tbuckley/cabot-search huggingface dataset:
Are schizophrenia and affective disorder related? preliminary data from a family study
Authors: M A Taylor, S A Berenbaum, V C Jampala, C R Cloninger
Journal: American Journal of Psychiatry (1993)

Most investigators presume that schizophrenia and affective disorder are separate diseases. Others have proposed alternatives to this Kraepelinian view. These alternatives were addressed by preliminary analyses of data from a family study of psychopathology.The authors identified 1,895 first-degree relatives of 166 patients with DSM-III schizophrenia, 71 patients with affective disorder, and 85 medical comparison probands; 949 relatives were blindly diagnosed.The risks for schizophrenia and affective disorder (unipolar melancholia and bipolar disorder combined) were significantly higher in the relatives of the schizophrenic probands and the relatives of the probands with affective disorder than in the relatives of the comparison probands. The morbid risk for nonmelancholic depressions was not significantly higher. Among the relatives of the schizophrenic probands, the risk for affective disorder was highest among the relatives of the patients with "core" schizophrenia, who were younger at illness onset, had chronic illness, had severe emotional blunting, and showed few affective features.Despite limitations, these preliminary analyses, consistent with other studies, suggest some familial relationship between schizophrenia and severe forms of affective disorder.
Phase I study of RG7155, a novel anti-CSF1R antibody, in patients with advanced/metastatic solid tumors.
Authors: Carlos Alberto Gomez-Roca, Philippe Alexandre Cassier, Antoine Italiano, Michael Cannarile, Carola Ries, Anne Brillouet, Claudia Mueller, Anna-Maria Jegg, Georgina Meneses-Lorente, Monika Baehner, Keelara Abiraj, Delphine Loirat, Maud Toulmonde, Sandra P. D'Angelo, Kristy Weber, Mario Campone, Dominik Ruettinger, Jean-Yves Blay, Jean-Pierre Delord, Christophe Le Tourneau
Journal: Journal of Clinical Oncology (2015)

3005 Background: Tumor associated macrophages (TAM) suppress anti-tumor immunity and have been associated with poor prognosis in several types of cancer. CSF-1 is a critical survival and differentiation factor for TAM. Preclinically, TAM depletion has been shown to enhance/restore the activity of several clinically established treatment modalities and also novel immunotherapies. Here, we report on the phase I study of a monoclonal antibody (RG7155) that blocks the dimerization interface of the CSF1 receptor (CSF1R). Methods: In this dose-escalation and extension study, patients with advanced solid tumors or locally advanced pigmented villonodular synovitis (PVNS, a CSF1-driven "model disease" for clinical investigation of CSF1R targeting approaches) received RG7155 IV at dose levels between 100 – 3000mg Q2W. Primary objectives were to assess safety, tolerability, pharmaco-kinetics and –dynamics. Clinical activity was evaluated using FDG-PET (at 4 weeks after treatment start; EORTC criteria) and CT/MRI (every 6 weeks; RECIST 1.1). PD markers in pre- and on-treatment biopsies of tumor and surrogate skin tissue as well as peripheral blood were analyzed. Results: To date, data is available for 44 patients with solid tumors and 29 patients with PVNS. RG7155 treatment led to significant reduction of CSF1R+ and CD68/CD163+ macrophages in tumor and surrogate skin tissue and rapid elimination of CD14DimCD16Bright peripheral monocytes. In solid tumors, partial metabolic responses (FDG-PET) and disease stabilization were observed in 5/44 and 6/40 patients, respectively. 24/28 patients with PVNS experienced an objective response (best time point response). RG7155 was well tolerated. The MTD was not reached. Grade 3/4 AEs assessed as related to RG7155 were reported in 18% of patients (21/114). Most frequent AEs (any grade) were asthenia (70% of patients), peripheral edema (44%) and pyrexia (27%). Conclusions: RG7155 was well tolerated and biologically highly active. RG7155 is now being tested as a promising combination partner with immunotherapies (e.g. Phase Ib study (NCT02323191) in combination with Mab-PDL1 (MPDL3280A) is ongoing). Clinical trial information: NCT01494688.
Methionine and Kynurenine Activate Oncogenic Kinases in Glioblastoma, and Methionine Deprivation Compromises Proliferation
Authors: Kamalakannan Palanichamy, Krishnan Thirumoorthy, Suman Kanji, Nicolaus Gordon, Rajbir Singh, John R. Jacob, Nikhil Sebastian, Kevin T. Litzenberg, Disha Patel, Emily Bassett, Brinda Ramasubramanian, Tim Lautenschlaeger, Steven M. Fischer, Abhik Ray-Chaudhury, Arnab Chakravarti
Journal: Clinical Cancer Research (2016)

