Unravelling the molecular mechanistic pathway underlying the anticancer effects of kaempferol in colorectal cancer: a reverse pharmacology network approach.

Colorectal cancer (CRC) is the third most diagnosed and highly fatal malignancy, presenting serious health concerns worldwide. The search for an effective cure for CRC is challenging and poses a serious concern. Kaempferol is a potent anti-cancerous bioactive compound often suggested for treating various cancers, including CRC. However, its underlying molecular mechanism against CRC remains unclear. The present study delves into kaempferol's molecular pathways and underlying molecular mechanisms against CRC targets. The target protein-coding genes for kaempferol were retrieved, and the CRC-associated genes were curated. Twelve common targets with a disease specificity index of > 0.6 were validated for their protein expression at different stages of CRC. Over-expressed USP1, SETD7, POLH, TDP1 and RACGAP1 were selected for further studies. The binding affinities of kaempferol to the corresponding proteins were evaluated using molecular docking and Molecular Dynamics (MD) simulations. SETD7 exhibited the highest binding affinity with the lowest binding energy (- 8.06 kcal/mol). Additionally, the MD simulation, and MM-PBSA conferred SETD7-kaempferol complex had the least root-mean-square deviation with lower interaction energy and higher conformational stability. The protein-protein interaction of SETD7 constructed revealed direct interactors, namely, DNMT1, FOXO1, FOXO3, FOXO4, H3-3B, H3-4, H3C12, H3C13, SETD7, SIRT1 and TP53, have a potential role in cancer progression through FOXO signalling. In summary, our study revealed kaempferol's multi-target and synergistic effect on multiple CRC targets and its underlying mechanisms. Finally, the study recommends in-vitro and in-vivo trials for validation of anti-cancerous drugs for CRC.

Validation of histopathological chronicity scores in native kidney biopsies using light microscopy and digital morphometry for predicting renal outcome.

Quantitative assessment of chronicity changes in native kidney biopsies offer valuable insights in to disease prognosis, despite the strength of qualitative information. Yet, standardization and reproducibility remain challenging. The present study aims to assess and compare the prognostic utility and reproducibility of two chronicity scoring systems based on light microscopy and whole slide imaging with morphometry and also to evaluate the prognostic utility of structural measurements: cortical non-sclerotic glomerular (NSG) density and NSG area/volume. We designed a retrospective longitudinal study involving 101 adult and paediatric patients who underwent native kidney biopsies. Chronicity scoring was performed using two semi-quantitative methods: Method 1 (method proposed in PMID: 28314581) and Method 2 (method proposed in PMID: 32516862), under light microscopy as well as on whole-slide scanned images, and assessed for prognostic utility. Kidney-Failure-Risk-Equation (KFRE) was employed in combination with chronicity-scoring-methods and assessed for predictive capability. Interobserver reproducibility for the two chronicity methods was studied among three renal pathologists. Structural measurements were performed on whole-slide- scanned-images. Both the chronicity scoring methods significantly predicted decline in estimated glomerular filtration rate (eGFR) and persistent need for renal replacement therapy in follow-up. Method 1 combined with KFRE, outperformed Method 2 in predicting renal survival. Method 2 however showed higher interobserver reproducibility. Combined KFRE plus histopathological scoring methods showed better predictive accuracy. The study validates the precision of chronicity scoring using whole slide scanned images. The morphometric structural measurements showed significant correlations with follow-up eGFR, thereby providing supplementary prognostic information.

Potential Signature Therapeutic Biomarkers TOP2A, MAD2L1, and CDK1 in Colorectal Cancer: A Systems Biomedicine-Based Approach.

