tbuckley/cabot-search huggingface dataset:
Antipsychotic augmentation vs. monotherapy in schizophrenia: systematic review, meta‐analysis and meta‐regression analysis
Authors: Britta Galling, Alexandra Roldán, Katsuhiko Hagi, Liz Rietschel, Frozan Walyzada, Wei Zheng, Xiao‐Lan Cao, Yu‐Tao Xiang, Mathias Zink, John M. Kane, Jimmi Nielsen, Stefan Leucht, Christoph U. Correll
Journal: World Psychiatry (2017)

Antipsychotic polypharmacy in schizophrenia is much debated, since it is common and costly with unclear evidence for its efficacy and safety. We conducted a systematic literature search and a random effects meta-analysis of randomized trials comparing augmentation with a second antipsychotic vs. continued antipsychotic monotherapy in schizophrenia. Co-primary outcomes were total symptom reduction and study-defined response. Antipsychotic augmentation was superior to monotherapy regarding total symptom reduction (16 studies, N=694, standardized mean difference, SMD=-0.53, 95% CI: -0.87 to -0.19, p=0.002). However, superiority was only apparent in open-label and low-quality trials (both p<0.001), but not in double-blind and high-quality ones (p=0.120 and 0.226, respectively). Study-defined response was similar between antipsychotic augmentation and monotherapy (14 studies, N=938, risk ratio = 1.19, 95% CI: 0.99 to 1.42, p=0.061), being clearly non-significant in double-blind and high-quality studies (both p=0.990). Findings were replicated in clozapine and non-clozapine augmentation studies. No differences emerged regarding all-cause/specific-cause discontinuation, global clinical impression, as well as positive, general and depressive symptoms. Negative symptoms improved more with augmentation treatment (18 studies, N=931, SMD=-0.38, 95% CI: -0.63 to -0.13, p<0.003), but only in studies augmenting with aripiprazole (8 studies, N=532, SMD=-0.41, 95% CI: -0.79 to -0.03, p=0.036). Few adverse effect differences emerged: D2 antagonist augmentation was associated with less insomnia (p=0.028), but more prolactin elevation (p=0.015), while aripiprazole augmentation was associated with reduced prolactin levels (p<0.001) and body weight (p=0.030). These data suggest that the common practice of antipsychotic augmentation in schizophrenia lacks double-blind/high-quality evidence for efficacy, except for negative symptom reduction with aripiprazole augmentation.
Polymorphisms in the survivin gene and the risk of lung cancer
Authors: S. B. Han, J. E. Choi, D. S. Hyun, J. Y. Park
Journal: Journal of Clinical Oncology (2008)

11069 Background: Survivin is an apoptosis inhibitor and plays an important role in the development and progression of cancer. Polymorphisms in the survivin gene may influence survivin production or activity, thereby modulating susceptibility to lung cancer. To test this hypothesis, we investigated the association between survivin polymorphisms and the risk of lung cancer in a Korean population. Methods: We first screened for polymorphisms in the survivin gene by direct sequencing of genomic DNA samples from 27 healthy Koreans. We selected identified SNPs based on their frequency, linkage disequilibrium (LD) status and haplotype tagging status, and then genotyped the selected SNPs in 582 lung cancer patients and 582 healthy controls who were frequency matched for age and gender. Results: We identified 8 single nucleotide polymorphisms (SNPs): 6 known SNPs [-644T>C, -625G>C, - 31C>G, 9194A>G (K129E), 9386T>C and 9809T>C] and 2 novel SNPs (9974C>T and 10347G>A). Among the SNPs studied, only the -31C>G genotype distribution was significantly different between the cases and controls (P = 0.04). Individuals with at least one -31G allele were at a significantly decreased risk of lung cancer compared to those individuals with the -31CC genotype [adjusted odds ratio (OR) = 0.74, 95% confidence interval (CI) = 0.57–0.96, P = 0.02]. When the lung cancer cases were categorized by tumor histology, the -31G allele was associated with a significantly decreased risk of adenocarcinoma (adjusted OR = 0.59, 95% CI = 0.41–0.84, P = 0.003). Consistent with the results of the genotyping analysis, the -625G/-31G/9194A/9809T haplotype carrying the -31G allele was associated with a significantly decreased risk of adenocarcinoma (adjusted OR = 0.56, 95% CI = 0.40–0.77, P = 0.0004). The promoter assay revealed the -31G allele to have a significantly lower promoter activity than the -31C allele. Conclusion: These results suggest that the survivin -31C>G polymorphism influences survivin expression, thus contributing to the genetic susceptibility to lung cancer. No significant financial relationships to disclose.
THE TME TRIAL AFTER A MEDIAN FOLLOW-UP OF 10 YEARS: RESULTS WILL BE REPORTED IN A LATE BRAKING ABSTRACT
Authors: W. Van Gijn, C. A. Marijnen, I. D. Nagtegaal, E. K. Kranenbarg, H. Putter, T. Wiggers, H. Rutten, L. Pahlman, B. Glimelius, J. W. Leer, C. J. H. Van de Velde
Journal: Annals of Oncology (2010)
Reduced Frequency of CD4+CD25++CD127low/-FOXP3+ Regulatory T Cells in Patients with Primary Myelofibrosis
Authors: Margherita Massa, Rita Campanelli, Gabriela Fois, Laura Villani, Elisa Bonetti, Paolo Catarsi, Valentina Poletto, Gianluca Viarengo, Vittorio Rosti, Giovanni Barosi
Journal: Blood (2015)
The Effects of Pay-for-Performance Programs on Health, Health Care Use, and Processes of Care
Authors: Aaron Mendelson, Karli Kondo, Cheryl Damberg, Allison Low, Makalapua Motúapuaka, Michele Freeman, Maya O'Neil, Rose Relevo, Devan Kansagara
Journal: Annals of Internal Medicine (2017)