Abstract Purpose: We employed a metabolomics-based approach with the goal to better understand the molecular signatures of glioblastoma cells and tissues, with an aim toward identifying potential targetable biomarkers for developing more effective and novel therapies. Experimental Design: We used liquid chromatography coupled with mass spectrometry (LC-MS/Q-TOF and LC-MS/QQQ) for the discovery and validation of metabolites from primary and established glioblastoma cells, glioblastoma tissues, and normal human astrocytes. Results: We identified tryptophan, methionine, kynurenine, and 5-methylthioadenosine as differentially regulated metabolites (DRM) in glioblastoma cells compared with normal human astrocytes (NHAs). Unlike NHAs, glioblastoma cells depend on dietary methionine for proliferation, colony formation, survival, and to maintain a deregulated methylome (SAM:SAH ratio). In methylthioadenosine phosphorylase (MTAP)-deficient glioblastoma cells, expression of MTAP transgene did not alter methionine dependency, but compromised tumor growth in vivo. We discovered that a lack of the kynurenine-metabolizing enzymes kynurenine monooxygenase and/or kynureninase promotes the accumulation of kynurenine, which triggers immune evasion in glioblastoma cells. In silico analysis of the identified DRMs mapped the activation of key oncogenic kinases that promotes tumorigenesis in glioblastoma. We validated this result by demonstrating that the exogenous addition of DRMs to glioblastoma cells in vitro results in oncogene activation as well as the simultaneous downregulation of Ser/Thr phosphatase PP2A. Conclusions: We have connected a four-metabolite signature, implicated in the methionine and kynurenine pathways, to the promotion and maintenance of glioblastoma. Together, our data suggest that these metabolites and their respective metabolic pathways serve as potential therapeutic targets for glioblastoma. Clin Cancer Res; 22(14); 3513–23. ©2016 AACR.
Nephrotoxicity of amphotericin B is attenuated by solubilizing with lipid emulsion.
Authors: E L Dórea, L Yu, I De Castro, S B Campos, M Ori, E M Vaccari, C da S Lacaz, A C Seguro
Journal: Journal of the American Society of Nephrology (1997)

Nephrotoxicity is the major adverse effect of conventional amphotericin B (AMB/D), often limiting administration of full dosage. The new liposomal amphotericin B seems to be less toxic. The new liposomal amphotericin B seems to be less toxic. In this study, it is proposed that solubilizing the standard AMB/D preparation with 10% lipid emulsion will attenuate nephrotoxicity. Rats were injected with either AMB/D (Fungizone), AMB, AMB/D plus lipid emulsion (AMB/D/LE), or sodium deoxycholate (D). Renal function studies were performed on day 5. To assess a direct tubular toxic effect, isolated rat proximal tubule suspensions and inner medullary collecting duct cells in culture were exposed to AMB/D, AMB, AMB/D/LE, liposomal amphotericin B, and D for 60 min in normoxia. Lactate dehydrogenase (LDH) release was assessed as an index of cell injury. Creatinine clearance (ml/min per 100 g) averaged 0.79 +/- 0.04 in control rats, 0.29 +/- 0.09 in AMB rats (P < 0.001 versus control), 0.38 +/- 0.04 in AMB/D rats, 0.46 +/- 0.05 in D rats, and 0.78 +/- 0.03 in AMB/LE rats. Renal blood flow (ml/min per 100 g) was 3.45 +/- 0.31 in control, 1.29 +/- 0.28 in AMB, 1.42 +/- 0.23 in AMB/D, 3.03 +/- 0.39 in D, and 2.71 +/- 0.21 in AMB/D/LE rats. The fractional excretion of potassium (%) was 27.3 +/- 1.18 in control rats, 61.6 +/- 7.00 in AMB/D rats, 58.4 +/- 15.32 in AMB rats, and 37.9 +/- 2.06 in AMB/D/LE rats. LDH release (%) in proximal tubules incubated with AMB/D and D was 43.6 +/- 3.39 and 58.6 +/- 4.20, respectively. Addition of lipid emulsion decreased LDH release: 21.6 +/- 1.22 for AMB/D/LE and 26.4 +/- 3.03 for deoxycholate plus lipid emulsion. AMB did not demonstrate any toxic effect in proximal tubule suspensions. D was not toxic to inner medullary collecting duct cells at 0.16 mg/ml, whereas D at a higher dose and AMB induced a significant LDH release. Addition of lipid emulsion did not affect the antifungal activity as assessed by the Etest method. In conclusion, an alternative way of administering standard AMB with reduced nephrotoxicity is proposed.
Experts seek ban on tackling in school rugby to prevent child injuries
Authors: Adrian O’Dowd
Journal: BMJ (2016)

