of toxic mutant SOD1 in the affected tissues. Here, we report an innovative molecular strategy for inducing substantial, widespread, and sustained reduction of mutant human SOD1 (hSOD1) levels throughout the body of SOD1G93A mice, leading to therapeutic effects in animals. Adeno-associated virus serotype rh10 vectors (AAV10) were used to mediate exon skipping of the hSOD1 pre-mRNA by expression of exon-2-targeted antisense sequences embedded in a modified U7 small-nuclear RNA (AAV10-U7-hSOD). Skipping of hSOD1 exon 2 led to the generation of a premature termination codon, inducing production of a deleted transcript that was subsequently degraded by the activation of nonsense-mediated decay. Combined intravenous and intracerebroventricular delivery of AAV10-U7-hSOD increased the survival of SOD1G93A mice injected either at birth or at 50 days of age (by 92% and 58%, respectively) and prevented weight loss and the decline of neuromuscular function. This study reports the effectiveness of an exon-skipping approach in SOD1-ALS mice, supporting the translation of this technology to the treatment of this as yet incurable disease. One of the most promising therapeutic approaches for familial amyotrophic lateral sclerosis linked to superoxide dismutase 1 (SOD1) is the suppression of toxic mutant SOD1 in the affected tissues. Here, we report an innovative molecular strategy for inducing substantial, widespread, and sustained reduction of mutant human SOD1 (hSOD1) levels throughout the body of SOD1G93A mice, leading to therapeutic effects in animals. Adeno-associated virus serotype rh10 vectors (AAV10) were used to mediate exon skipping of the hSOD1 pre-mRNA by expression of exon-2-targeted antisense sequences embedded in a modified U7 small-nuclear RNA (AAV10-U7-hSOD). Skipping of hSOD1 exon 2 led to the generation of a premature termination codon, inducing production of a deleted transcript that was subsequently degraded by the activation of nonsense-mediated decay. Combined intravenous and intracerebroventricular delivery of AAV10-U7-hSOD increased the survival of SOD1G93A mice injected either at birth or at 50 days of age (by 92% and 58%, respectively) and prevented weight loss and the decline of neuromuscular function. This study reports the effectiveness of an exon-skipping approach in SOD1-ALS mice, supporting the translation of this technology to the treatment of this as yet incurable disease.
Retrospective analysis of prognostic factors in patients undergoing surgical resection for multiple brain metastases.
Authors: Carlos Petitto, Liana Valente Lage, Inacelli Queiroz De Souza Caires, Karla T Souza, Angelo Bezerra de Souza Fede, Olavo Feher, Paulo M. Hoff, Veridiana Camargo, Ana Mencarini, Rodrigo Ramella Munhoz, Manoel Jacobsen Teixeira, Guilherme Lepski
Journal: Journal of Clinical Oncology (2014)

e20551 Background: Brain metastases represent the main neurological complication of cancer. In some instances, patients presenting multiple brain metastases benefit from surgical resection. Notwithstanding this decision is challenging and this issue has not been directly assessed so far. Methods: The main objective was to identify prognostic and predictive variables of two different populations ( survival ≤ 2 months vs. > 12 months) of patients harboring multiple brain metastases (BM) submitted to surgical resection. Retrospective analysis that included 87 consecutive patients from 2008 to 2012. All patients had multiple BM and were submitted to surgical resection. The following variables were evaluated: age, sex, body mass index, histological type, pre-operative Karnofsky Performance Score (KPS), platelet number, lactate dehydrogenase level, time between cancer diagnosis and brain surgery, presence of extra-cranial disease, number of intracranial lesions, Graded Prognostic Assessment (GPA), post-op whole brain irradiation (WBR), radiological pattern, lesion in the posterior fossa, volume of the largest intracranial lesion, neurological symptoms at admission. The primary outcomes were: survival ≤ 2 months after surgery and survival longer than one year. The first outcome was evaluated by means of bivariate logistic regression, whereas the second was by Cox bivariate regression. Results: On the first group (survival ≤ 2 months) pre-operative KPS and WBR were the only variables correlated to survival (p<0.001 for both). On the second group (survival > 12 months), KPS and post-operative irradiation (whole brain) were also related with survival (p<0.05 for both). Conclusions: In this analysis, WBR and KPS were the two most important factors associated with survival after surgical resection in multiple brain metastases patients. Unfortunately, besides KPS we were unable to find other predictive variables for both very poor and good survival that could help in the decision of supportive care only versus active treatment.
Zoledronic acid inhibits gastric cancer cells by induction of apoptosis
Authors: Jun Yamada, Hirokazu N. Tsuno, Joji Kitayama, Satomi Yoneyama, Takeshi Tsuchiya, Masahiro Asakage, Yurai Okaji, Koki Takahashi, Hirokazu Nagawa
Journal: Cancer Research (2006)

