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Article: Alternative Polyadenylation Characterizes Epithelial and Fibroblast Phenotypic Heterogeneity in Pancreatic Ductal Adenocarcinoma.

Venkat, Swati / Feigin, Michael E

2024 Volume 16, Issue 3

Abstract: Human tumors are characterized by extensive intratumoral transcriptional variability within the cancer cell and stromal compartments. This variation drives phenotypic heterogeneity, producing cell states with differential pro- and anti-tumorigenic ... ...

Abstract	Human tumors are characterized by extensive intratumoral transcriptional variability within the cancer cell and stromal compartments. This variation drives phenotypic heterogeneity, producing cell states with differential pro- and anti-tumorigenic properties. While bulk RNA sequencing cannot achieve cell-type-specific transcriptional granularity, single-cell sequencing has permitted an unprecedented view of these cell states. Despite this knowledge, we lack an understanding of the mechanistic drivers of this transcriptional and phenotypic heterogeneity. 3' untranslated region alternative polyadenylation (3' UTR-APA) drives gene expression alterations through regulation of 3' UTR length. These 3' UTR alterations modulate mRNA stability, protein expression and protein localization, resulting in cellular phenotypes including differentiation, cell proliferation, and migration. Therefore, we sought to determine whether 3' UTR-APA events could characterize phenotypic heterogeneity of tumor cell states. Here, we analyze the largest single-cell human pancreatic ductal adenocarcinoma (PDAC) dataset and resolve 3' UTR-APA patterns across PDAC cell states. We find that increased proximal 3' UTR-APA is associated with PDAC progression and characterizes a metastatic ductal epithelial subpopulation and an inflammatory fibroblast population. Furthermore, we find significant 3' UTR shortening events in cell-state-specific marker genes associated with increased expression. Therefore, we propose that 3' UTR-APA drives phenotypic heterogeneity in cancer.
Language	English
Publishing date	2024-02-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16030640
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Article ; Online: Unintended Effects of GPCR-Targeted Drugs on the Cancer Phenotype.

Cornwell, Abigail C / Feigin, Michael E

Trends in pharmacological sciences

2020 Volume 41, Issue 12, Page(s) 1006–1022

Abstract: G protein-coupled receptors (GPCRs) are the most common class of therapeutic targets, accounting for ~35% of all FDA-approved drugs. Cancer patients receive numerous medications not only to combat cancer but also to alleviate pain, nausea, and anxiety, ... ...

Abstract	G protein-coupled receptors (GPCRs) are the most common class of therapeutic targets, accounting for ~35% of all FDA-approved drugs. Cancer patients receive numerous medications not only to combat cancer but also to alleviate pain, nausea, and anxiety, many of which target GPCRs. Emerging evidence has implicated GPCRs as drivers of cancer progression, therapeutic resistance, and metastasis. Therefore, the effects of commonly prescribed GPCR-targeted drugs must be reevaluated in the context of cancer. Epidemiological and experimental evidence indicate that widely used GPCR-targeted drugs may promote or inhibit cancer progression. It is crucial that we more fully understand the indirect effects of GPCR-targeted drugs on the cancer phenotype. This review summarizes recent advances in characterizing these interactions and highlights future research opportunities.
MeSH term(s)	Drug Delivery Systems ; Humans ; Neoplasms ; Pharmaceutical Preparations ; Phenotype ; Receptors, G-Protein-Coupled/genetics
Chemical Substances	Pharmaceutical Preparations ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2020-10-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	282846-7
ISSN	1873-3735 ; 0165-6147
ISSN (online)	1873-3735
ISSN	0165-6147
DOI	10.1016/j.tips.2020.10.001
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Zs.A 1513: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Regulation of Cyclin D1 Degradation by Ubiquitin-Specific Protease 27X Is Critical for Cancer Cell Proliferation and Tumor Growth.

Alam, Shamshad / Zunic, Amanda / Venkat, Swati / Feigin, Michael E / Atanassov, Boyko S

Molecular cancer research : MCR

2023 Volume 20, Issue 12, Page(s) 1751–1762

Abstract: Cyclin D1 (CCND1) is a critical regulator of cell proliferation and its overexpression has been linked to the development and progression of several malignancies. CCND1 overexpression is recognized as a major mechanism of therapy resistance in several ... ...