Leading clinicians and academics have called for a ban on tackling in rugby played at schools, in an open letter to government officials in the United Kingdom.1

The 73 signatories included public health professionals, academics, GPs, and sports scholars from across the globe, who voiced their concerns over the harms that can be caused by tackling during this school sport activity. Rugby representatives and the government, however, have argued that the sport helps build character and that safety is taken seriously and monitored carefully.

Rugby is a high impact collision sport, said the letter, …
Rarer Manifestations of Herpes Zoster
Authors: T. Parkinson
Journal: BMJ (1948)

Herpes zoster usually presents as a mild illness with a characteristic rash accompanied by local pain and preceded by a varying degree of constitutional disturbance.Post- herpetic neuralgia is a common sequel, but complications are rare.Of the complications which have been recorded a concomitant varicelliform eruption is perhaps the most common.
Discovery of microRNAs in tumor tissue predictive of time to progression and overall survival in patients with colorectal cancer treated with first-line capecitabine, oxaliplatin, and bevacizumab.
Authors: Mogens Karsboel Boisen, Christian Dehlendorff, Dorte Linnemann, Kristina Ranc, Benny V. Jensen, Estrid V. Høgdall, Jim S. Larsen, Svend Erik Nielsen, Klaus Kaae Andersen, Julia S. Johansen
Journal: Journal of Clinical Oncology (2012)

461 Background: The aim was to identify predictive and prognostic microRNAs (miRNAs) in cancer tissue samples from patients with metastatic colorectal cancer (mCRC) treated with 1.-line capecitabine, oxaliplatin, and bevacizumab (CapOxBev). Methods: Patients with mCRC treated with 1.-line CapOxBev were identified from 7 hospital databases and clinical and pathological data was extracted retrospectively. Formalin-fixed paraffin-embedded (FFPE) tissue samples from primary tumors were collected and RNA was purified from 3 x 10 µm sections, without micro-dissection. MiRNA expression was measured using TaqMan® Array Human MicroRNA A and B cards (Applied Biosystems) profiling 754 miRNAs. Raw miRNA expression values were checked for outliers and data was corrected using spike-in values. In a univariate selection method, each miRNA was related to time-to-progression (TTP) and overall survival (OS) using Cox proportional hazards model (threshold p &lt; 0.001). Candidate miRNAs were tested using Akaike’s Information Criterion in a multivariate analysis corrected for age, sex, histology, number of metastatic sites, primary location, and prior adjuvant treatment. Results: Samples from 212 patients were profiled and 205 and 192 had acceptable miRNA and outcome data available for final analysis of OS and TTP, respectively. Four miRNAs were found to be predictive for TTP and two for OS. Higher expression of miRNAs A, B, and C and lower expression of miRNA D was predictive of longer TTP, and higher expression of miRNAs E and F predicted longer OS. Conclusions: Four miRNAs measured in archival FFPE samples of primary CRC tumors from patients treated with 1.-line CapOxBev were predictors of TTP and two others of OS. Three of the miRNAs found have reported roles in angiogenesis pathways indicating that they may be biomarkers for bevacizumab efficacy. A validation study in 500 patients is on-going. [Table: see text]
Monitoring colonoscopy withdrawal time significantly improves the adenoma detection rate and the performance of endoscopists
Authors: Stephan Vavricka, Michael Sulz, Lukas Degen, Roman Rechner, Michael Manz, Luc Biedermann, Christoph Beglinger, Shajan Peter, Ekaterina Safroneeva, Gerhard Rogler, Alain Schoepfer
Journal: Endoscopy (2016)

