tbuckley/cabot-search huggingface dataset:
New Targets for Drug Treatment of Obesity
Authors: Georgios Valsamakis, Panagiota Konstantakou, George Mastorakos
Journal: The Annual Review of Pharmacology and Toxicology (2017)

Antiobesity medical management has shown unsatisfactory results to date in terms of efficacy, safety, and long-term maintenance of weight loss. This poor performance could be attributed to the complexity of appetite regulation mechanisms; the serious drug side effects; and, crucially, the lack of profile-matching treatment strategies and individualized, multidisciplinary follow-up. Nevertheless, antiobesity pharmacotherapy remains a challenging, exciting field of intensive scientific interest. According to the latest studies, the future of bariatric medicine lies in developing drugs acting at multiple levels of the brain-gut axis. Currently, research is focused on the generation of combination treatments based on gut hormones in a way that mimics changes underlying surgically induced weight loss, in addition to centrally acting agents; these aim to restore energy balance disruptions and enhance energy expenditure. Collectively, the pharmacological resolution of obesity could potentially be achieved with combination regimens targeting different molecules and levels of the energy homeostasis system, in parallel with matching patients' needs, resulting in a favorable metabolic profile.
NIMG-14IDENTIFICATION OF TRUE FUNCTIONAL ACTIVITY USING RADIOMIC TEXTURE ANALYSIS OF FUNCTIONAL MRI ECHO PLANNAR IMAGING
Authors: Islam Hassan, Aikaterini Kotrotsou, Sean Guillory, Pascal O. Zinn, Rivka Colen
Journal: Neuro-Oncology (2015)

BACKGROUND: FMRI maps commonly show multiple areas of false positive activity. We aimed to identify areas of true fMRI activation by using complex MRI texture analysis (TA) of raw EPI data, thus enhancing the identification of true activity. METHODS: 12 right handed healthy volunteers were recruited (IRB approved). All scans were performed on a 3.0T GE MR scanner. FMRI consisted of a high resolution 3D T1 weighted structural scan and a gradient echo EPI functional scan. FMRI data analysis was performed using SPM8 software for a sentence completion block design task. T map for each individual was displayed using xjview toolbox and thresholded individually to optimize visualization of language area. Each activity cluster was selected and saved. Board-certified neuroradiologists and neuroscientists classified different clusters into two separate groups Expected (E) and Non Expected (NE) based on their anatomical locations. TA was performed using the mean EPI volume for each individual, and 20 invariant texture features were obtained. Efficacy of TA in fMRI was assessed by decision tree and validated using a 4 fold cross validation. RESULTS: fMRI areas of activity in individual scans were identified based on their texture features with 95.3% accuracy, sensitivity 95.3% and specificity 95.3%. Sum of Variance, Cluster shade, sum of average and information measure of correlation were the most important texture features. These features had higher texture values in the NE ROIs indicating more homogeneous areas. Texture features were able to significantly differentiate areas of true versus false activity. CONCLUSIONS: Extracted features indicated that true activity has more heterogeneous texture compared to non-expected activity Quantitative TA of functional MRI using texture feature can enhance the accuracy and sensitivity of the test to true activity and help eliminate false activation
OP26DELINEATING INTRA-TUMOUR METABOLOMIC AND PHOSPHO-PROTEOMIC HETEROGENEITY IN PATIENT GLIOBLASTOMAS THROUGH ADVANCED ANALYTICAL METHODS
Authors: Jennifer H. Ward, James A. Wood, Dong-Hyun Kim, David Tooth, Martin Wilson, Jiying Zheng, Anbarasu Lourdusamy, Andrew C. Peet, Robert Layfield, David A. Barrett, Stuart J. Smith, Ruman Rahman
Journal: Neuro-Oncology (2015)