Background: The benefits of pay-for-performance (P4P) programs are uncertain. Purpose: To update and expand a prior review examining the effects of P4P programs targeted at the physician, group, managerial, or institutional level on process-of-care and patient outcomes in ambulatory and inpatient settings. Data Sources: PubMed from June 2007 to October 2016; MEDLINE, PsycINFO, CINAHL, Business Economics and Theory, Business Source Elite, Scopus, Faculty of 1000, and Gartner Research from June 2007 to February 2016. Study Selection: Trials and observational studies in ambulatory and inpatient settings reporting process-of-care, health, or utilization outcomes. Data Extraction: Two investigators extracted data, assessed study quality, and graded the strength of the evidence. Data Synthesis: Among 69 studies, 58 were in ambulatory settings, 52 reported process-of-care outcomes, and 38 reported patient outcomes. Low-strength evidence suggested that P4P programs in ambulatory settings may improve process-of-care outcomes over the short term (2 to 3 years), whereas data on longer-term effects were limited. Many of the positive studies were conducted in the United Kingdom, where incentives were larger than in the United States. The largest improvements were seen in areas where baseline performance was poor. There was no consistent effect of P4P on intermediate health outcomes (low-strength evidence) and insufficient evidence to characterize any effect on patient health outcomes. In the hospital setting, there was low-strength evidence that P4P had little or no effect on patient health outcomes and a positive effect on reducing hospital readmissions. Limitation: Few methodologically rigorous studies; heterogeneous population and program characteristics and incentive targets. Conclusion: Pay-for-performance programs may be associated with improved processes of care in ambulatory settings, but consistently positive associations with improved health outcomes have not been demonstrated in any setting. Primary Funding Source: U.S. Department of Veterans Affairs.
Testicular germ cell tumors with bony metastases: Diagnosis, management, and outcomes (a case series).
Authors: Anna Karpathakis, Mariam Jamal-Hanjani, Amy Kwan, Danish Mazhar, Sarah Maria Rudman, Thomas Powles, Jonathan Shamash, Simon Chowdhury
Journal: Journal of Clinical Oncology (2012)

343 Background: Metastasis of testicular germ cell tumour (GCT) to bone is a rare event and there is little evidence on optimal curative management. Methods: A retrospective review of case records of germ cell tumour patients within the Anglian Germ Cell Cancer Group between 10/01/2005 and 14/03/2011 was conducted. Results: 2,550 cases of testicular germ cell tumour were reviewed and 19 patients with bone metastases were identified, median age 38yrs. Average duration of follow-up was 21.7 months. Most were NSGCT (11/19), or seminoma (3/19). Five patients were treated on the basis of markers alone. Bone metastases present at diagnosis 12/19, and diagnosed at relapse/progression in 6/19 cases. Bony metastases were most commonly found in the vertebrae (15/19), pelvis (5/19) and ribs (3/19). In 10 cases a single bone metastasis was found, in 9 cases multiple areas of bone metastasis occurred. The imaging modality diagnostic of bone metastases was most frequently CT scan (11/19), FDG-PET (4/19) or MRI (3/19). The majority of these cases received only one line of chemotherapy (13/19), others received up to a maximum of seven line of systemic treatment (Table). Six patients (31.6%) died during follow up after an average of 17.5months and 3.3 lines of systemic treatment. Conclusions: Bone metastasis in GCT is rare, and is believed to confer poor prognosis. This series of patient outcomes following standard first-line platinum based chemotherapy is small but appears to support this conclusion. [Table: see text]
Effect of Chemotherapy on IRC 741 Leukemia in Fischer Rats II. Sublines Developed by Treatment with Dimethylbenzimidazole
Authors: Veronica Armaghan
Journal: Cancer Research (1963)

