tbuckley/cabot-search huggingface dataset:
DNA methylation downregulated ZDHHC1 suppresses tumor growth by altering cellular metabolism and inducing oxidative/ER stress-mediated apoptosis and pyroptosis
Authors: Xin Le, Junhao Mu, Weiyan Peng, Jun Tang, Qin Xiang, Shaorong Tian, Yixiao Feng, Sanxiu He, Zhu Qiu, Guosheng Ren, Ailong Huang, Yong Lin, Qian Tao, Tingxiu Xiang
Journal: Theranostics (2020)

Cancer progression is an intricate biological process profiled by not only unscheduled proliferation, but also altered metabolism mechanisms. In this article, we introduced a novel tumor suppressor gene (TSG), Zinc Finger DHHC-Type Containing 1 (ZDHHC1, also known as ZNF377), frequently silenced due to epigenetic modification among various cancers, which exerts significant anti-tumor effects through metabolic regulation. Methods: Quantitative reversed-transcription PCR (qRT-PCR), reverse transcription PCR (RT-PCR) and Western blot were employed to demonstrate transcriptional and protein levels of targeted regulators. Methylation of ZDHHC1 promoter was detected by bisulfite genomic sequencing (BGS) and methylation specific PCR (MSP). Proteomics were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) and gas chromatography-mass spectrometry (GC-MS) were utilized for metabolomics analysis. Cellular functions were examined via corresponding approaches. Nude mice were used for xenograft tumor models. Indirect immunofluorescence staining was utilized to obtain precise location and expression of target proteins. Oxidative and ER stress indicators were detected using specific kits. Results: We found that ZDHHC1 expression was frequently silenced in multiple tumor cells and specimens due to methylation. Restoration of ZDHHC1 expression can curb cancer cell progression via stimulating apoptosis and cell cycle arrest, repressing metastasis, and reversing EMT transition and cell stemness. ZDHHC1's salient anti-tumor abilities were recognized in vivo as well. Metabolomic and proteomic analyses predicted inhibitory role of ZDHHC1 in glucose metabolism pathways in a CYGB-dependent manner, and in pentose phosphate pathway (PPP), which was validated by examining altered key factors. Moreover, we unraveled that ZDHHC1 dedicates to the increment of oxidative stress and endoplasmic reticulum (ER) stress to promote pyroptosis for anticancer purposes. Conclusion: Our study for the first time indicates ZDHHC1 is a potential tumor-suppressor frequently silenced due to promoter methylation, capable of negatively regulating metabolisms of tumor cells while stimulating oxidative stress and ER stress to expedite cell death through induction of pyroptosis and apoptosis, which can be exploited for development of new cancer prevention and therapies.
Multimodality Imaging in Evaluation of Cardiovascular Complications in Patients With COVID-19
Authors: Lawrence Rudski, James L. Januzzi, Vera H. Rigolin, Erin A. Bohula, Ron Blankstein, Amit R. Patel, Chiara Bucciarelli-Ducci, Esther Vorovich, Monica Mukherjee, Sunil V. Rao, Rob Beanlands, Todd C. Villines, Marcelo F. Di Carli
Journal: Journal of the American College of Cardiology (2020)
Lung Cancer in Poland
Authors: Mariusz Adamek, Wojciech Biernat, Joanna Chorostowska-Wynimko, Joanna A. Didkowska, Katarzyna Dziadziuszko, Tomasz Grodzki, Jacek Jassem, Lucyna Kępka, Dariusz Kowalski, Paweł Krawczyk, Maciej Krzakowski, Jacek Nikliński, Renata Langfort, Włodzimierz Olszewski, Tadeusz Orłowski, Rodryg Ramlau, Witold Rzyman, Anna Wrona, Marcin Zieliński, Rafał Dziadziuszko
Journal: Journal of Thoracic Oncology (2020)
OP0134 Nonsteroidal antiinflammatory drugs and hospitalizations for gastrointestinal complications in china
Authors: SL Chen, SX Kong, CD Bao, P Mavros, S Chen, J Pei
