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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Magnetic characterization of radio frequency heat affected micron size Fe3O4 powders: a bio-application perspective.

Micron size Fe3O4 powders were chemically prepared and processed by radio frequency (13.56 MHz) oxygen plasma irradiation technique at different elevated temperatures using low radio frequency (RF) power level. Low magnetic field RF superconducting quantum interference device (SQUID) magnetization studies were performed up to a maximum magnetic field of 100 Oe, which was well below the magnetic field tolerance factor of human beings and at different temperatures (down to 5 K). Heat-treated powders in RF oxygen plasma showed significant changes in blocking temperature, magnetization and susceptibility, which are important parameters for bio-applications. It is observed that blocking temperature is decreased under identical RF heat treatment in oxygen plasma and noted to be dependent on average particle size. Microscopic rise in electron temperature during RF heating may likely to enhance the electron-hopping rate between Fe(+2) and Fe(+3) in the octahedral site of Fe3O4 molecular crystal structure, which in turn exhibit changes in blocking temperature including low field magnetization and susceptibility. These properties of Fe3O4 fine powder are likely to play important role in generating and processing biocompatible Ferro-fluid down to nanoscopic size for biomaterials applications.

Effect of sublethal exposure of Cartap on hypothalamo-neurosecretory system of the freshwater spotted murrel, Channa punctatus (Bloch).

In order to record the effect of carbamate pesticide on hypothalamus of Channa punctatus, fish were exposed to sublethal concentration (0.18 mg l(-1), 30% LC50 for 96 hr) of Cartap for 24, 48, 72 and 96 hr under static bioassay condition. Hypothalamo-neurosecretory complex of the murrel consisted mainly of nucleus preopticus (NPO), nucleus lateralis tuberis (NLT) and their axonal tracts. NPO is a paired structure situtated on either side of the third ventricle anterodorsal to the optic chiasma and looked inverted L-shape in the sagittal section. NPO is morphologically divisible into a dorsal pars magnocellularis (PMC) consisting of large neurons and ventral pars parvocellularis (PPC) formed of smaller neurosecretory cells. NLT cells are distributed in the infundibular floor adjacent to the pituitary stalk. Sublethal Cartap treatment induced an initial hypertrophy of the neurosecretory cells of NPO and NLT followed by loss of staining affinity as well as varying degrees of cytoplasmic vacuolization and necrosis. Herring bodies (HB) were also encountered in the neurohypophysis of the treated fishes.

Spectrum of Haemoglobinopathies in a Tertiary Care Hospital of Armed Forces.

BACKGROUND: Thalassaemia and other structural haemoglobinopathies are the major genetic disorders prevalent in certain parts of the world including India. This study presents the pattern of haemoglobinopathies amongst the referred patients of anaemia in a two-year period. METHODS: A total of 1032 patients were studied during a two-year period for anaemia investigation. Haematological indices, sickling test and haemoglobin electrophoresis with quantification of the bands was done in all cases. RESULT: Out of 1032 cases, 774 (75%) were normal and 258 (25%) cases had abnormal haemoglobin pattern. Of the 258 abnormal cases, 136 (53%) were males and 122 (47%) were females. Of all cases of anaemia 370 (36%) were microcytic hypochromic, 237 (23%) macrocytic, 151 (15%) were dimorphic and the rest (26%) had normocytic normochromic picture. 82% of microcytic hypochromic anaemias had reduced serum iron and elevated total iron binding capacity (TIBC), whereas 85% had decreased serum ferritin levels. Spectrum of haemoglobinopathies prevalent were ß-Thalassemia trait (17%), followed by sickle cell trait (2.3%). Other haemoglobinopathies in descending order of frequency were sickle cell disease (1.7%), Hb D trait (1%), Hb E trait (0.8%), sickle cell - ß thalassemia, Hb E disease, E - ß thalassemia (0.6% each) and thalassemia major (0.4%). CONCLUSION: This study provides a comprehensive database on the spectrum of haemoglobinopathies in the Armed Forces. It is suggested that detection of HbA2 should be carried out in all the high-risk groups with anaemia.

Total synthesis of munchiwarin, a triprenylated chalcone from Crotalaria medicagenia.

An efficient method is developed for the synthesis of the modified triprenylated chalcone, munchiwarin (1), isolated from the roots of Crotalaria medicagenia. The synthesis of 1 utilizes a Claisen-Schmidt condensation between 2,4-dihydroxy-3,5-C-diprenyl acetophenone and 4-methoxy benzaldehyde in the presence of Ba(OH)2 to yield the unusual chalcone 5 that contains a nine-membered ether ring. Further prenylation of 5 with 1-bromo-3-methylbut-2-ene and its subsequent demethylation with BBr3 gave munchiwarin (1).

Nonprogressive juvenile-onset spinal muscular atrophy: A clinico-radiological and CAG repeat study of androgen receptor gene.