<b>Background and study aims:</b> The recommended minimum withdrawal time for screening colonoscopy is 6 minutes. Adenoma detection rates (ADRs) increase with longer withdrawal times. We aimed to compare withdrawal times and ADRs of endoscopists unaware of being monitored vs. aware. <b>Patients and methods:</b> Seven experienced gastroenterologists prospectively performed 558 screening colonoscopies during a 9-month period in a Swiss University hospital. Colonoscopy withdrawal times were first measured without the gastroenterologists' knowledge of being monitored (n = 355 colonoscopies) and then with their knowledge (n = 203 colonoscopies). <b>Results:</b> The median withdrawal time when gastroenterologists were unaware of being monitored was 4.5 minutes (interquartile range [IQR] 4 – 5.5 minutes) without intervention and 6 minutes (IQR 4 – 9 minutes) with intervention, increasing significantly to 7.3 minutes (IQR 6.5 – 9 minutes) and 8 minutes (IQR 7 – 11 minutes), respectively, when they were aware of being monitored (<i>P</i> < 0.001 both for colonoscopies with and without intervention). The ADR increased from 21.4 % when the gastroenterologists were unaware of being monitored to 36.0 % when they were aware (<i>P</i> < 0.001). In the multivariate regression model, the endoscopists knowing they were being monitored was the strongest factor associated with ADR (odds ratio 4.417; 95 % confidence interval [CI] 2.241 – 8.705; <i>P</i> < 0.001). <b>Conclusions:</b> Colonoscopy withdrawal time in unmonitored gastroenterologists is shorter than recommended and increases with awareness of monitoring. ADR significantly increases when gastroenterologists are aware of being monitored. Implementation of systematic monitoring, and analysis of withdrawal time and ADR for each endoscopist may help to increase the ADR.
Effect of Epidermal Growth Factor on Proliferation of Human Tumor Cells in Soft Agar&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: A W Hamburger, C P White, R W Brown
Journal: JNCI Journal of the National Cancer Institute (1981)

The effect of epidermal growth factor (EGF) and fibroblast feeder layers on the proliferation of human tumor cells in soft agar was examined. The addition of EGF to medium supporting growth of tumor cells significantly increased (P≤0.02) the number of colonies grown from the cells of 36 of 58 patients (62%) with a variety of neoplasms. The increase in the number of colonies was dependent on the concentration of EGF and was maximal at a concentration of 50 ng EGF/ml. The addition of glucocorticoids did not potentiate the effect of EGF. Lethally irradiated fibroblast feeder layers alone only slightly increased the number of colonies. However, the addition of fibroblasts to cultures significantly increased the mitogenic effect of EGF. The results suggest that a proportion of epithelial-derived tumors retain responsiveness in vitro to physiologic growth regulators such as EGF.
Morpho-mathematic biomarkers of bronchodilators' response in COPD patients during resting spontaneous breathing
Authors: Pierantonio Laveneziana, Christian Straus, Thomas Similowski, Patrick Hanusse
Journal: European Respiratory Journal (2014)

