A Comprehensive Review of the Diverse Spectrum Activity of 1,2,3-Triazole-linked Isatin Hybrids.

Heterocyclic compounds containing 1,2,3-triazole and isatin as core structures have emerged as promising drug candidates due to their diverse biological activities such as anti-cancer, antifungal, antimicrobial, antitumor, anti-epileptic, antiviral, and more. The presence of 1,2,3-triazoles and isatin heterocycles in these hybrids, both individually known for their medicinal significance, has increasingly piqued the interest of drug discovery researchers, as they seek to delve deeper into their extensive pharmacological potential for enhancing therapeutic efficacy. Moreover, these hybrid compounds are synthetically accessible using readily available materials. Therefore, there is a pressing need to provide a comprehensive overview of the existing knowledge in this field, offering valuable insights to readers and paving the way for the discovery of novel 1,2,3-triazole-linked isatin hybrids with therapeutic potential.

Salvage Using Polatuzumab Vedotin Based Therapy in Relapsed Refractory Large B-Cell Lymphomas: Early Experience from a Real-World Middle-Income Setting Using Named-Patient Compassionate Access Program.

Polatuzumab vedotin is a novel immunotherapy antibody-drug conjugate targeting CD79b. It has been used in relapsed/refractory (R/R) large B-cell lymphomas since its FDA approval in 2019. Presently, this drug is unaffordable or unavailable for patients in Lower-Middle Income Countries (LMIC) like India. This is a retrospective study of adult (> 18 years) patients with R/R large B-cell lymphoma failing two prior lines of therapy, who received Polatuzumab based salvage therapy on a compassionate or named-patient access program. Between May 2019 and April 2022, 10 patients received Polatuzumab vedotin, and 9 were evaluable. The most common regimen used was Polatuzumab-Bendamustine-Rituximab. Out of 43 infusions administered, the adverse event profile was manageable [One grade-2 infusion reaction, 4 patients developed grade 3-4 hematological toxicity and none had grade 3-4 non-hematological toxicities]. Ten infusions were administered in the day care service. After a median of 4.5 cycles (range 1-8), 4 patients achieved CR, 2 had partial response (PR), and 3 had progressive disease (PD). With a median follow up of 491 days (range 8-1048 days), four patients are alive (three in CR and one in PR), three patients have died and three patients were lost to follow up. Early real-world experience from a LMIC setting demonstrates feasibility and a favourable safety profile of Polatuzumab vedotin based approach, along with encouraging response rates in a subset of patients.

Structural Analysis of Diastereomeric Cardiac Glycosides and Their Genins Using Ultraperformance Liquid Chromatography-Tandem Mass Spectrometry.

Ultraperformance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) is an economical and indispensable tool in natural product research to investigate novel metabolites, biomarker discovery, chemical diversity exploration, and structure elucidation. In this study, the structural analysis of 38 naturally occurring cardiac glycosides (CGs) in various tissues of Nerium oleander was achieved by the extensive use of mass spectrometry. The chemical diversity of CGs was described on the basis of characteristic MS/MS fragmentation patterns, accurate mass measurement, and published scientific information on CGs from Nerium oleander. It was observed that only six genins, viz., Δ16anhydrogitoxigenin, Δ16adynerigenin, gitoxigenin, oleandrigenin, digitoxigenin, and adynerigenine, produce 38 diverse chemical structures of CGs. Among them, 20 were identified as diastereomers having a difference in a sugar (l-oleandrose, ß-d-diginose, and ß-d-sarmentose) unit. However, the differentiation of diastereomeric CGs was not possible by only MS/MS fragments. Thus, the diastereomer's chromatographic elution order was assigned on the basis of the relative retention time (RRt) of two reference standards (odoroside A and oleandrin) among their diastereomers. Besides this, the in-source fragmentation of CGs and the MS/MS of m/z 325 and 323 disaccharide daughter ions also exposed the intrinsic structure information on the sugar units. The daughter ions m/z 162, 145, 113, 95, and 85 in MS/MS spectra indicated the abundance of l-oleandrose, ß-d-diginose, and ß-d-sarmentose sugars. At the same time, m/z 161, 143, 129, and 87 product ions confirmed the presence of a ß-d-digitalose unit. As a result, the UPLC-ESI/TQD system was successfully utilized for the structure characterization of CGs in Nerium oleander tissues.

