Publications by authors named "Tushar Patel"

241 Publications

Extracellular RNA transfer from non-malignant human cholangiocytes can promote cholangiocarcinoma growth.

FEBS Open Bio 2021 Sep 12. Epub 2021 Sep 12.

Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology / Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.

Extracellular vesicles (EV) within the cellular secretome are emerging as modulators of pathological processes involved in tumor growth through their ability to transfer donor derived RNA into recipient cells. While the effects of tumor and stromal cell EVs within the tumor microenvironment have been studied, less is known about the contributions of normal, non-transformed cells. We examined the impact of EVs within the cellular secretome from non-malignant cells on transformed cell growth and behavior in cholangiocarcinoma cells. These effects were enhanced in the presence of the pro-fibrogenic mediator TGF-β. We identified miR-195 as a TGF-β responsive miRNA in normal cells that can be transferred via EV to tumor cells and regulate cell growth, invasion and migration. The effects of miR-195 involve modulation of the epithelial-mesenchymal transition through direct effects on the transcription factor Snail. These studies provide in vitro and in vivo evidence for the impact of normal cellular secretome on transformed cell growth, show the importance of EV RNA transfer, and identify mechanisms of EV-mediated transfer of miRNA as a contributor to tumor development, which may provide new therapeutic opportunities for targeting human cholangiocarcinoma.
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http://dx.doi.org/10.1002/2211-5463.13294DOI Listing
September 2021

Biochemical Safety of Ablative Yttrium-90 Radioembolization for Hepatocellular Carcinoma as a Function of Percent Liver Treated.

J Hepatocell Carcinoma 2021 30;8:861-870. Epub 2021 Jul 30.

Division of Interventional Radiology, Mayo Clinic Florida, Jacksonville, FL, USA.

Purpose: Transarterial radioembolization can serve as an ablative therapy for early-stage hepatocellular carcinoma (HCC). Given the volumetric variability of liver segments, this study aimed to characterize the safety of ablative radioembolization by determining percent liver treated (%LT) thresholds associated with biochemical toxicity.

Patients And Methods: Patients with HCC receiving a single ablative radioembolization treatment using glass microspheres from 2017 through 2020 were reviewed. %LT was calculated as treatment angiosome volume divided by whole liver volume. Biochemical toxicities were defined as increases in Albumin-Bilirubin (ALBI) grade or Child-Pugh (CP) class compared to baseline and albumin or bilirubin adverse events (AEs) per the Common Terminology Criteria for Adverse Events. Receiver operating characteristic curves and multivariate logistic regression analyses were performed to assess the impact of %LT on toxicities.

Results: Of 141 patients analyzed, 53% (n=75) were ALBI 1, 45% (n=64) ALBI 2, 79% (n=111) CP-A, and 21% (n=30) CP-B. A %LT ≥14.5% was associated with grade/class increases in ALBI 2 (≤0.01) and CP-B patients (=0.026). In multivariate analysis, a %LT ≥14.5% was an independent predictor of increases in the ALBI 2 and CP-B groups (<0.01). No significant %LT threshold was found for ALBI 1 and CP-A patients. No grade 3/4 albumin or bilirubin AEs were reported, while grade 2 AEs were related to an initial whole liver volume <1.3 L (≤0.01).

Conclusion: Patients with ALBI 2 and CP-B liver function are less likely to have an increase in their respective grade/class when treating <14.5% of the liver using glass microspheres. ALBI 1 and CP-A patients showed no definitive %LT threshold for biochemical toxicity within the range of this study.
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http://dx.doi.org/10.2147/JHC.S319215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335548PMC
July 2021

Fabrication and Characterization of a Biomaterial Based on Extracellular-Vesicle Functionalized Graphene Oxide.

Front Bioeng Biotechnol 2021 9;9:686510. Epub 2021 Jun 9.

Department of Transplantation, Mayo Clinic, Jacksonville, FL, United States.

Mesenchymal stem cell (MSC) derived extracellular vesicles (EV) are emerging as acellular therapeutics for solid organ injury and as carriers for drug delivery. Graphene-based materials are novel two-dimensional crystal structure-based materials with unique characteristics of stiffness, strength and elasticity that are being explored for various structural and biological applications. We fabricated a biomaterial that would capture desirable properties of both graphene and stem cell derived EV. Metabolically engineered EV that express azide groups were cross-linked with alkyne-functionalized graphene oxide (GO) via a copper catalyzed alkyne-azide cycloaddition (CuAAC) reaction. The crosslinking between EV and GO was accomplished without the need for ligand expression on the metal. Scanning electron and fluorescence microscopy demonstrated excellent cross-linking between EV and GO. Biological effects were assessed by phagocytosis studies and cell viability studies. The uptake of GO or sonicated GO (sGO) resulted in a durable pro-inflammatory immune response. Cell studies further showed that crosslinked GO-EV scaffolds exhibited cell-type dependent cytotoxicity on liver cancer cells whereas there was minimal impact on healthy hepatocyte proliferation. , neither GO-EV nor sGO-EV induced DNA strand breaks. studies in zebrafish revealed gross developmental malformations but treatment-induced mortality was only seen with the highest doses of GO-EV and sGO-EV. With these advantages, this engineered biomaterial combining the versatility of graphene with the therapeutic effects of MSC-EV has potential for applications in tissue engineering and regenerative medicine.
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http://dx.doi.org/10.3389/fbioe.2021.686510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220207PMC
June 2021

Detection of Circulating RNA Using Nanopore Sequencing.

Methods Mol Biol 2021 ;2348:273-284

Mayo Clinic, Jacksonville, FL, USA.

RNA sequencing using nanopore sequencing is a powerful method for transcriptome analysis. The approach is appropriate for comprehensive profiling of the wide range of long noncoding RNAs. Use of nanopore-based sequencing can provide information on novel transcripts, sequence polymorphisms, and splicing variants, and thus has advantages over other gene expression profiling methods such as microarrays. Circulating extracellular long noncoding RNAs are of particular interest because of their potential use as biomarkers. Here, we describe a protocol for cDNA-PCR sequencing of circulating RNA for biomarker discovery in whole blood samples using commercially available kits and nanopore sequencing.
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http://dx.doi.org/10.1007/978-1-0716-1581-2_19DOI Listing
September 2021

Quantitation of Long Noncoding RNA Using Digital PCR.

