Unraveling the protein post-translational modification landscape: Neuroinflammation and neuronal death after stroke.

The impact of stroke on global health is profound, with both high mortality and morbidity rates. This condition can result from cerebral ischemia, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). The pathophysiology of stroke involves secondary damage and irreversible loss of neuronal function. Post-translational modifications (PTMs) have been recognized as crucial regulatory mechanisms in ischemic and hemorrhagic stroke-induced brain injury. These PTMs include phosphorylation, glycosylation, ubiquitination, SUMOylation, acetylation, and succinylation. This comprehensive review delves into recent research on the PTMs landscape associated with neuroinflammation and neuronal death specific to cerebral ischemia, ICH, and SAH. This review aims to explain the role of PTMs in regulating pathologic mechanisms and present critical techniques and proteomic strategies for identifying PTMs. This knowledge helps us comprehend the underlying mechanisms of stroke injury and repair processes, leading to the development of innovative treatment strategies. Importantly, this review underscores the significance of exploring PTMs to understand the pathophysiology of stroke.

Glyphosate-based herbicides reduced overwintering population and reproduction of agrobiont spiders.

Spiders are important in ecosystem and serve as predators in the biological control of pest insects in agroecosystem, where they encounter various harsh challenges including pesticides and low temperature in winter. Glyphosate-based herbicides (GBH) are widely and frequently applied to diminish weeds, exposing spiders a disturbed habitat, especially to overwintering spiders. We conducted a study combining field surveys and lab assays, to assess the effects of a GBH on the overwintering of the agrobiont wolf spider, Pardosa pseudoannulata. The GBH significantly reduced the overall overwintering spider population by about 69 %, and reduced the number of vulnerable juveniles by about 80 %. The survivors exhibited substantial fitness costs such as reproductive dysfunctions and enhanced oxidative stress responses. We then mimicked the overwinter process in lab. We housed spiders on soil patches with and without weeds to examine whether weeds contributed to the GBH's sublethal effects. Spiders overwintered independent of weeds when GBH was not applied. When GBH was applied before or during overwintering, juvenile spiders overwintered in weedy habitats exhibited reduced survival and fecundity, and increased oxidative stress compared to their counterparts in weed-free habitats. Therefore, GBH-containing weeds contributed to the persistent adverse effects of GBH on overwintering spiders. The findings revealed the cross-talk among weeds, herbicides, low temperature, and non-target organisms. The study provides novel information on the environmental risk assessment of pesticides and rational scheduling of pesticide application.

Immunosuppression and phenotypic plasticity in an atlas of human hepatocholangiocarcinoma.

Background: Hepatocholangiocarcinoma (H-ChC) has the clinicopathological features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) and is a more aggressive subtype of primary hepatic carcinoma than HCC or iCCA. Methods: We sequenced 91,112 single-cell transcriptomes from 16 human samples to elucidate the molecular mechanisms underlying the coexistence of HCC and iCCA components in H-ChC. Results: We observed two molecular subtypes of H-ChC at the whole-transcriptome level (CHP and CIP), where a metabolically active tumour cell subpopulation enriched in CHP was characterized by a cellular pre-differentiation property. To define the heterogeneity of tumours and their associated microenvironments, we observe greater tumour diversity in H-ChC than HCC and iCCA. H-ChC exhibits weaker immune cell infiltration and greater CD8+ exhausted T cell (Tex) dysfunction than HCC and iCCA. Then we defined two broad cell states of 6,852 CD8+ Tex cells: GZMK+ CD8+ Tex cells and terminal CD8+ Tex cells. GZMK+ CD8+ Tex cells exhibited higher infiltration of after treatment in H-ChC, the effector scores and expression of the immune checkpoints of them greatly increased after immunotherapy, which indicated that H-ChC might be more sensitive than HCC or iCCA to immunotherapy. Conclusions: In this paper, H-ChC was explored, hoping to contribute to the study of mixed tumours in other cancers.

PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis.

