tbuckley/cabot-search huggingface dataset:
B-F1RST: Assessment of novel blood-based biomarkers in patients with first-line advanced or metastatic NSCLC receiving atezolizumab monotherapy.
Authors: Edward S. Kim, Mark A. Socinski, Shaker R. Dakhil, Niklas J. Mackler, Nadeem Ikhlaque, Tarek Mekhail, Fabio Volterra, Christian Antoine El Khoury, Joan H. Schiller, Michaela L. Tsai, Fadi Hayek, Jeffrey D. Neidhart, Brian Hunis, Sylvia Hu, Sarah M. Paul, David S. Shames, See-Chun Phan, Cindy Yun, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2017)

TPS9103 Background: The anti–PD-L1 monoclonal antibody atezolizumab inhibits the interaction of PD-L1 with its receptors PD-1 and B7.1, thereby restoring T-cell immunity. In the Phase III OAK study, patients with previously treated advanced NSCLC had improved mOS in the atezolizumab arm (13.8 mo) vs the docetaxel arm (9.6 mo) (HR 0.73 [95%CI: 0.62, 0.87]; P= 0.0003), irrespective of PD-L1 expression or histology. A Phase III clinical trial of atezolizumab monotherapy for first-line, PD-L1–selected patients with NSCLC is underway; however, first-line atezolizumab monotherapy for NSCLC treatment in a biomarker-unselected population has not yet been investigated. Current assays to measure PD-L1 expression by IHC require tumor biopsies, which can be difficult to obtain in some patients. Novel blood-based biomarkers will be evaluated retrospectively in B-F1RST (Blood-First-Line Ready Screening Trial) in patients receiving atezolizumab monotherapy in first-line NSCLC. Methods: A Phase II, open-label, single-arm study, B-F1RST (NCT02848651), will evaluate the efficacy and safety of atezolizumab in PD-L1–unselected patients with first-line locally advanced or metastatic NSCLC. Eligibility criteria include stage IIIB-IVB NSCLC, ECOG PS 0-1, measurable disease per RECIST v1.1 and adequate hematologic and end-organ function. Exclusion criteria include the presence of EGFRmutations or ALKfusions, active CNS metastases and prior immunotherapy for NSCLC. Patients will receive atezolizumab 1200 mg IV q3w until disease progression or loss of clinical benefit. Prospective collection of blood samples is mandatory; collection of tissue biopsies is optional. The co-primary endpoints of the study are investigator-assessed ORR per RECIST v1.1 for the efficacy objective and PFS per RECIST v1.1 for evaluating blood-based predictive biomarkers for atezolizumab efficacy, including mutation status. Approximately 150 patients will be enrolled at 25 or more centers in the United States. Clinical trial information: NCT02848651.
Long-term results of a phase II randomized controlled trial (RCT) of a psychological intervention (Conquer Fear) to reduce clinical levels of fear of cancer recurrence in breast, colorectal, and melanoma cancer survivors.