BACKGROUND: Occurrence of nonprogressive juvenile-onset spinal muscular atrophy (SMA) predominantly in males suggests a possibility of X-linked disorder but there is no such report addressing this problem. AIMS: To evaluate CAG repeat expansion of androgen receptor (AR) gene in patients with nonprogressive juvenile-onset SMA. SETTING: Tertiary medical teaching institute. SUBJECTS AND METHODS: Patients fulfilling the diagnostic criteria of nonprogressive juvenile-onset SMA were included. Detailed clinical evaluation and pedigree charting were done in all. Nerve conduction study, electromyography and cervical spinal MRI were carried out. From peripheral venous blood, DNA was separated and AR gene CAG repeat exon polymorphism was assayed using polymerase chain reaction (PCR) in conjugation with genotyping and Gene scan soft ware. Number of CAG repeats was compared with normal controls. RESULTS: 25 patients with nonprogressive juvenile-onset SMA from 24 families were included and their mean age was 22.2 years. Age at the time of disease onset ranged between 15 and 30 years with a mean duration of illness 2.6 years. None of the patients had testicular atrophy or gynecomastia. C7-T1 myotomal wasting and weakness although was unilateral to begin with but became bilateral in 16 and 4 more patients had evidences of subclinical involvement of the other side as revealed by EMG. Spinal MRI revealed cord atrophy at C6-8 vertebral level in 16 patients. CAG repeat study of AR gene was carried out in 16 patients. The number of CAG repeats in patients ranged between 15 and 39 (median 21) which were within the normal range. CONCLUSION: Abnormal CAG repeat expansion of AR gene is not found in patients with nonprogressive juvenile-onset SMA.

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.

Evaluation of Suspected Monoclonal Gammopathies: Experience in a Tertiary Care Hospital.

BACKGROUND: Monoclonal gammopathies occurs in patients with malignant diseases of plasma cells and lymphocytes and in few benign conditions. The objective of this study was to assess the precision, accuracy and confirmation of monoclonal gammopathies on serum protein electrophoresis (SPE) and the clinical relevance of detection and characterization of M component. METHODS: All samples received for serum electrophoresis in the last 3 years were analysed for data on M band positivity and correlating it with clinical profile of the patients. Immunofixation (IFE), Immunoelectrophoresis (IEP) and IgG, IgM estimation were carried out in few cases. The follow up of cases was done by serial monitoring of SPE and ß2 microglobulin levels. RESULTS: 1155 samples were received during the 3 years period. 282 (24.4%) samples were positive for M component on SPE. Of these, 239 (84.8%) patients had M spike in λ region and 43 patients had M spike in ß region. The mean load of the M protein band in the λ region was 37.8% and in ß region was 35.8%. IgG with κ chain was seen in 40%, IgG with λ chain was seen in 50%, 5% patients each had IgM with κ and IgA with λ light chain. 246 samples (96.5%) had high levels of ß2 microglobulin. Of the 116 cases of multiple myeloma, IgG levels was more commonly raised (5%) as compared to IgA (6.9%) and IgM (5.2%). CONCLUSION: It is recommended that SPE should be performed in patients having unexplained weakness, anaemia, back pain, osteoporosis, osteolytic lesions, fractures, renal insufficiency or recurrent infections.

Hypercoagulable State.

BACKGROUND: The hypercoagulable state results from a complex interplay of blood coagulation factors, coagulation-inhibitory factors, platelets and the vascular endothelium. Imbalance of the complex interplay between these factors results in thrombosis often complicated by embolism. The causes of thrombosis are varied and maybe congenital or acquired. The current interest is centered on the congenital deficiency of coagulation inhibitors as there is an increasing awareness of their involvement in thrombosis, especially in the young. METHODS: A total of 42 patients with thrombosis were studied. The most common clinical presentation was deep vein thrombosis. All the cases were evaluated for coagulation inhibitors Antithrombin, resistance to activated protein C, Protein C and Protein S using standard assay kits. RESULTS: Resistance to activated protein C (n=10) was seen to be the commonest cause of thrombophilia. This was followed by deficiency of Antithrombin (n-4), Protein C (n=3) and Protein S (n=2). Majority of our cases were in the third decade of life. CONCLUSION: The identification of the underlying aetiology is important for instituting specific therapy and patient management.

Leucodepletion and Blood Products.

BACKGROUND: Leucoreduction of blood products is increasingly being employed to produce blood products with residual WBCs < 5 × 10(6) per unit (99.9 percent or a log 3 leucoreduction). Clinical data suggests that non-haemolytic febrile transfusion reactions can be prevented by leucodepletion. The procedure also prevents alloimmunisation to HLA antigens in patients who will repeatedly require transfusion of blood/blood products. METHOD: Of the methods available to reduce the number of WBC in blood products washing of red cells, freezing and deglycerolisation are effective and yield a product with only a 24 hour shelf life. Other methods such as leucodepletion filters are relatively inexpensive, simple and the final product has a normal shelf life. Modern generation of leucoreduction filters and apheresis machines can provide greater than 4 log reduction of WBC. RESULTS: After the introduction of leucodepletion of blood for Thalassemics at our center in 2003, the incidence of non haemolytic febrile transfusion reactions (NHFTR) fell from 4% in 2002 to 1% in 2003. CONCLUSION: In patients undergoing long-term blood transfusion therapy e.g. Thalassemics, alloimmunisation against the HLA antigens on donor white cells is prevented by leucodepletion and prevents NHFTRs.