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> It has been well established that nonsteroidal antiinflammatory drugs (NSAID) cause gastrointestinal (GI) adverse events, ranging from minor symptoms to major complications leading to hospitalisation or death. <h3>Objectives</h3> Assess the association between NSAID use and GI hospitalizations in China. <h3>Methods</h3> The Shanghai Ren Ji Hospital is a tertiary medical centre located in central Shanghai, China. With 700 beds, the hospital has about 10,000 admissions per year. We identified cases from the hospital medical records from 1995 to 1999 based on modes of presentation [acute abdominal pain, vomiting, hematemesis, melena, shock (pulse &gt;100 bpm/systolic &lt;100 mmHg), asymptomatic anaemia, other GI problems, or reason unknown with a discharge diagnosis related to GI complications]. One control was identified for each case, matched by age, sex, and admission date. Data were collected on demographics, history, diagnoses and treatment during the hospitalisation from the medical records. NSAID exposure was determined by drug use during the 1-year period prior to admission noted by the admitting physician. Logistic regression analysis was used to determine the association between NSAID use and GI complications after adjusting for age, sex, marital status, smoking history, and prior GPA use. <h3>Results</h3> 939 patients with upper GI problems were identified as cases and of these 435 had upper GI complications as the primary diagnosis. 939 patients admitted without any GI problems were identified as controls. The mean age was 53 years and 87% were male in both groups. During the 1-year period prior to admission, cases were more likely to be NSAID users than controls (8.5% vs. 5.0%, p &lt; 0.05). Similarly, use of gastroprotective agents (GPA, proton pump inhibitors and H2-antagonists) in the same time period was higher among cases than controls (35.9% vs. 0.6%, p &lt; 0.05). Based on an analysis of the 939 cases and the corresponding controls, the odds ratio (OR) for GI hospitalizations of NSAID users versus nonusers adjusted by age, sex, marital status and history of smoking were 1.9 (95% CI: 1.3–2.7). Similar analysis using only the 435 cases with upper GI complications as the primary diagnosis resulted in an OR estimate of 3.1 (95% CI: 2.1–4.8). Adjusting for GPA use prior to hospital admission did not change the results. <h3>Conclusion</h3> Among patients hospitalised in Shanghai, GI cases were significantly more likely to have used NSAIDs in the prior year than were controls. This suggests that use of NSAIDs is a significant, independent risk factor for GI hospitalisation in Shanghai, as has been demonstrated in numerous studies in developed countries.
Glucose Management Indicator Based on Sensor Data and Laboratory HbA1c in People With Type 1 Diabetes From the DPV Database: Differences by Sensor Type
Authors: Julia M. Grimsmann, Simone von Sengbusch, Markus Freff, Uwe Ermer, Kerstin Placzek, Thomas Danne, Elke Hammer, Reinhard W. Holl
Journal: Diabetes Care (2020)

The glucose management indicator (GMI) estimates HbA1c from continuous glucose monitoring (CGM) profiles. The formula was developed with real-time CGM (rtCGM) sensors (1). As previous data indicated discrepancies between observed laboratory HbA1c and CGM-derived estimates of HbA1c for some individuals and sensor types (1,2), we aimed to compare observed HbA1c and GMI using both rtCGM and intermittent scanning CGM (iscCGM) profiles collected during routine care in people with type 1 diabetes.

We analyzed 132,361 CGM days from a total of 1,973 individuals with type 1 diabetes for ≥1 year from the German/Austrian/Swiss/Luxembourgian Prospective Diabetes Follow-up Registry (DPV) (3). As measurement ranges of the CGM devices differed, we truncated glucose values to the same range (40–400 mg/dL). We calculated the GMI from up to 90 CGM days per individual (median \[interquartile range] 77 [46–89] days per individual) as GMI (%) = 3.31 + 0.02392 ⋅ [mean glucose (mg/dL)\] (1). We compared GMI and observed HbA1c at the end of the 90-day period overall and by age-group. Absolute differences between GMI and observed HbA1c were illustrated for rtCGM vs. iscCGM and stratified by glucose variability, normal weight vs. overweight, and HbA1c  90th percentile for individuals aged  25 kg/m2 …
Comment on: ‘Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry’ by Gianfrancesco<i>et al</i>