Methods Mol Biol 2021 ;2348:113-121

Mayo Clinic, Jacksonville, FL, USA.

Long noncoding RNAs (lncRNAs) are implicated in many physiological or disease processes and alterations in their expression may contribute to the development of various diseases. Accurate quantitation of lncRNA can be useful in measuring changes in expression in different settings such as in the circulation where the measurement of lncRNA may be useful as a biomarker of disease. However, the low levels of lncRNA expression require the use of highly sensitive detection technologies for accurate quantitation. Digital polymerase chain reaction (dPCR) is a sensitive method for absolute quantification of lncRNA and can be useful for measurement of gene expression when transcript levels are low. By providing a direct measurement without normalization, the use of dPCR may provide advantages for quantitation of low-abundance targets.
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http://dx.doi.org/10.1007/978-1-0716-1581-2_7DOI Listing
September 2021

Comparison of Clinical Features and Outcomes between Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma in the United States.

Hepatology 2021 Jun 11. Epub 2021 Jun 11.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background & Aims: Intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) are the most common primary liver cancers. Differences in their clinical features and outcomes have not been investigated in a large-scale study. We aim to investigate the differences in clinical features and outcomes between iCCA and HCC.

Approach & Results: The Surveillance, Epidemiology, and End Results Program 18 Database (2000-2017) was used to extract demographic and clinical features of HCC and iCCA patients. Logistic regression analysis was performed to identify factors associated with iCCA diagnosis vs. HCC. Cox regression analysis was utilized to assess factors affecting overall survival (OS). There were 13,611 iCCA and 96,151 HCC patients. Half of iCCA (50.7%) and three-quarters of HCC (76.3%) patients were male. Diagnosis in recent year, age (<50 or ≥65), female sex, non-Hispanic white race, higher income, rural area, and higher tumor burden were independently associated with iCCA diagnosis vs. HCC. Patients with iCCA had worse OS than those with HCC (9 vs. 13 months, P<0.001). However, OS was comparable between iCCA and HCC in multivariable analysis (adjusted hazard ratio [aHR]=1.02, 95% confidence interval [CI]=0.99-1.05). In subgroup analyses, iCCA was associated with better OS than HCC in patients with tumor ≥ 5 cm (aHR=0.83, 95% CI=0.80-0.86), lymph node involvement (aHR=0.76, 95% CI=0.72-0.81), distant metastasis (aHR=0.76, 95% CI=0.73-0.79), poorly/undifferentiated tumors (aHR=0.88, 95% CI=0.83-0.94), and those receiving non-curative treatment (aHR=0.96, 95% CI=0.93-0.98).

Conclusions: We identified the demographic, socioeconomic, and clinical features associated with iCCA diagnosis over HCC among patients with primary liver cancer. Although iCCA patients presented at an advanced stage, OS was similar between iCCA and HCC in multivariable analysis. iCCA was associated with longer OS for subgroups with poor prognostic features.
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http://dx.doi.org/10.1002/hep.32007DOI Listing
June 2021

Development and Validation of a Deep Learning Model to Quantify Interstitial Fibrosis and Tubular Atrophy From Kidney Ultrasonography Images.

JAMA Netw Open 2021 May 3;4(5):e2111176. Epub 2021 May 3.

M&H Research, LLC, San Antonio, Texas.

Importance: Interstitial fibrosis and tubular atrophy (IFTA) is a strong indicator of decline in kidney function and is measured using histopathological assessment of kidney biopsy core. At present, a noninvasive test to assess IFTA is not available.

Objective: To develop and validate a deep learning (DL) algorithm to quantify IFTA from kidney ultrasonography images.

Design, Setting, And Participants: This was a single-center diagnostic study of consecutive patients who underwent native kidney biopsy at John H. Stroger Jr. Hospital of Cook County, Chicago, Illinois, between January 1, 2014, and December 31, 2018. A DL algorithm was trained, validated, and tested to classify IFTA from kidney ultrasonography images. Of 6135 Crimmins-filtered ultrasonography images, 5523 were used for training (5122 images) and validation (401 images), and 612 were used to test the accuracy of the DL system. Kidney segmentation was performed using the UNet architecture, and classification was performed using a convolution neural network-based feature extractor and extreme gradient boosting. IFTA scored by a nephropathologist on trichrome stained kidney biopsy slide was used as the reference standard. IFTA was divided into 4 grades (grade 1, 0%-24%; grade 2, 25%-49%; grade 3, 50%-74%; and grade 4, 75%-100%). Data analysis was performed from December 2019 to May 2020.

Main Outcomes And Measures: Prediction of IFTA grade was measured using the metrics precision, recall, accuracy, and F1 score.

Results: This study included 352 patients (mean [SD] age 47.43 [14.37] years), of whom 193 (54.82%) were women. There were 159 patients with IFTA grade 1 (2701 ultrasonography images), 74 patients with IFTA grade 2 (1239 ultrasonography images), 41 patients with IFTA grade 3 (701 ultrasonography images), and 78 patients with IFTA grade 4 (1494 ultrasonography images). Kidney ultrasonography images were segmented with 91% accuracy. In the independent test set, the point estimates for performance matrices showed precision of 0.8927 (95% CI, 0.8682-0.9172), recall of 0.8037 (95% CI, 0.7722-0.8352), accuracy of 0.8675 (95% CI, 0.8406-0.8944), and an F1 score of 0.8389 (95% CI, 0.8098-0.8680) at the image level. Corresponding estimates at the patient level were precision of 0.9003 (95% CI, 0.8644-0.9362), recall of 0.8421 (95% CI, 0.7984-0.8858), accuracy of 0.8955 (95% CI, 0.8589-0.9321), and an F1 score of 0.8639 (95% CI, 0.8228-0.9049). Accuracy at the patient level was highest for IFTA grade 1 and IFTA grade 4. The accuracy (approximately 90%) remained high irrespective of the timing of ultrasonography studies and the biopsy diagnosis. The predictive performance of the DL system did not show significant improvement when combined with baseline clinical characteristics.

