tbuckley/cabot-search huggingface dataset:
IGF-Child-Turcotte-Pugh score as a predictor of treatment outcome in Child-Pugh A, advanced hepatocellular carcinoma patients undergoing sorafenib therapy.
Authors: Yehia I. Mohamed, Aliya Qayyum, Manal Hassan, Lianchun Xiao, Dan G. Duda, Rikita Hatia, Sunyoung S. Lee, Robert A. Wolff, Jeffrey Morris, Lina Altameemi, James C. Yao, Hesham M. Amin, Ahmed Omar Kaseb
Journal: Journal of Clinical Oncology (2020)

e16660 Background: Sorafenib is the first systemic therapy approved for advanced HCC treatment; with no accurate tool available to help predict survival and treatment outcome and to guide therapy decisions. Our novel blood-based insulin-like growth factor-1 (IGF)-Child-Turcotte-Pugh (CTP) score comprises levels of IGF-1, bilirubin, INR, and albumin. IGF-CP score significantly improved the prediction of HCC survival in our recently published studies. The current prospective study aimed to compare the overall survival (OS) and progression free survival (PFS) of 116 patients with CTP-A HCC treated with sorafenib whose score is reclassified as IGF-A (AA) to that of patients whose score is reclassified as IGF-B/C (AB/AC). Methods: After the approval of the institutional review boards and signing written informed consent, a total of 116 patients with HCC were prospectively enrolled and started on sorafenib and followed until progression or death. We calculated IGF-CTP scores, used Kaplan-Meier method and log rank test to estimate and compare time to event outcomes between subgroups of patients. Results: 116 patients were CTP class A, 87 of the patients with CTP class A were classified as IGF-CTP-A and had median OS of 13.16 ms (95% CI = 12.04 to 22.6 ms), and a median PFS of 5.82 months (ms) (95% CI = 4.34 to 9.14 ms), whereas 29 patients were reclassified as intermediate risk (IGF-CTP-B) and had had a higher risk of death with a shorter OS of 7.6 months (95% CI = 5.23 to 24.47 months) and shorter PFS of 3.49 months (95% CI = 2.53 to 5.26 months). There was higher overall rate of adverse events in the CTP-A patients reclassified as IGF-CTP B than IGF-CTP A especially in grade III-IV adverse events, upper GI Bleeding, lower GI Bleeding, nose bleeding, renal failure, liver failure, encephalopathy, fatigue, weight loss, anorexia, and vomiting. Conclusions: The results of this study support our biologically-driven hypothesis that among HCC patients with CTP-A class treated with sorafenib, those reclassified as IGF-CTP-B/C will have poorer prognosis in terms of shorter OS and PFS. Thus, our study provides an objective non-invasive strategy to better predict the outcome in HCC patients undergoing systemic therapy. Future validation of our IGF-1 score may lead to adopting it as a stratification tool in clinical trials as well as to predict HCC outcome and guide therapy decision in routine practice.
Pelvic radiotherapy in combination with radical resection of the primary tumor improves survival in patients with metastatic rectal adenocarcinoma: A national cancer database analysis (NCDB).
Authors: Paul B. Renz, Shaakir Hasan, Rodney E Wegner, Gene Grant Finley, Dulabh K. Monga, Moses S. Raj, James McCormick, Alexander V. Kirichenko
Journal: Journal of Clinical Oncology (2019)

