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As genetic testing becomes increasingly accessible and affordable, the uniform and accurate interpretation of genetic variants becomes essential. The ACMG/AMP joint guidelines provide the basis for systematic and uniform interpretation of pathogenicity of genetic variants. However, the application of these in routine clinical interpretation at-scale has largely been limited by the lack of resources providing harmonized data especially at a population-scale. Here we describe BRCAIndica, a resource for BRCA1 and BRCA2 variants conforming to the ACMG & AMP joint guidelines to aid uniform clinical interpretation of genetic tests with a specific focus on variants reported in the Indian population. We collected and harmonized variants from across several resources including population-scale datasets, literature survey and other variant datasets. We then classified them according to the ACMG/AMP guidelines.We have collected a total of 10,490 unique variants, of which 2261 Pathogenic and 43 Likely Pathogenic variants belong to BRCA1 and 2694 Pathogenic and 20 Likely Pathogenic variants to BRCA2 respectively. BRCAIndica can be accessed at:https://clingen.igib.res.in/brcaindica/ . In conclusion, BRCAIndica is a powerful resource that offers researchers and clinicians with ACMG/AMP annotated BRCA variants., Competing Interests: Declarations Ethics approval and consent Not applicable. Conflict of interest The authors declare that they have no conflicting interests to report. The funding body had no role in the study design, collection, analysis, or interpretation of data., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Chemotherapeutics are most often used to treat cancer, but side effects, drug resistance, and toxicity often compromise their effectiveness. In contrast, phytocompound plumbagin possesses a distinct pleiotropic nature, targeting multiple signaling pathways, such as ROS generation, cell death, cellular proliferation, metastasis, and drug resistance, and is shown to enhance the efficacy of chemotherapeutic drugs. Plumbagin has been shown to act synergistically with various chemotherapeutic drugs and enhance their efficacy in drug-resistant cancers. The pleiotropic nature is believed to be due to plumbagin's unique structure, which contains a naphthoquinone ring and a hydroxyl group responsible for plumbagin's various biological responses. Despite limitations such as restricted bioavailability and delivery, recent developments aim to address these challenges and harness the potential of plumbagin as an anticancer therapeutics. This review delves into the structural aspect of the plumbagin molecule contributing to its pleiotropic nature, explores the diverse mechanism that it targets, and discusses emerging strategies to overcome its limitations., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Needle stick injury (NSI) is one of the significant and serious health hazards encountered by healthcare workers (HCWs), as it is a risk factor for transmission of blood-borne infections like HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV). This study aims to describe the frequency and distribution of the NSIs reported in the institution over a period of four years, the factors associated with it and the immediate post-exposure prophylaxis administered., Methods: A record-based retrospective analysis of the NSIs suffered by HCWs working in the Pradyumna Bal Memorial Hospital (PBMH), Kalinga Institute of Medical Sciences (KIMS), Bhubaneswar over a period of four years (2019 - 2022) was conducted. Data was extracted from the Exposure Prevention Information Network (EPINet) using a researcher-made proforma and analysed using Epi Info software 7.3.2., Results: There were a total of 115 reported cases of NSIs, the incidence being 2.52%, 1.55%, 0.85% and 1.64% in the years 2019,2020,2021 and 2022 respectively. The most commonly affected age group was 18-30 years with females constituting the majority. Nurses were more commonly affected in the first two years of the study (2019 and 2020) whereas in 2021 and 2022 housekeeping staff suffered more injuries. The highest incidence of NSIs (40%-59%) was noted to have occurred in the morning shift. Inpatient department (IPD) contributed the maximum number of cases of NSIs. Out of the 93 cases with known source patient, HIV serological status was negative for all, while HBV and HCV status was positive in nine and two cases respectively. The serology status for the three viral markers (HIV, HBV and HCV) was unknown in 22 cases. After evaluation for the necessity of post-exposure prophylaxis (PEP), initial PEP was given to 14 persons for prevention of HBV and to 20 persons for HIV prevention., Conclusion: Of the total NSIs reported over the four years, the incidence of NSIs per thousand HCWs showed a declining trend; with the younger age group and female gender reporting a higher incidence. Job category wise, housekeeping staff and nursing staff suffered more NSIs. Highest number of NSIs were reported from IPD. A greater proportion of NSIs were due to hollow bore needles. Most of the injuries occurred during daytime. Source patient could be identified in majority of the cases. HCWs who were identified to be at risk received immediate PEP as per the institutional policy. Stringent documentation of NSIs can assist in root cause analysis and to implement measures to prevent their occurrence., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Institutional Ethics Committee, Kalinga Institute of Medical Sciences issued approval KIIT/KIMS/IEC/1054/2022. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Singh et al.)

Psychotropic polypharmacy presents a diagnostic challenge that may be further complicated by inadequate medication history and underappreciation of the cognitive effects of such polypharmacy. Here we present the case of a 57-year-old man who presented to our memory clinic with progressive cognitive decline and a prior neuropsychological evaluation supporting the diagnosis of a neurodegenerative disorder. He was taking multiple psychotropic medications at the time, but the exact dosages were unclear due to a lack of collateral history. He was also taking prescribed opioids and a combination of buprenorphine and naloxone for pain relief, again with unclear dosages at the time of presentation. Brain imaging and cerebrospinal spinal fluid biomarker testing were negative for Alzheimer pathophysiologic processes. Months later, the patient was taken to the emergency room after an overdose caused by overuse of opioid medications. Once he was taken off all psychoactive medications, the patient's cognitive impairment completely reversed, and he became independent in activities of daily living. Psychotropic polypharmacy can have a myriad of cognitive manifestations which need to be better recognized by clinicians. Deprescription of such medications should be attempted whenever clinically appropriate., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

New Ursolic Acid (UA) conjugates were synthesized using optimized synthetic protocols through the molecular hybridization approach at C-3 and C-28. This resulted in the targeted molecules being produced in good yields. Some of the synthesized conjugates showed significantly relevant bioactivity against mammalian cells and in animal models of cancers. Selected UA conjugates were tested against bladder and breast cancer cell lines. The conjugates showed moderate to significantly enhanced antiproliferative activities against Triple Negative Breast Cancer (TNBC; MDA-MB 231), which is an aggressive tumor making up about 10-15 % of all breast cancers and bladder (T24 and 5637) cancer cell lines. These properties were superior to the parent UA. Among all the synthesized compounds, 18 c and 18 d have exhibited promising antiproliferative and cytotoxic properties against all tested cancer cell lines. However, 18 d has proved to be exceptionally selective for cancer cell lines, showing more cytotoxicity towards them than normal epithelial cells (MCF-12A). Compound 18 d has demonstrated cytotoxicity against tumor cells, including those intrinsically resistant to chemotherapy drugs such as 2-difluoro-deoxy cytidine (Gemcitabine). The activity of the UA conjugates on tumor cells was mediated by multiple cytotoxic mechanisms, including drug-induced cytotoxic autophagy and programmed cell death, indicating a novel possibility of combination therapy., (© 2024 Wiley-VCH GmbH.)