Abstract	Cyclin D1 (CCND1) is a critical regulator of cell proliferation and its overexpression has been linked to the development and progression of several malignancies. CCND1 overexpression is recognized as a major mechanism of therapy resistance in several cancers; tumors that rely on CCND1 overexpression to evade cancer therapy are extremely sensitive to its ablation. Therefore, targeting CCND1 is a promising strategy for preventing tumor progression and combating therapy resistance in cancer patients. Although CCND1 itself is not a druggable target, it can be targeted indirectly by inhibiting its regulators. CCND1 steady-state levels are tightly regulated by ubiquitin-mediated degradation, and defects in CCND1 ubiquitination are associated with increased CCND1 protein levels in cancer. Here, we uncover a novel function of ubiquitin-specific protease 27X (USP27X), a deubiquitinating enzyme (DUB), in regulating CCND1 degradation in cancer. USP27X binds to and stabilizes CCND1 in a catalytically dependent manner by negatively regulating its ubiquitination. USP27X expression levels correlate with the levels of CCND1 in several HER2 therapy-resistant breast cancer cell lines, and its ablation leads to a severe reduction of CCND1 protein levels, inhibition of tumor growth, and resensitization to targeted therapy. Together, the results presented in our study are the first to expose USP27X as a major CCND1 deubiquitinase and provide a mechanistic explanation for how this DUB fosters tumor growth. Implications: As a deubiquitinating enzyme, USP27X is a druggable target. Our study illuminates new avenues for therapeutic intervention in CCND1-driven cancers.
MeSH term(s)	Humans ; Female ; Cyclin D1/genetics ; Cyclin D1/metabolism ; Ubiquitin-Specific Proteases/genetics ; Ubiquitin-Specific Proteases/metabolism ; Breast Neoplasms/pathology ; Cell Proliferation ; Proteolysis ; Cell Line, Tumor
Chemical Substances	Cyclin D1 (136601-57-5) ; Ubiquitin-Specific Proteases (EC 3.4.19.12)
Language	English
Publishing date	2023-01-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-22-0259
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Zs.A 5744: Show issues

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Article ; Online: Drivers of Gene Expression Dysregulation in Pancreatic Cancer.

Venkat, Swati / Alahmari, Abdulrahman A / Feigin, Michael E

Trends in cancer

2021 Volume 7, Issue 7, Page(s) 594–605

Abstract: Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a poor prognosis. The functional consequences of common genetic aberrations and their roles in treatment strategies have been extensively reviewed. In addition to these genomic ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease with a poor prognosis. The functional consequences of common genetic aberrations and their roles in treatment strategies have been extensively reviewed. In addition to these genomic aberrations, consideration of non-genetic drivers of altered oncogene expression is essential to account for the diversity in PDAC phenotypes. In this review we seek to assess our current understanding of mechanisms of gene expression dysregulation. We focus on four drivers of gene expression dysregulation, including mutations, transcription factors, epigenetic regulators, and RNA stability/isoform regulation, in the context of PDAC pathogenesis. Recent studies provide much-needed insight into the role of gene expression dysregulation in dissecting tumor heterogeneity and stratifying patients for the development of personalized treatment strategies.
MeSH term(s)	Animals ; Carcinoma, Pancreatic Ductal/genetics ; Cell Line, Tumor ; Disease Models, Animal ; Epigenesis, Genetic ; Gene Expression Regulation, Neoplastic ; Genetic Heterogeneity ; Humans ; Mice ; Mutation ; Pancreatic Neoplasms/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Tumor Microenvironment/genetics ; Xenograft Model Antitumor Assays
Chemical Substances	Transcription Factors
Language	English
Publishing date	2021-02-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2852626-0
ISSN	2405-8025 ; 2405-8033 ; 2405-8033
ISSN (online)	2405-8025 ; 2405-8033
ISSN	2405-8033
DOI	10.1016/j.trecan.2021.01.008
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Article ; Online: Harnessing the genome for characterization of G-protein coupled receptors in cancer pathogenesis.

Feigin, Michael E

The FEBS journal

2013 Volume 280, Issue 19, Page(s) 4729–4738

Abstract: G-protein coupled receptors (GPCRs) mediate numerous physiological processes and represent the targets for a vast array of therapeutics for diseases ranging from depression to hypertension to reflux. Despite the recognition that GPCRs can act as ... ...

