tbuckley/cabot-search huggingface dataset:
Comprehensive review of cardiovascular toxicity of drugs and related agents
Authors: Přemysl Mladěnka, Lenka Applová, Jiří Patočka, Vera Marisa Costa, Fernando Remiao, Jana Pourová, Aleš Mladěnka, Jana Karlíčková, Luděk Jahodář, Marie Vopršalová, Kurt J. Varner, Martin Štěrba
Journal: Medicinal Research Reviews (2018)

Cardiovascular diseases are a leading cause of morbidity and mortality in most developed countries of the world. Pharmaceuticals, illicit drugs, and toxins can significantly contribute to the overall cardiovascular burden and thus deserve attention. The present article is a systematic overview of drugs that may induce distinct cardiovascular toxicity. The compounds are classified into agents that have significant effects on the heart, blood vessels, or both. The mechanism(s) of toxic action are discussed and treatment modalities are briefly mentioned in relevant cases. Due to the large number of clinically relevant compounds discussed, this article could be of interest to a broad audience including pharmacologists and toxicologists, pharmacists, physicians, and medicinal chemists. Particular emphasis is given to clinically relevant topics including the cardiovascular toxicity of illicit sympathomimetic drugs (e.g., cocaine, amphetamines, cathinones), drugs that prolong the QT interval, antidysrhythmic drugs, digoxin and other cardioactive steroids, beta-blockers, calcium channel blockers, female hormones, nonsteroidal anti-inflammatory, and anticancer compounds encompassing anthracyclines and novel targeted therapy interfering with the HER2 or the vascular endothelial growth factor pathway.
E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the <i>EGFR</i> and <i>c-MET</i> Oncogenes by Destabilizing the Histone Demethylase KDM5C
Authors: Xiaohua Chen, Jun Xian Loo, Xin Shi, Wenjun Xiong, Yong Guo, Haiqiang Ke, Mingkun Yang, Yanping Jiang, Siyu Xia, Min Zhao, Shan Zhong, Chunjiang He, Li Fu, Feng Li
Journal: Cancer Research (2018)

The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes EGFR and c-MET Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bidirectional enhancer RNA transcription. Depletion of KDM5C or HPV16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by HR HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like EGFR and c-METSignificance: This study suggests a novel explanation for why infections with certain HPV isotypes are associated with elevated cancer risk by identifying an epigenetic mechanism through which E6 proteins expressed by those isotypes can drive expression of key oncogenes. Cancer Res; 78(6); 1418-30. ©2018 AACR.
Recurrent Wheeze After Hospital Discharge Among Preschool Children Hospitalized With Acute Wheezing: 18-Months Follow-Up of A Multi-Center Study
Authors: Patrada Thanee, Paskorn Sritipsukho, Orapan Poachanukoon, Araya Satdhabudha, Khlongtip Matchimmadamrong, Sasawan Chinratanapisit, Jitladda Deerojanawong, Pantipa Chatchatee, Narissara Suratannon
Journal: Journal of Allergy and Clinical Immunology (2018)
Increased Mmp-9/timp-1 Ratio Is Associated With Increased Mortality-Report From The Obstructive Lung Disease In Northern Sweden (olin) COPD Study
Authors: Robert Linder, Jamshid Pourazar, Anders Blomberg, Anne Lindberg
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Increased Mmp-9/timp-1 Ratio Is Associated With Increased Mortality-Report From The Obstructive Lung Disease In Northern Sweden (olin) COPD Study
Tumor-Specific T-Cells Engineered to Overcome Tumor Immune Evasion Induce Clinical Responses in Patients With Relapsed Hodgkin Lymphoma
Authors: Catherine M. Bollard, Tamara Tripic, Conrad Russell Cruz, Gianpietro Dotti, Stephen Gottschalk, Vicky Torrano, Olga Dakhova, George Carrum, Carlos A. Ramos, Hao Liu, Meng-Fen Wu, Andrea N. Marcogliese, Cecilia Barese, Youli Zu, Daniel Y. Lee, Owen O’Connor, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, Cliona M. Rooney
Journal: Journal of Clinical Oncology (2018)