BACKGROUND: Cerebral aneurysms are life-threatening cerebrovascular disorders. Currently, there are no effective treatments for preventing disease progression. Mendelian randomisation (MR) is widely used to repurify licensed drugs and identify new therapeutic targets. Therefore, this study aims to investigate effective drug targets for preventing the formation and rupture of cerebral aneurysms and analyse their potential mechanisms. METHODS: We performed a comprehensive study integrating two-sample MR analysis, colocalisation analysis and summary data-based Mendelian randomisation (SMR) to assess the causal effects of blood and brain druggable cis-expression quantitative trait loci (cis-eQTLs) on intracranial aneurysm (IA), unruptured intracranial aneurysm (UIA) and subarachnoid haemorrhage of IA rupture (SAH). Druggable genes were obtained from the study by Chris Finan et al, cis-eQTLs from the eQTLGen and PsychENCODE consortia. Results were validated using proteomic and transcriptomic data. Single-gene functional analyses probed potential mechanisms, culminating in the construction of a drug-gene regulation network. RESULTS: Through the MR analysis, we identified four potential drug targets in the blood, including prolylcarboxypeptidase (PRCP), proteasome 20S subunit alpha 4 (PSMA4), LTBP4 and GPR160 for SAH. Furthermore, two potential drug targets (PSMA4 and SLC22A4) were identified for IA and one potential drug target (KL) for UIA after accounting for multiple testing (P(inverse-variance weighted)<8.28e-6). Strong evidence of colocalisation and SMR analysis confirmed the relevance of PSMA4 and PRCP in outcomes. Elevated PRCP circulating proteins correlated with a lower SAH risk. PRCP gene expression was significantly downregulated in the disease cohort. CONCLUSIONS: This study supports that elevated PRCP gene expression in blood is causally associated with the decreased risk of IA rupture. Conversely, increased PSMA4 expression in the blood is causally related to an increased risk of IA rupture and formation.

Elevated Fibrinogen-to-Albumin Ratio Correlates with Incident Stroke in Cerebral Small Vessel Disease.

Purpose: We aimed to explore the association between fibrinogen-to-albumin ratio (FAR) and the risk of incident stroke (IS) in a cohort of cerebral small vessel disease (CSVD) patients. Patients and Methods: Participants were screened from a prospective CSVD database. Clinical data, hematologic measures and imaging findings were collected. The primary outcome was IS during follow-up, with a secondary outcome of composite vascular events (CVE) including IS, myocardial infarction (MI), and vascular deaths. Univariate and multivariate COX proportional risk models, along with competing risk models, were employed to identify factors associated with outcomes. Restricted cubic spline (RCS) and subgroup analyses were conducted to assess the association between FAR and the risk of IS and CVE in CSVD patients. Results: In the final analysis of 682 CSVD patients over a median observation period of 34.0 [24.0-53.0] months, there were 33 cases of IS (4.84%, 1.55/100 person-years), 4 incidents of MI (0.59%, 0.19/100 person-years), 15 non-vascular deaths (2.20%, 0.70/100 person-years), and 37 occurrences of CVE (5.43%, 1.74/100 person-years). Multivariate Cox regression analysis revealed a significant positive correlation between elevated FAR and both IS (HR 1.146; 95% CI 1.043-1.259; P=0.004) and CVE (HR 1.156; 95% CI 1.063-1.257; P=0.001) in CSVD patients. Multivariate competing risk model showed the similar results (IS: HR 1.16; 95% CI 1.06-1.27; P=0.001, CVE: HR 1.15; 95% CI 1.05-1.26; P=0.003). RCS analysis indicated a linear relationship between FAR and the risks of both IS (P for non-linearity =0.7016) and CVE (P for non-linearity =0.6475), with an optimal cutoff value of 8.69, particularly in individuals over 60 years of age. Conclusion: Elevated FAR demonstrated an independent and linear association with IS and the development of CVE in CSVD patients.

A chromosome-level genome assembly of Prosopocoilus inquinatus Westwood, 1848 (Coleoptera: Lucanidae).

Lucanidae (Coleoptera: Scarabaeidae) are fascinating beetles exhibiting significant dimorphism and are widely used as beetle evolutionary study models. However, lacking high-quality genomes prohibits our understanding of Lucanidae. Herein, we proposed a chromosome-level genome assembly of a widespread species, Prosopocoilus inquinatus, combining PacBio HiFi, Illumina, and Hi-C data. The genome size reaches 649.73 Mb, having the scaffold N50 size of 59.50 Mb, and 99.6% (647.13 Mb) of the assembly successfully anchored on 12 chromosomes. The BUSCO analysis of the genome exhibits a completeness of 99.6% (n = 1,367), including 1,362 (98.5%) single-copy BUSCOs and 15 (1.1%) duplicated BUSCOs. The genome annotation identifies that the genome contains 61.41% repeat elements and 13,452 predicted protein-coding genes. This high-quality Lucanidae genome provides treasured genomic information to our knowledge of stag beetles.

