tbuckley/cabot-search huggingface dataset:
A Phase II Pilot Study of Kinase Inhibition in Relapsed/Refractory Acute Leukemias: Using an in Vitro Kinase Inhibitor Panel to Select Individualized, Targeted Therapies
Authors: Stephen E Spurgeon, Rachel Cook, Elie Traer, Uma Borate, Richard T. Maziarz, Jeffrey W. Tyner, Brian J. Druker, Tara Macey, Kristen Werth, Brian Junio, Cristina E. Tognon, Motomi Mori, Marc Loriaux
Journal: Blood (2016)
Survival improvement by systemic chemotherapy in adult patients with recurrent glioblastoma multiforme treated with two courses of radiotherapy
Authors: C. Nieder, A. L. Grosu, S. Astner, N. Andratschke, M. Molls
Journal: Journal of Clinical Oncology (2006)

1578 Background: We evaluated the added value of systemic chemotherapy (CTx) in adult patients with recurrent supratentorial glioblastoma multiforme (GBM) selected to receive local re-treatment (administered as a 2nd course of radiotherapy, RTx). Methods: Retrospective comparison of two patient cohorts treated subsequently during different time periods. All patients had histologically confirmed recurrent GBM. Minimum recurrence-free interval was 4 months. The first cohort (n=26) had surgical resection and standard postoperative external beam RTx followed by a second course of external beam RTx for recurrence (median cumulative dose 102 Gy). None of these patients ever received CTx during the whole course of disease. The more recently treated cohort (after 1999) of 19 patients also had surgical resection and 2 courses of external beam RTx (median cumulative dose 90 Gy). After primary local treatment, 9 of these patients had adjuvant nitrosourea-based CTx. At recurrence, all 19 patients received temozolomide 150–200 mg/m 2 /day for five days every 4 weeks in addition to RTx. Results: The cohort without CTx had less favorable baseline characteristics, because of their significantly lower median KPS at recurrence (70 vs. 90%, p&lt;0.01) and shorter interval between primary diagnosis and recurrence (12 vs. 16 months, p&lt;0.05). However, these patients were non-significantly younger (median age 44 vs. 50 years, p&gt;0.05). The percentage of patients with secondary GBM was similar (21 vs. 23%, p&gt;0.5). Median survival from re-irradiation was significantly better in the RTx plus CTx group, 9 vs. 5 months (p&lt;0.05). In multivariate analysis, prognosis was significantly improved by CTx. Importantly, there was also an advantage when overall survival from first diagnosis was evaluated, median 24 vs. 19 months (p&lt;0.05). Conclusion: The current data suggest that re-irradiation plus temozolomide is better than re-irradiation alone. CTx led to a prolongation of overall survival from first diagnosis by 5 months. The most intensively treated, prognostically favourable de-novo GBM patients had surgical resection, 2 courses of RTx and 2 different systemic CTx regimens. [Table: see text]
Adjuvant trastuzumab in the treatment of small HER2-positive tumors: A single institution experience.
Authors: Maria Vita Sanò, Eleonora Taibi, Marco Ali, Rosanna Di Marco, Alessandra Zacchia, Maurizio Chiarenza, Giuseppina Fallica, Silvia Clementi, Rosa Anna Aiello, Michele Caruso
Journal: Journal of Clinical Oncology (2014)