3806  BACKGROUND AND AIM: Zoledronic acid, the 3rd generation bisphosphonate, is clinically available for skeletal complications, such as cancer-induced osteolysis and osteoporosis. Additionally, it has been reported to exert strong anti-cancer activities, against breast cancer, prostate cancer, leukemia, among others. Here, we aimed to investigate the anti-tumor effect of Zoledronic acid on gastric cancer, which is one of the most popular diseases in East Asia, and especially in Japan. METHODS: The gastric adenocarcinoma cell lines, namely MKN-45, and MKN74, were used. Zoledronic acid was kindly gifted by Novartis pharma, and tested at various concentrations (5, 10, 25, 50 and 100 μmol/L). The proliferative activity of gastric cancer cells was assessed by the MTS assay. The annexin V / PI staining was used to analyze the induction of apoptosis. In addition, to clarify the mechanisms of the apoptosis induction, the activation of caspases-8, -9 and -3 was evaluated by flow-cytometry. And Western blotting was performed to analyze the expression of apoptosis-associated proteins. RESULTS: Zoledronic acid treatment for 24-72h resulted in a dose- and time-dependent inhibition of the proliferative activity of both gastric cancer cell lines tested. This inhibitory effect was dependent on induction of apoptosis, as confirmed by the annexin V / PI staining. Both the caspase-8 and -9 cascades were activated in the apoptotic cells. However, the expression of the apoptosis-associated proteins investigated, namely Bcl-2, Bcl-xL, and Bax, were not changed. The Ras protein expression, analyzed by Western blot, was not changed in the whole cell lysates. CONCLUSION: Zoledronic acid caused a dose- and time-dependent inhibition of the proliferative activity of gastric cancer cells, by induction of cell apoptosis. The probable mechanism of apoptosis induction is the inhibition of Ras protein plenylation, as demonstrated by the change of Ras protein distribution from the cytosol to the membrane fraction. It should be considered a promising anti-gastric cancer agent, and since it is already available for clinical use, clinical trials should be started to confirm its properties in human beings.
Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment
Authors: A Paulus, S Akhtar, H Yousaf, A Manna, S M Paulus, Y Bashir, T R Caulfield, M Kuranz-Blake, K Chitta, X Wang, Y Asmann, R Hudec, W Springer, S Ailawadhi, A Chanan-Khan
Journal: Blood Cancer Journal (2017)

Abstract Although ibrutinib is highly effective in Waldenstrom macroglobulinemia (WM), no complete remissions in WM patients treated with ibrutinib have been reported to date. Moreover, ibrutinib-resistant disease is being steadily reported and is associated with dismal clinical outcome (overall survival of 2.9–3.1 months). To understand mechanisms of ibrutinib resistance in WM, we established ibrutinib-resistant in vitro models using validated WM cell lines. Characterization of these models revealed the absence of BTK C481S and CXCR4 WHIM-like mutations. BTK-mediated signaling was found to be highly attenuated accompanied by a shift in PI3K/AKT and apoptosis regulation-associated genes/proteins. Cytotoxicity studies using the AKT inhibitor, MK2206±ibrutinib, and the Bcl-2-specific inhibitor, venetoclax±ibrutinib, demonstrated synergistic loss of cell viability when either MK22016 or venetoclax were used in combination with ibrutinib. Our findings demonstrate that induction of ibrutinib resistance in WM cells can arise independent of BTK C481S and CXCR4 WHIM-like mutations and sustained pressure from ibrutinib appears to activate compensatory AKT signaling as well as reshuffling of Bcl-2 family proteins for maintenance of cell survival. Combination treatment demonstrated greater (and synergistic) antitumor effect and provides rationale for development of therapeutic strategies encompassing venetoclax+ibrutinib or PI3K/AKT inhibitors+ibrutinib in ibrutinib-resistant WM.
Variation in Emergency Department vs Internal Medicine Excess Charges in the United States
Authors: Tim Xu, Angela Park, Ge Bai, Sarah Joo, Susan M. Hutfless, Ambar Mehta, Gerard F. Anderson, Martin A. Makary
Journal: JAMA Internal Medicine (2017)

