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Ning Lou,1,* Xiangui Meng,2,* Tiexi Yu,2,* Weiquan Li,2,* Xin Lv,3,* Weiwei Han,1 Wen Xiao,2 Ying Shi2 1Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 3Department of Urology, Central Hospital of Hefeng County, Enshi, 445800, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen Xiao; Ying Shi, Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province, 430022, People’s Republic of China, Tel +86-17088353610, Fax +85776343, Email xiaowenx11@163.com; yingshi_whxh@hust.edu.cnBackground: Studies have found that RNA-binding proteins (RBPs) are participated in the occurrence or development of tumours. However, the role of processing of precursor family (POP family) in clear cell renal cell carcinoma (ccRCC) has not been studied yet. Here, we analyzed the expression and prognostic value of POP family in ccRCC analyzed and subsequently revealed the relationship between POP7 and immune infiltration in ccRCC patients.Methods: POP family expression in cancer and normal tissues was analyzed in Cancer Genome Atlas pan-cancer (TCGA-pan-cancer). Kaplan–Meier (KM) survival analysis, univariable and multivariable analysis demonstrated the survival of ccRCC with POP family in Kidney Clear Cell Carcinoma (TCGA-KIRC). POP7 mRNA and protein expression were verified by Gene Expression Omnibus (GEO) data, the quantitative real-time polymerase chain reaction (qRT-PCR), and Office of Cancer Clinical Proteomics Research (CPTAC). The diagnostic ability of POP7 mRNA and protein expression was achieved with ROC curves. Gene Set Enrichment Analysis (GSEA) and TiMER2 evaluated pathogenesis role and immune infiltration of POP7in ccRCC.Results: There is a significant difference in expression of POP family in TCGA-pan-cancer, especially in ccRCC. KM survival analysis, univariable and multivariable analysis demonstrated low expression of POP7 and was associated with poor OS and poor DFS. GEO data, the qRT-PCR, and CPTAC verified the high expression of POP7 mRNA and protein in ccRCC. ROC curves verified a valuable diagnostic ability of POP7 in mRNA and protein expression. GSEA demonstrated POP7 was associated with CD8+cells, CD4+cells, natural killer (NK) cells, and helper T (TH1) cells. TiMER2 results indicated POP7 had a positive correlation with T cell regulatory (Tregs) and myeloid-derived suppressor cells (MDSC) in ccRCC and was an immunosuppressor for ccRCC.Conclusion: POP7 was a reliable immunosuppressor, predictor and biomarker for ccRCC.Keywords: POP7, ccRCC, immunotherapy, prognostic indicator

Xuegang Wang,1,&ast; Weiquan Li,2,&ast; Ning Lou,3,&ast; Weiwei Han,3 Bo Hai,2 Wen Xiao,2 Xiaoping Zhang2 1Department of Urology, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, People’s Republic of China; 2Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China; 3Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen Xiao; Bo, Hai, Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province, 430022, People’s Republic of China, Tel +86-17088353610, Fax +86 85776343, Email xiaowenx11@163.com; Haibo2022@hust.edu.cnBackground: Invasion and metastasis led to poor prognosis and death of clear cell renal cell carcinoma (ccRCC) patients. The deoxynucleotidyl transferase terminal interacting protein 1 (DNTTIP1) was reported to promote multiple tumor progression. However, there is no research about DNTTIP1 in ccRCC.Methods: Kaplan–Meier survival analysis, multivariate analysis demonstrated the prognostic indicator in overall survival (OS) and disease-free survival (DFS) of ccRCC with DNTTIP1 expression in the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC). Receiver operator characteristic (ROC) curve analyzed diagnostic ability of DNTTIP1 in TCGA-KIRC and validation dataset. The quantitative real-time polymerase chain reaction (qRT-PCR) detected the DNTTIP1 expression in renal cancer tissues, and the Office of Cancer Clinical Proteomics Research (CPTAC) verified the protein expression of DNTTIP1. Moreover, nomogram predicted the role of DNTTIP1 in ccRCC patient. Single-sample Gene Set Enrichment Analysis (SsGSEA) and GSEA evaluated the pathogenesis role of DNTTIP1 in TCGA-KIRC.Results: DNTTIP1 expression was higher in ccRCC tumor tissues. High expression of DNTTIP1 was associated with poor OS (HR = 1.618, P < 0.0001), and poor DFS (HR = 1.789, P < 0.0001). SsGSEA and GSEA showed DNTTIP1 was associated with hypoxia, epithelial-mesenchymal transition (EMT), angiogenesis, G2M checkpoint. DNTTIP1 had a positive correlation with EMT biomarkers in ccRCC, and might be an effective target for ccRCC.Conclusion: This study provided that higher expression of DNTTIP1 predicted poor prognosis in ccRCC, and DNTTIP1 might be a novel detection biomarker and therapeutic target of tumor malignant in the future.Keywords: DNTTIP1, ccRCC, gene therapy, prognostic indicator

