Nevin Manimala

Front Immunol. 2025 Nov 11;16:1684089. doi: 10.3389/fimmu.2025.1684089. eCollection 2025.

ABSTRACT

OBJECTIVE: To investigate the impact of co-mutations of EGFR with TP53 or KRAS on the prognosis of non-small cell lung cancer (NSCLC) patients, and the efficacy of platinum-based doublet chemotherapy plus immunotherapy after EGFR-TKI resistance.

METHODS: This was a retrospective study that included 168 patients with locally advanced or advanced NSCLC who had next-generation sequencing (NGS) performed at our institution between January 1, 2021, and October 31, 2023. Based on their genomic profiles, patients were categorized into three groups: EGFR single mutation, EGFR/TP53 co-mutation, and EGFR/KRAS co-mutation. Baseline clinical data were collected, including gender, age, smoking history, histological subtype, clinical stage, ECOG performance status, gene testing results, and treatment regimens. All patients were treated with EGFR tyrosine kinase inhibitors (TKIs) as first-line therapy, including first-, second-, or third-generation agents. Upon disease progression, patients received platinum-based doublet chemotherapy plus immunotherapy as second-line treatment. The primary endpoint was progression-free survival (PFS). Survival curves were generated using the Kaplan-Meier method and compared by log-rank test. Baseline characteristics among the three groups were compared using the chi-square test. Multivariate Cox regression analysis was performed to evaluate independent prognostic factors for PFS by incorporating all baseline clinical variables and gene mutation status into the model.

RESULTS: A total of 168 patients were included in the analysis: 36 with EGFR single mutation, 80 with EGFR/TP53 co-mutation, and 52 with EGFR/KRAS co-mutation. There were no statistically significant differences among the three groups with respect to baseline characteristics, including gender, age, smoking history, histological type, clinical stage, and ECOG performance status (P > 0.05). Immune-related marker expression was significantly different between the EGFR single mutation group and the two co-mutation groups (P < 0.05), while no significant difference was observed between the co-mutation groups (P = 0.945). Following first-line EGFR-TKI therapy, the EGFR single mutation group showed a significantly longer median PFS compared with the EGFR/TP53 and EGFR/K-RAS co-mutation groups (P < 0.0001). No significant difference in PFS was observed between the two co-mutation groups (P = 0.174). Following progression on EGFR-TKIs, all patients received platinum-based doublet chemotherapy plus immunotherapy. In second-line treatment, the median PFS in the EGFR single-mutation group, which was shorter than in the EGFR/TP53 and EGFR/KRAS co-mutation groups (overall log-rank P < 0.0001), with no significant difference between the two co-mutation cohorts (P = 0.174). However, in multivariable Cox models adjusting for age, sex, smoking history, clinical stage, histology, and ECOG performance status, both EGFR/TP53 and EGFR/KRAS co-mutations were independently associated with a higher hazard of progression. ECOG PS ≥2 was associated with a numerically higher hazard that did not reach statistical significance. No significant associations were observed for other covariates (age, sex, smoking history, clinical stage, histology; all P>0.05).

CONCLUSION: In the first-line setting, patients with an EGFR single mutation treated with EGFR-TKIs had a longer median PFS than those with EGFR/TP53 and EGFR/KRAS co-mutations (14.1 vs 10.4 and 10.9 months, respectively; both P < 0.0001), whereas no statistically significant difference was observed between the two co-mutation subgroups (P = 0.174). Following the development of resistance, all patients received platinum-based doublet chemotherapy plus immunotherapy; in the second-line setting, median PFS was modestly longer in the co-mutation groups compared with the single-mutation group (EGFR/TP53: 5.2 months; EGFR/KRAS: 5.0 months; EGFR single mutation: 3.9 months; overall log-rank P < 0.0001), with no significant difference between the TP53 and KRAS subgroups (P = 0.174). These associations were evident on Kaplan-Meier curves (with numbers at risk) and log-rank testing, and were supported by multivariable Cox models adjusted for age, sex, smoking history, clinical stage, histology, and ECOG performance status.

