High IC Research Articles

Low test cost adaptive testing method for high yield IC products

Low test cost adaptive testing method for high yield IC products

Green synthesized Zn-based mono and bi-metallic nanoparticles for improved micronutrient delivery: A futuristic study in hydroponic crop culture system.

Green synthesized Zn-based mono and bi-metallic nanoparticles for improved micronutrient delivery: A futuristic study in hydroponic crop culture system.

Synthesis of 5-(2-hydroxyphenyl)-5-methyl-6H-benzo[c]carbazole-6-ones and their antitumor activities.

Synthesis of 5-(2-hydroxyphenyl)-5-methyl-6H-benzo[c]carbazole-6-ones and their antitumor activities.

Potential biomarker of PD-L1 expression phenotypes in tumor and immune cells for combined PD-1 and CTLA-4 blockade therapies in advanced NSCLC.

8524 Background: Pembrolizumab-based chemo-immunotherapies (Pembro) and nivolumab plus ipilimumab-based immunotherapies with or without 2 cycles of chemotherapies (Nivo+Ipi) have improved survival in patients with advanced NSCLC compared to the conventional chemotherapy. However, biomarkers to support appropriate choice in these immunotherapies remain unclear. Methods: From 2019 to 2023, this multicenter, observational study retrospectively reviewed advanced NSCLC patients who received first-line Pembro or Nivo+Ipi and had evaluable PD-L1 expression status on tumor cells (tumor proportion score [TPS], 22C3) and immune cells (immune cell [IC] score, SP142). Survival curve comparisons between treatments were conducted using restricted mean survival time (RMST) estimation in place of Log-rank test, when the proportional hazard assumption was not met. Additionally, the genomic and expression profiles associated with TPS and IC score were assessed using whole-exome sequencing and RNA sequencing in available NSCLC samples. Results: A total of 198 patients were included (Pembro/Nivo+Ipi: 137/61). In the Pembro cohort, patients with high TPS (≥ 50%) had significantly longer progression-free survival (PFS) than those with low TPS (< 50%) (median PFS [mPFS, months]: 8.1 vs. 7.1, P = 0.02; hazard ratio [HR] = 0.59 [0.38–0.92]), while no significant difference in PFS was observed based on IC score (high vs. low: mPFS 7.4 vs. 6.8, P = 0.11, HR = 0.72 [0.49–1.07]). In the Nivo+Ipi cohort, PFS did not significantly differ by TPS (high vs. low: mPFS 4.0 vs. 4.0, P = 0.26; HR = 0.51 [0.16–1.68]), whereas patients with high IC score (≥ 1) had significantly longer PFS than those with low IC score (= 0) (mPFS: 7.7 vs. 2.8, P = 0.04; HR = 0.53 [0.28–0.98]). A durable PFS benefit of Nivo+Ipi over Pembro was observed only in patients with low TPS/high IC score (mPFS: 12.4 vs. 6.6; Schoenfeld individual test: P < 0.05; RMST Nivo+Ipi /RMST Pembro [2 years] = 1.5, P = 0.049, Table). Sequence analyses revealed that tumors with low TPS/high IC score had significantly higher tumor mutational burden (TMB) than other tumors (median TMB: 18.2 vs. 1.9 [/mb]; P < 0.001) and showed distinct enrichment in antigen presentation and T-cell receptor signaling pathways. Conclusions: Nivolumab plus ipilimumab-based immunotherapies demonstrated superior durable response compared to pembrolizumab-based chemo-immunotherapies in patients with low TPS/high IC score. PD-L1 phenotypes based on TPS and IC score could guide the optimal selection of immunotherapies for advanced NSCLC patients. Efficacy comparison in patients with low TPS (< 50%)/high IC score (≥ 1). Treatments mPFS (months) PFS rate at 2 years RMST at 2 years RMST Nivo+Ipi /RMST Pembro at 2 years P value Pembrolizumab-based chemo-immunotherapies 6.6 6% 8.5 1.5 [1.0–2.3] 0.049 Nivolumab plus ipilimumab-based immunotherapies 12.4 41% 12.9

Cytotoxic activity, phenolic content, and fatty acid of brown algae from tropical reefs