Morpho-Structural, Electrical and Magnetic Behavior of Chemically Synthesized Multiferroic GdMnO3 Ceramic.

The observations of room temperature ferroelectricity and ferromagnetism for GdMnO3 (GMO) ceramics have been reported in this paper. The nanocrystalline GMO powder was synthesized by chemical route and then sintered in the form of bulk pellet at 850 °C for 24 h by following slow step sintering schedule. Bulk GMO sample is observed to be polycrystalline in nature having orthorhombic perovskite structure and Pbnm space group. Well connected grains are observed with higher percentage of porosity in the micrographs obtained from field emission scanning electron microscope. The dielectric anomaly has been observed for the sintered sample at 338 K and a wide ferroelectric hysteresis loop has also been observed at room temperature. Room temperature dielectric constant (ε) value of the sample is high (~2736) at the frequency of 100 Hz. The zero field cooled (ZFC) and field cooled (FC) magnetizations shows the antiferromagnetic behavior around 12 K. Sample shows a weak ferromagnetic behavior at 3 K.

Temperature Controlled Evolution of Silver Polypods from Biomass Encapsulated Nano-Droplets.

Silver nanoparticles are produced by a novel biosynthesis technique using fungus Penicillium purpurogenum NPMF (MTCC 7356). The biomass when subjected to heat treatment up to 700 °C produces the nanoparticles of silver due to the presence of free carbon which acts as encapsulation for silver nanoparticles. Increase in temperature above 700 °C causes a reduction in concentration of free carbon so that the nanoparticles come close to each other and form clusters in the shape of tetrapods to polypods. The micro-Raman analysis supports the formation of mesoporous carbon with increase in the calcined temperature. The formation of Ag nanostructures has been explained in terms of free energy diagram i.e., the crystal favors more to grow on (100) facet or (110) facet rather than on (111) facet by the addition of silver atoms and thereby, it releases more energy. The release of energy has been confirmed from the differential thermo gravimetric analysis. In fact, it is the dynamics of the minimization of the free energy of the system which governs the reorientation and rearrangement of Ag themselves leading to formation of various types of polypods. A formation mechanism is presented schematically.

Mixed-phenotypic acute leukemia series from tertiary care center.

INTRODUCTION: Mixed-phenotype acute leukemias (MPALs) are a heterogeneous group of rare leukemias constituting approximately 2%-5% of all leukemias, in which assigning a single lineage of origin is not possible. They are diagnosed by either the presence of antigens of more than one lineage or by the presence of dual population of blasts belonging to two or more lineages. We highlight the clinicopathological, immunophenotype, and genetic data of a cohort (n = 14) of patients diagnosed and treated at our center. MATERIALS AND METHODS: We retrospectively analyzed consecutive cases of MPAL diagnosed in our flow cytometry laboratory from May 2012 to August 2015. These cases were diagnosed based on immunophenotyping of peripheral blood/bone marrow aspirates and morphology/genetics wherever available as per the World Health Organization (WHO) 2008 guideline. RESULTS: Among 628 consecutive acute leukemia (AL) cases diagnosed and evaluated during this period, we identified 14 (2.2%) patients with MPAL fulfilling WHO 2008/EGIL criteria for immunological characterizing of AL criteria. Majority of these were males (n = 8, male:female ratio 1.3:1) and adults (n = 11, 78.5%). The median age of this cohort was 41 years (range 2-80). These cases were further classified as: B/myeloid (n = 9), T/myeloid (n = 4), and B/T MPAL (n = 1). Cytogenetics was available in 12 out of 14 cases, out of which, three cases had normal karyotype, three with t(9;22)(q34;q11), and two cases with complex karyotype. We also came across a rare case of B + T lymphoid MPAL who had mixed-lineage leukemia gene t(v; 11q23) rearrangement. CONCLUSION: MPAL is a complex entity with heterogeneous clinical, immunophenotypic, cytogenetic, and molecular features. Multiparametric flowcytometry by using comprehensive antibody panels is a valuable tool for diagnosis. Subsequent cytogenetic and molecular analysis for further prognostic stratification and treatment modalities are important.