Colorectal cancer is the third deadliest and fourth most diagnosed cancer. It is heterogeneously driven by varied mutations and mutagens, and thus, it is challenging for targeted therapy. The rapid advancement of high-throughput technology presents considerable opportunities for discovering new colon cancer biomarkers. In the present study, we have explored and identified the biomarkers based on molecular interactions. We curated cancer datasets that were not micro-dissected and performed gene expression analysis. The protein-protein interactions were curated, and a network was constructed for the up-regulated genes. The hub genes were analyzed using 12 different topological parameters. The correlation analysis selected TOP2A, CDK1, CCNB1, AURKA, and MAD2L1 as hub genes. Further, survival analysis was performed to determine the effectiveness of the hub gene on the patient's survival rate. Our findings explore various transcription factors such as E2F4, FOXM1, E2F6, MAX, and SIN3A, along with kinases CSNK2A1, MAPK14, CDK1, CDK4, and CDK2, as potential molecular signatures and aid researchers in understanding the pathophysiological mechanisms underlying CRC development and thus providing novel therapeutic and diagnostic recourse. Furthermore, investigating miRNAs, we focused on hsa-miR-215-5p, hsa-miR-192-5p, and hsa-miR-193b-3p due to their observed impact on a diverse set of colorectal cancer genes. Thereby, the current approach brings into light CRC- related genes at the RNA and protein levels that can potentially act as novel biomarkers opening doors to diagnostic and treatment purposes.

A comprehensive review on genomics, systems biology and structural biology approaches for combating antimicrobial resistance in ESKAPE pathogens: computational tools and recent advancements.

In recent decades, antimicrobial resistance has been augmented as a global concern to public health owing to the global spread of multidrug-resistant strains from different ESKAPE pathogens. This alarming trend and the lack of new antibiotics with novel modes of action in the pipeline necessitate the development of non-antibiotic ways to treat illnesses caused by these isolates. In molecular biology, computational approaches have become crucial tools, particularly in one of the most challenging areas of multidrug resistance. The rapid advancements in bioinformatics have led to a plethora of computational approaches involving genomics, systems biology, and structural biology currently gaining momentum among molecular biologists since they can be useful and provide valuable information on the complex mechanisms of AMR research in ESKAPE pathogens. These computational approaches would be helpful in elucidating the AMR mechanisms, identifying important hub genes/proteins, and their promising targets together with their interactions with important drug targets, which is a crucial step in drug discovery. Therefore, the present review aims to provide holistic information on currently employed bioinformatic tools and their application in the discovery of multifunctional novel therapeutic drugs to combat the current problem of AMR in ESKAPE pathogens. The review also summarizes the recent advancement in the AMR research in ESKAPE pathogens utilizing the in silico approaches.

Correction of metabolic acidosis improves muscle mass and renal function in chronic kidney disease stages 3 and 4: a randomized controlled trial.

BACKGROUND: Metabolic acidosis (MA) is associated with a loss of muscle mass and faster deterioration of kidney function in patients with chronic kidney disease (CKD). A few single-centre randomized trials have reported favourable outcomes following correction of MA. Additional good quality evidence on the safety and efficacy of alkali supplementation is required in epidemiologically different patient subsets with CKD. METHODS: A single-centre, open-label, randomized, prospective parallel-group study was conducted to assess the effect of correction of MA on body composition and kidney function. A total of 188 patients with CKD stages 3 and 4, with venous bicarbonate levels <22 mEq/L were randomized. The intervention arm received standard care as per Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines along with oral sodium bicarbonate supplementation to maintain venous bicarbonate levels at 24-26 mEq/L, whereas the control group received standard care alone. The mid-arm muscle circumference (MAMC), lean body mass (LBM) and estimated glomerular filtration rate (eGFR) were compared between the groups at the end of 6 months. RESULTS: The intervention arm showed a higher LBM {36.8 kg [95% confidence interval (CI) 36.5-37.1] versus 36 [35.7-36.4]; P = 0.002} and MAMC [22.9 cm (95% CI 22.8-23) versus 22.6 (22.5-22.7); P = 0.001] when compared with the control group. The GFR in the intervention arm was higher [32.74 mL/1.73 m2 (95% CI 31.5-33.9) versus 28.2 (27-29.4); P ≤ 0.001]. A rapid decline in GFR was documented in 39 (41.5%) patients in the control arm and 19 (20.2%) patients in the intervention arm (P = 0.001). CONCLUSIONS: Alkali supplementation to increase venous bicarbonate levels to 24-26 mEq/L is associated with preservation of LBM and kidney function in patients with CKD stages 3 and 4.

Reliability of Anthropometry-Based Equations Compared to Dual Energy Absorptiometry for Assessing Body Composition in Predialysis Chronic Kidney Disease-A Longitudinal Study.

