Fasting mimicking diet extends lifespan and improves intestinal and cognitive health.

Caloric restriction is an effective means of extending a healthy lifespan. Fasting mimicking diet (FMD) is a growing pattern of caloric restriction. We found that FMD significantly prolonged the lifespan of prematurely aging mice. In naturally aging mice, FMD improved cognitive and intestinal health. Through a series of behavioral experiments, we found that FMD relieved anxiety and enhanced cognition in aged mice. In the intestine, the FMD cycles enhanced the barrier function, reduced senescence markers, and maintained T cell naïve-memory balance in the lamina propria mucosa. To further explore the causes of immune alterations, we examined changes in the stool microbiota using 16S rRNA sequencing. We found that FMD remodeled gut bacterial composition and significantly expanded the abundance of Lactobacillus johnsonii. Our research revealed that FMD has in-depth investigative value as an anti-aging intervention for extending longevity and improving cognition, intestinal function, and gut microbiota composition.

Microbial metabolite enhances immunotherapy efficacy by modulating T cell stemness in pan-cancer.

The immune checkpoint blockade (ICB) response in human cancers is closely linked to the gut microbiota. Here, we report that the abundance of commensal Lactobacillus johnsonii is positively correlated with the responsiveness of ICB. Supplementation with Lactobacillus johnsonii or tryptophan-derived metabolite indole-3-propionic acid (IPA) enhances the efficacy of CD8+ T cell-mediated αPD-1 immunotherapy. Mechanistically, Lactobacillus johnsonii collaborates with Clostridium sporogenes to produce IPA. IPA modulates the stemness program of CD8+ T cells and facilitates the generation of progenitor exhausted CD8+ T cells (Tpex) by increasing H3K27 acetylation at the super-enhancer region of Tcf7. IPA improves ICB responsiveness at the pan-cancer level, including melanoma, breast cancer, and colorectal cancer. Collectively, our findings identify a microbial metabolite-immune regulatory pathway and suggest a potential microbial-based adjuvant approach to improve the responsiveness of immunotherapy.

Leveraging Nonstrained C-C Bonds for Selective Carboacylation of an Unactivated Alkyne via Transient Dearomatization.

Carboacylation of an unsaturated bond represents a powerful transformation. However, only a few examples of carboacylation of alkyne have been reported through C-C bond scission and reconnection. Here, we report a method of carboacylation of an unactivated alkyne by utilizing nonstrained C-C bonds under gold(I) catalysis. The density functional theory computational and experimental studies reveal that the reaction proceeds through a C-to-C formal 1,3-acyl migration via a solvent cage-nested acylium cation.

ß-Nicotinamide mononucleotide supplementation prolongs the lifespan of prematurely aged mice and protects colon function in ageing mice.

Ageing is defined as the degeneration of physiological functions in numerous tissues and organs of an organism, which occurs with age. As we age, the gut undergoes a series of changes and weaknesses that may contribute to overall ageing. Emerging evidence suggests that ß-nicotinamide mononucleotide (NMN) plays a role in regulating intestinal function, but there is still a lack of literature on its role in maintaining the colon health of ageing mice. In our research, Zmpste24-/- mice proved that NMN prolonged their life span and delayed senescence. This study was designed to investigate the effects of long-term intervention on regulating colon function in ageing mice. Our results indicated that NMN improved the pathology of intestinal epithelial cells and intestinal permeability by upregulating the expression of intestinal tight junction proteins and the number of goblet cells, increasing the release of anti-inflammatory factors, and increasing beneficial intestinal bacteria. NMN increased the expression of the proteins SIRT1, NMNAT2, and NMNAT3 and decreased the expression of the protein P53. It also regulated the activity of ISCs by increasing Wnt/ß-catenin and Lgr5. Our findings also revealed that NMN caused a significant increase in the relative abundance of Akkermansia muciniphila and Bifidobacterium pseudolongum and notable differences in metabolic pathways related to choline metabolism in cancer. In summary, NMN supplementation can delay frailty in old age, aid healthy ageing, and delay gut ageing.

Serum ferritin and neutrophil-to-lymphocyte ratio predict all-cause mortality in patients receiving maintenance hemodialysis: a prospective study.