One-step global parameter estimation of kinetic inactivation parameters for Bacillus sporothermodurans spores under static and dynamic thermal processes.

Bacillus sporothermodurans produces highly heat-resistant endospores, that can survive under ultra-high temperature. High heat-resistant sporeforming bacteria are one of the main causes for spoilage and safety of low-acid foods. They can be used as indicators or surrogates to establish the minimum requirements for heat processes, but it is necessary to understand their thermal inactivation kinetics. The aim of the present work was to study the inactivation kinetics under both static and dynamic conditions in a vegetable soup. Ordinary least squares one-step regression and sequential procedures were applied for estimating these parameters. Results showed that multiple dynamic heating profiles, when analyzed simultaneously, can be used to accurately estimate the kinetic parameters while significantly reducing estimation errors and data collection.

Simultaneous quantitative determination of multiple bioactive markers in Ocimum sanctum obtained from different locations and its marketed herbal formulations using UPLC-ESI-MS/MS combined with principal component analysis.

INTRODUCTION: Ocimum sanctum L., with phenolic acids, flavonoids, propenyl phenols and terpenoids as active pharmacological constituents, is a popular medicinal herb and is present as an ingredient in many herbal formulations. Therefore, development of a reliable analytical method for simultaneous determination of the pharmacologically active constituents of O. sanctum is of high importance. OBJECTIVE: To develop and validate a new, rapid, sensitive and selective UPLC-ESI/MS/MS method for simultaneous determination of 23 bioactive markers including phenolic acids, flavonoids, propenyl phenol and terpenoid in the leaf extract and marketed herbal formulations of O. sanctum. METHODS: An UPLC-ESI/MS/MS method using negative electrospray ionisation (ESI) in multiple-reaction-monitoring (MRM) mode was used for simultaneous determination. Chromatographic separation was achieved on an Acquity UPLC BEH C18 -column using a gradient elution with 0.1% formic acid in water and 0.1% formic acid in acetonitrile. Principal component analysis (PCA) was applied to correlate and discriminate eight geographical collections of O. sanctum based on quantitative data of the analytes. RESULTS: The developed method was validated as per International Conference on Harmonization guidelines and found to be accurate, with overall recovery in the range 95.09-104.84% (RSD ≤ 1.85%), precise (RSD ≤ 1.98%) and linear (r(2) ≥ 0.9971) over the concentration range of 0.5-1000 ng/mL. Ursolic acid was found to be the most abundant marker in all the samples investigated, except for the marketed tablet. CONCLUSION: The method established is simple, rapid and sensitive, hence it can be reliably utilised for the quality control of O. sanctum and derived herbal formulations.

Sebaceous gland carcinoma of the eyelid: clinicopathological features and outcome in Asian Indians.

PURPOSE: To study the clinical and histopathological features of eyelid sebaceous gland carcinoma (SGC) and to evaluate the prognosis in the Asian-Indian population. METHODS: This is a retrospective study of 191 patients with SGC. RESULTS: The mean age at presentation of eyelid SGC was 57 years (median, 56 years). The tumor epicenter was most commonly located in the upper eyelid (n=125, 65%). The mean tumor basal diameter was 15 mm (median, 10 mm). There was evidence of tumor extension into the orbit (n=30, 16%), paranasal sinuses (n=3, 2%), and brain (n=1, 1%). Wide excision biopsy (n=146, 78%) was the most common treatment modality. Tumor recurrence was noted in 42 (24%) patients over a mean follow-up period of 29 months (median, 20 months). On the basis of the Kaplan-Meier estimate, lymph node metastasis occurred in 18%, systemic metastasis was detected in 10%, and death occurred in 2% of patients at 10 years. On multivariate analysis, the factors predicting locoregional lymph node and systemic metastasis were medial canthal involvement (P=0.004; P=0.013), lateral canthal involvement (P=0.013; P=0.025), tumor basal diameter >10 mm (P=0.002; P=0.002), and perivascular invasion (P=0.043; P<0.001), respectively. The factors predicting death due to metastasis on multivariate analysis were medial canthal involvement (P=0.012) and tumor basal diameter >10 mm (P=0.001). CONCLUSION: Advanced eyelid SGC is a tumor associated with poor prognosis. In this study, canthal involvement, larger tumor diameter, and perivascular invasion were poor prognostic factors.

