tbuckley/cabot-search huggingface dataset:
Perspectives of Patients With Cancer on the Ethics of Rapid-Learning Health Systems
Authors: Reshma Jagsi, Kent A. Griffith, Aaron Sabolch, Rochelle Jones, Rebecca Spence, Raymond De Vries, David Grande, Angela R. Bradbury
Journal: Journal of Clinical Oncology (2017)

Purpose To inform the evolving implementation of CancerLinQ and other rapid-learning systems for oncology care, we sought to evaluate perspectives of patients with cancer regarding ethical issues. Methods Using the GfK Group online research panel, representative of the US population, we surveyed 875 patients with cancer; 621 (71%) responded. We evaluated perceptions of appropriateness (scored from 1 to 10; 10, very appropriate) using scenarios and compared responses by age, race, and education. We constructed a scaled measure of comfort with secondary use of deidentified medical information and evaluated its correlates in a multivariable model. Results Of the sample, 9% were black and 9% Hispanic; 38% had completed high school or less, and 59% were age ≥ 65 years. Perceptions of appropriateness were highest when consent was obtained and university researchers used data to publish a research study (weighted mean appropriateness, 8.47) and lowest when consent was not obtained and a pharmaceutical company used data for marketing (weighted mean appropriateness, 2.7). Most respondents (72%) thought secondary use of data for research was very important, although those with lower education were less likely to endorse this (62% v 78%; P < .001). Overall, 35% believed it was necessary to obtain consent each time such research was to be performed; this proportion was higher among blacks/Hispanics than others (48% v 33%; P = .02). Comfort with the use of deidentified information from medical records varied by scenario and overall was associated with distrust in the health care system. Conclusion Perceptions of patients with cancer regarding secondary data use depend on the user and the specific use of the data, while also frequently differing by patient sociodemographic factors. Such information is critical to inform ongoing efforts to implement oncology learning systems.
Association of humoral antitumor response with clinical benefit in catumaxomab-treated malignant ascites patients: Results from a phase IIIb study.
Authors: Peter Ruf, Ivonne Suckstorff, Michael Jäger, Christine Ernst, Diane Seimetz, Horst Lindhofer
Journal: Journal of Clinical Oncology (2012)

2584 Background: The bispecific antibody catumaxomab (anti-EpCAM x anti-CD3) which is approved for the treatment of malignant ascites (MA) patients (pts) in the EU elicits a humoral immune response against tumor-associated antigens. Here we present follow up data analyzing the influence of this antibody response on puncture free (PFS) and overall survival (OS). Methods: In the course of the phase IIIb study CASIMAS, MA pts with EpCAM positive tumors were treated with/without prednisolone premedication by 4 infusions of 10, 20, 50 and 150 µg of catumaxomab over 11 days (d). EpCAM and HER2-specific antibody responses in plasma samples of 23 pts were measured by ELISA. Additionally, samples of 5 pts receiving a second treatment cycle were analyzed. Pts with significant increase (≥ 2) or de novo development of anti-tumor antibodies within 38 d after treatment start were defined as responders (R). Non responders (NR) showed no humoral response by d 38 or died before. PFS and OS of R and NR were compared by Kaplan Meier analysis. Results: 11 of 23 pts (48%) showed an anti-EpCAM response and 14 of 23 pts (61%) developed HER2-specific antibodies. 6 pts (26%) reacted positive against both antigens, 4 pts (17%) had neither response. In contrast to the EpCAM R group where 73% of pts displayed detectable antibodies prior to therapy, antibodies against HER2 developed de novo. Of note, 4 of 5 individuals who received a second treatment cycle after recurring MA demonstrated an anti-HER2 Ig booster reaction which was stronger and faster in comparison to pts who received only one treatment cycle (median values at d 18: 65 vs. 11 ng/ml). Most important, there was an almost 6 fold increase in median PFS between the HER2 R and NR group (68 vs 12 d, p = 0.044 (log-rank). There was also a trend towards improved OS for pts showing either anti-HER2 and/or anti-EpCAM responses (n=19) in comparison to pts with no response at all (n=4; 143 vs. 67 d, median, p = 0.054). Conclusions: The results indicate that active anti-tumor immunization triggered by catumaxomab treatment in MA pts is associated with improved clinical outcome. Further investigations of these vaccine-like effects with higher pts numbers are warranted.
Response to Comment on “Epigenetic activation of the drug transporter OCT2 sensitizes renal cell carcinoma to oxaliplatin”
Authors: Xiaoli Zheng, Yanqing Liu, Qinqin Yu, Hua Wang, Fuqing Tan, Qianying Zhu, Lingmin Yuan, Huidi Jiang, Su Zeng, Lushan Yu
Journal: Science Translational Medicine (2017)