Background: Oleanolic acid (OA) and Ursolic acid (UA) are bioactive triterpenoids. Reported activities vary with the dose used for testing their activities in vitro. Studies using doses of ≥20 µM showed apoptosis activities in cancer cells. However, reported drug levels in circulation achieved by oral administration of UA and OA are ≤2 µM, thus limiting their use for treatment or delivering a combination treatment., Materials and Methods: The present report demonstrates the efficacy of OA, UA, and OA + UA on tumor cell-specific cytotoxicity at low doses (5 µM to 10 µM) in breast cancer (BrCa) cell lines MCF7 and MDA-MB231., Results: The data show that both OA and UA killed BrCa cells at low doses, but were significantly less toxic to MCF-12A, a non-tumorigenic cell line. Moreover, OA + UA at ≤10 µM was lethal to BrCa cells. Mechanistic studies unraveled the significant absence of apoptosis, but their cytotoxicity was due to the induction of excessive autophagy at a OA + UA dose of 5 µM each. A link to drug-induced cytotoxic autophagy was established by demonstrating a lack of their cytotoxicity by silencing the autophagy-targeting genes (ATGs), which prevented OA-, UA-, or OA + UA-induced cell death. Further, UA or OA + UA treatment of BrCa cells caused an inhibition of PI3 kinase-mediated phosphorylation of Akt/mTOR, the key pathways that regulate cancer cell survival, metabolism, and proliferation., Discussion: Combinations of a PI3K inhibitor (LY294002) with OA, UA, or OA + UA synergistically inhibited BrCa cell survival. Therefore, the dominance of cytotoxic autophagy by inhibiting PI3K-mediated autophagy may be the primary mechanism of PTT-induced anticancer activity in BrCa cells., Conclusion: These results suggest it would be worthwhile testing combined OA and UA in clinical settings.

Introduction: Non-fermenting gram-negative bacilli (NFGNB) infections have emerged as a serious health concern in ICUs. Multi-drug resistant (MDR) strains of NFGNB can evolve by acquiring resistance genes to at least one agent in three or more antibacterial categories. This study aimed to analyse the prevalence of NFGNB, the distribution of MDR strains, and antibiotic resistance trends of NFGNB in different ICUs of a tertiary care hospital over a period of five years., Materials and Methods: This retrospective study was conducted in a tertiary care teaching hospital in eastern India, including a total of 20,256 samples received from various ICUs over five years. Data retrieved from the Laboratory Information System (LIS) of the hospital, and repetitive isolates from the same patients, were excluded. All samples were processed according to standard microbiological protocols by automated systems. Data were entered into a Microsoft Excel spreadsheet (Microsoft® Corp., Redmond, WA, USA), analysed using Epi Info software, and presented using descriptive statistics. Chi-square and Fisher's exact tests (where appropriate) were used as tests of significance, with a p-value of <0.05 considered statistically significant., Results: A total of 18,032 culture-positive samples out of 20,256 samples showed growth of 18,659 bacteria. Out of these, 952 isolates were NFGNB. The prevalence of NFGNB was found to be 5.10% among all isolated bacteria. The predominant sources were respiratory samples (37.3%). Acinetobacter spp. emerged as the most prevalent NFGNB (46.5%), followed by Pseudomonas spp. (31%) and Burkholderia spp. (14.3%). Among the NFGNB isolates, 61.76% exhibited MDR, with the highest prevalence of MDR strains seen in Elizabethkingia spp. (94.7%). Among the most prevalent NFGNB, Acinetobacter spp., 64.8% were MDR strains. Trend analysis of antibiotic resistance patterns of Acinetobacter spp. indicated a substantial increase for trimethoprim-sulfamethoxazole by 18.5%, minocycline (44.4%), amikacin (20.4%), and ceftazidime (7.4%), whereas there was a reduced trend in resistance to carbapenems (6.5%), ciprofloxacin (4.7%), and cefepime (3.7%) over five years. In Pseudomonas spp., resistance to meropenem increased by 17.4%, and for ceftazidime (11.8%), amikacin (10.6%), and piperacillin-tazobactam (7.9%), whereas resistance to aztreonam diminished by 13.9%. Burkholderia spp. exhibited a 23.5% escalation in resistance to meropenem and ceftazidime (5.9%), while resistance to levofloxacin experienced a decrease of 30.2%., Conclusions: The study showed the prevalence of various NFGNB as 5.10% in ICU settings, with Acinetobacter spp. (46.5%) being the most common isolated bacteria. Notably, 61.76% of the isolates were MDR. Antibiotic trend analysis over five years showed increasing resistance of Acinetobacter spp. to trimethoprim-sulfamethoxazole, minocycline, and ceftazidime, with improved susceptibility for carbapenems, ciprofloxacin, and cefepime. Pseudomonas spp. showed increased susceptibility to aztreonam and rising resistance for meropenem, piperacillin-tazobactam, ceftazidime, and amikacin. In Burkholderia spp., there was increased susceptibility to levofloxacin and rising resistance to meropenem and ceftazidime. These findings focus on the need for vigilant antibiotic stewardship, with the adoption of appropriate infection prevention and control practices to restrict the emergence and spread of MDR NFGNB infections in ICU settings of hospitals., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Dash et al.)

Pure intertubular seminoma (PITS) of the testis is described as the presence of seminoma cells within the interstitium of testis without any evidence of diffuse growth pattern or mass lesion of classical seminoma. These tumors are clinically and grossly inconspicuous and are diagnosed incidentally or during investigations for testicular pain, infertility or other symptoms. Rarely metastasis is the first presentation. Microscopic identification can be difficult and poses a diagnostic challenge in the absence of a mass lesion. Seminomas with exclusive intertubular growth patterns were gathered in an international cohort. Diagnoses were confirmed by fellowship-trained or specialized urologic pathologists. Cases with the presence of a classical diffuse or nested pattern of seminoma or any other germ cell tumor component were excluded. The patient's age, tumor characteristics and additional clinicopathologic features were recorded and analyzed. 15 patients of pure intertubular seminoma (PITS) were collated. The mean age of presentation was 29 years. Patients presented with variable symptoms, including undescended testis (26%, n = 4/15), testicular heaviness/pain (20%, n = 3/15) infertility (20%, n = 3/15) and metastasis (6%, n = 1/15); presentation was unknown in 4 patients. Of note, none of the patients presented because of testicular mass. Serum markers were within normal limits in most patients (93%, n = 14/15) with available data. No tumors were identified macroscopically; however, an ill-defined, grey-white, firm area was noted in one orchiectomy specimen. Microscopically, tumor cells were seen in intertubular spaces as dispersed individual cells or small clusters. Tumor cells were round to polygonal with large nuclei and prominent nucleoli. Mild to moderate lymphocytic infiltrates were seen admixed with tumor cells in 40% (n = 6/15) of the tumors. GCNIS was present in association with most PITS (73%, n = 11/15). Tubular atrophy with thickening of the basement membrane and Leydig cell hyperplasia was observed in one tumor. Thirty-three percent (n = 5/15) of the tumors showed pagetoid involvement of rete testis, including the tumor with metastasis. All tumors showed the classical immunohistochemical profile of seminoma, with PLAP, c-KIT, OCT3/4, D2-40 and SALL4 positivity. PITS can be clinically & pathologically inconspicuous, difficult to stage and liable to be misdiagnosed especially if presented with metastasis. Despite the inconspicuousness, PITS may represent an aggressive growth pattern of seminoma with the propensity for rete testis invasion., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Mir Hashim Rasool reports was provided by Islamic University of Science and Technology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10-15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2's cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers.

