Prostate fibroblasts and prostate cancer associated fibroblasts exhibit different metabolic, matrix degradation and PD-L1 expression responses to hypoxia.

Fibroblasts are versatile cells that play a major role in wound healing by synthesizing and remodeling the extracellular matrix (ECM). In cancers, fibroblasts play an expanded role in tumor progression and dissemination, immunosuppression, and metabolic support of cancer cells. In prostate cancer (PCa), fibroblasts have been shown to induce growth and increase metastatic potential. To further understand differences in the functions of human PCa associated fibroblasts (PCAFs) compared to normal prostate fibroblasts (PFs), we investigated the metabolic profile and ECM degradation characteristics of PFs and PCAFs using a magnetic resonance imaging and spectroscopy compatible intact cell perfusion assay. To further understand how PFs and PCAFs respond to hypoxic tumor microenvironments that are often observed in PCa, we characterized the effects of hypoxia on PF and PCAF metabolism, invasion and PD-L1 expression. We found that under normoxia, PCAFs displayed decreased ECM degradation compared to PFs. Under hypoxia, ECM degradation by PFs increased, whereas PCAFs exhibited decreased ECM degradation. Under both normoxia and hypoxia, PCAFs and PFs showed significantly different metabolic profiles. PD-L1 expression was intrinsically higher in PCAFs compared to PFs. Under hypoxia, PD-L1 expression increased in PCAFs but not in PFs. Our data suggest that PCAFs may not directly induce ECM degradation to assist in tumor dissemination, but may instead create an immune suppressive tumor microenvironment that further increases under hypoxic conditions. Our data identify the intrinsic metabolic, ECM degradation and PD-L1 expression differences between PCAFs and PFs under normoxia and hypoxia that may provide novel targets in PCa treatment.

Blood flow restriction therapy with exercise are no better than exercise alone in improving athletic performance, muscle strength, and hypertrophy: a systematic review and meta-analysis.

BACKGROUND: The benefits of Blood Flow Restriction Therapy (BFRT) have gained attention in recent times. OBJECTIVE: This review aimed to evaluate the immediate (up to 24 hours), intermediate (up to 6 weeks), and long term (6-10 weeks) effects of BFRT plus exercises (EX) compared to EX only on athletic performance (sprint and jump performance), muscle strength, and hypertrophy in athletes and physically active population. METHODS: A literature search was conducted to select randomized controlled trials across four electronic databases from inception till April 2021. The search yielded twenty-seven studies in total. RESULTS: Based on eligibility criteria, twenty-one studies were analyzed. No differences were found between both groups for immediate (standardized mean difference [SMD] -0.02, 95% confidence interval [CI] -0.31, 0.27) and long-term effects (SMD -0.30, 95%CI -0.90, 0.30) on sprint performance. For jump performance, no significant effect was observed immediately (SMD -0.02 (95% CI -1.06, 1.02) and long term (SMD -0.40 (95% CI -1.46, 0.67). Similarly, muscle torque at intermediate (SMD 0.90 (95% CI -1.01, 2.81) and long term (SMD -0.54 (95% CI -1.19, 0.12), muscle strength at intermediate (SMD 1.12 (95% CI 0.20, 2.04) , and long term (SMD -0.07 (95% CI -0.56, 0.42) also showed non-significant effects. Muscle hypertrophy at intermediate (SMD 0.16 (95% CI -0.31, 0.63) and long term (SMD -0.20 (95% CI -0.90, 0.50) were not statistically significant. CONCLUSIONS: There was no significant difference observed in BFRT plus EX group compared to the EX-group on athletic performance, muscle strength, and muscle hypertrophy.

Cancer insights from magnetic resonance spectroscopy of cells and excised tumors.