Purpose Transforming growth factor-β (TGF-β) production in the tumor microenvironment is a potent and ubiquitous tumor immune evasion mechanism that inhibits the expansion and function of tumor-directed responses; therefore, we conducted a clinical study to discover the effects of the forced expression of a dominant-negative TGF-β receptor type 2 (DNRII) on the safety, survival, and activity of infused tumor-directed T cells. Materials and Methods In a dose escalation study, eight patients with Epstein Barr virus-positive Hodgkin lymphoma received two to 12 doses of between 2 × 10
PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis
Authors: Max L. Senders, Xuchu Que, Young Seok Cho, Calvin Yeang, Hannah Groenen, Francois Fay, Claudia Calcagno, Anu E. Meerwaldt, Simone Green, Phuong Miu, Mark E. Lobatto, Thomas Reiner, Zahi A. Fayad, Joseph L. Witztum, Willem J.M. Mulder, Carlos Pérez-Medina, Sotirios Tsimikas
Journal: Journal of the American College of Cardiology (2018)
The importance of a potential phosphorylation site in enamelin on enamel formation
Authors: Wen-Juan Yan, Pan Ma, Ye Tian, Jing-Ya Wang, Chun-Lin Qin, Jian Q Feng, Xiao-Fang Wang
Journal: International Journal of Oral Science (2017)

Enamelin (ENAM) has three putative phosphoserines (pSers) phosphorylated by a Golgi-associated secretory pathway kinase (FAM20C) based on their distinctive Ser-x-Glu (S-x-E) motifs. Fam20C-knockout mice show severe enamel defects similar to those in the Enam-knockout mice, implying an important role of the pSers in ENAM. To determine the role of pSer55 in ENAM, we characterized ENAMRgsc514 mice, in which Ser55 cannot be phosphorylated by FAM20C due to an E57>G57 mutation in the S-x-E motif. The enamel microstructure of 4-week-old mice was examined by scanning electron microscopy. The teeth of 6-day-old mice were characterized by histology and immunohistochemistry. The protein lysates of the first lower molars of 4-day-old mice were analyzed by Western immunoblotting using antibodies against ENAM, ameloblastin and amelogenin. ENAMRgsc514 heterozygotes showed a disorganized enamel microstructure, while the homozygotes had no enamel on the dentin surface. The N-terminal fragments of ENAM in the heterozygotes were detained in the ameloblasts and localized in the mineralization front of enamel matrix, while those in the WT mice were secreted out of ameloblasts and distributed evenly in the outer 1/2 of enamel matrix. Surprisingly, the ~15 kDa C-terminal fragments of ameloblastin were not detected in the molar lysates of the homozygotes. These results suggest that the phosphorylation of Ser55 may be an essential posttranslational modification of ENAM and is required for the interaction with other enamel matrix molecules such as ameloblastin in mediating the structural organization of enamel matrix and protein-mineral interactions during enamel formation. Research in mice has provided new insight into the mechanisms through which the protein enamelin contributes to formation of tooth enamel. Enamelin is one of several proteins that make up the enamel matrix and is secreted from ameloblasts, the cells responsible for enamel formation. Previous work has shown that mutation of enamelin to prevent its phosphorylation at a specific site disrupts enamel formation. Xiaofang Wang from the Texas A&M University College of Dentistry, USA, and colleagues showed that the mutation caused a fragment of enamelin that is normally secreted to remain inside ameloblasts, altering the enamel matrix and affecting cellular processing of ameloblastin, another essential component of the enamel matrix. The finding shows that preventing phosphorylation of enamelin at the mutated site hinders interactions of the proteins required for enamel formation.
Identification and Validation of Molecular Markers of Tumor Cell Resistance to Natural Killer Cells through CRISPR-Based Screens and Large-Scale Phenotypic Screens of Pooled Tumor Cell Lines
Authors: Michal Sheffer, Lotte Wieten, Channing Yu, Yiguo Yu, Olga Dashevsky, Emily Lowry, Jennifer Roth, Aviad Tsherniak, Chris C Mader, Sam Bender, Jordan Bryan, Cong Zhu, Li Wang, Ricardo De Matos Simoes, Sara Gandolfi, Eugen Dhimolea, Megan Bariteau, Todd R. Golub, Constantine S. Mitsiades
Journal: Blood (2017)
Synergistic interaction of bortezomib and dexamethasone in human cancer cells
Authors: Ralf Hilger, Siegfried Seeber, Ralf Angermund, Dirk Strumberg
Journal: Cancer Research (2007)