714 Background: With recent advances in systemic therapies and increased survival of patients with metastatic rectal cancer, the role of primary tumor resection may be of increased importance and is often debated. However, the role of combining radiotherapy to surgical resection in the metastatic setting is unknown. Accordingly, we utilized the NCDB to quantify survival in metastatic rectal adenocarcinoma patients with primary tumor resection with and without pelvic radiotherapy. Methods: Of the 15,643 Stage IV rectal adenocarcinoma patients receiving chemotherapy from 2004 to 2014, 4051 patients had primary tumor resection with sufficient follow up for analysis. Patients were stratified by receipt of pelvic radiotherapy (n = 1882) or no pelvic radiotherapy (n = 2169). Univariable/multivariable analyses and propensity-adjusted Cox proportional hazard ratios for survival were performed. Results: Median age was 63 years (18-90) with median follow up of 32.3 months (3.02-151.29). There were more patients with T3/T4 disease (69.6% vs 46.5%) or N1 disease (41.5% vs 27.3%) in the surgery plus radiotherapy arm. Metastatic burden was confined to one organ in 40.5% of patients and was equally distributed between radiotherapy and non-radiotherapy groups (OR 0.92; 95%CI 0.81-1.04). Median survival was 46.3 months vs. 35.3 months in favor of adding radiotherapy (p &lt; 0.001). The 2, 5 and 10-year overall survival were 68.4%, 24.8%, and 9.5% for surgical resection alone compared to 77.2%, 39.6%, and 22.3% for surgery + radiotherapy. On multivariable analysis radiotherapy was associated with a statistically significant reduction in the risk of death (HR 0.718; 95% CI 0.661-0.780). This benefit was upheld on propensity matched analysis (HR 0.722; 95% CI 0.0665-0.784). Conclusions: Our study indicates that adding radiotherapy to surgical management of the primary tumor in patients receiving systemic chemotherapy for metastatic rectal adenocarcinoma improves survival. Prospective investigation of the management of the rectal primary tumor with chemotherapy, pelvic radiotherapy, and surgical resection is warranted.
Baricitinib Prevents and Treats GvHD through Both Immune Modulation and Enhancement of Tissue Repair
Authors: Kidist Ashami, Kiran R. Vij, Julie Ritchey, Srikanth Santhanam, Karl W. Staser, Sora Lim, Sena Kim, Matthew L. Cooper, Feng Gao, Matthew Ciorba, John F. DiPersio, Jaebok Choi
Journal: Blood (2018)
Myeloid‐Derived Suppressor Cells in Hematologic Diseases: Promising Biomarkers and Treatment Targets
Authors: Nikoleta Bizymi, Sunčica Bjelica, Astrid Olsnes Kittang, Slavko Mojsilovic, Maria Velegraki, Charalampos Pontikoglou, Mikael Roussel, Elisabeth Ersvær, Juan Francisco Santibañez, Marie Lipoldová, Helen A. Papadaki
Journal: HemaSphere (2019)

Abstract Myeloid‐derived suppressor cells (MDSC) are a heterogeneous group of immature myeloid cells that exist at very low numbers in healthy subjects but can expand significantly in malignant, infectious, and chronic inflammatory diseases. These cells are characterized as early‐MDSCs, monocytic‐MDSCs, and polymorphonuclear‐MDSCs and can be studied on the basis of their immunophenotypic characteristics and their functional properties to suppress T‐cell activation and proliferation. MDSCs have emerged as important contributors to tumor expansion and chronic inflammation progression by inducing immunosuppressive mechanisms, angiogenesis and drug resistance. Most experimental and clinical studies concerning MDSCs have been mainly focused on solid tumors. In recent years, however, the implication of MDSCs in the immune dysregulation associated with hematologic malignancies, immune‐mediated cytopenias and allogeneic hemopoietic stem cell transplantation has been documented and the potential role of these cells as biomarkers and therapeutic targets has started to attract a particular interest in hematology. The elucidation of the molecular and signaling pathways associated with the generation, expansion and function of MDSCs in malignant and immune‐mediated hematologic diseases and the clarification of mechanisms related to the circulation and the crosstalk of MDSCs with malignant cells and other components of the immune system are anticipated to lead to novel therapeutic strategies. This review summarizes all available evidence on the implication of MDSCs in hematologic diseases highlighting the challenges and perspectives arising from this novel field of research.
Abstract 14821: Long-Term Consistent Expression of Apolipoprotein B mRNA-Specific Hammerhead Ribozymes, Delivered via scAAV8.2 Vector, Promises Atherosclerosis Inhibition in Mice
Authors: Hersharan Nischal, Hua Sun, Yunchun Wang, David A Ford, Babie Teng
Journal: Circulation (2013)

Target substrate-specific hammerhead ribozymes cleave the specific mRNA efficiently and result in the inhibition of gene expression. In humans, elevated levels of apolipoprotein B (apoB) is positiv...
Abstract 15265: Clopidogrel Response Variability is Associated With Endothelial Dysfunction in Coronary Artery Disease Patients Receiving Dual Antiplatelet Therapy
Authors: Evangelos Oikonomou, Gerasimos Siasos, Marina Zaromitidou, Konstantinos Maniatis, Konstantinos Mourouzis, Eleni Kokkou, Alexis Antonopoulos, Theodoros Zografos, Sotiris Tsalamandris, Stathis Dimitropoulos, Konstantinos Zisimos, Stamatis Kioufis, Athanasios G Papavasiliou, Dimitris Tousoulis
Journal: Circulation (2015)