Multinuclear ex vivo magnetic resonance spectroscopy (MRS) of cancer cells, xenografts, human cancer tissue, and biofluids is a rapidly expanding field that is providing unique insights into cancer. Starting from the 1970s, the field has continued to evolve as a stand-alone technology or as a complement to in vivo MRS to characterize the metabolome of cancer cells, cancer-associated stromal cells, immune cells, tumors, biofluids and, more recently, changes in the metabolome of organs induced by cancers. Here, we review some of the insights into cancer obtained with ex vivo MRS and provide a perspective of future directions. Ex vivo MRS of cells and tumors provides opportunities to understand the role of metabolism in cancer immune surveillance and immunotherapy. With advances in computational capabilities, the integration of artificial intelligence to identify differences in multinuclear spectral patterns, especially in easily accessible biofluids, is providing exciting advances in detection and monitoring response to treatment. Metabolotheranostics to target cancers and to normalize metabolic changes in organs induced by cancers to prevent cancer-induced morbidity are other areas of future development.

Effect of low-level laser therapy plus exercise therapy on pain, range of motion, muscle strength, and function in knee osteoarthritis - a systematic review and meta-analysis.

BACKGROUND: Knee osteoarthritis (KOA) is commonly associated with multiple musculoskeletal impairments. OBJECTIVE: The purpose of this review was (1) to investigate the effectiveness of LLLT plus ET on pain, ROM, muscle strength, and function in KOA immediately after therapy and (2) whether the effectiveness of LLLT plus ET could be sustained at follow-up (4 - 32 weeks). METHODS: Six databases were systematically searched upto December 2021 to find relevant articles. Included studies were RCTs written in English, which compared LLLT plus ET with placebo LLLT plus ET in KOA. Three independent reviewers extracted data and assessed the quality of included studies. Standard mean difference (SMD) was used in meta-analysis using random effect model. RESULT: Of the 6307 articles, 14 RCTs (820 patients) met the inclusion criteria. The results demonstrated that there was a significant difference in pain immediately after therapy (SMD: -0.58, p = 0.001) and at follow-up (SMD: -1.35, p = 0.05) in LLLT plus ET group. There were no significant differences in knee ROM, muscle strength, and knee function outcomes immediately and at follow-up. CONCLUSION: Our findings indicate that LLLT plus ET could be considered to alleviate pain in the KOA. LLLT reduces pain at 4-8J with a wavelength of 640-905nm per point applied for 10-16 sessions at a frequency of 2 sessions/week. An exercise therapy program at prescribed dosage involving major muscle groups might help. However, LLLT plus ET is no more effective than placebo LLLT plus ET in improving ROM, muscle strength, and function in KOA.

Characterization of lipomatous tumors with high-resolution 1H MRS at 17.6T: Do benign lipomas, atypical lipomatous tumors and liposarcomas have a distinct metabolic signature?

Background: Distinguishing between some benign lipomas (BLs), atypical lipomatous tumors (ALTs), and dedifferentiated liposarcomas (DDLs) can be challenging due to overlapping magnetic resonance imaging characteristics, and poorly understood molecular mechanisms underlying the malignant transformation of liposarcomas. Purpose: To identify metabolic biomarkers of the lipomatous tumor spectrum by examining human tissue specimens using high-resolution 1H magnetic resonance spectroscopy (MRS). Materials and methods: In this prospective study, human tissue specimens were obtained from participants who underwent surgical resection for radiologically-indeterminate lipomatous tumors between November 2016 and May 2019. Tissue specimens were obtained from normal subcutaneous fat (n=9), BLs (n=10), ALTs (n=7) and DDLs (n=8). Extracts from specimens were examined with high-resolution MRS at 17.6T. Computational modeling of pattern recognition-based cluster analysis was utilized to identify significant differences in metabolic signatures between the lipomatous tumor types. Results: Significant differences between BLs and ALTs were observed for multiple metabolites, including leucine, valine, branched chain amino acids, alanine, acetate, glutamine, and formate. DDLs were distinguished from ALTs by increased glucose and lactate, and increased phosphatidylcholine. Multivariate principal component analysis showed clear clustering identifying distinct metabolic signatures of the tissue types. Conclusion: Metabolic signatures identified in 1H MR spectra of lipomatous tumors provide new insights into malignant progression and metabolic targeting. The metabolic patterns identified provide the foundation of developing noninvasive MRS or PET imaging biomarkers to distinguish between BLs, ALTs, and DDLs.

