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Drivers of flash floods in the Indian sub-continental river basins
No full textFlash floods occur every year during the summer monsoon season in India, causing substantial damage to agriculture, infrastructure, and human life. Despite their profound implications, flash flood hotspots remain unknown, hindering adaptation efforts. Here, we use hydrological and geomorphological characteristics to map the flash flood prone sub-basins in the Indian sub-continent. Flash flood hotspots are mainly centered in Himalayas, West Coast, and Central India, with geomorphological factors driving flash floods in the Himalayas and hydrological factors (flashiness) in the West Coast and Central India. The combination of extreme precipitation and wet antecedent conditions trigger most (~ 3/4th) flash floods while the remaining (~ 1/4th) are solely driven by extreme precipitation. Several non-flash flood prone basins have experienced a significant increase in extreme precipitation frequency and intensity, highlighting that the warming climate can lead to newer flash flood hotspots in the future
Evaluation of invivo anti-lithiatic activity of polyherbal formulation in ameliorating calcium oxalate kidney stones and integrated invitro-insilico studies
No full textThe present study validates invivo anti-lithiatic activity of a polyherbal formulation (URO-5) on calcium oxalate (CaOx) stones. The effect of URO-5 on CaOx crystallization was tested invitro and Insilico molecular docking was conducted to explore the mechanism of action. Invitro studies showed that URO-5 drastically reduces the number of CaOx crystals and facilitate the efflux due to alteration in their morphology. It promotes the formation of dihydrate type of crystals. The inhibition (IC50) of crystal nucleation and aggregation at low concentration of 4.51 and 11.17 mg/ml suggests antagonistic action on crystallization. URO-5 characterized through high performance liquid chromatography showed the presence of eight bioactive metabolites and insilico data suggest that anti-lithiatic activity of URO-5 was mediated via calcium, oxalate, and antioxidant dependent pathways. Invivo activity (500 mg/kg) reveals that CaOx crystals efflux were prominent ( 80 %) in URO-5 and is at par with Cystone®. The decrease in tissue calcium and increase in urine calcium was significant (p > 0.05) at 15.14 and 74.08 μg/mg. Interestingly, URO-5 also repairs the tissue damage caused by CaOx stones and was non-toxic under the tested conditions. In nutshell, URO-5 is a safe and efficacious alternative and can be used as an adjuvant therapy in urolithiasis
Post-Translational Modifications Orchestrate Repair of Trapped Topoisomerase-Induced DNA Breaks via TDP1 and TDP2
No full textDNA topoisomerases are critical for maintaining DNA topology and facilitating replication, transcription, and chromatin organization in both nuclear and mitochondrial genomes. When covalently trapped on DNA as topoisomerase cleavage complexes (Topcc's), notably Top1ccs and Top2ccs, these enzymes generate cytotoxic DNA lesions that disrupt genomic integrity and threaten cell viability. Tyrosyl-DNA phosphodiesterase (TDP1 and TDP2) has emerged as key player in the resolution of these lesions, with broader roles in the repair of diverse DNA end structures. Post-translational modifications (PTMs) dynamically regulate the DNA damage response by modulating the activity, localization, and interactions of repair factors. This review provides a comprehensive overview of the mechanisms by which PTMs modulate the activity of Top1 and Top2, and the repair of their covalently trapped complexes. We further delineate how PTMs fine-tune the functional networks of TDP1 and TDP2, enhancing their efficiency in resolving Topccs and preserving genome stability. Together, these insights highlight the multilayered regulatory mechanisms that safeguard genomic integrity and offer potential avenues for therapeutic intervention
IBCL-245: Clinicopathological profile and survival outcomes in follicular lymphoma: An institutional analysis from India
No full textBackground:
Follicular lymphoma (FL) is the second most common subtype of non-Hodgkin lymphoma (NHL) in India. There is limited information available on FL from India. This study evaluates the clinicopathological profile, treatment outcomes, and prognostic factors in FL at a single tertiary-care center.