New cancer therapies development is a huge demand. This research evaluated cytotoxic activity against normal and cancer cells of brown algae (Dictyotales) extracts with high antioxidant activity. Canistrocarpus cervicornis, Dictyopteris delicatula and Lobophora variegata extracts from two beaches of Pernambuco were obtained by two serial maceration method: 1° Extraction—dichloromethane and methanol (2:1 v/v) and subsequently water at 60 °C; 2° Extraction—dichloromethane and methanol (2:1 v/v), subsequently ethanol and finally water at 80 °C. Phenolic compounds and cytotoxicity against normal cell lines L-929 (murine fibroblast), PBMC (human peripheral blood mononuclear cells) and J774A1 (mouse macrophages), and cancer cell lines P815 (murine mastocytoma), S-180 (murine Sarcoma), NCI-H292 (human lung mucoepidermoid carcinoma), HCT-116 (human colorectal carcinoma), JUKART (human T cell leukaemia) and MCF-7 (human breast adenocarcinoma) were assessed. Only for L-929 strain, among normal cells, extracts presented cytotoxicity. Organic extracts showed moderate to high cytotoxic activity against P815, MCF-7 and HCT-116 cancer cell lines. Organic extract L. variegata Jaguaribe 2° Extraction exhibited the best cytotoxic activity with high IC50 values (28–35 µg/mL). Thus, we evaluate its acids profile that showed important polyunsaturated fatty acids and carboxylic acid, such as arachidonic acid and cinnamic acid that is being reported to L. variegata for the first time. Various research demonstrated the anticancer activity of this substance. Therefore, the high cytotoxic activity of our most active extract could be due to the presence of fatty acids and carboxylic acid, acting synergically, including cinnamic acid. These results encourage macroalgae use as an anticancer metabolites source for human therapies.

Chemical profiling and anticancer activity of Alnus incana dichloromethane fraction on HeLa cells via cell cycle arrest and apoptosis

BackgroundCervical cancer remains a global health challenge with persistently high incidence and mortality rates despite advancements in conventional treatments. The therapeutic potential of natural products has gained attention, particularly for their selective cytotoxicity and ability to modulate cancer pathways. Alnus incana (L.) Moench, a species-rich in bioactive compounds, shows potential as an anticancer agent; however, the cytotoxic effects of its leaves dichloromethane (DCM) extract remain underexplored. This study investigates the DCM fraction’s cytotoxicity on various cancer cell lines, with a primary focus on HeLa cells.MethodsThe cytotoxic effects of the A. incana DCM fraction were evaluated in a dose-dependent manner using the MTT assay on several cancer cell lines, with particular emphasis on HeLa cells. Flow cytometry was used to assess cell cycle arrest and apoptosis, while RT-qPCR quantified changes in the expression of apoptotic markers (Bax, Bcl-2, and p53). Chemical composition analysis was conducted using gas chromatography-mass spectrometry/flame ionization detection (GC-MS/FID) to identify the major bioactive compounds within the fraction.ResultsThe DCM fraction exhibited dose-dependent cytotoxicity in HeLa cells, with an IC50 value of 135.6 µg/mL and a selectivity index (SI) of 2.72 relative to normal cells. Flow cytometry analysis revealed G0/G1 cell cycle arrest, significantly hindering progression through the S and G2/M phases. Moreover, there was a significant increase in both early and late apoptotic cell populations, correlating with the upregulation of pro-apoptotic genes (Bax and p53) and the downregulation of the anti-apoptotic gene Bcl-2. The chemical analysis identified 22 compounds in the unsaponifiable fraction, chiefly terpenoids such as phytol (65.74%). The saponifiable fraction presented a balanced composition of saturated (48.69%) and unsaturated (51.29%) fatty acids, with palmitic acid, linolenic acid, and linoleic acid as the predominant compounds.ConclusionWhile the DCM fraction’s relatively high IC50 value may limit its utility as a standalone treatment, its ability to induce cell cycle arrest and apoptosis demonstrates its promise as a co-therapeutic agent with conventional anticancer drugs. Further research is essential to elucidate its precise mechanisms of action and to evaluate its efficacy in combination therapies, potentially advancing its role in cervical cancer treatment.

Novel pyrazole carboxylate derivatives as lonazolac bioisosteres with selective COX-2 inhibition: design, synthesis and anti-inflammatory activity.