Introduction: Maintenance hemodialysis is an effective treatment for end-stage renal disease patients. A critical factor contributing to the deterioration and death of maintenance hemodialysis patients is inflammation. Therefore, we focused on two inflammatory markers, serum ferritin and neutrophil-to-lymphocyte ratio, to speculate whether they could predict the prognosis of maintenance hemodialysis patients. Patients and methods: We followed 168 patients with maintenance hemodialysis from July 2019 to July 2022 with the endpoint of all-cause death or follow-up completion. Receiver operating characteristic curves were plotted to assess the values of serum ferritin, neutrophil-to-lymphocyte ratio and serum ferritin combined with neutrophil-to-lymphocyte ratio to predict the outcomes of maintenance hemodialysis patients. Kaplan-Meier survival curves were constructed to compare survival rates over time. Results: Receiver operating characteristic curves demonstrated that the best cut-off value of serum ferritin for predicting the prognosis of maintenance hemodialysis patients was 346.05 µg/L, and that of neutrophil-to-lymphocyte ratio was 3.225. Furthermore, a combination of both had a more excellent predicting value than either index (p < 0.05). Kaplan-Meier survival curve analyses revealed that low serum ferritin levels and low neutrophil-to-lymphocyte ratio had a higher probability of survival than high ferritin levels and high neutrophil-to-lymphocyte ratio, separately. Conclusion: Elevated serum ferritin and neutrophil-to-lymphocyte ratio are closely related to all-cause mortality among maintenance hemodialysis patients, for which they may be predictors of all-cause mortality. Additionally, the combination of the two has a much higher predictor value for the prognosis of maintenance hemodialysis patients.

L-arginine metabolism ameliorates age-related cognitive impairment by Amuc_1100-mediated gut homeostasis maintaining.

Aging-induced cognitive impairment is associated with a loss of metabolic homeostasis and plasticity. An emerging idea is that targeting key metabolites is sufficient to impact the function of other organisms. Therefore, more metabolism-targeted therapeutic intervention is needed to improve cognitive impairment. We first conducted untargeted metabolomic analyses and 16S rRNA to identify the aging-associated metabolic adaption and intestinal microbiome change. Untargeted metabolomic analyses of plasma revealed L-arginine metabolic homeostasis was altered during the aging process. Impaired L-arginine metabolic homeostasis was associated with low abundance of intestinal Akkermansia muciniphila (AKK) colonization in mice. Long-term supplementation of AKK outer membranes protein-Amuc_1100, rescued the L-arginine level and restored cognitive impairment in aging mice. Mechanically, Amuc_1100 acted directly as a source of L-arginine and enriched the L-arginine-producing bacteria. In aged brain, Amuc_1100 promoted the superoxide dismutase to alleviated oxidation stress, and increased nitric oxide, derivatives of L-arginine, to improve synaptic plasticity. Meanwhile, L-arginine repaired lipopolysaccharide-induced intestinal barrier damage and promoted growth of colon organoid. Our findings indicated that aging-related cognitive impairment was closely associated with the disorders of L-arginine metabolism. AKK-derived Amuc_1100, as a potential postbiotic, targeting the L-arginine metabolism, might provide a promising therapeutic strategy to maintain the intestinal homeostasis and cognitive function in aging.

Novel Plastid Genome Characteristics in Fugacium kawagutii and the Trend of Accelerated Evolution of Plastid Proteins in Dinoflagellates.

