Publications by authors named "Rajiv Kumar"

667 Publications

Longitudinal study of prognostic factors for localized cutaneous melanoma in patients who have been disease-free for five years.

Eur J Dermatol 2021 Apr 19. Epub 2021 Apr 19.

Department of Dermatology, Instituto Valenciano de Oncología, València, Spain, School of Medicine, Universidad Católica de Valencia, Spain.

Most relapses in melanoma patients occur during the first five years after diagnosis. Identifying characteristics associated with recurrence after this period could help delineate guidelines, specifically for follow-up protocols. Objectives: The aim of this study was to identify the prognostic factors for relapse and death caused by melanoma in patients who have been disease-free for five years. We designed a longitudinal retrospective cohort to study Stage I/II cutaneous melanoma patients who have been free of disease for more than five years (late relapse cohort). Prognostic factors for disease-free and melanoma-specific survival were evaluated using the Kaplan-Meier method and Cox regression models. A series of 746 patients who had Stage I-II cutaneous melanoma and were free of disease for five years was selected. After a median follow-up of 64 months (124 months since melanoma diagnosis), 51 (6.8%) patients relapsed and 18 (2.4%) died from melanoma. Acral location and presence of ulceration, as well as intermediate growth rate (0.11-0.50 mm/month), were significantly associated with relapse or death due to melanoma. The initial recurrence site was associated with distant metastasis in 48% of the cases. In this study, we have identified melanoma characteristics in patients who have been disease-free for five years that may allow us to establish groups at increased risk of relapse or death due to melanoma, which could be helpful for melanoma management.
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http://dx.doi.org/10.1684/ejd.2021.4022DOI Listing
April 2021

Risk of Symptomatic Kidney Stones During and After Pregnancy.

Am J Kidney Dis 2021 Apr 8. Epub 2021 Apr 8.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN. Electronic address:

Rationale & Objective: There are several well-known anatomical and physiological changes during pregnancy that could contribute to kidney stone formation, but evidence that they increase the risk of kidney stones during pregnancy is lacking. We determined whether there was an increased risk of a first-time symptomatic kidney stone during and after pregnancy.

Study Design: A population-based matched case-control study.

Setting & Participants: 945 female first-time symptomatic kidney stone formers aged 15-45 years and 1,890 age-matched female controls in Olmsted County, MN, from 1984-2012. The index date was the date of onset of a symptomatic kidney stone for both the case and her matched controls.

Exposure: The primary exposure was pregnancy with assessment for variation in risk across different time intervals before, during, and after pregnancy. Medical records were manually reviewed to determine the conception and delivery dates for pregnancies.

Outcome: Medical record-validated first-time symptomatic kidney stone.

Analytical Approach: Conditional and unconditional multivariable logistic regression analysis.

Results: Compared with nonpregnant women, the odds of a symptomatic kidney stone forming in women was similar in the first trimester (OR, 0.92; P=0.8), began to increase during the second trimester (OR, 2.00; P=0.007), further increased during the third trimester (OR, 2.69; P=0.001), peaked at 0 to 3 months after delivery (OR, 3.53; P<0.001), and returned to baseline by 1year after delivery. These associations persisted after adjustment for age and race or for diabetes mellitus, hypertension, and obesity. These results did not significantly differ by age, race, time period, or number of prior pregnancies. Having a prior pregnancy (delivery date>1year ago) was also associated with a first-time symptomatic kidney stone (OR, 1.27; P=0.01).

Limitations: Observational study design in a predominantly White population. The exact timing of stone formation cannot be determined.

Conclusions: Pregnancy increases the risk of a first-time symptomatic kidney stone. This risk peaks close to delivery and then improves by 1 year after delivery, though a modest risk of a kidney stone still exists beyond 1 year after delivery.
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http://dx.doi.org/10.1053/j.ajkd.2021.01.008DOI Listing
April 2021

Molecular characterization of lung squamous cell carcinoma tumors reveals therapeutically relevant alterations.

Oncotarget 2021 Mar 16;12(6):578-588. Epub 2021 Mar 16.

Integrated Cancer Genomics Laboratory, Advanced Centre for Treatment Research Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra 410210, India.

Introduction: Unlike lung adenocarcinoma patients, there is no FDA-approved targeted-therapy likely to benefit lung squamous cell carcinoma patients.

Materials And Methods: We performed survival analyses of lung squamous cell carcinoma patients harboring therapeutically relevant alterations identified by whole exome sequencing and mass spectrometry-based validation across 430 lung squamous tumors.

Results: We report a mean of 11.6 mutations/Mb with a characteristic smoking signature along with mutations in and among lung squamous cell carcinoma patients of Indian descent. In addition, therapeutically relevant mutations occur in 5.8% patients, significantly higher than as reported among Caucasians. In overall, our data suggests 13.5% lung squamous patients harboring druggable mutations have lower median overall survival, and 19% patients with a mutation in at least one gene, known to be associated with cancer, result in significantly shorter median overall survival compared to those without mutations.

Conclusions: We present the first comprehensive landscape of genetic alterations underlying Indian lung squamous cell carcinoma patients and identify and as potentially important therapeutic and prognostic target.
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http://dx.doi.org/10.18632/oncotarget.27905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984830PMC
March 2021

Hyperphosphatemia with elevated serum PTH and FGF23, reduced 1,25(OH)D and normal FGF7 concentrations characterize patients with CKD.

BMC Nephrol 2021 Mar 30;22(1):114. Epub 2021 Mar 30.

Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, 200 1st Street SW, MN, 55905, Rochester, USA.

Background: Hyperphosphatemia confers adverse cardiovascular outcomes, and commonly occurs in late-stage CKD. Fibroblast growth factor 7 (FGF7) is a phosphaturic peptide which decreases renal phosphate transport in vitro and in vivo. Serum FGF7 concentrations are reduced in hyperphosphatemic patients with hypophosphatasia and are elevated in some hypophosphatemic patients with tumor-induced osteomalacia. No data, however, are available on whether circulating FGF7 concentrations increase to compensate for phosphate retention in CKD patients.

Methods: This was a cross-sectional study performed among 85 adult patients with varying estimated glomerular filtration rates (eGFR). We measured serum intact FGF7 (iFGF7) concentration using an iFGF7 immunoassay and determined its associated factors. Relationships between eGFR and mineral metabolism biomarkers [phosphate, iFGF7, iFGF23, parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25(OH)D)] were explored.