Methods:
The clinicopathological profile, treatment outcome, and prognostic factors for survival were assessed retrospectively in 107 FL patients treated at our tertiary center over 11 years (2012–2023).
Results:
There were 61 males and 46 females, with a median age of 53 years (range, 27–70). Common presenting symptoms were lymphadenopathy (60%) and fatigue (20%). The mean duration of symptoms before presentation was 7 months. The Ann Arbor stage distribution was: stage 1 (8%), 2 (10%), 3 (20%), and 4 (62%). Bone marrow involvement and bulky disease were observed in 38 (36%) and 29 (27%) patients, respectively, while extranodal involvement occurred in 65%. Based on the FLIPI-1, 19% were low risk, 24% intermediate risk, and 57% high risk. Histologically, 35 (32%) were grade 1, 51 (48%) grade 2, and 21 (20%) grade 3. Ninety-five (89%) received treatment at presentation. Regimens included BR (bendamustine and rituximab) in 64, RCHOP in 16, LR (lenalidomide and rituximab) in 6, and others in 9 patients. Rituximab maintenance therapy was given to 45 (42%), limited by financial constraints. The overall response rate (ORR) was 84%, with complete remission (CR) in 65%. During follow-up, 30 (28%) patients relapsed, and 10 transformed to diffuse large B-cell lymphoma (DLBCL). At a median follow-up of 60 months, median OS was not reached; median PFS was 114 months. Common toxicities included skin rash (13%) and febrile neutropenia (10%). Grade 3/4 toxicities occurred in 11%. Failure to attain CR (aHR, 0.45; 95% CI, 0.22–0.90; P = 0.024) was associated with poor PFS.
Conclusion:
FL in our population presents predominantly at advanced stages (3/4) with high FLIPI scores compared to Western data. BR is the most commonly used frontline regimen. Failure to attain CR is the most significant prognostic factor for poor outcomes
Plasma levels of hydroxychloroquine and seroconversion in health care workers during COVID prophylaxis: Retrospective evaluation using pharmacokinetic simulation
No full textObjectives:
Hydroxychloroquine (HCQ) was repurposed for prophylactic use against coronavirus disease-19. However, justification for the different regimens used for prophylaxis lacks rationale. Thus, this study retrospectively assessed the therapeutic plasma levels of HCQ using simulation-based pharmacokinetic estimates for rationalising the dose of HCQ.
Materials and Methods:
A total of 246 healthcare workers (HCWs) took the HCQ prophylaxis as per the Indian Council of Medical Research (ICMR) dosing. Besides, healthy volunteers (HWs) consumed HCQ following the ICMR regimen. Serum levels of HCQ in HCWs and HWs were analysed using liquid chromatography tandem mass spectrometry (LC-MS/MS). The detected HCQ levels pharmacokinetic parameters were derived and used for the simulation studies to predict free drug and lung (tissue) levels. The HCQ levels were correlated with seroconversion, and adverse effects and correlated with predicted levels.
Results:
The HCQ plasma concentration of HCWs falls into the therapeutic window of HCQ as predicted by the simulation studies. The simulated data showed that the ratio of plasma to lung (tissue levels) as well as to epithelial lining fluid levels (free drug levels) could reach in adequate levels of reported IC50. Poor correlation was observed for the HCQ concentration and duration of prophylactic treatment in HCWs, while the seropositivity was negatively correlated with the HCQ levels in non-responders in HCWs.
Conclusion:
The study revealed that adequate plasma HCQ levels were reached following the prophylaxis schedule to exhibit protection against severe acute respiratory syndrome coronavirus 2. However, the lack of any advantages in the clinical studies highlights the paradox of the absence of in vitro-in vivo correlation
Clinicopathologic characteristics and survival outcome of patients with mantle cell lymphoma: A North Indian tertiary care center experience
No full textPurpose:
Mantle cell lymphoma (MCL) is a rare aggressive variant of non-Hodgkin lymphoma. Clinical and survival data from India are scarce.