Typical (peridinin-containing) dinoflagellates possess plastid genomes composed of small plasmids named "minicircles". Despite the ecological importance of dinoflagellate photosynthesis in corals and marine ecosystems, the structural characteristics, replication dynamics, and evolutionary forcing of dinoflagellate plastid genomes remain poorly understood. Here, we sequenced the plastid genome of the symbiodiniacean species Fugacium kawagutii and conducted comparative analyses. We identified psbT-coding minicircles, features previously not found in Symbiodiniaceae. The copy number of F. kawagutii minicircles showed a strong diel dynamics, changing between 3.89 and 34.3 copies/cell and peaking in mid-light period. We found that F. kawagutii minicircles are the shortest among all dinoflagellates examined to date. Besides, the core regions of the minicircles are highly conserved within genus in Symbiodiniaceae. Furthermore, the codon usage bias of the plastid genomes in Heterocapsaceae, Amphidiniaceae, and Prorocentraceae species are greatly influenced by selection pressure, and in Pyrocystaceae, Symbiodiniaceae, Peridiniaceae, and Ceratiaceae species are influenced by both natural selection pressure and mutation pressure, indicating a family-level distinction in codon usage evolution in dinoflagellates. Phylogenetic analysis using 12 plastid-encoded proteins and five nucleus-encoded plastid proteins revealed accelerated evolution trend of both plastid- and nucleus-encoded plastid proteins in peridinin- and fucoxanthin-dinoflagellate plastids compared to plastid proteins of nondinoflagellate algae. These findings shed new light on the structure and evolution of plastid genomes in dinoflagellates, which will facilitate further studies on the evolutionary forcing and function of the diverse dinoflagellate plastids. The accelerated evolution documented here suggests plastid-encoded sequences are potentially useful for resolving closely related dinoflagellates.

Lactobacillus Intestinalis Primes Epithelial Cells to Suppress Colitis-Related Th17 Response by Host-Microbe Retinoic Acid Biosynthesis.

Gut microbiome is integral to the pathogenesis of ulcerative colitis. A novel probiotic Lactobacillus intestinalis (L. intestinalis) exerts a protective effect against dextran sodium sulfate-induced colitis in mice. Based on flow cytometry, colitis-associated Th17 cells are the target of L. intestinalis, which is supported by the lack of protective effects of L. intestinalis in T cell-null Rag1-/- mice or upon anti-IL-17-A antibody-treated mice. Although L. intestinalis exerts no direct effect on T cell differentiation, it decreases C/EBPA-driven gut epithelial SAA1 and SAA2 production, which in turn impairs Th17 cell differentiation. Cometabolism of L. intestinalis ALDH and host ALDH1A2 contributed to elevated biosynthesis of retinoic acid (RA), which accounts for the anti-colitis effect in RAR-α -mediated way. In a cohort of ulcerative colitis patients, it is observed that fecal abundance of L. intestinalis is negatively associated with the C/EBPA-SAA1/2-Th17 axis. Finally, L. intestinalis has a synergistic effect with mesalazine in alleviating murine colitis. In conclusion, L. intestinalis and associated metabolites, RA, have potential therapeutic effects for suppressing colonic inflammation by modulating the crosstalk between intestinal epithelia and immunity.

Characteristics and application in cheese making of newly isolated milk-clotting enzyme from Bacillus megaterium LY114.

Milk-clotting enzyme (MCE) is a crucial active agent in cheese making. It is necessary to find traditional MCE substitutes due to the limited production of traditional MCE (e.g., calf rennet) and increased cheese consumption. Bacillus megaterium strain LY114 with good milk-clotting activity (MCA) (448 SU/mL) and a high MCA/proteolytic activity (PA) ratio (6.0) was isolated and identified from agricultural soil in Laiyang (Shandong, China) through 16S rRNA sequencing of 45 strains. The Bacillus megaterium LY114 MCE had a remarkable specific activity (7532 SU/mg) and displayed a 4.83-fold purification yield with 34.17% recovery through ammonium sulfate fractionation and DEAE-Sepharose Fast Flow. The purified LY114 MCE was a metalloprotease with a molecular weight of 30 kDa. LY114 MCE was stable at pH 5.0-7.0 and temperature <40 °C. The highest MCA appeared at a substrate pH of 5.5 with 30 mM CaCl2. The Michaelis constant (Km) and maximal velocity (Vm) for casein were 0.31 g/L and 14.16 µmol/min, respectively. LY114 MCE preferred to hydrolyze α-casein (α-CN) rather than ß-casein (ß-CN) and had unique α-CN, ß-CN and κ-casein (κ-CN) cleavage sites. LY114 MCE hydrolyzed casein to generate significantly different peptides compared with calf rennet and fungal MCE as determined by SDS-PAGE analysis. Chemical index analysis and sensory evaluation confirmed the usefulness of LY114 MCE in cheese making. LY114 MCE had the potential to be used in dairy processing and enriched traditional MCE substitutes.