Aims: Metabolic disease is a multifaceted condition characterized by the disruption of numerous metabolic parameters within the host. Its prevalence has surged significantly in recent years and it has become a prominent non-communicable disease worldwide. The effect of gut microbiota on various beige fat induction is well studied, while the mechanisms behind the link remain unclear. Given that gut microbiota-derived metabolites (meta-metabolites) secreted in the gut serve as a key mode of communication with their host through direct circulation or indirect host physiology modification, understanding the effect of meta-metabolites on adipose tissue is essential., Methodology: In our previous in-vivo studies, we observed a correlation between gut microbiota and the formation of beige fat. In this study, we further aimed to validate this correlation by treating the adipocyte cell line (3T3-L1) with meta-metabolites collected from the cecum of mice exhibiting beige adipose tissue formation. Additionally, we treated the adipocyte cell line with known beige fat inducers (L-Rhamnose and Ginsenoside) to assess meta-metabolites' efficacy on beige fat formation., Key Findings: Upon treatment with the meta-metabolites from the antibiotic-treated mice, we observed a significant increase in lipid metabolism and beige-specific gene expression. Analyzing the metabolites in these cells revealed that a set of metabolites potentially govern adipocytes, contributing to a metabolically active state. These effects were at par or even better than those of cells treated with L-Rhamnose or Ginsenoside., Significance: This research sheds light on the intricate interplay between microbial metabolites and adipose tissue, offering valuable clues for understanding and potentially manipulating these processes for therapeutic purposes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A direct ortho-Csp 2 -H acylalkylation of 2-aryl-2,3-dihydrophthalazine-1,4-diones with unsubstituted and substituted allyl alcohols is achieved in high yields through Rh(III)-catalyzed C-H bond activation process. The additional employment of Cu(OAc) 2 ⋅2H 2 O as an oxidant detour the reaction towards [4+1] annulation, producing 13-(2-oxopropyl)-13H-indazolo[1,2-b]phthalazine-6,11-diones in moderate yields. Interestingly, Lawesson's reagent-mediated conditions accomplished intramolecular cyclization in ortho-(formylalkylated)-2,3-dihydrophthalazine-1,4-diones to produce diazepino[1,2-b]phthalazine-diones in moderate yields. Furthermore, allyl alcohol showcased distinct reactivity in presence of different additives to produce ortho-allylated, oxidative and non-oxidative [4+2] annulated products., (© 2024 Wiley-VCH GmbH.)

Background: The study aimed to assess functional and radiological outcomes of the suprapatellar approach (SPA) and infrapatellar approaches (IPA) of tibial nailing in patients with closed tibia shaft fractures., Method: After Institutional Ethical Committee (IEC) and Clinical Trials Registry- India (CTRI) approval, patients with Orthopaedic Trauma Association (OTA) fracture type 42 were enrolled from August 2021 and August 2022 at a level I trauma centre and randomized to SPA and IPA with informed consent. Demographics, American Society of Anaesthesiologists (ASA) physical grading, intraoperative fluoroscopy time, operative duration, bleeding, postoperative radiographic alignment, and union were compared among both approaches. Functional parameters like Lysholm knee score, Anterior knee pain (AKP), Visual Analog Scale (VAS) Score upon kneeling, Knee Injury and Osteoarthritis outcome score (KOOS), KOOS Patellofemoral score (KOOS PF), EuroQol (EQ5D5L), Forgotten joint score (FJS), Range of motion (ROM) of knee and any complications were assessed at 3,6 and 12 months postoperatively., Results: Per protocol analysis of 50 patients (25 SPA, 25 IPA) done at the end of the study. SPA group had significantly lesser fluoroscopy time (91.28 ± 12.40s vs. 105.36 ± 9.23s, p < 0.001) and operative duration (mins) (123.80 ± 24.25 vs. 130.00 ± 18.20, p < 0.001) than IPA. No significant differences were noted in Lysholm knee score at three months (p = 0.094), six months (p = 0.406), and 12 months (p = 0.071). The SPA group showed significantly lower VAS Score upon kneeling at six months (p < 0.0001). Similarly, KOOS (p < 0.001), KOOS PF (p = 0.01), and EQ 5D5L (p = 0.03) were significantly better in the SPA group at six months postoperatively. Lower Coronal translation was found in SPA [0 (0-1.8) vs. 1.4 (0.9-1.8), p = 0.010]. Whereas, IPA had higher range of flexion at 3 months [130.0 (129.0-135.0) vs 123.1 (120.0-130.5), p = 0.047]. However, no significant differences were noted in blood loss, AKP, FJS, EQ-VAS, coronal angulation, sagittal malalignment, time to union, return to work and postoperative complications among the groups., Conclusion: SPA has lesser surgery time, more straightforward anatomic fracture reduction, better fracture alignment, lesser radiation exposure for both patients and surgeons, quicker recovery time, and promotes early kneeling activities with similar long-term functional outcomes and union rates, and can be considered in routine clinical practice than conventional IPA., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Delhi Orthopedic Association. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Exosomes play a pivotal part in cancer progression and metastasis by transferring various biomolecules. Recent research highlights their involvement in tumor microenvironment remodeling, mediating metastasis, tumor heterogeneity and drug resistance. The unique cargo carried by exosomes garners the interest of researchers owing to its potential as a stage-specific biomarker for early cancer detection and its role in monitoring personalized treatment. However, unanswered questions hinder a comprehensive understanding of exosomes and their cargo in this context. This review discusses recent advancements and proposes novel ideas for exploring exosomes in cancer progression, aiming to deepen our understanding and improve treatment approaches., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Pyridyloxy-directed Ir(III)-catalyzed diacylmethylation of protected tyrosines was achieved with alkyl and (hetero)aryl sulfoxonium ylides, furnishing tyrosine-based unnatural amino acids in good yields. Furthermore, the late stage exemplification of the strategy was successfully accomplished in tyrosine-containing dipeptides, tripeptides and tetrapeptides in moderate yields. This methodology is distinguished by its site-selectivity, tolerance of sensitive functional groups, scalability, and retention of the chiral configuration for tyrosine motifs.

Background: Epithelial cell adhesion molecule (EpCAM) has been widely studied as a tumor antigen due to its expression in varieties of solid tumors. Moreover, the glycoprotein contributes to critical cancer-associated cellular functionalities via its extracellular (EpEX) and intracellular (EpICD) domains. In colorectal cancer (CRC), EpCAM has been implicated in the Wnt signaling pathway, as EpICD and β-Catenin are coordinately translocated to the nucleus. Once in the nucleus, EpICD transcriptionally regulates EpCAM target genes that; however, remains unclear whether Wnt signaling is modulated by EpICD activity., Methods: Patient-derived organoids (PDOs), patient-derived xenografts (PDXs), and various CRC cell lines were used to study the roles of EpCAM and EpICD in Wnt receptor expression. Fluorescence and confocal microscopy were used to analyze tumors isolated from PDX and other xenograft models as well as CRC cell lines. EpCAM signaling was intervened with our humanized form of EpCAM neutralizing antibody, hEpAb2-6. Wnt receptor promoters under luciferase reporters were constructed to examine the effects of EpICD. Luciferase reporter assays were performed to evaluate promoter, γ-secretase and Wnt activity. Functional assays including in vivo tumor formation, organoid formation, spheroid and colony formation experiments were performed to study Wnt related phenomena. The therapeutic potential of EpCAM suppression by hEpAb2-6 was evaluated in xenograft and orthotopic models of human CRC., Results: EpICD interacted with the promoters of Wnt receptors (FZD6 and LRP5/6) thus upregulated their transcriptional activity inducing Wnt signaling. Furthermore, activation of Wnt-pathway-associated kinases in the β-Catenin destruction complex (GSK3β and CK1) induced γ-secretase activity to augment EpICD shedding, establishing a positive-feedback loop. Our hEpAb2-6 antibody blocked EpICD-mediated upregulation of Wnt receptor expressions and conferred therapeutic benefits in both PDX and orthotopic models of human CRC., Conclusions: This study uncovers relevant functions of EpCAM where Wnt receptors are upregulated via the transcriptional co-factor activity of EpICD. The resultant enhancement of Wnt signaling induces γ-secretase activity further stimulating EpICD cleavage and its nuclear translocation. Our humanized anti-EpCAM antibody hEpAb2-6 blocks these mechanisms and may thereby provide therapeutic benefit in CRC., (© 2024. The Author(s).)