OBJECTIVES: Skinfold thickness measurements for assessing body composition are reported to have good reproducibility compared to the reference method of dual energy absorptiometry (DXA). In the current study, we compared the level of agreement between body composition measured with DXA and skinfold thickness (SFT) in CKD Stage 3 and 4, at 2 occasions, 6 months apart. METHODS: Body composition was assessed in 177 Indian patients with CKD Stage 3 and 4 using DXA and anthropometry (SFT). The body fat mass obtained by the 2 methods was compared by paired t-test, intraclass correlation coefficients, regression analysis, and Bland-Altman plots. A linear regression analysis was done to identify the patient-related parameters which would account for the intermethod differences between DXA and SFT. RESULTS: Compared to DXA, SFT underestimated the fat mass at baseline as well as 6 months [DXA vs. SFT at entry: 15.85 kg (95% confidence interval, CI 15.07-16.65) vs. 13.71 kg (95% CI 13.21-14.32), P < .001; at 6 months: 16.13 (95% CI 15.33-16.93) vs. 13.85 (95% CI 13.25-14.45), P < .001]. The intraclass correlation coefficients at entry and 6 months were 0.894 (0.857-0.921) and 0.896 (0.860-0.923), respectively. The intermethod differences between DXA and SFT at baseline and 6 months were comparable: 2.08 kg (95% CI 1.66-2.5) at baseline versus 2.27 kg (95% CI 1.83-2.71) at 6 months, P = 0.200. Gender and body mass index turned out to be the significant predictors of intermethod differences at base line and exit (P < .001). CONCLUSIONS: SFT-based measurements show good reproducibility compared to DXA over a period of 6 months. However, SFT systematically underestimates the fat mass by 2 Kg compared to DXA.

Body Fat Analysis in Predialysis Chronic Kidney Disease: Multifrequency Bioimpedance Assay and Anthropometry Compared With Dual-Energy X-Ray Absorptiometry.

OBJECTIVES: Body composition analysis is required for accurate assessment of nutritional status in patients with predialysis chronic kidney disease (CKD). The reference method for assessing body fat is dual-energy X-ray absorptiometry (DXA), but it is relatively expensive and often not available for widespread clinical use. There is only limited data on the utility of less expensive and easily available alternatives such as multifrequency bioimpedance assay (BIA) and skinfold thickness (SFT) measurements for assessing body fat in predialysis CKD. The study intends to assess the utility of BIA and SFT in measuring body fat compared to the reference method DXA in subjects with predialysis CKD. METHODS: Body composition analysis was done in 50 subjects with predialysis CKD using multifrequency BIA, SFT, and DXA. The agreement between the body fat percentages measured by reference method DXA and BIA/SFT was assessed by paired t-test, intraclass correlation coefficients (ICCs), regression, and Bland-Altman plots. RESULTS: Percentage of body fat measured by BIA was higher compared to the measurements by DXA, but the difference was not significant (30.44 ± 9.34 vs. 28.62 ± 9.00; P = .071). The ICC between DXA and BIA was 0.822 (confidence interval: 0.688, 0.899; P = .000). The mean values of body fat percentages measured by anthropometry (SFT) was considerably lower when compared to DXA (23.62 ± 8.18 vs. 28.62 ± 9.00; P = .000). The ICC between DXA and SFT was .851 (confidence interval: 0.739, 0.915; P = .000). Bland-Altman plots showed that BIA overestimated body fat by a mean of 1.8% (standard deviation, 6.98), whereas SFT underestimated body fat by 5% (standard deviation, 4.01). Regression plots showed a better agreement between SFT and DXA (R(2) = .79) than BIA (R(2) = .50). Overall, SFT showed better agreement with the DXA. Body mass index (BMI) showed a moderate positive correlation with body fat measured by DXA whereas serum albumin failed to show good correlation. CONCLUSIONS: SFT showed relatively better agreement with the reference method DXA, compared to BIA. SFT can be used as a tool for assessing nutritional status in predialysis patients with CKD.

Acute Interstitial Nephritis Following Snake Envenomation: A Single-Center Experience.