Heat-inactivated Bifidobacterium adolescentis ameliorates colon senescence through Paneth-like-cell-mediated stem cell activation.

Declined numbers and weakened functions of intestinal stem cells (ISCs) impair the integrity of the intestinal epithelium during aging. However, the impact of intestinal microbiota on ISCs in this process is unclear. Here, using premature aging mice (telomerase RNA component knockout, Terc-/-), natural aging mice, and in vitro colonoid models, we explore how heat-inactivated Bifidobacterium adolescentis (B. adolescentis) affects colon senescence. We find that B. adolescentis could mitigate colonic senescence-related changes by enhancing intestinal integrity and stimulating the regeneration of Lgr5+ ISCs via Wnt/ß-catenin signaling. Furthermore, we uncover the involvement of Paneth-like cells (PLCs) within the colonic stem-cell-supporting niche in the B. adolescentis-induced ISC regeneration. In addition, we identify soluble polysaccharides (SPS) as potential effective components of B. adolescentis. Overall, our findings reveal the role of heat-inactivated B. adolescentis in maintaining the ISCs regeneration and intestinal barrier, and propose a microbiota target for ameliorating colon senescence.

Prediction models for cardiovascular disease risk among people living with HIV: A systematic review and meta-analysis.

Background: HIV continues to be a major global health issue. The relative risk of cardiovascular disease (CVD) among people living with HIV (PLWH) was 2.16 compared to non-HIV-infections. The prediction of CVD is becoming an important issue in current HIV management. However, there is no consensus on optional CVD risk models for PLWH. Therefore, we aimed to systematically summarize and compare prediction models for CVD risk among PLWH. Methods: Longitudinal studies that developed or validated prediction models for CVD risk among PLWH were systematically searched. Five databases were searched up to January 2022. The quality of the included articles was evaluated by using the Prediction model Risk Of Bias ASsessment Tool (PROBAST). We applied meta-analysis to pool the logit-transformed C-statistics for discrimination performance. Results: Thirteen articles describing 17 models were included. All the included studies had a high risk of bias. In the meta-analysis, the pooled estimated C-statistic was 0.76 (95% CI: 0.72-0.81, I 2 = 84.8%) for the Data collection on Adverse Effects of Anti-HIV Drugs Study risk equation (D:A:D) (2010), 0.75 (95% CI: 0.70-0.79, I 2 = 82.4%) for the D:A:D (2010) 10-year risk version, 0.77 (95% CI: 0.74-0.80, I 2 = 82.2%) for the full D:A:D (2016) model, 0.74 (95% CI: 0.68-0.79, I 2 = 86.2%) for the reduced D:A:D (2016) model, 0.71 (95% CI: 0.61-0.79, I 2 = 87.9%) for the Framingham Risk Score (FRS) for coronary heart disease (CHD) (1998), 0.74 (95% CI: 0.70-0.78, I 2 = 87.8%) for the FRS CVD model (2008), 0.72 (95% CI: 0.67-0.76, I 2 = 75.0%) for the pooled cohort equations of the American Heart Society/ American score (PCE), and 0.67 (95% CI: 0.56-0.77, I 2 = 51.3%) for the Systematic COronary Risk Evaluation (SCORE). In the subgroup analysis, the discrimination of PCE was significantly better in the group aged ≤40 years than in the group aged 40-45 years (P = 0.024) and the group aged ≥45 years (P = 0.010). No models were developed or validated in Sub-Saharan Africa and the Asia region. Conclusions: The full D:A:D (2016) model performed the best in terms of discrimination, followed by the D:A:D (2010) and PCE. However, there were no significant differences between any of the model pairings. Specific CVD risk models for older PLWH and for PLWH in Sub-Saharan Africa and the Asia region should be established.Systematic Review Registration: PROSPERO CRD42022322024.

Barriers and facilitators to maintaining a high level of polypharmacy adherence in people living with HIV: A scoping review.