4777   Introduction: Glucocorticoids have been widely used in the treatment of multiple myeloma, both as single agents and combined with conventional and novel agents. Dexamethasone is active in 25% of patients with disease resistant to alkylating agents. Blockade of IL-6 signaling seems to be essential for dexamethasone-induced cell death because apoptotic pathways activated by dexamethasone can be abrogated by IL-6. The dipeptide boronic acid analogue bortezomib is a potent, highly selective, and reversible proteasome inhibitor that targets 26S proteasome complex and inhibits its function. Preclinical in vitro and in vivo studies show remarkable anti-multiple myeloma activity of the proteasome inhibitor bortezomib even in multiple myeloma cells refractory to multiple prior therapies, including dexamethasone, melphalan, and thalidomide.  Purpose of the study: In these studies, we have examined the effects of combining dexamethasone, melphalan, bendamustine, doxorubicin and thalidomide with bortezomib in the chemotherapy refractory cell line RPMI-8226 and the chemotherapy sensitive human multiple myeloma cell line OPM-2.  >Methods: The sensitivity of the different cell lines against the tested chemotherapeutic drugs was assessed using the MTT test system. The therapeutic index was calculated from isobologram analyses.  >Results: Comparing two cell lines from multiple myeloma (IgG lambda type), the RPMI-8226 line was much more resistant to the tested conventionally used drugs doxorubicin (resistance factor (RF) = 2), melphalan (RF = 15), bendamustine (RF = 1.5), thalidomide (RF = 2.5) and dexamethasone (RF = 300) compared to the OPM-2 cell line. Relative resistance to bortezomib of the RPMI-8226 cell line in this comparison was determined to a RF of 3. Isobologram analysis of cytotoxicity assays revealed that there is a strong synergistic interaction between dexamethasone and bortezomib in both cell lines. In general, a sequence of short time exposure (1 h) of conventional cytostatics (ctx) to the tested cell lines prior to the administration of bortezomib shows a higher therapeutic index than the sequence bortezomib prior to ctx.  >Conclusion: Our findings of a strong synergistic interaction between dexamethasone and bortezomib give evidence for a combination therapy in patients suffering multiple myeloma even in a dexamethasone resistant situation.
Precursors of human CD4 <sup>+</sup> cytotoxic T lymphocytes identified by single-cell transcriptome analysis
Authors: Veena S. Patil, Ariel Madrigal, Benjamin J. Schmiedel, James Clarke, Patrick O’Rourke, Aruna D. de Silva, Eva Harris, Bjoern Peters, Gregory Seumois, Daniela Weiskopf, Alessandro Sette, Pandurangan Vijayanand
Journal: Science Immunology (2018)

