Exploring the geotechnical and microstructural properties of composite mixtures for landfill liner materials: an experimental investigation.

The present study directs the need for the development of an economical composite mix comprised locally available soil and industrial waste which satisfy the design parameters of the municipal solid waste (MSW) landfill. The local soil, bentonite, and fly ash mixtures are mixed in different proportions to evaluate the geotechnical and microstructural characteristics for suggesting an optimum composite mix that fulfills the design parameters of landfill liners. The curing periods of different mixes are also considered while evaluating the unconfined compressive strength (UCS) characteristics. The microstructure of the mixtures is examined using advanced imaging techniques, including X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDAX) to gain insights into the changes at the microscale level due to the inclusion of fly ash. It is observed that soil-bentonite-fly ash composite mix in a ratio of 65:15:20 aligns with the optimal design characteristics required for a landfill liner. Notably, for this composite mix, both liquid limit (LL) and plastic limit (PL) show a significant increase of 48.57% and 32.33% respectively, while the optimum moisture content (OMC) rises by 11.25%. Conversely, maximum dry density (MDD) experiences an 8.79% decrease. Moreover, the free swell index (FSI) escalates by 113%, whereas hydraulic conductivity (HC) records a substantial reduction of 96.04%. Moreover, the UCS exhibited a notable increase of 209% after a 28-day curing period. The highest strength is achieved initially by soil mixed with 20% fly ash, followed by a blend containing 15% bentonite. Therefore, proper fly ash content in filler and other binder materials is an effective and sustainable approach that not only solves the disposal issue but also enhances the material's engineering characteristics, justifying its suitability to be used as a landfill liner.

Cell-free DNA methylation in the clinical management of lung cancer.

The clinical use of cell-free DNA (cfDNA) methylation in managing lung cancer depends on its ability to differentiate between malignant and healthy cells, assign methylation changes to specific tissue sources, and elucidate opportunities for targeted therapy. From a technical standpoint, cfDNA methylation analysis is primed as a potential clinical tool for lung cancer screening, early diagnosis, prognostication, and treatment, pending the outcome of elaborate validation studies. Here, we discuss the current state of the art in cfDNA methylation analysis, examine the unique features and limitations of these new methods in a clinical context, propose two models for applying cfDNA methylation data for lung cancer screening, and discuss future research directions.

Proteomic and metabolomic insights into seed germination of Ferula assa-foetida.

Cold stratification is known to affect the speed of seed germination; however, its regulation at the molecular level in Ferula assa-foetida remains ambiguous. Here, we used cold stratification (4 °C in the dark) to induce germination in F. assa-foetida and adopted a proteomic and metabolomic approach to understand the molecular mechanism of germination. Compared to the control, we identified 209 non-redundant proteins and 96 metabolites in germinated F. assa-foetida seed. Results highlight the common and unique regulatory mechanisms like signaling cascade, reactivation of energy metabolism, activation of ROS scavenging system, DNA repair, gene expression cascade, cytoskeleton, and cell wall modulation in F. assa-foetida germination. A protein-protein interaction network identifies 18 hub protein species central to the interactome and could be a key player in F. assa-foetida germination. Further, the predominant metabolic pathways like glucosinolate biosynthesis, arginine and proline metabolism, cysteine and methionine metabolism, aminoacyl-tRNA biosynthesis, and carotenoid biosynthesis in germinating seed may indicate the regulation of carbon and nitrogen metabolism is prime essential to maintain the physiology of germinating seedlings. The findings of this study provide a better understanding of cold stratification-induced seed germination, which might be utilized for genetic modification and traditional breeding of Ferula assa-foetida. SIGNIFICANCE: Seed germination is the fundamental checkpoint for plant growth and development, which has ecological significance. Ferula assa-foetida L., commonly known as "asafoetida," is a medicinal and food crop with huge therapeutic potential. To date, our understanding of F. assa-foetida seed germination is rudimentary. Therefore, studying the molecular mechanism that governs dormancy decay and the onset of germination in F. assa-foetida is essential for understanding the basic principle of seed germination, which could offer to improve genetic modification and traditional breeding.

Exploring the Influence of Nanocrystalline Structure and Aluminum Content on High-Temperature Oxidation Behavior of Fe-Cr-Al Alloys.