BACKGROUND: Molecularly targeted approaches informing next-generation glioblastoma (GBM) chemotherapy must account for the intra-heterogeneous genome landscape and aim to eradicate invasive residual sub-populations. We outline an analytical strategy that forms a functional genomic corollary to existing genome-wide mutation and gene expression studies. METHODS: Biopsies from spatially distinct intra-GBM regions were surgically resected via Stealth and 5-ALA fluorescence guidance, including core, enhancing and invasive margin regions. Cellular intra-tumour heterogeneity (ITH) was confirmed by immunohistochemistry and qPCR arrays, whilst molecular analytics were conducted using liquid chromatography-mass spectrometry (metabolomic/lipidomic) magnetic resonance spectroscopy (metabolic) and SDS PAGE phosphoprotein enrichment (proteomic). RESULTS: Cellular ITH was confirmed via distinct neural stem cell expression in medial and posterior rims relative to the central enhancement region. Metabolites present in the invasive margin (5-ALA-determined), central enhancement and peri-necrotic core were distinct within each GBM. Controlling for the high proportion of normal brain cells surrounding the invasive margin, high tumour-specific glutamine levels were consistently present. Relative abundance of cytosolic phosphoproteins distinguished active protein pathways within intra-GBM regions, including invasive margin. Metabolomic network analyses confirmed that GBM residual disease is distinct from core ITH regions with respect to metabolic dependence. CONCLUSIONS: This innovative concept is the first to address ITH with multi-region biopsies using advanced analytical bioscience techniques. Identification of metabolites, lipids and phospho-proteins that are functional determinants of GBM infiltration reveal putative molecular targets on residual disease cells and represent a route to expedite new chemotherapy agents to clinic within a precision medicine framework.
Treatment of Tuberculosis in HIV-Infected Patients in Zaire
Authors: A M Elliott, B Halwiindi, A G Mwinga
Journal: New England Journal of Medicine (1995)

In many developing countries the rates of cure without relapse in tuberculosis patients 91% overall and 87% in those infected with human immunodeficiency virus (HIV) who survived and were treated for 6 months that were seen in the study of Perriens and colleagues would reflect great success.  The question is whether this level of compliance could be reached outside the research setting.  The 6-month regimen was significantly less effective than the 12-month regimen in HIV-positive patients.  This suggests that 6 months of drug therapy is insufficient or that the intermittent administration of drugs is unsatisfactory in treating this group.  However if incomplete compliance interfered with the implementation of the regimen the treatment program rather than the efficacy of the drugs was being tested.  That this was the case is supported by the recurrence rate in the HIV-negative group; it was higher than would be expected if compliance was complete and it was not significantly different from that in the HIV-positive group treated for 6 months.  In Zambia occasionally difficult cases require directly observed intermittent therapy but compliance is impeded because patients cannot make the difficult trip to the clinic.  Compliance with a daily regimen of streptomycin during the intensive phase of outpatient therapy is poorer than a regimen of oral drugs taken outside the clinic according to patient reports.  The urban population of Lusaka Zambia is very mobile and patients often fail to appear for their tuberculosis treatment for a week or more.
PD-1 blockade in mismatch repair deficient non-colorectal gastrointestinal cancers.
Authors: Dung T. Le, Jennifer N. Uram, Hao Wang, Holly Kemberling, Aleksandra Eyring, Bjarne Bartlett, Richard M. Goldberg, Todd S. Crocenzi, George A. Fisher, James J. Lee, Tim F. Greten, Dan Laheru, Nilofer Saba Azad, Ross C. Donehower, Brandon Luber, Minori Koshiji, James R. Eshleman, Robert A Anders, Bert Vogelstein, Luis A. Diaz
Journal: Journal of Clinical Oncology (2016)

195 Background: Mismatch repair (MMR) deficient tumors harbor hundreds to thousands of mutations that may produce neoantigens that can be recognized and targeted by T cells. We have shown that MMR deficiency can serve as a predictive biomarker for selection of tumors across tumor histologies that may respond to programmed death-1 (PD-1) blockade. MMR deficiency is present in 15% of colorectal (CRC) however is also detected in 2-20% of gastric, small bowel, and hepatobiliary cancers. Methods: We conducted a phase II study to evaluate anti-PD-1, pembrolizumab, in patients with previously-treated, progressive, advanced cancer. Twenty-one patients with MMR deficient tumors were enrolled onto the non-CRC cohort with an additional 50 patient expansion underway. The pembrolizumab dose is 10mg/kg intravenously every 2 weeks. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) will be reported in at least the first 17 patients with non-CRC gastrointestinal (GI) cancers. Results: As of September 18, 2015, 17 patients with non-CRC GI cancers have been enrolled on the protocol with additional patients identified. The diseases represented are ampullary (N=4), pancreas (N=4), biliary (N=3), small bowel (N=3), and gastric (N=3) cancers. For the 10 evaluable patients at the time of abstract admission, ORR is 50 % (N=5/10), disease control rate is 70% (N=7/10), OS is 21 months and the median duration of response (range 5.5-17+ months) and PFS have not been reached. The median follow up duration is 7.6 months. Conclusions: PD-1 blockade shows promising activity in mismatch repair deficient GI cancers. Clinical trial information: NCT01876511.
Effect of Generic Competition on Atorvastatin Prescribing and Patients’ Out-of-Pocket Spending
Authors: Jing Luo, John D. Seeger, Macarius Donneyong, Joshua J. Gagne, Jerry Avorn, Aaron S. Kesselheim
Journal: JAMA Internal Medicine (2016)