CD4+ cytotoxic T lymphocytes (CD4-CTLs) have been reported to play a protective role in several viral infections. However, little is known in humans about the biology of CD4-CTL generation, their functional properties, and heterogeneity, especially in relation to other well-described CD4+ memory T cell subsets. We performed single-cell RNA sequencing in more than 9000 cells to unravel CD4-CTL heterogeneity, transcriptional profile, and clonality in humans. Single-cell differential gene expression analysis revealed a spectrum of known transcripts, including several linked to cytotoxic and costimulatory function that are expressed at higher levels in the TEMRA (effector memory T cells expressing CD45RA) subset, which is highly enriched for CD4-CTLs, compared with CD4+ T cells in the central memory (TCM) and effector memory (TEM) subsets. Simultaneous T cell antigen receptor (TCR) analysis in single cells and bulk subsets revealed that CD4-TEMRA cells show marked clonal expansion compared with TCM and TEM cells and that most of CD4-TEMRA were dengue virus (DENV)-specific in donors with previous DENV infection. The profile of CD4-TEMRA was highly heterogeneous across donors, with four distinct clusters identified by the single-cell analysis. We identified distinct clusters of CD4-CTL effector and precursor cells in the TEMRA subset; the precursor cells shared TCR clonotypes with CD4-CTL effectors and were distinguished by high expression of the interleukin-7 receptor. Our identification of a CD4-CTL precursor population may allow further investigation of how CD4-CTLs arise in humans and, thus, could provide insights into the mechanisms that may be used to generate durable and effective CD4-CTL immunity.
Proteomic diversity of high‐density lipoprotein explains its association with clinical outcome in patients with heart failure
Authors: Johanna Elisabeth Emmens, Donald J.L. Jones, Thong H. Cao, Daniel C.S. Chan, Simon P.R. Romaine, Paulene A. Quinn, Stefan D. Anker, John G. Cleland, Kenneth Dickstein, Gerasimos Filippatos, Hans L. Hillege, Chim C. Lang, Piotr Ponikowski, Nilesh J. Samani, Dirk J. van Veldhuisen, Faiz Zannad, Aeilko H. Zwinderman, Marco Metra, Rudolf A. de Boer, Adriaan A. Voors, Leong L. Ng
Journal: European Journal of Heart Failure (2017)
Effects of a novel apoptotic peptide (nefm1) on human breast cancers
Authors: Harvey Bumpers, Ming-Bo Huang, Willie Harrington, Michael Powell, Vincent Bond
Journal: Cancer Research (2008)