Summary  This is a report showing that attenuation of malignancy induced in IRC 741 leukemia of Fischer rats, following early treatment with dimethylbenzimidazole (DMBZ), persisted for more than 40 transfer generations without treatment. The survival of rats bearing the attenuated tumor, IRC 741/A546, ranged from 24 to 43 days compared with 11 to 18 days9 survival of rats bearing implants of IRC 741 tumor tissue. Resistance to DMBZ was developed in IRC 741 by initiating treatment 10 days after transplantation and in the attenuated subline, IRC 741/A546R, by initiating treatment of the host 20 days after tumor transplantation. Rats bearing implants of IRC 741R (DMBZ) lived 13–14 days after tumor transplantation, and A546R lived 21–39 days. Daily treatment of the sensitive subline proved to be twice as effective as treatment on alternate days. Daily treatment of the resistant subline was no more effective than treatment on alternate days. It was possible to cure some of the isologous hosts of IRC 741/A546 leukemia by initiating treatment 10–22 days after transplantation; but none of the rats given inoculations of IRC 741 were cured when treatment was initiated later than 4 days after transplantation. Rats cured of established tumors were resistant or immune to reinoculation with the altered and/or the parent tumor.
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary
Authors: Claus F. Vogelmeier, Gerard J. Criner, Fernando J. Martinez, Antonio Anzueto, Peter J. Barnes, Jean Bourbeau, Bartolome R. Celli, Rongchang Chen, Marc Decramer, Leonardo M. Fabbri, Peter Frith, David M.G. Halpin, M. Victorina López Varela, Masaharu Nishimura, Nicolas Roche, Roberto Rodriguez-Roisin, Don D. Sin, Dave Singh, Robert Stockley, Jørgen Vestbo, Jadwiga A. Wedzicha, Alvar Agusti
Journal: European Respiratory Journal (2017)

This Executive Summary of the Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) 2017 Report focuses primarily on the revised and novel parts of the document. The most significant changes include: 1) the assessment of chronic obstructive pulmonary disease has been refined to separate the spirometric assessment from symptom evaluation. ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations; 2) for each of the groups A to D, escalation strategies for pharmacological treatments are proposed; 3) the concept of de-escalation of therapy is introduced in the treatment assessment scheme; 4) nonpharmacologic therapies are comprehensively presented and; 5) the importance of comorbid conditions in managing COPD is reviewed.
In Silico Modeling of Oncogenic Drivers in Waldenstrom Macroglobulinemia to Assess Additional Therapeutic Targets within the BCR Signaling Pathway Identifies MEK1/2 As a Target: Potential Therapeutic Role of Binimetinib
Authors: Aneel Paulus, Sharoon Akhtar, Shireen Vali, Ansu Kumar, Neeraj Kumar Singh, Shahabuddin Usmani, Himanshu Grover, Taher Abbasi, Asher Alban Chanan-Khan
Journal: Blood (2015)
Impact of Treatment Intensity and Factor VIII Products On the Development On High Titre Inhibitors in Children with Severe Hemophilia A: Results of a Non-Concurrent Cohort Study.
Authors: Karin Kurnik, Susan Halimeh, Daniela Manner, Susanne Holzhauer, Carmen Escuriola Ettingshausen, Rosemarie Schobess, Ulrike Nowak-Gottl
Journal: Blood (2009)
First Results of a Phase-II Study with the New CXCR4 Antagonist POL6326 to Mobilize Hematopoietic Stem Cells (HSC) In Multiple Myeloma (MM)
Authors: Stefan Schmitt, Niels Weinhold, Klaus Dembowsky, Kai Neben, Mathias Witzens-Harig, Manfred Braun, Jennifer Klemmer, Patrick Wuchter, Christian Ludin, Anthony D. Ho, Hartmut Goldschmidt
Journal: Blood (2010)
Impact of different definitions of high-risk prostate cancer on survival after radical prostatectomy.
Authors: Kenneth Gerard Nepple, Gurdarshan S Sandhu, Dorina Kallogjeri, Seth A. Strope, Robert L. Grubb, Eric A. Klein, Andrew J. Stephenson, Adam Stuart Kibel
Journal: Journal of Clinical Oncology (2012)