Conclusions And Relevance: These findings suggest that a DL algorithm can accurately and independently predict IFTA from kidney ultrasonography images.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.11176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144924PMC
May 2021

Discovery and Optimization of DNA Gyrase and Topoisomerase IV Inhibitors with Potent Activity against Fluoroquinolone-Resistant Gram-Positive Bacteria.

J Med Chem 2021 05 30;64(9):6329-6357. Epub 2021 Apr 30.

Piramal Discovery Solutions, Pharmaceutical Special Economic Zone, Sarkhej Bavla Highway, Ahmedabad, Gujarat 382213, India.

Herein, we describe the discovery and optimization of a novel series that inhibits bacterial DNA gyrase and topoisomerase IV binding to, and stabilization of, DNA cleavage complexes. Optimization of this series led to the identification of compound , which has potent activity against Gram-positive bacteria, a favorable safety profile, and excellent pharmacokinetic properties. Compound was found to be efficacious against fluoroquinolone-sensitive infection in a mouse thigh model at lower doses than moxifloxacin. An X-ray crystal structure of the ternary complex formed by topoisomerase IV from , compound , and cleaved DNA indicates that this compound does not engage in a water-metal ion bridge interaction and forms no direct contacts with residues in the quinolone resistance determining region (QRDR). This suggests a structural basis for the reduced impact of QRDR mutations on antibacterial activity of compared to fluoroquinolones.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00375DOI Listing
May 2021

Real versus simulated galactic cosmic radiation for investigating cancer risk in the hematopoietic system - are we comparing apples to apples?

Life Sci Space Res (Amst) 2021 May 16;29:8-14. Epub 2021 Jan 16.

Department of Neurology, Mayo Clinic, FL, United States.

Deep space exploration missions need strategies to mitigate the potentially harmful exposure to galactic cosmic radiation. This form of radiation can cause significant damage to biological systems and organisms, which include radiation-induced carcinogenesis in the hematopoietic system. Ongoing studies investigate these effects using cell- and animal-based studies in low earth orbit. The logistic challenges and costs involved with sending biological specimens to space have prompted the development of surrogate ground-based radiation experiments to study the mechanisms of biological injury and cancer risk. However, simulating galactic cosmic radiation has proven difficult and current studies are only partially succeeding at replicating the complexity of this radiation and its downstream injury pathways. Accurate simulation of chronic, low dose galactic radiation will improve our ability to test mitigation strategies such as drug development and improved shielding materials that could be crucial and essential for successful space exploration.
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http://dx.doi.org/10.1016/j.lssr.2021.01.001DOI Listing
May 2021

Biological Nanotherapeutics for Liver Disease.

Hepatology 2021 Apr 7. Epub 2021 Apr 7.

Department of Transplantation, Mayo Clinic, Jacksonville, FL.

Extracellular vesicles (EVs) are a heterogeneous group of biological nano-sized vesicles that are released from cells and contribute to intercellular communication. Emerging knowledge about their biogenesis, composition, release, and uptake has resulted in broad interest in elucidating their potential roles in disease pathophysiology. The distinct biological properties of these biological nanoparticles emphasize several appealing advantages for potential therapeutic applications compared with the use of synthetic nanoparticles. When administered systemically, EVs are taken up and sequestered within the liver, further emphasizing opportunities for therapeutic use. Consequently, there is growing interest in their use for liver diseases. EVs can be used directly as therapeutics, and several studies have highlighted the intrinsic therapeutic properties of mesenchymal stem cell-derived EVs for chronic and acute liver diseases. Alternatively, EVs can be modified to facilitate their use for the delivery of therapeutic cargo. In this review, we discuss the cellular sources of EV, provide a concise overview of their potential use in diverse processes, and outline several promising applications for the use of EV-based therapeutics for liver diseases. The use of EV-based therapeutics provides a viable approach to target hepatic pathophysiology.
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http://dx.doi.org/10.1002/hep.31847DOI Listing
April 2021

Aspirin and Statin Use and the Risk of Gallbladder Cancer.

Cancers (Basel) 2021 Mar 9;13(5). Epub 2021 Mar 9.

Department of Oncology, Mayo Clinic, Rochester, MN 55902, USA.

Aspirin and statin drugs have been associated with reduced risk of several gastrointestinal cancers, but their association with gallbladder cancer (GBC) has not been well established. We evaluated the association of aspirin and statins with the risk of GBC. Patients with GBC managed at Mayo Clinic between 2000 and 2019 were matched 1:2 with a general patient pool by age and sex. Univariable and multivariable logistic regression models were used to assess associations between GBC and aspirin or statin use. The analysis included 795 cases and 1590 controls, with a median age of 67 years. Aspirin or statin use alone or in combination was higher in controls ( < 0.001). Univariate analysis showed that the use of aspirin [odds ratio (OR): 0.11; 95%CI: 0.08-0.15] or statins (OR: 0.29; 95%CI: 0.20-0.40) and their combined use (OR: 0.18; 95%CI: 0.13-0.24) was associated with lower risk of GBC. Multivariable analysis revealed that aspirin (OR: 0.12; 95%CI: 0.09-0.16) and combined statins and aspirin (OR: 0.46; 95%CI: 0.31-0.67) were associated with lower risk of GBC. Aspirin alone or in combination with statins is associated with a strongly reduced risk of GBC. Further prospective studies are needed to confirm these results and to elucidate their mechanisms.
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http://dx.doi.org/10.3390/cancers13051186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967123PMC
March 2021

Mechanistic insight of cell anti-proliferative activity of fluoroquinolone drug-based Cu(II) complexes.

Mol Divers 2021 Mar 1. Epub 2021 Mar 1.

Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, Gujarat, 388 120, India.