Authors: Jane McNeil Beith, Belinda Thewes, Jane Turner, Jemma Gilchrist, Louise Sharpe, Afaf Girgis, Allan 'Ben' Smith, Joanna Fardell, Stephanie Tesson, Rachel O'Connell, Rebecca Asher, Phyllis Butow
Journal: Journal of Clinical Oncology (2017)

LBA10000 Background: Up to 70% of cancer survivors report clinically significant fear of cancer recurrence (FCR). This parallel RCT evaluated the impact of a psychological intervention, Conquer Fear (CF), on FCR in cancer survivors. Methods: Participants were disease-free stage I-III breast, colorectal or melanoma cancer survivors, 2 months to 5 years post-treatment, who scored above the clinical cut-off (≥13) on the FCR Inventory (FCRI) severity subscale. CF included 5 sessions incorporating attention training, detached mindfulness, challenging unhelpful metacognitions, values clarification and psycho-education. Participants were randomised to the intervention ( n= 121) or a relaxation training (RT) control arm ( n= 101) (target n= 260). The primary end-point was reduction in FCR (FCRI total) immediately after intervention completion. Follow-up assessments occurred immediately, 3- and 6-months post-treatment. Data analysis was by intention to treat. The differences in change in FCR from baseline between CF and RT and secondary outcomes were tested using independent t-tests. A difference of 14.5 points in FCR was considered clinically significant. Long-term changes in FCR and secondary outcomes were evaluated using linear regression models fitted with generalized estimating equations (GEE), adjusted for baseline FCR. Results: Reduction in FCR between baseline and immediately post-treatment was significantly more in CF participants compared to RT. (Difference in change (95% CI): -10.5 (-16.1, -4.9); p &lt; 0.001). Greater FCR reductions were also observed amongst CF participants at 3 months (-7.6 (-13.9, -1.4), p = 0.02) and 6 months (-7.8 (-14.2, -1.4), p = 0.02) compared with RT. The pattern of change in outcomes over time was consistent between treatment groups as no significant linear trends in treatment effects over time were observed. Conclusions: Conquer Fear is a theoretically-grounded intervention to reduce FCR and its associated psychological morbidity which leads to significantly greater reductions in FCR in the first 6 months following treatment than relaxation training. Clinical trial information: ACTRN12612000404820.
Food protein–induced enterocolitis syndromes with and without bloody stool have distinct clinicopathologic features
Authors: Hideaki Morita, Hiroko Suzuki, Kanami Orihara, Kenichiro Motomura, Akio Matsuda, Yukihiro Ohya, Hirohisa Saito, Ichiro Nomura, Kenji Matsumoto
Journal: Journal of Allergy and Clinical Immunology (2017)
First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study.
Authors: Ian Flinn, Richard van der Jagt, Julie E. Chang, Peter Wood, Tim E. Hawkins, David MacDonald, Judith Trotman, David Simpson, Kathryn S. Kolibaba, Samar Issa, Doreen M. Hallman, Ling Chen, John M. Burke
Journal: Journal of Clinical Oncology (2017)

7500 Background: BRIGHT, a phase 3, open-label, noninferiority study comparing efficacy and safety of bendamustine plus rituximab (BR) vs rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or rituximab with cyclophosphamide, vincristine and prednisone (R-CVP) in treatment-naive patients (pts) with indolent non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL), showed that the complete response rate for first-line BR was statistically noninferior to R-CHOP/R-CVP ( Blood 2014). Pts were monitored for ≥5 years (yr) to assess the overall effect of BR or R-CHOP/R-CVP in a controlled clinical setting. This analysis reports the time-to-event variables of the 5-yr follow-up (FU) study. Methods: Pts with iNHL or MCL randomized to 6-8 cycles of BR or R-CHOP/R-CVP underwent complete assessments at end of treatment, then were monitored regularly. Progression-free survival (PFS), event-free survival (EFS), duration of response (DOR) and overall survival (OS) were compared using a stratified log-rank test. Results: Of 447 randomized pts, 224 received BR, 104 R-CHOP, and 119 R-CVP; 419 entered the FU. The median FU time was 65.0 and 64.1 months for BR and R-CHOP/R-CVP, respectively. The 5-yr PFS rate was 65.5% (95% CI 58.5-71.6) and 55.8% (48.4-62.5), and OS was 81.7% (75.7-86.3) and 85% (79.3-89.3) for BR and R-CHOP/R-CVP, respectively. The hazard ratio (95% CI) for PFS was 0.61 (0.45-0.85; P= .0025), EFS 0.63 (0.46-0.84; P= .0020), DOR 0.66 (0.47-0.92; P= .0134), and OS 1.15 (0.72-1.84; P= .5461) comparing BR vs R-CHOP/R-CVP. Similar results were found in iNHL [PFS 0.70 (0.49-1.01; P= .0582)] and MCL [PFS 0.40 (0.21-0.75; P= .0035)], with the strongest effect in MCL. Use of R maintenance was similar, 43% in BR and 45% in R-CHOP/R-CVP. B was included as second-line in 27 (36%) of the 75 pts requiring therapy who originally received R-CHOP/R-CVP. Comparable safety profiles with expected adverse events were observed in the FU study in BR vs R-CHOP/R-CVP. Conclusions: The long-term FU of the BRIGHT study has confirmed that PFS, EFS, and DOR were significantly better for BR, and OS was not statistically different between BR and R-CHOP/R-CVP. The safety profile was as previously reported. Clinical trial information: NCT00877006.