Ji Lin,1,* Weiteng Zhang,1,* Yunshi Huang,1 Weisheng Chen,1 Ruisen Wu,1 Xiaodong Chen,1 Neng Lou,2 Pengfei Wang1 1Department of Gastrointestinal Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China; 2Department of General Surgery, Zhejiang University Huzhou Hospital, Huzhou, Zhejiang, China *These authors contributed equally to this work Purpose: Sarcopenia is distinguished by decreased skeletal muscle plus low muscle strength and/or physical performance. This study was designed to demonstrate the relationship between sarcopenia and systemic inflammatory response (neutrophil/lymphocyte ratio [NLR], platelet/lymphocyte ratio [PLR], and large platelet/lymphocyte ratio [LPLR]) prior to radical gastrectomy for gastric cancer. Patients and methods: We conducted a prospective study of gastric cancer patients who underwent radical gastrectomy. The clinical utility of the NLR, PLR, and LPLR was evaluated by receiver operating characteristic curves. Sarcopenia components including skeletal muscle index, handgrip strength, and 6 m usual gait speed were measured. Logistic analysis was used to identify the independent indices associated with sarcopenia. Results: A total of 670 patients were included, representing 504 men and 166 women. Of these, 104 patients (15.5%) were diagnosed with sarcopenia and 567 (84.5%) were non-sarcopenia. PLR has a diagnostic sensitivity of 91.3% for sarcopenia. In addition to the indicators of preoperative age, nutritional risk screening, body mass index, preoperative albumin, and diabetes, the NLR and PLR were independent predictors for sarcopenia (P

Abstract Biological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At the molecular level, one example is heteromeric complexes replacing homomeric ones following gene duplication. Here, we build a biophysical model and simulate the evolution of homodimers and heterodimers following gene duplication using distributions of mutational effects inferred from available protein structures. We keep the specific activity of each dimer identical, so their concentrations drift neutrally without new functions. We show that for more than 60% of tested dimer structures, the relative concentration of the heteromer increases over time due to mutational biases that favor the heterodimer. However, allowing mutational effects on synthesis rates and differences in the specific activity of homo- and heterodimers can limit or reverse the observed bias toward heterodimers. Our results show that the accumulation of more complex protein quaternary structures is likely under neutral evolution, and that natural selection would be needed to reverse this tendency.

