Recent Insights into Osimertinib Analogues against EGFR Positive Non-small Cell Lung Cancer.

BACKGROUND: Lung cancer is a highly lethal malignancy with a poor prognosis and the leading cause of mortality worldwide. The development of mutations makes lung cancer treatment more challenging and expensive. Successful identification of epidermal growth factor receptor (EGFR) mutations led to the discovery of various third-generation tyrosine kinase inhibitors. Osimertinib is one of the promising and efficacious third-generation EGFR inhibitors and is mainly employed in the treatment of non-small cell lung cancer. Despite the initial effective response, osimertinib causes resistance in most of the patients after around 10 months of therapy, resulting in disease progression. To mitigate the effect of developed resistance, different osimertinib derivatives have been synthesized and evaluated by numerous research groups across the globe. METHODS: Present article illustrates recent research advancements for the utilization of osimertinib and its derivatives in non-small cell lung cancer (NSCLC). Last seven years literature search has been conducted from PubMed, ScienceDirect, and Google Scholar databases, etc. Result: The present review emphasizes the recent advancements of osimertinib analogues that lead to enhanced antitumor potential and safety profile against non-small cell lung cancer. This manuscript also summarizes the different synthetic schemes involved in the synthesis of osimertinib analogues against EGFR reported by different research groups. CONCLUSION: Anticancer mechanistic insights, analytical prospects, drug interactions, pharmacokinetic considerations, and resistance profile of osimertinib are highlighted in the current manuscript.

Recent insights into antibacterial potential of benzothiazole derivatives.

Antimicrobial resistance (AMR) is a worldwide concern among infectious diseases due to increased mortality, morbidity and treatment cost. According to WHO 2019 report, among the 32 antibiotics in the clinical trials, only six were classified as innovative and containing novel moiety. The remaining antibiotics from this list contain previously known moiety (WHO AMR 2019). Therefore, the development of novel antibiotics to control resistance problems is crucial. Benzothiazole derivatives are of great interest due to their wide range of biological activities and medicinal applications. Reported data indicated that benzothiazole derivatives displayed antibacterial activity by inhibiting the dihydroorotase, DNA gyrase, uridine diphosphate-n-acetyl enol pyruvyl glucosamine reductase (MurB), peptide deformylase, aldose reductase, casdihydrofolate reductase, enoyl acyl carrier protein reductase, dialkylglycine decarboxylase, dehydrosqualene synthase, dihydropteroate synthase and tyrosine kinase. The present review analyzed the synthesis, structure-activity relationship (SAR) and mechanism of action studies of benzothiazole derivatives as antibacterial agents reported by various research groups in the last five years (2018-2022). Different patents on the antimicrobial activity of benzothiazole derivatives have also been summarized. The finding of the present review will be beneficial for the researchers in the development of novel antibacterial molecules based on benzothiazole moiety.

Quinoline Hydrazide/Hydrazone Derivatives: Recent Insights on Antibacterial Activity and Mechanism of Action.

Antibiotics are becoming gradually ineffective due to drug resistance, leading to greater difficulty in the treatment of infectious diseases. Therefore, the development of new chemical entities with different mechanisms of action is essential in the fight against resistant microorganisms. Various studies have shown that quinoline hydrazide/hydrazone derivatives possess several biological activities, such as antimalarial, antitubercular, anticancer, anti-inflammatory, and antimicrobial. Among these activities, the antibacterial activity of quinoline hydrazide/hydrazone derivatives is noteworthy. The synthetic flexibility of the quinoline ring has led to the development of a wide range of structurally diverse quinoline hydrazide/hydrazone derivatives, which can act at various bacterial targets such as DNA gyrase, glucosamine-6-phosphate synthase, enoyl ACP reductase, and 3-ketoacyl ACP reductase. This review emphasizes the antibacterial potential of various reported quinoline hydrazide/hydrazone derivatives based on substitution in the quinoline ring. The antibacterial activity of various metal-quinoline hydrazide/hydrazone complexes is also discussed. The aim of this review is to assemble and scrutinize the latest reports in this promising area of drug development.

Diagnostic Accuracy of Parents' Evaluation of Developmental Status (PEDS), PEDS Developmental Milestones, and PEDS Combined in Indian Children Aged Less than 2 Years.

