Immunotherapy in resectable NSCLC: Answering the question or questioning the answer?

As immunotherapy makes its way into the perioperative setting, a growing number of clinical trials are expanding the evidence base for resectable non-small cell lung cancer (NSCLC) management. Identifying the optimal treatment pattern-whether it's neoadjuvant, adjuvant, or a combination of both-is a crucial next step, particularly in pinpointing which patients benefit the most. This decision-making process requires a multi-disciplinary treatment team capable of utilizing tissue and plasma genomic testing to inform therapeutic choices. Leveraging the perioperative treatment platform, it remains pivotal to integrate circulating tumor DNA (ctDNA) monitoring into clinical trial design efficiently and provide clear guidance on treatment.

Dipeptidyl peptidase 4 inhibitors vs. metformin for new-onset dementia: a propensity score-matched cohort study.

BACKGROUND: Hypoglycemic pharmacotherapy interventions for alleviating the risk of dementia remains controversial, particularly about dipeptidyl peptidase 4 (DPP4) inhibitors versus metformin. Our objective was to investigate whether the initiation of DPP4 inhibitors, as opposed to metformin, was linked to a reduced risk of dementia. METHODS: We included individuals with type 2 diabetes over 40 years old who were new users of DPP4 inhibitors or metformin in the Chinese Renal Disease Data System (CRDS) database between 2009 and 2020. The study employed Kaplan-Meier and Cox regression for survival analysis and the Fine and Gray model for the competing risk of death. RESULTS: Following a 1:1 propensity score matching, the analysis included 3626 DPP4 inhibitor new users and an equal number of metformin new users. After adjusting for potential confounders, the utilization of DPP4 inhibitors was associated with a decreased risk of all-cause dementia compared to metformin (hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.45-0.89). Subgroup analysis revealed that the utilization of DPP4 inhibitors was associated with a reduced incidence of dementia in individuals who initiated drug therapy at the age of 60 years or older (HR 0.69, 95% CI 0.48-0.98), those without baseline macrovascular complications (HR 0.62, 95% CI 0.41-0.96), and those without baseline microvascular complications (HR 0.67, 95% CI 0.47-0.98). CONCLUSION: In this real-world study, we found that DPP4 inhibitors presented an association with a lower risk of dementia in individuals with type 2 diabetes than metformin, particularly in older people and those without diabetes-related comorbidities.

Effect of Neutral Protease on Freshness Quality of Shucked Pacific Oysters at Different Storage Conditions.

The aim of this study was to investigate the effect of neutral protease treatment on the biochemical properties of various parts of Pacific oysters (Crassostrea gigas) under different storage conditions. The mechanism of quality degradation in the mantle, adductor muscle, gill, and trunk of treated oysters stored at -1.5 °C (superchilling) or 4 °C (refrigeration) for several days using different storage methods was studied. The results showed that the oyster treated with the enzyme exhibited higher glycogen content, flavor nucleotide content, and sensory scores compared to the control group. Superchilling at -1.5 °C was observed to slow the increase in total volatile basic nitrogen (TVB-N), total viable count (TVC), and pH, while maintaining sensory scores better than refrigeration at 4 °C. Both wet superchilling (WS) and dry exposed superchilling (DeS) methods effectively preserved freshness and quality at -1.5 °C. The freshness of the oysters' body trunk changed most significantly. K value, K' value, and AEC value, as the evaluation indexes of oyster freshness, were affected by the storage medium. Therefore, neutral protease enhances the flavor of oysters in a short time, and oysters stored in wet superchilling or dry exposed superchilling conditions have an extended shelf life.

Association of metabolic syndrome and sarcopenia with all-cause and cardiovascular mortality: a prospective cohort study based on the NHANES.

