First-Line Nivolumab and Relatlimab Plus Chemotherapy for Gastric or Gastroesophageal Junction Adenocarcinoma: The Phase II RELATIVITY-060 Study.

PURPOSE: Open-label phase II study (RELATIVITY-060) to investigate the efficacy and safety of first-line nivolumab, a PD-1-blocking antibody, plus relatlimab, a lymphocyte-activation gene 3 (LAG-3)-blocking antibody, plus chemotherapy in patients with previously untreated advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC). METHODS: Patients with unresectable, locally advanced or metastatic GC/GEJC were randomly assigned 1:1 to nivolumab + relatlimab (fixed-dose combination) + chemotherapy or nivolumab + chemotherapy. The primary end point was objective response rate (ORR; per RECIST v1.1 by blinded independent central review [BICR]) in patients whose tumors had LAG-3 expression ≥1%. RESULTS: Of 274 patients, 138 were randomly assigned to nivolumab + relatlimab + chemotherapy and 136 to nivolumab + chemotherapy. Median follow-up was 11.9 months. In patients with LAG-3 expression ≥1%, BICR-assessed ORR (95% CI) was 48% (38 to 59) in the nivolumab + relatlimab + chemotherapy arm and 61% (51 to 71) in the nivolumab + chemotherapy arm; median progression-free survival (95% CI) by BICR was 7.0 months (5.8 to 8.4) versus 8.3 months (6.9 to 12.1; hazard ratio [HR], 1.41 [95% CI, 0.97 to 2.05]), and median overall survival (95% CI) was 13.5 months (11.9 to 19.1) versus 16.0 months (10.9 to not estimable; HR, 1.04 [95% CI, 0.70 to 1.54]), respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 69% and 61% of all treated patients, and 42% and 36% of patients discontinued because of any-grade TRAEs in the nivolumab + relatlimab + chemotherapy and nivolumab + chemotherapy arms, respectively. CONCLUSION: RELATIVITY-060 did not meet its primary end point of improved ORR in patients with LAG-3 expression ≥1% when relatlimab was added to nivolumab + chemotherapy compared with nivolumab + chemotherapy. Further studies are needed to address whether adding anti-LAG-3 to anti-PD-1 plus chemotherapy can benefit specific GC/GEJC patient subgroups.

SUMO protease FUG1, histone reader AL3 and chromodomain protein LHP1 are integral to repeat expansion-induced gene silencing in Arabidopsis thaliana.

Epigenetic gene silencing induced by expanded repeats can cause diverse phenotypes ranging from severe growth defects in plants to genetic diseases such as Friedreich's ataxia in humans. The molecular mechanisms underlying repeat expansion-induced epigenetic silencing remain largely unknown. Using a plant model with a temperature-sensitive phenotype, we have previously shown that expanded repeats can induce small RNAs, which in turn can lead to epigenetic silencing through the RNA-dependent DNA methylation pathway. Here, using a genetic suppressor screen and yeast two-hybrid assays, we identified novel components required for epigenetic silencing caused by expanded repeats. We show that FOURTH ULP GENE CLASS 1 (FUG1)-an uncharacterized SUMO protease with no known role in gene silencing-is required for epigenetic silencing caused by expanded repeats. In addition, we demonstrate that FUG1 physically interacts with ALFIN-LIKE 3 (AL3)-a histone reader that is known to bind to active histone mark H3K4me2/3. Loss of function of AL3 abolishes epigenetic silencing caused by expanded repeats. AL3 physically interacts with the chromodomain protein LIKE HETEROCHROMATIN 1 (LHP1)-known to be associated with the spread of the repressive histone mark H3K27me3 to cause repeat expansion-induced epigenetic silencing. Loss of any of these components suppresses repeat expansion-associated phenotypes coupled with an increase in IIL1 expression with the reversal of gene silencing and associated change in epigenetic marks. Our findings suggest that the FUG1-AL3-LHP1 module is essential to confer repeat expansion-associated epigenetic silencing and highlight the importance of post-translational modifiers and histone readers in epigenetic silencing.

Age-related changes in the gut melatonin levels and its possible role in the regulation of feeding and digestibility, with the development of the gut from fingerling to adult stages of carp, Catla catla.