Pefloxacin-based mixed ligand Cu(II) complexes with substituted isatin of type [Cu(Isatin)(Pefloxacin)Cl] were synthesized, and characterized by EPR, mass, FT-IR, electronic spectrometry, metal content, magnetic moment, and conductance measurement. The g factors g [Formula: see text] > g [Formula: see text] > 2.0023 observed in EPR suggest a square-pyramidal environment of ligands around the copper metal. The compounds were screened for diverse biological activities. The compounds inhibit efficiently the cell proliferation of HCT 116 cancer cells. To take the insight of anticancer activity mechanism, we investigated compound-1 for further cellular assay-based biological activities like trypan blue assay, cell morphological alteration assay, colony formation assay, cell apoptosis, and cell necrosis assay. The compound-1 induced distinct morphological alteration in cells, inhibits cell viability, decreases % plating efficiency, and decreases the clonogenic ability of the HCT 116 cells. The cell death mechanism was confirmed by annexin V-FITC / PI assay and LDH release assay. The positive annexin V/PI stained cells in presence of compound-1 and the absence of a significant amount of lactate dehydrogenase suggest cell apoptosis mechanism for anticancer activity of compounds. We also screened compounds for in vitro antibacterial and cytotoxic activities. Synthesis, characterization, antibacterial, anticancer, and cytotoxicity activities of pefloxacin based Cu(II) complexes were studied. The compound -1 is more potent than standard anticancer drugs and it induced apoptosis to the HCT 116 cells.
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http://dx.doi.org/10.1007/s11030-021-10199-2DOI Listing
March 2021

Pathologic Response of Hepatocellular Carcinoma Treated with Yttrium-90 Glass Microsphere Radiation Segmentectomy Prior to Liver Transplantation: A Validation Study.

J Vasc Interv Radiol 2021 04 4;32(4):518-526.e1. Epub 2021 Feb 4.

Department of Transplant, Mayo Clinic Florida, Jacksonville, Florida.

Purpose: To evaluate the pathologic outcomes of hepatocellular carcinoma (HCC) treated with Yttrium-90 radiation segmentectomy using glass microspheres prior to liver transplantation and explore parameters associated with pathologic necrosis.

Materials And Methods: A single-institution retrospective analysis of HCC patients who received radiation segmentectomy prior to liver transplantation from November 2016 to May 2020 was performed. Patients were included if the treatment angiosome encompassed the entire tumor and could be correlated with available gross pathology. Archived histology slides were reviewed for percentage of pathologic necrosis. Thirty-three patients with 37 tumors were evaluated. The median tumor size was 2.3 cm (range, 1-6.7 cm).

Results: All tumors received a single treatment. The median time from radiation segmentectomy to transplantation was 206 days (range, 58-550 days). Objective response per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was 92% (complete response, 76%; partial response, 16%). A total of 68% (n = 25) of tumors demonstrated ≥99% pathologic necrosis. Complete pathologic necrosis was present in 53% and 75% of tumors treated with >190 Gy (n = 18) and >500 Gy (n = 8) single-compartment Medical Internal Radiation Dose, respectively. Complete response per mRECIST, posttreatment angiosome T1 hypointensity, dose >190 Gy, microsphere specific activity >297 Bq, and a longer time between treatment and transplant were associated with ≥99% tumor necrosis (P < .05). No posttransplant tumor recurrences occurred within a median follow-up of 604 days (range, 138-1,223 days).

Conclusions: Radiation segmentectomy can serve as an ablative modality for the treatment of HCC prior to liver transplant.
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http://dx.doi.org/10.1016/j.jvir.2020.12.019DOI Listing
April 2021

Dysfunctional EGFR and oxidative stress-induced PKD1 signaling drive formation of DCLK1+ pancreatic stem cells.

iScience 2021 Jan 5;24(1):102019. Epub 2021 Jan 5.

Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL 32224, USA.

Doublecortin-like kinase 1 (DCLK1)-positive pancreatic cancer stem cells develop at a precancerous stage and may contribute to the lack of efficacy of pancreatic cancer therapy. Although PanIN cells express oncogenic KRas and have an increased activity of epidermal growth factor receptor (EGFR), we demonstrate that, in DCLK1 PanIN cells, EGFR signaling is not propagated to the nucleus. Mimicking blockage of EGFR with erlotinib in PanIN organoid culture or in p48;Kras mice led to a significant increase in DCLK1 PanIN cells. As a mechanism of how EGFR inhibition leads to formation of DCLK1 cells, we identify an increase in hydrogen peroxide contributing to activation of Protein Kinase D1 (PKD1). Active PKD1 then drives stemness and abundance of DCLK1 cells in lesions. Our data suggest a signaling mechanism that leads to the development of DCLK1 pancreatic cancer stem cells, which can be exploited to target this population in potential therapeutic approaches.
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http://dx.doi.org/10.1016/j.isci.2020.102019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820128PMC
January 2021

Prognostic Significance of Neutrophil to Lymphocyte Ratio Dynamics in Patients with Hepatocellular Carcinoma Treated with Radioembolization Using Glass Microspheres.

Eur J Nucl Med Mol Imaging 2021 07 13;48(8):2624-2634. Epub 2021 Jan 13.

Division of Vascular/Interventional Radiology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA.

Purpose: To study the prognostic significance of neutrophil and lymphocyte dynamics in patients with hepatocellular carcinoma (HCC) treated with radioembolization.

Methods: A retrospective, single-center review of clinical records and treatment parameters (liver volume treated, administered activity, and radiation dose) in consecutive patients who received radioembolization for HCC was performed between August 20, 2015, and May 24, 2019. Neutrophil and lymphocyte variables associated with overall survival (OS) were determined by Barcelona Clinic Liver Cancer (BCLC) stage and were correlated with radioembolization treatment parameters. Statistical methods included Wilcoxon signed-rank test, univariate, and multivariate Cox regression analysis; receiver operating characteristic analysis; and the Kaplan-Meier method.

Results: One hundred sixty-three patients with a median 67.0 years of age were included for analysis. Eighty-one percent of patients received segmental radioembolization with a median treatment dose of 358 Gray (interquartile range 256-497). The post-treatment lymphocyte count decreased significantly in 94.5 % (p < 0.001) of patients but was not predictive of OS (p = 0.248). The pre-procedure neutrophil to lymphocyte ratio (NLR) was not predictive of OS (p = 0.891), and the 1-month post-procedure NLR was a borderline independent predictor of OS (p = 0.05). The NLR ratio (NLRR = NLR/NLR) (Hazard ratio [HR], 1.31; 95% Cl, 1.04-1.66) and change in NLR (ΔNLR= NLR - NLR) (HR, 1.09; 95% CI, 1.02-1.15) were associated with worse OS in BCLC C patients. NLRR (> 3.17) and ΔNLR (> 3.74) were independent predictors when adjusted for tumor presentation, treatment parameters, and liver function. Volume of liver treated and administered activity positively correlated with NLRR and ΔNLR (p < 0.001).