Results: For eGFRs of ≥ 60 (n = 31), 45-59 (n = 16), 30-44 (n = 11), 15-29 (n = 15), and < 15 mL/min/1.73 m (n = 12), median (IQ25-75) iFGF7 concentrations were 46.1 (39.2-56.9), 43.1 (39.0-51.5), 47.3 (38.3-66.5), 47.7 (37.7-55.8), and 49.6 (42.5-65.6) pg/mL, respectively (P = 0.62). Significant increases in serum iFGF23, PTH, and phosphate were observed at eGFRs of < 33 (95 % CI, 26.40-40.05), < 29 (95 % CI, 22.51-35.36), and < 22 mL/min/1.73 m (95 % CI, 19.25-25.51), respectively, while significant decreases in serum 1,25(OH)D were observed at an eGFR of < 52 mL/min/1.73 m (95 % CI, 42.57-61.43). No significant correlation was found between serum iFGF7 and phosphate, iFGF23, PTH or 1,25(OH)D. In multivariable analyses, body mass index (per 5 kg/m increase) was independently associated with the highest quartile of serum iFGF7 concentration (OR, 1.20; 95 % CI, 1.12-1.55).

Conclusions: Compensatory decreases in circulating 1,25(OH)D and increases in circulating iFGF23 and PTH, but not iFGF7, facilitate normalization of serum phosphate concentration in early stages of CKD. Whether other circulating phosphaturic peptides change in response to phosphate retention in CKD patients deserves further study.
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http://dx.doi.org/10.1186/s12882-021-02311-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011073PMC
March 2021

On point identification of species origin of food animals by recombinase polymerase amplification-lateral flow (RPA-LF) assay targeting mitochondrial gene sequences.

J Food Sci Technol 2021 Apr 16;58(4):1286-1294. Epub 2020 Jul 16.

Division of Livestock Products Technology, GADVASU, Ludhiana, India.

The present study was aimed to develop and standardize Recombinase polymerase amplification-lateral flow (RPA-LF) assays for on point identification of species origin of food animals viz: cattle, buffalo and pig. Species specific RPA primers sets for cattle, buffalo and pig were designed by homology comparisons of the sequences of mitochondrial cytochrome b gene and d-loop region from common food species viz: cattle, buffalo, sheep, goat, pig and chicken. The RPA assays for designed primers sets were optimized using the reaction components from Twist Amp basic kit and instructions in its manual. Endpoint detection of species specific amplified RPA products were made by gel electrophoresis and designed species specific RPA-LFA strips. The developed assays were evaluated for their specificity, diagnostic sensitivity, and validated on coded samples and binary meat admixtures with relative percentage of 20, 10, 5 & 1% target species. The developed RPA assays resulted in amplification of DNA template exclusively of cattle, buffalo and pig origin to product sizes of 294, 405 and 283 bp respectively. The diagnostic sensitivities of developed assays were up to 10 pg of genomic DNA and highly correlated with species specific PCR assays taken as gold standard. Developed species specific RPA assays also identified the target species in coded samples and binary meat admixture up to 1%.
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http://dx.doi.org/10.1007/s13197-020-04637-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925745PMC
April 2021

Review of nanotheranostics for molecular mechanisms underlying psychiatric disorders and commensurate nanotherapeutics for neuropsychiatry: The mind knockout.

Nanotheranostics 2021 1;5(3):288-308. Epub 2021 Mar 1.

Institute of Nuclear Medicine and Allied Sciences (INMAS) Brig. S. K. Mazumdar Marg Delhi 110054, India.

Bio-neuronal led psychiatric abnormalities transpired by the loss of neuronal structure and function (neurodegeneration), pro-inflammatory cytokines, microglial dysfunction, altered neurotransmission, toxicants, serotonin deficiency, kynurenine pathway, and excessively produced neurotoxic substances. These uncontrolled happenings in the etiology of psychiatric disorders initiate further changes in neurotransmitter metabolism, pathologic microglial, cell activation, and impaired neuroplasticity. Inflammatory cytokines, the outcome of dysfunctional mitochondria, dysregulation of the immune system, and under stress functions of the brain are leading biochemical factors for depression and anxiety. Nanoscale drug delivery platforms, inexpensive diagnostics using nanomaterials, nano-scale imaging technologies, and ligand-conjugated nanocrystals used for elucidating the molecular mechanisms and foremost cellular communications liable for such disorders are highly capable features to study for efficient diagnosis and therapy of the mental illness. These theranostic tools made up of multifunctional nanomaterials have the potential for effective and accurate diagnosis, imaging of psychiatric disorders, and are at the forefront of leading technologies in nanotheranostics openings field as they can collectively and efficiently target the stimulated territories of the cerebellum (cells and tissues) through molecular-scale interactions with higher bioavailability, and bio-accessibility. Specifically, the nanoplatforms based neurological changes are playing a significant role in the diagnosis of psychiatric disorders and portraying the routes of functional restoration of mental disorders by newer imaging tools at nano-level in all directions. Because of these nanotherapeutic platforms, the molecules of nanomedicine can penetrate the Blood-Brain Barrier with an increased half-life of drug molecules. The discoveries in nanotheranostics and nanotherapeutics inbuilt unique multi-functionalities are providing the best multiplicities of novel nanotherapeutic potentialities with no toxicity concerns at the level of nano range.
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http://dx.doi.org/10.7150/ntno.49619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961125PMC
May 2021

Chemical Characterization and Quantification of Circulating Intact PTH and PTH Fragments by High-Resolution Mass Spectrometry in Chronic Renal Failure.

Clin Chem 2021 Mar 6. Epub 2021 Mar 6.

Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Background: The precise concentrations of full-length parathyroid hormone (PTH1-84) and the identity and concentrations of PTH fragments in patients with various stages of chronic renal failure are unknown.

Methods: We developed a liquid chromatography-high resolution mass spectrometry (LC-HRMS) method to characterize and quantify PTH1-84 and PTH fragments in serum of 221 patients with progressive renal dysfunction. Following capture by matrix-bound amino-terminal or carboxyl-terminal region-specific antibodies and elution from matrix, PTH1-84 and PTH fragments were identified and quantitated using LC-HRMS. PTH was simultaneously measured using an intact PTH (iPTH) immunoassay.