Exploring the link: magnesium intake and hepatic steatosis in Americans.

Purpose: The connection between magnesium and hepatic steatosis has not been well-studied. This study aimed to explore the link between magnesium intake and hepatic steatosis, utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2017-2020. Materials and methods: The analysis included 5,935 participants, excluding individuals with hepatitis infection or substantial alcohol consumption. Magnesium intake assessment was based on 24-h dietary recalls. Hepatic steatosis evaluation employed the controlled attenuation parameter (CAP), measured via transient elastography. Multivariate regression and subgroup analyses were conducted to scrutinize the relationship between magnesium intake and CAP values. Results: A higher magnesium intake was associated with lower CAP values, after adjusting for potential confounders. Subgroup analyses indicated an inverted U-shaped correlation between magnesium intake and CAP in women, White people, and non-hypertensive individuals, with respective inflection points at 126, 124.5, and 125 mg/day, respectively. Below these thresholds, a higher magnesium intake correlated with increased CAP values, while above these points, it was associated with decreased CAP. Conclusion: This extensive population-based study indicates an inverse relationship between magnesium intake and hepatic steatosis in Americans. This relationship displays an inverted U-curve, varying before and after specified inflection points in women, White people, and non-hypertensive individuals. These findings offer insights into tailored magnesium supplementation strategies for preventing and treating liver steatosis, based on gender and ethnicity.

Gut microbiota and metabolites signatures of clinical response in anti-PD-1/PD-L1 based immunotherapy of biliary tract cancer.

BACKGROUND: Accumulating evidence suggests that the gut microbiota and metabolites can modulate tumor responses to immunotherapy; however, limited data has been reported on biliary tract cancer (BTC). This study used metagenomics and metabolomics to identify characteristics of the gut microbiome and metabolites in immunotherapy-treated BTC and their potential as prognostic and predictive biomarkers. METHODS: This prospective cohort study enrolled 88 patients with BTC who received PD-1/PD-L1 inhibitors from November 2018 to May 2022. The microbiota and metabolites significantly enriched in different immunotherapy response groups were identified through metagenomics and LC-MS/MS. Associations between microbiota and metabolites, microbiota and clinical factors, and metabolites and clinical factors were explored. RESULTS: Significantly different bacteria and their metabolites were both identified in the durable clinical benefit (DCB) and non-durable clinical benefit (NDB) groups. Of these, 20 bacteria and two metabolites were significantly associated with survival. Alistipes were positively correlated with survival, while Bacilli, Lactobacillales, and Pyrrolidine were negatively correlated with survival. Predictive models based on six bacteria, four metabolites, and the combination of three bacteria and two metabolites could all discriminated between patients in the DCB and NDB groups with high accuracy. Beta diversity between two groups was significantly different, and the composition varied with differences in the use of immunotherapy. CONCLUSIONS: Patients with BTC receiving immunotherapy have specific alterations in the interactions between microbiota and metabolites. These findings suggest that gut microbiota and metabolites are potential prognostic and predictive biomarkers for clinical outcomes of anti-PD-1/PD-L1-treated BTC.

Conversion surgery intervention versus continued systemic therapy in patients with a response after PD-1/PD-L1 inhibitor-based combination therapy for initially unresectable biliary tract cancer: a retrospective cohort study.