Two novel series of di-aryl/tri-aryl substituted pyrazole ester derivatives 15a-h and 19a-d were designed, synthesized as novel non-acidic lonazolac analogs and tested for its COX-2, 5-LOX, 15-LOX, iNOS, pro-inflammatory cytokines TNF-α and PGE2 inhibitory activities. All the tested compounds showed excellent COX-2 inhibitory activity (IC50 = 0.059-3.89μM), compared to that of celecoxib (IC50 = 0.22μM), where derivatives 15c, 15d, 15h and 19d were found to be the most potent showing COX-2 selectivity index in range of (S.I. = 28.56-98.71) compared to celecoxib (S.I. = 13.65). Moreover, the most potent four derivatives 15c, 15d, 15h and 19d showed outstanding 5-LOX and 15-LOX inhibitory activities (IC50 = 0.24-0.81, 0.20-2.2 respectively, compared to zileuton IC50 = 1.52 and 0.54, respectively). Further investigation of the anti-inflammatory mechanistic study of derivatives 15c, 15d, 15h and 19d revealed that these four compounds exhibited comparable TNF-α and PGE2 (LPS-induced pro-inflammatory cytokines) inhibitory activities (IC50 = 0.77-1.20μM and 0.28-0.52μM respectively) when compared to celecoxib (IC50 = 0.87μM and 0.38μM respectively) as reference drug using lipopolysaccharide-activated RAW 264.7 macrophages. Based on the advanced inhibitory activity of compounds 15c, 15d, 15h and 19d against LPS-induced pro-inflammatory mediators (TNF-α and PGE2), inducible nitric oxide synthase (iNOS) inhibition assay was carried out. Remarkably, compounds 15c, 15d, 15h and 19d showed higher potency with lower IC50 (0.41-0.61µM) when compared to the reference drug celecoxib (0.48µM). Prior to in vivo anti-inflammatory activity screening, cytotoxicity testing was performed to ascertain safe and non-toxic concentrations of each compound. Safe doses of compounds were determined using lipopolysaccharide-activated RAW 264.7 macrophages, moreover results showed that compounds 15c, 15d, 15h and 19d were more safer (less cytotoxic) with higher IC50 (178.95-301.40µM) when compared to the reference drug celecoxib (148.90µM). In vivo anti-inflammatory activity of the target compounds 15c, 15d, 15h and 19d reinforced the results of in vitro screening as the derivatives 15c, 15d, 15h and 19d showed (ED50 = 8.22-31.22mg/kg, respectively) and were more potent than celecoxib (ED50 = 40.39mg/kg). All screened derivatives 15c, 15d, 15h and 19d were less ulcerogenic (ulcer indexes = 1.22-3.93) than lonazolac (ulcer index = 20.30) and comparable to celecoxib (ulcer index = 3.02). In silico docking and ADME studies were carried out in order to clarify the interactions of the most active derivatives 15c, 15d, 15h and 19d with the target enzymes and their pharmacokinetic parameters.

Intrinsic capacity trajectories and cardiovascular disease incidence among Chinese older adults: a population-based prospective cohort study

BackgroundIntrinsic capacity (IC), a composite of physical and mental capacities, is a marker of healthy aging. However, the association between changes in IC and trajectories in older adults and the onset of cardiovascular diseases (CVD) remains unclear.ObjectiveTo identify IC trajectories over time and assess the associations between IC trajectories and the incidence of CVD among older adults.MethodsThe prospective cohort study used data from the China Health and Retirement Longitudinal Study (CHARLS) between 2011 and 2020. To determine IC trajectory during 2011–2015, we included adults aged 60 years or older without CVD at baseline, who completed the follow-up visits in 2013 and 2015. We assessed IC through five domains (locomotion, sensory, vitality, cognition, and psychology) using the WHO framework. We determined the onset of CVD by self-reported diagnoses of heart disease or stroke. We performed a group-based trajectory model to identify IC trajectory, and cox proportional hazard models to estimate the adjusted hazard ratio (HR) for CVD incident across different IC trajectory groups, adjusting for sociodemographic factors, lifestyle health behaviors, and cardiovascular metabolic factors.ResultsThe study included 3 336 adults without CVD at baseline, with the mean age of 66.64 (SD:5.53) years, and 49.4% were male. The baseline mean IC score was 5.40 (SD:1.70). We identified three IC trajectory: (1) moderate IC with subsequent increase (61.3%), (2) low IC with slow decline (27.61%), and (3) high IC with subsequent decline (11.09%). During the average follow-up of 6.78 years, we identified 1,351 cases of incident CVD. After adjusting for covariates, adults who in the low IC with slow decline group were 1.68 (95% CI: 1.38–2.04) times more likely to develop CVD, compared to adults in the high IC with subsequent decline group.ConclusionIC trajectory among Chinese older adults is heterogeneous. Low IC with slow declining is associated with an increased risk of CVD incidence.