Background: Metabolic syndrome (MetS) and sarcopenia (SP) have emerged as significant public health concerns in contemporary societies, characterized by shared pathophysiological mechanisms and interrelatedness, leading to profound health implications. In this prospective cohort study conducted within a US population, we aimed to examine the influence of MetS and SP on all-cause and cardiovascular mortality. Methods: This study analyzed data from the National Health and Nutrition Examination Survey (NHANES) III for the years 1999-2006 and 2011-2018, and death outcomes were ascertained by linkage to National Death Index (NDI) records through December 31, 2019. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for all-cause and cardiovascular mortality. In addition, subgroup and sensitivity analyses were conducted to test the robustness of the results. Results: Over a median follow-up period of 13.3 years (95% CI: 12.8-13.8), 1714 deaths were observed. The groups characterized by MetS-/SP+, MetS+/SP-, and MetS+/SP+ exhibited higher all-cause mortality rates in comparison to the MetS-/SP- group, with the MetS+/SP+ group (HR 1.76, 95% CI: 1.37-2.25) displaying the highest all-cause mortality. Increased cardiovascular mortality was observed in the MetS+/SP- (HR 1.84, 95% CI: 1.24-2.72), and MetS+/SP+ groups (HR 2.39, 95% CI: 1.32-4.35) compared to the MetS-/SP- group, whereas it was not statistically significant in the MetS-/SP+ group. However, among males and individuals aged < 60, the presence of both MetS and SP (MetS+/SP+ group) was found to be significantly associated with a higher risk of all-cause and cardiovascular mortality. Conclusion: The coexistence of MetS and SP increased the risk of all-cause and cardiovascular mortality, particularly in males and in nonelderly populations. Individuals with either MetS or SP may require more careful management to prevent the development of other diseases and thereby reduce mortality.

Evaluation of the modified MRI vertebral bone quality score for bone quality in lumbar degenerative disorders.

OBJECTIVE: The traditional VBQ scoring method may lead to overestimation due to the concentration of intravertebral fat and vascular structures in the posterior half of vertebral bodies, potentially resulting in false-positive outcomes. This study aims to modify the measurement method of VBQ score (Modified-VBQ) and evaluate its effectiveness in evaluating bone quality of lumbar degenerative diseases. METHODS: Retrospective analysis was conducted on clinical data from patients undergoing lumbar surgery for degenerative diseases between September 2022 and September 2023. Preoperative lumbar t1-weighted Magnetic resonance imaging was used for both modified and traditional VBQ scoring. Computed tomography (CT) images and dual-energy X-ray absorptiometry (DEXA) data were collected through the picture archiving and communication system. The effectiveness of the modified VBQ score was evaluated, considering P < 0.05 as statistically significant. RESULTS: The study included 212 patients, revealing a significant difference between the modified VBQ and VBQ scores (P < 0.0001). Notably, patients with a history of hyperlipidemia exhibited a significant difference between the two scores (P = 0.0037). The area under the ROC curve (AUC) for the modified VBQ was 0.86, surpassing the VBQ score (AUC = 0.74). Linear regression analysis demonstrated a moderate to strong correlation between the modified VBQ and DEXA T-score (r = - 0.49, P < 0.0001) and a high correlation with CT Hounsfield units (HU) values (r = - 0.60, P < 0.0001). CONCLUSION: The modified VBQ score provides a simple, effective, and relatively accurate means of assessing bone quality in lumbar degenerative diseases. Preoperative implementation of the modified VBQ score facilitates rapid screening for patients with abnormal bone quality.

Effect of the mitochondrial uncoupling agent BAM15 against the Toxoplasma gondii RH strain and Prugniaud strain.

BACKGROUND: Toxoplasmosis is a zoonotic disease caused by the infection of the protozoa Toxoplasma gondii (T. gondii), and safe and effective therapeutic drugs are lacking. Mitochondria, is an important organelle that maintains T. gondii survival, however, drugs targeting mitochondria are lacking. METHODS: The cytotoxicity of BAM15 was detected by CCK-8 and the in vitro effects of BAM15 was detected by qPCR, plaque assay and flow cytometry. Furthermore, the ultrastructural changes of T. gondii after BAM15 treatment were observed by transmission electron microscopy, and further the mitochondrial membrane potential (ΔΨm), ATP level and reactive oxygen species (ROS) of T. gondii after BAM15 treatment were detected. The pharmacokinetic experiments and in vivo infection assays were performed in mice to determine the in vivo effect of BAM15. RESULTS: BAM15 had excellent anti-T. gondii activity in vitro and in vivo with an EC50 value of 1.25 µM, while the IC50 of BAM15 in Vero cells was 27.07 µM. Notably, BAM15 significantly inhibited proliferation activity of T. gondii RH strain and Prugniaud strain (PRU), caused T. gondii death. Furthermore, BAM15 treatment induced T. gondii mitochondrial vacuolation and autolysis by TEM. Moreover, the decrease in ΔΨm and ATP level, as well as the increase in ROS production further confirmed the changes CONCLUSIONS: Our study identifies a useful T. gondii mitochondrial inhibitor, which may also serve as a leading molecule to develop therapeutic mitochondrial inhibitors in toxoplasmosis.'