Introduction: Dual antiplatelet therapy with aspirin and a platelet P2Y12 ADP receptor antagonist is the cornerstone of treatment following percutaneous coronary intervention (PCI). Several clinical and genetic factors can cause suboptimal clopidogrel response. Hypothesis: Endothelial dysfunction affects clopidogrel response variability in subjects with stable coronary artery disease (CAD) after PCI. Methods: We consecutively enrolled 198 patients with stable CAD one month after successful PCI. All patients were receiving dual antiplatelet therapy (clopidogrel 75mg and aspirin 100mg/day). Platelet reactivity was measured by VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). VerifyNow reports its results in P2Y12 reaction units (PRU) and the diagnostic cut-off value is 230. Endothelial function was evaluated by flow mediated dilation (FMD). Results: Patients with high on treatment platelet reactivity (32% of the study population), compared to subjects with low on treatment platelet reactivity, presented decreased FMD (4.35±2.22% vs. 5.74±3.29%, p=0.01). Moreover, an inverse association between endothelial function measurement and platelet reactivity (r=-0.24, p=0.001) was founded. Importantly, multivariate analysis after adjustment for age, gender and confounders revealed by the univariate analysis (left ventricle ejection fraction, body mass index, coronary lesion number) revealed that for every decrease in FMD by 1% there is an anticipated increased in P2Y12 reactive units by 10 units [b=-9.9, 95%CI(-19.0, -0.7), p=0.04]. Conclusions: Endothelial dysfunction is associated with clopidogrel response variability in patients after PCI receiving dual antiplatelet therapy. These findings shed some light on the mechanisms affecting individual platelet response to antiplatelet therapy and may explain the non-straight forward association between clopidogrel dose, platelet inhibition and cardiovascular outcome.
Comprehensive -omic analysis of 152 CRC patients allows greater subclassification than CMS or sidedness alone.
Authors: Christopher Szeto, Kevin Kazmierczak, Andrew Chambers, Yeoun Jin Kim, Andrew Nguyen, Iain B. Tan, Stephen Charles Benz, Charles Joseph Vaske
Journal: Journal of Clinical Oncology (2019)

601 Background: Despite relatively high TMB in CRC, immune checkpoint inhibition (ICI) response is lower than in similarly mutated tissues such as melanoma (ORR 10-20% vs. 20-50%). MSI-status can be used to pre-select likely-responders, however MSI is rare. There is a need to guide ICI candidacy in CRC. Four transcriptomic-based CRC consensus molecular subtypes (CMS) have been described with ad hocclinical associations. We sought to confirm these subtypes in proteomic assays and their clinical associations. Methods: 152 CRC tumors from the National Cancer Centre Singapore were available for analysis. Tumor/normal-paired DNAseq (WGS or WES) and deep RNAseq was performed. Mass-spec based global proteomics was successfully performed on 143/152 samples. Consensus between RNAseq and global proteomics was confirmed by correlation significance analysis. MSI-status was determined by both PCR and WGS/WES profiles. CMS types, checkpoint expression, and immune-infiltration deconvolution were calculated upon RNAseq data. A CMS-like clustering of proteomic data was identified by analyzing homogeneity of candidate clusterings with CMS types. Significant enrichment for MSI, immune status, CMS types, and clinical covariates was analyzed. Results: DNAseq-based MSI and PCR-based MSI were statistically equivalent (adj. p &lt; 1.4E-14). 3075/5135 genes were significantly correlated between RNAseq and global proteomic assays. The most correlated genes within COSMIC cancer-related genes were enriched for MHC binding processes. Clustering of immune-expression deconvolution bifurcated into hot and cold tumors. Significant association was found between CMS1, MSI, transverse sides, and being immune hot. Conversely, CMS2 was found to be significantly MSS, left-sided, and immune cold. A semi-supervised clustering of global proteomic data significantly recapitulated some CMS subtypes, but grouped CMS1 (MSI enriched) and CMS3 (Ras mt enriched) subtypes. Genes driving this association were significantly enriched for ECM organization. Conclusions: CMS1 tumors are the best candidates for ICI therapy. CMS3 co-clusters with CMS1 in ECM genes within proteomic data, warranting further research of CMS3 ICI outcomes.
Safe Nanocomposite‐Mediated Efficient Delivery of MicroRNA Plasmids for Autosomal Dominant Polycystic Kidney Disease (ADPKD) Therapy
Authors: Yen‐Chang Tsai, I‐Ling Teng, Si‐Tse Jiang, Yi‐Che Lee, Yuan‐Yow Chiou, Fong‐Yu Cheng
Journal: Advanced Healthcare Materials (2019)