Susceptibility profile of the population to artemether, lumefantrine, dihydroartemisinin and piperaquine for samples transported in a formulated transport media and ethylenediamine tetraacetic acid anticoagulants: a study conducted in Maseno area, Western

Background: In vitro sensitivity testing is one of the preferred methods of measuring susceptibility and undertaking surveillance of antimalarial drug efficacy. This method is able to measure Plasmodium falciparum susceptibility to several antimalarial drugs simultaneously, away from the influence of host immune related factors. The technique is being transitioned to ex vivo requiring tests on fresh sample. Such in vitro studies of field P. falciparum have been attributed to diminished viability as they transition from host ecosystem to lab conditions due to lack of a proper medium to stabilize the parasites. It is therefore imperative to calibrate the sample stabilization media to reduce artificial effects to the assay This study was meant to evaluate the effect of a formulated transport medium (TM) on viability of Plasmodium. The study assayed standard clones (W2 and 3D7), field isolates and compared the results with other published findings to come up with antimalarial susceptibility profile of the region. Methods: Blood samples were collected from 322 assenting individuals from Maseno division visiting Chulaimbo Sub county hospital and confirmed positive for malaria. Each sample, split in to EDTA versus TM was analysed for susceptibility to artemether (ART), lumefantrine (LUM), dihydroartemisinin (DHA) and piperaquine (PPQ) using malaria SYBR green assay. IC50 was determined for each sample between TM and EDTA using dose response curves. Results: Results showed that the IC50 values of the field isolates in EDTA were higher although not significant (p=0.99, 0.74, 0.68, 0.82 for ART, LUM, DHA and PPQ respectively) than those in the TM. Among the clones, PPQ was the only drug with a high significant IC50 decrease (p<0.001) in TM for the W2 and a moderately significant decrease (p=0.028) in EDTA for 3D7 clone. Conclusions: Lower IC50 values recorded by the field isolates against the antimalarials were indicative of their high susceptibility to the drugs.

Abstract 744: Exploration of potential biomarkers associated with treatment outcomes in locally advanced esophageal squamous cell carcinoma patients receiving neoadjuvant nivolumab plus paclitaxel and cisplatin chemoradiotherapy

Abstract Background: In a phase II trial (neo-NTP-CRT, NCT05130684), the efficacy of adding nivolumab to paclitaxel and cisplatin-based neoadjuvant chemoradiotherapy (CRT) was tested in patients with locally advanced esophageal squamous cell carcinoma (ESCC) (n=17). The study reported a pathological complete response (pCR) rate of 24%, a median relapse-free survival and overall survival (OS) of 8 and 16 months, respectively. We conducted this exploratory analysis to investigate the potential immune-related biomarkers. Materials and Methods: Pretreatment endoscopy-biopsied tumor tissues were analyzed. Immunohistochemistry (IHC) was used to measure PD-L1 expression by clone SP142 (Ventana, Tucson, AZ, USA) on tumor cells (PD-L1-TC), immune cells (PD-L1-IC), and combined positive score (CPS), and to define mature tertiary lymphoid structure (mTLS) according to CD20 and CD23 expression (n=16). The expression of immune-related genes in ESCC tumor tissues was quantitated by PanCancer Immune Profiling and analyzed by nCounter® Analysis System (nanoString, Seattle, WA, USA) (n=12). 12-chemokine TLS signature was also analyzed. The association of PD-L1-TC, PD-L1-IC, CPS, mTLS, and TLS signature with pCR was examined by Chi-square test; the association with OS was examined by log rank test. The differences of various immune cells and immune-related functions between patients with and without pCR was investigated by t-test. Results: pCR rate was significantly higher in the patients with positive PD-L1 TC (100% vs 18%, p=0.019), high PD-L1 IC (100% vs 18%, p=0.019), and CPS≥5 (100% vs 10%, p=0.0006), and trended to be higher in patients with mTLS (50% vs 14%, p=0.19) and higher 12-chemokine TLS signature (75% vs 17%, p=0.077). OS trended to be longer in patients with positive PD-L1 TC (median: not reached vs 15 months; HR: 0.24, p=0.05) and CPS≥5 (median: 26 vs 15 months; HR: 0.19, p=0.069), and patients with high PD-L1 IC had numerically longer OS (median: 25 vs 16 months; HR: 0.42, p=0.38). mTLS was not associated with OS (median: 25 vs 25 months; HR: 0.91, p=0.88); however, patients with higher 12-chemokine TLS signature had better OS (median: 25 vs 14 months; HR: 0.23, p=0.042). The analysis of immune-related gene expression revealed patients with pCR had significantly higher abundance of TILs, lower amounts of Treg, exhausted CD8 T cells, and macrophages. Significantly higher B cell function, cytotoxicity function, and Toll-like receptor function was found in tumors of pCR patients. Conclusion: We found that PD-L1 expression and 12-chemokine TLS signature may be a potential predictor of the response to neoadjuvant nivolumab plus paclitaxel and cisplatin-based CRT. (grants: NCTRC200909, MOST 108-2314-B-002-076-MY3, MOHW 111-TDU-B-221-114006) Citation Format: Ta-Chen Huang, Jhe-Cyuan Guo, Chia-Chi Lin, Hung-Yang Kuo, Chien-Huai Chuang, Jason Chia-Hsien Cheng, Feng-Ming Hsu, Jang-Ming Lee, Pei-Ming Huang, Chih-Hung Hsu. Exploration of potential biomarkers associated with treatment outcomes in locally advanced esophageal squamous cell carcinoma patients receiving neoadjuvant nivolumab plus paclitaxel and cisplatin chemoradiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 744.