Results: Full-length PTH1-84 and 8 PTH fragments (PTH28-84, 34-77, 34-84, 37-77, 37-84, 38-77, 38-84, and 45-84) were unequivocally identified and were shown to increase significantly when an eGFR declined to ≤17-23 mL/min/1.73m2. Serum concentrations of PTH1-84 were similar when measured by LC-HRMS following capture by amino-terminal or carboxyl-terminal immunocapture methods. In patients with an eGFR of <30 mL/min/1.73 m2, serum PTH concentrations measured using LC-HRMS were significantly lower than PTH measured using an iPTH immunoassay. PTH7-84 and oxidized forms of PTH1-84 were below the limit of detection (30 and 50 pg/mL, respectively).

Conclusions: LC-HRMS identifies circulating PTH1-84, carboxyl-terminal PTH fragments, and mid-region PTH fragments, in patients with progressive renal failure. Serum PTH1-84 and its fragments markedly rise when an eGFR decreases to ≤17-23 mL/min/1.73 m2. PTH concentrations measured using LC-HRMS tend to be lower than those measured using an iPTH immunoassay, particularly in severe chronic renal failure. Our data do not support the existence of circulating PTH7-84 and oxidized PTH1-84.
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http://dx.doi.org/10.1093/clinchem/hvab013DOI Listing
March 2021

IL-10 and TGF-β Induced Arginase Expression Contributes to Deficient Nitric Oxide Response in Human Visceral Leishmaniasis.

Front Cell Infect Microbiol 2020 18;10:614165. Epub 2021 Feb 18.

Department of Human Genetics, Guru Nanak Dev University, Amritsar, India.

Nitric oxide (NO) is an anti-microbial effector of the innate immune system which plays major role in non-specific killing of various pathogens including protozoan parasites. However, due to subversion of the host's immune processes by pathogens, suboptimal production of NO is frequently found in many infection models. Previous studies have shown suppressed NO production during infection, the causative agent of visceral leishmaniasis (VL). Availability of L-Arginine, a semi-essential amino acid is required for inducible nitric oxide synthase (iNOS) mediated NO production. However, arginase is another enzyme, which if expressed concomitantly, may strongly compete for L-Arginine, and suppress NO production by iNOS. In the present study, plasma nitrite and arginase levels were measured in VL patients before and after successful drug treatment, endemic and non-endemic healthy donors. We observed significantly lower NO levels in the plasma of VL patients as compared to endemic controls, which improved significantly post-treatment. Significantly elevated arginase activity was also observed in the plasma of VL patients, which may be associated with NO deficiency. VL patients also showed significantly higher levels of IL-10 and TGF-β, which are known to regulate expression of arginase in various immune cells. In vitro studies with human peripheral blood mononuclear cells (PBMCs) further corroborated the role of IL-10 and TGF-β in arginase mediated suppression of NO production.
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http://dx.doi.org/10.3389/fcimb.2020.614165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930829PMC
February 2021

Distribution and clinical role of KIT gene mutations in melanoma according to subtype: a study of 492 Spanish patients.

Eur J Dermatol 2021 Mar 1. Epub 2021 Mar 1.

Department of Dermatology, Fundación Instituto Valenciano de Oncología, València, Spain, School of Medicine, Universidad Católica de Valencia San Vicente Mártir, València, Spain.

Background: KIT mutations are primarily associated with acral and mucosal melanoma, and have been reported to show higher prevalence in chronic sun-damaged (CSD) than non-CSD melanomas.

Objectives: To investigate the prevalence of KIT mutations in melanoma according to subtype, and determine the clinical role of such mutations.

Material & Methods: We present results from a study of a Spanish population of 492 melanomas, classified according to the latest World Health Organization (WHO) guidelines. We analysed the mutational status of KIT and correlated with different clinical variables related to sun exposure and family history.

Results: KIT mutations were significantly more frequent in acral (3/36; 8.3%) and mucosal (4/8; 50%) melanomas than non-acral cutaneous melanomas. No significant difference was observed in KIT mutational status between CSD and non-CSD melanomas.

Conclusion: Our results suggest that KIT mutations in melanoma tumours are unrelated to the development of nevi or chronic sun damage, but their presence is associated with aggressive melanomas which show ulceration, vascular invasiveness, and increased Breslow thickness. These findings are consistent with those reported by The Cancer Genome Atlas network.
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http://dx.doi.org/10.1684/ejd.2021.3971DOI Listing
March 2021

Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD.

Blood Cancer J 2021 Feb 27;11(2):42. Epub 2021 Feb 27.

Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.

Chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity after allogeneic stem cell transplantation (alloSCT). The individual risk of severe cGVHD remains difficult to predict and may involve CXCR3 ligands. This study investigated the role of single-nucleotide polymorphisms (SNPs) of CXCL4, CXCL9, CXCL10, and CXCL11, and their day +28 serum levels, in cGVHD pathogenesis. Eighteen CXCR3 and CXCL4, CXCL9-11 SNPs as well as peri-transplant CXCL9-11 serum levels were analyzed in 688 patients without (training cohort; n = 287) or with statin-based endothelial protection cohort (n = 401). Clinical outcomes were correlated to serum levels and SNP status. Significant polymorphisms were further analyzed by luciferase reporter assays. Findings were validated in an independent cohort (n = 202). A combined genetic risk comprising four CXCR3 ligand SNPs was significantly associated with increased risk of severe cGVHD in both training cohort (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.33-4.64, P = 0.004) and validation cohort (HR 2.95, 95% CI 1.56-5.58, P = 0.001). In reporter assays, significantly reduced suppressive effects of calcineurin inhibitors in constructs with variant alleles of rs884304 (P < 0.001) and rs884004 (P < 0.001) were observed. CXCL9 serum levels at day +28 after alloSCT correlated with both genetic risk and risk of severe cGVHD (HR 1.38, 95% CI 1.10-1.73, P = 0.006). This study identifies patients with high genetic risk to develop severe cGVHD.
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http://dx.doi.org/10.1038/s41408-021-00434-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914250PMC
February 2021

Adventitial delivery of nanoparticles encapsulated with 1α, 25-dihydroxyvitamin D attenuates restenosis in a murine angioplasty model.

Sci Rep 2021 Feb 26;11(1):4772. Epub 2021 Feb 26.