PMID:41306958 | PMC:PMC12645222 | DOI:10.3389/fimmu.2025.1684089

J Biomed Opt. 2025 Nov;30(11):117002. doi: 10.1117/1.JBO.30.11.117002. Epub 2025 Nov 25.

ABSTRACT

SIGNIFICANCE: Photoplethysmography (PPG) is a widely used optical technique for the noninvasive monitoring of cardiovascular parameters. However, its accuracy may be affected by variations in skin pigmentation due to the strong absorption properties of melanin, particularly at visible wavelengths.

AIM: We aimed to investigate how skin tone influences PPG signal signals by developing a pulsatile vascular finger phantom with interchangeable skin layers, characterizing their optical properties across green, red, and infrared wavelengths and evaluating their impact on PPG signal features.

APPROACH: The finger phantom included three optically characterized, interchangeable skin layers representing pale, medium, and dark tones, as well as a custom-made silicone vessel embedded in an anatomically and mechanically characterized structure. PPG signals were recorded in reflectance mode using a custom-made finger clip probe in an in vitro cardiovascular system. Signal features, including signal-to-noise ratio, peak-to-peak amplitude, and area under the curve, were analyzed.

RESULTS: Analysis revealed statistically significant differences ( $p<0.001$ ) between skin tones, with signal degradation increasing with skin pigmentation.

CONCLUSIONS: These findings suggest there is a measurable impact of skin pigmentation on the PPG signal and highlight the need for further research to improve the equity of light-based sensing technologies across all populations. We provide an advancement for future work in developing in vitro models to assess optical sensing performance across diverse skin tones.

PMID:41306936 | PMC:PMC12646468 | DOI:10.1117/1.JBO.30.11.117002

BMC Plant Biol. 2025 Nov 26;25(1):1644. doi: 10.1186/s12870-025-07647-8.

ABSTRACT

BACKGROUND: The Impatiens plants are one of the world’s top three flower bed floriferous plants with important ornamental and horticultural values, vivid floral colors are more likely to attract pollinators, and one of the important ornamental traits of flowers. This study was conducted to determine whether the flower color of Impatiens can be altered after induction, with the aim of clarifying the molecular basis underlying its variation and to offer a vital reference for developing novel Impatiens varieties. Compared with diploids, the flower color of colchicine-induced Impatiens showed obvious changes, the flowers changed from pinkish purple to orange.

RESULTS: Integrated metabolomics and transcriptomics were comprehensively utilized to reveal the metabolic pathways of anthocyanin biosynthesis in non-mutant purple flowers and mutant orange. The floral hue discrepancies between Ih-WT and Ih-MU in Impatiens hybrida ‘Solarscape’ exhibit marked variations in luminance (L*), the red-green axis (a*), the yellow-blue axis (b*), and color intensity (Chroma c*). Specifically, the L* value of Ih-WT is significantly higher than that of Ih-MU, and the a*, b*, and Chroma c* values of Ih-WT are significantly greater than those of Ih-MU. Metabolomics identified 93 differential metabolites, most of which were Cyanidin and Pelargonidin-like metabolites, and the accumulation of Cyanidin and Pelargonidin was the principal factor underlying the petal color transition to orange in I. hybrida ‘Solarscape’. Analysis of the transcriptome identified 1888 differentially expressed genes (DEGs), including key genes for anthocyanin synthesis (IhC4H, IhUFGT, IhDFR, and IhANS) and regulators (IhMYB308, IhNAC56, and IhMYC2) with high levels of expression of Ih-MU in orange flowers, indicating that they play a role in the regulation of anthocyanin biosynthesis. These genes may be pivotal for the biosynthesis of orange anthocyanins. Co-expression analysis of differentially expressed genes and the relative levels of differentially expressed anthocyanins revealed that each anthocyanin is strongly associated with multiple genes, indicating that the anthocyanin accumulation process is governed by multiple genes. The expression levels of these genes exhibited a statistically significant positive correlation with the relative concentrations of Pelargonidin-3-O-sophoroside, Cyanidin-3-O-(6-O-p-coumaroyl)-glucoside, and Cyanidin-3-O-sophoroside.