The present study examines the high-temperature (500-800 °C) oxidation behavior of Fe-10Cr-(3,5) Al alloys and studies the effect of nanocrystalline structure and Al content on their resistance to oxidation. The nanocrystalline (NC) alloy powder was synthesized via planetary ball milling. The prepared NC alloy powder was consolidated using spark plasma sintering to form NC alloys. Subsequently, an annealing of the NC alloys was performed to transform them into microcrystalline (MC) alloys. It was observed that the NC alloys exhibit superior resistance to oxidation compared to their MC counterparts at high temperatures. The superior resistance to oxidation of the NC alloys is attributed to their considerably finer grain size, which enhances the diffusion of those elements to the metal-oxide interface that forms the protective oxide layer. Conversely, the coarser grain size in MC alloys limits the diffusion of the oxide-forming components. Furthermore, the Fe-10Cr-5Al alloy showed greater resistance to oxidation than the Fe-10Cr-3Al alloy.

Clinical outcomes of ROS1-positive non-small cell lung cancer with limited access to ROS1-tyrosine kinase inhibitors (TKIs): experience from an Indian tertiary referral centre.

Introduction: ROS1 as a driver mutation is observed in approximately 1%-2% of all non-small cell lung cancer (NSCLC). Given its rarity, we share our experience regarding ROS1-positive NSCLC including the access to ROS1 tyrosine kinase inhibitors (TKIs) in a low-middle income country like India. Methods: It is a retrospective analysis of ROS1-positive NSCLC patients registered between January 2015 to December 2021 for demographics, treatment patterns and outcomes i.e., overall survival (OS) and progression free survival (PFS). Results: Baseline characteristics were available for 70 patients of 78 patients positive for ROS1 by fluorescent in situ hybridisation. Median age at presentation was 52 years, 39 (55.7%) were males, most (51, 72.86%) were non-smokers and ten patients (14.3%) had poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) i.e., PS >2 at presentation. A total of 67 patients receiving cancer directed therapy were analysed for survival. The first line (1L) therapies included - ROS1 TKIs in 38, chemotherapy in 20, epidermal growth factor receptor TKI in eight and chemotherapy-bevacizumab in one only. ROS1 TKI was provided to 20 patients as part of an assistance programme. The median OS for patients who received ROS1 TKI was not attained (95% CI 37.85-NA), while it was 8.11 (95% CI 6.31-NA) months for those who did not (HR-0.1673). The median PFS for the 1L ROS1 TKI compared to the no-TKI group was 27.07 (95% CI 24.28-NA) months versus 5.78 (95% CI 3.42-12) months (HR: 0.2047). Poor ECOG PS at presentation was the only independent prognosticator for survival. Conclusion: Using ROS1 TKI improves clinical outcomes in all-comers though statistically not significant. To further improve outcomes, future trials should pay special attention to patients with poor PS and find a way to increase the current limited access to TKI.

Altered IL-7 signaling in CD4+ T cells from patients with visceral leishmaniasis.

BACKGROUND: CD4+ T cells play a central role in control of L. donovani infection, through IFN-γ production required for activation of macrophages and killing of intracellular parasites. Impaired control of parasites can in part be explained by hampered CD4+ T cells effector functions in visceral leishmaniasis (VL) patients. In a recent studies that defined transcriptional signatures for CD4+ T cells from active VL patients, we found that expression of the IL-7 receptor alpha chain (IL-7Rα; CD127) was downregulated, compared to CD4+ T cells from endemic controls (ECs). Since IL-7 signaling is critical for the survival and homeostatic maintenance of CD4+ T cells, we investigated this signaling pathway in VL patients, relative to ECs. METHODS: CD4+ T cells were enriched from peripheral blood collected from VL patients and EC subjects and expression of IL7 and IL7RA mRNA was measured by real time qPCR. IL-7 signaling potential and surface expression of CD127 and CD132 on CD4+ T cell was analyzed by multicolor flow cytometry. Plasma levels of soluble IL-7 and sIL-7Rα were measured by ELISA. RESULT: Transcriptional profiling data sets generated previously from our group showed lower IL7RA mRNA expression in VL CD4+ T cells as compared to EC. A significant reduction was, however not seen when assessing IL7RA mRNA by RT-qPCR. Yet, the levels of soluble IL-7Rα (sIL-7Rα) were reduced in plasma of VL patients compared to ECs. Furthermore, the levels of soluble IL-7 were higher in plasma from VL patients compared to ECs. Interestingly, expression of the IL-7Rα protein was higher on VL patient CD4+ T cells as compared to EC, with activated CD38+ CD4+ T cells showing higher surface expression of IL-7Rα compared to CD38- CD4+ T cells in VL patients. CD4+ T cells from VL patients had higher signaling potential baseline and after stimulation with recombinant human IL-7 (rhIL-7) compared to EC, as measured by phosphorylation of STAT5 (pSTAT5). Interestingly, it was the CD38 negative cells that had the highest level of pSTAT5 in VL patient CD4+ T cells after IL-7 stimulation. Thus, despite unaltered or potentially lowered IL7RA mRNA expression by CD4+ T cells from VL patients, the surface expression of the IL-7Rα was higher compared to EC and increased pSTAT5 was seen following exposure to rhIL-7. Accordingly, IL-7 signaling appears to be functional and even enhanced in VL CD4+ T cells and cannot explain the impaired effector function of VL CD4+ T cells. The enhanced plasma IL-7 may serve as part of homeostatic feedback mechanism regulating IL7RA expression in CD4+ T cells.