The present study aims to understand the feeding-related age-bound changes in gut histoarchitecture and its response to gut melatonin (GM) titer regulating major digestive enzymes in carp, Catla catla. Therefore, gut samples were collected from different growth stages of carp, viz. (i) fingerling (FL), body weight (BW) ≥ 3 g to ≤ 20 g; (ii) advanced fingerling (AFL), BW > 20 g to ≤ 40 g; (iii) early juvenile (EJv), BW > 40 g to ≤ 70 g; (iv) juvenile (Jv), BW > 70 g to ≤ 200 g; (v) late juvenile (LJv), BW > 200 g to ≤ 300 g; (vi) preadult (PA), BW > 300 g to ≤ 500 g; (vii) subadult (SA), BW > 500 g to ≤ 1.00 kg; and (viii) adult (AD), BW > 1 kg to ≤ 2.5 kg. Data analysis revealed that the highest titer of GM was noted in FL, moderate in AFL, Jv, and PA, lower in EJv, SA, and AD, and lowest in LJv. Results depicted a negative correlation between the development of the gut and its melatonin content. Moreover, GM was positively associated with feeding intensity and gastro-somatic index (GaSI) and negatively related to ovarian onset and development. Following correlation and principal component analysis, several pieces of evidence were recorded on the role of gut melatonin in regulating digestive physiology. Finally, it indicates that gut melatonin has a progressively influential role in improving digestion, particularly protein and microbial digestion, with the development of an adult gut from the fingerling stage.

Immunohematological evaluation of red cell alloimmunization and statistical assessment of various adsorption techniques in warm autoimmune hemolytic anemia.

Adsorption techniques are widely applied to detect underlying masked alloantibodies in warm autoimmune hemolytic anemia (WAIHA). We established various adsorption techniques with an aim to detect alloimmunization in WAIHA This study conducted over a period of nine years included 298 patients of WAIHA. Complete immunohematological evaluation was performed on these 298 samples following departmental protocols. Clinical and laboratory details of patients were obtained from patient files. Various adsorption methods were performed and statistically evaluated in the study. Out of 479 cases of autoimmune hemolytic anemia, WAIHA comprised of 62.2 % (N = 298). A total of 139 (46.6 %) serum samples revealed autoantibodies. Adsorption study was performed in 101 (72.7 %) indicated samples and 24 (23.8 %) of these showed 26 alloantibodies. Among the patients subjected to adsorption study hemolytic marker were significantly deranged in the alloimmunization group (p < 0.01). Polyethylene glycol (PEG) adsorption was the quickest (52.2-54.6 min) of all adsorption techniques with minimum (1.3-1.5) numbers of adsorptions needing for complete removal of serum antibodies. The LISS-papain (LP) technique was found to be more sensitive and specific compared to the other two techniques. The agreement between PEG adsorption and LP adsorption was found to be 'perfect' (96.4 %) with a Cohen's kappa (k) value of 0.9. We conclude that identification of alloantibody specificities underlying a warm autoantibody is critical for a safe and effective transfusion. All WAIHA patients with history of blood transfusion, pregnancy or both should be subjected to adsorption study. Selection of a suitable adsorption technique depends on multiple important factors.

Climate change will accelerate the high-end risk of compound drought and heatwave events.

Compound drought and heatwave (CDHW) events have garnered increased attention due to their significant impacts on agriculture, energy, water resources, and ecosystems. We quantify the projected future shifts in CDHW characteristics (such as frequency, duration, and severity) due to continued anthropogenic warming relative to the baseline recent observed period (1982 to 2019). We combine weekly drought and heatwave information for 26 climate divisions across the globe, employing historical and projected model output from eight Coupled Model Intercomparison Project 6 GCMs and three Shared Socioeconomic Pathways. Statistically significant trends are revealed in the CDHW characteristics for both recent observed and model simulated future period (2020 to 2099). East Africa, North Australia, East North America, Central Asia, Central Europe, and Southeastern South America show the greatest increase in frequency through the late 21st century. The Southern Hemisphere displays a greater projected increase in CDHW occurrence, while the Northern Hemisphere displays a greater increase in CDHW severity. Regional warmings play a significant role in CDHW changes in most regions. These findings have implications for minimizing the impacts of extreme events and developing adaptation and mitigation policies to cope with increased risk on water, energy, and food sectors in critical geographical regions.

Clinical and immunohematological characterization of autoimmune hemolytic anemia in children.