Genome-wide association and Mendelian randomisation analysis among 30,699 Chinese pregnant women identifies novel genetic and molecular risk factors for gestational diabetes and glycaemic traits.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is the most common disorder in pregnancy; however, its underlying causes remain obscure. This study aimed to investigate the genetic and molecular risk factors contributing to GDM and glycaemic traits. METHODS: We collected non-invasive prenatal test (NIPT) sequencing data along with four glycaemic and 55 biochemical measurements from 30,699 pregnant women during a 2 year period at Shenzhen Baoan Women's and Children's Hospital in China. Genome-wide association studies (GWAS) were conducted between genotypes derived from NIPTs and GDM diagnosis, baseline glycaemic levels and glycaemic levels after glucose challenges. In total, 3317 women were diagnosed with GDM, while 19,565 served as control participants. The results were replicated using two independent cohorts. Additionally, we performed one-sample Mendelian randomisation to explore potential causal associations between the 55 biochemical measurements and risk of GDM and glycaemic levels. RESULTS: We identified four genetic loci significantly associated with GDM susceptibility. Among these, MTNR1B exhibited the highest significance (rs10830963-G, OR [95% CI] 1.57 [1.45, 1.70], p=4.42×10-29), although its effect on type 2 diabetes was modest. Furthermore, we found 31 genetic loci, including 14 novel loci, that were significantly associated with the four glycaemic traits. The replication rates of these associations with GDM, fasting plasma glucose levels and 0 h, 1 h and 2 h OGTT glucose levels were 4 out of 4, 6 out of 9, 10 out of 11, 5 out of 7 and 4 out of 4, respectively. Mendelian randomisation analysis suggested that a genetically regulated higher lymphocytes percentage and lower white blood cell count, neutrophil percentage and absolute neutrophil count were associated with elevated glucose levels and an increased risk of GDM. CONCLUSIONS/INTERPRETATION: Our findings provide new insights into the genetic basis of GDM and glycaemic traits during pregnancy in an East Asian population and highlight the potential role of inflammatory pathways in the aetiology of GDM and variations in glycaemic levels. DATA AVAILABILITY: Summary statistics for GDM; fasting plasma glucose; 0 h, 1 h and 2h OGTT; and the 55 biomarkers are available in the GWAS Atlas (study accession no.: GVP000001, https://ngdc.cncb.ac.cn/gwas/browse/GVP000001) .

The immune system of prokaryotes: potential applications and implications for gene editing.

Gene therapy has revolutionized the treatment of genetic diseases. Spearheading this revolution are sophisticated genome editing methods such as TALENs, ZFNs, and CRISPR-Cas, which trace their origins back to prokaryotic immune systems. Prokaryotes have developed various antiviral defense systems to combat viral attacks and the invasion of genetic elements. The comprehension of these defense mechanisms has paved the way for the development of indispensable tools in molecular biology. Among them, restriction endonuclease originates from the innate immune system of bacteria. The CRISPR-Cas system, a widely applied genome editing technology, is derived from the prokaryotic adaptive immune system. Single-base editing is a precise editing tool based on CRISPR-Cas system that involves deamination of target base. It is worth noting that prokaryotes possess deamination enzymes as part of their defense arsenal over foreign genetic material. Furthermore, prokaryotic Argonauts (pAgo) proteins, also function in anti-phage defense, play an important role in complementing the CRISPR-Cas system by addressing certain limitations it may have. Recent studies have also shed light on the significance of Retron, a reverse transcription transposon previously showed potential in genome editing, has also come to light in the realm of prokaryotic immunity. These noteworthy findings highlight the importance of studying prokaryotic immune system for advancing genome editing techniques. Here, both the origin of prokaryotic immunity underlying aforementioned genome editing tools, and potential applications of deaminase, pAgo protein and reverse transcriptase in genome editing among prokaryotes were introduced, thus emphasizing the fundamental mechanism and significance of prokaryotic immunity.