BACKGROUND: The role of conversion surgery in patients with unresectable biliary tract cancer who responded positively to PD-1/PD-L1 inhibitor-based therapy remains unclear. This study aimed to assess the outcomes in patients with or without conversion surgery. METHODS: In this cohort study, patients with advanced biliary tract cancer who received combination therapy with PD-1/PD-L1 inhibitors from July 2019 to January 2023 were retrospectively. Patients who exhibited positive responses and met the criteria for conversion surgery were enrolled, and their surgical and oncological outcomes were analyzed. RESULTS: Out of 475 patients, 34 who met the conversion resection criteria were enrolled. The median follow-up was 40.5 months postinitiation of systemic therapy. Ultimately, 13 patients underwent conversion surgery, while 21 received continuation of systemic treatment alone (nonsurgical group). The median interval from the initial antitumor therapy to surgery was 6.7 [interquartile range (IQR) 4.9-9.2] months. Survival with conversion surgery was significantly longer than the nonsurgical cohort, with a median progression-free survival (PFS) [unreached vs. 12.4 months; hazard ratio 0.17 (95% CI: 0.06-0.48); P =0.001] and overall survival (OS) [unreached vs. 22.4 months; hazard ratio 0.28 (95% CI: 0.09-0.84); P =0.02], respectively. After a median postoperative follow-up of 32.2 months in the surgical cohort, eight patients survived without recurrence. The estimated 3-year OS, PFS, and recurrence-free survival rate in the surgical cohort were 59.9, 59.2, and 60.6%, respectively. The R0 resection rate reached 92.3%, with two achieving a pathological complete response. One patient experienced a Clavien-Dindo grade 3 complication without surgery-related mortality. No serious adverse events or surgical delays were observed. Multivariate analysis indicated that conversion surgery was independently associated with OS ( P =0.03) and PFS survival ( P =0.003). CONCLUSION: Conversion surgery appears safe and offers survival benefits to patients responding to immune checkpoint inhibitors-based combinations. However, further studies are required to validate this strategy in the era of immunotherapy.

Novel inflammatory and insulin resistance indices provide a clue in cerebral amyloid angiopathy.

This study investigated the correlation of newly identified inflammatory and insulin resistance indices with cerebral amyloid angiopathy (CAA), and explored their potential to differentiate CAA from hypertensive arteriopathy (HA). We retrospectively analyzed 514 consecutive patients with cerebral small vessel disease (CSVD)-related haemorrhage, comparing the differences in novel inflammatory and insulin resistance indices between patients with CAA and HA. Univariate regression, LASSO and multivariate regression were used to screen variables and construct a classification diagnosis nomogram. Additionally, these biomarkers were explored in patients with mixed haemorrhagic CSVD. Inflammatory indices were higher in CAA patients, whereas insulin resistance indices were higher in HA patients. Further analysis identified neutrophil-to-lymphocyte ratio (NLR, OR 1.17, 95% CI 1.07-1.30, P < 0.001), and triglyceride-glucose index (TyG, OR = 0.56, 95% CI 0.36-0.83, P = 0.005) as independent factors for CAA. Therefore, we constructed a CAA prediction nomogram without haemorrhagic imaging markers. The nomogram yielded an area under the curve (AUC) of 0.811 (95% CI 0.764-0.865) in the training set and 0.830 (95% CI 0.718-0.887) in the test set, indicating an ability to identify high-risk CAA patients. These results show that CSVD patients can be phenotyped using novel inflammatory and insulin resistance indices, potentially allowing identification of high-risk CAA patients without haemorrhagic imaging markers.

LMNB1/CDKN1A Signaling Regulates the Cell Cycle and Promotes Hepatocellular Carcinoma Progression.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies in the world. Lamin B1 (LMNB1) is a key component of the nuclear skeleton structure. Recent studies have found that LMNB1 is overexpressed in tumor tissues and is associated with the prognosis of patients. However, the underlying mechanism remains unclear in HCC. OBJECTIVE: This study aims to explore the clinical significance and molecular mechanisms of LMNB1 in HCC. METHODS: The expression level of LMNB1 and its clinical values were analyzed with public databases, and the level of LMNB1 in HCC tissues and adjacent normal tissues was confirmed by qRT-PCR and IHC. Functional assays were conducted to explore the impact of LMNB1 knockdown on cell proliferation both in vivo and in vitro. Additionally, Genes and Genomes enrichment analysis, recovery analysis, and ChIP assays were employed to investigate its underlying molecular mechanisms. Finally, we carried out an analysis of the relationship between LMNB1 and immune cell infiltration in HCC. RESULTS: LMNB1 was found to be overexpressed in HCC and correlated with the pathological stage and unfavorable prognosis. Functional assays demonstrated that LMNB1 promotes HCC proliferation both in vitro and in vivo. Further analysis revealed that LMNB1 promotes the progression of HCC by regulating CDKN1A expression. Furthermore, the infiltration of immune cells in HCC tissues suggests a potential correlation between immune infiltration cell markers and the expression of LMNB1. CONCLUSIONS: LMNB1 emerged as a promising therapeutic target and prognostic biomarker for HCC, with its expression showing a correlation with several immune infiltration cell markers.

Role of alternative splicing in fish immunity.