OBJECTIVES: To identify the clinical and histopathological characteristics of patients who develop acute interstitial nephritis (AIN) following snake envenomation. METHODS: A retrospective analysis of patients diagnosed with snake envenomation-induced AIN from October 2013 to November 2014. RESULTS: After snake envenomation, 88 patients developed acute kidney injury (AKI). Biopsies were performed on 7 patients due to nonrecovery of kidney function. Among these, 5 patients had AIN. Thus, AIN accounted for 5.7% of snakebite-related acute kidney injury. All patients had severe envenomation at presentation and had prolonged renal failure. Kidney biopsy found a mixed infiltrate composed of predominantly lymphocytes, with variable proportions of other cells including eosinophils neutrophils and plasma cells. The response rate to corticosteroids was 80%. CONCLUSIONS: AIN after snake bite is not uncommon. AIN needs to be considered in patients with persistent renal failure after snake envenomation. Identifying this complication is of utmost importance because of the potentially reversible nature.

Marine Compound-Carpatamide D as a Potential Inhibitor Against TOP2A and Its Mutant D1021Y in Colorectal Cancer: Insights from DFT, MEP and Molecular Dynamics Simulation.

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally, hence there is an urgent need for new and effective therapeutic options. DNA topoisomerase 2A (TOP2A) plays a crucial role in the cell cycle and is involved in CRC progression, making it essential to identify structural and functional relevant alterations. Among the 24 mutations, our findings indicated that mutation D1021Y has the most deleterious effect on the TOP2A protein. Based on virtual screening of 31,561 compounds, we identified three lead candidates: 17683 (nigrospoxydon C), 28461 (carpatamide D), and 28853 (6'-O-acetyl-isohomaarbutin), which showed promising inhibitory effect against TOP2A and its mutant form. These compounds were assessed for their stability using density functional theory (DFT) analysis, where carpatamide D possessed the least energy gap of 4.398 eV showing its high reactivity among all. Further, molecular docking also shows the carpatamide D as the top candidate, which exhibited favourable docking energy against the TOP2A wild type (- 7.47 kcal/mol) and with D1021Y mutant (- 7.62 kcal/mol) as compared to reference compound PK1, which showed - 6.11 kcal/mol TOP2A wild type and - 6.24 kcal/mol against mutant type. The molecular dynamics simulation was performed to analyse the dynamics and stability of complex, which revealed TOP2A_28641 and D1021Y_28641 complexes to be stable with least root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF). Molecular mechanics/Poisson-Boltzmann surface area calculations indicated that TOP2A_28641 and D1021Y_28641 complexes exhibited the lowest binding energy of - 23.55 kcal/mol and - 25.03 kcal/mol, respectively. Our findings suggest carpatamide D as a promising lead compound for the TOP2A_D1021Y targeted cancer therapies, which needs further experimental validation.

Comparison between opposite clear corneal incision versus toric intraocular lens in correcting astigmatism.

PURPOSE: To compare the visual outcomes and efficacy of opposite clear corneal incision (OCCI) and toric intraocular lens (IOL) implantation in correcting preexisting astigmatism (PEA) in patients undergoing phacoemulsification. METHODS: This prospective interventional comparative study was conducted between June 2022 and January 2023 in patients having cataract with PEA undergoing phacoemulsification. Patients were divided into two groups - group A underwent phacoemulsification with OCCI and group B underwent phacoemulsification with toric IOL implantation. Uncorrected distance visual acuity (UDVA), manifest refractive cylinder, and corneal astigmatism using corneal tomography were measured preoperatively and at 6 weeks postoperatively. The eyes were categorized into three groups with PEA ranging from 1 to 1.5 D, 1.6 to 2 D, and 2.1 to 3 D. Depending upon the white-to-white corneal diameter, the eyes were also categorized into four groups with corneal diameter ranging from 10.5 to 10.9 mm, 11 to 11.4 mm, 11.5 to 11.9 mm, and 12 to 12.4 mm. RESULTS: Sixty eyes of 60 patients were studied. At postoperative 6 weeks, 83.3% (25 eyes) in the OCCI group and 96.7% (29 eyes) in the toric IOL group achieved UDVA of 6/9 or better. No statistically significant difference was noted between the groups ( P = 0.37). The reduction in mean corneal astigmatism was 0.63 ± 0.37 D in the OCCI group and 0.15 ± 0.12 D in the toric IOL group ( P < 0.001). The residual mean refractive cylinder was 0.60 ± 0.38 D in the OCCI group and 0.05 ± 0.15 D in the toric IOL group at 6 weeks ( P = 0.007). CONCLUSION: Both OCCI and toric IOL are effective in correcting PEA. However, in a resource-limited setting, OCCI is a better alternative surgical option for correcting astigmatism of 1-1.5 D during phacoemulsification without requiring additional skills or instruments.