Authors: Samet Karahan, Ali Cetinkaya, Kaniye Aydin, Hatice Aslan Sirakaya
Journal: Annals of the Rheumatic Diseases (2020)

We read with great interest the article by Gianfrancesco et al concerning characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. In this study, the authors mentioned that glucocorticoid exposure of ≥10 mg/day is associated with higher odds of hospitalisation and antitumour necrosis factor with decreased odds of hospitalisation in patients with rheumatic disease.1 We also aimed to present a case of microscopic polyanitis (MPA) with a diagnostic challenge with COVID-19 pneumonia. A previously healthy man in his 70s, who had complaints of malaise, fever, cough, tachypnea, dyspnoea was admitted to the emergency. Chest CT (CCT) scan revealed peripheral focal ground-glass opacities (GGOs) and infiltrations in the lower and upper lobes on the right and the left middle zones (figure 1). The patient was admitted to the intensive care unit with a prediagnosis of COVID-19 pneumonia and was intubated due to severe acute respiratory failure. Two nasopharyngeal swabs had …
A Phase I/II Study of Inotuzumab Ozogamicin in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) for Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia
Authors: Nicholas J Short, Hagop M. Kantarjian, Farhad Ravandi, Xuelin Huang, Nitin Jain, Naval Daver, Deborah A Thomas, Naveen Pemmaraju, Rita Khouri, Joseph David Khoury, Jeffrey L. Jorgensen, Yesid Alvarado, Koji Sasaki, Marina Konopleva, Guillermo Garcia-Manero, Tapan Kadia, Jorge E. Cortes, Christopher B Benton, Gautam Borthakur, Jan A. Burger, Maro Ohanian, William G Wierda, Zeev Estrov, Steven Kornblau, Courtney D. DiNardo, Alessandra Ferrajoli, Jovitta Jacob, Ameena Manzoor, Rebecca Garris, Susan M. O'Brien, Elias J. Jabbour
Journal: Blood (2017)
Spatial Density and Distribution of Tumor-Associated Macrophages Predict Survival in Non–Small Cell Lung Carcinoma
Authors: Xiang Zheng, Andreas Weigert, Simone Reu, Stefan Guenther, Siavash Mansouri, Birgit Bassaly, Stefan Gattenlöhner, Friedrich Grimminger, Soni Savai Pullamsetti, Werner Seeger, Hauke Winter, Rajkumar Savai
Journal: Cancer Research (2020)

The respective antitumoral and protumoral roles of M1 and M2 tumor-associated macrophages (TAM) typify the complexity of macrophage function in cancer. In lung cancer, density and topology of distinct TAM phenotypes at the tumor center (TC) versus the invasive margin (IM) are largely unknown. Here, we investigated TAM subtype density and distribution between TC and IM in human lung cancer and TAM associations with overall survival. Macrophages isolated from adjacent nontumor tissue (NM), the TC (TC-TAM), and the IM (IM-TAM) were analyzed with RNA-sequencing (RNA-seq). Lung tumor tissue microarrays from 104 patient samples were constructed. M1 and M2 TAMs were identified using multiplex immunofluorescence staining and a tumor cell-TAM proximity analysis was performed. RNA-seq identified marked differences among NM, TC-TAM, and IM-TAM. On the basis of a panel of five selected markers (CD68, IL12, CCR7, CD163, and ALOX15), M2 predominance over M1 and M2 proximity to tumor cells was observed, especially at IM. Tumor cell proximity to TAM was linked with tumor cell survival and hypoxia was associated with accumulation of M2 TAM. Notably, lower density of M1 TC-TAM and higher proximity of tumor cells to M2 IM-TAM or lower proximity to M1 IM-TAM were linked with poor survival. In addition, three novel molecules (UBXN4, MFSD12, and ACTR6) from RNA-seq served as potential prognostic markers for lung cancer, and M2 predominance and juxtaposition of M2 TAM near tumor cells were associated with poor survival. Together, our results reveal the marked heterogeneity of TAM populations in different tumor regions, with M2 TAM predominance, particularly at IM. SIGNIFICANCE: This study underlines the significance of the density, spatial distribution, and gene expression of TAM phenotypes as prognostic factors for overall survival in lung cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4414/F1.large.jpg.