2385  Introduction: The chemokine receptor/ ligand, CXCR4/SDF-1α, is critically important to angiogenesis and vascular remodeling, and has been shown to be involved in tumorigenesis, proliferation, and metastasis of human carcinomas. We have shown that a novel peptide from HIV-1 Nef (NefM1) induces apoptosis through the CXCR4 receptor. We would like to exploit this as a cancer therapeutic agent. Methods:Breast cancer cell lines, MDA-MB231 (231), MDAMB468 (468), MCF-7, DU4475, and HMEC were each evaluated for their response to NefM1. Apoptosis was assessed using TUNEL staining and caspase-3 activation. The presence of CXCR4 receptors on the tumor cells was determined using immunohistochemistry and PCR analyses. Xenografts derived from CXCR4+ cells were propagated in SCID mice and evaluated for the persistence of the receptor and the effects of NefM1 on growth and metastasis. The growing tumors underwent volumetric measurements weekly and comparisons were made between those treated with NefM1 biweekly, by i.p. injections, and those untreated. Human breast cancer xenografts generated from fresh surgical specimens were studied for the effects of NefM1 on their growth and metastasis in SCID mice. Results:Breast cell lines that were positive for CXCR4 receptors all underwent apoptosis when treated with Nef, as did those CXCR4-negative cells that were transfected with CXCR4. The corresponding xenografts derived from CXCR4+ 231 cells demonstrated high levels of the receptor. Breast xenografts derived from 231 cells demonstrated smaller primaries and significantly smaller metastatic tumors in the Nef treated group. Conclusion: NefM1 causes apoptotic reduction in in vitro and in vivo growth of breast cancer cells and tumor xenografts, respectively. Metastatic lesions were smaller in the treated group.
Study of Specific IgE Recognition of New Potential Synthetic Antigenic Determinants for α-Amino-Cephalosporins
Authors: Angela Martin-Serrano Ortiz, Cristobalina Mayorga, Esther Barrionuevo, Alba Rodriguez-Nogales, Ezequiel Perez-Inestrosa, Maria Jose Torres Jaén, Maria Isabel Montañez
Journal: Journal of Allergy and Clinical Immunology (2018)
High-Risk <i>TP53</i> Mutations Are Associated with Extranodal Extension in Oral Cavity Squamous Cell Carcinoma
Authors: Vlad C. Sandulache, Chieko Michikawa, Pranav Kataria, Frederico O. Gleber-Netto, Diana Bell, Sanchit Trivedi, Xiayu Rao, Jing Wang, Mei Zhao, Samar Jasser, Jeffrey N. Myers, Curtis R. Pickering
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Development of extranodal extension (ENE) has been associated with poor survival in patients with oral cavity squamous cell carcinoma (OSCC). Here, we sought to confirm the role of ENE as a poor prognostic factor, and identify genomic and epigenetic markers of ENE in order to develop a predictive model and improve treatment selection. Experimental Design: An institutional cohort (The University of Texas MD Anderson Cancer Center) was utilized to confirm the impact of ENE on clinical outcomes and evaluate the genomic signature of primary and ENE containing tissue. OSCC data from The Cancer Genome Atlas (TCGA) were analyzed for the presence of molecular events associated with nodal and ENE status. Results: ENE was associated with decreased overall and disease-free survival. Mutation of the TP53 gene was the most common event in ENE+ OSCC. The frequency of TP53 mutation in ENE+ tumors was higher compared with ENE− tumors and wild-type (WT) TP53 was highly represented in pN0 tumors. pN+ENE+ patients had the highest proportion of high-risk TP53 mutations. Both primary tumors (PT) and lymph nodes with ENE (LN) exhibited a high rate of TP53 mutations (58.8% and 58.8%, respectively) with no significant change in allele frequency between the two tissue sites. Conclusions: ENE is one of the most significant markers of OSCC OS and DFS. There is a shift toward a more aggressive biological phenotype associated with high-risk mutations of the TP53 gene. Prospective clinical trials are required to determine whether TP53 mutational status can be used for personalized treatment decisions. Clin Cancer Res; 24(7); 1727–33. ©2018 AACR.
Pay attention to a “window-blind” appearance of the distal rectal muscle layer during endoscopic submucosal dissection
Authors: Yoshikazu Hayashi, Masahiro Okada, Hisashi Fukuda, Yoshimasa Miura, Keijiro Sunada, Alan Lefor, Hironori Yamamoto
Journal: Endoscopy (2018)

Endoscopic submucosal dissection (ESD) is increasingly used as a minimally invasive technique for treating superficial gastrointestinal tumors. Rectal ESD using the pocket-creation method (PCM) [1] is relatively easy for endoscopists who are used to performing submucosal endoscopy (e. g. peroral endoscopic myotomy [POEM]), even if they have not performed many ESD procedures.
Response to: ‘Prognosis of immune-tolerant phase chronic hepatitis B’ by Chu and Liaw
Authors: Gi-Ae Kim, Young-Suk Lim
Journal: Gut (2018)