OCT2 plays a key role in synergy between decitabine and oxaliplatin in renal cell carcinoma cell lines.
Gursharan Singh Chhatwal
Authors: J K Anand, Friedrich Flachsbart
Journal: BMJ (2017)

Gursharan Singh Chhatwal was born in Patiala, Punjab, India. At university he collected numerous academic prizes. After qualifying he worked at the Haffkine Institute in Bombay, where, in 1975, he completed his PhD on the venoms of Indian elapid snakes (cobras). From 1976 to 1978 he was a fellow of the Japan …
TRTH-33. COMPARATIVE PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS OF BRAF AND MEK INHIBITORS IN A NONHUMAN PRIMATE MODEL
Authors: Louis Rodgers, Cynthia M Lester McCully, Andrea Gross, Cody Peer, Rafael Cruz, William D Figg, Brigette Widemann, Katherine Warren
Journal: Neuro-Oncology (2017)

PURPOSE: BRAFV600E mutations are present in several pediatric CNS tumors, particularly pilocytic astrocytomas, gangliogliomas and pleomorphic xanthochromic astrocytomas. Several BRAF inhibitors are under clinical investigation, alone and in combination with MEK inhibitors. To guide the clinical development of BRAF and MEK inhibitors, we evaluated CNS penetration of dabrafenib, selumetinib, vemurafenib, and trametinib (using CSF as a surrogate) in a nonhuman primate model predictive of pharmacokinetics (PK) in pediatric populations. METHODS: This study was approved by the NCI Animal Care and Use Committee. Agents were administered orally to rhesus macaques (n=4), with human equivalent dosing as follows: dabrafenib (161 mg/m2) and selumetinib (50 mg/m2). Planned studies include vemurafenib (516 mg/m2) and trametinib (1.1 mg/m2). Serial, paired plasma and CSF samples were collected from 0–24 hr for dabrafenib and 0–48 hr for selumetinib. Dabrafenib was quantified using a validated ultra HPLC-MS/MS method (lower limit of quantitation (LLOQ) in plasma and CSF = 1 and 0.1 ng/mL, respectively). Selumetinib was quantified by Covance Bioanalytical Services (LLOQ = 0.5 ng/mL in plasma and CSF). PK parameters were calculated using noncompartmental methods. RESULTS: In plasma, mean half-life and dose-normalized AUCinf for dabrafenib were 3.2 (±1.2) hr and 73.9 (±34.0) hr*ng/mL/mg, respectively, and for selumetinib, 10.8 (± 2.5) hr and 122 (± 17.8) hr*ng/mL/mg, respectively. In CSF, 5.0 (±1.7) hr and 0.43 (±0.21) hr*ng/mL/mg, respectively. CSF levels of selumetinib were detectable in one animal, with an AUCinf of 0.39 hr*ng/mL/mg. CSF penetration of dabrafenib and selumetinib were poor (0.57 (±0.18) % and 0.4%, respectively). CONCLUSIONS: Quantifiable concentrations of dabrafenib were found in plasma and CSF for 24 hr after administration, but, as with selumetinib, CSF penetration was low. Due to inter-animal variability, an additional animal will be studied. Alternate delivery methods (intranasal and intrathecal) may be useful to evaluate in efforts to increase CNS exposure.
Disrupted development and integrity of frontal white matter in patients treated for pediatric medulloblastoma
Authors: John O Glass, Robert J Ogg, Jung W Hyun, Julie H Harreld, Jane E Schreiber, Shawna L Palmer, Yimei Li, Amar J Gajjar, Wilburn E Reddick
Journal: Neuro-Oncology (2017)