Outcome of Atypical & Complex Clubfoot Managed by Modified Ponseti Method-A Prospective Study.

Atypical or complex clubfoot constitutes a small number of cases. Due to the difference in complexity of anatomy, standard deformity correction by Ponseti is not effective. Hence a modified Ponseti method was advised which focuses on deformity differences for treatment. We conducted a prospective study to analyze the outcome in atypical or complex clubfoot treated with the modified Ponseti method. All the children of age less than 1 year were included in the study with atypical or complex clubfoot. Every case was treated according to the modified Ponseti method and tenotomy. Pirani scores were measured at pretreatment, each visit, before application of a brace, and at the latest follow-up. Statistical analysis of all continuous and categorical variables was done. A total of 30 patients (47 feet) were included in the study. Mean Pirani score improved from 5.69 at presentation to 0.45 at time of brace application and latest follow-up 0.34 (p < .001). Six patients (9 feet) had a relapse which was managed with recasting. The mean Pirani score of relapse was 0.72, which after correction reduced to 0.11 (p = .008). Six patients had cast-related complications which were managed with conservative treatment. With an increase in popularity of the Ponseti method, a greater number of complex clubfoot cases are seen due to inadequate reduction or slippage of cast or improper cast application techniques. All these need to be identified at an early age. This helps in proper treatment and improves the quality of life as well as foot appearance.

Dose-response and temporal ergogenic effects of ginseng supplementation in athletes and active participants: A systematic review and meta-analysis.

This review sought to assess the dose-response, i.e., low (<300 mg/day) and high (>300 mg/day), and temporal effects of ginseng, i.e., immediate, short-term (up to 4 weeks) and long-term (>4 weeks) in comparison to placebo on physical performance [visual analogue scale (VAS) level, vertical jump(VJ), rating of perceived exertion (RPE), peak power output (PPO)] and physiological measures [VO2 max, creatine kinase(CK), heart rate(HR)], in athletes and active participants. Search in four databases with English language constraints yielded 492 studies. Fourteen studies were shortlisted through PEDro scale by methodological quality evaluation. Ginseng exhibited significant short-term effect at high dosage for VJ improvement (SMD: -8.17, 95% CI: -16.28 to -0.06, p= 0.05). Ginseng had no effect on VAS (SMD: -0.65, 95% CI: -1.35 to 0.06, p= 0.07), RPE (SMD: -1.11, 95% CI: -2.57 to 0.35, p= 0.14), PPO (SMD: -0.70, 95% CI: -1.78 to 0.38, p= 0.20), HR (SMD: -0.54, 95% CI: -2.05 to 0.96, p= 0.48), CK (SMD: 0.33, 95% CI: -0.18 to 0.84, p= 0.21) and VO2 max (SMD: 0.08, 95% CI: -0.69 to 0.85, p= 0.08).The ginseng supplementation was found to have significant short-term effect at high dose only for VJ in athletic and active participants. Methodologically strong research is warranted to further consolidate these findings.

Brain metabolites in cholinergic and glutamatergic pathways are altered by pancreatic cancer cachexia.