Alternative splicing serves as a pivotal source of complexity in the transcriptome and proteome, selectively connecting various coding elements to generate a diverse array of mRNAs. This process encodes multiple proteins with either similar or distinct functions, contributing significantly to the intricacies of cellular processes. The role of alternative splicing in mammalian immunity has been well studied. Remarkably, the immune system of fish shares substantial similarities with that of humans, and alternative splicing also emerges as a key player in the immune processes of fish. In this review, we offer an overview of alternative splicing and its associated functions in the immune processes of fish, and summarize the research progress on alternative splicing in the fish immunity. Furthermore, we review the impact of alternative splicing on the fish immune system's response to external stimuli. Finally, we present our perspectives on future directions in this field. Our aim is to provide valuable insights for the future investigations into the role of alternative splicing in immunity.

Exploring the association between dietary fiber intake and hepatic steatosis: insights from NHANES.

PURPOSE: The link between dietary fiber intake and Non-alcoholic fatty liver disease (NAFLD) is under exploration, yielding inconsistent findings. Considering the limitations of previous research and the significance of dietary fiber in hepatic steatosis, this study investigates the association between dietary fiber intake and Controlled Attenuation Parameter (CAP) among 5935 participants from the National Health and Nutrition Examination Survey (NHANES). MATERIALS AND METHODS: Multivariable regression was used to evaluate the association between dietary fiber intake and CAP. Smoothed curve fitting and threshold effect analysis techniques were applied to illustrate non-linear relationships. RESULTS: After adjusting for other variables, a negative correlation emerged between dietary fiber intake and CAP. Subgroup analysis by gender and race/ethnicity revealed a sustained negative association between dietary fiber intake and CAP among females and Whites. Additionally, an inverted U-shaped relationship was observed between dietary fiber intake and CAP among women and other race, with inflection points at 13.80 g/day and 33.45 g/day, respectively. CONCLUSION: Our research indicates that in the majority of Americans, there is an inverse relationship between dietary fiber intake and hepatic steatosis. This relationship exhibits an inverted U-shaped curve in women and other race, with a threshold effect. The findings of this study hold potential significance for clinical nutrition interventions, personalized dietary guidance, and advancing research into the diet-disease mechanism relationship.

Analysis of the Relationship between Recent Small Subcortical Infarcts and Autonomic Nervous Dysfunction.

OBJECTIVE: Autonomic Nervous System (ANS) dysfunction may be involved in the pathogenesis of Cerebral Small Vessel Disease (CSVD). The study aimed to explore the relationship between Recent Small Subcortical Infarct (RSSI) and Blood Pressure Variability (BPV), and Heart Rate Variability (HRV). METHODS: A total of 588 patients from the CSVD registration research database of Henan Province were included in this study, and were divided into two groups according to the presence of RSSI. Clinical data, including demographic characteristics, disease history, laboratory indexes, 24-hour ambulatory blood pressure and electrocardiogram indicators, and imaging markers of CSVD, were collected. Univariate and binary logistic regression analyses were used to study the relationship between RSSI and indicators of laboratory, HRV and BPV in the CSVD population. RESULTS: Multivariate analysis showed that higher 24-hour mean Diastolic Blood Pressure (DBP)[Odds Ratios (OR)=1.083,95% Confidence Intervals (CI)=(1.038,1.129), p < 0.001], Standard Deviation (SD) of 24-hour DBP [OR=1.059,95%CI=(1.000,1.121), p = 0.049], nocturnal mean Systolic Blood Pressure (SBP) [OR=1.020,95%CI=(1.004,1.035), p = 0.012], nocturnal mean DBP [OR=1.025,95%CI=(1.009,1.040), p = 0.002] were independent risk factors for RSSI. In contrast, the decrease of the standard deviation of N-N intervals (SDNN) [OR=0.994,95%CI=(0.989,1.000), p = 0.035] was beneficial to the occurrence of RSSI. In addition, neutrophil counts [OR=1.138,95%CI=(1.030,1.258), p = 0.011], total cholesterol (TC) [OR=1.203,95%CI=(1.008,1.437), p = 0.041] and High-Density Lipoprotein (HDL) [OR=0.391, 95%CI=(0.195,0.786), p = 0.008] were also independently associated with the occurrence of RSSI. After adjusting for confounding factors, except for TC, the other factors remained associated with the occurrence of RSSI. CONCLUSION: Increased 24-hour mean DBP, nocturnal mean SBP and DBP, SD of 24-hour DBP and decreased SDNN were independently correlated with RSSI occurrence, suggesting that sympathetic overactivity plays a role in the pathogenesis of RSSI.