Monitoring of response to therapy with imatinib mesylate in Chronic Myeloid Leukemia in chronic phase (CML-CP).

BACKGROUND: The BCR-ABL tyrosine kinase is a well validated therapeutic target in Chronic Myeloid Leukemia (CML). Imatinib mesylate (IM), a tyrosine kinase inhibitor is highly effective in the treatment of chronic phase CML. BCR - ABL transcripts have been well established as a molecular marker to document response to therapy in CML. Periodic monitoring of this marker helps in evolving therapeutic strategies with IM and also in diagnosing early relapse. This study was undertaken to monitor therapeutic response to IM in CML in chronic phase (CML-CP) by assessing BCR-ABL by real time quantitative PCR (RQ-PCR) techniques and to determine the effectiveness of the Indian generic IM. METHODS: One hundred consecutive patients of CML in chronic phase (CML-CP) were treated with an Indian generic of IM. Eighty-five patients were evaluable at 12 months of therapy. At entry, diagnosis of CML-CP was confirmed by FISH and RQ-PCR. Response to therapy was monitored by assessing BCR-ABL levels by RQ-PCR at 6 and 12 months of therapy. Regular follow up of patients was done to evaluate the safety profile of IM used in these patients. RESULTS: Complete hematological response (CHR) rates at 3, 6, 9 and 12 months were 92%, 94%, 100% and 100% respectively. The total molecular response at 12 months was 43.52% of which complete molecular response (CMR) was noted in 17.64% and major molecular response (MMR) was observed in 25.88%. A cumulative survival probability of 0.8 was observed. CONCLUSION: The Indian generic molecule of IM is effective in the treatment of CML-CP. The cost of Indian generic molecule is less than Rs. 10,000 per month there by making this affordable for large number of CML-CP patients in India.

Nymphaea rubra ameliorates TNF-α-induced insulin resistance via suppression of c-Jun NH2-terminal kinase and nuclear factor-κB in the rat skeletal muscle cells.

In this work, we demonstrated insulin signaling and the anti-inflammatory effects by the chloroform fraction of ethanolic extract of Nymphaea rubra flowers in TNF-α-induced insulin resistance in the rat skeletal muscle cell line (L6 myotubes) to dissect out its anti-hyperglycemic mechanism. N. rubra enhances the GLUT4-mediated glucose transport in a dose dependent manner and also increases the tyrosine phosphorylation of both IR-ß and IRS-1, and the IRS-1 associated PI-3 kinase activity in TNF-α-treated L6 myotubes. Moreover, N. rubra decreases Ser(307) phosphorylation of IRS-1 by the suppression of JNK and NF-κB activation. In conclusion, N. rubra reverses the insulin resistance by the inhibition of c-Jun NH2-Terminal Kinase and Nuclear-κB.

Vibrio cholerae O1 Ogawa El Tor strains with the ctxB7 allele driving cholera outbreaks in south-western India in 2012.

Cholera has been a recurrent epidemic disease in human populations for the past 200years. We present herein a comparative characterization of clinical Vibrio cholerae strains isolated from two consecutive cholera outbreaks in 2012 and associated environmental strains from western India. The clinical and toxigenic environmental isolates were identified as hybrid V. cholerae O1, serotype Ogawa, biotype El Tor carrying the variant ctxB7 allele. Partial sequences of SXT integrase from the isolates revealed 100% identity to ICEVchInd5 (Sevagram, India, 1994) and VC1786ICE (Haiti, 2013). The full clonal relationship of the strains established by RAPD, Box PCR, ERIC PCR and MLST (pyrH, recA and rpoA) analyses, and the short time between the two outbreaks, strongly supported that both outbreaks were due to a single strain. The study corroborated that faecal contamination of the potable water supply was the main reason for the first outbreak, which further spread to other areas and resulted in the second outbreak. The study concluded that the circulating El Tor variant strains of epidemic potential in the region can be a serious concern in the future.