BACKGROUND: Cachexia is a major cause of morbidity in pancreatic ductal adenocarcinoma (PDAC) patients. Our purpose was to understand the impact of PDAC-induced cachexia on brain metabolism in PDAC xenograft studies, to gain new insights into the causes of cachexia-induced morbidity. Changes in mouse and human plasma metabolites were characterized to identify underlying causes of brain metabolic changes. METHODS: We quantified metabolites, detected with high-resolution 1 H magnetic resonance spectroscopy, in the brain and plasma of normal mice (n = 10) and mice bearing cachexia (n = 10) or non-cachexia (n = 9) inducing PDAC xenografts as well as in human plasma obtained from normal individuals (n = 24) and from individuals with benign pancreatic disease (n = 20) and PDAC (n = 20). Statistical significance was defined as a P value ≤0.05. RESULTS: The brain metabolic signature of cachexia-inducing PDAC was characterized by a significant depletion of choline of -27% and -21% as well as increases of glutamine of 13% and 9% and formate of 21% and 14%, relative to normal controls and non-cachectic tumour-bearing mice, respectively. Good to moderate correlations with percent weight change were found for choline (r = 0.70), glutamine (r = -0.58), and formate (r = -0.43). Significant choline depletion of -38% and -30%, relative to normal controls and non-cachectic tumour-bearing mice, respectively, detected in the plasma of cachectic mice likely contributed to decreased brain choline in cachectic mice. Similarly, relative to normal controls and patients with benign disease, choline levels in human plasma samples of PDAC patients were significantly lower by -12% and -20% respectively. A comparison of plasma metabolites from PDAC patients with and without weight loss identified significant changes in glutamine metabolism. CONCLUSIONS: Disturbances in metabolites of the choline/cholinergic and glutamine/glutamate/glutamatergic neurotransmitter pathways may contribute to morbidity. Metabolic normalization may provide strategies to reduce morbidity. The human plasma metabolite changes observed may lead to the development of companion diagnostic markers to detect PDAC and PDAC-induced cachexia.

Identification of potential urine biomarkers in idiopathic parkinson's disease using NMR.

INTRODUCTION: Parkinson's disease (PD) is the most common neurodegenerative disease caused by the loss of dopamine chemicals resulting in urinary incontinence, gastrointestinal dysfunction, gait impairment and mitochondrial dysfunction. Study investigated urinary metabolic profiles of patients with idiopathic PD as compared to healthy controls (HC) to identify the potential biomarkers. METHODS: Urine samples were collected from 100 PD subjects and 50 HC using standard protocol. Metabolomic analyses were performed using high resolution nuclear magnetic resonance (NMR) spectroscopy. The integral values of 17 significant metabolites were estimated and concentration values were calculated, which were subjected to univariate and multivariate statistical analysis. RESULTS: We found significantly increased levels of ornithine, phenylalanine, isoleucine, ß-hydroxybutyrate, tyrosine and succinate in the urine of patients with PD in comparison with HC. These metabolites exhibited area under the curve greater than 0.60 on ROC curve analysis. We also observed a significant association between succinate concentration and UPDRS motor scores of PD. DISCUSSION: Metabolic pathway alterations were observed in aromatic amino acid metabolism, ketone bodies synthesis, branched chain amino acid metabolism and ornithine metabolism. Comprehensive metabolomic profiling revealed variations in urinary signatures associated with severity of idiopathic PD. This profiling relies on non-invasive sampling and is complementary to existing clinical modalities.

Red herrings in crossmatching kidneys for transplant.

Crossmatching of prospective renal transplant donors against recipients is a mandatory component of the transplant workup, being performed for over 40 years now. Allografting patients with human leukocyte antigens which are recognized by preformed antibodies constitutes the main cause of hyperacute or acute rejections. The existence of these donor-specific anti-human leukocyte antigen antibodies (DSAs) is regarded as a contraindication for graft trans-plantation, both cadaveric and live kidney. We present two unusual cases in which both complement-dependent cytotoxicity crossmatch and DSA by Luminex were falsely positive due to autoimmune and infectious causes, but single-antigen bead assay showed these antibodies to be against nondonor antigens. After treating their basic disease, thought to be responsible for false-positive DSA, these patients became DSA negative and underwent transplantation with an uneventful posttransplant period. Our aim through these examples is to highlight the problem of false-positive crossmatch in potential renal allograft transplant recipients. Further, we propose antigenic determination of donor-specific antibodies in such patients where we suspect the immune system to be chronically activated to pick up false-positive cases and therefore increase the donor pool without compromising the transplant outcome.

Discovery of Arginine Ethyl Ester as Polyglutamine Aggregation Inhibitor: Conformational Transitioning of Huntingtin N-Terminus Augments Aggregation Suppression.