Vascular and Interventional Radiology Translational Laboratory, Department of Radiology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

Percutaneous transluminal angioplasty (PTA) of stenotic arteriovenous fistulas (AVFs) is performed to maintain optimal function and patency. The one-year patency rate is 60% because of venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation. Immediate early response gene X-1 (Iex-1) also known as Ier3 increases in response to wall shear stress (WSS), and can cause VNH/VS formation in murine AVF. In human stenotic samples from AVFs, we demonstrated increased gene expression of Ier3. We hypothesized that 1α, 25-dihydroxyvitamin D, an inhibitor of IER3 delivered as 1α, 25-dihydroxyvitamin D encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles loaded in Pluronic F127 hydrogel (1,25 NP) to the adventitia of the stenotic outflow vein after PTA would decrease VNH/VS formation by reducing Ier3 and chemokine (C-C motif) ligand 2 (Ccl2) expression. In our murine model of AVF stenosis treated with PTA, increased expression of Ier3 and Ccl2 was observed. Using this model, PTA was performed and 10-μL of 1,25 NP or control vehicle (PLGA in hydrogel) was administered by adventitial delivery. Animals were sacrificed at day 3 for unbiased whole genome transcriptomic analysis and at day 21 for immunohistochemical analysis. Doppler US was performed weekly after AVF creation. At day 3, significantly lower gene expression of Ier3 and Ccl2 was noted in 1,25 NP treated vessels. Twenty-one days after PTA, 1,25 NP treated vessels had increased lumen vessel area, with decreased neointima area/media area ratio and cell density compared to vehicle controls. There was a significant increase in apoptosis, with a reduction in CD68, F4/80, CD45, pro-inflammatory macrophages, fibroblasts, Picrosirius red, Masson's trichrome, collagen IV, and proliferation accompanied with higher wall shear stress (WSS) and average peak velocity. IER3 staining was localized to CD68 and FSP-1 (+) cells. After 1,25 NP delivery, there was a decrease in the proliferation of α-SMA (+) and CD68 (+) cells with increase in the apoptosis of FSP-1 (+) and CD68 (+) cells compared to vehicle controls. RNA sequencing revealed a decrease in inflammatory and apoptosis pathways following 1,25 NP delivery. These data suggest that adventitial delivery of 1,25 NP reduces VNH and venous stenosis formation after PTA.
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http://dx.doi.org/10.1038/s41598-021-84444-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910622PMC
February 2021

1α,25-Dihydroxyvitamin D Encapsulated in Nanoparticles Prevents Venous Neointimal Hyperplasia and Stenosis in Porcine Arteriovenous Fistulas.

J Am Soc Nephrol 2021 Feb 24. Epub 2021 Feb 24.

Department of Radiology, Vascular and Interventional Translational Laboratory, Mayo Clinic, Rochester, Minnesota

Background: Few therapies prevent venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation in arteriovenous fistulas (AVF). Expression of the immediate early response gene X-1 (), also known as is associated with VNH and stenosis in murine AVFs. The study aimed to determine if local release of long-acting inhibitor 1α,25(OH)D from poly(lactic-co-glycolic acid) (PLGA) nanoparticles embedded in a thermosensitive Pluronic F127 hydrogel (1,25 NP) could affect VNH/VS formation in a large animal model.

Methods: Immediately after AVF creation in a porcine model of renal failure, 1,25 NP or vehicle control was injected into the adventitia space of AVF outflow veins. Scanning electron microscopy and dynamic light scattering characterized drug and control nanoparticles. Animals were sacrificed 3 and 28 days later for gene expression, immunohistologic, magnetic resonance imaging and angiography, and ultrasound analyses. Whole transcriptome RNA sequencing with differential gene expression analysis was performed on outflow veins of AVF.

Results: Encapsulation of 1α,25(OH)D in PLGA nanoparticles formed nanoparticles of uniform size that were similar to nanoparticles without 1α,25(OH)D. The 1,25 NP-treated AVFs exhibited lower VNH/VS, gene expression, and IER-3, MCP-1, CD68, HIF-1α, and VEGF-A immunostaining, fibrosis, and proliferation. Blood flow and lumen area increased significantly, whereas peak systolic velocity and wall shear stress decreased. Treatment increased Young's modulus and correlated with histologic assessment of fibrosis and with no evidence of vascular calcification. RNA sequencing analysis showed changes in the expression of genes associated with inflammatory, TGFβ1, and apoptotic pathways.

Conclusions: Local release of 1,25 NP improves AVF flow and hemodynamics, and reduces stenosis in association with reduction in inflammation, apoptosis, and fibrosis in a porcine model of arteriovenous fistula.
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http://dx.doi.org/10.1681/ASN.2020060832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017547PMC
February 2021

Paper-based loop-mediated isothermal amplification and lateral flow (LAMP-LF) assay for identification of tissues of cattle origin.

Anal Chim Acta 2021 Mar 20;1150:338220. Epub 2021 Jan 20.

Department of Livestock Products Technology, CVASc, DUVASU, Mathura, India. Electronic address:

The present study was made with the objectives of development and standardization of cattle specific paper-based loop-mediated isothermal amplification cum lateral flow assay (LAMP-LFA), as a Point-of-care test (POCT) for identification of tissue of cattle origin. The components of standardized LAMP reaction utilizing cattle specific primer sets were lyophilized over paper buttons, identified best as the carrier of LAMP reagents. Based on probable LAMP amplicon, a pair of probes was designed, tagged and its hybridization with the amplified product of paper LAMP reaction was optimized. The components of lateral flow assay for detection of probe hybridized LAMP products were standardized. Analysis of successful amplification was made by using HNB dye, LAMP-LFA strip, and also by the typical ladder-like pattern on gel electrophoresis. The assay was found highly specific for cattle with an analytical sensitivity of 0.1 pg of absolute DNA. Laboratory validation carried out on samples from different individuals of cattle, coded samples, binary meat admixture, and heat-processed cattle tissues substantiated the accuracy of the assay. Comparison with pre-standardized species-specific PCR assay taken as gold standards revealed 100% conformity. The field utility of the developed assay was further established by its compatibility with the commercial kit eliminating the lengthy DNA extraction step and storage stability of LAMP reagent carrier buttons for 4 months under refrigeration. Thus, the developed assay capable of the result within 3 h in resource-limited settings can be used as POCT for identification of tissue of cattle origin.
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http://dx.doi.org/10.1016/j.aca.2021.338220DOI Listing
March 2021

Improving accuracy of 18F-fluorodeoxyglucose PET computed tomography to diagnose nodal involvement in non-small cell lung cancer: utility of using various predictive models.