Autoimmune Hemolytic Anemia (AIHA) in childhood is uncommon and estimated to be three per million annually under 18 years of age. Detailed immunohematological and clinical characterizations are essential for correct diagnosis of the disease and its management. In this study we described AIHA in children with regards to patient demography, underlying etiology, disease classification, antibody characterization, clinical features, degree of in vivo hemolysis and transfusion management. The prospective observational study was conducted over a period of 6 years and included 29 children with newly diagnosed AIHA. Patient details were obtained from the hospital information system and patient treatment file. The median age of the children was 12 years with a female preponderance. Secondary AIHA was observed in 62.1% patients. The mean hemoglobin and reticulocyte were 7.1 gm/dL and 8.8 percentages respectively. The median polyspecific direct antiglobulin test (DAT) grading was 3+. Red cell bound multiple autoantibodies were found in 27.6% children. Free serum autoantibodies were present in 62.1% patients. Twenty six of the 42 units transfused were "best match" or "least incompatible". Follow-up of 21 children showed clinical and laboratory improvement with DAT still positive at the end of 9 months. AIHA in childhood requires advanced and efficient clinical, immunohematological and transfusion support. Detailed characterization of AIHA is important, as they determine degree of in vivo hemolysis, disease severity, serological incompatibility and necessity of blood transfusion. Although blood transfusion in AIHA is a challenge but it should not be withheld in critically ill patients.

Interaction between dry and hot extremes at a global scale using a cascade modeling framework.

Climate change amplifies dry and hot extremes, yet the mechanism, extent, scope, and temporal scale of causal linkages between dry and hot extremes remain underexplored. Here using the concept of system dynamics, we investigate cross-scale interactions within dry-to-hot and hot-to-dry extreme event networks and quantify the magnitude, temporal-scale, and physical drivers of cascading effects (CEs) of drying-on-heating and vice-versa, across the globe. We find that locations exhibiting exceptionally strong CE (hotspots) for dry-to-hot and hot-to-dry extremes generally coincide. However, the CEs differ strongly in their timescale of interaction, hydroclimatic drivers, and sensitivity to changes in the soil-plant-atmosphere continuum and background aridity. The CE of drying-on-heating in the hotspot locations reaches its peak immediately driven by the compounding influence of vapor pressure deficit, potential evapotranspiration, and precipitation. In contrast, the CE of heating-on-drying peaks gradually dominated by concurrent changes in potential evapotranspiration, precipitation, and net-radiation with the effect of vapor pressure deficit being strongly controlled by ecosystem isohydricity and background aridity. Our results help improve our understanding of the causal linkages and the predictability of compound extremes and related impacts.

Influence of immunohematological markers on severity of in vivo hemolysis in human warm autoimmune haemolytic anemia.

Autoantibody production in autoimmune haemolytic anemia (AIHA) is the result of the loss of self-immunological tolerance of the host. Here we investigated the various immunohematological markers that may influence the severity of in vivo hemolysis in warm AIHA (WAIHA). Complete direct antiglobulin test (DAT) evaluation and immunohematological characterization were performed in 247 patients of WAIHA following departmental protocols. Clinical and laboratory details of patients were obtained from patient file. The median age of WAIHA patients was 47 years with a female preponderance. Lymphoproliferative diseases were the major underlying causes of secondary WAIHA. The mean haemoglobin (Hb) and reticulocyte count (Retic) were 6.43 gm/dL and 7.58% respectively. Single autoantibody bound to red cells was investigated in 151 patients. The main IgG subclass was IgG1. Multiple autoantibodies like IgG+ C, IgG+IgA and IgG+IgA+C were found in 87 (35.2%) patients. Free autoantibodies were observed in 112 patients with a median indirect antiglobulin test (IAT) reactivity of 2+. Derangement of haematological and biochemical values was statistically significant with increase in DAT reactivity, presence of multiple autoantibodies on red cells, coating of red cells by IgG3 or multiple IgG subclass, higher DAT dilution and increasing IAT reactivity. We conclude that several important but simple immunohematological parameters may influence the degree of in vivo hemolysis in WAIHA. Since a set of common haematological and biochemical test determines the severity of in vivo hemolysis therefore a comprehensive clinical and immunohematological evaluation is advisable for a correct diagnostic and therapeutic workup of WAIHA.

Structure-Based Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation of VEGF inhibitors for the clinical treatment of Ovarian Cancer.