Huntington's disease (HD) is a genetic disorder caused by a CAG expansion mutation in the huntingtin gene leading to polyglutamine (polyQ) expansion in the N-terminal part of huntingtin (Httex1). Expanded polyQ, through a complex aggregation pathway, forms aggregates in neurons and presents a potential therapeutic target. Here we show Httex1 aggregation suppression by arginine and arginine ethyl ester (AEE) in vitro, as well as in yeast and mammalian cell models of HD, bearing expanded polyQ. These molecules also rescue locomotion dysfunction in HD Drosophila model. Both molecules alter the hydrogen bonding network of polyQ to enhance its aqueous solubility and delay aggregation. AEE shows direct binding with the NT17 part of Httex1 to induce structural changes to impart an enhanced inhibitory effect. This study provides a platform for the development of better arginine based therapeutic molecules against polyQ-rich Httex1 aggregation.

Vitamin D, 1,25-Dihydroxyvitamin D, FGF23, and Graft Function after Renal Transplantation.

Vitamin-D has immuno-modulatory properties besides its role in mineral and bone disorder (MBD) and could have a role in allograft outcome. Fifty-two chronic kidney disease patients on dialysis going for transplantation were prospectively studied before and after renal transplantation. FGF23, 25(OH) vitamin D, 1,25-Dihydroxyvitamin D, PTH, serum Ca, serum PO4, and e-GFR status were evaluated. Vitamin D deficiency was seen in 25.0% of recipients before transplant (26.09 ± 12.19 ng/mL) and in 48.1% at 6 months post-transplant (23.36 ± 15.11 ng/mL). 1,25-(OH)2D levels before transplant were 102.37 ± 108.44 pmol/L, which were less than control (143.30 ± 108.0 pmol/L) and decreased further to 46.20 ± 42.11 pmol/mL at 3 months and started increasing to 78.37 ± 60.12 pmol/mL at 6 months post-transplantation without vitamin D supplementation. The prevalence of hypophosphatemia after transplantation was 32.0%, hyperkalemia was 12.0%, elevated intact PTH levels at 3 and 6 months after transplant were seen in 66.7% and 30.8% patients, respectively. FGF-23 levels were high in 72.5% of patients before transplant (495.94 ± 690.68 pg/mL) and decreased to normal levels at 3 months post-transplant (31.63 ± 14.17 pg/m) (control 32.07 ± 9.78 pg/mL). Serum intact PTH levels were 379.54 ± 281.27 pg/mL before transplant and came down to 103.96 ± 68.34 at 3 months and 69.87 ± 116.03 at 6 months post-transplantation. There was trend of higher e-GFR at 1 year post-transplant in patients without vitamin D deficiency (levels ≥30 ng/mL). The dysregulated mineral metabolism continues in post-transplant despite improvement in renal function and normalization of FGF-23.

Ameliorative effect of fermentable fibres on adiposity and insulin resistance in C57BL/6 mice fed a high-fat and sucrose diet.

The consumption of diets rich in fat and refined sugars is recognized to be one of the causes of lifestyle disorders, and dietary fibres are being advocated to ameliorate the complications associated with these disorders. In the present study, the effects of two soluble fermentable fibres, viz., gum acacia and inulin on the progression of adiposity, insulin resistance, and the expression of genes related to metabolism were examined in C57BL/6 mice fed a high-fat and sucrose diet for 18 weeks. The feeding of either type of fibre resulted in decrease in body weight, epididymal fat mass, adipocyte size, hyperlipidaemia, hyperglycaemia and hyperinsulinemia. In the fibre-fed groups, the expressions of adiponectin and glucose transporter 4 in the epididymal fat increased significantly, while the expressions of leptin, interleukin 6 and tumor necrosis factor alpha decreased significantly. Moreover, the expressions of genes related to beta-oxidation, viz., carnitine palmitoyltransferase 1, peroxisome proliferator-activated receptor gamma co-activator 1ß, and peroxisome proliferator-activated receptor alpha in the liver tissue of the fibre-fed groups enhanced significantly. Furthermore, due to the feeding of either type of fibre, the expressions of zonula occludens 1 and fasting-induced adipose factor in the distal ileum and proglucagon in the colon increased significantly. From the results of the present study, it can be concluded that the beneficial effects of the fibres are mediated due to enhanced energy expenditure, improved intestinal integrity, and reduced inflammation.