Increased Levels of Endothelial Dysfunction Markers and Matrix Metalloproteinases in Patients with Severe Post-Thrombotic Syndrome
Authors: Luis Fernando Bittar, Fernanda Andrade Orsi, Kiara Cristina Senger Zapponi, Bruna Moraes Mazetto, Erich Vinicius De Paula, Joyce Maria Annichino-Bizzacchi
Journal: Blood (2016)
Abstract 3: Targeted Inhibition Of Transforming Growth Factor Beta In Cardiac Myocytes Prevents Myocardial Rupture After Infarction
Authors: Peter P Rainer, Norimichi Koitabashi, Scarlett Hao, Djahida Bedja, David A Kass
Journal: Circulation Research (2012)

Introduction Coronary artery disease is the leading cause of death and myocardial infarction (MI) its most severe manifestation.TGFb is a major switch governing the myocardial response to injury and global inhibition is detrimental following MI. Recently, cell-specific gene manipulation models have enabled investigation of cardiomyocyte (CM) versus non-CM TGFb signaling on maladaptive remodeling. We found CM TGFb to be central to pressure-overload disease. Here, we tested the hypothesis that CM TGFb modifies acute post-MI remodeling, and thus benefits rather than worsens outcome as observed with antibody-based inhibition that primarily targets interstitial/vascular cells. Methods Mice with cardiac-specific conditional knockdown of TgfbR1 or 2 (aMHC - MCM TgfbR fl/fl) or injection of TGFb-neutralizing antibody were subjected to proximal LAD-ligation and followed by echocardiography and continuous ECG monitoring. Expression and activity of the major matrix metalloproteinases MMP2/MMP9 and TIMP1 were assessed by qRT-PCR, immunoblot, and zymography, respectively. Only mice surviving &gt;24h after surgery (&gt;90%) were included in analyses. Results LAD ligation decreased fractional shortening on day 1 to 18±2% (61±1% in sham animals) with no differences between genotypes (n≥8). Similarly, echocardiographic parameters of myocardial dimensions and function did not differ at weeks 1 or 3. Early mortality (day 4 - 10) was strikingly lower in knockdown mice as compared to controls (10% vs 48%, p&lt;0.05, n≥10). Remarkably, systemic TGFb inhibition resulted in 100% mortality (n=8) by day 5. The cause of death was established by necropsy and continuous ECG monitoring and was myocardial rupture in all cases. MMP9 expression and gelatinolytic activity was reduced by CM TGFbR knockdown at day 3 after MI, as was TIMP1 expression, while MMP2 expression/activity was not altered. Conclusion TGFb inhibition exhibits differential effects in wound healing following MI. Where global inhibition is deleterious, CM-targeted knockdown powerfully protects the heart from rupture. This highlights potent cross-talk between the CM TGFb signal and matrix remodeling and the importance of targeted inhibition to benefit cardiac disease.
Chromatin Accessibility Landscape of Cutaneous T Cell Lymphoma and Dynamic Response to HDAC Inhibitors
Authors: Kun Qu, Lisa C. Zaba, Ansuman T. Satpathy, Paul G. Giresi, Rui Li, Yonghao Jin, Randall Armstrong, Chen Jin, Nathalie Schmitt, Ziba Rahbar, Hideki Ueno, William J. Greenleaf, Youn H. Kim, Howard Y. Chang
Journal: Cancer Cell (2017)
State-of-the-Art Methods for Brain Tissue Segmentation: A Review
Authors: Lingraj Dora, Sanjay Agrawal, Rutuparna Panda, Ajith Abraham
Journal: IEEE Reviews in Biomedical Engineering (2017)

Brain tissue segmentation is one of the most sought after research areas in medical image processing. It provides detailed quantitative brain analysis for accurate disease diagnosis, detection, and classification of abnormalities. It plays an essential role in discriminating healthy tissues from lesion tissues. Therefore, accurate disease diagnosis and treatment planning depend merely on the performance of the segmentation method used. In this review, we have studied the recent advances in brain tissue segmentation methods and their state-of-the-art in neuroscience research. The review also highlights the major challenges faced during tissue segmentation of the brain. An effective comparison is made among state-of-the-art brain tissue segmentation methods. Moreover, a study of some of the validation measures to evaluate different segmentation methods is also discussed. The brain tissue segmentation, content in terms of methodologies, and experiments presented in this review are encouraging enough to attract researchers working in this field.