CONCLUSIONS: This study showed substantial alterations in color and anthocyanin synthesis in chemically mutagenized I. hybrida ‘Solarscape’ flowers, and these findings could provide some insight into the relationship between Impatiens and other flowers could offer a theoretical foundation for the breeding improvement of Impatiens and other flowers.

PMID:41299230 | DOI:10.1186/s12870-025-07647-8

BMC Bioinformatics. 2025 Nov 26;26(1):285. doi: 10.1186/s12859-025-06286-y.

ABSTRACT

BACKGROUND: The functional annotation of uncharacterized microbial enzymes from metagenomic data remains a significant challenge, limiting our understanding of microbial metabolic dynamics. Traditional annotation methods often rely on sequence homology, which can fail to identify remote homologs or enzymes with structural rather than sequence conservation. To address this gap, we developed CAZyLingua, the first annotation tool to use protein language models (pLMs) for the accurate classification of carbohydrate-active enzyme (CAZyme) families and subfamilies.

RESULTS: CAZyLingua demonstrated high performance, maintaining precision and recall comparable to state-of-the-art hidden Markov model-based methods while outperforming purely sequence-based approaches. When applied to a metagenomic gene catalog from mother/infant pairs, CAZyLingua identified over 27,000 putative CAZymes missed by other tools, including horizontally-transferred enzymes implicated in infant microbiome development. In datasets from patients with Crohn’s disease and IgG4-related disease, CAZyLinuga uncovered disease-associated CAZymes, highlighting an expansion of carbohydrate esterases (CEs) in IgG4-related disease. A CE17 enzyme predicted to be overabundant in Crohn’s disease was functionally validated, confirming its catalytic activity on acetylated manno-oligosaccharides.

CONCLUSIONS: CAZyLingua is a powerful tool that effectively augments existing functional annotation pipelines for CAZymes. By leveraging the deep contextual information captured by pLMs, our method can uncover novel CAZyme diversity and reveal enzymatic functions relevant to health and disease, contributing to a further understanding of biological processes related to host health and nutrition.

PMID:41299229 | DOI:10.1186/s12859-025-06286-y

Int J Emerg Med. 2025 Nov 26. doi: 10.1186/s12245-025-01068-y. Online ahead of print.

ABSTRACT

BACKGROUND: Ambulance offload delay (AOD) indicates the persistent and increasingly visible problem of Emergency Department (ED) crowding. AOD is defined as the extended time from ambulance arrival at the ED until patient care is transferred to ED staff. Despite its negative consequences and international attention, AOD is currently not monitored within the Dutch Emergency Care. It is also unknown whether or not AOD is associated with the ambulance diversion (AD) status. In the Dutch ED the AD status is monitored by means of the traffic light system. This study aims to monitor AOD at the EDs of Franciscus Gasthuis & Vlietland (FGV).

METHODS: A 10-week observational study was conducted at both the EDs of FGV. Ambulance personnel was queried regarding AOD duration and traffic light statuses by means of paper questionnaires. Descriptive statistics are reported as frequencies, medians and interquartile ranges (IQR). Associations between the traffic light status and categorical AOD data were analyzed using Chi-square tests.

RESULTS: During the study period, 2967 ambulances arrived at the EDs. In 229 cases (7.7%), the definition of AOD was met. The median AOD was 16 min (IQR: 10-25 min). In 95.6% (n = 2830) of the cases the handover time was less than 15 min. No statistically significant association was found between the traffic light status (green, orange, red) and offload delay categories (p = 0.109). A non-significant difference remained (p = 0.075) when comparing median AOD in the absence of an AD with the median AOD during an (impending) AD.

CONCLUSION: This is the first observational study conducted in the Netherlands collecting data regarding the AOD. The limited observation period, the reliance of self-reported data and the single-center design restricts the generalizability of the data. Consequently, the authors conclude hypothesis-generating findings which warrant validation through planned multicenter research. Nevertheless, besides the existing traffic light system, this unique study provides policy makers with a candidate complementary quality indicator for ED-crowding in the Dutch context.

PMID:41299224 | DOI:10.1186/s12245-025-01068-y

Foot Ankle Int. 2025 Nov 26:10711007251388432. doi: 10.1177/10711007251388432. Online ahead of print.