OBJECTIVE: To assess the diagnostic accuracy of Parent's Evaluation of Developmental Status (PEDS), PEDS Developmental Milestones (PEDS:DM) and PEDS Combined for developmental screening of Indian children aged less than 2 y. METHOD: A hospital-based study of diagnostic accuracy was conducted over 17 mo. Children under 24 mo (n = 180) were enrolled after exclusion of severe illnesses or known neurodevelopment disorders. The index tools included standardized Hindi translations of PEDS and PEDS:DM. The reference tool was Developmental Assessment Scale for Indian Infants (DASII). Both were administered by blinded researchers. Parameters of diagnostic accuracy were computed. RESULTS: There were 13 (7.2%) failures in PEDS, 119 (66.1%) in PEDS:DM and 119 (66.1%) in PEDS Combined. DASII identified 3 children with developmental delay. Sensitivity (Sn) [95% CI] of PEDS was 33.3 [0.8-90.6] and Specificity (Sp) 93.2 [88.5-96.5]. The Sn and Sp of both PEDS:DM and PEDS Combined were 100 [29.2-100] and 34.5 [27.5-42.0], respectively. CONCLUSIONS: Hindi translations of PEDS, PEDS:DM and PEDS Combined are not suitable for developmental screening of children less than 2 y due to suboptimal diagnostic accuracy.

Sources, controls, and probabilistic health risk assessment of fluoride contamination in groundwater from a semi-arid region in Gujarat, Western India: An isotope-hydrogeochemical perspective.

Fluoride contamination in groundwaters of a rural region in semi-arid Western India has been studied using combination of geochemical-and-isotopic techniques, in conjunction with Health Quotient assessment approach. The objective of this study is to determine the sources and controls on fluoride content and to evaluate probabilistic non-carcinogenic risk associated with its long-term consumption. F- ranges from 0.3 to 12 mg L-1, shows high spatial variability, and ~ 35% of the samples have F- > 1.5 mg L-1 (WHO maximum limit for drinking). Two sources are identified: high F- results from water-rock interaction of F-bearing minerals in granites and gneisses, while phosphate fertilizers can contribute up to ~ 0.46 mg L-1 of groundwater F- that can be significant for low F- samples. High F- samples are characterized by high pH, Na and alkalinity, and low Ca. Calcite precipitation drives the solubility of F-bearing minerals. Kinetic fractionation of water isotopes (18O and 2H) demonstrates that evaporation plays role in enriching groundwater F-. Non-carcinogenic risk, estimated by Hazard Quotient ([Formula: see text]), ranges from 0.13-5.72 to 0.26-11.86 for adult and children, respectively. Conservative estimate shows that ~ 0.467 million of adults and~0.073 million of children in four sub-districts are under the risk of fluorosis-while the residents of other five sub-districts remain safe from it. Finally, we suggest stakeholders to install F- treatment plants to ensure the health safety of local residents in the high-risk zones, create awareness in farmers for optimum use of fertilizers, and promote rainwater harvesting, for better management of groundwater resources and quality in the region.

Immunohistochemical characterization of molecular subtypes of invasive breast cancer: a study from North India.

In recent years breast cancer has been classified on the basis of its molecular characteristics by gene expression profiling. A similar classification using immunohistochemistry has been identified so that it has a wider application. This study was designed to define the precise prevalence of molecular subtypes of invasive breast carcinoma using immunohistochemistry in patients from north India and to correlate it with known clinical and histological prognostic factors. Based on ER/PR/Her2/neu expression, 100 cases of invasive breast cancer were categorized into: ER+ and / or PR+ and Her2/neu- (47%), ER+ and/or PR+ and Her2/neu+ (15%), ER- and / or PR- and Her2/neu+ (Her2/neu overexpressing, 21%), ER-, PR- and Her2/neu- (Triple negative, 17%). All cases demonstrated positivity for the luminal Cytokeratins 8/18. In addition, 10% of these tumours showed expression of the basal markers (CK4/14, CK5/6). Among the 17 triple negative cases, eight cases were positive for one of the basal markers and two cases with basal marker expression were Her2/neu overexpressing. The basal markers showed significant correlations only with histological grade and ER negative status. On the basis of hormone receptor, Her-2/neu and cytokeratin expressions, distinct subclasses of breast cancer have been identified which show significant differences in relation to histological grade and ER status. Expression of basal markers is needed to define basal-like breast cancer.