Materials and Methods:
We retrospectively analyzed clinicopathologic data of 98 patients with MCL treated at our center in the past 10 years. STATA 13.0 was used for overall survival (OS) and event-free survival (EFS) assessment by Kaplan-Meier analysis. Univariate and multivariate analyses (Cox proportional hazards) were used to identify predictors of survival. P value < .05 defined statistical significance.
Results:
Median age was 60.0 years. There was extranodal involvement in 77/98 (79.0%) patients. Ninety-one of 98 (93.0%) and 54/97 (56.0%) patients, respectively, were in advanced stage (III/IV) and high-risk MCL International Prognostic Index score at presentation. There was bulky disease in 19/98 (19.0%) patients. Classical histology and interstitial/paratrabecular bone marrow (BM) infiltration was most frequent. Sixteen percent had BM without peripheral blood involvement. Most patients, 83/96 (86.0%), received rituximab-based induction chemotherapy. Fifty-one of 96 (53.0%) patients were alive with a median follow-up of 63.0 months. Median OS was 43.0 months. Estimated 3.0-year OS and EFS were 60.0% and 35.0%, respectively. Rituximab maintenance (RM) improved both OS (P < .01) and EFS (P < .01). Median OS was lower in the non-RM group (37.0 months v not reached; adjusted hazard ratio, 0.31 [95% CI, 0.13 to 0.72], P < .01). Age >60 years, Eastern Cooperative Oncology Group performance status ≥2, advanced stage, and leukocytosis at presentation were associated with poor OS.
Conclusion:
Our study was a comprehensive analysis of patients with MCL from India. To our knowledge, this was the first study of its kind demonstrating OS and EFS benefit of RM in MCL from this part of the world
Role of non-invasive preimplantation genetic testing-aneuploidy using spent culture media and its concordance with trophectoderm biopsy: a proof of concept and validation study
No full textBackground:
While trophectoderm (TE) biopsy with next-generation sequencing (NGS) remains the gold standard for preimplantation genetic testing for aneuploidy (PGT-A), the discovery of cell-free DNA (cfDNA) in spent culture media (SCM) has sparked interest in non-invasive PGT-A (NiPGT-A) as a potential alternative.
Aim:
The study was conducted to assess the feasibility of cell cfDNA from SCM as a tool for NiPGT-A in patients undergoing IVF for advanced age, repeated implantation failure or severe male factor infertility.
Settings and Design:
This is a prospective study where a total of 44 embryos having TE biopsy for aneuploidy testing and their respective SCM collected at day 5/6 were analysed.
Materials and Methods:
All aneuploid blastocysts (WB) were subjected to DNA extraction and amplification using Sureplex DNA amplification system followed by library preparation using VeriSeq™ PGS Library Prep kit and sequencing on MiSeq (Illumina, California, USA).
Statistical Analysis Used:
Copy Number Variation visualisation and analysis were carried out using BlueFuse Multi Software (Illumina). The statistical data were analysed by STATA version 14.
Results:
Informative results were obtained in 36/44 (81.2%) SCM samples. The reads were analysable in 26 paired (SCM and TE biopsy) samples. Concordant NGS results for both TE biopsy and SCM sample were obtained in 17/26 (65.38%) embryos. The per chromosome concordance rate was 85.13% (487/572) and the sex chromosome concordance rate was 73% (19/26). The sensitivity and specificity of NiPGT-A were 66.6% and 60%, respectively. On comparing the ploidy concordance rate, poor morphology embryos had better, but not statistically significant concordance rate (83.33%) as compared to good morphology embryos (50%, P = 0.16). Although not significant, day 6 embryos had better per chromosome as well as sex chromosome concordance rate as compared to day 5 embryos.