Neighbouring effect of land use changes and fire emissions on atmospheric CO2 and CH4 over suburban region of India (Shadnagar).

The present study investigated the effects of land use/land cover (LU/LC) changes on atmospheric carbon dioxide (CO2) and methane (CH4) concentrations over the sub-urban region of India (Shadnagar) using continuous decadal CO2 and CH4in-situ data measured by the greenhouse gas analyser (GGA). Data was collected from 2013 to 2022 at a 1 Hz frequency. Analysis of the current study indicates that during pre-monsoon, the seasonal maximum of CO2 was 409.91 ± 9.26 ppm (µ ± 1σ), while the minimum during monsoon was about 401.64 ± 7.13 ppm. Post-monsoon has a high seasonal mean CH4 concentration of 2.08 ± 0.06 ppm, while monsoon has a low seasonal mean CH4 concentration of 1.88 ± 0.03 ppm. The primary classes, such as forest, crop, and built-up, were considered to estimate the effect of LU/LC changes on atmospheric CO2 and CH4 concentrations. Between 2005 and 2021, the study's results show that the built-up area at radii of 10 km, 20 km, and 50 km increased by 0.17 %, 0.10 %, and 0.4 %, respectively. While other LU/LC categories declined by 30 %, agriculture areas increased by 30 % on average. As a result, the CO2 and CH4 concentrations at the study site are increased by 6 % (26 ppm) and 6.5 % (140 ppb), respectively. The present study utilised the fire-based carbon emissions data from the Global Fire Emissions Database (GFED) to understand the impact on atmospheric CO2 and CH4. Analysis of the present work investigated the influence of transported airmass on CO2 and CH4 during the pre-monsoon and post-monsoon seasons using the HYSPLIT trajectories and found emissions were from the northwest, southeast, and northeast of the study site. Further, in-situ CO2 and CH4 records are compared against the MIROC4-ACTM simulation, and strong agreement was found with bias of 1.80 ppm and 0.98 ppb for CO2 and CH4, respectively.

Functional trait correlation network and proteomic analysis reveal multifactorial adaptation mechanisms to a climatic gradient associated with high altitude in the Himalayan region.

Globally occurring changes in environmental conditions necessitate extending our knowledge of the system-level mechanisms underlying plant adaptation to multifactorial stress conditions or stress combinations. This is crucial for designing new strategies to maintain plant performance under simultaneous abiotic pressure. Here, we conducted our study at Rohtang Pass and sampled Picrorhiza kurroa leaves along high-altitude gradient (3400, 3800 and 4100 meters above sea level) in the western Himalayas. The results showed the functional traits associated with morpho-anatomical structures and eco-physiological performances are highly variable. The air temperature and relative humidity represent dominant environmental factors among others that significantly regulate plant's physiological performance by adjusting the functional traits in altitude-specific manner. A trait coordination network is developed among significantly altered plant functional traits, which reveals high-altitude associated trait-based adaptation. Moreover, it reveals leaf area shows the highest degree, while photochemical quenching reflects the weighted degree of centrality in the network. Proteomic analysis reveals various stress-responsive proteins, including antioxidants were accumulated to deal with combined stress factors. Furthermore, a high-altitudinal protein interaction network unravels key players of alpine plant adaptation processes. Altogether, these systems demonstrate a complex molecular interaction web extending the current knowledge of high-altitudinal alpine plant adaptation, particularly in an endangered medicinal herb, P. kurroa.