e11514 Background: According to St.Gallen Criteria, a high risk node-negative patients will be defined as a patients with negative lymph node involvement and at least one of following factors:tumor size > 2 cm, HR negative, histological and/or nuclear grade 2-3 or age < 35 years.However some patients with HER2 positive cancers develop a recurrence despite small tumor size (< 2 cm) and none of these factors. Six phase III multi-centre trials confirmed the potential benefit of incorporating trastuzumab in adjuvant regimens as a standard treatment. The effectiveness of adjuvant trastuzumab has been demonstrated either for node negative pT1c patients and for diseases at a higher risk. These trial were not able to provide any information regarding the outcome of patients with node negative tumours <1cm. Methods: From Jannuary 2005 to November 2013 in our istitution 101 patients with small Her2 positive and negative nodes breast cancers underwent surgery. 83/101(82,2%) patients had quadrantectomy and local radiotherapy, 18/101( 17,8 %) patients had radical mastectomy. Median age at diagnosis was 50,3 years (range 27- 76). All patients were staged as pT1 N0 M0 : 9/101(8,9 %) patients are pT1a N0, 21/101 (20,8 %) patients pT1b pN0 and 72/101 (71,2 %) patients pT1c pN0. 96/101 (95 %) patients were treated with adjuvant anthracyclines regimens for 4 or 6 cycles followed by one year of trastuzumab ( 52 weeks).70/101 patients follow-up was at least 1 year, median follow up was 46 months ( range 13 months – 108 months). The Left Ejection Ventricular Fraction (LEVF) was assessed at baseline and every three months. Results: 2/70 (1.4%) patients relapsed (one lung metastasis during treatment, one local recurrence 13 months after the last dose). An asymptomatic absolute decrease in LVEF by 10% was reported in five patients. No patients discontinued the treatment. Conclusions: The use of trastuzumab in HER2 positive small tumor seems safe and effective. More data should be available for tumors smaller than 1 cm.
Abstract 12057: Mitral Valve Annuloplasty in Addition to Coronary Artery Bypass Grafting in Moderate Functional Ischemic Mitral Regurgitation Reverses Left Ventricular Remodelling and Restores Left Ventricular Geometry: Preliminary Results of the Randomised Ischemic Mitral Evaluation Trial
Authors: K. M. John Chan, Ricardo Wage, Karen Symmonds, Isabelle Roussin, Marcus Flather, Dudley J Pennell, Sanjay K Prasad, Philip J Kilner, John R Pepper
Journal: Circulation (2011)

BACKGROUND: The optimal treatment of moderate functional ischemic mitral regurgitation (FIMR) is uncertain. There is controversy over whether the addition of mitral valve annuloplasty (MVA) to coro...
Abstract 14619: Ultrasound-stimulated Microbubbles for Drug/gene Delivery: Microbubble-generated Shear Stress Induces Pores in Cellular Membranes
Authors: Brandon Helfield, Bin Qin, Xucai Chen, Flordeliza Villanueva
Journal: Circulation (2015)

Background: Ultrasound (US)-stimulated microbubbles (MBs) are emerging as novel target-specific non-viral gene/drug delivery vectors for treatment of vascular disease, e.g. to deliver VEGF plasmid DNA to promote arteriogenesis. The nature of the MB-target cell interactions that facilitate nucleic acid delivery across cell membranes, and hence strategies to optimize the efficiency of this platform, are poorly understood. The objective of this study was to gain mechanistic insight into MB-mediated increases in cell membrane permeability. Methods: Phospholipid coated MBs were allowed to lay adjacent to cultured human umbilical vein endothelial cells (HUVEC) at 37C. Propidium iodide (PI) was put into the media before US exposure to assess membrane permeability (sonoporation). Individual MB-cell pairs (n=351) were exposed to a single US pulse at 0.5, 1, or 2 MHz, with a duration of 4, 8 or 16 μs and pressures 0.1-0.8 MPa. Ultrafast microscopy recorded MB oscillations (Fig. 1a); a second camera simultaneously recorded fluorescence (PI uptake, Fig. 1b). US-induced MB radius change (excursion) was measured and used to calculate shear stress. HUVEC membranes were fluorescently labeled to visualize pore features. Results: Absolute MB excursion distance and associated shear stress were strong threshold indicators of sonoporation (PI uptake). For an 8 μs pulse, the oscillation (shear stress) threshold above which HUVECs porate was 3.9, 2.6, and 1.4 μm (7.8, 14.5, 22.7 kPa) at 0.5, 1 and 2 MHz respectively. At a given US frequency, increases in pulse duration decreased the required excursion and shear stress. Cell membrane imaging showed that MBs can induce apical and basal pores (sub-μm to μm sizes) that reseal (Fig. 1c). Conclusions: Sonoporation is related to absolute MB excursion distance and its associated shear stress and can occur with various US parameters and MB sizes. This data has implications on intelligent US-MB design for their use as payload delivery vehicles.
Reply: Partial gastrectomy: A risk factor for pancreatic cancer?
Authors: Thomas M. Mack, M.D., M.P.H.
Journal: JNCI Journal of the National Cancer Institute (1986)

Reply: Partial Gastrectomy: A Risk Factor for Pancreatic Cancer? Thomas M. Mack, M.D., M.P.H. Thomas M. Mack, M.D., M.P.H. Department of Preventive Medicine, School of Medicine, University of Southern California, 2025 Zonal Avenue, Los Angeles, California 90033 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 77, Issue 2, August 1986, Page 592, https://doi.org/10.1093/jnci/77.2.592 Published: 01 August 1986
ICAMs support B cell interactions with T follicular helper cells and promote clonal selection
Authors: Irina Zaretsky, Ofir Atrakchi, Roei D. Mazor, Liat Stoler-Barak, Adi Biram, Sara W. Feigelson, Alexander D. Gitlin, Britta Engelhardt, Ziv Shulman
Journal: The Journal of Experimental Medicine (2017)