Artificial insemination 12 h following observed standing estrus is a standard estimate of the fertility levels of cattle. The main objective of this study was to determine if controlling ovarian development with a fertility program could alter the fertility of lactating dairy cows. Lactating dairy cows (n = 1356) 60–66 days in milk (DIM) were randomly assigned to receive timed AI following Presynch-11/Ovsynch (Presynch-11) or a combination of estrus detection and timed AI using the Presynch-11/Ovsynch program (Estrus + TAI). Cows in standing estrus, following the first two cloprostenol sodium (CLO) injections, in the Estrus + TAI group were artificially inseminated using the AM/PM rule. Cows in this group that were not observed in standing estrus received Ovsynch and TAI beginning 11 d after the second CLO injection. Cows in the Presynch-11 group received two injections of 500 µg CLO 14 d apart but were not observed for estrus. The first GnRH (100 µg) of Ovsynch was administered 11 d following the second CLO injection. All cows in the Presynch-11-Ovsynch group received TAI following Ovsynch. Cows in this treatment were then assigned randomly to receive either CLO or dinoprost 7 d following the first GnRH of Ovsynch. The final GnRH of Ovsynch was administered 56 h later and TAI 16 h after the final GnRH. Pregnancies/AI (P/AI) were greater (p < 0.001) for the Presynch-11 group compared with the Estrus + TAI group (45 vs. 31%). Primiparous cows had greater fertility following observed standing estrus compared with multiparous cows. Days in milk at the first AI were greater (p < 0.01) in the Presynch-11 group vs. the Estrus + TAI group (98 vs. 80) but less variable (p < 0.01). The range of DIM at the first AI was 95 to 101 in the Presynch-11 group and 60 to 101 in the Estrus + TAI group. Within the Presynch-11 group, there were no differences in the rate of luteolysis or P/AI for the prostaglandin type at the final PGF2α of Ovsynch. Multiparous cows treated with Presynch-11 had >60% chance of pregnancy compared with multiparous cows receiving AI following standing estrus. In summary, lactating dairy cows receiving timed AI following the Presynch-11/Ovsynch program had improved fertility compared with a group of cows that received AI following standing estrus or, if not observed in estrus, timed AI. This comparison indicated that controlling ovarian development with GnRH and PGF2α positively impacted the fertility of lactating dairy cows.

How changes in the different steps of protein synthesis-transcription, translation and degradation-contribute to differences of protein abundance among genes is not fully understood. There is however accumulating evidence that transcriptional divergence might have a prominent role. Here, we show that yeast paralogous genes are more divergent in transcription than in translation. We explore two causal mechanisms for this predominance of transcriptional divergence: an evolutionary trade-off between the precision and economy of gene expression and a larger mutational target size for transcription. Performing simulations within a minimal model of post-duplication evolution, we find that both mechanisms are consistent with the observed divergence patterns. We also investigate how additional properties of the effects of mutations on gene expression, such as their asymmetry and correlation across levels of regulation, can shape the evolution of paralogs. Our results highlight the importance of fully characterizing the distributions of mutational effects on transcription and translation. They also show how general trade-offs in cellular processes and mutation bias can have far-reaching evolutionary impacts.

CRISPR-Cas9 loss of function (LOF) and base editing screens are powerful tools in genetics and genomics. Yeast is one of the main models in these fields, but has only recently started to adopt this new toolkit for high throughput experiments. We developed a double selection strategy based on co-selection that increases LOF mutation rates using the Target-AID base editor. We constructed the pDYSCKO vector, which is amenable to high throughput double selection experiments, and show that the improvement in Target-AID efficiency generalizes across loci. Using modeling, we show that this improvement in efficiency provides the required increased in detection power to measure the fitness effects of thousands of mutations in typical yeast pooled screens. We show that double selection can also improve Cas9 mediated LOF rates, but that this multiplex genome editing causes programmable chromosomal translocations at high frequency. This suggests that multiplex LOF editing should be performed with caution and that base-editors could be preferable tools for some screens in yeast. Base editing using double selection is simple and straightforward and provides an alternative to homology directed repair based high throughput variant strain construction methods.

In colonised territories all over the world, place-based identity has been interrupted by invading displacement cultures. Indigenous identities have become more complex in response to and because of racist and genocidal government policies that have displaced Indigenous peoples. This paper is a personal account of the identity journey of the author, that demonstrates how macrocosmic colonial themes of racism, protectionism, truth suppression, settler control of Indigenous relationships, and Indigenous resistance and survivance responses can play out through an individual’s journey. The brown skinned author started life being told that she was (a white) Australian; she was told of her father’s Aboriginality in her 20s, only to learn at age 50 of her mother’s affair and that her biological father is Māori. The author’s journey demonstrates the way in which Indigenous identities in the colonial era are context driven, and subject to affect by infinite relational variables such as who has the power to control narrative, and other colonial interventions that occur when a displacement culture invades place-based cultures.