Associations of thyroid feedback quantile-based index with diabetes in euthyroid adults in the United States and China.

BACKGROUND: We aimed to investigate the associations between thyroid hormone sensitivity indices and diabetes in euthyroid adults in the United States and China. METHODS: 2296 euthyroid adults from the NHANES in the United States and 8319 euthyroid adults from the SPEED-Shunde in China were involved. The thyroid sensitivity indices, namely TFQIFT4 and TFQIFT3, were calculated. Multivariable logistic regression, restricted cubic spline analysis, and general ordinal logit regression were utilized. RESULTS: In the NHANES, compared with participants in quartile 1st (Q1), those in Q4 of TFQIFT3 (OR 2.12, 95% CI (1.18, 3.81)) and those in Q3 of TFQIFT4 (OR 2.31, 95% CI (1.18, 4.53)) (both P for trend < 0.05) were associated with a greater prevalence of diabetes. In the SPEED-Shunde, compared with participants in Q1, those in Q4 of TFQIFT3 had a greater prevalence of diabetes (OR 1.36, 95% CI (1.11, 1.66) (P for trend < 0.05), while no significant associations between TFQIFT4 and diabetes were found. CONCLUSIONS: TFQIFT3 was associated with a higher prevalence of diabetes both in the United States and China. However, TFQIFT4 was only associated with a higher prevalence of diabetes in the United States, not in China. Further prospective cohort studies are necessary to validate these findings.

Elastic porous microspheres/extracellular matrix hydrogel injectable composites releasing dual bio-factors enable tissue regeneration.

Injectable biomaterials have garnered increasing attention for their potential and beneficial applications in minimally invasive surgical procedures and tissue regeneration. Extracellular matrix (ECM) hydrogels and porous synthetic polymer microspheres can be prepared for injectable administration to achieve in situ tissue regeneration. However, the rapid degradation of ECM hydrogels and the poor injectability and biological inertness of most polymeric microspheres limit their pro-regenerative capabilities. Here, we develop a biomaterial system consisting of elastic porous poly(l-lactide-co-ε-caprolactone) (PLCL) microspheres mixed with ECM hydrogels as injectable composites with interleukin-4 (IL-4) and insulin-like growth factor-1 (IGF-1) dual-release functionality. The developed multifunctional composites have favorable injectability and biocompatibility, and regulate the behavior of macrophages and myogenic cells following injection into muscle tissue. The elicited promotive effects on tissue regeneration are evidenced by enhanced neomusle formation, vascularization, and neuralization at 2-months post-implantation in a male rat model of volumetric muscle loss. Our developed system provides a promising strategy for engineering bioactive injectable composites that demonstrates desirable properties for clinical use and holds translational potential for application as a minimally invasive and pro-regenerative implant material in multiple types of surgical procedures.

Patient-derived Immunocompetent Tumor Organoids: A Platform for Chemotherapy Evaluation in the Context of T-cell Recognition.

Most of the anticancer compounds synthesized by chemists are primarily evaluated for their direct cytotoxic effects at the cellular level, often overlooking the critical role of the immune system. In this study, we developed a patient-derived, T-cell-retaining tumor organoid model that allows us to evaluate the anticancer efficacy of chemical drugs under the synergistic paradigm of antigen-specific T-cell-dependent killing, which may reveal the missed drug hits in the simple cytotoxic assay. We evaluated clinically approved platinum (Pt) drugs and a custom library of twenty-eight PtIV compounds. We observed low direct cytotoxicity of Pt drugs, but variable synergistic effects in combination with immune checkpoint inhibitors (ICIs). In contrast, the majority of PtIV compounds exhibited potent tumor-killing capabilities. Interestingly, several PtIV compounds went beyond direct tumor killing and showed significant immunosynergistic effects with ICIs, outstanding at sub-micromolar concentrations. Among these, Pt-19, PtIV compounds with cinnamate axial ligands, emerged as the most therapeutically potent, demonstrating pronounced immunosynergistic effects by promoting the release of cytotoxic cytokines, activating immune-related pathways and enhancing T cell receptor (TCR) clonal expansion. Overall, this initiative marks the first use of patient-derived immunocompetent tumor organoids to explore and study chemotherapy, advancing their path toward more effective small molecule drug discovery.