The germinal center (GC) reaction begins with a diverse and expanded group of B cell clones bearing a wide range of antibody affinities. During GC colonization, B cells engage in long-lasting interactions with T follicular helper (Tfh) cells, a process that depends on antigen uptake and antigen presentation to the Tfh cells. How long-lasting T–B interactions and B cell clonal expansion are regulated by antigen presentation remains unclear. Here, we use in vivo B cell competition models and intravital imaging to examine the adhesive mechanisms governing B cell selection for GC colonization. We find that intercellular adhesion molecule 1 (ICAM-1) and ICAM-2 on B cells are essential for long-lasting cognate Tfh–B cell interactions and efficient selection of low-affinity B cell clones for proliferative clonal expansion. Thus, B cell ICAMs promote efficient antibody immune response by enhancement of T cell help to cognate B cells.
Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition
Authors: Rona Yaeger, Zhan Yao, David M. Hyman, Jaclyn F. Hechtman, Efsevia Vakiani, HuiYong Zhao, Wenjing Su, Lu Wang, Andrew Joelson, Andrea Cercek, Jose Baselga, Elisa de Stanchina, Leonard Saltz, Michael F. Berger, David B. Solit, Neal Rosen
Journal: Cancer Research (2017)

Abstract BRAF V600E colorectal cancers are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, but resistance invariably develops through undefined mechanisms. In this study, we determined that colorectal cancer progression specimens invariably harbored lesions in elements of the RAS–RAF–MEK–ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in colorectal cancer patients that was not seen in similarly resistant melanomas. We show that wild-type RAS amplification increases receptor tyrosine kinase-dependent activation of RAS more potently in colorectal cancer than in melanoma and causes resistance only in the former. Currently approved RAF inhibitors inhibit RAF monomers but not dimers. All the drug-resistant lesions we identified activate BRAF V600E dimerization directly or by elevating RAS-GTP. Overall, our results show that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant colorectal cancer. Cancer Res; 77(23); 6513–23. ©2017 AACR.
SMARCB1 is required for widespread BAF complex–mediated activation of enhancers and bivalent promoters
Authors: Robert T Nakayama, John L Pulice, Alfredo M Valencia, Matthew J McBride, Zachary M McKenzie, Mark A Gillespie, Wai Lim Ku, Mingxiang Teng, Kairong Cui, Robert T Williams, Seth H Cassel, He Qing, Christian J Widmer, George D Demetri, Rafael A Irizarry, Keji Zhao, Jeffrey A Ranish, Cigall Kadoch
Journal: Nature Genetics (2017)
Non-Contrast T1-Mapping is a Novel Diagnostic Tool for Acute Myocarditis on Cardiovascular Magnetic Resonance Imaging
Authors: V M Ferreira, S K Piechnik, E Dall'Armellina, T D Karamitsos, J M Francis, R P Choudhury, A Kardos, M G Friedrich, Robson, S Neubauer
Journal: Circulation (2011)
Schizophrenia and the neurodevelopmental continuum:evidence from genomics
Authors: Michael J. Owen, Michael C. O'Donovan
Journal: World Psychiatry (2017)

The idea that disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, often referred to as the neurodevelopmental hypothesis, has become widely accepted. Despite this, the disorder is viewed as being distinct nosologically, and by implication pathophysiologically and clinically, from syndromes such as autism spectrum disorders, attention‐deficit/hyperactivity disorder (ADHD) and intellectual disability, which typically present in childhood and are grouped together as “neurodevelopmental disorders”. An alternative view is that neurodevelopmental disorders, including schizophrenia, rather than being etiologically discrete entities, are better conceptualized as lying on an etiological and neurodevelopmental continuum, with the major clinical syndromes reflecting the severity, timing and predominant pattern of abnormal brain development and resulting functional abnormalities. It has also been suggested that, within the neurodevelopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual disability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder. Recent genomic studies have identified large numbers of specific risk DNA changes and offer a direct and robust test of the predictions of the neurodevelopmental continuum model and gradient hypothesis. These findings are reviewed in detail. They not only support the view that schizophrenia is a disorder whose origins lie in disturbances of brain development, but also that it shares genetic risk and pathogenic mechanisms with the early onset neurodevelopmental disorders (intellectual disability, autism spectrum disorders and ADHD). They also support the idea that these disorders lie on a gradient of severity, implying that they differ to some extent quantitatively as well as qualitatively. These findings have important implications for nosology, clinical practice and research.
Ciliated Cells of the Thyroid of the Mouse
Authors: Dunn, Thelma B.
Journal: JNCI Journal of the National Cancer Institute (1944)