Vascular endothelial growth factor (VEGF) and its receptor play an important role both in physiologic and pathologic angiogenesis, which is identified in ovarian cancer progression and metastasis development. The aim of the present investigation is to identify a potential vascular endothelial growth factor inhibitor which is playing a crucial role in stimulating the immunosuppressive microenvironment in tumor cells of the ovary and to examine the effectiveness of the identified inhibitor for the treatment of ovarian cancer using various in silico approaches. Twelve established VEGF inhibitors were collected from various literatures. The compound AEE788 displays great affinity towards the target protein as a result of docking study. AEE788 was further used for structure-based virtual screening in order to obtain a more structurally similar compound with high affinity. Among the 80 virtual screened compounds, CID 88265020 explicates much better affinity than the established compound AEE788. Based on molecular dynamics simulation, pharmacophore and comparative toxicity analysis of both the best established compound and the best virtual screened compound displayed a trivial variation in associated properties. The virtual screened compound CID 88265020 has a high affinity with the lowest re-rank score and holds a huge potential to inhibit the VGFR and can be implemented for prospective future investigations in ovarian cancer.

Synthesis and thermal behaviour of thiophene-based oxazine-ring substituted benzoxazine monomers & polymers.

The latest fourth-generation oxazine-ring substituted thiophene-based benzoxazine monomers and polymers with variation in the degree of phenyl substitution (with and without) in the oxazine-ring were synthesized and characterized. Thiophene-based di-substituted benzoxazine undergoes ring-opening polymerization at a low temperature with a minimal mass loss during polymerization as supported by molecular geometry-guided intramolecular interactions. This class of monomers provides ample opportunities to design at the molecular level high-performance polybenzoxazines with promising smart applications.

Quantifying splice-site usage: a simple yet powerful approach to analyze splicing.

RNA splicing, and variations in this process referred to as alternative splicing, are critical aspects of gene regulation in eukaryotes. From environmental responses in plants to being a primary link between genetic variation and disease in humans, splicing differences confer extensive phenotypic changes across diverse organisms (1-3). Regulation of splicing occurs through differential selection of splice sites in a splicing reaction, which results in variation in the abundance of isoforms and/or splicing events. However, genomic determinants that influence splice-site selection remain largely unknown. While traditional approaches for analyzing splicing rely on quantifying variant transcripts (i.e. isoforms) or splicing events (i.e. intron retention, exon skipping etc.) (4), recent approaches focus on analyzing complex/mutually exclusive splicing patterns (5-8). However, none of these approaches explicitly measure individual splice-site usage, which can provide valuable information about splice-site choice and its regulation. Here, we present a simple approach to quantify the empirical usage of individual splice sites reflecting their strength, which determines their selection in a splicing reaction. Splice-site strength/usage, as a quantitative phenotype, allows us to directly link genetic variation with usage of individual splice-sites. We demonstrate the power of this approach in defining the genomic determinants of splice-site choice through GWAS. Our pilot analysis with more than a thousand splice sites hints that sequence divergence in cis rather than trans is associated with variations in splicing among accessions of Arabidopsis thaliana. This approach allows deciphering principles of splicing and has broad implications from agriculture to medicine.

Review on the Accelerated and Low-Temperature Polymerization of Benzoxazine Resins: Addition Polymerizable Sustainable Polymers.

Due to their outstanding and versatile properties, polybenzoxazines have quickly occupied a great niche of applications. Developing the ability to polymerize benzoxazine resin at lower temperatures than the current capability is essential in taking advantage of these exceptional properties and remains to be most challenging subject in the field. The current review is classified into several parts to achieve this goal. In this review, fundamentals on the synthesis and evolution of structure, which led to classification of PBz in different generations, are discussed. Classifications of PBzs are defined depending on building block as well as how structure is evolved and property obtained. Progress on the utility of biobased feedstocks from various bio-/waste-mass is also discussed and compared, wherever possible. The second part of review discusses the probable polymerization mechanism proposed for the ring-opening reactions. This is complementary to the third section, where the effect of catalysts/initiators has on triggering polymerization at low temperature is discussed extensively. The role of additional functionalities in influencing the temperature of polymerization is also discussed. There has been a shift in paradigm beyond the lowering of ring-opening polymerization (ROP) temperature and other areas of interest, such as adaptation of molecular functionality with simultaneous improvement of properties.

Multi-walled carbon nanotubes elicit concordant changes in DNA methylation and gene expression following long-term pulmonary exposure in mice.