Ethambutol-induced optic neuropathy in renal disorder: a clinico-electrophysiological study.

OBJECTIVE: To report the spectrum of ethambutol induced optic neuropathy in a group of renal patients with tuberculosis and the role of visual evoked response (VER) in evaluating this disorder. METHODS: Twenty-three renal patients who were started on ethambutol as a part of anti-tubercular treatment for tuberculosis in India, were divided into 4 groups based on glomerular filtration rate (GFR): group 1-chronic kidney disease (CKD) with GFR < 10 mL/min; group 2-CKD with GFR 10-30 mL/min; group 3-GFR > 30 ≤ 60 mL/min; and group 4-GFR > 60 < 90 mL/min. Detailed clinical and electrophysiological (VER) examinations were carried out in all patients before starting the treatment with ethambutol and at a 3-month interval. Twenty healthy subjects formed the control group. RESULTS: Ethambutol optic neuropathy developed in 6 (26%) patients with higher incidence (40%) in end-stage renal disease (group 1: CKD on dialysis). Vision was recovered in 4 cases on stoppage of ethambutol, whereas 2 patients (group 1: CKD on dialysis) developed bilateral severe irreversible visual loss and also had associated hepatic dysfunction. Three patients of ethambutol optic neuropathy showed increased latency in VER recording prior to visual loss and 1 patient showed demyelinating lesions in both optic nerves and optic radiation. CONCLUSIONS: Ethambutol should be avoided in renal disorder patients in view of the high incidence of toxic optic neuropathy. Follow-up VER can detect sub-clinical ethambutol toxicity and would be useful for early diagnosis of optic neuropathy.

Acute cortical necrosis in pregnancy still an important cause for end-stage renal disease in developing countries.

Renal cortical necrosis (RCN) is a serious complication of acute kidney injury (AKI) and pregnancy is a clinical state closely associated with it with poor renal outcomes. The incidence is much higher in obstetrical AKI compared to other causes of RCN. Despite better medical care facilities available, this continues to be an important cause of morbidity and mortality in developing countries. This is a retrospective analysis among all pregnant females presenting with AKI from January 1999 to December 2014 at a tertiary care center in the northern part of India. We looked for the incidence of obstetrical-related RCN in our renal biopsies performed in the last 15 years and to evaluate precipitating factors responsible for RCN. RCN constituted 8.3% of pregnancy-related AKI cases in our institution. The overall incidence has been declining which was 9.09% from 1999 to 2008 to 7.8% from 2009 to 2014. The patient's median age was 29.3 ± 5.2 years. The average time to presentation from the day of delivery was 8.7 ±2.1 days. The mortality was observed in 11.7% of them with sepsis and multiorgan dysfunction present in all of them. The most common etiology for RCN was found to be septic abortion and puerperal sepsis accounting for - 15.3% each. Postpartum hemorrhage was a cause in 9.09% of patients. The most important cause of RCN was postpartum thrombotic microangiopathy which was observed in 48.7% of patients. Kidney biopsy was helpful in diagnosis in 31 patients while computed tomography scan abdomen alone helped in diagnosis in five patients. Patchy cortical necrosis in histology was seen in 35.4% of patients and morbidity in terms of prolonged hospitalization was seen in 22.7% while dialysis dependency in 61.5% of the study population. In conclusion, strategies need to be implemented in reducing the preventable causes for RCN which is not only catastrophic in terms of renal outcomes but also for social and psychological perspectives as well.

Isolated bilateral renal mucormycosis in apparently immunocompetent patients-a case series from India and review of the literature.