Nucl Med Commun 2021 May;42(5):535-544

Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Hospital, Homi Bhabha National Institute.

Purpose: To determine predictive models (PM) that could improve the accuracy for identifying metastatic regional nodes in non-small cell lung cancer based on both PET and CT findings seen on 18F-FDG PET CT.

Methods: Three hundred thirty-nine biopsy-proven NSCLC patients who underwent surgical resection and had a staging 18F-FDG PET CT were enrolled. PET parameters obtained were (1) presence of visual PET positive nodes, (2) SUVmax of nodes (NSUV), (3) ratio of node to aorta SUVmax (N/A ratio) and (4) ratio of node to primary tumour SUVmax (N/T ratio). CT parameters obtained were (1) short-axis diameter and (2) Hounsfield units (HU) of PET-positive nodes. PET and CT parameters were correlated with nodal histopathology to find out the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and overall accuracy. Different PM combining these parameters were devised and the incremental improvement in accuracy was determined.

Results: Visual PET positivity showed sensitivity, specificity, PPV, NPV and accuracy of 72.4, 76.1, 30.1, 95.1 and 75.6, respectively. PM2 which combined visual PET positivity, NSUV and HU appears more clinically relevant and showed sensitivity, specificity, PPV, NPV and accuracy of 53.5, 96.5, 68.9, 93.6 and 91.2, respectively. PM6 which combined visual PET positivity, NSUV, N/A ratio and HU showed the maximum PPV (80.0%), specificity (98.3%) and accuracy of (91.9%).

Conclusion: PM combining parameters like nodal SUVmax, N/A ratio, N/T ratio and HU values have shown to improve the PPV, specificity and overall accuracy of 18FDG PET CT in the preoperative diagnosis of nodal metastases.
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http://dx.doi.org/10.1097/MNM.0000000000001367DOI Listing
May 2021

In-vitro functional efficacy of extracts from Phyllanthus emblica, Eucalyptus globulus, Tinospora cordifolia as pancreatic lipase inhibitor and source of anti-oxidant in goat meat nuggets.

Food Chem 2021 Jun 19;348:129087. Epub 2021 Jan 19.

Division of Livestock Products Technology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, UP 243122, India.

The present study was aimed to evaluate the functional efficacy of plant extracts as a source of pancreatic lipase inhibitor and antioxidant in goat meat nuggets to address the fat paradox issue of red meat. The PPLIA, antioxidant potential, and resistance against fat digestion were in the order ofPhyllanthus emblica > Eucalyptus globulus > Tinospora cordifolia.PPL inhibition activities of water and ethanolic extracts fromPhyllanthus emblicausing DNPB and Triolein as substrate were 63.76, 67.94 and 56.17 and 64.36 percent respectively whereas, TPC, DPPH RSA, FRPA were 40.82 and 59.52 (mgGAE/g), 54.89 and 59.84 (percent), 1.26 and 1.61 (OD) respectively. The average diameter of fat globules in digest was maximum (8.91 µm) withPhyllanthus emblicafruits extracts whereas; TBARs (0.347 mg MDA/Kg) and FFA (4.47 µg/g) values were lowest. This study showed that extracts from plants can act as a promising natural alternative in the development of healthy meat products.
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http://dx.doi.org/10.1016/j.foodchem.2021.129087DOI Listing
June 2021

Metastasis to Appendix Presenting as Acute Appendicitis-A Rare Case Report and Review of Literature.

J Gastrointest Cancer 2021 Jan 23. Epub 2021 Jan 23.

Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India.

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http://dx.doi.org/10.1007/s12029-021-00586-1DOI Listing
January 2021

Targeting AGE-RAGE signaling pathway by Saxagliptin prevents myocardial injury in isoproterenol challenged diabetic rats.

Drug Dev Res 2021 Jan 17. Epub 2021 Jan 17.

Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.

The role of Saxagliptin in diabetes-associated cardiovascular complications is controversial. This study aimed to investigate whether Saxagliptin could prevent Isoproterenol-induced myocardial changes in diabetic rats and to identify the possible mechanism as well. The high-fat diet/low-dose Streptozotocin-induced type 2 diabetic rats were divided into 3 groups: the control group (0.25% CMC for 28 days), the Isoproterenol group (85 mg/kg Isoproterenol for the last 2 days plus 0.25% CMC for 28 days), and the treatment group (10 mg/kg Saxagliptin for 28 days plus 85 mg/kg Isoproterenol for the last 2 days). Hemodynamic measurements were performed, and samples were examined for RAGE and NF-κB expressions, histopathological and ultrastructural changes, AGEs level, myocardial injury markers, oxidative stress, and apoptosis. Saxagliptin significantly recovered cardiac function (p < .001), reverted myocardial injury and oxidative stress levels back to the control value (p < .05 to p < .001). Saxagliptin alleviates Isoproterenol-induced myocardial injury in diabetic rats by suppressing AGE-RAGE pathway.
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http://dx.doi.org/10.1002/ddr.21779DOI Listing
January 2021

Methylarginine metabolites are associated with attenuated muscle protein synthesis in cancer-associated muscle wasting.

J Biol Chem 2020 12;295(51):17441-17459

Endocrine Research Unit, Division of Endocrinology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA. Electronic address:

Cancer cachexia is characterized by reductions in peripheral lean muscle mass. Prior studies have primarily focused on increased protein breakdown as the driver of cancer-associated muscle wasting. Therapeutic interventions targeting catabolic pathways have, however, largely failed to preserve muscle mass in cachexia, suggesting that other mechanisms might be involved. In pursuit of novel pathways, we used untargeted metabolomics to search for metabolite signatures that may be linked with muscle atrophy. We injected 7-week-old C57/BL6 mice with LLC1 tumor cells or vehicle. After 21 days, tumor-bearing mice exhibited reduced body and muscle mass and impaired grip strength compared with controls, which was accompanied by lower synthesis rates of mixed muscle protein and the myofibrillar and sarcoplasmic muscle fractions. Reductions in protein synthesis were accompanied by mitochondrial enlargement and reduced coupling efficiency in tumor-bearing mice. To generate mechanistic insights into impaired protein synthesis, we performed untargeted metabolomic analyses of plasma and muscle and found increased concentrations of two methylarginines, asymmetric dimethylarginine (ADMA) and N-monomethyl-l-arginine, in tumor-bearing mice compared with control mice. Compared with healthy controls, human cancer patients were also found to have higher levels of ADMA in the skeletal muscle. Treatment of C2C12 myotubes with ADMA impaired protein synthesis and reduced mitochondrial protein quality. These results suggest that increased levels of ADMA and mitochondrial changes may contribute to impaired muscle protein synthesis in cancer cachexia and could point to novel therapeutic targets by which to mitigate cancer cachexia.
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http://dx.doi.org/10.1074/jbc.RA120.014884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762938PMC
December 2020

FISH patterns of ROS1, MET, and ALK with a correlation of ALK immunohistochemistry in lung cancer: a case for introducing ALK immunohistochemistry 'Equivocal' interpretation category in the Ventana anti-ALK (D5F3) CDx assay - A tertiary cancer center experience.