Fracture Risk Among Living Kidney Donors 25 Years After Donation.

Importance: Living kidney donors may have an increased risk of fractures due to reductions in kidney mass, lower concentrations of serum 1,25-dihydroxyvitamin D, and secondary increases in serum parathyroid hormone. Objective: To compare the overall and site-specific risk of fractures among living kidney donors with strictly matched controls from the general population who would have been eligible to donate a kidney but did not do so. Design, Setting, and Participants: This survey study was conducted between December 1, 2021, and July 31, 2023. A total of 5065 living kidney donors from 3 large transplant centers in Minnesota were invited to complete a survey about their bone health and history of fractures, and 16 156 population-based nondonor controls without a history of comorbidities that would have precluded kidney donation were identified from the Rochester Epidemiology Project and completed the same survey. A total of 2132 living kidney donors and 2014 nondonor controls responded to the survey. Statistical analyses were performed from May to August 2023. Exposure: Living kidney donation. Main Outcomes and Measures: The rates of overall and site-specific fractures were compared between living kidney donors and controls using standardized incidence ratios (SIRs). Results: At the time of survey, the 2132 living kidney donors had a mean (SD) age of 67.1 (8.9) years and included 1245 women (58.4%), and the 2014 controls had a mean (SD) age of 68.6 (7.9) years and included 1140 women (56.6%). The mean (SD) time between donation or index date and survey date was 24.2 (10.4) years for donors and 27.6 (10.7) years for controls. The overall rate of fractures among living kidney donors was significantly lower than among controls (SIR, 0.89; 95% CI, 0.81-0.97). However, there were significantly more vertebral fractures among living kidney donors than among controls (SIR, 1.42; 95% CI, 1.05-1.83). Conclusions and Relevance: This survey study found a reduced rate of overall fractures but an excess of vertebral fractures among living kidney donors compared with controls after a mean follow-up of 25 years. Treatment of excess vertebral fractures with dietary supplements such as vitamin D3 may reduce the numbers of vertebral fractures and patient morbidity.

Cholesterol Homeostasis, Mechanisms of Molecular Pathways, and Cardiac Health: A Current Outlook.

The metabolism of lipoproteins, which regulate the transit of the lipid to and from tissues, is crucial to maintaining cholesterol homeostasis. Cardiac remodeling is referred to as a set of molecular, cellular, and interstitial changes that, following injury, affect the size, shape, function, mass, and geometry of the heart. Acetyl coenzyme A (acetyl CoA), which can be made from glucose, amino acids, or fatty acids, is the precursor for the synthesis of cholesterol. In this article, the authors explain concepts behind cardiac remodeling, its clinical ramifications, and the pathophysiological roles played by numerous various components, such as cell death, neurohormonal activation, oxidative stress, contractile proteins, energy metabolism, collagen, calcium transport, inflammation, and geometry. The levels of cholesterol are traditionally regulated by 2 biological mechanisms at the transcriptional stage. First, the SREBP transcription factor family regulates the transcription of crucial rate-limiting cholesterogenic and lipogenic proteins, which in turn limits cholesterol production. Immune cells become activated, differentiated, and divided, during an immune response with the objective of eradicating the danger signal. In addition to creating ATP, which is used as energy, this process relies on metabolic reprogramming of both catabolic and anabolic pathways to create metabolites that play a crucial role in regulating the response. Because of changes in signal transduction, malfunction of the sarcoplasmic reticulum and sarcolemma, impairment of calcium handling, increases in cardiac fibrosis, and progressive loss of cardiomyocytes, oxidative stress appears to be the primary mechanism that causes the transition from cardiac hypertrophy to heart failure. De novo cholesterol production, intestinal cholesterol absorption, and biliary cholesterol output are consequently crucial processes in cholesterol homeostasis. In the article's final section, the pharmacological management of cardiac remodeling is explored. The route of treatment is explained in different steps: including, promising, and potential strategies. This chapter offers a brief overview of the history of the study of cholesterol absorption as well as the different potential therapeutic targets.