BRCA1-methylated sporadic breast cancers are BRCA-like in showing a basal phenotype and absence of ER expression.

BRCA1 mutations have been associated with hereditary breast cancer only. Recent studies indicate that a subgroup of sporadic breast cancer might also be associated with reduction in BRCA1 mRNA levels and protein expression. However, the mechanism of reduced mRNA and protein expression is yet not fully elucidated. This study aims to assess BRCA1 protein expression and the role of BRCA1 promoter methylation in sporadic breast cancer in North Indian population and to correlate these with known prognostic factors and molecular profiles of breast cancer. BRCA1 protein expression was normal (>50 % tumour cells) in 41 (43 %) cases, reduced (20-50 % tumour cells) in 33 (35 %) cases and absent/markedly reduced (<20 % tumour cells) in 21 (22.1 %) cases. Cases which were negative for BRCA1 protein were more frequently positive for basal markers (29 versus 5 %) and were more often ER-negative (62 versus 39 %) than BRCA1-positive tumours. Methylation of BRCA1 promoter region was seen in 11/45 cases (24 %). All 11 cases showing BRCA1 methylation had absent (eight cases) or reduced (three cases) BRCA1 protein expression. BRCA1 protein-negative tumours were more frequently basal marker-positive and ER-negative, highlighting the 'BRCAness' of sporadic breast cancer with loss of BRCA1 protein expression through promoter hypermethylation similar to hereditary breast cancer with BRCA1 mutations. Loss of BRCA1 in sporadic breast cancer suggests that therapeutics targeting BRCA1 pathway in hereditary breast cancer like PARP inhibitors might be used as therapeutic targets for sporadic breast tumours.

Melasma: treatment strategy.

Melasma, a hypermelanosis of the face, is a common skin problem of middle-aged women of all racial groups, especially with dark complexion. Its precise etio-pathogenesis is evasive, genetic influences, exposure to sunlight, pregnancy, oral contraceptives, estrogen-progesterone therapies, thyroid dysfunction, cosmetics, and drugs have been proposed. Centro-facial, malar, and mandibular are well-recognized. Epidermal pigmentation appears brown/black, while dermal is blue in color, and can be distinguished by Wood's lamp illumination. The difference may be inapparent with mixed type of melasma in skin types V and VI. An increase in melanin in epidermis: basal and suprabasal layers and/or dermis is the prime defect. There is an increased expression of tyrosinase related protein-1 involved in eumelanin synthesis. The use of broad-spectrum sunscreen is important, lightening agents like retinoic acid (tretinoin), azelaic acid, and combination therapies containing hydroquinone, tretinoin, and corticosteroids, have been used in the treatment of melasma, and are thought to have increased efficacy as compared with monotherapy. Quasi-drugs, placental extracts, ellagic acid, chamomilla extract, butylresorcinol, tranexamic acid, methoxy potassium salicylate, adenosine monophosphate disodium salt, dipropyl-biphenyl-2,2'-diol, (4-hydroxyphenyl)-2-butanol, and tranexamic acid cetyl ester hydrochloride, in addition to kojic and ascorbic acid have been used. Chemical peeling is a good adjunct. Laser treatment is worthwhile.

Development and quality evaluation of honey based carrot candy.

Candy was prepared with 3 different combinations of honey and carrot by using 750 g honey + 1,000 g carrot (T1), 1,000 g honey + 1,000 g carrot (T2) and 1,250 g honey + 1,000 g carrot (T3). To establish the best product, sensory evaluation was done on 9-point Hedonic scale. T1 was found to be most preferred candy. Further the T1 candy was assessed for overall quality during storage at room temperature (25-30 °C) for 6 months. Candy can be preserved safely for 6 months in both glass and LDPE packaging materials.

Male adnexal tumour of wolffian origin: the first report of metastatic disease.

The first case of a male adnexal tumour of probable wolffian duct origin to develop metastatic disease is reported. The characteristic histological appearance and immunohistochemical profiles of the primary and metastatic male tumours are discussed. The scanty experience relating to metastatic disease makes decisions about the most appropriate treatment challenging.