Cardiovascular toxicity with CTLA-4 inhibitors in cancer patients: A meta-analysis.

Background: With the emergence of cytotoxic T lymphocyte-associated protein-4 (CTLA-4) inhibitors, the outcomes of patients with malignant tumors have improved significantly. However, the incidence of cardiovascular adverse events has also increased, which can affect tumor treatment. In this study, we evaluated the incidence and severity of adverse cardiovascular events caused by CTLA-4 inhibitors by analyzing reported trials that involved CTLA-4 inhibitor therapy. Methods: Randomized clinical trials published in English from January 1, 2013, to November 30, 2022, were searched using the Cochrane Library and PubMed databases. All included trials examined all grade and grades 3-5 cardiac and vascular adverse events. These involved comparisons of CTLA-4 inhibitors to placebo, CTLA-4 inhibitors plus chemotherapy to chemotherapy alone, CTLA-4 inhibitors combined with PD-1/PD-L1 inhibitors to PD-1/PD-L1 inhibitors alone, and CTLA-4 inhibitors plus target agent to PD-1/PD-L1 inhibitors plus target agent. The odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel method. Results: Overall, 20 trials were included. CTLA-4 inhibitors significantly increased the incidence of all-grade cardiovascular toxicity (OR = 1.33, 95% CI: 1.00-1.75, p = 0.05). The incidence of all-grade cardiovascular toxicity increased in malignant tumor patients who received single-agent CTLA-4 inhibitors (OR = 1.73, 95% CI: 1.13-2.65, p = 0.01), as well as the incidence rate of grades 3-5 cardiovascular adverse events (OR = 2.00, 95% CI: 1.08-3.70, p = 0.03). Compared with the non-CTLA-4 inhibitor group, CTLA-4 inhibitors plus chemotherapy, PD-1/PD-L1 inhibitors, or target agent did not significantly affect the incidence of cardiac and vascular toxicity. The incidence of grades 3-5 cardiac failure, hypertension, pericardial effusion, myocarditis, and atrial fibrillation were much higher among patients exposed to CTLA-4 inhibitor, but the data were not statistically significant. Conclusion: Our findings suggest that the incidence rate of all cardiovascular toxicity and severe cardiovascular toxicity increased in patients who were administered CTLA-4 inhibitors. In addition, the risk of serious cardiovascular toxic events was independent of the type of adverse event. From these results, physicians should assess the benefits and risks of CTLA-4 inhibitors when treating malignancies.

S100 protein family: Emerging role and mechanism in digestive tract cancer (Review).

Digestive tract cancer is one of the most common types of cancers globally, with ~4.8 million new cases and 3.4 million cancer­associated deaths in 2018, accounting for 26% of cancer incidence and 35% of cancer­related deaths worldwide. S100 protein family is involved in regulating cancer cell proliferation, angiogenesis, epithelial­mesenchymal transition (EMT), metastasis, metabolism and immune microenvironment homeostasis. The critical role of S100 protein family in digestive tract cancer involves complicated mechanisms, such as cancer stemness remodeling, anaerobic glycolysis regulation, tumor­associated macrophage differentiation and EMT. The present study systematically reviewed published studies on the compositions, function and the underlying molecular mechanisms of the S100 family, as well as guidance for diagnosis, treatment and prognosis of digestive tract cancer. Systematic review of the roles and underlying molecular mechanisms of S100 protein family may provide new insight into exploring potential cancer biomarkers and the optimized therapeutic strategies for digestive tract cancer.

Muscle quality index and cardiovascular disease among US population-findings from NHANES 2011-2014.