The article discusses the use of power management integrated circuits (PMIC), particularly the bipolar- complementary metal-oxide semiconductor (CMOS)-double-diffused MOS (BCDMOS), for green energy applications. It states that PMICs deliver power efficiently with the help of lateral double-diffused MOS (LDMOS) transistors and logic functions by CMOS. It mentions that BDMOS has become the mixed-signal process for implementing PMICs.

Introducción: El 25 de septiembre de 2005 más de un centenar de reclusos presentaron síntomas de gastroenteritis, casi un 5% de los 1.800 reclusos de una prisión. El objetivo del estudio fue confirmar la existencia de un brote, identificar los factores de riesgo, implementar medidas de control y establecer recomendaciones. Métodos: Se realizó un análisis de cohortes de una muestra aleatoria estratificada de todos los internos, un análisis de cohortes de uno de los módulos de la prisión y una investigación medioambiental. Resultados: Se seleccionaron 221 internos de toda la prisión, de los cuales se entrevistó a 196. Un 28% eran casos, cuya sintomatología principal fue dolor abdominal (85%) y diarrea (71%). Todos los alimentos consumidos presentaron tasas de ataque similares. Se asoció con la enfermedad el hecho de comer toda la ración de salpicón de marisco de la comida (riesgo relativo [RR]= 2; intervalo de confianza [IC] del 95%, 1,1-3,8) o toda la ración de gambas rebozadas en la cena (RR = 1,8; IC del 95%, 1,1-3,1) del día 24 de septiembre. En el análisis de uno de los módulos de la prisión se obtuvo resultados similares a la muestra aleatoria. En una muestra de salpicón de marisco se aislaron Clostridium perfringens, Bacillus cereus y Escherichia coli. Conclusión: Se confirmó un brote de gastroenteritis por varios patógenos. Tanto los síntomas como el período de incubación corresponden a los patógenos aislados. La preparación de los alimentos en centros penitenciarios debe cumplir los estándares mínimos de seguridad, que incluya la refrigeración y la educación de los manipuladores.Background: On September 25 2005, more than 100 inmates (almost 5% of the 1,800 prison population) experienced sudden onset gastroenteritis. This outbreak was the largest foodborne outbreak described in a prison population in Spain. Our objective was to confirm the outbreak, identify risk factors, implement control measures, and provide recommendations. Methods: We conducted a cohort analysis of a stratified random sample of all the inmates, a cohort analysis of the one of the prison blocks, and an environmental investigation. Results: A total of 221 inmates were selected, of which 196 were interviewed. Twenty-eight percent had gastroenteritis and the main symptoms were abdominal pain (85%) and diarrhea (71%). All foods consumed caused similar attack rates. Factors associated with the risk of illness were eating the entire portion of seafood cocktail at lunch or all of the fried shrimp at dinner on September 24 (RR = 2; 95% CI, 1.1-3.8, and RR = 1.8; 95% CI, 1.1-3.1). Analysis of one of the prison blocks yielded results similar to those of the random sample. Clostridium perfringens, Bacillus cereus and Escherichia coli were isolated from a sample of the seafood cocktail. Conclusion: A gastroenteritis outbreak caused by several pathogens was confirmed. Both the reported symptoms and the calculated incubation periods corresponded to the pathogens isolated. Preparation of food in prison facilities should meet minimum safety standards, including refrigeration and training of food handlers.