Effect of PEDF on the migration, M1 polarization, and phagocytic activity in macrophages: A new way to inhibit PCa?
Authors: Dalia Marin-Martinez, Thomas Nelius, Stephanie Filleur
Journal: Journal of Clinical Oncology (2015)

e16058 Background: Macrophages have been described as one of the main inflammatory components involved in prostate cancer (PCa) development. PEDF (Pigment Epithelium-Derived Factor) is a secreted angio-inhibitor with differentiation and suggested immune-modulating activities. PEDF expression has been shown to be down-regulated in PCa compared to normal tissues. Previously, we have demonstrated that PEDF re-expression in PCa cells curbs tumor growth in vivo and prolongs the survival of tumor-bearing mice. Others have shown that PEDF increased the recruitment of tumor-cytotoxic macrophages into MatLyLu rat prostate tumors suggesting a link between PEDF and inflammation in PCa. However, PEDF modes of action on macrophages still remain unknown and need further investigation. Methods: THP-1, RAW264.7 and primary macrophages treated with PEDF, its derived active P18 peptide or ctrl were used as models. Migration was assessed using Boyden chamber and 3D PCa spheroid assays. M1/tumor-cytotoxic polarization was tested by qPCR, WB and multiplex ELISA. PEDF expression levels and macrophage density were measured in human prostate by immunohistochemistry. Phagocytosis was tested in macrophages-PCa cocultures. PEDF receptors (ATP5B/PNPLA2/LRP6) were measured by qPCR and WB. Results: Our data showed that PEDF stimulates the migration of macrophages in vitro. Accordingly, PEDF expression positively correlated with macrophage density in human prostate. In both cells and prostate, PEDF induces the polarization of macrophages towards a M1 pathway. As a result, PEDF stimulates the phagocytosis of PCa cells. PEDF’s migratory, differentiation and phagocytic function were reproduced by the P18 peptide. Finally, two of the known PEDF receptors were found highly expressed in macrophages and up-regulated by PEDF and P18. Conclusions: Our data demonstrate that by acting directly on macrophages, PEDF and its synthetic peptide induce the migration and M1 polarization of macrophages resulting in the phagocytosis of PCa cells. These findingssuggest a new way by which PEDF inhibits prostate tumor.This project may lead to the identification of new therapeutic targets for PCa and other inflammation-related diseases.