Abstract 6580: Impact of copy number variations on EV-miRNA profiles in ovarian cancer

Abstract [Objective] Ovarian cancer has poor prognosis due to its late diagnosis and the development of drug resistance, particularly in advanced stages. High-grade serous ovarian carcinoma (HGSOC), the most common subtype, is characterized by extensive genomic alterations, including TP53 mutations and copy number variations (CNVs). However, the functional impact of CNVs remains largely unclear. This study aimed to investigate how CNVs influence extracellular vesicle (EV)-associated microRNA (miRNA) profiles to identify potential diagnostic biomarkers and therapeutic targets. [Methods] Clinical and genomic data from 489 ovarian cancer patients in The Cancer Genome Atlas (TCGA) dataset were initially reviewed. From these, TP53-mutant cases (n=247) were selected and classified into CNV-high (n=21) and CNV-low (n=62) groups. Additionally, 23 TP53-mutant ovarian cancer cell lines were divided into CNV-high (n=17) and CNV-low (n=6) groups. miRNA expression profiles were compared to identify CNV-associated miRNAs. Selected miRNAs were further analyzed through prognostic assessments, tumor validation, and functional assays. Finally, in vitro assays were performed to confirm miRNA expression levels and cisplatin resistance. [Results] Compared to the CNV-low group, patients in the CNV-high group exhibited shorter OS within 30 months. In 23 cell lines, a comparative analysis of miRNA expression profiles revealed that 7 miRNAs were significantly upregulated, while 9 were downregulated in the CNV-high group (p < 0.05). Among the upregulated miRNAs, miR-203a showed the highest expression levels in CNV-high cell lines and was strongly correlated with poor prognosis. Tumor tissue analysis confirmed that miR-203a expression was significantly higher in ovarian cancer tissues compared to adjacent normal tissues (p < 0.01), and elevated miR-203a levels were also detected in the serum of ovarian cancer patients. Furthermore, EVs isolated from TP53-mutant CNV-high cell lines (CAOV3, OVCAR3, RMUGS) were found to secrete miR-203a in abundance. Functional assays demonstrated that overexpression of miR-203a in these cell lines led to increased resistance to cisplatin, as evidenced by a higher IC50, particularly in the CNV-high group. Knockdown of miR-203a in CNV-high cell lines resulted in enhanced sensitivity to cisplatin and reduced cell proliferation. [Conclusion] Elevated miR-203a expression was linked to poor prognosis and chemoresistance in ovarian cancer patients with high CNV levels. Detection of miR-203a in EVs indicates its potential as a non-invasive biomarker for early diagnosis. Targeting CNV-associated miR-203a may provide new therapeutic strategies to overcome platinum resistance in HGSOC, offering insights into molecular mechanisms and potential treatment approaches. Citation Format: Hajime Araki, Yokoi Akira, Kosuke Yoshida, Kazuhiro Suzuki, Hironori Suzuki, Masami Kitagawa, Eri Asano-Inami, Hiroaki Kajiyama. Impact of copy number variations on EV-miRNA profiles in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6580.