Proteinuria in predicting adverse outcomes in women with severe features of pre-eclampsia from a developing country: A prospective cohort study.

OBJECTIVE: To study the adverse maternal and perinatal outcomes in women with severe pre-eclampsia (SPE) among different ranges of proteinuria. METHODS: This prospective cohort study was conducted in Jawaharlal Institute of Postgraduate Medical Education and Research, India. After obtaining informed written consent, the 202 singleton women fulfilling the criteria of severe features of pre-eclampsia were stratified based on the value of urine protein-creatinine ratio (UPCR) as mild, moderate, severe, and massive proteinuria during pregnancy. Clinical outcomes were assessed and patients were followed up until 12 weeks postpartum to identify persistent proteinuria and hypertension. RESULTS: Of the 202 women with SPE, adverse maternal outcomes were seen in 34.65% (n = 70) and adverse perinatal outcomes in 75.74% (n = 153). The demographic and clinical factors were similar among women with increasing severity of proteinuria, except for mean systolic blood pressure, serum creatinine and total serum protein. UPCR was found to have a significant correlation with composite adverse perinatal outcome (P < 0.001) and individual outcomes of neonatal intensive care unit admission for >48 h (P = 0.01) and neonatal sepsis (P = 0.02) but not adverse maternal outcomes (P = 0.201). The optimum UPCR cutoff for adverse perinatal outcomes was 1.6 (sensitivity, 73.2%; specificity, 52.7%). In addition, 14.85% of the women had a persistently elevated UPCR and 3.96% had hypertension at 3 months postpartum. CONCLUSION: In women with SPE, severe and massive proteinuria were related to composite adverse perinatal outcome but not composite adverse maternal outcome. Moreover, antenatal 24-h proteinuria was significantly associated with persistent proteinuria. Significant proteinuria in women with SPE poses a risk for chronic renal dysfunction, requiring follow-up.

Renal Functional Reserve in Acute Kidney Injury Patients Requiring Dialysis.

The incidence of acute kidney injury (AKI) has increased in the recent past. Patients with AKI have an increased risk of mortality. They are also at increased risk of developing chronic kidney disease (CKD). AKI can lead to irreversible loss of renal function despite complete clinical recovery. Currently, no tools are available to diagnose this subclinical loss of renal function. Renal functional reserve (RFR) can serve as an essential tool for analyzing this subclinical loss of renal function, and patients with loss of RFR post-AKI may be closely followed for the development of CKD. This prospective observational study, conducted at the Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), aimed to investigate RFR in 223 patients with AKI requiring dialysis. The study excluded patients with CKD and obstructive uropathy. Methods included RFR assessment three months post-AKI recovery, utilizing technetium-99m (Tc-99m) diethylenetriaminepentaacetic acid (DTPA) plasma clearance during amino acid infusion. Statistical analyses and logistic regression were applied, receiving ethical approval. Results revealed a high in-hospital mortality rate of 78.02%, associated with elevated Sequential Organ Failure Assessment (SOFA) scores. Among 24 patients with complete AKI recovery, the RFR at three months was 10.06% (interquartile range (IQR) 5.60-20.15), with the measured GFR significantly lower than the estimated glomerular filtration rate (GFR). The study concludes that AKI requiring dialysis is linked to high mortality and emphasizes the predictive value of SOFA scores. Additionally, RFR testing at three months post-recovery provides insights into potential long-term impacts on renal function. This study contributes valuable insights into the prognosis of AKI patients requiring dialysis. It underscores the need for further research on RFR as a diagnostic tool and the lasting consequences of AKI.

Pan-genome and reverse vaccinology approaches to design multi-epitope vaccine against Epstein-Barr virus associated with colorectal cancer.