Cancer remains a formidable global health challenge, with current treatment modalities such as chemotherapy, radiotherapy, surgery, and targeted therapy often hindered by low efficacy and adverse side effects. The indole scaffold, a prominent heterocyclic structure, has emerged as a promising candidate in the fight against cancer. This review consolidates recent advancements in developing natural and synthetic indolyl analogs, highlighting their antiproliferative activities against various cancer types over the past five years. These analogs are categorized based on their efficacy against common cancer types, supported by biochemical assays demonstrating their antiproliferative properties. In this review, emphasis is placed on elucidating the mechanisms of action of these compounds. Given the limitations of conventional cancer therapies, developing targeted therapeutics with enhanced selectivity and reduced side effects remains a critical focus in oncological research.

Introduction: The rising incidence of carbapenem resistance in Enterobacterales and Pseudomonas aeruginosa is a concern. Since carbapenemase production is the primary resistance mechanism, detecting and identifying the genes responsible for it is crucial to effectively monitor its spread., Objective: This study aims to detect positivity for the modified carbapenem inactivation method (mCIM) and ethylenediaminetetraacetic acid (EDTA)-carbapenem inactivation method (eCIM) for the detection of carbapenemase-producing Enterobacterales and Pseudomonas aeruginosa ., Methods: Methods: A cross-sectional study was carried out at a tertiary care hospital, including 250 clinical isolates of Enterobacterales and Pseudomonas aeruginosa . These isolates exhibited resistance to at least one of the carbapenems as determined by the VITEK AST 2 System (bioMérieux, USA). The isolates were subjected to mCIM testing, and those that tested positive were further tested using eCIM. The results were interpreted in accordance with the guidelines provided by the Clinical and Laboratory Standards Institute (CLSI) 2023., Results: Out of the total 250 carbapenem-resistant Enterobacterales and Pseudomonas aeruginosa isolates, 151 (60.4%) were Klebsiella pneumonia, 44 (17.6%) were Escherichia coli, 10 (4.0%) were Enterobacter cloacae , 6 (2.4%) were Providencia spp ., 4 (1.6%) were Serratia marcescens , 4 (1.6%) were Proteus mirabilis and 31 (12.4%) were Pseudomonas aeruginosa . Positivity for the mCIM was observed in 96% (240 out of 250) of the isolates. Of the mCIM-positive isolates, 234 (97.5%) also tested positive for eCIM, indicating metallo-β-Lactamase (MLB) production. A statistically significant association was found between both mCIM and eCIM positivity and the degree of resistance to carbapenem (p<0.05) . Conclusion: This study shows that the inexpensive method, a combination of mCIM and eCIM assists in differentiating between serine carbapenemase producers and MLB producers, thereby guiding the selection of appropriate therapy and useful in infection control in resource-limited settings., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee at Kalinga Institute of Medical Sciences, Bhubaneswar issued approval KIIT/KIMS/IEC/1344/2023. The study was approved by the Institutional Ethics Committee (reference no. KIIT/KIMS/IEC/1344/2023. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Verma et al.)

Advanced urinary bladder cancer is characterized by rapid progression and development of therapy resistance. About 30% of the patients are diagnosed with high-grade tumors (grade > T2a). A typical nonsurgical treatment is systemic chemotherapy using cisplatin (C) and gemcitabine (G). However, treatment failure and subsequent disease progression are common in treated patients, and adjuvant therapies are not significantly effective. The therapeutic potential of a molecular hybrid of ursolic acid (UA), a pentacyclic-triterpene conjugated to N-methyl piperazine (UA4), was tested on both naïve (WT) and gemcitabine-resistant (GemR) variants of two human invasive bladder cancer cell lines, 5637 and T24. UA4 killed 5637 (4 µmol/L), T24 (4 µmol/L) WT, and GemR cells in vitro at equal potency. Pretreatment with UA4 followed by G synergistically killed WT and GemR cells by >50% compared with G followed by UA4. Oral gavage of UA4 (100 mg/kg) inhibited WT and GemR tumor growth in athymic mice. UA4 + G was more effective against GemR tumors than either drug alone. Studies revealed cytotoxic autophagy as a mechanism of UA4 cytotoxicity. UA4 induced moderate apoptosis in T24 but not in 5637 cells. Mitochondrial integrity and function were most affected by UA4 because of high levels of reactive oxygen species, disruption of mitochondrial membrane, and cell cycle arrest. These effects were enhanced in the UA4 + G combination. UA4 was well-tolerated in mice, and oral gavage led to a serum level >1 µmol/L with no systemic toxicity. These results show the potential of UA4 as a nontoxic alternative treatment for high-grade bladder cancer., (©2024 American Association for Cancer Research.)

Purpose: Colorectal cancer (CRC) in young adults is a rising concern in developing countries such as India. This study investigates clinicopathologic profiles, treatment patterns, and outcomes of CRC in young adults, focusing on adolescent and young adult (AYA) CRC in a low- and middle-income country (LMIC)., Methods: A retrospective registry study from January 2018 to December 2020 involved 126 young adults (age 40 years and younger) with CRC. Patient demographics, clinical features, tumor characteristics, treatment modalities, and survival outcomes were analyzed after obtaining institutional ethics committees' approval., Results: Among 126 AYA patients, 62.70% had colon cancer and 37.30% had rectal cancer. Most patients (67%) were age 30-39 years, with no significant gender predisposition. Females had higher metastatic burden. Abdominal pain with obstruction features was common. Adenocarcinoma (65%) with signet ring differentiation (26%) suggested aggressive behavior. Limited access to molecular testing hindered mutation identification. Capecitabine-based chemotherapy was favored because of logistical constraints. Adjuvant therapy showed comparable recurrence-free survival in young adults and older patients. For localized colon cancer, the 2-year median progression-free survival was 74%, and for localized rectal cancer, it was 18 months. Palliative therapy resulted in a median overall survival of 33 months (95% CI, 18 to 47). Limited access to targeted agents affected treatment options, with only 27.5% of patients with metastatic disease receiving them. Chemotherapy was generally well tolerated, with hematologic side effect being most common., Conclusion: This collaborative study in an LMIC offers crucial insights into CRC in AYA patients in India. Differences in disease characteristics, treatment patterns, and limited access to targeted agents highlight the need for further research and resource allocation to improve outcomes in this population.