Objectives: With the prolongation of life span and increasing incidence of comorbidities, polypharmacy has become a challenge for people living with HIV/AIDS (PLWH). This review aimed to identify barriers and facilitators to maintaining a high level of polypharmacy adherence in people living with HIV/AIDS. Methods: Nine electronic databases were searched for studies from 1996 to October 2021. Studies were included if they were conducted with adults living with HIV/AIDS and reported barriers and facilitators to maintaining a high level of polypharmacy adherence. This review presents a conceptual framework model to help understand the barriers and facilitators. Results: Twenty-nine studies were included. The majority of publications were observational studies. Eighty specific factors were identified and further divided into five categories, including individual factors, treatment-related factors, condition-related factors, healthcare provider-related factors, and socioeconomic factors, based on the multidimensional adherence model (MAM). Conclusion: Eighty factors associated with polypharmacy adherence among people living with HIV/AIDS were identified and grouped into five major categories. Healthcare providers can make decisions based on the five categories of relevant factors described in this paper when developing interventions to enhance polypharmacy adherence. It is recommended that medications be evaluated separately and that an overall medication evaluation be conducted at the same time to prevent inappropriate polypharmacy use.

PLK1 protects intestinal barrier function in sepsis: A translational research.

BACKGROUND: Sepsis and its related complications are very challenging in the intensive care unit, among which intestinal barrier injury is a general manifestation. Polo-like kinase 1 (PLK1) is widely studied in cancer, while its role in sepsis is poorly understood. In this study, the efficiency of PLK1 as a marker of intestinal barrier function as well as a predictor of mortality in sepsis was evaluated. METHODS: The level of serum PLK1 was measured in septic patients (n = 51) and controls (n = 20); subsequently, its correlation with serum diamine oxidase (DAO), d-lactate, and endotoxin levels and its ability topredict mortality were analysed. The survival rate and barrier injury degree were also assessed in septic mice. RESULTS: Serum PLK1 levels were elevated in septic patients, were negatively correlated with serum DAO, d-lactate, and endotoxin levels, and had a high predictive value for 28-day mortality in patients. The serum PLK1 level in non-survivors was lower. The expression of PLK1 in the intestine was decreased in septic mice, and overexpression or inhibition of PLK1 alleviated or aggravated intestinal barrier injury, respectively, as evaluated by Chiu's score, serum levels of DAO and d-lactate, and expression of tight junction proteins. Overexpressing PLK1 also decreased the 72-hour death rate of septic mice. Further study also revealed the negative correlation of PLK1 and IL-6 in patients, and increasing or interfering with PLK1 expression reduced or increased the serum IL-6 level in mice. CONCLUSIONS: PLK1 plays a critical role in intestinal barrier function during sepsis, providing a novel perspective for sepsis therapy in the clinic.

An evaluation of aging measures: from biomarkers to clocks.

With the increasing number of aged population and growing burden of healthy aging demands, a rational standard for evaluation aging is in urgent need. The advancement of medical testing technology and the prospering of artificial intelligence make it possible to evaluate the biological status of aging from a more comprehensive view. In this review, we introduced common aging biomarkers and concluded several famous aging clocks. Aging biomarkers reflect changes in the organism at a molecular or cellular level over time while aging clocks tend to be more of a generalization of the overall state of the organism. We expect to construct a framework for aging evaluation measurement from both micro and macro perspectives. Especially, population-specific aging clocks and multi-omics aging clocks may better fit the demands to evaluate aging in a comprehensive and multidimensional manner and make a detailed classification to represent different aging rates at tissue/organ levels. This framework will promisingly provide a crucial basis for disease diagnosis and intervention assessment in geroscience.

Distribution and characterization of extrachromosomal circular DNA in colorectal cancer.