Epstein-Barr virus (EBV) is a global lymphotropic virus and has been associated with various malignancies, among which colorectal cancer (CRC) is the prevalent one causing mortality worldwide. In the recent past, numerous research efforts have been made to develop a potential vaccine against this virus; however, none is effective possibly due to their low throughput, laboriousness, and lack of sensitivity. In this study, we designed a multi-epitope subunit vaccine that targets latent membrane protein (LMP-2B) of EBV using pan-genome and reverse vaccinology approaches. Twenty-three major histocompatibility complex (MHC) epitopes (five class-I and eighteen class-II) and eight B-cell epitopes, which have been found to be antigenic, immunogenic, and non-toxic, were selected for the vaccine construction. Furthermore, 24 vaccine constructs (VCs) were designed from the predicted epitopes and out of which VC1 was selected and finalized based on its structural parameters. The functionality of VC1 was validated through molecular docking with different immune receptors (MHC class-I, MHC class-II, and TLRs). The binding affinity, molecular and immune simulation revealed that the VC1 had more stable interaction and is believed to elicit good immune responses against EBV. HIGHLIGHTS: Pan-genome and reverse vaccinology approaches were used to design a multi-epitope subunit vaccine against LMP-2B protein of EBV. Epitopes were selected based on the antigenic, immunogenic, and non-toxic properties. Twenty-four vaccine constructs (VCs) were designed from the predicted epitopes. Designed vaccine VC1 has shown good binding affinity and molecular and immune simulation. VC1 was validated using molecular docking with different immune receptors.

Indian TrANslational GlomerulonephrItis BioLogy nEtwork (I-TANGIBLE): Design and Methods.

Background and Aim: Primary glomerular disease accounts for one-sixth of all chronic kidney diseases (CKDs) in India. We remain limited in our ability to effectively treat these conditions because of lack of understanding of the disease mechanisms and lack of predictors to identify the clinical course and therapeutic responsiveness. We propose to develop a network of investigators in glomerular diseases, collect information in a systematic fashion to understand the clinical outcomes, answer translational research questions better, and identify and recruit patients for clinical trials. Materials and Methods: This is a prospective, observational study. The Indian TrANslational GlomerulonephrItis BioLogy nEtwork (I-TANGIBLE) cohort will enroll patients (>18 years) with biopsy-proven minimal change disease (MCD), focal segmental glomerulonephritis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), or membranoproliferative glomerulonephritis (MPGN) (immune complex- and complement-mediated), with first biopsy taken within 2 years of enrollment. Patients with estimated glomerular filtration (eGFR) rate <15 ml/min/1.73 m2 for >3 months at the time of screening, kidney transplant or bone marrow transplant recipients, patients with active malignancy, and patients with active hepatitis B/C replication or human immunodeficiency virus (HIV)-I/II will be excluded. Clinical details including history, medication history and details, and family history will be obtained. Consenting patient's blood and urine samples will be collected and stored, aligned to their clinical follow-up. Expected Outcomes: The network will allow accurate ascertainment of disease burden of glomerular diseases across study sites, establishment of the treatment pattern of common glomerular diseases, investigation of medium- and long-term outcomes (remission, relapse, rate of eGFR decline), and building a suitable infrastructure to carry out clinical trials in primary glomerular disease.

Network metrics, structural dynamics and density functional theory calculations identified a novel Ursodeoxycholic Acid derivative against therapeutic target Parkin for Parkinson's disease.

Parkinson's disease (PD) has been designated as one of the priority neurodegenerative disorders worldwide. Although diagnostic biomarkers have been identified, early onset detection and targeted therapy are still limited. An integrated systems and structural biology approach were adopted to identify therapeutic targets for PD. From a set of 49 PD associated genes, a densely connected interactome was constructed. Based on centrality indices, degree of interaction and functional enrichments, LRRK2, PARK2, PARK7, PINK1 and SNCA were identified as the hub-genes. PARK2 (Parkin) was finalized as a potent theranostic candidate marker due to its strong association (score > 0.99) with α-synuclein (SNCA), which directly regulates PD progression. Besides, modeling and validation of Parkin structure, an extensive virtual-screening revealed small (commercially available) inhibitors against Parkin. Molecule-258 (ZINC5022267) was selected as a potent candidate based on pharmacokinetic profiles, Density Functional Theory (DFT) energy calculations (ΔE = 6.93 eV) and high binding affinity (Binding energy = -6.57 ± 0.1 kcal/mol; Inhibition constant = 15.35 µM) against Parkin. Molecular dynamics simulation of protein-inhibitor complexes further strengthened the therapeutic propositions with stable trajectories (low structural fluctuations), hydrogen bonding patterns and interactive energies (>0kJ/mol). Our study encourages experimental validations of the novel drug candidate to prevent the auto-inhibition of Parkin mediated ubiquitination in PD.