FEV 1  is largely used to evaluate the bronchodilators9 response in COPD patients, but under conditions that do not reflect the usual ventilatory constraints. In humans, tidal spontaneous ventilation (V9 E ) exhibits breath-by-breath variability and features mathematical complexity that is compatible with a chaotic structure. Breath-by-breath variability and nonlinear complexity have already been shown to be reliable mathematical biomarkers to describe the ventilatory flow in COPD patients during resting spontaneous breathing (Respir Physiol Neurobiol 2013; 185: 477-80). The current work aims at evaluating the resting ventilatory flow by applying a new technique called “anharmonic morphological analysis of the respiratory signals” (AMARS) which produces objective, accurate and specific measures of the shape of the ventilatory flow.  24 stable COPD patients were studied (16 males; 40-86 years old; FEV 1  = 71±21% pred). Resting V9 E  was recorded for 5-10 minutes before and after a short-acting inhaled bronchodilator (BD). After BD, FEV 1  and inspiratory capacity (IC) increased by 0.14L and 0.21L, respectively; V9 E , tidal volume (V T ) and respiratory frequency (R f ) did not change significantly.  The AMARS identified a subgroup of COPD patients (subgroup A) in which some morpho-mathematic parameters were significantly modified by the BD, and a subgroup B in which no change was detected. Differences between subgroup A and B were related to the BD9 response in IC (A = increase of IC vs. B = no change of IC after BD).  These preliminary data suggest that AMARS is potentially able to identify a BD-related increase in IC only from recording resting spontaneous V9 E  in stable COPD patients.
Human dermal broblasts ameliorate in vitro graft-versushost reactions and are functionally indistinguishable from bone marrow mesenchymal stromal cells
Authors: MA Haniffa, XN Wang, U Holtick, MC Rae, S Alshemali, NJ Reynolds, AM Dickinson, JD Isaacs, Cmu Hilkens, MP Collin
Journal: British Journal of Dermatology (2007)
Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus
Authors: Caroline von Spee-Mayer, Elise Siegert, Dimas Abdirama, Angelika Rose, Anika Klaus, Tobias Alexander, Philipp Enghard, Birgit Sawitzki, Falk Hiepe, Andreas Radbruch, Gerd-Rüdiger Burmester, Gabriela Riemekasten, Jens Y Humrich
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> Defects in regulatory T cell (Treg) biology have been associated with human systemic autoimmune diseases, such as systemic lupus erythematosus (SLE). However, the origin of such Treg defects and their significance in the pathogenesis and treatment of SLE are still poorly understood. <h3>Methods</h3> Peripheral blood mononuclear cells (PBMC) from 61 patients with SLE and 52 healthy donors and in vitro IL-2 stimulated PBMC were characterised by multicolour flow cytometry. Five patients with refractory SLE were treated daily with subcutaneous injections of 1.5 million IU of human IL-2 (aldesleukin) for five consecutive days, and PBMC were analysed by flow cytometry. <h3>Results</h3> Patients with SLE develop a progressive homeostatic dysbalance between Treg and conventional CD4+ T cells in correlation with disease activity and in parallel display a substantial reduction of CD25 expression on Treg. These Treg defects resemble hallmarks of IL-2 deficiency and lead to a markedly reduced availability of functionally and metabolically active Treg. In vitro experiments revealed that lack of IL-2 production by CD4+ T cells accounts for the loss of CD25 expression in SLE Treg, which could be selectively reversed by stimulation with low doses of IL-2. Accordingly, treatment of patients with SLE with a low-dose IL-2 regimen selectively corrected Treg defects also in vivo and strongly expanded the Treg population. <h3>Conclusions</h3> Treg defects in patients with SLE are associated with IL-2 deficiency, and can be corrected with low doses of IL-2. The restoration of endogenous mechanisms of immune tolerance by low-dose IL-2 therapy, thus, proposes a selective biological treatment strategy, which directly addresses the pathophysiology in SLE.
Abstract 11298: Absence of Rare Coding Sequence Variants of Large Effect in GWAS Loci for High-Density Lipoprotein Cholesterol
Authors: Aniruddh P Patel, Daniel B Larach, Gina M Peloso, James P Pirruccello, Namrata Gupta, Daniel J Rader, Sekar Kathiresan
Journal: Circulation (2013)