Uninsured and insured but out-of-network emergency department (ED) patients are often billed hospital chargemaster prices, which exceed amounts typically paid by insurers.To examine the variation in excess charges for services provided by emergency medicine and internal medicine physicians.Retrospective analysis was conducted of professional fee payment claims made by the Centers for Medicare & Medicaid Services for all services provided to Medicare Part B fee-for-service beneficiaries in calendar year 2013. Data analysis was conducted from January 1 to July 31, 2016.Markup ratios for ED and internal medicine professional services, defined as the charges submitted by the hospital divided by the Medicare allowable amount.Our analysis included 12 337 emergency medicine physicians from 2707 hospitals and 57 607 internal medicine physicians from 3669 hospitals in all 50 states. Services provided by emergency medicine physicians had an overall markup ratio of 4.4 (340% excess charges), which was greater than the markup ratio of 2.1 (110% excess charges) for all services performed by internal medicine physicians. Markup ratios for all ED services ranged by hospital from 1.0 to 12.6 (median, 4.2; interquartile range [IQR], 3.3-5.8); markup ratios for all internal medicine services ranged by hospital from 1.0 to 14.1 (median, 2.0; IQR, 1.7-2.5). The median markup ratio by hospital for ED evaluation and management procedure codes varied between 4.0 and 5.0. Among the most common ED services, laceration repair had the highest median markup ratio (7.0); emergency medicine physician review of a head computed tomographic scan had the greatest interhospital variation (range, 1.6-27.7). Across hospitals, markups in the ED were often substantially higher than those in the internal medicine department for the same services. Higher ED markup ratios were associated with hospital for-profit ownership (median, 5.7; IQR, 4.0-7.1), a greater percentage of uninsured patients seen (median, 5.0; IQR, 3.5-6.7 for ≥20% uninsured), and location (median, 5.3; IQR, 3.8-6.8 for the southeastern United States).Across hospitals, there is wide variation in excess charges on ED services, which are often priced higher than internal medicine services. Our results inform policy efforts to protect uninsured and out-of-network patients from highly variable pricing.
Comparison of 2 Doses of Intravenous (IV) Temsirolimus (Temsr) in Patients with Relapsed/Refractory Mantle Cell Lymphoma (MCL)
Authors: Wojciech Jurczak, Sundra Ramanathan, Pratyush Giri, Francesco Di Raimondo, Heidi Mocikova, Jill Clancy, Mariajose Lechuga, Michelle Casey, Joseph P Boni, Agnieszka Giza, Georg Hess
Journal: Blood (2016)
Wooden heads and glass jaws: the long-term effects of recurrent concussion and american football exposure on resting state networks
Authors: Michael Clark, Jason Mihalik, Kevin Guskiewicz
Journal: British Journal of Sports Medicine (2017)

Objective To elucidate the association between recurrent concussion and subconcussive head impacts andb the efficiency of resting state neural networks in retired American football athletes. Design Cross-sectional. Subjects 32 former college football athletes and 32 former professional football athletes matched on age, position, and self-reported concussion history (age: 58.5±3.6 y). Of those, 61 subjects had quality imaging data (31 College, 30 Professional). Subjects were stratified by concussion history (High, 3+, N=31; Low, 0–1, N=30). Outcome measures IVs: Concussion history (Low/High) and football exposure (College/Professional). DVs: Mean local efficiency (LE) and clustering coefficients (CC) for seven anatomically defined neural subnetworks: frontal, temporal, occipital, medial temporal, subcortical, parietal, and cerebellar. Outcomes were analysed across several correlational thresholds (r=0–0.9). Results The high concussion group had lower frontal LE and CC than the low concussion group (Effect size range: 0.260 – 0.437, P&lt;0.05). A crossover history-by-exposure interaction was observed in the cerebellar network (P=0.0063), such that former college athletes with high concussion history demonstrated lower LE and CC than college athletes with low concussion history. Interestingly, professional athletes with high concussion history demonstrated greater LE and CC than those with low concussion history. No other associations were observed across the five remaining neural networks. Conclusions These data challenge the notion that subconcussive head impact exposure is linked to long-term neurological dysfunction. Our data point to a potential heightened cerebellar network resiliency among retired professional athletes with a high number of concussions. Subconcussive head impact exposure alone does not appear to affect widespread cortical and cerebellar network function among retired American football athletes. Competing interests None. Member of the Mackey-White committee of the NFL Players Association and member of the Head, Neck, and Spine Committee of the NFL.
Unmanipulated Haploidentical Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Using Post Transplant Cyclophosphamide Anti-Gvhd Prophylaxis
Authors: Luca Castagna, Alberto Mussetti, Raynier Devillier, Alida Dominietto, Magda Marcatti, Giuseppe Milone, Francesco Maura, Benedetto Bruno, Sabine Furst, Didier Blaise, Paolo Corradini, Vittorio Montefusco
Journal: Blood (2016)