BACKGROUND & AIMS:Point mutations in the coding region of the interleukin 28 gene (rs12979860) have recently been identified for predicting the outcome of treatment of hepatitis C virus infection. This polymorphism detection was based on whole blood DNA extraction. Alternatively, DNA for genetic diagnosis has been derived from buccal epithelial cells (BEC), dried blood spots (DBS), and genomic DNA from serum. The aim of the study was to investigate the reliability and accuracy of alternative routes of testing for single nucleotide polymorphism allele rs12979860CC. METHODS:Blood, plasma, and sera samples from 200 patients were extracted (400 µL). Buccal smears were tested using an FTA card. To simulate postal delay, we tested the influence of storage at ambient temperature on the different sources of DNA at five time points (baseline, 48 h, 6 days, 9 days, and 12 days). RESULTS:There was 100% concordance between blood, plasma, sera, and BEC, validating the use of DNA extracted from BEC collected on cytology brushes for genetic testing. Genetic variations in HPTR1 gene were detected using smear technique in blood smear (3620 copies) as well as in buccal smears (5870 copies). These results are similar to those for whole blood diluted at 1/10. A minimum of 0.04 µL, 4 µL, and 40 µL was necessary to obtain exploitable results respectively for whole blood, sera, and plasma. No significant variation between each time point was observed for the different sources of DNA. IL28B SNPs analysis at these different time points showed the same results using the four sources of DNA. CONCLUSION:We demonstrated that genomic DNA extraction from buccal cells, small amounts of serum, and dried blood spots is an alternative to DNA extracted from peripheral blood cells and is helpful in retrospective and prospective studies for multiple genetic markers, specifically in hard-to-reach individuals.

Disease-associated microglia (DAM), initially described in mouse models of neurodegenerative diseases, have been classified into two related states; starting from a TREM2-independent DAM1 state to a TREM2 dependent state termed DAM2, with each state being characterized by the expression of specific marker genes 1 . Recently, single-cell (sc)RNA-Seq studies have reported the existence of DAMs in humans 2-6 ; however, whether DAMs play beneficial or detrimental roles in the context of neurodegeneration is still under debate 7,8 . Here, we present a pharmacological approach to mimic human DAM in vitro by exposing different human microglia models to selected histone deacetylase (HDAC) inhibitors. We also provide an initial functional characterization of our model system, showing a specific increase of amyloid beta phagocytosis along with a reduction of MCP-1 secretion. Additionally, we report an increase in MITF expression, a transcription factor previously described to drive expression towards the DAM phenotype. We further identify CADM1 , LIPA and SCIN as DAM-marker genes shared across various proposed DAM signatures and in our model systems. Overall, our strategy for targeted microglial polarization bears great potential to further explore human DAM function and biology.

Immunosenescence (ISC), the aging of the immune system, has largely been studied in populations of European descent. Here, circulating immune cell cytometric data from African-American, Hispanic, and non-Hispanic White participants were generated. Known and novel age effects were identified using either a meta-analysis approach or a parallel genetic approach. Most results are consistent across the three populations, but some cell populations display evidence of heterogeneity, such as a PD-L1 + CD56 + NK cell subset. The study estimated "Immunological Age" (IA) during physiologic aging. While we found no relation of IA to Multiple Sclerosis, IA is associated with entorhinal cortex atrophy, a presymptomatic feature of Alzheimer's disease, linking neurodegeneration and peripheral immunity. ISC trajectories were also inferred, highlighting age, CMV status, and genetic ancestry as key influences. Our assessment offers reference ISC trajectories for personalization of assessments of immune function over the life course in diverse populations.