Background: The urinary biomarker response precedes the appearance of any renal structural or functional derangement. Transforming growth factor-β1 (TGF-β1), neutrophil gelatinase associated lipocalin (NGAL), and Cystatin C (CysC) can act as the early prognostic markers in posterior urethral valve (PUV) patients., Aim: To compare the urinary levels of TGF-β1, NGAL, and CysC between PUV cases and age matched controls and to correlate these with renal structural and functional parameters., Materials and Methods: This prospective study included children with PUV diagnosed using the standard investigations and an equal number of age-matched controls with nonurological problems. For the study subjects, the urinary samples were collected at three different time points (pre- and postoperatively at 3 and 6 months), whereas for controls, only single-voided samples were studied. The urinary levels of TGF-β1, NGAL, and CysC were estimated by the standardized techniques using the ELISA kits. Statistical methods were used to drive the comparisons between cases and controls., Results: Fifteen children with a median age of 10 (5-48) months were enrolled in each of the two groups. The mean uTGF-β1 in the case group was significantly higher at all three time points (43.20 ± 6.13 pg/ml, 43.33 ± 11.89 pg/ml and 40.71 ± 9.01 pg/ml) as compared to the control group (29.12 ± 8.31 pg/ml) ( P ≤ 0.001). The median uNGAL in the case group was also higher (17.78 ng/ml, 2.35 ng/ml and 2.536 ng/ml) as compared to the control group (1.31 ng/ml). However, the difference was significant only preoperatively ( P = 0.02). The median uCysC in case group was similarly higher (0.347 μg/ml, 0.439 μg/ml, and 0.382 μg/ml) than the control group (0.243 μg/ml) ( P > 0.05). Serum creatinine in the case group (0.49 mg/dl) showed no significant rise above that of control (0.24 mg/dl). A cutoff value of uTGF-β1 = 36.55 pg/ml ( P < 0.001), uNGAL = 0.879 ng/ml ( P = 0.02), and uCysC = 0.25 μg/ml ( P = 0.22) was found to be associated with renal damage in PUV. A significant correlation was found between uNGAL and S. creatinine at 3 months ( r = 0.43, P = 0.017) and 6 months ( r = 0.47, P = 0.08)., Conclusion: The elevated uTGF-β1, a decline in uNGAL and an increase in uCysC suggests ongoing inflammation, improvement in hydronephrosis and a prolonged proximal tubular dysfunction in PUV patients, respectively., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Indian Association of Pediatric Surgeons.)

Background Ischemic stroke is a major health crisis with significant consequences. Microalbuminuria, a sign of endothelial dysfunction, has been linked to adverse outcomes in ischemic stroke. Early neurological deterioration (END) is a critical factor influencing the patient's prognosis. This study aimed to determine the prevalence of microalbuminuria, its predictive value in assessing END, and its prognostic implications in acute ischemic stroke (AIS). Methodology This study conducted at Pradyumna Bal Memorial Hospital, Kalinga Institute of Medical Sciences Bhubaneswar (November 2020-April 2022) included 114 AIS patients over 18 years who presented within 24 hours of stroke onset. Demographics, vascular risk factors, National Institutes of Health Stroke Scale (NIHSS) scores (admission and day three), modified Rankin scores (day 10), urinary albumin-to-creatinine ratios, and carotid artery Doppler studies were collected. Results The mean age of the patients was 61.87 years, with males constituting 72.8% of the population. Hypertension (50.9%) and diabetes mellitus (28.9%) were the most common comorbid conditions. The mean NIHSS stroke severity at presentation was 11.30. END occurred in 38.6% of patients. Overall, 43.9% of cases showed carotid stenosis, and the mean carotid intimal media thickness was 1.08 mm. Notably, the presence of microalbuminuria significantly increased the chances of both END (39.45 times higher risk) and worse functional outcomes (odds ratio = 19.147, p = 0.001). Conclusions Microalbuminuria emerges as a robust independent predictor of END and a poor prognosis in AIS. These findings highlight the importance of early microalbuminuria identification and intervention to reduce END risk and potentially improve outcomes in AIS patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Pavuluri et al.)

Lung cancer remains a significant global health concern with limited treatment options and poor prognosis, particularly in advanced stages. Small extracellular vesicles such as exosomes, secreted by cancer cells, play a pivotal role in mediating drug resistance in lung cancer. Exosomes have been found to facilitate intercellular communication by transferring various biomolecules between cancer cells and their microenvironment. Additionally, exosomes can transport signaling molecules promoting cancer cell survival and proliferation conferring resistance to chemotherapy. Moreover, exosomes can modulate the tumor microenvironment by inducing phenotypic changes hindering drug response. Understanding the role of exosomes in mediating drug resistance in lung cancer is crucial for developing novel therapeutic strategies and biomarkers to overcome treatment limitations. In this review, we summarize the current knowledge on conventional and emerging drug resistance mechanisms and the involvement of exosomes as well as exosome-mediated factors mediating drug resistance in lung cancer., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Aims: The use of antibiotics affects health. The gut microbial dysbiosis by antibiotics is thought to be an essential pathway to influence health. It is important to have optimized energy utilization, in which adipose tissues (AT) play crucial roles in maintaining health. Adipocytes regulate the balance between energy expenditure and storage. While it is known that white adipose tissue (WAT) stores energy and brown adipose tissue (BAT) produces energy by thermogenesis, the role of an intermediate AT plays an important role in balancing host internal energy. In the current study, we tried to understand how treating an antibiotic cocktail transforms WAT into BAT or, more precisely, into beige adipose tissue (BeAT)., Methods: Since antibiotic treatment perturbs the host microbiota, we wanted to understand the role of gut microbial dysbiosis in transforming WAT into BeAT in C57BL/6 mice. We further correlated the metabolic profile at the systemic level with this BeAT transformation and gut microbiota profile., Key Findings: In the present study, we have reported that the antibiotic cocktail treatment increases the Proteobacteria and Actinobacteria while reducing the Bacteroidetes phylum. We observed that prolonged antibiotic treatment could induce the formation of BeAT in the inguinal and perigonadal AT. The correlation analysis showed an association between the gut microbiota phyla, beige adipose tissue markers, and serum metabolites., Significance: Our study revealed that the gut microbiota has a significant role in regulating the metabolic health of the host via microbiota-adipose axis communication., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Purvish M ParikhS-1 (5-fluorouracil prodrug [tegafur] in combination with 5-chloro-2,4-dihydroxypyridine [CDHP] and potassium oxonate [OXO]) was first approved in 1999. In order to make it easy for community oncologists, we decided to put together this expert consensus guideline for its use in gastrointestinal (GI) malignancies. A total of 15 subject matter experts used modified Delphi method to discuss, analyze, and vote on key aspects regarding practical approach to use of S-1 in GI cancers, a process involving 6 months of work. The consensus guidelines specify how S-1 use can be optimized in patients with colorectal, gastric, and pancreatic tumors. The voting for the 17 key points resulted in a majority consensus for all the statements (approval ranging from 13/15 [87%] to 15/15 [100%]). S-1 is a combination of three drugs (tegafur, CDHP, and OXO) specifically designed to reduce toxicity and enhance efficacy; clinical data and meta-analysis confirm both factors; and it is recommended as standard of care for GI cancers. S-1 is approved and one of the standards of care for all lines of therapy in colorectal cancer and pancreatic cancers. S-1 with oxaliplatin is the standard of care for gastric cancers., Competing Interests: Conflict of Interest None declared., (MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