Treatment of pediatric medulloblastoma is associated with known neurocognitive deficits that we hypothesize are caused by microstructural damage to frontal white matter (WM).Longitudinal MRI examinations were collected from baseline (after surgery but before therapy) to 36 months in 146 patients and at 3 time points in 72 controls. Regional analyses of frontal WM volume and diffusion tensor imaging metrics were performed and verified with tract-based spatial statistics. Age-adjusted, linear mixed-effects models were used to compare patient and control images and to associate imaging changes with Woodcock-Johnson Tests of Cognitive Abilities.At baseline, WM volumes in patients were similar to those in controls; fractional anisotropy (FA) was lower bilaterally (P < 0.001) and was associated with decreased Processing Speed (P = 0.014) and Broad Attention (P = 0.025) performance at 36 months. During follow-up, WM volumes increased in controls but decreased in patients (P < 0.001) bilaterally. Smaller WM volumes in patients at 36 months were associated with concurrent decreased Working Memory (P = 0.026) performance.Lower FA in patients with pediatric medulloblastoma compared with age-similar controls indicated that patients suffer substantial acute microstructural damage to supratentorial frontal WM following surgery but before radiation therapy or chemotherapy. Additionally, this damage to the frontal WM was associated with decreased cognitive performance in executive function 36 months later. This early damage also likely contributed to posttherapeutic failure of age-appropriate WM development and to the known association between decreased WM volumes and decreased cognitive performance.
Melatonin Suppresses Neuropathic Pain via MT2-Dependent and -Independent Pathways in Dorsal Root Ganglia Neurons of Mice
Authors: Jia-Ji Lin, Ye Lin, Tian-Zhi Zhao, Chun-Kui Zhang, Ting Zhang, Xiao-Li Chen, Jia-Qi Ding, Ting Chang, Zhuo Zhang, Chao Sun, Dai-Di Zhao, Jun-Lin Zhu, Zhu-Yi Li, Jin-Lian Li
Journal: Theranostics (2017)

Melatonin (Mel) and its receptors (MT1 and MT2) have a well-documented efficacy in treating different pain conditions. However, the anti-nociceptive effects of Mel and Mel receptors in neuropathic pain (NP) are poorly understood. To elucidate this process, pain behaviors were measured in a dorsal root ganglia (DRG)-friendly sciatic nerve cuffing model. We detected up-regulation of MT2 expression in the DRGs of cuff-implanted mice and its activation by the agonist 8-M-PDOT (8MP). Also, Mel attenuated the mechanical and thermal allodynia induced by cuff implantation. Immunohistochemical analysis demonstrated the expression of MT2 in the DRG neurons, while MT1 was expressed in the satellite cells. In cultured primary neurons, microarray analysis and gene knockdown experiments demonstrated that MT2 activation by 8MP or Mel suppressed calcium signaling pathways via MAPK1, which were blocked by RAR-related orphan receptor alpha (RORα) activation with a high dose of Mel. Furthermore, expression of nitric oxide synthase 1 (NOS1) was down-regulated upon Mel treatment regardless of MT2 or RORα. Application of Mel or 8MP in cuff-implanted models inhibited the activation of peptidergic neurons and neuro-inflammation in the DRGs by down-regulating c-fos, calcitonin gene-related peptide [CGRP], and tumor necrosis factor-1α [TNF-1α] and interleukin-1β [IL-1β]. Addition of the MT2 antagonist luzindole blocked the effects of 8MP but not those of Mel. In conclusion, only MT2 was expressed in the DRG neurons and up-regulated upon cuff implantation. The analgesic effects of Mel in cuff-implanted mice were closely associated with both MT2-dependent (MAPK-calcium channels) and MT2-independent (NOS1) pathways in the DRG.
Age and sport are associated with higher odds of playing through a concussion and delayed removal from play
Authors: Scott L Zuckerman, Andrew W Kuhn, Aaron M Yengo-Kahn, Zachary Y Kerr, Doug J Totten, Gary S Solomon, Allen K Sills
Journal: British Journal of Sports Medicine (2017)

Objective To elucidate situational factors and individual characteristics related to playing through a sport-related concussion (SRC) and delayed removal from play. Design Retrospective cross-sectional analysis. Setting A single comprehensive sports-concussion centre. Participants 250 middle school, high school, and collegiate athletes who sustained an SRC and presented to a regional concussion center between 2011 and 2015. Intervention Standardised in-depth phone interviews. Outcome measures Gender, race, age, competition level, sport, concussion history, practice/game, and collision awareness, among other variables, were incorporated into a multivariate regression model to determine if any of these variable could significantly predict the likelihood of playing through a sport-related concussion versus immediate removal from play. Main results Age (p=0.047) and sport (p=0.006) were both significantly associated with playing through a concussion. For every additional year of age, the odds of playing through an SRC decreased by 1.32 [95% CI: 1.00–1.72]. Football players were much more likely to attempt to “play through” a concussion when compared to baseball/softball, basketball, cheerleading, lacrosse, rugby and volleyball athletes (OR 5.41 [95% CI: 1.62–18.2] to 71.4 [95% CI: 4.93–1,000] times the odds of playing through an SRC for various sports, with all differences reaching statistical significance). Conclusions Younger age and certain sports (football) were significantly associated with delayed removal from play after a SRC in middle school, high school, and collegiate athletes. Given these results, sports medicine practitioners may be better able to identify situational and individual characteristics of athletes who may be more likely play through a SRC. Competing interests GS Solomon receives consulting fees from the Tennessee Titans (NFL), the Nashville Predators (NHL), and the athletic departments of several universities, all fees paid to institution. In addition he is a member of the ImPACT Scientific Advisory Board, and receives reimbursement for expenses to board meetings. AK Sills is a consulting physician to the Nashville Predators (uncompensated) and also serves as an unaffiliated neurotrauma consultant for the NFL. SL Zuckerman, AW Kuhn, AM Yengo-Kahn, ZY Kerr, DJ Totten, report no conflicts of interest.
Effectiveness of psychoeducational interventions for family carers of people with psychosis: A systematic review and meta-analysis
Authors: Jacqueline Sin, Steve Gillard, Debbie Spain, Victoria Cornelius, Tao Chen, Claire Henderson
Journal: Clinical Psychology Review (2017)