Conclusion: A decrease in lymphocyte count is common after radioembolization, but of little clinical impact. Neither pre-treatment or post-treatment NLR was a predictor of survival in our study population. NLRR and ΔNLR were independent predictors of survival in BCLC stage C disease and had positive correlations with volume of liver tissue treated and administered activity.
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http://dx.doi.org/10.1007/s00259-020-05186-yDOI Listing
July 2021

Characterization of the adiponectin promoter + Cre recombinase insertion in the Tg(Adipoq-cre)1Evdr mouse by targeted locus amplification and droplet digital PCR.

Adipocyte 2021 12;10(1):21-27

Section on Growth and Obesity and Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health , Bethesda, MD, USA.

The Tg(Adipoq-cre)1Evdr mouse has become an important tool in adipose tissue biology. However, the exact genomic transgene integration site has not been established. Using Targeted Locus Amplification (TLA) we found the transgene had integrated on mouse chromosome 9 between exons 6 and 7 of . We detected transgene-transgene fusion; therefore, we used droplet digital polymerase chain reaction to identify copy number. In two separate experiments, we digested with BAMHI and with HindIII to separate potentially conjoined sequences. We found one copy of intact present in each experiment, indicating transgene-transgene fusion in other parts of the BAC that would not contribute to tissue-specific expression. copy number for Tg(Adipoq-cre)1Evdr mice can be potentially used to identify homozygous mice.
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http://dx.doi.org/10.1080/21623945.2020.1861728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781622PMC
December 2021

Case study: diagnosis and operative management of de Garengeot hernia without appendectomy during the COVID-19 pandemic.

J Surg Case Rep 2020 Nov 30;2020(11):rjaa464. Epub 2020 Nov 30.

Princeton University, Princeton, NJ, USA.

de Garengeot herniae have been reported in <100 cases in literature. They are characterized by an incarcerated femoral hernia containing the appendix. We present the case of a 45-year-old female who, upon emergency intraoperative consultation to a general surgeon while having a right groin exploration by a plastic surgeon, was found to have an appendix incarcerated within a femoral hernia. There was no evidence of appendicitis; thus, appendix was reduced and the hernia was repaired with a mesh plug. The patient did well postoperatively, with no complications and returned to complete activities. This occurred during the coronavirus disease (COVID-19) pandemic. Due to the common failure in preoperative diagnosis, it is important for surgeons to have a clinical suspicion for de Garengeot herniae for patients, presenting with a right groin bulge. Appendectomy may be safely avoided, eliminating appendectomy-associated morbidity and avoiding hospital transfer and the associated risk of COVID-19 exposure.
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http://dx.doi.org/10.1093/jscr/rjaa464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700796PMC
November 2020

Resistin mitigates stemness and metabolic profile of human adipose-derived mesenchymal stem cells via insulin resistance.

Cytokine 2021 02 30;138:155374. Epub 2020 Nov 30.

Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India. Electronic address:

During obesity adipose tissue abundantly secrete pro-inflammatory adipokines like Tumour Necrosis factor-alpha (TNFα), resistin, leptin, etc. but reduced anti-inflammatory adipokines like adiponectin, interleukin (IL)-10, and IL-4. In our recent clinical study, it was observed that both gene expressions and stored levels of resistin were elevated in adipose tissue of metabolically obese Indians. Resistin profoundly increases obesity, mitigates lipid metabolism, and causes peripheral insulin resistance. It dysregulates the metabolism of human adipocytes but, its effects on human adipose-derived mesenchymal stem cells (hADSC) are sparsely explored. Therefore, the present study was designed to explore the repercussion of resistin on stemness and metabolic profile of hADSC. hADSC were isolated from a healthy individual followed by immunophenotyping. Purified cells were treated with resistin and proliferation was monitored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and Cell Cycle experiments. Gene expressions of pluripotent markers, inflammatory mediators, and lipogenic genes were scrutinized. Insulin sensitivity was examined by western blot and glucose uptake assay. Further, consequences of resistin on differentiation potentials of hADSC were examined by temporal expressions of phospho (p)SMAD1/5/8 protein complex, non-phosphorylated beta (β) catenin, and their dependent adipogenic transcription factors (ATF) and osteogenic transcription factors (OTF). MTT and cell cycle analysis revealed that resistin hampered proliferation of hADSC. Expressions of inflammatory markers and lipogenic genes were elevated. Resistin impaired insulin sensitivity and thus embarked insulin resistance in hADSC. Resistin increased adipogenesis and osteogenesis by altering expressions of activated pSMAD1/5/8 complex, activated β catenin, ATF and OTF temporally. Downregulation of CCAAT/enhancer-binding proteins (C/EBP)α and adiponectin in adipocytes and Sirtuin (SIRT)1 in osteocytes denote that resistin induces immaturity and insulin resistance in adipocytes and osteocytes. This is the first study which, reports that resistin mitigates the stemness of hADSC by reducing proliferation, inducing insulin resistance, and hampering maturation of adipocyte and osteocyte which could lead to metabolic disorders.
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http://dx.doi.org/10.1016/j.cyto.2020.155374DOI Listing
February 2021

Utilizing Telemedicine for Group Visit Provider Encounters: A Feasibility and Acceptability Study.

Int J Diabetes Metab Syndr 2020 2;1(1):1-6. Epub 2020 Aug 2.

Department of Medicine, Baylor College of Medicine, United States.

Background: The value of telemedicine has been underscored during the coronavirus pandemic. Utilizing telemedicine could markedly enhance group visit scalability and sustainability. However, there are limited data demonstrating telemedicine use for group visits.

Objective: To evaluate the feasibility and acceptability of provider encounters conducted via telemedicine in group visits.

Materials And Methods: We conducted a 6-month diabetes group visit program and compared in-person (months 1-3) versus telemedicine (videoconferencing) (months 4-6) patient-provider encounters. Participants completed the Telehealth Usability Questionnaire (TUQ) at 6-months (primary outcome). To ensure telemedicine did not negatively affect clinical outcomes, we compared in-person versus telemedicine differences in HbA1c, blood pressure, body mass index (BMI), and attendance.