113 Background: Multiple definitions of high risk prostate cancer exist. Studies have primarily correlated these definitions with biochemical recurrence and not with survival. We applied six previously described high risk definitions to men treated with radical prostatectomy and evaluated their ability to predict survival outcomes in a multi-institutional cohort. Methods: The study population included 6477 men treated with radical prostatectomy between 1995 and 2005 and followed for a median of 67 months. The six high risk definitions were 1) preoperative PSA≥20ng/ml, 2) biopsy Gleason score 8-10, 3) clinical stage≥T2c, 4) clinical stage T3, 5) D’Amico definition, or 6) National Comprehensive Cancer Network definition. Survival was evaluated with the Kaplan-Meier method to generate unadjusted prostate cancer survival estimates. To control for the competing risks of age and comorbidity, multivariable Cox proportional hazard regression models were used to estimate the hazard ratio for prostate cancer specific mortality (PCSM) and overall mortality (OM) in high risk patients compared to low/intermediate risk. Results: High risk patients comprised between 0.7% (cT3) and 8.2% (D’Amico) of the study population. The 10-year Kaplan Meier prostate cancer survival estimates varied from 89.7% for PSA≥20 to 69.7% for cT3. On multivariable analysis controlling for age and comorbidity, high risk prostate cancer (of all definitions) had an increased risk of PCSM compared to low/intermediate risk with a hazard ratio (HR) ranging from 4.38 for PSA≥20 to 19.97 for cT3 (all p&lt;0.0001). For OM, again controlling for age and comorbidity, high risk patients of all definitions except preoperative PSA≥20 (HR=0.98, p=0.99) were associated with increased risk of OM (HR range: 1.72 for D’Amico, 1.73 for stage≥T2c, 1.88 for NCCN, 2.63 for Gleason 8-10, 3.31 for cT3; all p&lt;0.01). Conclusions: In a contemporary cohort of men with high risk prostate cancer treated with radical prostatectomy, the majority of men experienced long term prostate cancer survival. However, heterogeneity in survival outcomes existed based on the definition of high risk used. Clinical stage T3 and high Gleason score were most strongly associated with PCSM and OM.
Emerging of Valproic Acid as an Anti-Myeloma Agent.
Authors: Kenichi Kitazoe, Masahiro Abe, Masahito Choraku, Kumiko Kagawa, Jin Asano, Kyoko Takeuchi, Masahiro Hiasa, Toshihiro Hashimoto, Shuji Ozaki, Asuka Oda, Hiroe Amou, Toshio Matsumoto
Journal: Blood (2006)
Long-Term Disease Control in Patients with Primary Central Nervous System Lymphoma
Authors: Ingo Schmidt-Wolf, Hendrik Pels, Annika Jürgens, Sabine Rogowski, Axel Glasmacher, Ulrich Herrlinger, Holger Schulz, Andreas Engert, Michael Linnebank, Gabriele Schackert, Heinz Reichmann, Frank Kroschinsky, Marlies Vogt-Schaden, Gertlinde Egerer, Carlo Schaller, Monika Lamprecht, Peter Hau, Martina Deckert, Rolf Fimmers, Christoph Bangard, Uwe Schlegel
Journal: Blood (2008)
Tumor microenvironment derived biomarkers for the early detection of pancreatic cancer (PDAC).
Authors: A. Y. Wehr, I. A. Blair, K. H. Yu
Journal: Journal of Clinical Oncology (2011)