Emerging role of miR-320a in lung cancer: a comprehensive review.

A specialized biomarker(s) for lung cancer is imperative owing to its high mortality. Continuing our earlier work demonstrating the role of miR-320a as a tumor suppressor, here we discuss the most recent updates on miR-320a in lung cancer pathogenesis. We found that miR-320a modulates levels of diverse cancer-associated molecules and signaling pathways, and is also involved in modulating the immune microenvironment of lung cancer during its pathogenesis. We also discuss how miR-320a encapsulated in exosomes inhibits invasive phenotypes of lung cancer. Therefore, based on the multimodal role of miR-320a in lung cancer development and progression, we believe that miR-320a may be utilized as a potential diagnostic/prognostic marker and therapeutic target for lung cancer patients.

Design, synthesis, biological evaluations and in silico studies of N-substituted 2,4-thiazolidinedione derivatives as potential a-glucosidase inhibitors.

Diabetes mellitus is considered as one of the principal global health urgencies of the twenty first century. In the present investigation, novel N-substituted 2,4-thiazolidinedione derivatives were designed, synthesized, and characterized by spectral techniques. All the newly synthesized N-substituted 2,4-thiazolidinedione derivatives were tested for in vitro α-glucosidase inhibitory activities and compounds A-12 and A-14 were found to be the most potent which were further subjected to in-vivo disaccharide loading test. The most potent compound was also found to be non-toxic in cytotoxicity studies. Further, docking studies were carried out to investigate the binding mode and key interactions with amino acid residues of α-glucosidase. Molecular dynamic simulations studies for the compounds acarbose, A2, A12, and A14 were done with α-glucosidase protein. Further, ΔG was calculated for acarbose, A2, A12, and A14. In silico studies and absorption, distribution, metabolism, excretion (ADME) prediction studies were also executed to establish the 'druggable' pharmacokinetic profiles. Here, we have developed novel N-substituted TZD analogues with different alkyl groups as α-glucosidase inhibitors.Communicated by Ramaswamy H. Sarma.

Clinical, histological, and molecular differences in melanoma due to different TERT promoter mutations subtypes. A retrospective cross-sectional study in 684 melanoma patients.

Differences in survival according to the pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT) have been observed. The present study aimed to describe the clinical as the histopathological and molecular cutaneous melanoma features according to the presence of the three most prevalent pTERT mutation subtypes (-124C > T, -146C > T, and tandem -138_139CC > TT). A retrospective cross-sectional study including 684 patients was designed, and a Partial Least-Squares Discriminant Analysis (PLS-DA) was performed. After the PSL-DA, it was observed that the tandem -138_139CC > TT subtype differs from the other subtypes. The model demonstrated that the -124C > T and the -138_139 CC > TT subtypes were associated with fast-growing melanomas (OR 0.5, CI 0.29-0.86, p = .012) and with Breslow >2 mm (OR 0.6, CI 0.37-0.97, p = .037), compared to the -146C > T mutation. Finally, the -124C > T appeared to be more associated with the presence of TILs (non-brisk) than the -146C > T (OR 0.6, CI 0.40-1.01, p = .05). These findings confirmed that the -124C > T and the tandem -138_139 CC > TT subtypes are both highly associated with the presence of features of aggressiveness; however, only the -124C > T was highly associated with TILs. This difference could explain the worse survival rate associated with the tandem -138_139CC > TT mutations.

Taenia solium excretory secretory proteins (ESPs) suppresses TLR4/AKT mediated ROS formation in human macrophages via hsa-miR-125.

BACKGROUND: Helminth infections are a global health menace affecting 24% of the world population. They continue to increase global disease burden as their unclear pathology imposes serious challenges to patient management. Neurocysticercosis is classified as neglected tropical disease and is caused by larvae of helminthic cestode Taenia solium. The larvae infect humans and localize in central nervous system and cause NCC; a leading etiological agent of acquired epilepsy in the developing world. The parasite has an intricate antigenic make-up and causes active immune suppression in the residing host. It communicates with the host via its secretome which is complex mixture of proteins also called excretory secretory products (ESPs). Understanding the ESPs interaction with host can identify therapeutic intervention hot spots. In our research, we studied the effect of T. solium ESPs on human macrophages and investigated the post-translation switch involved in its immunopathogenesis. METHODOLOGY: T. solium cysts were cultured in vitro to get ESPs and used for treating human macrophages. These macrophages were studied for cellular signaling and miR expression and quantification at transcript and protein level. CONCLUSION: We found that T. solium cyst ESPs treatment to human macrophages leads to activation of Th2 immune response. A complex cytokine expression by macrophages was also observed with both Th1 and Th2 cytokines in milieu. But, at the same time ESPs modulated the macrophage function by altering the host miR expression as seen with altered ROS activity, apoptosis and phagocytosis. This leads to activated yet compromised functional macrophages, which provides a niche to support parasite survival. Thus T. solium secretome induces Th2 phenomenon in macrophages which may promote parasite's survival and delay their recognition by host immune system.