Journal Article Ciliated Cells of the Thyroid of the Mouse Get access Thelma B. Dunn Thelma B. Dunn research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 4, Issue 6, June 1944, Pages 555–557, https://doi.org/10.1093/jnci/4.6.555 Published: 01 June 1944
Integrated Analysis Reveals Tubal- and Ovarian-Originated Serous Ovarian Cancer and Predicts Differential Therapeutic Responses
Authors: Dapeng Hao, Jingjing Li, Shanshan Jia, Yuan Meng, Chao Zhang, Li Wang, Li-jun Di
Journal: Clinical Cancer Research (2017)

Purpose: The relative importance of fallopian tube (FT) compared with ovarian surface epithelium (OSE) in the genesis of serous type of ovarian cancer (SOC) is still unsettled. Here, we followed an integrated approach to study the tissue origin of SOC, as well as its association with clinical outcome and response to therapeutic drugs.Experimental Design: A collection of transcriptome data of 80 FTs, 89 OSEs, and 2,668 SOCs was systematically analyzed to determine the characteristic of FT-like and OSE-like tumors. A molecular signature was developed for identifying tissue origin of SOC and then was used to reevaluate the prognostic genes and therapeutic biomarkers of SOC of different tissue origins. IHC staining of tissue array and functional experiments on a panel of ovarian cancer cell lines were used to further validate the key findings.Results: The expression patterns of tissue-specific genes, prognostic genes, and molecular markers all support a dualistic tissue origin of SOC, from either FT or OSE. A molecular signature was established to identify the tissue identity of SOCs. Surprisingly, the signature showed a strong association with overall survival (OSE-like vs. FT-like, HR = 4.16; 95% CI, 2.67-6.48; P < 10-9). The pharmacogenomic approach revealed AXL to be a therapeutic target of the aggressive OSE-derived SOC.Conclusions: SOC has two subtypes originated from either FT or OSE, which show different clinical and pathologic features. Clin Cancer Res; 23(23); 7400-11. ©2017 AACR.
Residential Air Pollution and Associations with Wheeze and Shortness of Breath in Adults: A Combined Analysis of Cross-Sectional Data from Two Large European Cohorts
Authors: Dany Doiron, Kees de Hoogh, Nicole Probst-Hensch, Stéphane Mbatchou, Marloes Eeftens, Yutong Cai, Christian Schindler, Isabel Fortier, Susan Hodgson, Amadou Gaye, Ronald Stolk, Anna Hansell
Journal: Environmental Health Perspectives (2017)

Background: Research examining associations between air pollution exposure and respiratory symptoms in adults has generally been inconclusive. This may be related in part to sample size issues, which also preclude analysis in potentially vulnerable subgroups. Objectives: We estimated associations between air pollution exposures and the prevalence of wheeze and shortness of breath using harmonized baseline data from two very large European cohorts, Lifelines (2006–2013) and UK Biobank (2006–2010). Our aim was also to determine whether the relationship between air pollution and respiratory symptom prevalence differed between individuals with different characteristics. Methods: Cross-sectional analyses explored associations between prevalence of self-reported wheeze and shortness of breath and annual mean particulate matter with aerodynamic diameter <2.5μm, 2.5–10μm, and <10μm (PM2.5, PMcoarse, and PM10, respectively) and nitrogen dioxide (NO2) concentrations at place of residence using logistic regression. Subgroup analyses and tests for interaction were performed for age, sex, smoking status, household income, obesity status, and asthma status. Results: All PM exposures were associated with respiratory symptoms based on single-pollutant models, with the largest associations seen for PM2.5 with prevalence of wheezing {odds ratio (OR)=1.16 per 5μg/m³ [95% confidence interval (CI): 1.11, 1.21]} and shortness of breath [OR=1.61 per 5μg/m³ (95% CI: 1.45, 1.78)]. The association between shortness of breath and a 5-μg/m³ increment in PM2.5 was significantly higher for individuals from lower-[OR=1.73 (95% CI: 1.52, 1.97)] versus higher-income households [OR=1.31 (95% CI: 1.11, 1.55); p-interaction=0.005), whereas the association between PM2.5 and wheeze was limited to lower-income participants [OR=1.30 (95% CI: 1.22, 1.38) vs. OR=1.02; (95% CI: 0.96, 1.08); p-interaction<0.001]. Exposure to NO2 also showed positive associations with wheeze and shortness of breath. Conclusion: Exposure to PM and NO2 air pollution was associated with the prevalence of wheeze and shortness of breath in this large study, with stronger associations between PM2.5 and both outcomes among lower- versus higher-income participants. https://doi.org/10.1289/EHP1353
Direct oral anticoagulants for the treatment of acute venous thromboembolism in patients with cancer: a meta-analysis of randomised controlled trials
Authors: Matteo Nicola Dario Di Minno, Walter Ageno, Roberta Lupoli, Giulia Conte, Nick van Es, Harry R. Buller, Francesco Dentali
Journal: European Respiratory Journal (2017)

