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Autologous hematopoietic stem cell transplant in pediatric solid tumours in India: A single centre experience of 15 years
No full textBackground and Aim - High-dose chemotherapy followed by autologous hematopoietic stem cell transplant(ASCT) remains a curative option for many pediatric solid tumours when standard-dose chemotherapy fails. The Indian data regarding the use of ASCT in the treatment of pediatric solid tumours is scarce and limited to neuroblastoma.
Method - In this study we report the outcomes of solid tumors in children, adolescents and young- adults (CAYA) who underwent ASCT in a tertiary centre of India. It includes patients from January 2008- August 2024.
Results - Out of 84 patients with solid tumours in the CAYA age group transplanted, the median age was 6y (2-24), with 70.7% males. The diagnoses of the patients were neuroblastoma (NB=52%), relapsed/refractory germ-cell tumours (GCT=15.5%), relapsed/refractory ewing sarcoma (EWS=22.6%), retinoblastoma(RB) and soft-tissue sarcoma(STS) 4.7% each. While 41(48.8%) patients underwent ASCT during relapse, rest 43(51.2%) patients underwent upfront ASCT(NB).
The conditioning regimens were: busulfan-melphalan or carboplatin-etoposide-melphalan for NB, melphalan or busulfan-melphalan for EWS, carboplatin-etoposide for GCT and thiotepa-carboplatin for STS/RB. Median stem-cell dose was 4.6 (1.8-20.1) million/kg, given after a median 13.5 days (4-110) days of cryopreservation. Toxicity details are given in Table 1. The median time to neutrophil engraftment was 11 days(9-25).
With a median follow-up of 441 days, the estimated 1-year overall survival (OS) and event-free survival (EFS) for the entire cohort was 77.0% and 58.4%, respectively, better in GCT than NB or EWS.
Conclusions - The evidence in support of ASCT in many pediatric solid tumours like relapsed-refractory GCT, high-risk/relapsed-refractory EWS, rhabdoid tumours and embryonal brain tumours is gradually increasing. Safe administration of this procedure in LMICs would improve
KDM6A, a novel prognosis-predictive marker of pediatric acute myeloid leukemia?
No full textBackground and Aim - Despite advancements in diagnostic techniques and the discovery of newer chemotherapeutic agents, the outcome of acute myeloid leukaemia (AML) remains dismal. H3K27me3 demethylase (KDM6a) is a novel gene with a suggestive role as a tumour suppressor, and loss of KDM6a expression in AML relapse has been previously linked to drug resistance in the adult population leading to poor prognosis. This study is aimed to investigate the role of KDM6a in pediatric AML.
Method - This prospective study was carried out from July 2021 to January 2024, where bone marrow aspirate or peripheral blood was taken from children (age ≤18) at diagnosis, remission (at first reported remission either PI-1 or PI-2) and relapse. The extracted RNA was converted to cDNA for expression analysis of KDM6a. The expression dynamics of KDM6a were analysed using qRT-PCR.
Results - A total of 74 patients with AML were enrolled in the study after the exclusion of 14 children due to exclusion criteria or low TLC. The most common symptoms observed were fever (78.8%), pallor (54.7%), fatigue (36.7%), and loss of appetite (45.5%). The most common cell surface markers detected were CD33 (100%), CD38 (91.67%), CD117 (87.80%), and CD13 (75%).
The expression was downregulated at the diagnosis stage (N=74) compared to the control population (p=<0.0001) (N=10). KDM6a was upregulated at remission compared to diagnosis (p=0.0034) (N=61), whereas its expression decreased on relapse of the disease in paired samples in comparison to remission (p=<0.0001) (N=8).