Association of sensitivity to thyroid hormones with all-cause mortality in euthyroid US adults: A nationwide cohort study.

Background This study aimed to examine the associations of thyroid hormone sensitivity indices, including free triiodothyronine to free thyroxine (FT3/FT4) ratio, thyroid feedback quantile-based index by FT4 (TFQIFT4), thyroid-stimulating hormone index (TSHI), and thyrotrophic thyroxine resistance index (TT4RI) with all-cause mortality in euthyroid adults. Methods The study included 6243 euthyroid adults from the National Health and Nutrition Examination Survey (NHANES) 2007-2012. FT3/FT4 ratio, TFQIFT4, TSHI, and TT4RI were calculated. The multivariable Cox proportional hazard regression, restricted cubic spline (RCS), and subgroup analysis were conducted. Results Individuals in quartile 4th (Q4) had lower all-cause mortality than those in quartile 1st (Q1) of FT3/FT4 ratio (OR 0.70, 95% CI (0.51, 0.94)). Regarding TFQIFT4, individuals in Q4 of TFQIFT4 had a 43% higher all-cause mortality than those in Q1 (OR 1.43, 95% CI (1.05, 1.96)) (P <0.05, all). Compared with participants in Q1, no associations of TSHI and TT4RI with mortality were found. TFQIFT4 was linearly and positively associated with mortality. However, the FT3/FT4 ratio showed a U-shaped association with mortality. Conclusions Increased risk for all-cause mortality was positively associated with TFQIFT4, suggesting that increased risk for all-cause mortality was associated with decreased central sensitivity to thyroid hormones. Furthermore, the FT3/FT4 ratio showed a U-shaped association with mortality, with an inflection point at 0.5. However, more cohort studies are needed to validate the conclusions.

Exosomes From IgE-Stimulated Mast Cells Aggravate Asthma-Mediated Atherosclerosis Through circRNA CDR1as-Mediated Endothelial Cell Dysfunction in Mice.

BACKGROUND: IgE has been known for mediating endothelial cell dysfunction and mast cell (MC) activation to fuel asthma-aggravated high-fat diet-induced atherosclerosis. However, it remains unclear for the mechanism of asthma-mediated atherosclerosis, especially the potential involvement of IgE in the exacerbation of asthma-mediated atherosclerosis with a standard laboratory diet, and the cross talk between endothelial cells and MCs. METHODS: Asthma-mediated atherosclerosis mice models under a standard laboratory diet and FcεR1 knock-out mice were used to determine the role of IgE-FcεR1 signaling in asthma-mediated atherosclerosis, which was assessed by Oil Red O staining and immunohistochemistry. Various in vitro assays including nanoparticle tracking analysis and transmission electron microscopy were used to evaluate exosome characteristics. Immunofluorescence and fluorescent in situ hybridization approaches were used to evaluate the effect and mechanism of MC-secreted exosomes encapsulated circular RNA CDR1as (cerebellar degeneration-related 1 antisense) on endothelial cells in vivo and in vitro. Finally, cohort studies examined the plasma CDR1as levels in patients with atherosclerosis with or without allergies. RESULTS: Asthma mice with a standard laboratory diet showed increased atherosclerotic lesions and inflammatory infiltration depending on IgE-FcεR1 signal. FcεR1 knockout mice and blockage of IgE-FcεR1 signaling with IgE monoclonal antibody, omalizumab, all significantly alleviated asthma-mediated atherosclerosis and vascular inflammatory remodeling. Anti-inflammation with dexamethasone and stabilization of MC with cromolyn partially alleviated atherosclerotic lesions and mitigated the inflammatory infiltration in arteries. Mechanistically, IgE stimulation upregulates MC CDR1as expression in exosomes and upregulates the endothelial cell adhesive factors VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) via the CDR1as-FUS (fused in sarcoma)-phos-p65 axis. Knockdown of CDR1as in vivo significantly decreased the endothelial adhesion function and mitigated asthma-mediated atherosclerosis. Furthermore, a cohort study indicated higher plasma CDR1as levels in patients with atherosclerosis with allergies than in patients with atherosclerosis and healthy controls. CONCLUSIONS: Exosomes from IgE-stimulated MCs aggravated atherosclerosis through circular RNA CDR1as-mediated endothelial dysfunction, providing a novel insight into asthma-mediated atherosclerosis and potential diagnostic and therapeutic targets.