Venous thromboembolism (VTE) is a common complication in cancer patients [1, 2], associated with an 8–10% annual bleeding risk during anticoagulant therapy and a 10–20% annual risk of VTE recurrence [1, 3]. DOACs have a marginally higher antithrombotic efficacy and a comparable safety than VKA in cancer patients with VTE <http://ow.ly/5lJN30dVVGF> Author contributions: M.N.D. Di Minno conceived and designed the study, performed the analysis, interpreted results and drafted the manuscript; F. Dentali conceived and designed the study, and performed literature searches, data extraction and manuscript drafting; R. Lupoli and G. Conte performed literature searches, data extraction and manuscript drafting; N. van Es, H. Büller and W. Ageno interpreted results and performed critical revision of the manuscript. All authors read and approved the final version of the manuscript.
Association of an APOBEC mutational signature, mutational load, and BRCAness with inflammation and PD-L1 expression in HNSCC.
Authors: Damian Tobias Rieke, Clemens Messerschmidt, Sebastian Ochsenreither, Konrad Friedrich Klinghammer, Inge Tinhofer, Korinna Jöhrens, Frederick Klauschen, Dieter Beule, Ulrich Keilholz
Journal: Journal of Clinical Oncology (2017)

e14613 Background: Immune checkpoints are an emerging treatment target in head and neck squamous cell carcinoma (HNSCC). Expression of PD-L1 and an IFNG immune signature have been shown as biomarkers of response. In this study we analyzed mutational signatures to identify recurrent mutational patterns associated with inflammation. Methods: HNSCC mutation and gene expression data were downloaded (n = 496, TCGA). Inflamed tumors were identified through upregulation of a predefined 6-gene IFNG immune signature. Mutational load, base exchange motifs and a BRCAness signature were analyzed in inflamed and non-inflamed tumors. Results were validated in independent datasets of cervical, urothelial and lung cancer (TCGA). Results: Total mutational load did not correlate with tumor inflammation (r = -0.03, p = 0.5). An APOBEC-associated tCw (thymine – cytosine – adenine/thymine) mutational signature was significantly associated with inflammation (r = 0.26, p = 2.923e-09). The tCw signature was furthermore correlated with the expression of PD-L1 and other immune checkpoints (r = 0.19, p = 1.723e-05). The TCW mutational signature correlated with the expression of APOBEC3 genes. Expression of APOBEC3 genes also correlated with tumor inflammation (r = 0.62, p &lt; 2.2e-16). As a second mutational signature, indels and an independent BRCAness signature were significantly enriched in non-inflamed tumors (p = 6.464e-14). Enrichment of an APOBEC mutational signature in inflamed tumors could be validated in cervical and urothelial carcinoma but not NSCLC. Conclusions: In HNSCC, overall mutational load is not associated with inflammation. BRCAness is significantly associated with immune-desertion whereas expression of APOBEC genes and an APOBEC mutational signature significantly correlates with the expression of PD-L1 and a T-cell inflamed signature. These findings suggest that a specific mutational pattern might serve as a biomarker for immune checkpoint inhibition in cancer.
Association Between Hepatic Steatosis, Measured by Controlled Attenuation Parameter, and Fibrosis Burden in Chronic Hepatitis B
Authors: Wai-Kay Seto, Rex W.H. Hui, Lung-Yi Mak, James Fung, Ka-Shing Cheung, Kevin S.H. Liu, Danny Ka-Ho Wong, Ching-Lung Lai, Man-Fung Yuen
Journal: Clinical Gastroenterology and Hepatology (2017)