A validated ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the first-ever simultaneous analysis of neratinib, curcumin and internal standard (imatinib) using acetonitrile as the liquid-liquid extraction medium. On a BEH C18 (100 mm × 2.1 mm, 1.7 μm) column, the analytes were separated isocratically using acetonitrile (0.1% formic acid):0.002M ammonium acetate. The flow rate was set at 0.5 mL.min-1. The authors utilized multiple reaction monitoring-based transitions for the precursor-to-product ion with m/z 557.099 → 111.928 for neratinib, m/z 369.231 → 176.969 curcumin and m/z 494.526 → 394.141 for imatinib during the study. Validation of the method as per United States Food and Drug Administration requirements for linearity (5-40 ng mL-1), accuracy and precision, stability, matrix effect, etc. were investigated and were observed to be acceptable. Afterward, we evaluated the method for establishing its greenness profile by using two greenness assessment tools and found it green. Overall, a reliable green UPLC-MS/MS method was devised and used to estimate neratinib and curcumin in human plasma simultaneously., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Targeted therapies against programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) have revolutionized the management in recent years. There is paucity of data on the significance of PD-L1 expression in NSCLC from India. We aimed to study the prevalence of PD-L1 expression and its relation with different clinico-pathological parameters in advanced NSCLC from a tertiary care center in Eastern India., Methods: All consecutive patients with advanced NSCLC diagnosed from January 2020 to December 2021 were prospectively evaluated for PD-L1 expression in formalin fixed-paraffin embedded tumor tissue specimens using immunohistochemistry analysis. A PD-L1 expression of < 1%, 1-49%, and ≥ 50% were considered negative, low, and high expression positive respectively, and association with various parameters was performed., Results: Out of the 94 patients (mean age 59.6 ± 14 years and 63.8% males), PD-L1 positivity was seen in 42 (44.7%) patients, with low positivity (1-49%) in 29 patients and high positivity (≥ 50%) in 13 patients. Epidermal Growth Factor Receptor (EGFR) mutations were seen in 28 patients (29.8%). There were no significant differences in PD-L1 positivity with respect to gender, age, and molecular mutation status. PD-L1 positivity was significantly associated with tobacco use (p = 0.04), advanced tumor stage (p < 0.001), and higher nodal stage (p < 0.001). Median overall survival in the cohort was 17 months and it was not significantly different between the PD-L1 positive and negative groups., Conclusions: Forty-five percent of advanced NSCLC patients in our cohort showed positive PD-L1 expression and it is associated with tobacco use and aggressive tumor characteristics., (© 2024. The Author(s).)

Purpose: The Shock Index Pediatric Age-Adjusted (SIPA) score is a useful tool for identifying pediatric trauma patients at a risk of poor outcomes and for triaging. We are studying the relationship between elevated SIPA score and specific outcomes in pediatric trauma patients., Materials and Methods: A retrospective study was conducted in which case records of 58 pediatric patients with blunt abdominal trauma were evaluated and tabulated for their SIPA scores only at the time of their initial presentation and categorized into two groups - normal SIPA and elevated SIPA. The primary outcomes were need for blood transfusion, need for any intervention, and need for emergency surgery, and the secondary outcomes were need for computed tomography (CT) scan, need for a ventilator, intensive care unit (ICU) stay, length of hospital stay, and mortality. Statistical methods were applied to find a relationship between elevated SIPA score and the primary and secondary outcomes., Results: An elevated SIPA score was noted in 27 (46%) patients. There was a significant relationship between elevated SIPA scores and patients needing blood transfusion (68.75%, n = 11) and length of hospital stay (10.48 ± 7.54 days). A significant relationship between elevated SIPA score and need for emergency surgery (54.54%, n = 6), need for a CT scan (56%, n = 14), and ICU stay (50%, n = 2) was not found., Conclusion: We have seen in our study that elevated SIPA scores at presentation are significantly related to need for blood transfusion and length of hospital stay. In more than half of the patients, elevated SIPA was associated with need for emergency surgery and requirement of CT scan, but it was statistically not significant. Therefore, assessment of this parameter can help in identifying such poor outcomes., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Indian Association of Pediatric Surgeons.)

Mining activities lead to severe particulate matter (PM) pollution that consequently has a detrimental effect on ecosystem. A study was therefore conducted in a coal mining area of Odisha, India with an objective to assess the particulate matter pollution on the basis of differential aerodynamic size (PM 10 and PM 2.5 ) of the particles, the metallic (Zn and Fe) composition, and also to evaluate their nature of deposition on two identified plant species. The results suggest a significant variation in particle and heavy metal fractions in the ambient air of different sites ( p  < 0.05). Fe dominated the finer particle (PM 2.5 ) fraction while Zn dominated the coarser counterpart (PM 10 ) in the ambient air. When evaluated for the particle and heavy metal deposition on leaf surface, Shorea robusta performed better in trapping the coarser particles (PM 10 ) while Holarrhena floribunda was found to be an efficient scrubber of the finer particles (PM 2.5 ). Fe deposition on surface of leaves was comparatively higher than Zn irrespective of plant species or size fractions. Therefore, it is concluded that both S. robusta and H. floribunda should be planted in a schematic manner to tackle the particulate pollution in coal mining areas.

Background: Programmed Death Ligand 1 (PD-L1) expression in tumor cells contribute to tumor immunity and therapies directed against it, have shown encouraging results in recent years. As there is limited data on the significance of PD-L1 expression in Head and Neck Squamous Cell Carcinoma (HNSCC) from India, we aimed to study the PD-L1 expression and its relation with different clinic-pathological parameters in patients of HNSCC from a tertiary care center in Eastern India., Methods: A prospective evaluation of HNSCC patients diagnosed and managed at our center over a period of two and half years, was performed. PD-L1 expression in formalin fixed-paraffin embedded tumor tissue specimens was measured using SP-263 (Ventana) and 22C3 (Dako). A PD-L1 expression of <1%, 1-19%, ≥20% were considered negative, low, and high expression, respectively, and was correlated with various parameters., Results: A total of 71 patients (mean age 50.8 ± 13.3 years, 86% males) were diagnosed with HNSCC (buccal mucosa-28, tongue-22, rest of oral cavity-8, larynx-7, nasopharynx-6). The tumor was poorly differentiated in 12 (17%). PD-L1 positivity was seen in a total of 51 (71.8%) patients (1-19%:18, ≥20%:33). Thirty (85.7%) patients among those aged <50 years and 58.3% of those aged ≥50 years showed PD-L1 positivity which was significant (P = 0.01). There were no statistically significant differences in PD-L1 positivity with respect to gender, tobacco use, tumor grade as well as tumor and nodal stage. Median follow up duration was 18 months (range 3-31 months) and there was significant difference in overall survival among PD-L1 positive and negative groups (31 vs 24 months; log rank P = 0.03)., Conclusions: 72% of HNSCC patients in our cohort showed PD-L1 positivity and it was not associated with any patient demographic characteristics or aggressive pathological features. Positive PD-L1 expression may have a beneficial effect on overall survival in HNSCC., (Copyright © 2023 Copyright: © 2023 Journal of Cancer Research and Therapeutics.)