Conclusions - The differential expression of KDM6a exclusively at the diagnosis and relapse stage indicates its role in the pathogenesis of pediatric AML. A study with deeper molecular analysis is required to understand the contribution of KDM6a in cellular changes leading to AML. Given the poor prognosis associated with AML, it is crucial to incorporate new disease markers for better risk assessment and to identify potential therapeutic targets
Cybersecurity investments in supply chains with two-stage risk propagation
No full textCyber-attacks present a significant threat to supply chains as their nodes are directly or indirectly vulnerable to risk propagation at various stages. The risk level varies depending on the type of attack. A cybersecurity insurance offers a practical method to mitigate this risk, and it is crucial to determine optimal cybersecurity investments for all supply chain nodes. Previous studies have overlooked the joint impact of the attack type, two-stage risk propagation, and cybersecurity insurance in optimizing cybersecurity investments. This paper addresses this research gap by examining optimal investments under targeted and opportunistic attacks in a two-stage supply chain using game theory. The findings indicate that optimal investments differ based on the type of attack. For instance, retailers should invest more in cybersecurity under opportunistic attacks, while suppliers need to spend more under targeted attacks. Additionally, the results show that under opportunistic attacks, members should reduce their investments. Conversely, under targeted attacks, investments should initially increase and then stabilize. In the case of opportunistic attacks, suppliers and retailers should prioritize reconfiguring their systems over investing heavily in cybersecurity. The model presented in this paper demonstrates that not all cyber risks are worth defending against and that cybersecurity insurance for the entire supply chain can be more cost-effective than addressing cybersecurity risks individually. The paper also explores the impact of joint decisions on cybersecurity insurance when firms are unwilling to invest individually. The insights obtained enable supply chains to identify their optimal cybersecurity investment strategies effectively
Evaluating bioeconomic potential of Phyllostachys mannii Gamble, a monopodial bamboo and Chimonocalamus griffithianus (Munro) Hsueh & T.P. Yi, a sympodial bamboo from north-eastern India
No full textThe bioeconomic potential of monopodial and sympodial bamboos is not well understood. Therefore, Net primary productivity (NPP), total biomass, carbon (C) stock, soil organic carbon (SOC), CO2 sequestration, and bioenergy potential were studied in a sympodial Chimonocalamus griffithianus and a monopodial Phyllostachys mannii bamboo in Meghalaya, north-eastern India. P. mannii stand with mean culm density 16,877 ha−1, height 14.8 m and diameter 4.4 cm, accumulated 107.56 Mg ha−1 biomass with a total NPP of 18.83 t ha−1yr−1. It stored 50.67 Mg C ha−1 in biomass, 77.28 Mg C ha−1 in soil, and had sequestration potential of 469.58 t CO2 ha−1. C. griffithianus stand with mean clump density 1065 ha−1, mean culm density 52,185 ha−1, height 7.19 m and diameter 3.04 cm, accumulated 67.08 Mg ha−1 biomass with a total NPP of 15.30 t ha−1 yr−1. It stored 31.30 Mg C ha−1 in biomass, 83.25 Mg C ha−1 in soil, and had sequestration potential of 420.40 t CO2 ha−1. Matured culms (>2–3 years old) of P. manni and C. griffithianus produced 143.08–166.65 MW h and 87.13–101.48 MW h of energy per ha, respectively. Although landuse history and site characteristics of the two stands were not 100 % identical, significantly greater (p < 0.05) standing biomass, NPP, growth rate, carbon sequestration potential, and energy values of P. mannii than C. griffithianus makes the monopodial bamboo a better choice for energy plantation and climate change mitigation tool than the sympodial
Temporal correlation in the inverse-gamma polymer
No full textUnderstanding the decay of correlations in time for (1+1)-dimensional polymer models in the KPZ universality class has been a challenging topic. Following numerical studies by physicists, concrete conjectures were formulated by Ferrari and Spohn [34] in the context of planar exponential last passage percolation. These have mostly been resolved by various authors. In the context of positive temperature lattice models, however, these questions have remained open. We consider the time correlation problem for the exactly solvable inverse-gamma polymer in \mathbb Z^2. We establish, up to constant factors, upper and lower bounds on the correlation between free energy functions for two polymers rooted at the origin (droplet initial condition) when the endpoints are either close together or far apart. We find the same exponents as predicted in [34]. Our arguments rely on the understanding of stationary polymers, coupling, and random walk comparison. We use recently established moderate deviation estimates for the free energy. In particular, we do not require asymptotic analysis of complicated exact formulae
Small deviation estimates and small ball probabilities for geodesics in last passage percolation
No full textFor the exactly solvable model of exponential last passage percolation on ℤ2, consider the geodesic Γn joining (0, 0) and (n, n) for large n. It is well known that the transversal fluctuation of Γn around the line x = y is n2/3+o(1) with high probability. We obtain the exponent governing the decay of the small ball probability for Γn and establish that for small δ, the probability that Γn is contained in a strip of width δn2/3 around the diagonal is exp(−Θ(δ−3/2)) uniformly in high n. We also obtain optimal small deviation estimates for the one point distribution of the geodesic showing that for t/2n bounded away from 0 and 1, we have ℙ(∣x(t) − y(t)∣ ≤ δn2/3) = Θ(δ) uniformly in high n, where (x(t), y(t)) is the unique point where Γn intersects the line x + y = t. Our methods are expected to go through for other exactly solvable models of planar last passage percolation and also, upon taking the n → ∞ limit, expected to provide analogous estimates for geodesics in the directed landscape
A UPLC-MS/MS method for quantification of β-N-methylamino-L-alanine (BMAA) in Cycas sphaerica roxb. and its use in validating efficacy of a traditional BMAA removal method