Indian J Cancer 2020 Nov 24. Epub 2020 Nov 24.

Division of Molecular Pathology, Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, Maharashtra, India.

Background: Mutations in ROS1, ALK, and MET genes are targetable alterations in non-small cell lung cancer (NSCLC). They can be evaluated by different techniques, most commonly fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).

Methods: We explored the prevalence of ROS1, ALK, MET mutations, discuss clinicopathological associations and FISH signal patterns on 413 consecutive cases of EGFR negative lung carcinoma from March 2016 to April 2017 using FISH for ALK, ROS1, and MET along with ALK (D5F3) IHC.

Results: ROS1 gene rearrangement, ALK positivity (IHC and/or FISH), and MET amplification were seen in 18/358 (5%) cases, 76/392 cases (19.4%), and 10/370 (2.7%) cases, respectively. ALK FISH and ALK IHC were positive in 51/300 (17%) and 58/330 cases (17.57%), respectively, while 8/330 (2.4%) cases were ALK IHC "equivocal" of which 3/8 (37.5%) were ALK FISH positive. Of ALK FISH and IHC co-tested cases, 43/238 (18.07%) cases were positive by both techniques, while 15/43 (34.88%) of ALK positive cases showed discordant ALK FISH and IHC results. All ROS1 rearranged and MET amplified cases were adenocarcinoma. Signet ring cell histology was associated with 78.57% likelihood of being either ALK or ROS1 positive. Genomic heterogeneity was seen in 30% of MET amplified cases.

Conclusions: ALK/ROS1/MET gene alterations were found in 25.18% of NSCLC cases. An ALK IHC "equivocal" interpretation category should be incorporated into practice. Atypical patterns of ROS1 and genomic heterogeneity need to be evaluated further for any clinical relevance.
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http://dx.doi.org/10.4103/ijc.IJC_470_19DOI Listing
November 2020

Telomere length in peripheral blood lymphocytes related to genetic variation in telomerase, prognosis and clinicopathological features in breast cancer patients.

Mutagenesis 2020 12;35(6):491-497

Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska, Prague, Czech Republic.

Disruption of telomere length (TL) homeostasis in peripheral blood lymphocytes has been previously assessed as a potential biomarker of breast cancer (BC) risk. The present study addressed the relationship between lymphocyte TL (LTL), prognosis and clinicopathological features in the BC patients since these associations are insufficiently explored at present. LTL was measured in 611 BC patients and 154 healthy controls using the monochrome multiplex quantitative Polymerase Chain Reaction assay. In addition, we genotyped nine TL-associated single-nucleotide polymorphisms that had been identified through genome-wide association studies. Our results showed that the patients had significantly (P = 0.001, Mann-Whitney U-test) longer LTL [median (interquartile range); 1.48 (1.22-1.78)] than the healthy controls [1.27 (0.97-1.82)]. Patients homozygous (CC) for the common allele of hTERT rs2736108 or the variant allele (CC) of hTERC rs16847897 had longer LTL. The latter association remained statistically significant in the recessive genetic model after the Bonferroni correction (P = 0.004, Wilcoxon two-sample test). We observed no association between LTL and overall survival or relapse-free survival of the patients. LTL did not correlate with cancer staging based on Union for International Cancer Control (UICC), The tumor node metastasis (TNM) staging system classification, tumour grade or molecular BC subtypes. Overall, we observed an association between long LTL and BC disease and an association of the hTERC rs16847897 CC genotype with increased LTL. However, no association between LTL, clinicopathological features and survival of the patients was found.
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http://dx.doi.org/10.1093/mutage/geaa030DOI Listing
December 2020

Burosumab for the Treatment of Tumor-Induced Osteomalacia.

J Bone Miner Res 2021 Apr 12;36(4):627-635. Epub 2021 Jan 12.

Yale University School of Medicine, New Haven, CT, USA.

Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..
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http://dx.doi.org/10.1002/jbmr.4233DOI Listing
April 2021

Multidisciplinary brain metastasis clinic: is it effective and worthwhile?

Ecancermedicalscience 2020 5;14:1136. Epub 2020 Nov 5.

Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai 400012, India.

Background: Management of brain metastasis is a complex multidisciplinary venture. Hence, we started a multidisciplinary brain metastasis clinic for the opinion on difficult brain metastasis cases. This is the review of the impact of this clinic on the treatment decisions.

Methods: The brain metastasis clinic (BMC) was started in April 2018 and meets once a week. Data of patients discussed between 27th April 2018 and 28th June 2019 were included for this analysis. Treatment decision made by clinicians (before sending the patient to the BMC) was compared with the decisions made in BMC. The decisions were broken on a predefined proforma as the intent of treatment (curative or palliative), modalities planned (surgery, radiation, chemotherapy) and type of therapy planned (details of each therapy) in each modality were collected both pre and post BMCs. In addition, compliance of the respective physicians to BMC decision was also calculated. SPSS version 20 was used for analysis. Descriptive statistics were performed.

Results: Ninety-nine patients were discussed in this time period. The median age was 51 (range 17-68) years. The gender distribution was 70 males (70.7%) and 29 females (29.3%). Lung was the predominant site of malignancy (79, 79.8%). Thirty-one patients (31.3%) had EGFR TKI domain activating mutation, while 17 (17.2%) had anaplastic lymphoma kinase (ALK) rearrangement. The treatment plan was changed in 46 patients (46.5%). The intent of treatment was changed from palliative to curative in 5%. Change in the treatment plan with respect to surgery in 9.1%, radiation in 37.4%, chemotherapy in15.2%, targeted therapy in 22.9% and intrathecal in 6.1% patients, respectively. The compliance with the BMC decision in patients in whom it was changed was 84.8% (39, = 46).