Alzheimer's disease (AD) has recently been associated with diverse cell states 1-11 , yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain's cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations-one drives amyloid-β proteinopathy while the other mediates the effect of amyloid-β on tau proteinopathy-as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: This retrospective longitudinal cohort study aimed to explore the best therapeutic regimen and treatment duration of cough variant asthma (CVA) in children., Methods: A total of 314 children with CVA were divided into receive inhaled corticosteroids (ICS) combined with long-acting beta2-agonist (LABA) group, ICS combined with leukotriene receptor antagonists (LTRA) group, ICS monotherapy group and LTRA monotherapy group. All clinical data were statistically analyzed. Logistic regression model was used to compare the advantages and disadvantages of different treatment schemes at each follow-up time point and the best treatment scheme. The Cox proportional hazard regression model based on inverse probability weighting was used to compare the effects of different medication regimens on adverse outcomes with asthma recurrence or progression as the end point., Results: (1) After comprehensive analysis, ICS + LABA group was the preferred control regimen for CVA within 8 weeks. After 8 weeks of diagnosis, the efficacy of ICS group or LTRA group was comparable to that of ICS + LABA group and ICS + LTRA group. (2) The ICS + LABA group showed a significant improvement in cough at an early stage, particularly at 4 weeks; the symptoms of ICS + LTRA and ICS groups were significantly improved at 36 weeks. The LTRA group alone showed significant improvement at 20 weeks., Conclusion: ICS + LABA, ICS + LTRA, ICS alone and LTRA alone can effectively treat CVA. ICS + LABA could improve the symptoms most quickly within 8 weeks after CVA diagnosis, followed by ICS + LATR group. After 8 weeks, it can be reduced to ICS alone to control CVA for at least 36 weeks based on the remission of symptoms in children., (© 2024 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: Emodin is a chemical compound found in traditional Chinese herbs. It possesses anti-inflammatory and many other pharmacological effects. Our previous study showed that emodin significantly alleviates the inflammation effect of severe acute pancreatitis (SAP). However, its poor solubility, high toxicity and limited pancreas retention time hinder its clinical application., Purpose: We aimed to prepare emodin nanocapsules with improved bioavailability to achieve the controlled release of emodin by targeting macrophages. Further, the mechanism of mannose-conjugated chitosan-coated lipid nanocapsules loaded with emodin (M-CS-E-LNC) in the treatment of SAP was explored., Methods: M-CS-E-LNC were prepared by the phase inversion method with slight modification. The expression of inflammation mediators and the anti-inflammation efficacy of M-CS-E-LNC were examined by ELISA, IHC and IF in macrophage cells and LPS-induced SAP mice. IVIS spectrum imaging and HPLC were applied to explore the controlled release of M-CS-E-LNC in the pancreas. LC-MS/MS was performed for lipidomics analysis of macrophages. Moreover, a vector-based short hairpin RNA (shRNA) method was used to silence CTP1 gene expression in macrophage cells., Results: The levels of inflammatory mediators in macrophages were markedly decreased after treatment with M-CS-E-LNC. The same anti-inflammation effects were detected in SAP mouse through the analysis of serum levels of amylase, TNF-α and IL-6. Importantly, M-CS-E-LNC allowed the emodin to selectively accumulate at pancreas and gastrointestinal tissues, thus exhibiting a targeted release. Mechanistically, the M-CS-E-LNC treatment group showed up-regulated expression of the carnitine palmitoyltransferase 1 (CPT1) protein which promoted intracellular long-chain fatty acid transport, thereby promoting the M2 phenotype polarization of macrophages., Conclusion: M-CS-E-LNC exhibited significantly improved bioavailability and water solubility, which translated to greater therapeutic effects on macrophage polarization. Our findings also demonstrate, for the first time, that CPT1 may be a new therapeutic target for SAP treatment., 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. Published by Elsevier GmbH.)

The accumulation of senescent cells is an important factor in the complex progression of aging, with significant implications for the development of numerous diseases. Thus, understanding the fundamental mechanisms of senescence is paramount for advancing preventive and therapeutic approaches to age-related conditions. Important to this pursuit is the precise identification and examination of senescent cells, contingent upon the recognition of specific biomarkers. Historically, detection methods relied on assessing molecular protein and mRNA levels and various staining techniques. While these conventional approaches have contributed substantially to the field, they possess limitations in capturing the dynamic evolution of cellular aging in real time. The emergence of novel technologies has led to a paradigm shift in senescence research. Gene-edited mouse models and the application of advanced probes have revolutionized our ability to detect senescent cells. These cutting-edge methodologies provide a more detailed and accurate means of dynamically monitoring, characterizing and potentially eliminating senescent cells, thus enhancing our understanding of the complex mechanisms of aging. This review comprehensively explores both traditional and innovative senescent cell detection methods, elucidating their advantages, limitations and implications for future investigations and could serve as a comprehensive guide and catalyst for further advancements in the understanding of aging and associated pathologies.