Pulmonary exposure to multi-walled carbon nanotubes (MWCNTs) causes inflammation and fibrosis. Our previous work has shown that industrially produced MWCNTs trigger specific changes in gene expression in the lungs of exposed animals. To elucidate whether epigenetic effects play a role for these gene expression changes, we performed whole genome bisulphite sequencing to assess DNA methylation patterns in the lungs 56 days after exposure to MWCNTs. Lung tissues were also evaluated with respect to histopathological changes and cytokine profiling of bronchoalveolar lavage (BAL) fluid was conducted using a multi-plex array. Integrated analysis of transcriptomics data and DNA methylation data revealed concordant changes in gene expression. Functional analysis showed that the muscle contraction, immune system/inflammation, and extracellular matrix pathways were the most affected pathways. Taken together, the present study revealed that MWCNTs exert epigenetic effects in the lungs of exposed animals, potentially driving the subsequent gene expression changes.

Gut melatonin: A potent candidate in the diversified journey of melatonin research.

After being discovered from the bovine pineal gland by Aaron Lerner and co-workers in the year 1958, various distinguished researchers have reported melatonin (5-methoxy-N-acetyl-tryptamine) from several extra-pineal sources, including the gastrointestinal tract (GIT). In the year 1974, Raikhlin and Kvetnoy first detected this molecule in the gastrointestinal tissue. Later, within the last 45 years, many renowned investigators found that the GIT is a rich source of melatonin, in addition to the pineal gland. In the carp gut, the estimation of Arylalkylamine-N-acetyltransferase (AANAT) mRNA/protein levels, which is the rate-determining enzyme for melatonin biosynthesis in the pineal gland, confirmed the endogenous synthesis of melatonin. The remarkable feature of the pineal gland melatonin is its rhythmic synthesis with a peak at dark-phase and lowest at light-phase in synchronization with seasonal environmental light-dark (LD) cycle. Recent studies on carp demonstrated that the melatonin concentrations and the AANAT protein intensities in different gut segments underwent significant daily fluctuations. However, compared to the melatonin rhythm in the pineal gland, the melatonin profiles in gut tissue displayed daily rhythm in parallel with the feeding cycle of the carp, irrespective of LD conditions of the environment. Notably, in carp, the temporal pattern of the gut melatoninergic system found to vary with the environmental non-photic signal(s), such as food entrainment factors (viz. availability of food, timing of food supply, number(s) of feed per day, quality of food) those act as the most dependable synchronizer(s) in daily rhythm characteristics of gut melatonin and AANAT. Thereby in this review, it appears meaningful to highlight the existing data on the mode of synthesis of melatonin in cells of the digestive tract, and most importantly, the regulation of its synthesis. Finally, in comparison with the dynamic actions of melatonin derived from the pineal gland, this review will lead to underline the role of gut-derived melatonin in a variety of physiological functions.

Detail data of reactive extraction of caproic acid using tri-Butyl phosphate and Sunflower and Soybean oils as diluents.

Caproic acid can be produced by fermentation technology. Reactive extraction method is a promising technology for separating the acid from the carboxylic mixture in the fermenter [1], [2], [3], [4]. To achieve it, tri­butyl phosphate (TBP) is used as the reactive extractant and sunflower and soybean oils are used as the diluents. The performance of both the physical and reactive extraction processes was analysed by different parameters like distribution coefficient, loading ratio, and extraction efficiency. To meet the purpose, concentration of caproic acid in aqueous phase was measured by doing acid-base titration by caustic solution Further, reaction equilibrium constant, stoichiometry and distribution of complex, free acid and dimer concentrations in the organic phase were analysed. The data are related to the published (https://doi.org/10.1016/j.cep.2020.107926) paper in Chemical Engineering and Processing: Process Intensification [5]. The data shown in the current article are not provided in the mentioned published paper. Moreover, data are useful for understanding the physical and chemical behavior of the caproic acid extraction process and also can be used to design the process in industrial scale.

Size-Dependent Pulmonary Impact of Thin Graphene Oxide Sheets in Mice: Toward Safe-by-Design.

Safety assessment of graphene-based materials (GBMs) including graphene oxide (GO) is essential for their safe use across many sectors of society. In particular, the link between specific material properties and biological effects needs to be further elucidated. Here, the effects of lateral dimensions of GO sheets in acute and chronic pulmonary responses after single intranasal instillation in mice are compared. Micrometer-sized GO induces stronger pulmonary inflammation than nanometer-sized GO, despite reduced translocation to the lungs. Genome-wide RNA sequencing also reveals distinct size-dependent effects of GO, in agreement with the histopathological results. Although large GO, but not the smallest GO, triggers the formation of granulomas that persists for up to 90 days, no pulmonary fibrosis is observed. These latter results can be partly explained by Raman imaging, which evidences the progressive biotransformation of GO into less graphitic structures. The findings demonstrate that lateral dimensions play a fundamental role in the pulmonary response to GO, and suggest that airborne exposure to micrometer-sized GO should be avoided in the production plant or applications, where aerosolized dispersions are likely to occur. These results are important toward the implementation of a safer-by-design approach for GBM products and applications, for the benefit of workers and end-users.