Results: The TUQ revealed that participants (N=19) found telemedicine useful and easy to use (4.9/5.0, 4.4/5.0, respectively) and with excellent interface (4.3/5.0), interaction (4.6/5.0), reliability (4.2/5.0), and satisfaction (4.4/5.0). There were no significant differences in clinical outcomes between arms: HbA1c (in-person: -0.60%, telemedicine: -0.52%, p=0.86), blood pressure (systolic: p=0.475, diastolic: p=0.683), weight (p=0.982), BMI (p=0.981), attendance (in-person: 75.44%, telemedicine: 70.12%, p=0.551).

Conclusion: Provider telemedicine encounters in group visits are feasible and acceptable. This is a promising model to address provider limitations in group visits and increase access to care. Larger studies are needed to further evaluate these findings.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7514109PMC
August 2020

SARS-CoV-2 viral sepsis with meningoencephalitis.

Indian J Med Microbiol 2020 Apr-Jun;38(2):219-221

Department of Infectious Diseases, Sterling Hospital, Ahmedabad, Gujarat, India.

SARS-CoV-2 predominantly involves the lungs producing acute lung injury, but it can also give rise to a variety of complications involving the central nervous system, gastrointestinal system, kidney and also viral sepsis. With this case report, we are discussing unusual series of complication from acute lung injury, followed by viral sepsis then encephalitis, followed by progressive macrophage activation syndrome.
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http://dx.doi.org/10.4103/ijmm.IJMM_20_291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710350PMC
September 2020

Associations of GlycA and high-sensitivity C-reactive protein with measures of lipolysis in adults with obesity.

J Clin Lipidol 2020 Sep - Oct;14(5):667-674. Epub 2020 Aug 4.

Section on Growth and Obesity, Division of Intramural Research (DIR), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA; Johns Hopkins Community Physicians at Howard County General Hospital, Johns Hopkins Medicine, Columbia, MD, USA; Department of Endocrinology, Diabetes and Metabolism, Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Obesity-associated inflammation promotes metabolic dysfunction. However, it is unclear how different inflammatory biomarkers predict dysregulation in specific tissues/organs, particularly adipose tissue.

Objective: The aim of our study was to examine whether GlycA, a nuclear magnetic resonance-measured biomarker of inflammation, is a better predictor of insulin-suppressible lipolysis and other measures of metabolic dysfunction compared with high-sensitivity C-reactive protein (hsCRP) in human obesity.

Methods: This was a cross-sectional study of 58 nondiabetic adults with obesity (body mass index: 39.8 ± 7.0 kg/m, age 46.5 ± 12.2 years, 67.2% female) who underwent a frequently sampled intravenous glucose tolerance test in the fasted state. Noninsulin-suppressible (l), insulin-suppressible (l), and maximal (l+l) lipolysis rates, as well as insulin sensitivity and acute insulin response to glucose, were calculated by minimal model analysis. Nuclear magnetic resonance was used to measure GlycA. Body composition was determined by dual-energy X-ray absorptiometry.

Results: GlycA was strongly correlated with hsCRP (r = +0.46; P < .001). GlycA and hsCRP were positively associated with l, l+l, and fat mass (Ps < .01). In linear regression models accounting for age, race, sex, and fat mass, GlycA remained significantly associated with l and l+l (Ps < .05), whereas hsCRP did not (Ps ≥ .20). Neither GlycA nor hsCRP was associated with l insulin sensitivity, or acute insulin response to glucose.

Conclusions: GlycA was associated with elevated lipolysis, independent of adiposity, in adults with obesity. Our findings suggest that GlycA and hsCRP have distinct inflammation-mediated metabolic effects, with GlycA having a greater association with adipose tissue dysfunction. Further studies are warranted to investigate the mechanisms underlying these associations.
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http://dx.doi.org/10.1016/j.jacl.2020.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642018PMC
September 2021

Safety and efficacy of tocilizumab in the treatment of severe acute respiratory syndrome coronavirus-2 pneumonia: A retrospective cohort study.

Indian J Med Microbiol 2020 Jan-Mar;38(1):117-123

Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, USA.

Background: Cytokine release storm (CRS) in severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) is thought to be the cause for organ damage and death which is independent of the actual viral burden. Tocilizumab (TCZ), an interleukin-6 receptor antagonist, is approved for the treatment of CRS. We describe the efficacy and safety of TCZ in SARS CoV-2 pneumonia.

Methods: This retrospective study was conducted at a tertiary care hospital from April 20 2020 to May 21 2020. The primary endpoint was the cumulative incidence of a composite of either need for admission to the intensive care unit (ICU) with invasive mechanical ventilation or death. Safety outcomes included an increase in liver transaminases and/or evidence of infection.

Results: A total of 20 patients received TCZ during the study period. The median age was 54 years (95% confidence interval [CI] 47-63). About 85% of the patients were male. Nearly 70% of the patients had at least one comorbidity. About 55% required ICU admission. The median duration of ICU stay was 11 days (95% CI: 3-13 days). The cumulative incidence of the requirement for mechanical ventilation, clinical improvement and mortality was 11% (95% CI: 0.03%-1%), 74% (95% CI 37%-89%) and 25% (95% CI: 11%-63%), respectively. There was no difference in outcomes according to age, gender or computed tomography severity score. Asymptomatic transaminitis was the most common drug reaction (55%), and one patient developed bacteraemia.

Conclusions: TCZ is likely a safe and effective modality of treatment for improving clinical and laboratory parameters of SARS CoV-2 patients with a reduction in ICU stay and ventilatory care need.
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http://dx.doi.org/10.4103/ijmm.IJMM_20_298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706820PMC
August 2020

Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria.

J Med Chem 2020 07 7;63(14):7773-7816. Epub 2020 Jul 7.

Novartis Institutes for BioMedical Research, Emeryville, California 94608, United States.