Introduction: Identifying new biomarkers for predicting immune checkpoint inhibitors (ICIs) response in non-small cell lung cancer (NSCLC) is crucial. We aimed to assess the variant allele frequency (VAF)-related profile as a novel biomarker for NSCLC personalized therapy., Methods: We utilized genomic data of 915 NSCLC patients via cBioPortal and a local cohort of 23 patients for model construction and mutational analysis. Genomic, transcriptomic data from 952 TCGA NSCLC patients, and immunofluorescence (IF) assessment with the local cohort supported mechanism analysis., Results: Utilizing the random forest algorithm, a 15-gene VAF-related model was established, differentiating patients with durable clinical benefit (DCB) from no durable benefit (NDB). The model demonstrated robust performance, with ROC-AUC values of 0.905, 0.737, and 0.711 across training (n = 313), internal validation (n = 133), and external validation (n = 157) cohorts. Stratification by the model into high- and low-score groups correlated significantly with both progression-free survival (PFS) (training: P < 0.0001, internal validation: P < 0.0001, external validation: P = 0.0066) and overall survival (OS) (n = 341) (P < 0.0001). Notably, the stratification system was independent of PD-L1 (P < 0.0001) and TMB (P < 0.0001). High-score patients exhibited an increased DCB ratio and longer PFS across both PD-L1 and TMB subgroups. Additionally, the high-score group appeared influenced by tobacco exposure, with activated DNA damage response pathways. Whereas, immune/inflammation-related pathways were enriched in the low-score group. Tumor immune microenvironment analyses revealed higher proportions of exhausted/effector memory CD8 + T cells in the high-score group., Conclusions: The mutational VAF profile is a promising biomarker for ICI therapy in NSCLC, with enhanced therapeutic stratification and management as a supplement to PD-L1 or TMB., (© 2024. The Author(s).)

With the increasing prevalence of type 2 diabetes mellitus (T2DM), it has become critical to identify effective treatment strategies. In recent years, the novel oral hypoglycaemic drug Imeglimin has attracted much attention in the field of diabetes treatment. The mechanisms of its therapeutic action are complex and are not yet fully understood by current research. Current evidence suggests that pancreatic β-cells, liver, and skeletal muscle are the main organs in which Imeglimin lowers blood glucose levels and that it acts mainly by targeting mitochondrial function, thereby inhibiting hepatic gluconeogenesis, enhancing insulin sensitivity, promoting pancreatic β-cell function, and regulating energy metabolism. There is growing evidence that the drug also has a potentially volatile role in the treatment of diabetic complications, including metabolic cardiomyopathy, diabetic vasculopathy, and diabetic neuroinflammation. According to available clinical studies, its efficacy and safety profile are more evident than other hypoglycaemic agents, and it has synergistic effects when combined with other antidiabetic drugs, and also has potential in the treatment of T2DM-related complications. This review aims to shed light on the latest research progress in the treatment of T2DM with Imeglimin, thereby providing clinicians and researchers with the latest insights into Imeglimin as a viable option for the treatment of T2DM., Competing Interests: Declaration of Competing Interest None of the contributing authors have any conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Masson SAS.)