BACKGROUND AND OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. However, current evidence on the association between muscle quality and CVD is limited. This study investigates the potential association between the muscle quality index (MQI) and the prevalence of CVD and CVD-related mortality. METHODS: Participants were selected from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Data on mortality and causes of death were obtained from the National Death Index (NDI) records through December 31, 2019. Statistical analysis used in this study, including weighted multivariable linear and logistic regression, cox regression and Kaplan-Meier (K-M) analysis, to estimate the association between MQI and all-cause mortality as well as CVD mortality. In addition, subgroup analysis was used to estimate the association between MQI and CVD subtypes, such as heart attack, coronary heart disease, angina, congestive heart failure, and stroke. RESULTS: A total of 5,053 participants were included in the final analysis. Weighted multivariable linear regression models revealed that a lower MQI.total level was independently associated with an increased risk of CVD development in model 3, with t value =-3.48, 95%CI: (-0.24, -0.06), P = 0.002. During 5,053 person-years of 6.92 years of follow-up, there were 29 deaths from CVD. Still, the association between MQI.total and CVD mortality, as well as all-cause mortality did not reach statistical significance in the fully adjusted model (HR = 0.58, 95% CI: 0.21-1.62, P = 0.30; HR = 0.91, 95% CI:0.65,1.28, P = 0.59, respectively). Subgroup analysis confirmed that MQI.total was negatively associated with congestive heart failure (OR = 0.35, 95% CI = 0.18,0.68, P = 0.01). CONCLUSION: This study highlights the potential of MQI as a measure of muscle quality, its negative correlation with congestive heart failure (CHF). However, MQI was not very useful for predicting the health outcomes such as CVD and mortality. Therefore, more attention should be paid to the early recognition of muscle weakness progression in CHF. Further studies are needed to explore more effective indicator to evaluate the association between muscle quality and health outcomes.

A normative model of brain responses to social scenarios reflects the maturity of children and adolescents' social-emotional abilities.

The rapid brain maturation in childhood and adolescence accompanies the development of socio-emotional functioning. However, it is unclear how the maturation of the neural activity drives the development of socio-emotional functioning and individual differences. This study aimed to reflect the age dependence of inter-individual differences in brain responses to socio-emotional scenarios and to develop naturalistic imaging indicators to assess the maturity of socio-emotional ability at the individual level. Using three independent naturalistic imaging datasets containing healthy participants (n = 111, 21 and 122), we found and validated that age-modulated inter-individual concordance of brain responses to socio-emotional movies in specific brain regions. The similarity of an individual's brain response to the average response of older participants was defined as response typicality, which predicted an individual's emotion regulation strategies in adolescence and theory of mind (ToM) in childhood. Its predictive power was not superseded by age, sex, cognitive performance or executive function. We further showed that the movie's valence and arousal ratings grounded the response typicality. The findings highlight that forming typical brain response patterns may be a neural phenotype underlying the maturation of socio-emotional ability. The proposed response typicality represents a neuroimaging approach to measure individuals' maturity of cognitive reappraisal and ToM.

Identification of a Self-Assembling Small-Molecule Cancer Vaccine Adjuvant with an Improved Toxicity Profile.

Protein or peptide cancer vaccines usually include immune potentiators, so-called adjuvants. However, it remains challenging to identify structurally simple, chemically accessible synthetic molecules that are effective and safe as vaccine adjuvant. Here, we present cholicamideß (6), a self-assembling small-molecule vaccine adjuvant with an improved toxicity profile and proven efficacy in vivo. We demonstrate that cholicamideß (6), which is less cytotoxic than its parent compound, forms virus-like particles to potently activate dendritic cells with the concomitant secretion of cytokines. When combined with a peptide antigen, cholicamideß (6) potentiated the antigen presentation on dendritic cells to induce antigen-specific T cells. As a therapeutic cancer vaccine adjuvant in mice, a mixture of cholicamideß (6) and a peptide antigen protected mice from the challenges of malignant cancer cells without overt toxicity. Cholicamideß (6) may offer a translational opportunity as an unprecedented class of small-molecule cancer vaccine adjuvants.

Prevalence and incidence of heart failure among community in China during a three-year follow-up.