Since their discovery over 5 decades ago, quinolone antibiotics have found enormous success as broad spectrum agents that exert their activity through dual inhibition of bacterial DNA gyrase and topoisomerase IV. Increasing rates of resistance, driven largely by target-based mutations in the GyrA/ParC quinolone resistance determining region, have eroded the utility and threaten the future use of this vital class of antibiotics. Herein we describe the discovery and optimization of a series of 4-(aminomethyl)quinolin-2(1)-ones, exemplified by , that inhibit bacterial DNA gyrase and topoisomerase IV and display potent activity against ciprofloxacin-resistant Gram-negative pathogens. X-ray crystallography reveals that occupies the classical quinolone binding site in the topoisomerase IV-DNA cleavage complex but does not form significant contacts with residues in the quinolone resistance determining region.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00347DOI Listing
July 2020

Cell apoptosis induced by ciprofloxacin based Cu(II) complexes: cytotoxicity, SOD mimic and antibacterial studies.

J Biomol Struct Dyn 2021 Aug 11;39(12):4555-4562. Epub 2020 Jun 11.

Department of Chemistry, C. U. Shah University, Wadhwancity, India.

The current cancer research focuses on the design and synthesis of chemical compounds that can modulate cell apoptosis or programmed cell death. So we synthesized and characterized ciprofloxacin based copper(II) complexes and studied their anticancer activity against HCT 116 cancer cells by MTT assay. We further investigated the influence of compound-2 (better IC value than cisplatin) on cancer cells to know the exact mechanism of anticancer activity. The distinct morphological change of cells due to compound-2 was observed in bright field microscopy. The trypan blue assay clearly demonstrated inhibition of cell viability. The clonogenic ability inhibition assay showed a low percentage of the plating efficiency of HCT 116 cells. The mechanism of cell death, either apoptotic or necrotic was distinguished by annexin V-FITC/PI (propidium iodide) staining assay and LDH (lactate dehydrogenase) release assay. The positive annexinV/PI cells in presence of compound-2 and absence of LDH in the LDH release assay confirmed the cell apoptotic mechanism of cell death. We also checked antibacterial activity of compounds against Gram and Gram bacteria in terms of MIC (minimum inhibitory concentration) and the data were in good agreement with the standard drug data. SOD mimic activity of synthesized Cu(II) complexes was also studied in terms of IC value. The brine shrimp lethality bioassay was also performed to evaluate the cytotoxic properties of the Cu(II) complexes.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1776641DOI Listing
August 2021

Colchicine's effects on metabolic and inflammatory molecules in adults with obesity and metabolic syndrome: results from a pilot randomized controlled trial.

Int J Obes (Lond) 2020 08 27;44(8):1793-1799. Epub 2020 May 27.

Section on Growth and Obesity, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, 20892-1103, USA.

Objective: Recent clinical trials have demonstrated that colchicine may have metabolic and cardiovascular and benefits in at-risk patients; however, the mechanisms through which colchicine may improve outcomes are still unclear. We sought to examine colchicine's effects on circulating inflammatory and metabolic molecules in adults with obesity and metabolic syndrome (MetS).

Methods: Blood samples were collected pre- and post-intervention during a double-blind randomized controlled trial in which 40 adults with obesity and MetS were randomized to colchicine 0.6 mg or placebo twice-daily for 3 months. Serum samples were analyzed for 1305 circulating factors using the SomaScan Platform. The Benjamini-Hochberg procedure was used to adjust the false discovery rate (FDR) for multiple testing.

Results: At baseline, age (48.0 ± 13.8 vs. 44.7 ± 10.3 years) and BMI (39.8 ± 6.4 vs. 41.8 ± 8.2 kg/m) were not different between groups. After controlling for the FDR, 34 molecules were significantly changed by colchicine. Colchicine decreased concentrations of multiple inflammatory molecules, including C-reactive protein, interleukin 6, and resistin, in addition to vascular-related proteins (e.g., oxidized low-density lipoprotein receptor, phosphodiesterase 5A). Conversely, relative to placebo, colchicine significantly increased concentrations of eight molecules including secreted factors associated with metabolism and anti-thrombosis.

Conclusions: In adults with obesity, colchicine significantly affected concentrations of proteins involved in the innate immune system, endothelial function and atherosclerosis, uncovering new mechanisms behind its cardiometabolic effects. Further research is warranted to investigate whether colchicine's IL-6 suppressive effects may be beneficial in COVID-19.
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http://dx.doi.org/10.1038/s41366-020-0598-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253147PMC
August 2020

One-carbon metabolism-related micronutrients intake and risk for hepatocellular carcinoma: A prospective cohort study.

Int J Cancer 2020 10 25;147(8):2075-2090. Epub 2020 Apr 25.

Division of Cancer Epidemiology and Genetics, The National Cancer Institute, Bethesda, Maryland, USA.

Deficient intake of micronutrients involved in one-carbon metabolism (eg, choline, methionine, vitamin B and folic acid) leads to hepatocellular carcinoma (HCC) development in rodents, but is under-investigated in humans. We investigated the association between one-carbon metabolism-related micronutrient intake and HCC risk in a prospective cohort of 494 860 participants with 16 years of follow-up in the NIH-AARP study. Dietary intakes and supplement use were ascertained at baseline using a food-frequency questionnaire. Total intake (diet plus supplements) of the following one-carbon metabolism-related micronutrients were calculated: folate, methionine and vitamins B (riboflavin), B (niacin), B and B . These micronutrients were examined both individually and simultaneously, with adjustment for covariates. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over the 16-year follow-up period, 647 incident HCC cases were diagnosed. When examined individually, higher total vitamin B intake was associated with a lower HCC risk (HR = 0.60; 95% CI = 0.42-0.85; P = .008), and the association remained significant when all six micronutrients were examined simultaneously (HR = 0.32; 95% CI = 0.18-0.55; P < .0001). Among participants with >3 years of follow-up, higher total vitamin B intake was again associated with lower risk (HR = 0.37; 95% CI = 0.20-0.68; P = .001), whereas higher total vitamin B intake was associated with higher risk (HR = 2.04; 95% CI = 1.02-4.07; P = .04). Restricted cubic spline analyses showed a dose-response inverse association between total vitamin B intake and HCC risk, and dose-response positive association between total vitamin B intake and HCC risk. The study suggests that higher vitamin B intake is associated with lower HCC risk, whereas higher vitamin B intake is associated with increased risk.
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http://dx.doi.org/10.1002/ijc.33007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875463PMC
October 2020

Trends in Ambulatory Surgery Center Utilization for Otolaryngologic Procedures among Medicare Beneficiaries, 2010-2017.