Lalatendu Moharana The Anaplastic lymphoma kinase inhibitors (ALKi) represent the standard of care for metastatic non-small cell lung cancer (NSCLC) patients with EML4-ALK rearrangements. Various ALKi agents are available; however, not all eligible patients receive treatment with them due to various reasons. Given the limited real-world data available in our country, we aimed to assess treatment outcomes through a multicenter collaboration. This retrospective, multi-institutional study was conducted under the Network of Oncology Clinical Trials India and included a total of 67 ALK-positive metastatic lung cancer patients from 10 institutes across India, with a median follow-up of 23 months. In the first line setting, the objective response rate (ORR) with ALKi was 63.6% (crizotinib: 60.7%, ceritinib: 70%, alectinib: 66.6%, p  = 0.508), while with chemotherapy, it was 26.1%. The median progression-free survival (mPFS) for the first line ALKi group was significantly higher than that for chemotherapy (19 vs. 9 months, p  = 0.00, hazard ratio [HR] = 0.30, 95% confidence interval [CI]: 0.17-0.54). The mPFS for crizotinib, alectinib, and ceritinib was 17, 22, and 19 months, respectively ( p  = 0.48). Patients who received ALKi upfront or after 1 to 3 cycles of chemotherapy or after 4 or more cycles of chemotherapy had mPFS of 16, 22, and 23 months, respectively ( p  = 0.47). ALKi showed superior mPFS compared to chemotherapy in the second line (14 vs. 5 months; p  = 0.002) and the third line (20 vs. 4 months; p  = 0.009). The median overall survival (OS) was significantly better in patients who received ALKi in any line of therapy (44 vs. 14 months, p  < 0.001, HR = 0.10, 95% CI: 0.04-0.23). Brain progression was higher among those who did not receive ALKi (69.2 vs. 31.5%). In conclusion, the use of ALKi as first line treatment for ALK-positive metastatic NSCLC patients resulted in improved PFS. PFS and ORR did not significantly differ between patients who received ALKi upfront or after initiating chemotherapy. Notably, patients who received ALKi in second or later lines demonstrated significantly better outcomes compared to those receiving chemotherapy. The use of ALKi in any line of therapy was associated with significantly prolonged OS., Competing Interests: Conflict of Interest None declared., (MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

Alkaloids found in multiple species, known as 'driver species', are more likely to be included in early-stage drug development due to their high biodiversity compared to rare alkaloids. Many synthetic approaches have been employed to hybridize the natural alkaloids in drug development. Click chemistry is a highly efficient and versatile reaction targeting specific areas, making it a valuable tool for creating complex natural products and diverse molecular structures. It has been used to create hybrid alkaloids that address their limitations and serve as potential drugs that mimic natural products. In this review, we highlight the recent advancements made in modifying alkaloids using click chemistry and their potential medicinal applications. We discuss the significance, current trends, and prospects of click chemistry in natural product-based medicine. Furthermore, we have employed computational methods to evaluate the ADMET properties and drug-like qualities of hybrid molecules.

Pyridyloxy-directed Rh(III)-catalyzed regioselective C3 Ar -H alkenylation of protected tyrosines was achieved with N -aryl and N -alkyl maleimides, furnishing a series of maleimide-appended tyrosine-based unnatural amino acids in good yields. Further, the late-stage exemplification of the strategy was successfully accomplished on tyrosine-containing dipeptides, tripeptides, and tetrapeptides in moderate reactivity. Also, the chemical applications of the strategy were successfully executed toward nailing tyrosine with other amino acids via a maleimide linker and intramolecular hydroarylation to produce tyrosine-centered stapled products and succinimide-glued macrocyclized products, respectively.

Microwave-assisted reaction of 3,5-bis((E)-ylidene)-1-phosphonate-4-piperidones 3a‒g with azomethine ylide (produced through interaction of isatins 4 and sarcosine 5) cycloaddition afforded the corresponding (dispiro[indoline-3,2'-pyrrolidine-3',3″-piperidin]-1″-yl)phosphonates 6a‒l in excellent yields (80-95%). Structure of the synthesized agents was evidenced by single crystal X-ray studies of 6d, 6i and 6l. Some of the synthesized agents revealed promising anti-SARS-CoV-2 properties in the viral infected Vero-E6 cell technique with noticeable selectivity indices. Compounds 6g and 6b are the most promising agents synthesized (R = 4-BrC 6 H 4 , Ph; R' = H, Cl, respectively) with considerable selectivity index values. M pro -SARS-CoV-2 inhibitory properties supported the anti-SARS-CoV-2 observations of the potent analogs synthesized. Molecular docking studies (PDB ID: 7C8U) are consistent with the M pro inhibitory properties. The presumed mode of action was supported by both experimentally investigated M pro -SARS-CoV-2 inhibitory properties and explained by docking observations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

There is now a deep interest in actively reconfigurable nanophotonics as they will enable the next generation of optical devices. Of the various alternatives being explored for reconfigurable nanophotonics, Chalcogenide phase change materials (PCMs) are considered highly promising owing to the nonvolatile nature of their phase change. Chalcogenide PCM nanophotonics can be broadly classified into integrated photonics (with guided wave light propagation) and Meta-optics (with free space light propagation). Despite some early comprehensive reviews, the pace of development in the last few years has shown the need for a topical review. Our comprehensive review covers recent progress on nanophotonic architectures, tuning mechanisms, and functionalities in tunable PCM Chalcogenides. In terms of integrated photonics, we identify novel PCM nanoantenna geometries, novel material utilization, the use of nanostructured waveguides, and sophisticated excitation pulsing schemes. On the meta-optics front, the breadth of functionalities has expanded, enabled by exploring design aspects for better performance. The review identifies immediate, and intermediate-term challenges and opportunities in (1) the development of novel chalcogenide PCM, (2) advance in tuning mechanism, and (3) formal inverse design methods, including machine learning augmented inverse design, and provides perspectives on these aspects. The topical review will interest researchers in further advancing this rapidly growing subfield of nanophotonics., (© 2023 IOP Publishing Ltd.)

Purvish M. ParikhCancer-associated anemia (CAA) remains a major unmet need that compromises overall survival (OS) and quality of life (QoL). Currently, available guidelines do not take into consideration the unique challenges in low- and middle-income countries (LMIC). Our CAA patients have to battle preexisting impaired nutritional status, depleted body iron stores, financial limitations, and difficulty in having easily accessible affordable healthcare. Hence, we fulfilled the need of guidelines for LMIC. A group of subject experts were put together, given background literature, met in a face-to-face discussion, voted using Delphi process, and finally agreed on the contents of this guideline document. As many as 50% of cancer patients will have significant anemia (hemoglobin < 10 g/dL) at initial diagnosis. It is most commonly seen with gastrointestinal malignancies, head and neck cancers, and acute leukemias. The hemoglobin falls further after initiation of cancer directed therapy, due to chemotherapy itself or heightened nutritional deficiency. Its evaluation should include tests for complete blood count, red blood cell morphology, reticulocyte count, Coombs test, and levels of vitamin B12 and folic acid. Iron status should be monitored using test to measure serum iron, total iron binding capacity, transferring saturation, and serum ferritin levels. A minimum of 50% of cancer patients with anemia require iron supplements. The preferred mode of therapy is with intravenous (IV) iron using ferric carboxymaltose (FCM). Most patients respond satisfactorily to single dose of 1000 mg. It is also safe and does not require use of a test dose. Significant anemia is found in at least half of all cancer patients in India, South Asian Association for Regional Cooperation region, and other LMIC countries. Its awareness among healthcare professionals will prevent it from remaining undiagnosed (in up to 70% of all cancer patients) and adversely affecting OS and QoL. The benefits of treating them with IV iron therapy are quick replenishment of iron stores, hemoglobin returning to normal, better QoL, and avoiding risk of infections/reactions with blood transfusions. Many publications have proven the value of single-dose FCM in such clinical situations. CAA has been proven to be an independent prognostic factor that adversely affects both QoL and OS in cancer patients. Use of FCM as single IV dose of 1000 mg is safe and effective in the majority of patients with CAA., Competing Interests: Conflict of Interest None declared., (MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

The COVID-19 pandemic has posed a significant threat to society in recent times, endangering human health, life, and economic well-being. The disease quickly spreads due to the highly infectious SARS-CoV-2 virus, which has undergone numerous mutations. Despite intense research efforts by the scientific community since its emergence in 2019, no effective therapeutics have been discovered yet. While some repurposed drugs have been used to control the global outbreak and save lives, none have proven universally effective, particularly for severely infected patients. Although the spread of the disease is generally under control, anti-SARS-CoV-2 agents are still needed to combat current and future infections. This study reviews some of the most promising repurposed drugs containing indolyl heterocycle, which is an essential scaffold of many alkaloids with diverse bio-properties in various biological fields. The study also discusses natural and synthetic indole-containing compounds with anti-SARS-CoV-2 properties and computer-aided drug design (in silico studies) for optimizing anti-SARS-CoV-2 hits/leads.