Background: Common non-coding DNA sequence variants at 47 genomic regions have been associated with plasma high-density lipoprotein cholesterol (HDL-C) in a recently published genome-wide associati...
Sleep duration and risk of all-cause mortality: A flexible, non-linear, meta-regression of 40 prospective cohort studies
Authors: Tong-Zu Liu, Chang Xu, Matteo Rota, Hui Cai, Chao Zhang, Ming-Jun Shi, Rui-Xia Yuan, Hong Weng, Xiang-Yu Meng, Joey S.W. Kwong, Xin Sun
Journal: Sleep Medicine Reviews (2016)
Brief Communication: Abnormal Clones Resembling Those Seen in Blast Crisis Arising in the Spleen in Chronic Myelocytic Leukemia2
Authors: F. Mitelman, P. G. Nilsson, L. Brandt
Journal: JNCI Journal of the National Cancer Institute (1975)

In a patient with chronic myelocytic leukemia, serial chromosome analyses of bone marrow and spleen cells by the Giemsa-banding technique demonstrated a clonal evolution if the Ph1-positive karyotype in the spleen and a probable metastatic colonization of the bone marrow by this clone. The results suggest that, in chronic myelocytic leukemia, the spleen may be a more important site for the development of the blastic transformation than the bone marrow.
Erratum to: ‘Expression of granzyme B sensitizes ALK+ ALCL tumour cells to apoptosis-inducing drugs’
Authors: Jodel D. Pearson, Jingxi Zhang, Zuoqiao Wu, Kayla D. Thew, Katelynn J. Rowe, Julinor T. C. Bacani, Robert J. Ingham
Journal: Molecular Cancer (2016)
Randomized phase II study of metronomic chemotherapy (MC) plus aromatase inhibitor (AI) versus MC alone in postmenopausal hormone receptor-positive, metastatic breast cancer (MBC), with correlative circulating endothelial cell (CEC), circulating endothelial progenitor cell (CEP), VEGF, and VEGFR levels.
Authors: N. Wong, K. Hui, F. Sun, Y. Yap, R. C. Ng, J. W. Chia, L. Ngo, S. Lo
Journal: Journal of Clinical Oncology (2010)

TPS127 Background: Neoadjuvant AI plus MC achieves greater suppression of Ki67 and VEGF in primary breast cancer compared to AI alone (Bottini A et al. J Clin Oncol; 24: 3623, 2006). We previously showed that this combination is active in MBC even among women previously exposed to AI, and hypothesized that MC may reverse AI resistance (T Wai Ming et al. 2009 IMPAKT Breast Cancer Conference, Abstract 308). This study aims to determine if continuation of AI enhances efficacy of MC compared to MC alone in MBC progressing on AI; and whether methotrexate and prednisolone are necessary components of MC. Methods: Primary Objectives: Clinical benefit (CR+PR+SD ≥ 24 weeks) of MC plus AI versus MC alone. Secondary Objectives: PFS, safety, correlating response with angiogenesis biomarkers, contribution of methotrexate and prednisolone to MC activity assessed by change in biomarkers during serial introduction of each drug over a 6 week lead in period. Study Design: Randomized phase II design, 35 patients per arm planned over 2 years, with 90% power to detect 15% Δ over baseline clinical benefit of 25%, 2 sided α 0.05, allowance for 10% dropout rate. Thirteen patients accrued to date. Inclusion Criteria: Postmenopausal, HR+ve MBC, PD on prior AI. Exclusion Criteria: HER2 overexpression, extensive visceral disease, pleural effusion/ascites. Treatment Arm 1: MC plus continuation of prior AI. Arm 2: MC alone MC comprises oral cyclophosphamide (CTX) for initial 2 weeks, then CTX plus methotrexate (MTX) for 2 weeks, then CTX, MTX and prednisolone from week 5 onwards. Correlative Studies: Plasma VEGF, VEGF-C, VEFGR-2 and VEGFR-3 ELISA immunoassays (QVE00B, DVEC00, DVR200, DY 349 respectively, R & D Systems) at baseline and appropriate intervals. BD FACS Canto II flow cytometer using anti-CD31, -CD34, -CD105, -CD106, -CD133, and -P1H12 and appropriate analysis gates will be used to enumerate resting and activated CEC and CEP. No significant financial relationships to disclose.