Clinical features and associated factors of coexisting intracerebral hemorrhage in patients with cerebral small vessel disease: a cross-sectional study.

Intracerebral hemorrhage (ICH) is generally considered to be closely related to cerebral small vessel disease (CSVD), leading to a poor prognosis. However, the coexistence of ICH in general CSVD patients and related factors remain underreported. In our cross-sectional study, we screened 414 CSVD patients from a database at the Department of Neurology, First Affiliated Hospital of Zhengzhou University (September 2018 to April 2022). Imaging biomarkers of CSVD and coexisting ICH lesion were assessed. Factors associated with coexisting ICH in CSVD were determined using multivariate logistic regression analysis. ICH was observed in 59 patients (14.3%). Multivariate logistic regression showed that previous history of ischemic stroke or transient ischemic attack (OR 5.189, 95%CI 2.572-10.467, P < 0.001), high-grade perivascular space in the basal ganglia (n > 10) (OR 2.051, 95%CI 1.044-4.027, P = 0.037) and low adjusted calcium-phosphorus product (OR 0.728 per 1 [mmol/L]2 increase, 95%CI 0.531-0.998, P = 0.049) were associated with coexisting ICH in CSVD patients. The considerable proportion of coexisting ICH and revelation of associated factors in general CSVD patients alert physicians of the potential risk of the reoccurrence of ICH, and might have a significant impact on therapeutic strategies.

Measurement of Fitness and Predatory Ability of Four Predatory Mite Species in Tibetan Plateau under Laboratory Conditions.

Predatory mites are biological control agents used in many countries against various vegetable pests, particularly spider mites. Despite the significant presence of predatory mites in the Tibetan plateau, there is limited research on their potential against spider mites in the area. This study investigated the fitness parameters and performance against TSSM of four predatory, including Amblyseius swirskii (Athias-Henriot) and three species from the genus Neoseiulus (Neoseiulus californicus (McGregor), Neoseiulus barkeri (Hughes), and Neoseiulus cucumeris (Oudemans)), originally collected from fields in the Tibetan Plateau. Compared to the other three predatory species, A. swirskii exhibited the highest fecundity (11.60 ± 0.34) and the highest pre-adult survival rate (83.33 ± 3.33%). Since their juvenile survival rate (SR) was extremely low (13.33% ± 5.77%), most N. barkeri nymphs died before emergence. Compared to the other three predatory mites, A. swirskii showed the highest predation capacity against adult TSSMs at 15 d post-release (14.28 ± 2.24). Based on the results, A. swirskii was the most effective, and N. barkeri was the least effective in controlling two-spotted mites in the Tibetan Plateau among the four species tested in this study. Collectively, these findings imply notable advantages in employing A. swirskii for controlling two-spotted mites in the Tibetan Plateau. This study informs the development of a feasible biological control method based on suitable predatory mite species to manage TSSMs in the Tibetan Plateau.

Biomarkers and prognostic factors of PD-1/PD-L1 inhibitor-based therapy in patients with advanced hepatocellular carcinoma.

Systemic therapies using programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors have demonstrated commendable efficacy in some patients with advanced hepatocellular carcinoma (HCC); however, other individuals do not respond favorably. Hence, identifying the biomarkers, the prognostic factors, and their underlying mechanisms is crucial. In this review, we summarized the latest advancements in this field. Within the tumor microenvironment, PD-L1 expression is commonly utilized to predict response. Moreover, the characteristics of tumor-infiltrating lymphocytes are associated with the effectiveness of immunotherapy. Preclinical studies have identified stimulatory dendritic cells, conventional dendritic cells, and macrophages as potential biomarkers. The emergence of single-cell sequencing and spatial transcriptomics has provided invaluable insights into tumor heterogeneity through the lens of single-cell profiling and spatial distribution. With the widespread adoption of next-generation sequencing, certain genomic characteristics, including tumor mutational burden, copy number alterations, specific genes (TP53, CTNNB1, and GZMB), and signaling pathways (WNT/ß-catenin) have been found to correlate with prognosis. Furthermore, clinical features such as tumor size, number, and metastasis status have demonstrated prognostic value. Notably, common indicators such as the Child-Pugh score and Eastern Cooperative Oncology Group score, which are used in patients with liver diseases, have shown potential. Similarly, commonly employed laboratory parameters such as baseline transforming growth factor beta, lactate dehydrogenase, dynamic changes in alpha-fetoprotein (AFP) and abnormal prothrombin, CRAFITY score (composed of C-reactive protein and AFP), and immune adverse events have been identified as predictive biomarkers. Novel imaging techniques such as EOB-MRI and PET/CT employing innovative tracers also have potential. Moreover, liquid biopsy has gained widespread use in biomarker studies owing to its non-invasive, convenient, and highly reproducible nature, as well as its dynamic monitoring capabilities. Research on the gut microbiome, including its composition, dynamic changes, and metabolomic analysis, has gained considerable attention. Efficient biomarker discovery relies on continuous updating of treatment strategies. Next, we summarized recent advancements in clinical research on HCC immunotherapy and provided an overview of ongoing clinical trials for contributing to the understanding and improvement of HCC immunotherapy.