Gut Microbiome and Stroke: a Bidirectional Mendelian Randomisation Study in East Asian and European Populations.

BACKGROUND AND AIMS: Observational studies have implicated the involvement of gut microbiome in stroke development. Conversely, stroke may disrupt the gut microbiome balance, potentially causing systemic infections exacerbated brain infarction. However, the causal relationship remains controversial or unknown. To investigate bidirectional causality and potential ethnic differences, we conducted a bidirectional two-sample Mendelian randomisation (MR) study in both East Asian (EAS) and European (EU) populations. METHODS: Leveraging the hitherto largest genome-wide association study (GWAS) summary data from the MiBioGen Consortium (n=18 340, EU) and BGI (n=2524, EAS) for the gut microbiome, stroke GWAS data from the GIGASTROKE Consortium(264 655 EAS and 1 308 460 EU), we conducted bidirectional MR and sensitivity analyses separately for the EAS and EU population. RESULTS: We identified nominally significant associations between 85 gut microbiomes taxa in EAS and 64 gut microbiomes taxa in EU with stroke or its subtypes. Following multiple testing, we observed that genetically determined 1 SD increase in the relative abundance of species Bacteroides pectinophilus decreased the risk of cardioembolic stroke onset by 28% (OR 0.72 (95% CI 0.62 to 0.84); p=4.22e-5), and that genetically determined 1 SD increase in class Negativicutes resulted in a 0.76% risk increase in small vessel stroke in EAS. No significant causal association was identified in the EU population and the reverse MR analysis. CONCLUSION: Our study revealed subtype-specific and population-specific causal associations between gut microbiome and stroke risk among EAS and EU populations. The identified causality holds promise for developing a new stroke prevention strategy, warrants further mechanistic validation and necessitates clinical trial studies.

Searching across-cohort relatives in 54,092 GWAS samples via encrypted genotype regression.

Explicitly sharing individual level data in genomics studies has many merits comparing to sharing summary statistics, including more strict QCs, common statistical analyses, relative identification and improved statistical power in GWAS, but it is hampered by privacy or ethical constraints. In this study, we developed encG-reg, a regression approach that can detect relatives of various degrees based on encrypted genomic data, which is immune of ethical constraints. The encryption properties of encG-reg are based on the random matrix theory by masking the original genotypic matrix without sacrificing precision of individual-level genotype data. We established a connection between the dimension of a random matrix, which masked genotype matrices, and the required precision of a study for encrypted genotype data. encG-reg has false positive and false negative rates equivalent to sharing original individual level data, and is computationally efficient when searching relatives. We split the UK Biobank into their respective centers, and then encrypted the genotype data. We observed that the relatives estimated using encG-reg was equivalently accurate with the estimation by KING, which is a widely used software but requires original genotype data. In a more complex application, we launched a finely devised multi-center collaboration across 5 research institutes in China, covering 9 cohorts of 54,092 GWAS samples. encG-reg again identified true relatives existing across the cohorts with even different ethnic backgrounds and genotypic qualities. Our study clearly demonstrates that encrypted genomic data can be used for data sharing without loss of information or data sharing barrier.

The Born in Guangzhou Cohort Study enables generational genetic discoveries.