In November 2011, the cholesterol level-lowering medication atorvastatin calcium became available in the United States as a generic drug. However, only a single generic form (from a manufacturer that qualified for market exclusivity by challenging several of Pfizer's patents) and an authorized generic form (a brand-name drug sold as a generic) were available for the first 180 days.To describe trends in the prescribing of generic atorvastatin after expiration of market exclusivity for the brand-name medication and the effect on patients' out-of-pocket spending.A US population-based study used commercial claims data from the Optum Clinformatics research database (UnitedHealth Group) from December 1, 2010, to May 31, 2013. Participants were 1 968 709 adults with commercial insurance who had been prescribed 1 or more statins (13 285 223 statin prescriptions). An interrupted times series model was used to examine the effect of limited and full generic competition on brand-name and generic atorvastatin prescriptions. Data were analyzed from December 1, 2010, to May 31, 2013.Prescription of brand-name atorvastatin, generic atorvastatin, and authorized generic atorvastatin were distinguished using National Drug Codes.Total number of prescriptions dispensed per month and out-of-pocket expenditures for a typical 30-day supply of 20-mg atorvastatin during the periods of brand-name availability only, limited generic competition (lasting 180 days after market exclusivity ended), and full generic competition.Of the 1 968 709 beneficiaries, 1 483 066 (58.8% male and 41.2% female; mean [SD] age, 55.6 [10.2] years) received a prescription for a single statin and were included in the analysis. The introduction of the first generic competitor was associated with a reduction in monthly brand-name atorvastatin fills by 20 896 prescriptions (level change, P = .001), an 18.1% change compared with the month preceding loss of exclusivity. Full generic competition reduced brand-name fills by 54 944 prescriptions (level change, P < .001), a 47.6% change relative to the month preceding loss of exclusivity. During the first 180 days of generic competition, no meaningful difference in monthly out-of-pocket spending was found between brand-name (median, $16.98; interquartile range [IQR], $8.76-$48.66) and generic (median, $19.98; IQR, $7.50-$54.90) atorvastatin. After full generic competition, estimated monthly out-of-pocket spending for generic atorvastatin (median $5.10; IQR, $3.36-$19.98) or authorized generic atorvastatin (median, $5.52; IQR, $3.48-$19.98) was substantially lower than that for brand-name atorvastatin (median, $30.00; IQR, $15.00-$91.38).Among patients with commercial health insurance, delays in generic uptake and high levels of out-of-pocket spending during the first 180 days after atorvastatin lost market exclusivity slowed changes in drug prescribing and decreases in patients' out-of-pocket costs.
Metabolic Stress-Induced Phosphorylation of KAP1 Ser473 Blocks Mitochondrial Fusion in Breast Cancer Cells
Authors: Chun-Ting Cheng, Ching-Ying Kuo, Ching Ouyang, Chien-Feng Li, Yiyin Chung, David C. Chan, Hsing-Jien Kung, David K. Ann
Journal: Cancer Research (2016)

Abstract Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here, we report that KAP1 (TRIM28), a transcriptional coadaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473 phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live-cell imaging and molecular studies revealed that during the first 6 to 8 hours of glucose starvation, mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner. Mechanistic investigations using phosphorylation-defective mutants revealed that KAP1 Ser473 phosphorylation limited mitochondrial hyperfusion in glucose-starved breast cancer cells, as driven by downregulation of the mitofusin protein MFN2, leading to reduced oxidative phosphorylation and ROS production. In clinical specimens of breast cancer, reduced expression of MFN2 corresponded to poor prognosis in patients. In a mouse xenograft model of human breast cancer, there was an association in the core region of tumors between MFN2 downregulation and the presence of highly fragmented mitochondria. Collectively, our results suggest that KAP1 Ser473 phosphorylation acts through MFN2 reduction to restrict mitochondrial hyperfusion, thereby contributing to cancer cell survival under conditions of sustained metabolic stress. Cancer Res; 76(17); 5006–18. ©2016 AACR.
Résultats de la mise en place d’une jéjunostomie percutanée endoscopique à l’aide d’un entéroscope à double ballon.
Authors: S. Lecleire
Journal: Endoscopy (2016)