Haitian variant ctxB producing Vibrio cholerae O1 with reduced susceptibility to ciprofloxacin is persistent in Yavatmal, Maharashtra, India, after causing a cholera outbreak.

Vibrio cholerae O1 biotype El Tor producing Haitian variant Cholera Toxin (HCT) and showing reduced susceptibility to ciprofloxacin caused a cholera outbreak associated with a high case fatality rate (4.5) in India. HCT-secreting strains responsible for severe cholera epidemics in Orissa (India), Western Africa and Haiti were associated with increased mortality. There is a pressing need for an integrated multidisciplinary approach to combat further spread of newly emerging variant strains. The therapeutic effect of ciprofloxacin was diminished whereas use of doxycycline in moderate to severe cholera patients was found to be effective in outbreak management.

Comparative organization and gene expression profiles of the porcine pseudoautosomal region.

The pseudoautosomal region (PAR) has important biological functions in spermatogenesis, male fertility and early development. Even though pig (Sus scrofa, SSC) is an agriculturally and biomedically important species, and its genome is sequenced, current knowledge about the porcine PAR is sparse. Here we defined the PAR in SSCXp/Yp by demarcating the sequence of the pseudoautosomal boundary at X:6,743,567 bp in intron 3-4 of SHROOM2 and showed that SHROOM2 is truncated in SSCY. Cytogenetic mapping of 20 BAC clones containing 15 PAR and X-specific genes revealed that the pig PAR is largely collinear with other mammalian PARs or Xp terminal regions. The results improved the current SSCX sequence assembly and facilitated distinction between the PAR and X-specific genes to study their expression in adult and embryonic tissues. A pilot analysis showed that the PAR genes are expressed at higher levels than X-specific genes during early development, whereas the expression of PAR genes was higher at day 60 compared to day 26, and higher in embryonic tissues compared to placenta. The findings advance the knowledge about the comparative organization of the PAR in mammals and suggest that the region might have important functions in early development in pigs.

Magnetic properties of nanocrystalline beta-SiC.

Four-hour ball-milled beta-SIC product synthesized by the thermal plasma technique shows room temperature ferromagnetism. The semi-lambda signature of the field-cooled magnetization (FCM) and zero field-cooled magnetization (ZFCM) curves suggest the possible signature of a glassy ferromagnetism state in the sample. The prominent fall in the magnetization value at around 50 K observed in ZFCM curve reveals the existence of a sharp transition from a ferromagnetic state to a glassy ferromagnetic state. The presence of glassy ferromagnetism at low temperature is confirmed from the M-H curve recorded at 5 K.

Polymorphisms in the vitamin D receptor and the androgen receptor gene associated with the risk of urolithiasis.

Transcriptional activity of the vitamin D receptor (VDR) gene is regulated by androgen receptor (AR) gene and both are associated with renal stone formation. We examined gene polymorphisms of VDR (PCR-RFLP) and AR (GeneScan analysis) in 125 stone formers and 150 controls from north India. Genotype Ff of Fok-I and Tt of Taq-I demonstrated significantly higher risk (P<0.001, OR=3.559 and P=0.019, 1.830 respectively). Variant f allele exhibited 1.7-folds higher risk. Ff of Fok-I and Aa of Apa-I gene polymorphism showed higher risk in males only. Mean CAG repeat was significantly higher in hypercalciuric patients as compared to normocalciuric (mean=21.62 ± 3.384 vs. 20.11 ± 3.182; P=0.034). Combined effects 1.8-folds higher risk in patients with Tt genotype of Taq-I and short CAG repeat. Thus, association of FokI and TaqI VDR gene polymorphisms suggest VDR as an important genetic marker for urolithiasis. Further, patients with combination of Tt of Taq-I and short CAG repeat were at higher risk for stone formation.