IGFBP7 Deletion Promotes Hepatocellular Carcinoma
Authors: Maaged Akiel, Chunqing Guo, Xia Li, Devaraja Rajasekaran, Rachel G. Mendoza, Chadia L. Robertson, Nidhi Jariwala, Fang Yuan, Mark A. Subler, Jolene Windle, Dawn K. Garcia, Zhao Lai, Hung-I Harry Chen, Yidong Chen, Shah Giashuddin, Paul B. Fisher, Xiang-Yang Wang, Devanand Sarkar
Journal: Cancer Research (2017)

Abstract Activation of IGF signaling is a major oncogenic event in diverse cancers, including hepatocellular carcinoma (HCC). In this setting, the insulin-like growth factor binding protein IGFBP7 inhibits IGF signaling by binding the IGF1 receptor (IGF1R), functioning as a candidate tumor suppressor. IGFBP7 abrogates tumors by inhibiting angiogenesis and inducing cancer-specific senescence and apoptosis. Here, we report that Igfbp7-deficient mice exhibit constitutively active IGF signaling, presenting with proinflammatory and immunosuppressive microenvironments and spontaneous liver and lung tumors occurring with increased incidence in carcinogen-treated subjects. Igfbp7 deletion increased proliferation and decreased senescence of hepatocytes and mouse embryonic fibroblasts, effects that were blocked by treatment with IGF1 receptor inhibitor. Significant inhibition of genes regulating immune surveillance was observed in Igfbp7−/− murine livers, which was associated with a marked inhibition in antigen cross-presentation by Igfbp7−/− dendritic cells. Conversely, IGFBP7 overexpression inhibited growth of HCC cells in syngeneic immunocompetent mice. Depletion of CD4+ or CD8+ T lymphocytes abolished this growth inhibition, identifying it as an immune-mediated response. Our findings define an immune component of the pleiotropic mechanisms through which IGFBP7 suppresses HCC. Furthermore, they offer a genetically based preclinical proof of concept for IGFBP7 as a therapeutic target for immune management of HCC. Cancer Res; 77(15); 4014–25. ©2017 AACR.
Abstract 119: PRMT5 Is A New Epigenetic Regulator In Cardiovascular Disease
Authors: Tobias S Merkel, David Hassel, Marcus Krüger, Dieter Weichenhan, Christoph Plass, Johannes Backs
Journal: Circulation Research (2013)

Protein arginine methylation is an abundant posttranslational modification involved in various cellular events such as DNA repair, splicing, and transcription. Protein arginine methyltransferases (PRMTs) catalyze the symmetric and asymmetric dimethylation of arginines and can be subdivided into two distinct families: type I enzymes catalyze the formation of asymmetric dimethylation whereas type II enzymes enhance the addition of symmetric methyl groups. Here, we report evidence that PRMT5 a type II enzyme serves as an important epigenetic regulator in myocardial disease. We identified PRMT5 via mass spectrometry as an interactant of class IIa histone deacetylases (HDACs). Additional cardiac interaction partners of PRMT5 were identified by a human cDNA library based yeast-two-hybrid screen. Thereby we elucidated Interleukin enhancer binding factor 3 (ILF3) as a putative interacting protein. ILF3 is a member of the NFAT family. NFAT signalling is known to be a potent driver of cardiomyocyte hypertrophy. Accordingly, we detected a 40% decrease in the size of neonatal rat ventricular myocytes in response to siRNA mediated knockdown of prmt5 . A dominant-negative version of PRMT5 is capable of interfering with the Calcineurin-NFAT axis and blocks NFAT activation. In vivo knockdown of endogenous prmt5 in the zebrafish led to a distinct cardiac phenotype with altered morphology and impaired function. To further elucidate prmt5 function in vivo we use mice with floxed prmt5 alleles. As a loss of prmt5 is lethal in the ES cell stadium we use an inducible α myosin heavy chain Mer-Cre-Mer system. Knockout mice display a complete loss of PRMT5 in cardiomyocytes. In line with our in vitro studies these mice are viable and show no phenotype under baseline conditions. Our work in progress investigates the hypothesis that class IIa HDACs serve as a scaffold to recruit PRMT5 to the DNA, forming a complex with ILF3 to block NFAT activity and the pro-hypertrophic gene program.