There is currently no cure for gene mutation-caused autosomal dominant polycystic kidney disease (ADPKD). Over half of patients with ADPKD eventually develop kidney failure, requiring dialysis or kidney transplantation. Current treatment modalities for ADPKD focus on reducing morbidity and mortality from renal and extrarenal complications of the disease. MicroRNA has been shown to be useful in treating ADPKD. This study combines anti-miRNA plasmids and iron oxide/alginate nanoparticles for conjugation with antikidney antibodies. These nanocomposites can specifically target renal tubular cells, providing a potential treatment for ADPKD. Magnetic resonance imaging and in vivo imaging system results show effective targeting of renal cells. Anti-miRNA plasmids released from the nanocomposites inhibit cell proliferation and cyst formation in the PKD cellular and animal models. The results suggest the novel combination of the anti-miRNA plasmids and nanomaterials provides potential clinical implications for ADPKD treatment.
Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium
Authors: Yu Matsuzawa-Ishimoto, Yusuke Shono, Luis E. Gomez, Vanessa M. Hubbard-Lucey, Michael Cammer, Jessica Neil, M. Zahidunnabi Dewan, Sophia R. Lieberman, Amina Lazrak, Jill M. Marinis, Allison Beal, Philip A. Harris, John Bertin, Chen Liu, Yi Ding, Marcel R.M. van den Brink, Ken Cadwell
Journal: The Journal of Experimental Medicine (2017)

A variant of the autophagy gene ATG16L1 is associated with Crohn's disease, an inflammatory bowel disease (IBD), and poor survival in allogeneic hematopoietic stem cell transplant recipients. We demonstrate that ATG16L1 in the intestinal epithelium is essential for preventing loss of Paneth cells and exaggerated cell death in animal models of virally triggered IBD and allogeneic hematopoietic stem cell transplantation. Intestinal organoids lacking ATG16L1 reproduced this loss in Paneth cells and displayed TNFα-mediated necroptosis, a form of programmed necrosis. This cytoprotective function of ATG16L1 was associated with the role of autophagy in promoting mitochondrial homeostasis. Finally, therapeutic blockade of necroptosis through TNFα or RIPK1 inhibition ameliorated disease in the virally triggered IBD model. These findings indicate that, in contrast to tumor cells in which autophagy promotes caspase-independent cell death, ATG16L1 maintains the intestinal barrier by inhibiting necroptosis in the epithelium.
Maximising the impact of patient reported outcome assessment for patients and society
Authors: Melanie Calvert, Derek Kyte, Gary Price, Jose M Valderas, Niels Henrik Hjollund
Journal: BMJ (2019)

Patient reported outcome measures can help drive global patient centred healthcare reform, but we need a more efficient coordinated approach to assessment if we are to fully realise benefits for patients and society, say <b>Melanie Calvert and colleagues</b>
Genomic Reorganization of Lamin-Associated Domains in Cardiac Myocytes Is Associated With Differential Gene Expression and DNA Methylation in Human Dilated Cardiomyopathy
Authors: Sirisha M. Cheedipudi, Scot J. Matkovich, Cristian Coarfa, Xin Hu, Matthew J. Robertson, Mary Sweet, Matthew Taylor, Luisa Mestroni, Joseph Cleveland, James T. Willerson, Priyatansh Gurha, Ali J. Marian
Journal: Circulation Research (2019)