ABSTRACT

BACKGROUND: The Infinity with Adaptis Total Ankle System (Stryker, Mahwah, NJ) is a low-profile, fixed-bearing implant that became available for use in October 2019. The aim of this study was to describe the early clinical and radiographic outcomes of the Infinity with Adaptis implant at minimum 2-year follow-up.

METHODS: A retrospective review of 71 ankles that underwent primary total ankle arthroplasty (TAA) with Infinity with Adaptis implants between November 2019 and November 2021 at a single institution was completed. Chart review was performed to identify complications, reoperations, and revision procedures. Preoperative and postoperative radiographs were measured to assess tibiotalar alignment and identify periprosthetic lucencies, cysts, or subsidence. Patient-Reported Outcomes Measurement Information System (PROMIS) scores were collected preoperatively and at 1 and 2 years postoperatively to assess clinical outcomes.

RESULTS: At final follow-up (average 2.7 ± 0.6 years), 68 of the 71 ankles remained implanted (95.8%). Three ankles were revised within 1.5 years of the index procedure (1 for talar component loosening and 2 for infection). There were an additional 5 (7.0%) reoperations at an average of 16.0 (range: 1.1-37.1) months postoperatively. Patients demonstrated both clinically and statistically significant improvements in preoperative to 1-year postoperative PROMIS scores (P < .0001). There was no statistically significant improvement in scores from 1 to 2 years postoperatively. There was improvement in radiographic alignment from the preoperative to postoperative radiographs (P < .001), and tibial component lucency was observed in 20 of 71 without progressive global lucency during the study window.

CONCLUSION: Patients who underwent total ankle arthroplasty with the Infinity with Adaptis Total Ankle Replacement demonstrated significant improvements in radiographic and clinical outcomes at a minimum of 2-year follow-up with 95.8% (68/71) implant retention and a tibial lucency rate of 28.2% in this cohort. These observational findings warrant mid- to long-term surveillance to determine the clinical significance of early lucencies and the durability of this design’s porous-surface osseointegration.

PMID:41299218 | DOI:10.1177/10711007251388432

Environ Mol Mutagen. 2025 Nov 26. doi: 10.1002/em.70037. Online ahead of print.

ABSTRACT

This interlaboratory evaluation of HepaRG CometChip was conducted to assess transferability and reproducibility of this new approach methodology (NAM) across four laboratories. Concentrations inducing up to ~70% relative cytotoxicity were determined by the organizing laboratory, and frozen chemical formulation blocks were sent to each participant. When noncytotoxic, 10 mM was the maximum dose. Cultures were exposed once daily for three consecutive days, and both cytotoxicity assessment, via ATP quantification, and comet analysis, commenced 3-4 h after initiation of the final exposure. Positive response was statistical pairwise significance (p < 0.05) with concentration-related increases in %Tail DNA across ≥ 2 consecutive exposures. For 8 of 11 compounds, all four labs generated unanimous test results, with four negative compounds (2-acetylaminofluorene [2-AAF], 2,4-dichlorophenol, eugenol and hydroquinone) and four positive compounds (azidothymidine, benzo(a)pyrene [BP], cyclophosphamide [CP], ethyl methanesulfonate).For the remaining chemicals, three of four labs generated negative calls for amitrole, cadmium chloride, and DMBA. In cases where bulky lesions were anticipated, the magnitude of %Tail DNA was low, due to the inherent insensitivity of the alkaline comet assay (not the CometChip per se) to detect bulky adducts repaired by nucleotide excision repair. This is supported by the small magnitude in %Tail DNA induced by BP and CP. Taken together, for all compounds there was majority agreement in CometChip results across participating laboratories supporting that the endpoint is readily transferable to new labs. Overall, this platform is a promising human-relevant NAM, with a physiologically relevant detoxification process that could be incorporated into rodent replacement strategies.

PMID:41299203 | DOI:10.1002/em.70037

J Int Med Res. 2025 Nov;53(11):3000605251395573. doi: 10.1177/03000605251395573. Epub 2025 Nov 26.