Psychoeducational interventions for family carers of people with psychosis are effective for improving compliance and preventing relapse. Whether carers benefit from these interventions has been little explored. This systematic review investigated the effectiveness of psychoeducation for improving carers' outcomes, and potential treatment moderators. We searched for randomised controlled trials (RCTs) published in English or Chinese in eight databases. Carers' outcomes included wellbeing, quality of life, global morbidities, burden, and expressed emotion. Thirty-two RCTs were included, examining 2858 carers. Intervention duration ranged from 4 to 52weeks, and contact times ranged from 6 to 42hours. At post intervention, findings were equivocal for carers' wellbeing (SMD 0.103, 95% CI -0.186 to 0.392). Conversely, psychoeducation was superior in reducing carers' global morbidities (SMD -0.230, 95% CI -0.386 to -0.075), perceived burden (SMD -0.434, 95% CI -0.567 to -0.31), negative caregiving experiences (SMD -0.210, 95% CI -0.396 to -0.025) and expressed emotion (SMD -0.161, 95% CI -0.367 to -0.045). The lack of available data precluded meta-analysis of outcomes beyond short-term follow-up. Meta-regression revealed no significant associations between intervention modality, duration, or contact time and outcomes. Further research should focus on improving carers' outcomes in the longer-term and identifying factors to optimise intervention design.
Abstract 245: Cardiac Stem Cells and Myocyte Regeneration in Diabetic Cardiomyopathy
Authors: Barbara Ogorek, Alex Matsuda, Ewa Wybieralska, James Kostyla, Giulia Borghetti, Maria Virginia Caballero, Antonio Canata, Andrea Sorrentino, Annarosa Leri, Piero Anversa, Marcello Rota, Jan Kajstura
Journal: Circulation Research (2013)

The mammalian heart contains a pool of resident c-kit-positive cardiac stem cells (CSCs), raising questions concerning their role in the etiology of the diabetic myopathy. The objective of the current study was to determine whether the negative effects of diabetes on the adult heart are dictated by defects in CSC growth and lineage commitment. Type I insulin-dependent diabetes mellitus was induced in mice by streptozotocin administration. The kinetics of CSCs and cardiomyocytes was measured 3, 7, 10, 20, and 30 days after the onset of diabetes, by implementing a hierarchically structured cell system, which allows the quantitative analysis of the rate of cell turnover. The multiple variables required to apply this mathematical model were measured by confocal microscopy. They included first the number of CSCs, LCCs (lineage committed cells: myocyte progenitors-precursors), transit amplifying myocytes, and post-mitotic myocytes in the left ventricular (LV) myocardium. Additionally, the fraction of cycling CSCs and the length of their cell cycle were measured, together with the number of cardiomyocytes dying by apoptosis and necrosis. The specificity of labeling was documented by spectral analysis. The diabetic heart was characterized by a severe time-dependent loss in LV post-mitotic myocytes, dictated primarily by a defect in cell renewal. Under control conditions, 20% of myocytes were replaced per month in the adult mouse heart through activation, cell cycle reentry, and differentiation of CSCs. This value decreased sharply to 6%, 1.4%, 0.5%, 0.07%, and 0.05% at 3, 7, 10, 20 and 30 days after the administration of streptozotocin. The myocardium showed a progressive increase in old cardiomyocytes expressing the senescence-associated protein p16INK4a and p53. Importantly, the severe impairment in myocyte regeneration was coupled with an increase in LV end-diastolic pressure, and a decrease in LV systolic pressure, LV developed pressure, positive and negative dP/dt. Thus, our data indicate that the diabetic myopathy has to be viewed as a stem cell disease in which the decrease in the number of myocytes is a secondary event, resulting from defects in replication and lineage specification of cardiac stem cells.
Preserving the Fogarty International Center — Benefits for Americans and the World
Authors: Paul K. Drain, Ramnath Subbaraman, Douglas C. Heimburger
Journal: New England Journal of Medicine (2017)