e14591 Background: The important role played by activated pancreatic stellate cells (aPSCs) in PDAC has only been recently appreciated. By shaping the tumor microenvironment, APSCs contribute to tumor growth, metastasis and drug resistance. Innovative stable isotope labeling with amino acids in cell culture (SILAC) and multiple reaction monitoring (MRM)-MS provide tools for interrogating human serum samples for aPSC derived biomarkers of PDAC. Methods: 600 proteins secreted by aPSCs were previously characterized (Wehr, 2010). Selected proteins were shown to be overexpressed in pancreatic tumors. An immortalized PSC cell line was SILAC labeled; secreted proteins were collected from activated cells and used as labeled internal standards. An MRM-MS method was developed to quantitate the 40 most abundant secreted aPSC proteins in serum. Internal standard proteins were added to human serum samples prior to immunoaffinity (IA) removal of abundant serum proteins, trypsin digested and analyzed by liquid chromatography (LC)/MRM-MS. Powered primary endpoint: characterize the sensitivity and specificity of biomarker panel in a case control study of 10 patients with PDAC and 10 healthy controls. Secondary endpoint: biological pathway analysis of discriminating biomarkers. Results: 183 unique peptides were identified for the selected 40 aPSC proteins. 69 peptides, representing 36 proteins, were reproducibly detected by MS. During method development, a prototypical biomarker candidate, MMP2, was monitored; Western blot and MS analysis showed that MMP2 was not lost by IA processing, and removal of abundant proteins was required for detection of MMP2 by MS. The method was found to be linear over a range of 4-100 fmol/µL media, and met precision criteria of < 15% RSD. Human serum samples from 10 patients with PDAC and 10 normal controls were compared. Samples will be analyzed using the described method, the discriminatory power will be assessed and pathway analysis on discriminatory biomarkers will be performed. Conclusions: This is the first LC/MRM-MS method developed to quantitate aPSC proteins in human serum. Results relating to the primary endpoint and performance of the biomarker panel will be presented at the meeting.
Gene Therapy Restores Balance and Auditory Functions in a Mouse Model of Usher Syndrome
Authors: Kevin Isgrig, Jack W. Shteamer, Inna A. Belyantseva, Meghan C. Drummond, Tracy S. Fitzgerald, Sarath Vijayakumar, Sherri M. Jones, Andrew J. Griffith, Thomas B. Friedman, Lisa L. Cunningham, Wade W. Chien
Journal: Molecular Therapy (2017)

Dizziness and hearing loss are among the most common disabilities. Many forms of hereditary balance and hearing disorders are caused by abnormal development of stereocilia, mechanosensory organelles on the apical surface of hair cells in the inner ear. The deaf whirler mouse, a model of human Usher syndrome (manifested by hearing loss, dizziness, and blindness), has a recessive mutation in the whirlin gene, which renders hair cell stereocilia short and dysfunctional. In this study, wild-type whirlin cDNA was delivered to the inner ears of neonatal whirler mice using adeno-associated virus serotype 2/8 (AAV8-whirlin) by injection into the posterior semicircular canal. Unilateral whirlin gene therapy injection was able to restore balance function as well as improve hearing in whirler mice for at least 4 months. Our data indicate that gene therapy is likely to become a treatment option for hereditary disorders of balance and hearing.
Chemogenetic stimulation of striatal projection neurons modulates responses to Parkinson’s disease therapy
Authors: Cristina Alcacer, Laura Andreoli, Irene Sebastianutto, Johan Jakobsson, Tim Fieblinger, Maria Angela Cenci
Journal: Journal of Clinical Investigation (2017)

Parkinson's disease (PD) patients experience loss of normal motor function (hypokinesia), but can develop uncontrollable movements known as dyskinesia upon treatment with L-DOPA. Poverty or excess of movement in PD has been attributed to overactivity of striatal projection neurons forming either the indirect (iSPNs) or the direct (dSPNs) pathway, respectively. Here, we investigated the two pathways' contribution to different motor features using SPN type-specific chemogenetic stimulation in rodent models of PD (PD mice) and L-DOPA-induced dyskinesia (LID mice). Using the activatory Gq-coupled human M3 muscarinic receptor (hM3Dq), we found that chemogenetic stimulation of dSPNs mimicked, while stimulation of iSPNs abolished the therapeutic action of L-DOPA in PD mice. In LID mice, hM3Dq stimulation of dSPNs exacerbated dyskinetic responses to L-DOPA, while stimulation of iSPNs inhibited these responses. In the absence of L-DOPA, only chemogenetic stimulation of dSPNs mediated through the Gs-coupled modified rat muscarinic M3 receptor (rM3Ds) induced appreciable dyskinesia in PD mice. Combining D2 receptor agonist treatment with rM3Ds-dSPN stimulation reproduced all symptoms of LID. These results demonstrate that dSPNs and iSPNs oppositely modulate both therapeutic and dyskinetic responses to dopamine replacement therapy in PD. We also show that chemogenetic stimulation of different signaling pathways in dSPNs leads to markedly different motor outcomes. Our findings have important implications for the design of effective antiparkinsonian and antidyskinetic drug therapies.
Clinical Trial of NPI-0052 (2nd generation proteasome inhibitor) in Patients Having Advanced Malignancies with Expanded RP2D Cohorts in Lymphoma and CLL
Authors: Timothy Price, Peeter Padrik, Amanda Townsend, Paul Mainwaring, Lawrence Catley, Angie M. Longenecker, Gillian Cropp, Michael A. Palladino, G. Kenneth Lloyd, Matthew A. Spear, Michael Millward
Journal: Blood (2008)