No full textThe presence of neurotoxin β-N-Methylamino-L-alanine (BMAA) in the seeds of Cycas sphaerica is reported for first time. We developed a UPLC-MS/MS method for BMAA quantification by derivatizing with dansyl chloride. The method successfully differentiated L-BMAA from its structural isomer 2,4-diaminobutyric acid (DAB). The extracting mixture 0.1M TCA: ACN 4:1 v/v had a recovery level of >95%. The method is a high throughput sensitive chromatographic technique with 16.42 ng g-1 Limit of Quantification. BMAA was present in the endosperm of C. sphaerica, and was not detected in the leaves and pith. Washing of seeds in running cold water for 48 h reduced BMAA content by 86%. The local communities also treat the seeds under running cold water, but only for 24 h. The results of the study thus validated the traditional BMAA removal process through cold water treatment, but recommend for increase in the treatment period to 48 h or more
Alterations in the mechanical properties of single dsDNA molecules, bare or cell-encapsulated, upon exposure to UVA-only radiation and sunlight
No full textExposure to ultraviolet radiation, which leads to the formation of mutagenic and cytotoxic DNA lesions such as cyclobutane pyrimidine dimers (CPDs) and 6–4 photoproducts (6–4 PPs), can be potentially fatal. The way UVA forms DNA lesions and alters DNA topology and mechanics is still unclear, unlike the cases of UVC and UVB. Herein, Atomic Force Microscopy (AFM) and AFM-based Force Spectroscopy (AFS) have been employed to investigate the topological and mechanical properties of single DNA molecules, bare or E. coli cell-encapsulated, with or without UVA (solar or from UV lamp) treatment. It is observed that both the dsDNA transitions, i.e., 'B' to stretched 'S' conformation and melting transition, are lost in UVA dose-dependent manner. Presumably, this is due to formation of the CPDs and 6–4 lesions that form inter-strand cross-links, causing dsDNA strand separation difficult. Gradual reduction in DNA extension length upon prolonged treatment with UVA-only radiation or sunlight (where, 95 % of solar UV is UVA) also indicates formation of the inter-strand cross-links, since such cross-links can reduce DNA flexibility and increase DNA stiffness. Although these observations are common for both bare and cell-encapsulated DNA, the UVA dose at which the distinctive reversible B-S and melting transition faded away varied widely from 240 kJ/m2 (bare DNA) to 900 kJ/m2 (cellular DNA). The UV-induced DNA damage was also evident in observation of increased number of open circular and linearized topologies, as formed due to single-strand and double-strand breaks, respectively, at damage sites, upon combined action of the apurinic/apyrimidinic site-specific endonucleases IV and V. The extent of DNA damage was further quantified by enzyme-linked immunosorbent assay, which is found to be correlated to the single molecule information
Climate, human settlement, and migration in South Asia from early historic to medieval period: Evidence from new archaeological excavation at Vadnagar, Western India
No full textBetween the second urbanisation of late Iron Age/Early historic and medieval period Indian subcontinent experienced repeated invasion/human migration of central Asian warriors from Greco-Bactrian conquests till Sultanate-Mughals of sixteenth century. Historians often argue whether such invasions/migrations in the past were driven by change in climate and/or social dynamics. We present results of first detailed archaeological excavation and chronology from a multi-cultural site of Vadnagar, Gujarat state, Western India. We document records of seven cultural stages of continuous human settlement from ca. 2754 calibrated (cal) years B.P. (contemporary to Late-Vedic/pre-Buddhist Mahajanapadas or oligarchic republics), Mauryan, Indo-Greek, Indo-Scythian or Shaka-Kshatrapas (AKA ‘Satraps’, descendants of provincial governors of ancient Achaemenid Empires), Hindu-Solankis, Sultanate-Mughal (Islamic) to Gaekwad-British colonial rule (∼318 years B.P.) and recent. We constrain the climate (Indian summer monsoons or ISM) at Vadnagar by both bulk and isotope sclerochronology (seasonality) of molluscan shells and show that each of these periods flourished during a good ISM phase. Conversely, the arid/hyper-arid phases witnessed decline in material culture, craftsmanship, and/or increased social instability yet the settlement was never abandoned thus making Vadnagar the oldest living city within a single fortification unearthed so far in India. We also compare the proxy climate data with the coupled General Circulation Climate (Earth system) model-generated precipitation over western India that is in anti-phase with Arid Central Asia (ACA). We suggest that the seven major phases of invasions/migration to India over the past 2200 years occurred during periods when the ACA was hyper-arid and uninhabitable, but the agrarian subcontinent was prosperous with relatively stronger IS
Spatio-temporal trends and variability in extreme temperature and precipitation indices in the Kashmir Valley, North Western Himalayas
No full textEarth's average air temperature is warming at a substantial rate leading to an increase in the frequency and severity of extremes with major environmental and socio-economic impacts. The present study discusses temperature and precipitation extremes in Kashmir Valley using observational data from six meteorological stations. An Expert Team on Climate Change Detection and Indices (ETCCDI) (http://etccdi.pacificclimate.org/) provides 25 extreme climate indices (15 for temperature and 10 for precipitation) to be used. The absolute extreme temperature indices (TXx, TXn, TNx, and TNn) exhibit increasing tendencies, according to the findings. The number of changes witnessed in daily maximum temperature was greater than the daily minimum temperature which was manifested by increasing diurnal temperature range (DTR; 0.012 °C/year). These changes in extremes have impacts that pose a threat to agriculture, snow day and cover, glaciers, water resources, ecosystem services, etc. of the study region. The region is undergoing significant urban and land system changes making it further vulnerable to natural hazards. The findings are expected to further augment the hazard and risk analysis and the necessary disaster risk reduction measures for climate-related disasters in the region. These analyses will be helpful for the development of strategies for climate risk management in Kashmir