Abstract 484: Mir-19b-3p Regulates Autophagy by Targeting Raf-1 During Hypertrophic Cardiomyopathy
Authors: Anupam Mittal, Perundurai S Dhandapany
Journal: Circulation Research (2017)

Hypertrophic cardiomyopathy (HCM) is a heterogenous disease predominantly caused by sarcomeric genes. However, 40-50% cases etiology are not known. RAF1 mutations cause syndromic and isolated childhood cardiomyopathies. Functional mutations in untranslated regions (UTRs) of RAF-1 gene are rare, and their role in cardiomyopathy is unexplored. UTRs are important sites for interaction of epigenetic regulators such as microRNAs (miR). miRs have exhibited as crucial regulators of the cardiac remodeling process. We identified a novel mutation in RAF-1 3’-UTR (an important site for binding of miR-19a-3p/19b-3p) in large family members associated with HCM. Whole exome sequencing revealed that these family members are negative for mutations in known cardiomyopathy associated genes. miR-19a/b are known to play a crucial role in cardiac hypertrophy. The aim of this study is to determine the role of miR-19a-3p/19b-3p in regulating RAF-1 expression and delineating the molecular and functional consequences of identified RAF-1 3’-UTR mutation. Our results show that the overexpression of miR-19b-3p, leads to downregulation of RAF-1 expression and regulation. Notably, miR-19b-3p was found to be pro-hypertrophic as its overexpression resulted in increasing hypertrophic markers including ANP and β-MHC expression. Moreover, findings from experiments using RAF1 +/+ and RAF1 -/- mouse embryo fibroblasts (MEFs) confirms the role of miR-19b-3p interaction and regulation of RAF-1 signaling axis. Interestingly, we also observed many autophagy markers (Atg3, Atg 12-5 complex, and LC3 II) are dysregulated by miR-19-b-3p overexpression. Our study uncovers a novel mechanism through which miR-19b-3p regulates autophagy by targeting RAF-1.
Lentinan-functionalized Selenium Nanoparticles target Tumor Cell Mitochondria via TLR4/TRAF3/MFN1 pathway
Authors: Hui-Juan Liu, Yuan Qin, Zi-Han Zhao, Yang Zhang, Jia-Huan Yang, Deng-Hui Zhai, Fang Cui, Ce Luo, Man-Xi Lu, Piao-Piao Liu, Heng-Wei Xu, Kun Li, Bo Sun, Shuang Chen, Hong-Gang Zhou, Cheng Yang, Tao Sun
Journal: Theranostics (2020)

Rationale: Malignant ascites caused by cancer cells results in poor prognosis and short average survival time. No effective treatment is currently available for malignant ascites. In this study, the effects of lentinan (LNT)-functionalized selenium nanoparticles (Selene) on malignant ascites were evaluated. Furthermore, the mechanism of Selene targeting mitochondria of tumor cells were also investigated. Methods: Selene were synthesized and characterized by TEM, AFM and particle size analysis. The OVCAR-3 and EAC cells induced ascites models were used to evaluate the effects of Selene on malignant ascites. Proteomic analysis, immunofluorescence, TEM and ICP-MS were used to determine the location of Selene in tumor cells. Mitochondrial membrane potential, ROS, ATP content, and caspase-1/3 activity were detected to evaluate the effect of Selene on mitochondrial function and cell apoptosis. Immunofluorescence, Co-IP, pull-down, duolink, Western blot, and FPLC were used to investigate the pathway of Selene targeting mitochondria. Results: Selene could effectively inhibit ascites induced by OVCAR-3 and EAC cells. Selene was mainly located in the mitochondria of tumor cells and induced apoptosis of tumor cells. The LNT in Selene was involved in caveolae-mediated endocytosis through the interaction between toll-like receptor-4 (TLR4) and caveolin 1 (CAV1). Furthermore, the Selene in the endocytic vesicles could enter the mitochondria via the mitochondrial membrane fusion pathway, which was mediated by TLR4/TNF receptor associated factor 3 (TRAF3)/mitofusin-1 (MFN1) protein complex. Conclusion: Selene is a candidate anticancer drug for the treatment of malignant ascites. And TLR4/TRAF3/MFN1 may be a specific nano-drug delivery pathway that could target the mitochondria.