Abstract 1247: Characterizing the evolution of osimertinib resistance in EGFR mutated non-small cell lung cancer

Abstract Osimertinib is a 3rd generation EGFR inhibitor and the newest FDA approved adjuvant therapy for non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R mutation. Although the drug can yield impressive initial responses, the majority of patients eventually progress due to the evolution of resistance. While the molecular mechanisms underlying resistance have been well studied, little is known about the ecological and evolutionary laws that govern the creation and subsequent expansion of these mutant populations. How frequently are different evolutionary routes taken and to what degree is evolution repeatable? To study the repeatability of osimertinib resistance evolution, we conducted a large-scale evolution experiment aimed at characterizing the distribution of resistant states that emerge, along with the pathways and vulnerabilities associated with their development. In our experimental design, we evolve PC-9, an EGFR-mutated NSCLC cell line to osimertinib independently 10 times (evolutionary replicates) for 10 cycles (serial passages). We also evolved 6 control replicates that undergo no treatment. At the end of the experiment, we will employ a multi-faceted approach to studying the resistance phenotype: 1) IC50 against osimertinib; 2) bulk RNA-seq; 3) DNA/mutational profiling; 4) a collateral sensitivity screening against 20 FDA approved drugs; and 5) a radiation sensitivity assay against 6 doses. The initial pretreatment dose response curve (DRC) against osimertinib showed a double plateau, suggesting the pre-existence of tolerant or even resistant subpopulation. In our control arms, we see consistent persistence of our double plateau throughout all 10 cycles, indicating this population is maintained in the absence of treatment but cannot expand. Conversely, across all 8 treated replicates we see a large shift in IC50 within the 1st treatment cycle, consistent with rapid selection and outgrowth of this population. More detailed analysis using time-lapse microscopy shows while these cells have a higher IC50, they also have a reduced growth rate, even if treatment is completely removed again (a “resistance cost”). This suggests potential evolutionary vulnerabilities which could be leveraged through strategic treatment breaks or drug sequences. Citation Format: Mina N. Dinh, Jinling Wu, Masahiro Hitomi, Maximilian Strobl, Jacob G. Scott. Characterizing the evolution of osimertinib resistance in EGFR mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1247.

Inhibitory Potential of Boscalid and Abamectin Towards Acetylcholinesterase and Butyrylcholinesterase: Computational and In Vitro Studies.

The growing demand for agricultural products has led to the misuse of pesticides, resulting in the use of higher concentrations of these substances. This has led to an increase in toxicity imposed on other beneficial organisms and to the bioaccumulation of toxic pesticide concentrations in the bodies of both pests and non-target organisms, as well as in their end users, including humans. In this study, the neurotoxic potential of the commonly used pesticides abamectin (an insecticide) and boscalid (a fungicide) was evaluated. Both in vitro and in silico studies showed that human butyrylcholinesterase is not a target for abamectins B1A and B1B. Boscalid showed a modest Glide score (-28.8 kJ/mol) and a considerably higher IC50 (308.8 µM) against human butyrylcholinesterase than the approved inhibitor (2-((1-(benzenesulfonyl)-1H-indol-4-yl)oxy)ethyl)(benzyl)amine (IC50 = 0.473 µM). However, due to its non-mutagenicity and low toxicity, structural analogues of boscalid might be considered as candidates for the symptomatic treatment of Alzheimer's disease. Molecular dynamics simulations over 100 ns confirmed the stability of boscalid within the active site of butyrylcholinesterase, where it maintained key interactions with catalytic residues such as Trp82 and His438. These findings highlight its potential as a starting point for structure-based drug design strategies aimed at optimizing cholinesterase inhibitors with improved pharmacokinetic properties. According to absorption, distribution, metabolism, elimination, and toxicity studies, boscalid is orally active, which cannot be attributed to abamectins B1A and B1B.