BACKGROUND: Isolated renal mucormycosis (IRM) is a potentially fatal disease affecting immunocompromised hosts. IRM affecting apparently immunocompetent patients is rare, with few previous reports, mostly from India. We describe 10 cases of bilateral IRM with no underlying risk factors. METHODS: We performed a retrospective analysis of cases of IRM from our hospital information system admitted between 2009 and 2016. We analyzed the data of this cohort of IRM, including epidemiological characteristics, clinical presentation, diagnostic procedures, treatment details and outcome. RESULTS: In all, 10 cases of bilateral IRM were identified. All of them were males with a mean age of 24.7 years (range 10-42). Most patients were initially managed as acute bacterial pyelonephritis with acute kidney injury. A total of eight patients were diagnosed antemortem. Diagnostic clues include sepsis not controlled with broad-spectrum antibiotics and enlarged kidneys with or without hypodensities on ultrasound/computed tomography imaging. Three patients also gave a specific history of passing white flakes in their urine. Eight patients received specific antifungal therapy with amphotericin B with or without posaconazole. Three patients in whom the disease was apparently confined to the pelvicalyceal system underwent local irrigation with Amp-B. One patient underwent bilateral nephrectomy. Four patients succumbed to the disease while five patients were successfully treated. One patient was discharged against medical advice. CONCLUSIONS: IRM is a rare, life-threatening disease associated with high mortality even in immunocompetent individuals. Typical clinical and radiological findings and a high index of suspicion may help in early diagnosis, but definitive diagnosis requires histopathological and/or microbiological confirmation. Early and rapid diagnosis along with aggressive multidisciplinary management including initiation of specific antifungal therapy with or without surgical debridement is vital for a successful outcome.

Metabolic fingerprinting in breast cancer stages through 1H NMR spectroscopy-based metabolomic analysis of plasma.

Breast cancer (BC) is one of the most common malignancies among women worldwide, which is indeed associated with metabolic reprogramming. However, BC is a very complex and heterogeneous disease, which can relate with the changes in metabolic profiles during BC progression. Hence, investigating the metabolic alterations during BC stage progression may reveal the deregulated pathways and useful metabolic signatures of BC. To demonstrate the metabolic insights, we opted 1H NMR spectroscopy based metabolomics of blood plasma of early and late stage BC (N = 72) with age and gender matched healthy subjects (N = 50). Further, the metabolic profiles were analyzed to delineate the potential signatures of BC by performing multivariate and nonparametric statistical analysis in early and late stages of BC in comparison with healthy subjects. Sixteen metabolites levels were differentially changed (p < 0.05) in the early and late stages of BC from healthy subjects. Among them, the levels of hydroxybutyrate, lysine, glutamate, glucose, N-acetyl glycoprotein, Lactate were highly distinguished in BC stages and showed a good biomarker potential using receiver-operating curves based diagnostic models. Furthermore, the significant modulation and good diagnostic performances of glutamate, N-acetyl glycoprotein and Lactate in LBC as compared to EBC give their significance in the BC progression. In general, our observations demonstrate that these panels of metabolites may act as vital component of the metabolism of early to late stage BC progression. Our results also open new avenue towards early and late stage BC diagnosis and intervention implying metabolomics approaches.

Efficacy and safety of sofosbuvir-based antiviral therapy to treat hepatitis C virus infection after kidney transplantation.