An organic acid, salicylic acid, and its derivatives are constituents of various natural products possessing remarkable bioactivity. O -Acetyl salicylate (aspirin) is a well-known life-saving drug. Its peptide derivative salicylamide has also been explored in the designing of peptide-based therapeutic drugs. An organic base, picolylamine has been recently explored for designing diagnostic probes. However, both the acid and base have common features as metal chelating with coordinating metals. Thus, these scaffolds could be used for designing inhibitors of various metalloenzymes. Their characteristic properties encourage us to design peptides containing both scaffolds (salicylic acid and picolylamine) at opposite terminals. So far there is no report available on such conjugated peptides. This report describes the synthesis, conformational analysis, and biochemical assessment of rationally designed N- salicyl-AA n - picolamide peptides. Pleasantly, we have obtained the crystal structures of representative peptides that confirm their roles in conformational changes. Our biological assessment as quorum sensing inhibitors has revealed that their di/tripeptides inhibit quorum sensing of the pathogenic bacterium PA14 strain. Hence, these peptides have promising foldameric and therapeutic values., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: Epithelial cell adhesion molecule (EpCAM) is known to highly expression and promotes cancer progression in many cancer types, including colorectal cancer. While metastasis is one of the main causes of cancer treatment failure, the involvement of EpCAM signaling in metastatic processes is unclear. We propose the potential crosstalk of EpCAM signaling with the HGFR signaling in order to govern metastatic activity in colorectal cancer., Methods: Immunoprecipitation (IP), enzyme-linked immunosorbent assay (ELISA), and fluorescence resonance energy transfer (FRET) was conducted to explore the extracellular domain of EpCAM (EpEX) and HGFR interaction. Western blotting was taken to determine the expression of proteins in colorectal cancer (CRC) cell lines. The functions of EpEX in CRC were investigated by proliferation, migration, and invasion analysis. The combined therapy was validated via a tail vein injection method for the metastasis and orthotopic colon cancer models., Results: This study demonstrates that the EpEX binds to HGFR and induces downstream signaling in colon cancer cells. Moreover, EpEX and HGF cooperatively mediate HGFR signaling. Furthermore, EpEX enhances the epithelial-to-mesenchymal transition and metastatic potential of colon cancer cells by activating ERK and FAK-AKT signaling pathways, and it further stabilizes active β-catenin and Snail proteins by decreasing GSK3β activity. Finally, we show that the combined treatment of an anti-EpCAM neutralizing antibody (EpAb2-6) and an HGFR inhibitor (crizotinib) significantly inhibits tumor progression and prolongs survival in metastatic and orthotopic animal models of colon cancer., Conclusion: Our findings illuminate the molecular mechanisms underlying EpCAM signaling promotion of colon cancer metastasis, further suggesting that the combination of EpAb2-6 and crizotinib may be an effective strategy for treating cancer patients with high EpCAM expression., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Mesosphaerum suaveolens (L.) Kuntze (Syn. Hyptis suaveolens (L.) Poit.) is a wild essential-oil-bearing plant having multiple uses in traditional medicine, perfumery, food, agriculture, and pharmaceutical industries. The present paper is the first report on the in vitro anti-inflammatory effects of the leaf essential oil of M. suaveolens (MSLEO) and unravels its molecular mechanism in LPS-stimulated RAW 264.7 macrophage cells. GC-MS analysis of the essential oil (EO) isolated from the leaves by hydro-distillation led to the identification of 48 constituents, accounting for 90.55% of the total oil, and β-caryophyllene (16.17%), phyllocladene (11.85%), abietatriene (11.46%), and spathulenol (7.89%) were found to be the major components. MSLEO treatment had no effect on the viability of RAW 264.7 cells up to a concentration of 100 μg/mL, and the EO was responsible for a reduction in proinflammatory cytokines like IL-6, IL-1β, and TNF-α, a decrease in intracellular ROS production, and the restoration of oxidative damage by elevating the levels of endogenous antioxidative enzymes like CAT, SOD, GPx, and GSH. RT-qPCR analysis indicated that MSLEO reduced the mRNA expression levels of iNOS and COX-2 as compared to the LPS-induced group. In addition, a confocal microscopy analysis showed that MSLEO inhibited the translocation of NF-κB from the cytosol to the nucleus. The results of this experiment demonstrate that MSLEO possesses significant anti-inflammatory potential by preventing the activation of NF-κB, which, in turn, inhibits the downstream expression of other inflammatory mediators associated with the activation of the NF-κB pathway in LPS-induced RAW 264.7 cells. Thus, the leaf essential oil of M. suaveolens may prove to be a promising therapeutic agent for the treatment of inflammation, and targeting the NF-κB signaling pathway may be considered as an attractive approach for anti-inflammatory therapies.

Soumya Surath PandaGastric cancer (GC) is often ignored at a young age, which frequently leads to tragic consequences. The worldwide incidence of GC is increasing at a young age. In view of the limited Indian publication, we sought to characterize clinicopathological parameters and risk factors in the adolescents and young adults (AYA) population. Retrospective data from six centers (which are part of the Network of Oncology Clinical Trials in India) from 2015 to 2020 were collected from patient (18-39 years of age) records. This study was approved by the institutional ethical committee of individual centers. All statistical analyses were performed using Microsoft Excel and SPSS (Version 20). Data interpretation along with the analysis of obtained results was carried out using the following tests: Qualitative data was expressed in terms of frequency/percentage. One-hundred fifty-two AYA GC patients were enrolled. The 31 to 39 years age group was most affected in which 76.3% were females. The majority of patients were nonalcoholic (93.4%), nonsmokers (98.0%), and without a family history (98.0%). The most common (MC) presenting symptom was abdominal pain (67.1%). MC site was antrum (48%). Among esophagogastric junction cancers, the majority were type I and II Siewert classifications (77% [20/26] patients in cardia), MC histology-signet ring cell (67.1%) followed by diffuse-type (65.1%). Most were poorly differentiated (65.1%) and were diagnosed at an advanced stage (III & IV= 54.6%). This is one of our country's first large multicenter studies on GC in the AYA population. There was a higher female prevalence, aggressive tumor behavior and the majority of patients were diagnosed at a more advanced stage. The majority were nonsmokers with a negative family history. Awareness among general people, researchers, clinicians, and policymakers must be improved to better the loss of life years in the younger population., Competing Interests: Conflict of Interest None declared., (MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)