Otolaryngol Head Neck Surg 2020 Jun 14;162(6):873-880. Epub 2020 Apr 14.

Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, Massachusetts, USA.

Objective: Surgical care is increasingly shifting to freestanding ambulatory surgical centers (ASCs). The extent to which otolaryngologists use ASCs has implications for patient safety and health care spending. This study characterizes trends in utilization and resultant financial implications for common otolaryngologic procedures performed at ASC and hospital outpatient departments (HOPDs).

Study Design: Retrospective cross-sectional analysis.

Setting: ASCs, HOPDs.

Subjects And Methods: Subjects included Medicare beneficiaries undergoing outpatient otolaryngologic procedures between 2010 and 2017. Procedures included the 20 highest-volume procedures performed by otolaryngologists at ASCs in 2017. Main outcomes included absolute and relative percentage difference in the proportion of procedures furnished at ASCs and HOPDs and estimated Medicare cost savings resulting from increased ASC utilization between 2011 and 2017.

Results: The proportion of outpatient otolaryngologic procedures performed at ASCs increased by 1.8% (relative difference: 10.0%; mean annual relative increase: 1.60%), and the proportion located at HOPDs decreased by 6.0% (relative difference: -11.8%; mean annual relative decrease: -1.6%) between 2010 and 2017. Rhinoplasty accounted for the largest absolute increase in ASC utilization over the study period (absolute [relative] 8.9% [33.5%]). Increased ASC utilization resulted in an estimated $7.1 million in cost savings to Medicare between 2011 and 2017.

Conclusion: Otolaryngologists shifted outpatient surgical care from HOPDs to ASCs between 2010 and 2017, with resultant reductions in Medicare expenditures. Further research is necessary to examine the impact of this shift on patient safety.
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http://dx.doi.org/10.1177/0194599820914298DOI Listing
June 2020

Independent and Joint Use of Statins and Metformin by Elderly Patients With Diabetes and Overall Survival Following HCC Diagnosis.

J Clin Gastroenterol 2020 May/Jun;54(5):468-476

Transplant Hepatology, Mayo Clinic, Jacksonville, FL.

Goal: To investigate associations of prediagnosis and postdiagnosis use of statins and metformin on overall survival of patients with diabetes who later developed HCC.

Background: Statins and metformin have received considerable interest as potential chemopreventive agents against hepatocellular carcinoma (HCC) development in individuals with type 2 diabetes mellitus (T2DM); however, their impact on overall survival of patients with T2DM who later develop HCC (diabetic HCC patients) is unclear.

Study: Data on 2499 elderly diabetic HCC patients obtained from the SEER-Medicare program (2009 to 2013) were analyzed. Patients were categorized based on use of statins only, metformin only, both, or neither (reference for all comparisons). The patients were further categorized based on: (1) metformin dose: ≤1500 or >1500 mg/d; (2) statins functional form: hydrophilic (pravastatin and rosuvastatin) or lipophilic (atorvastatin, fluvastatin, lovastatin, and simvastatin); (3) statins potency: high (atorvastatin, rosuvastatin, and simvastatin) or low (fluvastatin, lovastatin, and pravastatin); and (4) individual statins type. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models.

Results: Prediagnosis use of metformin dose ≤1500 mg/d was associated with lower risk of death after HCC diagnosis in patients with T2DM (HR, 0.72; 95% CI, 0.58-0.91), adjusting for postdiagnosis metformin dose, diabetes severity, Charlson comorbidity index, tumor characteristics, and other relevant factors. No association was found for prediagnosis metformin dose >1500 mg/d or postdiagnosis metformin use. Further, no association was found for either prediagnosis or postdiagnosis statins use.

Conclusions: Prediagnosis use of metformin dose ≤1500 mg/d is associated with longer overall survival of elderly diabetic HCC patients.
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http://dx.doi.org/10.1097/MCG.0000000000001182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150664PMC
June 2021

Influence of obese phenotype on metabolic profile, inflammatory mediators and stemness of hADSC in adipose tissue.

Clin Nutr 2020 12 6;39(12):3829-3835. Epub 2020 Mar 6.

Molecular Endocrinology and Stem Cell Research Lab, Department of Biochemistry, Faculty of Science, The M. S. University of Baroda, Vadodara, Gujarat, India. Electronic address:

Background: Unhealthy dietary practices, sedentary life style and lack of physical exercise in developing countries like India are major contributors of metabolic syndrome like obesity and diabetes. Obesity in Indians is defined at Body Mass Index (BMI, kg/m) >25 and characterized as metabolically obese.

Objective: A preliminary study performed to explore ramification of obesity on metabolic profile of adipose tissue and adipose derived stem cells (ADSC) from control and obese Indians.

Methods: Adipose tissue/lipoaspirates from both control (BMI ≤ 23) subjects, and non-diabetic obese Indians subjects (BMI ≥ 25), were scrutinized for expressions of lipogenic genes, inflammatory mediators, stored adipokine levels, and insulin signaling proteins. Further, hADSC were isolated and immune-phenotyped from both the subject groups. Comparative assessments between chADSC and ohADSC were carried out for growth kinetics, expressions of pluripotent genes, adipogenic transcriptional factors, RUNX2, inflammatory mediators (IM), insulin signaling proteins, adipogenic and osteogenic differentiation.

Results: Adipose tissue of obese subjects depicted high leptin and resistin levels with reduced adiponectin levels. Expressions of IM and insulin signaling proteins were elevated compared to those of control subjects. hADSC of obese subjects demonstrated diminished proliferation, altered pluripotent genes, aggravated inflammation, adipogenesis with reduced osteogenesis. hADSC of obese had established insulin resistance compared to those of control subjects.

Conclusion: This is the first study that describes hADSC of metabolically obese Indians have insulin resistance at lower BMI compared to Caucasians exemplifying plausible role in diminishing stemness of hADSC. Study alarms Indians to restore healthy dietary habits and assess quality of hADSC in regenerative therapy.
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http://dx.doi.org/10.1016/j.clnu.2020.02.032DOI Listing
December 2020
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