Next-Generation Sequencing Reveals Differential Responses to Acute versus Long-Term Exposures to Graphene Oxide in Human Lung Cells.

Numerous studies have addressed the biological impact of graphene-based materials including graphene oxide (GO), yet few have focused on long-term effects. Here, RNA sequencing is utilized to unearth responses of human lung cells to GO. To this end, the BEAS-2B cell line derived from normal human bronchial epithelium is subjected to repeated, low-dose exposures of GO (1 or 5 µg mL-1 ) for 28 days or to the equivalent, cumulative amount of GO for 48 h. Then, samples are analyzed by using the NovaSeq 6000 sequencing system followed by pathway analysis and gene ontology enrichment analysis of the differentially expressed genes. Significant differences are seen between the low-dose, long-term exposures and the high-dose, short-term exposures. Hence, exposure to GO for 48 h results in mitochondrial dysfunction. In contrast, exposure to GO for 28 days is characterized by engagement of apoptosis pathways with downregulation of genes belonging to the inhibitor of apoptosis protein (IAP) family. Validation experiments confirm that long-term exposure to GO affects the apoptosis threshold in lung cells, accompanied by a loss of IAPs. These studies reveal the sensitivity of RNA-sequencing approaches and show that acute exposure to GO is not a good predictor of the long-term effects of GO.

In Silico Insights on GD2 : A Potential Target for Pediatric Neuroblastoma.

BACKGROUND: Originating from the abnormal growth of neuroblasts, pediatric neuroblastoma affects the age group below 15 years. It is an aggressive heterogenous cancer with a high morbidity rate. Biological marker GD2 synthesised by the GD2 gene acts as a powerful predictor of neuroblastoma cells. GD2 gangliosides are sialic acid-containing glycosphingolipids. Differential expression during brain development governs the function of the GD2. The present study explains the interaction of the GD2 with its established inhibitors and discovers the compound having a high binding affinity against the target protein. Technically, during the development of new compounds through docking studies, the best drug among all pre-exist inhibitors was filtered. Hence in reference to the best docked compound, the study proceeded further. METHODOLOGY: The In silico approach provides a platform to determine and establish potential inhibitor against GD2 in Pediatric neuroblastoma. The 3D structure of GD2 protein was modelled by homology base fold methods using Smith-Watermans' Local alignment. A total of 18 established potent compounds were subjected to molecular docking and Etoposide (CID: 36462) manifested the highest affinity. The similarity search presented 336 compounds similar to Etoposide. RESULTS: Through virtual screening, the compound having PubChem ID 10254934 showed a better affinity towards GD2 than the established inhibitor. The comparative profiling of the two compounds based on various interactions such as H-bond interaction, aromatic interactions, electrostatic interactions and ADMET profiling and toxicity studies were performed using various computational tools. CONCLUSION: The docking separated the virtual screened drug (PubChemID: 10254934) from the established inhibitor with a better re-rank score of -136.33. The toxicity profile of the virtual screened drug was also lesser (less lethal) than the established drug. The virtual screened drug was observed to be bioavailable as it does not cross the blood-brain barrier. Conclusively, the virtual screened compound obtained in the present investigation is better than the established inhibitor and can be further augmented by In vitro analysis, pharmacodynamics and pharmacokinetic studies.

Design of PD-L1 inhibitors for lung cancer.

The progression of lung cancer is associated with inactivation of programmed cell death protein 1, abbreviated as PD- 1 which regulates the suppression of the body's immune system by suppressing T- cell inflammatory activity and is responsible for preventing cancer cell growth. It is of interest to identify inhibitors for PD-L1 dimeric structure through molecular docking and virtual screening. The virtual screened compound XGIQBUNWFCCMAS-UHFFFAOYSA-N (PubChem CID: 127263272) displays a high affinity with the target protein. ADMET analysis and cytotoxicity studies further add weight to this compound as a potential inhibitor of PD-L1. The established compound BMS-202 still shows the high re-rank score, but the virtual screened drug possesses a better ADMET profile with a higher intestinal absorption value and lower toxicity.