Conclusion:
Aneuploidy testing using cf DNA in SCM is a promising technique but needs more research on larger cohort size to improve the sensitivity, specificity and concordance rate
Characterizations of complex symmetric Toeplitz operators
No full textWe characterize Toeplitz operators that are complex symmetric. This follows as a by-product of characterizations of conjugations on Hilbert spaces. Notably, we prove that every conjugation admits a canonical factorization. As a consequence, we prove that a Toeplitz operator is complex symmetric if and only if the Toeplitz operator is S-Toeplitz for some unilateral shift S and the transpose of the Toeplitz operator matrix is equal to the matrix of the Toeplitz operator corresponding to the basis of the unilateral shift S. Also, we characterize complex symmetric Toeplitz operators on the Hardy space over the open unit polydisc. Our results are related to a question raised by K. Guo and S. Zhu
Skin‐Integrated Electrogenetic Regulation of Vasculature for Accelerated Wound Healing.
No full textNeo-vascularization plays a key role in achieving long-term viability of engineered cells contained in medical implants used in precision medicine. Moreover, strategies to promote neo-vascularization around medical implants may also be useful to promote the healing of deep wounds. In this context, a biocompatible, electroconductive borophene–poly(ε-caprolactone) (PCL) 3D platform is developed, which is called VOLT, to support designer cells engineered with a direct-current (DC) voltage-controlled gene circuit that drives secretion of vascular endothelial growth factor A (VEGFA). The VOLT platform consists of a 3D-printed borophene-PCL honeycomb-shaped matrix decorated with borophene-PCL nanofibers by electrospinning. The honeycomb structure provides mechanical stability, while the nanofibers facilitate the adhesion, migration, and proliferation of the engineered cells. The cells incorporate a DC-powered reactive oxygen species (ROS)-sensing gene circuit wired to an engineered synthetic promoter that triggers secretion of VEGFA to promote vascularization in the adjacent extracellular matrix. Cells engineered with this gene circuit and enclosed in the VOLT matrix, termed the VOLTVEGFA system, can be simply triggered using off-the-shelf AA batteries, utilizing the established ability of a brief DC bias to generate non-cytotoxic levels of ROS. For proof-of-concept, a subcutaneous wound-healing model in rats is chosen. Electrostimulation of a VOLTVEGFA implant (5 V, 20 s per day) induced secretion of VEGFA, and significantly accelerated neovascularization and granulation tissue formation, resulting in faster wound closure compared with non-stimulated controls. Complete re-epithelialization and dermal regeneration are observed within 15 days of application
Methionine cycle in C. elegans serotonergic neurons regulates diet-dependent behaviour and longevity through neuron-gut signaling
No full textThe folate and methionine cycles (Met-C) are regulated by vitamin B12 (B12), obtained exclusively from diet and microbiota. Met-C supports amino acid, nucleotide, and lipid biosynthesis and provides one-carbon moieties for methylation reactions. While B12 deficiency and polymorphisms in Met-C genes are clinically attributed to neurological and metabolic disorders, less is known about their cell-non-autonomous regulation of systemic physiological processes. Using a B12-sensitive Caenorhabditis elegans mutant, we show that the neuronal Met-C responds to differential B12 content in diet to regulate p38-MAPK activation in the intestine, thereby modulating cytoprotective gene expression, osmotic stress tolerance, behaviour and longevity. Mechanistically, our data suggest that B12-driven changes in the metabolic flux through the Met-C in the mutant's serotonergic neurons increase serotonin biosynthesis. Serotonin activates its receptor, MOD-1, in the post-synaptic interneurons, which then secretes the neuropeptide FLR-2. FLR-2 binding to its intestinal receptor, FSHR-1, induces the phase transition of the SARM domain protein TIR-1, thereby activating the p38-MAPK pathway. Together, we reveal a dynamic neuron-gut signalling axis that helps an organism modulate life history traits based on the status of neuronal Met-C, determined by B12 availability in its diet