We appreciate the interest given to our article1 by Chu and Liaw.2 

Determining disease phases of patients with chronic hepatitis B (CHB) is essential for assessing patient prognosis and need for treatment. Distinguishing between the immune-tolerant and immune-active phases among patients with hepatitis B e antigen (HBeAg)-positive CHB is best determined by identifying significant necroinﬂammation and/or ﬁbrosis through liver biopsy. However, given the dynamic nature of CHB and the risks and costs of repeated liver biopsy, this recommendation may not always be realistic, especially …
Detergent and alcohol free formulation of cabazitaxel: Safety and pharmacokinetics of escalating dose of cabazitaxel lipid suspension (CLS) in patients with advanced solid maliganancies.
Authors: Ateeq Ahmad, Saifuddin Sheikh, Mahesh Paithankar, Gururaj Deshpande, K.C. Lakshmaiah, Tanveer M Maksud, Ajay Khatri, Manjunath K, Prashant Kale, Ronak Patel, Hanmant Barkate, Imran Ahmad
Journal: Journal of Clinical Oncology (2016)

e14019 Background: Cabazitaxel commercially called JEVTANA is a treatment for metastatic castration-resistant prostate cancer (mCRPC) patients progressing after docetaxel therapy. Cabazitaxel Lipid Suspension (CLS) is a detergent and alcohol-free aqueous based lipid formulation that can circumvent the toxicity and hypersensitivity reactions caused by excipients (polysorbate 80 and ethanol) of JEVTANA. Methods: An open label and multicentric clinical study was conducted to evaluate the safety and Pharmacokinetics (PK) at escalating doses (15, 20 and 25 mg/m2) of CLS and at 25 mg/m2 dose of JEVTANA in solid tumor cancer patients. A total of 23 venous blood samples were collected per patient and PK parameters were calculated by non-compartmental model using Phoenix WinNonlin version 6.4. Dose proportionality in CLS treated patients was evaluated using PROC MIXED of SAS version 9.3. Results: A total of 32 adverse events (AEs) were reported in 11 patients during the conduct of study. At 15 mg/m2, 7 adverse events (AEs) were observed, 3 AEs occurred in patients at the dose of 20 mg/m2 whereas, 11 AEs were reported in patients who received 25 mg/m2 in each arm of CLS and JEVTANA. PK evaluation showed that Cmax increases with increasing dose of CLS. AUC0-t and AUC 0-∞ obtained for all dose levels of CLS were found to be comparable to JEVTANA dose of 25 mg/m2. The Tmax , t1/2 , Vd and Cl were comparable for all dose levels of CLS and independent of dose tested. Total Cabazitaxel estimate for the ln-transformed PK parameter AUC0-48 was very close to unity (i.e. 1). The 90% CI for ln-transformed PK parameters Cmax , AUC0-t and AUC0-48 contains unity within the range for total Cabazitaxel. Hence, Cmax , AUC0-t and AUC 0-48 for total Cabazitaxel increase in proportional manner within dose range of 15 mg/m2 to 25 mg/m2of CLS. Similarly, dose proportionality was also obtained for Free Cabazitaxel at all the 3 doses. Conclusions: Overall, the CLS was found to be well tolerated in cancer patients. The pharmacokinetics of CLS demonstrates its therapeutic potential in mCRPC patients. Clinical trial information: CTRI/2015/06/005948.
Interstitial lung abnormalities and self-reported health and functional status
Authors: Gisli Thor Axelsson, Rachel K Putman, Tetsuro Araki, Sigurdur Sigurdsson, Elias Freyr Gudmundsson, Gudny Eiriksdottir, Thor Aspelund, Ezra R Miller, Lenore J Launer, Tamara B Harris, Hiroto Hatabu, Vilmundur Gudnason, Gary Matt Hunninghake, Gunnar Gudmundsson
Journal: Thorax (2018)

We investigated the association between interstitial lung abnormalities (ILA) and self-reported measures of health and functional status in 5764 participants from the Age, Gene/Environment Susceptibility-Reykjavik study. The associations of ILA to activities of daily living (ADLs), general health status and physical activity were explored using logistic regression models. Participants with ILA were less likely to be independent in ADLs (OR 0.70; 95% CI 0.55 to 0.90) to have good or better self-reported health (OR 0.66; 95% CI 0.52 to 0.82) and to participate in physical activity (OR 0.72; CI 0.56 to 0.91). The results demonstrate ILA's association with worsening self-reported health and functional status.