Nanotoxicity of multifunctional stoichiometric cobalt oxide nanoparticles (SCoONPs) with repercussions toward apoptosis, necrosis, and cancer necrosis factor (TNF-α) at nano-biointerfaces.

Introduction: Apoptosis, necrosis, and cancer necrosis factor (TNF-a) are all impacted by the nanotoxicity of multifunctional stoichiometric cobalt oxide nanoparticles (SCoONPs) at nano-biointerfaces. The creation of multi-functional nanoparticles has had a considerable impact on the transport of drugs and genes, nanotheranostics (in-vivo imaging, concurrent diagnostics), interventions for external healing, the creation of nano-bio interfaces, and the instigation of desired changes in nanotherapeutics. Objectives: The quantitative structure-activity relationships, chemical transformations, biological interactions as well as toxicological analyses are considered as main objectives. Discrete dimensions of SCoNPs-cell interaction interfaces, their characteristic physical features (size, shape, shell structure, and surface chemistry), impact on cell proliferation and differentiation are the key factors responsible for nanotoxicity. Methods: The development of multi-functional nanoparticles has been significant in drug/gene delivery, nanotheranostics (in-vivo imaging, coinciding diagnostics), and external healing interventions, designing a nano-bio interface, as well as inciting desired alterations in nanotherapeutics. Every so often, the cellular uptake of multi-functional cobalt [Co, CoO, Co2(CO)8 and Co3O4] nanoparticles (SCoONPs) influences cellular mechanics and initiates numerous repercussions (oxidative stress, DNA damage, cytogenotoxicity, and chromosomal damage) in pathways, including the generation of dysregulating factors involved in biochemical transformations. Results: The concerns and influences of multifunctional SCoNPs on different cell mechanisms (mitochondria impermeability, hydrolysis of ATP, the concentration of Ca2+, impaired calcium clearance, defective autophagy, apoptosis, and necrosis), and interlinked properties (adhesion, motility, and internalization dynamics, role in toxicity, surface hydrophilic and hydrophobicity, biokinetics and biomimetic behaviors of biochemical reactions) have also been summarized. SCoONPs have received a lot of interest among the nanocarriers family because of its advantageous qualities such as biodegradability, biocompatibility, nontoxicity, and nonimmunogenicity. Conclusion: Various applications, such as bio-imaging, cell labeling, gene delivery, enhanced chemical stability, and increased biocompatibility, concerning apoptosis, necrosis, and nano-bio interfaces, along with suitable examples. In this analysis, the multi-functional cobalt [Co, CoO, Co2(CO)8 and Co3O4] nanoparticles (SCoNPs) intricacies (cytogenotoxicity, clastogenicity, and immunomodulatory), nanotoxicity, and associated repercussions have been highlighted and explained.

Long-Term Outcomes of Crizotinib Treated ALK-Positive Lung Cancer Patients: A Retrospective Audit of Prospective Data from Resource-Constrained Settings.