Abstract	G-protein coupled receptors (GPCRs) mediate numerous physiological processes and represent the targets for a vast array of therapeutics for diseases ranging from depression to hypertension to reflux. Despite the recognition that GPCRs can act as oncogenes and tumour suppressors by regulating oncogenic signalling networks, few drugs targeting GPCRs are utilized in cancer therapy. Recent large-scale genome-wide analyses of multiple human tumours have uncovered novel GPCRs altered in cancer. However, work aiming to determine which GPCRs from these lists are the drivers of tumourigenesis, and hence valid therapeutic targets, comprises a formidable challenge. The present review highlights recent studies providing evidence that GPCRs are relevant targets for cancer therapy through their effects on known cancer signalling pathways, tumour progression, invasion and metastasis, and the microenvironment. Furthermore, the review also explores how genomic analysis is beginning to highlight GPCRs as therapeutic targets in the age of personalized medicine.
MeSH term(s)	Animals ; Computational Biology ; Genomics ; Humans ; Neoplasms/genetics ; Receptors, G-Protein-Coupled/genetics ; Signal Transduction/genetics ; Signal Transduction/physiology
Chemical Substances	Receptors, G-Protein-Coupled
Language	English
Publishing date	2013-09-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.12473
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Article ; Online: CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone mRNA processing.

Alahmari, Abdulrahman A / Chaubey, Aditi H / Jonnakuti, Venkata S / Tisdale, Arwen A / Schwarz, Carla D / Cornwell, Abigail C / Maraszek, Kathryn E / Paterson, Emily J / Kim, Minsuh / Venkat, Swati / Gomez, Eduardo Cortes / Wang, Jianmin / Gurova, Katerina V / Yalamanchili, Hari Krishna / Feigin, Michael E

RNA (New York, N.Y.)

2024 Volume 30, Issue 3, Page(s) 281–297

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3' ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3' endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that
MeSH term(s)	Humans ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Histones/genetics ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/metabolism ; Polyadenylation ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
Chemical Substances	Histones ; RNA, Messenger ; CPSF3 protein, human
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.079931.123
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Zs.A 4777: Show issues

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Article ; Online: Challenges and Opportunities in Modeling Pancreatic Cancer.

Feigin, Michael E / Tuveson, David A

Cold Spring Harbor symposia on quantitative biology

2016 Volume 81, Page(s) 231–235

Abstract: The ability to faithfully model complex processes lies at the heart of experimental biology. Although a reductionist approach necessarily reduces this complexity, it is nevertheless required for untangling the contributions and interactions of the ... ...

Abstract	The ability to faithfully model complex processes lies at the heart of experimental biology. Although a reductionist approach necessarily reduces this complexity, it is nevertheless required for untangling the contributions and interactions of the various system components. It has long been appreciated that cancer is a complex process that involves positive and negative interactions between tumor cells, normal host tissue, and the associated cells of the tumor microenvironment. However, accurate models for studying these complex interactions in vitro have remained elusive. We seek to generate models of mouse and human pancreatic cancer that are relevant to disease biology and useful for elucidating poorly understood facets of this deadly disease. The ability to model, manipulate, and predict the therapeutic response of an individual's disease outside their body represents the promise of precision medicine. Therefore, these models are patient-specific and allow the identification of new biomarkers and novel treatment modalities for rapid translation to the clinic. In this perspective we will discuss recent advances in modeling pancreatic cancer in vitro, the discoveries these models have enabled, and future challenges and opportunities awaiting further investigation.
MeSH term(s)	Animals ; Biomarkers/analysis ; Disease Models, Animal ; Humans ; Neoplasm Invasiveness/pathology ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Proto-Oncogene Proteins p21(ras)/metabolism ; Tumor Microenvironment
Chemical Substances	Biomarkers ; KRAS protein, human ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ISSN	1943-4456 ; 0091-7451
ISSN (online)	1943-4456
ISSN	0091-7451
DOI	10.1101/sqb.2016.81.031104
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Article ; Online: Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study.