LMNA (Lamin A/C), a nuclear membrane protein, interacts with genome through lamin-associated domains (LADs) and regulates gene expression. Mutations in the LMNA gene cause a diverse array of diseases, including dilated cardiomyopathy (DCM). DCM is the leading cause of death in laminopathies.To identify LADs and characterize their associations with CpG methylation and gene expression in human cardiac myocytes in DCM.LMNA chromatin immunoprecipitation-sequencing, reduced representative bisulfite sequencing, and RNA-sequencing were performed in 5 control and 5 LMNA-associated DCM hearts. LADs were identified using enriched domain detector program. Genome-wide 331±77 LADs with an average size of 2.1±1.5 Mbp were identified in control human cardiac myocytes. LADs encompassed ≈20% of the genome and were predominantly located in the heterochromatin and less so in the promoter and actively transcribed regions. LADs were redistributed in DCM as evidenced by a gain of 520 and loss of 149 genomic regions. Approximately, 4500 coding genes and 800 long noncoding RNAs, whose levels correlated with the transcript levels of coding genes in cis, were differentially expressed in DCM. TP53 (tumor protein 53) was the most prominent among the dysregulated pathways. CpG sites were predominantly hypomethylated genome-wide in controls and DCM hearts, but overall CpG methylation was increased in DCM. LADs were associated with increased CpG methylation and suppressed gene expression. Integrated analysis identified genes whose expressions were regulated by LADs or CpG methylation, or by both, the latter pertained to genes involved in cell death, cell cycle, and metabolic regulation.LADs encompass ≈20% of the genome in human cardiac myocytes comprised several hundred coding and noncoding genes. LADs are redistributed in LMNA-associated DCM in association with markedly altered CpG methylation and gene expression. Thus, LADs through genomic alterations contribute to the pathogenesis of DCM in laminopathies.
The transcription factor Duxbl mediates elimination of pre-T cells that fail β-selection
Authors: Fabian Klein, Mladen Mitrovic, Julien Roux, Corinne Engdahl, Lilly von Muenchow, Llucia Alberti-Servera, Hans Jörg Fehling, Pawel Pelczar, Antonius Rolink, Panagiotis Tsapogas
Journal: The Journal of Experimental Medicine (2019)

T cell development is critically dependent on successful rearrangement of antigen-receptor chains. At the β-selection checkpoint, only cells with a functional rearrangement continue in development. However, how nonselected T cells proceed in their dead-end fate is not clear. We identified low CD27 expression to mark pre-T cells that have failed to rearrange their β-chain. Expression profiling and single-cell transcriptome clustering identified a developmental trajectory through β-selection and revealed specific expression of the transcription factor Duxbl at a stage of high recombination activity before β-selection. Conditional transgenic expression of Duxbl resulted in a developmental block at the DN3-to-DN4 transition due to reduced proliferation and enhanced apoptosis, whereas RNA silencing of Duxbl led to a decrease in apoptosis. Transcriptome analysis linked Duxbl to elevated expression of the apoptosis-inducing Oas/RNaseL pathway. RNaseL deficiency or sustained Bcl2 expression led to a partial rescue of cells in Duxbl transgenic mice. These findings identify Duxbl as a regulator of β-selection by inducing apoptosis in cells with a nonfunctional rearrangement.
The peculiar aging of human liver: A geroscience perspective within transplant context
Authors: Cristina Morsiani, Maria Giulia Bacalini, Aurelia Santoro, Paolo Garagnani, Salvatore Collura, Antonia D’Errico, Magda de Eguileor, Gian Luca Grazi, Matteo Cescon, Claudio Franceschi, Miriam Capri
Journal: Ageing Research Reviews (2019)

An appraisal of recent data highlighting aspects inspired by the new Geroscience perspective are here discussed. The main findings are summarized as follows: i) liver has to be considered an immunological organ, and new studies suggest a role for the recently described cells named telocytes; ii) the liver-gut axis represents a crucial connection with environment and life style habits and may influence liver diseases onset; iii) the physiological aging of liver shows relatively modest alterations. Nevertheless, several molecular changes appear to be relevant: a) an increase of microRNA-31-5p; -141-3p; -200c-3p expressions after 60 years of age; b) a remodeling of genome-wide DNA methylation profile evident until 60 years of age and then plateauing; c) changes in transcriptome including the metabolic zones of hepatocyte lobules; d) liver undergoes an accelerated aging in presence of chronic inflammation/liver diseases in a sort of continuum, largely as a consequence of unhealthy life styles and exposure to environmental noxious agents. We argue that chronic liver inflammation has all the major characteristics of "inflammaging" and likely sustains the onset and progression of liver diseases. Finally, we propose to use a combination of parameters, mostly obtained by omics such as transcriptomics and epigenomics, to evaluate in deep both the biological age of liver (in comparison with the chronological age) and the effects of donor-recipient age-mismatches in the context of liver transplant.