BACKGROUND: The objectives of this pilot study were to assess the efficacy and safety of an interferon-free sofosbuvir and ribavirin combination regimen to treat chronic hepatitis C virus (HCV) infection in kidney transplant recipients and to study the impact of sofosbuvir on calcineurin inhibitor (CNI) drug levels. METHODS: A total of 10 kidney transplant recipients with chronic HCV infection were included in the study. All received sofosbuvir and ribavirin combination therapy. The virological response to therapy and the adverse effects of the drugs were studied. The area under the curve (AUC) and pharmacokinetic data of levels of CNI were compared while the patients were receiving sofosbuvir and ribavirin drugs and when they were no longer on these drugs. RESULTS: In all, 9 of 10 patients (90%) achieved rapid virological response (RVR) with undetectable HCV RNA at 4 weeks and the remaining patient achieved undetectable HCV RNA at 8 weeks. A sustained virological response was seen at 3, 6 and 12 months and was maintained in all 10 patients (100%). The important aspect of the study is the effect of treatment with the sofosbuvir-ribavirin combination regimen on the CNI AUC levels, which resulted in a reduction in the CNI AUC. While used as part of triple-drug immunosuppression, no change in the dose of CNI (tacrolimus and cyclosporine) was required based on measurement of C0 levels. CONCLUSIONS: The sofosbuvir and ribavirin combination therapy is effective and safe to treat HCV infection in the post-renal transplant setting. There is a need for close CNI level monitoring while these patients are on sofosbuvir therapy. With therapy and viral clearance, there could be reduction in CNI levels due to increased clearance of CNI drugs, which is shown by the AUC measurements. This could be important for patients at high risk for rejection.

Early versus late institution of plasma exchange therapy in pregnancy induced thrombotic microangiopathy and its effects on clinical outcomes-A case series.

PURPOSE: To look for incidence of pregnancy associated TMA, clinical presentation and impact of early diagnosis and institution of plasma exchange on overall renal outcomes METHODS: -This is a retrospective study among all female patients who presented with acute kidney injury post pregnancy between October 2002 to April 2016 in department of nephrology in a tertiary care hospital in northern India and diagnosed as pregnancy induced TMA. The patient were assessed for duration of onset of renal failure to time of diagnosis of TMA, role of modality of treatment ie plasmpaharesis to outcome. These patients were assessed for complete, partial or no recovery in renal functions at 60 days after admission. RESULTS: Patients whose time of onset of renal failure to a correct diagnosis of TMA was ≤15 days and age less than 30 years was also associated with good prognosis. The patients who received plasma exchange and that to within 72 h of admission had more chances of recovery. CONCLUSIONS: Early diagnosis of disease and early institution of plasma exchange therapy improves renal outcomes in postpartum TMA.

Predicting miRNA Association with Corresponding Target Genes and Single Nucleotide Polymorphisms in Altered Renal Pathophysiology.

BACKGROUND: Translational research on miRNAs develops reliable biomarkers for diagnosis and prognosis of renal diseases. Bioinformatic analyses and systems biology could drive the research for knowing new informative miRNA targets. OBJECTIVES: This study proposes an approach to identify miRNA specific significant target genes, and single nucleotide polymorphisms (SNPs) associated with renal pathophysiology. METHODS: miRNAs were selected after removing duplicity, on the basis of techniques used, and disease spectrum width score. Target genes were predicted from different databases like miRWalk, miRTarBase, and DIANA-TarBase. SNPs were prioritized on the basis of target score and conserved energy score available in MirSNP database. miRNAs were characterized as "specific", "strong", "likely", "unlikely", and "irrelevant" biomarkers. PCR-SSP based genotyping was carried out to access the molecular profiling of hsa-miR-192 and TGF-ß1 followed by quantitative real time PCR to analyze expression level of TGF-ß1. The relative expression levels of mRNAs were analyzed by 2-ΔΔCt method. RESULTS: 170 renal associated miRNAs were found to be up-regulated, down-regulated or differentially expressed. Noticeably hsa-miR-192-3p expression was reported in nine diseases. 117 genes were associated with basic kidney diseases and end stage renal disease (ESRD). Threshold > 80% for 93 target genes was observed from mirSVR. Mutant genotypes for hsa-miR-192 (OR=4.64, p-value ≤ 0.0001) and its corresponding target gene TGF-ß1 (OR = 0.70, p-value = 0.0351) showed susceptible association with ESRD. More so, patients possessing mutant allele of TGF-ß1 showed elevated mRNA expression (Fold change = 9.83). CONCLUSION: Study proposed a new approach to identify specific miRNA biomarkers for particular diseases with corresponding target genes and SNPs and also highlighted the importance of hsa-miR-192 in renal diseases.