Reilmann, Ralf / Anderson, Karen E / Feigin, Andrew / Tabrizi, Sarah J / Leavitt, Blair R / Stout, Julie C / Piccini, Paola / Schubert, Robin / Loupe, Pippa / Wickenberg, Anna / Borowsky, Beth / Rynkowski, Gail / Volkinshtein, Rita / Li, Thomas / Savola, Juha-Matti / Hayden, Michael / Gordon, Mark Forrest

The Lancet. Neurology

2024 Volume 23, Issue 3, Page(s) 243–255

Abstract: Background: Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction ... ...

Abstract	Background: Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss in patients with Huntington's disease. Methods: LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21-55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington's disease with a Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to treatment assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were assessed in the safety analysis set (ie, all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02215616, and EudraCT, 2014-000418-75, and is now complete. Findings: Between Oct 28, 2014, and June 19, 2018, 352 adults with Huntington's disease (179 [51%] men and 173 [49%] women; mean age 43·9 [SD 7·6] years and 340 [97%] White) were randomly assigned: 107 to laquinimod 0·5 mg, 107 to laquinimod 1·0 mg, 30 to laquinimod 1·5 mg, and 108 to matching placebo. Least squares mean change from baseline in UHDRS-TMS at week 52 was 1·98 (SE 0·83) in the laquinimod 1·0 mg group and 1·2 (0·82) in the placebo group (least squares mean difference 0·78 [95% CI -1·42 to 2·98], p=0·4853). Least squares mean change in caudate volume was 3·10% (SE 0·38) in the 1·0 mg group and 4·86% (0·38) in the placebo group (least squares mean difference -1·76% [95% CI -2·67 to -0·85]; p=0·0002). Laquinimod was well tolerated and there were no new safety findings. Serious adverse events were reported by eight (7%) patients on placebo, seven (7%) on laquinimod 0·5 mg, five (5%) on laquinimod 1·0 mg, and one (3%) on laquinimod 1·5 mg. There was one death, which occurred in the placebo group and was unrelated to treatment. The most frequent adverse events in all laquinimod dosed groups (0·5 mg, 1·0 mg, and 1·5 mg) were headache (38 [16%]), diarrhoea (24 [10%]), fall (18 [7%]), nasopharyngitis (20 [8%]), influenza (15 [6%]), vomiting (13 [5%]), arthralgia (11 [5%]), irritability (ten [4%]), fatigue (eight [3%]), and insomnia (eight [3%]). Interpretation: Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington's disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments. Funding: Teva Pharmaceutical Industries.
MeSH term(s)	Adult ; Male ; Humans ; Female ; Huntington Disease/drug therapy ; Treatment Outcome ; Quinolones/therapeutic use ; Germany ; Double-Blind Method
Chemical Substances	laquinimod (908SY76S4G) ; Quinolones
Language	English
Publishing date	2024-01-24
Publishing country	England
Document type	Randomized Controlled Trial ; Multicenter Study ; Clinical Trial, Phase II ; Journal Article
ZDB-ID	2081241-3
ISSN	1474-4465 ; 1474-4422
ISSN (online)	1474-4465
ISSN	1474-4422
DOI	10.1016/S1474-4422(23)00454-4
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Zs.A 5955: Show issues

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Article ; Online: Postoperative urinary retention following hip or knee arthroplasty under spinal anaesthesia with intrathecal morphine: a retrospective cohort study.

Dana, Elad / Ben-Zur, Oz / Dichtwald, Sara / Feigin, Guy / Brin, Noa / Markushevich, Michael / Fredman, Brian / Brin, Yaron Shraga

Singapore medical journal

2023

Abstract: Introduction: Postoperative urinary retention (POUR) frequently complicates the course of patients following hip and knee arthroplasty. Intrathecal morphine (ITM) was identified as a significant risk factor for POUR. The objective of this study was to ... ...