SAT0194 Hplc method for pentosidine determination in urine and serum
Authors: P Spacek, M Adam
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Pentosidine (PEN) is the most known representative from the so-called AGE derivatives, whose concentration is elevated in some pathological conditions,<sup>1</sup> (e.g. in diabetes, renal failure, osteoarthritis (OA), inflammatory diseases, etc.). PEN determination is therefore often used for characterisation of the disease activity. <h3>Objectives</h3> The aim of this study is to elaborate precise and sensitive HPLC method for PEN determination, apply it the for evaluation in urine samples in the OA patients and in healthy controls, and to test possible correlation between urine pyridinoline<sup>2</sup> and pentosidine. <h3>Methods</h3> Liquid chromatograph of the firm SHIMADZU type CLASS VP version 5.0 was on line controlled by means of special software in Windows 98 milieu. Glass column Separon SGX C18, 150 × 3 mm (Tessek, Prague, Czech Republic) as the stationary phase and mobile phase 0.02 M heptafluorobutyric acid (HFBA), 0.01 M (NH4)2SO4 with variable acetonitrile (ACN) concentration was used. <h3>Results</h3> Pentosidine standard was synthesised utilising simple polymer analogical reaction and kindly quantified by HPLC in foreign lab.<sup>3</sup> Variation in the reproducibility (RSD) of the HPLC alone was slightly above 1%, RSD of the whole method (i.e. including sample hydrolysis and purification) was 4.44%, recovery was 77 ± 3.5%, HPLC sensitivity limit was 17.6 femtomoles. Urine PEN concentrations were determined in the OA patients (N = 37, age 66.97 ± 9.89 years) and in control individuals (N = 15, age 30.01 ± 8.67 years). PEN-age dependence was eliminated by extrapolation in the sense of known measured PEN-age dependence.<sup>4</sup> In OA PEN urine concentrations were significantly higher (almost four times) compared with healthy controls (8.0 ± 7.2 vs. 2.1 ± 0.5 nmol/mmol creat., P = 0.00002). Slight correlation exists between urinary pentosidine and urinary pyridinoline in OA (U-PEN = 0.0773*U-PD +2.2595, r = 0.4), probably partially evoked by immunity response of the organism due to the toxic action of PEN-containing molecular domains,<sup>5,6 s</sup>ary leading to accelerated resorption kinetics and thus to the additional increasing pyridinoline level. <h3>Conclusion</h3> Sensitive and accurate HPLC method for pentosidine determination was elaborated, optimised and quantified with prepared PEN standard. Urine samples of OA patients and healthy controls were evaluated. Results can probably yield useful additional information about activity of the disease. <h3>References</h3> Sell DR, Monnier VM. J Biol Chem. 1989;264(36):21697–702 paèek P, Hulejová H, Adam M. J Liq Chrom Rel Technol. 1997;20(12):1921–30 VM Monnier, Sell DR. Case Western Reserve University, Cleveland, OH 44106 Takahashi M, Suzuki M, Kushida K, Miyamoto S, Inoue T. Br J Rheumatol. 1997;<b>36</b>:637–42 Vlassara H. Diabetes 1997;46(2):S19-25 Sullivan R. Arch Physiol Biochem. 1996;104(7):797–806
Inhibition of mast cells: a novel mechanism by which nintedanib may elicit anti-fibrotic effects
Authors: Catherine Overed-Sayer, Elena Miranda, Rebecca Dunmore, Elena Liarte Marin, Lorea Beloki, Doris Rassl, Helen Parfrey, Alan Carruthers, Amina Chahboub, Sofia Koch, Gülin Güler-Gane, Michael Kuziora, Arthur Lewis, Lynne Murray, Richard May, Deborah Clarke
Journal: Thorax (2020)

Background Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease which presents a grave prognosis for diagnosed patients. Nintedanib (a triple tyrosine kinase inhibitor) and pirfenidone (unclear mechanism of action) are the only approved therapies for IPF, but have limited efficacy. The pathogenic mechanisms of this disease are not fully elucidated; however, a role for mast cells (MCs) has been postulated. Objectives The aim of this work was to investigate a role for MCs in IPF and to understand whether nintedanib or pirfenidone could impact MC function. Methods and results MCs were significantly elevated in human IPF lung and negatively correlated with baseline lung function (FVC). Importantly, MCs were positively associated with the number of fibroblast foci, which has been linked to increased mortality. Furthermore, MCs were increased in the region immediately surrounding the fibroblast foci, and co-culture studies confirmed a role for MC–fibroblast crosstalk in fibrosis. Nintedanib but not pirfenidone inhibited recombinant stem cell factor (SCF)–induced MC survival. Further evaluation of nintedanib determined that it also inhibited human fibroblast-mediated MC survival. This was likely via a direct effect on ckit (SCF receptor) since nintedanib blocked SCF-stimulated ckit phosphorylation, as well as downstream effects on MC proliferation and cytokine release. In addition, nintedanib ablated the increase in lung MCs and impacted high tissue density frequency (HDFm) in a rat bleomycin model of lung fibrosis. Conclusion Nintedanib inhibits MC survival and activation and thus provides a novel additional mechanism by which this drug may exert anti-fibrotic effects in patients with IPF.