Genome-wide scanning for genetic markers associated with anti-malarial drugs sensitivity of Plasmodium falciparum isolates from the China-Myanmar border region

BackgroundUnderstanding the emergence and spread of anti-malarial resistance, particularly to artemisinin and its partner drugs, is essential for eradicating malaria in worldwide. To identify genetic markers associated with susceptibility to common anti-malarial drugs, the in vitro sensitivities of anti-malarial drugs were evaluated, and a genome-wide association study of Plasmodium falciparum susceptibility in vitro to multiple anti-malarial drugs was conducted.MethodsGenomic DNA from 34 samples of P. falciparum collected between 2007 and 2010 in the Nabang-Lazan Valley along the China-Myanmar border was extracted and subjected to whole-genome sequencing. The standard SYBR Green I-based fluorescence assay and RSA assay were used to evaluated the in vitro sensitivities of anti-malarial drugs. Plink v1.90 was used to investigate the associations of genome-wide SNP with in vitro sensitivities to anti-malarial drugs.ResultsThe proportion of isolates showed reduced-susceptible to CQ,SP,QN,PPQ and PND were 88.24%,92.59%,8.82%,8.82%,5.88%, respectively. 93.54% of isolates showed high level of the IC50 values of CQ have a pfcrt CIETS mutations. The isolates with pfdhfr IRNI, NRNL and IRNL mutations showed high SP IC50 values. SNPs on pfhsp90 and pfevp1 showed significant association with IC50 values of CQ. Of particular interest is the significant association found between a locus on chromosome 13 and the sensitivity to dihydroartemisinin. This locus is situated within the gene encoding the inner membrane complex protein 1F (IMC1F),which has been found to be associated with the kelch13 compartment in schizont stages of P. falciparum.ConclusionsMultiple genetic markers correlating with anti-malarial drug susceptibility were identified in the study, which provide a reference for further investigations into the association between oxidative stress-mediated activity and anti-malarial drugs susceptibility.

Trajectories of intrinsic capacity decline and related factors in old persons: A 15-year community-based cohort study in Beijing

Trajectories of intrinsic capacity decline and related factors in old persons: A 15-year community-based cohort study in Beijing

Effect of 6,6-Substitution on 2,2'-Bipyridine and Probing Biomolecular Interaction Through Experimental and Computational Studies Towards Anticancer Potency.

The current study focuses on the cytotoxicity assessment of 6,6'-substituted 2,2'-bipyridine derivatives containing functional groups, namely methyl (-CH3, L1), acid (-COOH, L2), ester (-COOCH3, L3), semicarbozone (-CONHNH2, L4). The ligands exhibited high solubility in dimethyl sulfoxide (DMSO) and moderately soluble in dimethyl formamide (DMF), acetonitrile (ACN) and low solubility in water. The ligands display a significant π→π* transition in the region of 270nm to 305nm. The emission spectra of the ligands reveal a prominent band in the 300nm to 450nm range, with a Stokes shift of 120cm- 1. UV-VIS spectra analysis, the ligands (L1-L4, 1mM) demonstrated stability in various environmental like water, glutathione (GSH, 1mM), and MTT condition (10% DMSO). The interaction of ligands with DNA was assessed through calf thymus deoxyribonucleic acid (ctDNA) binding assay, viscosity studies, and ethidium bromide (EtBr) displacement assay, with L1 and L4 exhibiting the highest interaction. The MTT assay was conducted for 24h and 48h using ligands (L1-L4) and doxorubicin in MCF-7, HeLa, and L929 cell lines. Ligand L4 showed high potency IC50 values after 48h in MCF-7 (1.28 µM) and HeLa (1.81 µM), but its potency is lower than doxorubicin. Overall, for the first time these results suggest that L4 has high anticancer activity at lower concentrations against breast and cervical cancers.

Ethnobotanical Survey of Medicinal Plants Used in the Treatment of Malaria in the Rural Commune of Luozi

This work presented the results of an ethnobotanical survey carried out in the Rural Commune of Luozi on the use of medicinal plants. Indeed, the results highlighted the frequent use of medicinal plants with a diversity including 15 species belonging to 13 families. The most used parts were the leaves 80% followed by the roots, fruits and bark 20%. Infusion was the predominant preparation method accounting for 53%, followed by fumigation 20%, oil 13%, juice 7% and decoction 7%. As for the analysis of quantitative indices, the cultural importance index varied between 0.04 and 0.56. Plants with a high IC index were: Cassia same 0.56, Bridelia micrantha 0.48, Senna occidentalis 0.48, Nauclea latifolia 0.44 and Ocimum gratissimum 0.32. However, only one plant had a FL value of 56% recorded for Cassia same.