La confection d’une jéjunostomie par voie endoscopique (JPE) est indiquée lorsque la gastrostomie per endoscopique (GPE) n’est techniquement pas faisable quelles qu’en soient les raisons (gastroparésie, résection oeso-gastrique,…). Le placement d’une sonde jéjunale à travers une GPE reste possible mais techniquement complexe et assez peu utilisé du fait d’une efficacité médiocre avec une sonde de nutrition qui remonte fréquemment dans l’estomac si l’angle de Treitz n’est pas franchi. La JPE fait classiquement appel à un coloscope pédiatrique ou à une entéroscopie poussée mais avec un taux de succès technique ne dépassant pas 68 % dans les meilleures séries.
The transcriptional repressor Hes1 attenuates inflammation by regulating transcription elongation
Authors: Yingli Shang, Maddalena Coppo, Teng He, Fei Ning, Li Yu, Lan Kang, Bin Zhang, Chanyang Ju, Yu Qiao, Baohong Zhao, Manfred Gessler, Inez Rogatsky, Xiaoyu Hu
Journal: Nature Immunology (2016)
A Bruising Loss
Authors: Christopher J. Gibson, Nancy Berliner, Amy L. Miller, Joseph Loscalzo
Journal: New England Journal of Medicine (2016)

A 32-year-old woman presented to her physician with a 3-week history of spontaneous bruising on her arms, legs, and back. The bruising began shortly after she had had sore throat, coryza, and malaise for several days, symptoms that had resolved without intervention.
A Strong B-cell Response Is Part of the Immune Landscape in Human High-Grade Serous Ovarian Metastases
Authors: Anne Montfort, Oliver Pearce, Eleni Maniati, Benjamin G. Vincent, Lisa Bixby, Steffen Böhm, Thomas Dowe, Edmund H. Wilkes, Probir Chakravarty, Richard Thompson, Joanne Topping, Pedro R. Cutillas, Michelle Lockley, Jonathan S. Serody, Melania Capasso, Frances R. Balkwill
Journal: Clinical Cancer Research (2016)

Abstract Purpose: In high-grade serous ovarian cancer (HGSOC), higher densities of both B cells and the CD8+ T-cell infiltrate were associated with a better prognosis. However, the precise role of B cells in the antitumor response remains unknown. As peritoneal metastases are often responsible for relapse, our aim was to characterize the role of B cells in the antitumor immune response in HGSOC metastases. Experimental Design: Unmatched pre and post-chemotherapy HGSOC metastases were studied. B-cell localization was assessed by immunostaining. Their cytokines and chemokines were measured by a multiplex assay, and their phenotype was assessed by flow cytometry. Further in vitro and in vivo assays highlighted the role of B cells and plasma cell IgGs in the development of cytotoxic responses and dendritic cell activation. Results: B cells mainly infiltrated lymphoid structures in the stroma of HGSOC metastases. There was a strong B-cell memory response directed at a restricted repertoire of antigens and production of tumor-specific IgGs by plasma cells. These responses were enhanced by chemotherapy. Interestingly, transcript levels of CD20 correlated with markers of immune cytolytic responses and immune complexes with tumor-derived IgGs stimulated the expression of the costimulatory molecule CD86 on antigen-presenting cells. A positive role for B cells in the antitumor response was also supported by B-cell depletion in a syngeneic mouse model of peritoneal metastasis. Conclusions: Our data showed that B cells infiltrating HGSOC omental metastases support the development of an antitumor response. Clin Cancer Res; 23(1); 250–62. ©2016 AACR.
An open-label, randomized, phase III trial of zalutumumab, a human monoclonal EGF receptor (EGFr) antibody, versus best supportive care, in patients with noncurable squamous cell carcinoma (SCCHN) of the head and neck who have failed standard platinum-based chemotherapy (ZALUTE).
Authors: J. H. Machiels, S. Subramanian, A. Ruzsa, G. Repassy, I. Lifrenko, A. Flygare, P. Sorensen, E. Ehrnrooth, O. Baadsgaard, P. M. Clement
Journal: Journal of Clinical Oncology (2010)