Myeloma Cast Nephropathy an Unusual Association with HIV Infection Presenting with Renal Dysfunction.

Human immunodeficiency virus (HIV)-associated renal disease is a pan-nephropathy, causing glomerular, tubular, and interstitial changes. The common lesion is the collapsing variant of focal segmental glomerulosclerosis. Multiple myeloma presenting as light chain cast nephropathy in an HIV-positive patient is very rare. A 45-year-old female retropositive patient presented with one episode of hematuria. Kidney biopsy was performed with a clinical diagnosis of acute interstitial nephritis (AIN). Biopsy showed unremarkable glomeruli. Tubules were dilated and showed a few periodic acid-Schiff (PAS) positive and many PAS-negative fractured casts surrounded by histiocytic reaction. Immunofluorescence and immunohistochemistry (IHC) showed lambda restriction by the casts. Bone marrow aspirate showed an increase in plasma cells, and the biopsy showed nodular aggregates of atypical plasma cells, which showed lambda restriction by IHC. PAS-negative fractured tubular casts are known to be associated with HIV-related nephropathy and need detailed hematological workup to rule out an associated plasma cell dyscrasia.

Role of Urinary Beta 2 Microglobulin and Kidney Injury Molecule-1 in Predicting Kidney Function at One Year Following Acute Kidney Injury.

BACKGROUND: There is only limited information on the utility of urinary biomarkers in predicting long-term kidney function following acute kidney injury (AKI). The current study assessed whether urinary beta 2 microglobulin/creatinine (B2M/creat) and kidney injury molecule-1/creatinine (KIM-1/creat) ratios, measured in the early recovery phase of AKI, are predictive of kidney function at one year. METHODS: This is a prospective study done in a tertiary care centre in South India, from March 2017 to December 2018. Adult patients who survived an episode of AKI were followed up for one year (n=125). B2M/creat and KIM-1/creat ratio were measured at two weeks and three months following AKI. RESULTS: In the AKI survivors, the B2M/creat ratio at 2 weeks [18.3mg/g (IQR 2.3, 52.9)] and KIM-1/creat ratio [1.1 µg/g (IQR 0.5, 4.0) at two weeks were higher compared to healthy controls [B2M/creat ratio 0.35 mg/g (0.17,0.58) and KIM-1/creat ratio 0.40 µg/g (0.23,1.00); P=<0.001]. After adjusting for covariates, the eGFR and urinary B2M/creat ratio at two weeks following AKI were predictive of eGFR at one year (P<0.001). KIM-1/ creat ratios were not predictive of eGFR at one year. A urinary B2M/creat ratio of 10.85 at two weeks following AKI had an 85.5% sensitivity (95% CI 74, 93) and 64.3% (95% CI 53, 75) specificity to predict CKD at one year. An eGFR cutoff of 60 mL/min/1.73 m2 at two weeks had a sensitivity of 81.8% (95% CI 69, 90) and specificity of 71.4% (95% CI 60, 81) for predicting CKD. The presence of either one criteria (urinary B2M/creat ratio >10.85 (mg/g) or eGFR <60 mL at two weeks) had a sensitivity of 100% (95% CI 94%, 100%) in predicting CKD at one year. CONCLUSION: An eGFR <60 mL/min/1.73m2 and elevated urinary B2M/creat ratio at two weeks following AKI is predictive of low eGFR at one year. Urinary KIM-1/creat ratios do not predict CKD progression.

Erratum: Prognosis and long-term outcomes of acute kidney injury due to snake envenomation.

[This corrects the article DOI: 10.1093/ckj/sfz055.][This corrects the article DOI: 10.1093/ckj/sfz055.].