Targeting Lung Cancer With Carvacrol-Triazole-Arylidene Hydrazide Hybrids: In Vitro and In Silico Cytotoxicity Assessments.

In this study, a series of 16 arylidene hydrazide derivatives (7a-7p), hybridized with the natural product carvacrol, were successfully synthesized starting from anthranilic acid methyl ester. The cytotoxic effects of these compounds were examined against two different cell lines, A549 and BEAS-2B. Additionally, in silico studies were conducted to investigate the ligand-protein binding modes and their stabilities. Lastly, the predicted absorption, distribution, metabolism, and excretion (ADME) properties were also explored. The compounds' structures were confirmed through meticulous NMR and MS spectral analyses. Biological assays indicated notable cytotoxic effects against human lung cancer (A549) and non-tumorigenic lung epithelial (BEAS-2B) cell lines, with compounds 7j, 7k, and 7l demonstrating high selectivity indices (SIs) and low IC50 values against A549 cells, signifying potent selective anticancer activity. Molecular docking and molecular dynamics (MD) simulations identified key binding interactions of these compounds with epidermal growth factor receptor (EGFR) and BRAF proteins, emphasizing the importance of residues such as Lys-745 and Phe-856 in EGFR and Lys-483 in BRAF. Stability of these complexes was confirmed through 100ns MD simulations. ADME analysis revealed favorable pharmacokinetic properties for the prominent compounds, particularly 7k. These results suggest that arylidene hydrazide derivatives, especially 7k, are promising selective anticancer agents with potential for further development.

Design and performance characterisation of 10 nm negative capacitance double gate MOSFET (NCDGMOSFET)

Abstract The major focus on any transistor-level design is to minimize the effects on switching speed and power consumption at smaller dimensions, which are crucial in VLSI design for low power applications. In this work, a double gate MOSFET design is proposed with p+ pocket in the channel region at 10 nm technology node. Further a ferroelectric material HfO2FE is also introduced between gate and oxide layer resulting a negative capacitance double gate MOSFET (NCDGMOSFET). Ferroelectric material shows negative capacitance that limits the subthreshold slope with dimension scaling. Increased gate control and high switching speed in NCDGMOSFET with lightly doped n-channel, is a promising transistor option for low-power high performance IC design. The proposed device design is characterised with different pocket dimensions for gate and drain voltage ranges from 0 V to 1.5 V. The contact resistance of drain and source is also varied to observe device ON/OFF performances. The electrostatic behaviour of the device is also analysed via observation of electric field and potential variations at different bias conditions. Adding a p+ pocket in the NCDGMOSFET structure further enhances the performance by modifying the channel properties with subthreshold slope and DIBL vales of 76 mV decade−1 and 36 mV/V respectively. This modification also leads to improved barrier to subthreshold conduction during the Ioff state of the transistor, while minimally impacting the Ion state. The proposed device design and performance analysis are conducted through TCAD 2D/3D device simulation software by Cogenda.

Synthesis, Antileishmanial Activity, and in silico Study of 2-Hydroxy-3-(1,2,3-triazolyl)propyl Vanillin Derivatives

This study details the preparation, antileishmanial assay, and in silico analysis of twenty 2-hydroxy-3-(1,2,3-triazolyl)propyl vanillin derivatives. These compounds were synthesized in three steps and evaluated against Leishmania infantum, Leishmania amazonensis, and Leishmania braziliensis promastigotes. Compounds 3s and 3t were the most effective, showing good activity against all Leishmania species tested. Molecular docking indicated that all compounds bind favorably to the sterol 14α-demethylase (CYP51) enzyme from L. infantum. ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis indicated good oral bioavailability, non-blood-brain barrier penetration, and high gastrointestinal absorption. Posaconazole and compounds 3e, 3s, and 3t remained stable in the CYP51 binding region during 100 ns molecular dynamics (MD) simulations. Root mean square deviation (RMSD) and root mean square fluctuations (RMSF) analyses from the MD trajectory revealed significant conformational fluctuations of the CYP51 N-terminal, suggesting occasional expulsion of 3e, potentially explaining its higher IC50 (half-maximal inhibitory concentration) values. Pairwise decomposition analyses from molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations highlighted the importance of hydrophobic residues in interacting with the synthesized derivatives.