LBA5506 Background: Zalutumumab is a novel, fully human IgG1 mAb targeting the EGFr that has shown encouraging activity in SCCHN. Methods: Patients with noncurable SCCHN with an ECOG PS of 0-2 and centrally documented radiographic progressive disease (PD) within 6 months after platinum-therapy were randomized between zalutumumab monotherapy and best supportive care (BSC) in a 2:1 ratio. Stratification parameter was ECOG PS. Methotrexate (MTX) was allowed in the BSC arm only. Individual dose-titration of zalutumumab was applied (max. exposure 16 mg/kg). The primary endpoint was overall survival (OS), with progression free survival (PFS) as the only secondary endpoint to be compared between groups, using log-rank test. 231 deaths were required to statistically differentiate OS between groups with 80% power. Results: 286 patients (34F, 252M) were randomized. The median age was 57 years (range 18-78), 65% had distant metastasis and 17% were ECOG PS 2, all similar between groups. 78% of patients in BSC arm received MTX. Although a median OS of 6.7 months was observed in the zalutumumab group compared to 5.2 in the BSC group, this was not statistically significant (p=0.065). A clear improvement in PFS (P=0.001) was demonstrated. Zalutumumab showed a safety profile as expected within this drug class. Conclusions: This is the first controlled study to demonstrate that an EGFr-targeted antibody given as monotherapy induces a clinically meaningful improvement in PFS in patients with SSCHN who have failed platinum-based chemotherapy. [Table: see text] [Table: see text]
Crossing the bridge from hematologic malignancies to solid tumors.
Authors: F R Appelbaum, E D Thomas
Journal: Journal of Clinical Oncology (1986)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1986.4.1.2 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 3510279 Crossing the bridge from hematologic malignancies to solid tumors. F R AppelbaumxF R AppelbaumSearch for articles by this author , E D ThomasxE D ThomasSearch for articles by this author https://doi.org/10.1200/JCO.1986.4.1.2 PDF "Crossing the bridge from hematologic malignancies to solid tumors.." Journal of Clinical Oncology, 4(1), pp. 2–3© 1986 by American Society of Clinical Oncology
Molecular characterization of glycation‐associated skin ageing: an alternative skin model to study <i>in vitro</i> antiglycation activity of topical cosmeceutical and pharmaceutical formulations
Authors: K.H. Lee, Y.P. Ng, P.S. Cheah, C.K. Lim, M.S. Toh
Journal: British Journal of Dermatology (2016)

Glycation is a nonenzymatic reaction that cross‐links a sugar molecule and protein macromolecule to form advanced glycation products (AGEs) that are associated with various age‐related disorders; thus glycation plays an important role in skin chronological ageing. To develop a novel in vitro skin glycation model as a screening tool for topical formulations with antiglycation properties and to further characterize, at the molecular level, the glycation stress‐driven skin ageing mechanism. The glycation model was developed using human reconstituted full‐thickness skin; the presence of Nε‐(carboxymethyl) lysine (CML) was used as evidence of the degree of glycation. Topical application of emulsion containing a well‐known antiglycation compound (aminoguanidine) was used to verify the sensitivity and robustness of the model. Cytokine immunoassay, quantitative real‐time polymerase chain reaction and histological analysis were further implemented to characterize the molecular mechanisms of skin ageing in the skin glycation model. Transcriptomic and cytokine profiling analyses in the skin glycation model demonstrated multiple biological changes, including extracellular matrix catabolism, skin barrier function impairment, oxidative stress and subsequently the inflammatory response. Darkness and yellowness of skin tone observed in the in vitro skin glycation model correlated well with the degree of glycation stress. The newly developed skin glycation model in this study has provided a new technological dimension in screening antiglycation properties of topical pharmaceutical or cosmeceutical formulations. This study concomitantly provides insights into skin ageing mechanisms driven by glycation stress, which could be useful in formulating skin antiageing therapy in future studies.