Conclusion: Multidisciplinary management of difficult brain metastasis cases in specialised clinics has a significant impact on treatment decisions.
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http://dx.doi.org/10.3332/ecancer.2020.1136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685765PMC
November 2020

Transdermal delivery of duloxetine-sulfobutylether-β-cyclodextrin complex for effective management of depression.

Int J Pharm 2021 Feb 1;594:120129. Epub 2020 Dec 1.

University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. Electronic address:

Aim of the study was to reduce the dose and dosing frequency of duloxetine HCl (DXT) by complexation with sulfobutylether-β-cyclodextrin (SBEβCD), an anionic cyclodextrin through permeation enhancement for more effective management of depression. Spray dried inclusion complexes of drug with SBEβCD were prepared and incorporated in medicated patches followed by their ex vivo permeation and skin retention studies. Then, in vivo efficacy and absorption of the drug from developed optimised patch was determined in Wistar rats by administering drug through oral route (free drug) and transdermal route (complexed drug). Swimming, immobility and climbing parameters in FST while ambulation and rearings parameters in LAT test were assessed. Addition of permeation enhancer (PE) increased drug permeation and the enhancement ratio (ER) was 3.05 and 1.67 for the patch having complexed DXT and spray dried sample of DXT in comparison to free DXT respectively. The amount of drug retained in skin and in optimized medicated patch after 72 h was relatively lower compared to the formulation having free DXT. Enhanced antidepressive activity was observed for complexed drug compared to free drug. We believe that spray dried complexation based transdermal patch can serve as potential innovative drug delivery system for DXT.
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http://dx.doi.org/10.1016/j.ijpharm.2020.120129DOI Listing
February 2021

Incremental value of endoscopic brush cytology in response assessment after chemo-irradiation for Esophageal cancer.

J Gastrointest Cancer 2020 Nov 26. Epub 2020 Nov 26.

Department of Nuclear Medicine and Molecular Imaging, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India.

Background: Response assessment after chemo-radiotherapy (CTRT) in locally advanced esophageal cancer is usually performed using a PET-CT scan, an upper GI endoscopy (UGIE) and histological correlation with biopsy or cytology. We aim to study the incremental value of brush cytology in addition to PET-CT for response assessment.

Materials And Methods: In this retrospective analysis, 40 patients with Stage II- IV carcinoma esophagus treated with radical intent between June 2015 and August 2019 were included. Patients were treated with either upfront concurrent CTRT or neo-adjuvant chemotherapy followed by CTRT. All patients underwent PET-CT and UGIE for initial staging and response assessment on follow-up. Patients with esophageal stricture (disease related or treatment induced) had brush cytology done during UGIE. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of brush cytology were calculated considering serial clinical follow-up as gold standard.

Results: Twenty-three male (57.5%) and 17 (42.5%) female patients with median age of 57 years (range: 27 - 79 years) were analyzed. Concurrent CTRT was delivered in 52.5%; 75% patients were treated with intensity-modulated radiotherapy (IMRT); median RT dose was 63 Gy (range- 41.4 to 64 Gy). At a median follow-up of 16 months (range 6- 54 months), 20 patients (55.5%) were clinically controlled, 9 (25%) had local recurrence, 5 (13.8%) had loco-regional recurrence and 2 had distant metastasis. Considering clinical follow-up as the gold standard, sensitivity, PPV and NPV of PET-CT combined with brush cytology improved compared to PET-CT alone and was found to be 75%, 90%, 85.7% and 81.8% respectively.

Conclusion: We found that brush cytology on endoscopy is a simple tool with high specificity which adds value to the findings of response assessment PET-CT scan and thereby can increase the confidence of the treating oncologist in making clinical decisions.
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http://dx.doi.org/10.1007/s12029-020-00555-0DOI Listing
November 2020

Real-world experience of eltrombopag in immune thrombocytopenia.

Am J Blood Res 2020 15;10(5):240-251. Epub 2020 Oct 15.

Dept of Clinical Hematology and Stem Cell Transplant, Army Hospital (Research & Referral) Delhi India.

Immune thrombocytopenia (ITP) is characterized by decreased platelet count in the peripheral circulation. The first-line therapy is corticosteroids with 53-80% overall response rate. Eltrombopag has been used as second-line therapy in ITP for over a decade now. The long-term efficacy and safety profile have been widely reported in the western world. However, the data from the resource-constraint settings of the developing world is scarce. We aim to present the real-life experience of efficacy and safety of eltrombopag from the resource-constraint settings. This was a retrospective, single-center study conducted at a tertiary care hospital in Northern India from 2012-2019. On audit of medical records, patients of ITP receiving eltrombopag were screened for inclusion. Patients whose treatment outcomes were not available were excluded. Finally, 53 patients were analyzed using statistical packages of Python v3.7. The patients' median age was 35 years (range 17-78), with 23 (43.4%) being female. The median time to response was 35 days (range 28-50 days) and the cumulative overall response rates (ORR) at day 30, day 60 and day 90 were 41.5%, 69.8%, and 81.1% respectively. A total of 10 patients on eltrombopag relapsed during follow up. The cumulative rate of relapse at one year, three years, and five years were 6.6%, 25.3%, and 47.7%, respectively. There was no significant difference in outcome (response rate or relapse) in any subgroups depending on age, sex, duration of disease, number of prior lines of treatment, splenectomy, or baseline platelet count. Six patients stopped eltrombopag after having a median sustained response for 796 days (range 658-1185), and after a median follow up of 624 days (range 92-1339), they continued to be in remission. Seventeen patients (17/53, 32%) reported one or more adverse events while on eltrombopag therapy. A total of 49 adverse events (n=4, grade ≥3 CTCAEv4) were noted. Anemia was the most frequent adverse event followed by hepatobiliary dysfunction as reflected by deranged AST/ALT or raised bilirubin. The use of eltrombopag among adult ITP patients in resource-constraint settings was well-tolerated and yielded excellent overall response. The benefit was found to be sustained on long-term follow up. However, events like anemia, hepatobiliary, and thrombotic complications merit closer follow up.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675127PMC
October 2020

Cleaning the molecular machinery of cells via proteostasis, proteolysis and endocytosis selectively, effectively, and precisely: intracellular self-defense and cellular perturbations.