Mechanism of Action of the Plateau-Adapted Gene PPARA in COPD.

Chronic obstructive pulmonary disease (COPD) is a complex respiratory disorder influenced by various factors and involving multiple genes. Respiratory dysfunction in COPD patients leads to hypoxia, resulting in limited oxygen uptake. Peroxisome proliferator-activated receptor alpha (PPARA) is a plateau-adapted gene that regulates respiratory function in populations adapted to high-altitude areas through multiple pathways. Interestingly, PPARA expression is higher in long-term inhabiting Tibetan populations that have adapted to the plateau environment. However, in patients with COPD, the expression of PPARA is downregulated, leading to dysregulation of the hypoxia-inducible factor pathway. Moreover, abnormal PPARA expression in lung epithelial cells triggers inflammatory responses, oxidative stress, and disrupted lipid metabolism, thereby exacerbating disease progression. Thus, this paper explored the mechanism underlying the role of plateau-adapted PPARA in COPD, providing essential theoretical insights into the treatment and prevention of COPD in high-altitude regions.

GSTP1 rs4147581 C>G and NLRP3 rs3806265 T>C as Risk Factors for Chronic Obstructive Pulmonary Disease: A Case-Control Study.

Background: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory ailment influenced by a blend of genetic and environmental factors. Inflammatory response and an imbalance in oxidative-antioxidant mechanisms constitute the primary pathogenesis of COPD. Glutathione S-transferase P1(GSTP1) plays a pivotal role as an antioxidant enzyme in regulating oxidative-antioxidant responses in the pulmonary system. The activation of the NOD-like receptor thermal protein domain (NLRP3) inflammatory vesicle can trigger an inflammatory response. Several investigations have implicated GSTP1 and NLRP3 in the progression of COPD; nonetheless, there remains debate regarding this mechanism. Methods: Employing a case-control study design, 312 individuals diagnosed with COPD and 314 healthy controls were recruited from Gansu Province to evaluate the correlation between GSTP1 (rs4147581C>G and rs1695A>G) and NLRP3 (rs3806265T>C and rs10754558G>C) polymorphisms and the susceptibility to COPD. Results: The presence of the GSTP1 rs4147581G allele substantially elevated the susceptibility to COPD (CGvs.CC:OR=3.11,95% CI=1.961-4.935, P<0.001;GGvs.CC:OR=2.065,95% CI=1.273-3.350, P=0.003; CG+GGvs.CC:OR=2.594,95% CI=1.718-3.916, P<0.001). Similarly, the NLRP3rs3806265T allele significantly increased the susceptibility to COPD (TC:TT:OR=0.432,95% CI=0.296-0.630; TC+CCvs.TT:OR=2.132,95% CI=1.479-3.074, P<0.001). However, no statistically significant association was discerned between the rs1695A>G and rs10754558G>C polymorphisms and COPD susceptibility (P>0.05). Conclusion: In summary, this study ascertained that the GSTP1 rs4147581C>G polymorphism is associated with increased COPD susceptibility, with the G allele elevating the risk of COPD. Similarly, the NLRP3 rs3806265T>C polymorphism is linked to elevated COPD susceptibility, with the T allele heightening the risk of COPD.

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma.

BACKGROUND: Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. METHODS: We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. RESULTS: Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. CONCLUSIONS: MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).