Extrachromosomal circular DNA (eccDNA) has been shown to play an important role in the amplification of tumor genes and the maintenance of intra-tumor genetic heterogeneity, although its complex functional mechanism still remains to be elucidated. As the top three common malignancies in the world, colorectal cancer (CRC) has been threatening human life and health, whose tumorigenesis and development may have elusive connection with eccDNAs. Here, we described the extensive distribution of eccDNAs in the CRC tissues using Circle-seq, which range in size from hundreds to thousands of base pairs (bp). The distribution in tumor tissues had aggregation and tendency compared with random in tumor-adjacent tissues, accompanied with smaller and more regular circle lengths. After sequencing and restoring, we found that the shedding sites of eccDNAs in CRC had similar tendency in chromosome distribution, and focused on tumor-associated genes. Meanwhile, we combined RNA sequencing to explore the correlation of eccDNA differential expression in the gene transcription and signaling pathways, confirming a connection between eccDNA and RNA somewhere. Subsequently, we validated eccDNAs in CRC cell lines and the potential consistency of the junction sites of eccDNAs in CRC tissues and cell lines. Using fragments of the cationic amino acid transporter SLC7A1 to synthesize eccDNAs, we discovered the role of eccDNAs in different regions within the gene.

Lactobacillus johnsonii alleviates colitis by TLR1/2-STAT3 mediated CD206+ macrophagesIL-10 activation.

Imbalance of gut microbiota homeostasis is related to the occurrence of ulcerative colitis (UC), and probiotics are thought to modulate immune microenvironment and repair barrier function. Here, in order to reveal the interaction between UC and gut microbiota, we screened a new probiotic strain by 16S rRNA sequencing from Dextran Sulfate Sodium (DSS)-induced colitis mice, and explored the mechanism and clinical relevance. Lactobacillus johnsonii (L. johnsonii), as a potential anti-inflammatory bacterium was decreased colonization in colitis mice. Gavage L. johnsonii could alleviate colitis by specifically increasing the proportion of intestinal macrophages and the secretion of Il-10 with macrophages depleted model and in Il10-/- mice. We identified this subset of immune cells activated by L. johnsonii as CD206+ macrophagesIL-10. Mechanistically, L. johnsonii supplementation enhanced the mobilization of CD206+ macrophagesIL-10 through the activation of STAT3 in vivo and in vitro. In addition, we revealed that TLR1/2 was essential for the activation of STAT3 and the recognition of L. johnsonii by macrophages. Clinically, there was positive correlation between the abundance of L. johnsonii and the expression level of MRC1, IL10 and TLR1/2 in UC tissues. L. johnsonii could activate native macrophages into CD206+ macrophages and release IL-10 through TLR1/2-STAT3 pathway to relieve experimental colitis. L. johnsonii may serve as an immunomodulator and anti-inflammatory therapeutic target for UC.

HOXC10 indicates poor survival outcome in gastric cancer and promotes G1/S cell cycle transition through transcriptional repression of p21.

Homeobox (HOX) genes encode proteins that function as transcription factors during embryogenesis and tumorigenesis. We have previously reported upregulation of HOXC10 in gastric cancer (GC) tissues using cDNA microarray analysis. Though the functional role of HOXC10 in GC has been briefly reported, its specific mechanism is not fully understood. We analyzed the expression of HOXC10 in GC tissues, as well as its correlation with the survival outcome. By in vitro and in vivo assays, we further investigated the role of HOXC10 on cell cycle control and proliferation. Finally, we screened potential downstream targets of HOXC10 by cDNA microarray and explored the role of HOXC10 in p21 transcriptional repression through a dual luciferase reporter and chromatin immunoprecipitation. We illustrated the upregulation of HOXC10 in GC tissues and high HOXC10 expression related to poor survival outcome. Multivariable COX regression analysis showed that HOXC10 was an independent predictor of survival (HR=1.863; 95% CI: 1.076-3.225). Functionally, HOXC10 could promote GC cell proliferation and tumor growth in nude mice. Overexpression of HOXC10 accelerated G1/S cell cycle transition, whereas knocking down HOXC10 induced cell cycle arrest at the G1 phase. Critical factors of G1/S cell cycle transition including p21, CDK2, and c-Myc, were regulated by HOXC10. Importantly, an inverse correlation between p21 and HOXC10 expression in GC cell lines and tissues was observed. HOXC10 could directly bind to the promoter region of p21 and repress its transcriptional activity. Collectively, we identified HOXC10 as a predictor of poor prognosis in GC patients, and a novel transcriptional regulator of p21 in the G1/S cell cycle transition.