Abstract 31: High-density Lipoprotein, a Feed-forward Forechecking Loop
Authors: A.-l. Behnke, F. Mockenhaupt, K. Willy, K. Winkler, R. Hetzer, E. Ermilov, G. Siegel
Journal: Circulation Research (2015)

Background: The protective effect of HDL is projected into the cholesterol back-transport of breakdown products of lipid metabolism to the liver. This is a feed-back circuit which controls cholesterol exit. Cholesterol entry could be safeguarded in a feed-forward forechecking loop at the proteoglycan (PG) receptor sites (syndecan, perlecan). HDL is the counter partner in the system of internalization and diffusion control for lipoprotein entry into the vascular wall. Based on stereochemical and chiral conformity with its PG receptor and the much higher negative charge density, HDL owns by far a higher affinity compared with LDL. Methods: Flow-dependent isometric tension, intracellularly recorded membrane potential and cAMP-cGMP were measured in segments of 25 coronaries from heart transplantations. Results and Discussion: Compared to Krebs solution, LDL (100 mg/dL) impaired flow-dilatation and caused a relative contraction by 18.5% (Table). In contrast, HDL (50 mg/dL) and HDL+LDL stimulated flow-dilatation by 31.1% and 41.4%, respectively (p &lt; 0.96). Thus, the contractile effect of LDL was absent in the Krebs-HDL-LDL solution. The same effects were apparent in the membrane potential and cAMP-cGMP-concentrations of the VSM cells. These results are confirmed by ellipsometry measurements, where nanoplaque formation by LDL is suppressed by preincubation with HDL [Siegel, Malmsten, Ermilov: Adv Coll Interface Sci 205 (2014) 275-318]. Conclusion: LDL-cholesterol entry into the vascular wall is effectfully controlled by HDL in a feed-forward forechecking loop (HDL 4х higher affinity constant to the PG receptor). The interaction between both is dominated by competition.
New mutant AQP2 proteins in nephrogenic diabetes insipidus confer water permeability to oocytes
Authors: S.M. Mulders, A.F. van Lieburg, J.P.L. Rijss, N.V.A.M. Knoers, L.A.H. Monnens, C.H. van Os, P.M.T. Deen
Journal: Journal of the American Society of Nephrology (1996)
Evaluation of PARP inhibition as a platinum sparing strategy in Brca2-deficient pancreatic tumors.
Authors: Maeve Aine Lowery, Alycia Lee, Ethan Tobias, Patricia Sung, Umeshkumar Bhanot, Reena Shakya, Thomas Ludwig, Eileen Mary O'Reilly, Maria Jasin, Mary Ellen Moynahan
Journal: Journal of Clinical Oncology (2014)

e15237 Background: BRCA1/2 mutations are found in up to 5% of patients with PAC. PARP inhibitors (PARPi) and platinum based chemotherapy may have increased anti-tumor efficacy in this population due to deficient DNA repair by homologous recombination (HR). We evaluated the use of cisplatin (CDDP) alone and in combination with the PARPi Olaparib (Ola) in a Brca2deficient murine model of PAC. Methods: KrasG12D/+; p53R270H/+; Pdx-1-Cre; Brca2mut mice were generated as previously described. Experimental mice began treatment at day 30 +/- 2 days with intraperitoneal (IP) CDDP 6mg/kg every 21 days with Ola 50mg/kg IP daily 5 days/week (n=11) or vehicle (n=11). A further 7 mice received Ola alone at same schedule and 8 mice received vehicle only. Pancreatic imaging was performed by T2 weighted MRI at regular intervals. For CDDP treated mice, treatment was held after dose #4 in the absence of visible pancreatic tumor on MRI for toxicity concerns and reinstated only at time of tumor growth. Mice were euthanized for weight loss >20% or failure to thrive/lethargy. Results: Median overall survival was significantly prolonged in CDDP treated mice compared to Ola alone or vehicle (p<0.001), with 48% continuing on treatment. The addition of Ola to CDDP increased time to pancreatic tumor identification and reduced the need for reintroduction of CDDP. Ola treatment compared to vehicle showed modest prolongation in survival and attenuation of tumor growth which did not reach statistical significance. Conclusions: DNA damaging chemotherapy has significantly greater efficacy than single agent PARPi in a HR repair deficient preclinical model of PAC, however the combination of CDDP with Ola prolongs time to primary tumor growth and time to retreatment with CDDP. A concurrent multicenter phase I/II clinical trial of gem/cisplatin +/- ABT-888 in patients with BRCA1/2mutation associated PAC led by MSKCC will prospectively evaluate the combination of CDDP and PARPi in a genetically selected repair deficient population. Treatment Median time to tumor on MRI (days) Median OS (days) CDDP & Olaparib 163 171 CDDP & vehicle 134 164 Olaparib 55 87 Vehicle 45 70