ABSTRACT

ObjectiveMammography and ultrasound are commonly used for early detection of breast cancer; however, they have several limitations and are outperformed by magnetic resonance imaging for screening and diagnosis because of its higher sensitivity. This study aimed to evaluate female awareness of magnetic resonance imaging as a tool for early breast cancer detection and to enhance early-stage diagnosis.MethodsA cross-sectional study was conducted using an online questionnaire. Data were analysed using Statistical Package for the Social Sciences software. Awareness was categorised as poor or good.ResultsA total of 498 women participated in this study. Although 98% of the participants recognised the importance of early breast cancer detection, only 42.6% were aware of the role of breast magnetic resonance imaging. Awareness of the ability of magnetic resonance imaging to detect intraductal carcinoma and small invasive tumours, particularly in dense breast tissue, was moderate, with a mean awareness score of 2.5 ± 1.1 out of 4. Awareness was significantly higher among older women, those with family history of breast cancer and those who practised self-examinations or had prior magnetic resonance experience (p ≤ 0.002).ConclusionsThis study highlights a deficiency in awareness regarding the value of magnetic resonance imaging in breast cancer screening, particularly among young women with dense breast tissue and those without prior exposure to magnetic resonance imaging.

PMID:41299197 | DOI:10.1177/03000605251395573

Pharm Stat. 2026 Jan-Feb;25(1):e70055. doi: 10.1002/pst.70055.

ABSTRACT

The International Conference on Harmonisation (ICH) adopted revision 2 (R2) of its Quality Guidance Q2 Validation of Analytical Procedures in 2023. The revision includes a new statement that confidence interval limits for validation performance characteristics (i.e., accuracy and precision) should be compatible with acceptance criteria, unless otherwise justified. It also allows for sponsors to use prior knowledge (e.g., from development or previous studies) to support the validation study conclusion. These two new aspects of ICH Q2(R2) present both opportunities and challenges for the validation of analytical procedures. In this paper, we provide comprehensive examples of how to compute confidence intervals for key validation performance characteristics under different modeling approaches. We also describe methodologies for combining prior knowledge with the validation study results, both from frequentist and Bayesian perspectives. The paper is written in tutorial style and is aimed at statisticians and analytical scientists responsible for validating analytical procedures in compliance with ICH Q2(R2).

PMID:41299187 | DOI:10.1002/pst.70055

Discov Oncol. 2025 Nov 26. doi: 10.1007/s12672-025-01773-3. Online ahead of print.

ABSTRACT

BACKGROUND: Chlormethine gel is a promising treatment for early-stage mycosis fungoides (MF) with strong efficacy and manageable side effects. This study evaluates its effectiveness as a second-line treatment in patients unresponsive to prior skin-directed therapies (SDTs) or combined systemic treatments, hypothesising significant therapeutic benefits with manageable adverse reactions.

METHODS: A retrospective observational study was conducted from April 2021 to December 2022, including adult patients with histologically confirmed MF who had not responded to at least one prior SDT. Patients received daily chlormethine gel applications, and responses were evaluated at 3, 6, and 12 months using the Modified Severity-Weighted Assessment Tool (mSWAT). Statistical analyses were performed using SPSS ver 26 (IBM), including one-way ANOVA and univariate regression.

RESULTS: The study included 21 patients (12 males, 9 females; mean age 61 years). 81% had early-stage MF, and 19% had advanced-stage disease. Chlormethine gel showed a 90% response rate, with 33.3% achieving complete response (CR) and 57.1% partial response (PR). Adverse reactions were primarily contact or irritative dermatitis, which were manageable and did not significantly affect outcomes. Median mSWAT scores significantly reduced from baseline at 3, 6, and 12 months (P = 0.002).

CONCLUSIONS: Chlormethine gel appeared to be efficacious and safe as a second-line treatment for MF, including in advanced stages. Despite limitations like small sample size and retrospective design, these findings highlight its potential in combination therapies and the importance of continued treatment for optimal outcomes. Future research should confirm these results in larger, prospective studies.

PMID:41299164 | DOI:10.1007/s12672-025-01773-3