Akhil KapoorPurpose Crizotinib has been one of the standard treatment options for the treatment of anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) based on higher progression-free survival (PFS) and objective response rates in phase III clinical trials. However, real-world data about the long-term efficacy and toxicity of crizotinib is limited. Methods A retrospective analysis of all patients with ALK-positive NSCLC, treated with crizotinib between March 2014 and December 2016, was performed. The main outcomes measured were PFS, overall survival (OS), and adverse effects. Results One hundred and eighty-eight patients treated with crizotinib during this period were included in this study. The median age was 50 years (range: 24-74) with a majority being males (73.2%) and 80.3% with a performance status of 0 to 1. The median duration of follow-up was 49.4 months (range: 3.4-86.3%). The median PFS of crizotinib was 17.3 months (95% confidence interval [CI], 13.0-21.6) and 12.8 months (95% CI, 8.1-17.6) when used in first line or subsequent lines, respectively. The median OS was 38.3 months (95% CI, 28.4-48.2). The patients who received crizotinib in the first line had a median OS of 45.5 months (95% CI, 29.6-61.4) as compared with 29.7 months (95% CI, 22.2-37.2) for those who received in subsequent line (hazard ratio, 0.6, 95% CI, 0.4-0.9, p =0.022). The most common all grade toxicities include transaminitis, anemia, fatigue, and corrected QT prolongation. Conclusion This real-world study confirms the long-term beneficial effects of crizotinib in ALK rearranged NSCLC with favorable toxicity profile like that of the registration studies, in resource constrained settings.

Bone marrow transplant: A two-decade single centre hematology experience.

Background: Bone Marrow Transplant (BMT) is a curative form of therapy for many hematological disorders in both the adult and pediatric patients. The availability of BMT in the AFMS at AHRR for the last 02 decades has been a game changer for the patients. Methods: We reviewed our BMT data since the inception of the program till Feb 2023. Results: Over 700 patients with more than 23 different types of hematological disorders have undergone this procedure 58%% patients underwent an Autologous BMT and 42% an allogenic BMT. Autologous BMT for Multiple Myeloma and Allogenic BMT for Aplastic Anemia and Acute Leukemias have been the most common indications. 73% patients were adults, and 27% patients were of the pediatric age group. The male: female ratio was 2:1. The spectrum of allogenic Hematopoietic Stem Cell Transplant (HSCT) has expanded from Matched Sibling Donor (MSD) transplants to Matched Unrelated Donor (MUD) Transplants and Haploidentical Donor Transplants. 93% of our Allogenic BMT patients underwent a MSD BMT, 1% MUD BMT and 06% Haploidentical BMT. Today no patient with a malignant hematological disorder requiring a BMT is denied the procedure due to the lack of an HLA donor due to the availability of haploidentical BMT. Conclusion: The evolution of a BMT program has a long learning curve and the expanded pool of eligible donors has led to a situation of "transplant for all". Haploidentical HSCT for nonmalignant hematological disorders is an unmet need. CART cell therapy and Cellular therapies need to be prioritized for future inclusion.

Successful T replete haploidentical HSCT with post-transplant cyclophosphamide in two patients with Wiskott-Aldrich syndrome.

We describe two young patients with Wiskott-Aldrich Syndrome (WAS) who were treated by T-replete hematopoietic stem cell transplantation (HSCT) from the HLA haploidentical father according to a modified Baltimore protocol. Whereas similar protocols have been successfully used in various malignant and non-malignant diseases, this is the first report for this particular disease. The data being presented pertains to the report about two successful haploidentical transplants with post transplant cyclophosphamide (PTCY) after busulfan-based conditioning.

A molecular signature for IL-10-producing Th1 cells in protozoan parasitic diseases.

Control of visceral leishmaniasis (VL) depends on proinflammatory Th1 cells that activate infected tissue macrophages to kill resident intracellular parasites. However, proinflammatory cytokines produced by Th1 cells can damage tissues and require tight regulation. Th1 cell IL-10 production is an important cell-autologous mechanism to prevent such damage. However, IL-10-producing Th1 (type 1 regulatory; Tr1) cells can also delay control of parasites and the generation of immunity following drug treatment or vaccination. To identify molecules to target in order to alter the balance between Th1 and Tr1 cells for improved antiparasitic immunity, we compared the molecular and phenotypic profiles of Th1 and Tr1 cells in experimental VL caused by Leishmania donovani infection of C57BL/6J mice. We also identified a shared Tr1 cell protozoan signature by comparing the transcriptional profiles of Tr1 cells from mice with experimental VL and malaria. We identified LAG3 as an important coinhibitory receptor in patients with VL and experimental VL, and we reveal tissue-specific heterogeneity of coinhibitory receptor expression by Tr1 cells. We also discovered a role for the transcription factor Pbx1 in suppressing CD4+ T cell cytokine production. This work provides insights into the development and function of CD4+ T cells during protozoan parasitic infections and identifies key immunoregulatory molecules.