Genomic research that targets large-scale, prospective birth cohorts constitutes an essential strategy for understanding the influence of genetics and environment on human health1. Nonetheless, such studies remain scarce, particularly in Asia. Here we present the phase I genome study of the Born in Guangzhou Cohort Study2 (BIGCS), which encompasses the sequencing and analysis of 4,053 Chinese individuals, primarily composed of trios or mother-infant duos residing in South China. Our analysis reveals novel genetic variants, a high-quality reference panel, and fine-scale local genetic structure within BIGCS. Notably, we identify previously unreported East Asian-specific genetic associations with maternal total bile acid, gestational weight gain and infant cord blood traits. Additionally, we observe prevalent age-specific genetic effects on lipid levels in mothers and infants. In an exploratory intergenerational Mendelian randomization analysis, we estimate the maternal putatively causal and fetal genetic effects of seven adult phenotypes on seven fetal growth-related measurements. These findings illuminate the genetic links between maternal and early-life traits in an East Asian population and lay the groundwork for future research into the intricate interplay of genetics, intrauterine exposures and early-life experiences in shaping long-term health.

Genetic determinants of IgG antibody response to COVID-19 vaccination.

Human humoral immune responses to SARS-CoV-2 vaccines exhibit substantial inter-individual variability and have been linked to vaccine efficacy. To elucidate the underlying mechanism behind this variability, we conducted a genome-wide association study (GWAS) on the anti-spike IgG serostatus of UK Biobank participants who were previously uninfected by SARS-CoV-2 and had received either the first dose (n = 54,066) or the second dose (n = 46,232) of COVID-19 vaccines. Our analysis revealed significant genome-wide associations between the IgG antibody serostatus following the initial vaccine and human leukocyte antigen (HLA) class II alleles. Specifically, the HLA-DRB1∗13:02 allele (MAF = 4.0%, OR = 0.75, p = 2.34e-16) demonstrated the most statistically significant protective effect against IgG seronegativity. This protective effect was driven by an alteration from arginine (Arg) to glutamic acid (Glu) at position 71 on HLA-DRß1 (p = 1.88e-25), leading to a change in the electrostatic potential of pocket 4 of the peptide binding groove. Notably, the impact of HLA alleles on IgG responses was cell type specific, and we observed a shared genetic predisposition between IgG status and susceptibility/severity of COVID-19. These results were replicated within independent cohorts where IgG serostatus was assayed by two different antibody serology tests. Our findings provide insights into the biological mechanism underlying individual variation in responses to COVID-19 vaccines and highlight the need to consider the influence of constitutive genetics when designing vaccination strategies for optimizing protection and control of infectious disease across diverse populations.

Transcriptome Sequencing and Mass Spectrometry Reveal Genes Involved in the Non-mendelian Inheritance-Mediated Feather Growth Rate in Chicken.

The feather growth rate in chickens included early and late feathering. We attempted to characterize the genes and pathways associated with the feather growth rate in chickens that are not in agreement with Mendelian inheritance. Gene expression profiles in the hair follicle tissues of late-feathering cocks (LC), early-feathering cocks (EC), late-feathering hens (LH), and early-feathering hens (EH) were acquired using RNA sequencing (RNA-seq), mass spectrometry (MS), and quantitative reverse transcription PCR (qRT­PCR). A total of 188 differentially expressed genes (DEGs) were ascertained in EC vs. LC and 538 DEGs were identified in EH vs. LH. We observed that 14 up-regulated genes and 9 down-regulated genes were screened both in EC vs. LC and EH vs. LH. MS revealed that 41 and 138 differentially expressed proteins (DEPs) were screened out in EC vs. LC and EH vs. LH, respectively. Moreover, these DEGs and DEPs were enriched in multiple feather-related pathways, including JAK-STAT, MAPK, WNT, TGF-ß, and calcium signaling pathways. qRT-PCR assay showed that the expression of WNT8A was decreased in LC compared with EC, while ALK and GRM4 expression were significantly up-regulated in EH relative to LH. This study helps to elucidate the potential mechanism of the feather growth rate in chickens that do not conform to genetic law.

Rechallenge of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) rechallenge in non-small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD-1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.