Cardiovascular adverse events induced by immune checkpoint inhibitors: A real world study from 2018 to 2022.

Background: The reported rate of cardiovascular adverse events (CAE) caused by immune checkpoint inhibitors (ICI) is low but potentially fatal. Assess the risk of CAE in cancer patients and compare the incidence of CAE between Chinese developed ICIs and imported ICIs. Methods: A retrospective analysis was performed on cancer patients treated with ICI for at least four cycles in the Second Affiliated Hospital of Dalian Medical University from January 2018 to March 2022. Baseline characteristics, physiological and biochemical values, electrocardiographic and echocardiographic findings were compared between patients with and without CAE. Results: Among 495 patients treated with ICIs, CAEs occurred in 64 patients (12.93%). The median time to the event was 105 days (61-202). The patients with low neutrophil-to-lymphocyte ratio (L-NLR) were significantly associated with the risk of developing CAE (hazard ratio HR 3.64, 95% confidence ratio CI 1.86-7.15, P = 0.000). Patients with higher comorbidity burden significantly increased the risk of developing CAE (HR 1.30, 95% CI 1.05-1.61, P = 0.014). Those who received a combination of ICI and vascular endothelial growth factor receptor (VEGFR) inhibitors (HR 2.57, 95% CI 1.37-4.84, P = 0.003) or thoracic radiation therapy (HR 32.93, 95% CI 8.81-123.14, P = 0.000) were at a significantly increased risk of developing CAE. Compared to baseline values, creatine kinase is -oenzymes (CK-MB) (95% CI -9.73 to -2.20, P = 0.003) and cardiac troponin I (cTnI) (95% CI -1.06 to -0.06, P = 0.028) were elevated, and the QTc interval prolonged (95% CI -27.07 to -6.49, P = 0.002). Using nivolumab as a control, there was no difference in CAE risk among the eight ICIs investigated. However, the results of the propensity matching showed that programmed death-ligand 1 (PD-L1) inhibitors had lower CAE occurrence compared with programmed cell death protein 1 (PD-1) inhibitors (adjusted HR = 0.38, P = 0.045). Conclusion: Patients who received concurrent VEGFR inhibitors and ICIs had a history of thoracic radiation therapy, L-NLR, and higher comorbidity burden had an increased risk of CAEs. Elevated cTnI, CK-MB, and QTc, can be used to monitor CAEs. There was no significant difference in CAE risks between Chinese domestic and imported ICIs. PD-L1 inhibitors had lower CAE occurrence than PD-1 inhibitors.

Common Pathogenetic Mechanisms Underlying Aging and Tumor and Means of Interventions.

Recently, there has been an increase in the incidence of malignant tumors among the older population. Moreover, there is an association between aging and cancer. During the process of senescence, the human body suffers from a series of imbalances, which have been shown to further accelerate aging, trigger tumorigenesis, and facilitate cancer progression. Therefore, exploring the junctions of aging and cancer and searching for novel methods to restore the junctions is of great importance to intervene against aging-related cancers. In this review, we have identified the underlying pathogenetic mechanisms of aging-related cancers by comparing alterations in the human body caused by aging and the factors that trigger cancers. We found that the common mechanisms of aging and cancer include cellular senescence, alterations in proteostasis, microbiota disorders (decreased probiotics and increased pernicious bacteria), persistent chronic inflammation, extensive immunosenescence, inordinate energy metabolism, altered material metabolism, endocrine disorders, altered genetic expression, and epigenetic modification. Furthermore, we have proposed that aging and cancer have common means of intervention, including novel uses of common medicine (metformin, resveratrol, and rapamycin), dietary restriction, and artificial microbiota intervention or selectively replenishing scarce metabolites. In addition, we have summarized the research progress of each intervention and revealed their bidirectional effects on cancer progression to compare their reliability and feasibility. Therefore, the study findings provide vital information for advanced research studies on age-related cancers. However, there is a need for further optimization of the described methods and more suitable methods for complicated clinical practices. In conclusion, targeting aging may have potential therapeutic effects on aging-related cancers.