Mol Omics 2021 02 2;17(1):11-28. Epub 2020 Nov 2.

NIET, National Institute of Medical Science, India.

Network coordinates of cellular processes (proteostasis, proteolysis, and endocytosis), and molecular chaperones are the key complements in the cell machinery and processes. Specifically, cellular pathways are responsible for the conformational maintenance, cellular concentration, interactions, protein synthesis, disposal of misfolded proteins, localization, folding, and degradation. The failure of cellular processes and pathways disturbs structural proteins and the nucleation of amyloids. These mishaps further initiate amyloid polymorphism, transmissibility, co-aggregation of pathogenic proteins in tissues and cells, prion strains, and mechanisms and pathways for toxicity. Consequently, these conditions favor and lead to the formation of elongated amyloid fibrils consisting of many-stranded β-sheets (N,N-terminus and C,C-terminus), and abnormal fibrous, extracellular, proteinaceous deposits. Finally, these β-sheets deposit, and cells fail to degrade them effectively. The essential torsion angles (φ, ψ, and ω) define the conformation of proteins and their architecture. Cells initiate several transformations and pathways during the regulation of protein homeostasis based on the requirements for the functioning of the cell, which are governed by ATP-dependent proteases. In this process, the kinetics of the molding/folding phenomenon is disturbed, and subsequently, it is dominated by cross-domain misfolding intermediates; however, simultaneously, it is opposed by small stretching forces, which naturally exist in the cell. The ubiquitin/proteasome system deals with damaged proteins, which are not refolded by the chaperone-type machinery. Ubiquitin-protein ligases (E3-Ub) participate in all the cellular activity initiated and governed by molecular chaperones to stabilize the cellular proteome and participate in the degradation phenomenon implemented for damaged proteins. Optical tweezers, a single-resolution based technique, disclose the folding pathway of linear chain proteins, which is how they convert themselves into a three-dimensional architecture. Further, DNA-protein conjugation analysis is performed to obtain folding energies as single-molecule kinetic and thermodynamic data.
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http://dx.doi.org/10.1039/d0mo00085jDOI Listing
February 2021

Association of HERV-K and LINE-1 hypomethylation with reduced disease-free survival in melanoma patients.

Epigenomics 2020 10 30;12(19):1689-1706. Epub 2020 Oct 30.

Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany.

To evaluate CpG methylation of long interspersed nuclear elements 1 (LINE-1) and human endogenous retrovirus K (HERV-K) retroelements as potential prognostic biomarkers in cutaneous melanoma. Methylation of HERV-K and LINE-1 retroelements was assessed in resected melanoma tissues from 82 patients ranging in age from 14 to 88 years. In addition, nevi from eight patients were included for comparison with nonmalignant melanocytic lesions. Methylation levels were lower in melanomas than in nevi. HERV-K and LINE-1 methylation were decreased in melanoma patients with clinical parameters associated with adverse prognosis, while they were independent of age and gender. Hypomethylation of HERV-K (but not LINE-1) was an independent predictor of reduced disease-free survival. : HERV-K hypomethylation can be a potential independent biomarker of melanoma recurrence.
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http://dx.doi.org/10.2217/epi-2020-0127DOI Listing
October 2020

Relationship Between Statin-associated Muscle Symptoms, Serum Vitamin D and Low-density Lipoprotein Cholesterol - A Cross-sectional Study.

Eur Endocrinol 2020 Oct 6;16(2):137-142. Epub 2020 Oct 6.

Department of Pharmacology, Government Medical College and Hospital, Chandigarh, India.

Introduction: Statin-associated muscle symptoms (SAMS) can lead to medication non-adherence among statin users. There is a complex relationship between SAMS, vitamin D and low-density lipoprotein cholesterol (LDL-C). The objective of this study was to evaluate the relationship between vitamin D, LDL-C and occurrence of SAMS.

Methods: This was a cross-sectional study in patients using statins. Thorough patient histories were taken, a clinical examination was conducted and SAMS were recorded. Levels of vitamin D, creatine phosphokinase (CPK) and LDL-C were measured. These parameters were compared amongst statin users with SAMS and those without SAMS. Levels of vitamin D and LDL-C were converted into percentiles and their relationship with SAMS was evaluated in terms of odds ratio. Receiver operating characteristics (ROC) were drawn, taking vitamin D and LDL-C as predictors of SAMS.

Results: A total of 121 statin users were enrolled in this study. Thirty-eight patients (31.4%) presented with SAMS. Significantly lower levels of serum vitamin D were observed amongst statin users with SAMS compared with those without SAMS (19.8 ± 9.67 ng/mL versus 25.0 ± 14.6 ng/mL; 95% confidence interval -10.4 to -0.07; p=0.04). With vitamin D levels less than or equal to 5th, 10th and 25th percentile, the chances of occurrence of SAMS were significantly higher, but not at the 50th percentile (corresponding vitamin D level of 20.21 ng/mL). LDL-C did not show any conclusive relationship with SAMS. ROC curves showed a significant discrimination for vitamin D levels, but not for LDL-C.

Conclusion: Statin users with low levels of vitamin D are at increased risk of developing SAMS. However, LDL-C status of statin users failed to predict any meaningful association with SAMS. Given the small sample size of this study, these results should be regarded as preliminary.
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http://dx.doi.org/10.17925/EE.2020.16.2.137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572163PMC
October 2020

Traditional Indian practices: Time to revisit and re-adopt for a healthier lifestyle.

J Anaesthesiol Clin Pharmacol 2020 Aug 25;36(Suppl 1):S166-S171. Epub 2020 Jul 25.

Department of Cardiology, Hero DMC Heart Institute, Ludhiana, Punjab, India.

The COVID-19 pandemic has affected human life significantly. In spite of significant advancement of medical technology, management is still focused on preventive strategies due to non availability of vaccine or any definitive treatment. The preventive strategies include hand hygiene, social distancing, isolation/quarantine along with the methods for boosting immunity. The ancient literature and several traditional practices of our country guide a hygienic life style and address several preventive aspects of transmission of infection across the society. Furthermore, healthy eating habits and use of various herbs and spices as regular food ingredients has been proven for boosting the immunity. In this review, we have tried to correlate the traditional practices with the available scientific evidences.
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http://dx.doi.org/10.4103/joacp.JOACP_299_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574014PMC
August 2020