Preserving Health Research Funding (08:48)Download The efforts of the NIH's Fogarty International Center have produced medical innovations that transcend borders. Its closure would not only be detrimental for global health but would also affect the health of Americans and impede training of U.S. scientists.
Abstract #1332: DNA promoter methylation mediates silencing of the tumor suppressor klotho in breast cancer cells
Authors: Michal Shulman, Tami Rubinek, Ido Wolf
Journal: Cancer Research (2009)

Klotho is a 1012 amino acid-long single pass transmembrane protein, which is expressed in the brain, kidney and in various endocrine-related tissues. Its extracellular domain is composed of two internal repeats, KL1 and KL2, which exhibit a weak similarity to each other, share sequence homology to \#946;-glucosidase, but lack glucosidase activity. We have recently discovered that klotho expression slows growth of breast cancer cells and inhibits the insulin growth factor (IGF)-1 pathway. Using breast tissue arrays, we analyzed klotho expression in 58 early stage invasive breast cancer samples, and 47 ductal carcinoma in situ (DCIS) samples. Normal tissue adjacent to DCIS and invasive breast cancer was also analyzed. High klotho expression was noted in 90% of the normal breast samples adjacent to IDC or DCIS, compared to only 17% in DCIS and 22% IDC (p  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1332.
Interferon-Free Regimens in Hepatitis B Surface Antigen/Anti–Hepatitis C Virus Positive Patients: The Need to Control Hepatitis B Virus Replication to Avoid Hepatitis B Virus Reactivation
Authors: Margherita Macera, Maria Stanzione, Vincenzo Messina, Giuseppe D'Adamo, Vincenzo Sangiovanni, Lucia Mioglioresi, Luca Fontanella, Stefania De Pascalis, Gianfranca Stornaiuolo, Alfonso Galeota Lanza, Tiziana Ascione, Evangelista Sagnelli, Ivan Gentile, Guido Piai, Giovanni Battista Gaeta, Nicola Coppola
Journal: Clinical Gastroenterology and Hepatology (2017)
LGG-07. LOW-GRADE GLIOMA COMBINATION CHEMOTHERAPY MAY BE EFFECTIVE IN BRAF V600E CODON-MUTATED OPTIC PATHWAY GANGLIOGLIOMAS
Authors: Jeffrey Murray, David Donahue, Hayden Head, Mandy Mansell, Linda Margraf
Journal: Neuro-Oncology (2017)

INTRODUCTION: Gangliogliomas (GG) are low-grade mixed glial/neuronal tumors typically seen in children and young adults. They commonly arise in the cerebrum, cerebellum and brainstem and are often associated with seizures. Management is typically surgical. Adjuvant radiation therapy is occasionally used, but primary treatment with chemotherapy is not considered standard. Very rarely, GG involves the optic pathway, with this location being rarely amenable to surgery, threatens vision and mandates creative treatment approaches. Many GG have mutations in the BRAF proto-oncogene, critical for regulating the MAP kinase/ERKs signaling pathway which affects cell division and differentiation. METHODS/RESULTS: A 4-year-old boy presented with a many-year history of abnormal eye movements and progressive visual decline. Ophthalmologic examination revealed esotropia, optic atrophy and poor visual acuity. MRI scanning revealed an extensive bilateral infiltrative tumor involving the optic pathway, hypothalamus, thalami, midbrain and temporal lobes. An image-guided stereotactic biopsy revealed a typical WHO grade 1 ganglioglioma and tumor cell pyrosequencing revealed a BRAF codon 600 (V600E) mutation. There was no clinical or imaging evidence of NF1. Given the tumor’s unresectability and the reticence to use ionizing radiation therapy at such a young age, combination chemotherapy using carboplatin and vincristine was started. Tumor extent and contrast enhancement decreased dramatically during the one year chemotherapy journey and ophthalmologic parameters stabilized. CONCLUSIONS: The management of GG is typically surgical, with careful use of radiation therapy for select circumstances. Chemotherapy is not typically considered an effective therapy. However, this case suggests that GG can be chemosensitive, to standard low-grade glioma chemotherapy. The presence of the BRAF V600E mutation is common in GG and may afford a therapeutic management strategy for select cases, using BRAF inhibitors such as vemurafenib and dabrafenib. We recommend the ongoing reporting of novel treatment strategies for challenging-site GG and suggest BRAF analysis for such tumors.