Chemoimmunotherapy has evolved as a standard treatment for advanced non-small cell lung cancer (aNSCLC). However, inevitable drug resistance has limited its efficacy, highlighting the urgent need for biomarkers of chemoimmunotherapy. A three-phase strategy to discover, verify, and validate longitudinal predictive autoantibodies (AAbs) for aNSCLC before and after chemoimmunotherapy was employed. A total of 528 plasma samples from 267 aNSCLC patients before and after anti-PD1 immunotherapy were collected, plus 30 independent formalin-fixed paraffin-embedded samples. Candidate AAbs were firstly selected using a HuProt high-density microarray containing 21,000 proteins in the discovery phase, followed by validation using an aNSCLC-focused microarray. Longitudinal predictive AAbs were chosen for ELISA based on responders versus non-responders comparison and progression-free survival (PFS) survival analysis. Prognostic markers were also validated using immunohistochemistry and publicly available immunotherapy datasets. We identified and validated a panel of two AAbs (MAX and DHX29) as pre-treatment biomarkers and another panel of two AAbs (MAX and TAPBP) as on-treatment predictive markers in aNSCLC patients undergoing chemoimmunotherapy. All three AAbs exhibited a positive correlation with early responses and PFS (p < 0.05). The kinetics of MAX AAb showed an increasing trend in responders (p < 0.05) and a tendency to initially increase and then decrease in non-responders (p < 0.05). Importantly, MAX protein and mRNA levels effectively discriminated PFS (p < 0.05) in aNSCLC patients treated with immunotherapy. Our results present a longitudinal analysis of changes in prognostic AAbs in aNSCLC patients undergoing chemoimmunotherapy., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Epidermal growth factor receptor ( EGFR ) T790M mutation is the standard predictive biomarker for third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. While not all T790M-positive patients respond to third-generation EGFR-TKIs and have a good prognosis, it necessitates novel tools to supplement EGFR genotype detection for predicting efficacy and stratifying EGFR -mutant patients with various prognoses. Mixture-of-experts (MoE) is designed to disassemble a large model into many small models. Meanwhile, it is also a model ensembling method that can better capture multiple patterns of intrinsic subgroups of enrolled patients. Therefore, the combination of MoE and Cox algorithm has the potential to predict efficacy and stratify survival in non-small cell lung cancer (NSCLC) patients with EGFR mutations., Methods: We utilized the electronic medical record (EMR) and pharmacokinetic parameters of 326 T790M-mutated NSCLC patients, including 283 patients treated with Abivertinib in phase I (n=177, for training) and II (n=106, for validation) clinical trials and an additional validation cohort 2 comprising 43 patients treated with BPI-7711. Furthermore, 18 patients underwent whole-exome sequencing for biological interpretation of CoxMoE. We evaluated the predictive performance for therapeutic response using the area under the curve (AUC) and the Concordance index (C-index) for progression-free survival (PFS)., Results: CoxMoE exhibited AUCs of 0.73-0.83 for predicting efficacy defined by best overall response (BoR) and achieved C-index values of 0.64-0.65 for PFS prediction in training and validating cohorts. The PFS of 198 patients with a low risk [median, 6.0 (range, 1.0-23.3) months in the abivertinib treated cohort; median 16.5 (range, 1.4-27.4) months in BPI-7711 treated cohort] of being non-responder increased by 43% [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.40-0.78; P=0.0013] and 50% (HR, 0; 95% CI, 0-0; P=0.01) compared to those at high-risk [median, 4.2 (range, 1.0-35) months in the abivertinib treated cohort; median, 11.0 (range, 1.4-25.1) months in BPI-7711 treated cohort]. Additionally, activated partial thromboplastin time (APTT), creatinine clearance (Ccr), monocyte, and steady-state plasma trough concentration utilited to construct model were found significantly associated with drug resistance and aggressive tumor pathways. A robust correlation was observed between APTT and Ccr with PFS (log-rank test; P<0.01) and treatment response (Wilcoxon test; P<0.05), respectively., Conclusions: CoxMoE offers a valuable approach for patient selection by forecasting therapeutic response and PFS utilizing laboratory tests and pharmacokinetic parameters in the setting of early-phase clinical trials. Simultaneously, CoxMoE could predict the efficacy of third-generation EGFR-TKI non-invasively for T790M-positive NSCLC patients, thereby complementing existing EGFR genotype detection., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-737/coif). X.L. is a current employee of Huawei Technologies Co., Ltd. C.X. and N.Q. are former employees of Huawei Technologies Co., Ltd. S.W. and W.S. are current employees of Hangzhou ACEA Pharmaceutical Research Co., Ltd. The other authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)