Abstract	Introduction: Postoperative urinary retention (POUR) frequently complicates the course of patients following hip and knee arthroplasty. Intrathecal morphine (ITM) was identified as a significant risk factor for POUR. The objective of this study was to investigate the incidence and risk factors for POUR in fast-track total joint arthroplasty (TJA) under spinal anaesthesia (SA) with ITM. Methods: We conducted a retrospective study of our institutional joint registry of patients who underwent primary TJA under SA with ITM between October 2017 and May 2021. Preoperative (baseline demographics) and perioperative data were collected. The primary outcome was the incidence of POUR after 8 h or earlier, either due to lack of voiding or according to patient's complaints of bladder distension. Univariate and adjusted analyses were performed to identify predictors of POUR. Results: Sixty-nine patients who underwent total knee arthroplasty (TKA) and 36 patients who underwent total hip arthroplasty (THA) under SA with ITM were included in the study. POUR requiring bladder catheterisation was diagnosed in 21% of patients. Independent predictors of POUR were age over 65 years and male gender. Conclusions: SA with ITM for TJA is associated with high rates of POUR in males older than 65 years of age. Other previously identified risk factors such as intraoperative fluid administration or comorbidities may not be as influential.
Language	English
Publishing date	2023-06-13
Publishing country	India
Document type	Journal Article
ZDB-ID	604319-7
ISSN	2737-5935 ; 0037-5675
ISSN (online)	2737-5935
ISSN	0037-5675
DOI	10.4103/singaporemedj.SMJ-2022-108
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Zs.B 589: Show issues

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Article ; Online: Lorazepam Stimulates IL6 Production and Is Associated with Poor Survival Outcomes in Pancreatic Cancer.

Cornwell, Abigail C / Tisdale, Arwen A / Venkat, Swati / Maraszek, Kathryn E / Alahmari, Abdulrahman A / George, Anthony / Attwood, Kristopher / George, Madison / Rempinski, Donald / Franco-Barraza, Janusz / Seshadri, Mukund / Parker, Mark D / Cortes Gomez, Eduardo / Fountzilas, Christos / Cukierman, Edna / Steele, Nina G / Feigin, Michael E

Clinical cancer research : an official journal of the American Association for Cancer Research

2023 Volume 29, Issue 18, Page(s) 3793–3812

Abstract: ... records. IHC, H&E, Masson's trichrome, RNAscope, and RNA sequencing were used to evaluate the impact ...

Abstract	Purpose: This research investigates the association between benzodiazepines (BZD) and cancer patient survival outcomes, the pancreatic cancer tumor microenvironment, and cancer-associated fibroblast (CAF) signaling. Experimental design: Multivariate Cox regression modeling was used to retrospectively measure associations between Roswell Park cancer patient survival outcomes and BZD prescription records. IHC, H&E, Masson's trichrome, RNAscope, and RNA sequencing were used to evaluate the impact of lorazepam (LOR) on the murine PDAC tumor microenvironment. ELISA and qPCR were used to determine the impact of BZDs on IL6 expression or secretion by human-immortalized pancreatic CAFs. PRESTO-Tango assays, reanalysis of PDAC single-cell sequencing/TCGA data sets, and GPR68 CRISPRi knockdown CAFs were used to determine the impact of BZDs on GPR68 signaling. Results: LOR is associated with worse progression-free survival (PFS), whereas alprazolam (ALP) is associated with improved PFS, in pancreatic cancer patients receiving chemotherapy. LOR promotes desmoplasia (fibrosis and extracellular matrix protein deposition), inflammatory signaling, and ischemic necrosis. GPR68 is preferentially expressed on human PDAC CAFs, and n-unsubstituted BZDs, such as LOR, significantly increase IL6 expression and secretion in CAFs in a pH and GPR68-dependent manner. Conversely, ALP and other GPR68 n-substituted BZDs decrease IL6 in human CAFs in a pH and GPR68-independent manner. Across many cancer types, LOR is associated with worse survival outcomes relative to ALP and patients not receiving BZDs. Conclusions: We demonstrate that LOR stimulates fibrosis and inflammatory signaling, promotes desmoplasia and ischemic necrosis, and is associated with decreased pancreatic cancer patient survival.
MeSH term(s)	Humans ; Animals ; Mice ; Lorazepam ; Interleukin-6/genetics ; Retrospective Studies ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/genetics ; Benzodiazepines ; Fibrosis ; Necrosis ; Tumor Microenvironment ; Receptors, G-Protein-Coupled ; Pancreatic Neoplasms
Chemical Substances	Lorazepam (O26FZP769L) ; Interleukin-6 ; Benzodiazepines (12794-10-4) ; GPR68 protein, human ; Receptors, G-Protein-Coupled ; GPR68 protein, mouse
Language	English
Publishing date	2023-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-0547
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