BACKGROUND: Epidemiological surveys on heart failure (HF) in Chinese community are relatively lacking. This study aimed to estimate the prevalence and incidence of HF among community residents in southern China. METHODS: Baseline data of this prospective study was collected from 2015 to 2017 among 12,013 permanent residents aged ≥ 35 years in Guangzhou, China. The same survey process was carried out for individuals aged ≥ 65 years after a three-year follow-up. RESULTS: The overall prevalence of HF in community residents aged ≥ 35 years was 1.06%. Male had significantly higher risk of HF prevalence [odds ratio (OR) = 1.50, P = 0.027]. The gender-adjusted risk of HF was 1.48 times higher per 10 years aging. HF prevalence was statistically associated with atrial fibrillation, valvular heart disease, hypertension and chronic obstructive pulmonary disease after adjusting for age and gender (OR = 8.30, 5.17, 1.11, 2.28, respectively; all P < 0.05). HF incidence in individuals aged ≥ 65 years were 847 per 100,000 person-years. Baseline atrial fibrillation, valvular heart disease, and diabetes mellitus were risk factors for HF incidence for individuals aged ≥ 65 years adjusting for age and gender (OR = 5.05, 3.99, 2.11, respectively; all P < 0.05). Besides, residents with new-onset atrial fibrillation and myocardial infarction were at significantly higher risk of progression to HF (OR = 14.41, 8.54, respectively; all P < 0.05). CONCLUSIONS: Both pre-existing and new-onset cardiovascular diseases were associated with HF incidence in southern China. Management of related cardiovascular diseases may be helpful to reduce the incidence of HF.

High-Power, Short-Duration Ablation under the Guidance of Relatively Low Ablation Index Values for Paroxysmal Atrial Fibrillation: Long-Term Outcomes and Characteristics of Recurrent Atrial Arrhythmias.

OBJECTIVE: The purpose of this study was to evaluate the difference in effectiveness and safety of high-power, short-duration (HPSD) radiofrequency catheter ablation (RFA) guided by relatively low ablation index (AI) values and conventional RFA in paroxysmal atrial fibrillation (PAF) patients. METHODS: The HPSD RFA strategy (40-50 W, AI 350-400 for anterior, 320-350 for posterior wall; n = 547) was compared with the conventional RFA strategy (25-40 W, without AI; n = 396) in PAF patients who underwent their first ablation. Propensity-score matching analyses were used to compare the outcomes of the two groups while controlling for confounders. RESULTS: After using propensity-score matching analysis, the HPSD group showed a higher early recurrence rate (22.727% vs. 13.636%, p = 0.003), similar late recurrence rate, and comparable safety (p = 0.604) compared with the conventional group. For late recurrent atrial arrhythmia types, the rate of regular atrial tachycardia was significantly higher in the HPSD group (p = 0.013). Additionally, the rate of chronic pulmonary vein reconnection and non-pulmonary vein triggers during repeat procedures was similar in both groups. CONCLUSIONS: For PAF patients, compared with the conventional RFA strategy, the HPSD RFA strategy at relatively low AI settings had a higher early recurrence rate, similar long-term success rate, and comparable safety.

Aberrant functional connectivity of the bed nucleus of the stria terminalis and its age dependence in children and adolescents with social anxiety disorder.

BACKGROUND: Social anxiety disorder (SAD) is a prevalent and impairing mental disorder among children and adolescents. The bed nucleus of the stria terminalis (BNST) plays a critical role in anxiety disorders, including valence surveillance and hypervigilance for potential threats. However, the role of BNST and its related functional network in children and adolescents with SAD has not been fully investigated. This study examined the aberration of BNST's functional connectivity and its age dependence in adolescents with SAD. METHODS: Using a sample of 75 SAD patients and 75 healthy controls (HCs) children aged 9-18 years old, we delineated the group-by-age interaction of BNST-seeded functional connectivity (FC) during resting state and movie-watching. The relationships between BNST-seeded FC and clinical scores were also examined. RESULTS: During movie viewing, the FC between the right BNST and the left amygdala, bilateral posterior cingulate cortex (PCC), bilateral superior temporal cortex, and right pericalcarine cortex showed a diagnostic group-by-age interaction. Compared to HCs, SAD patients showed a significant enhancement of the above FC at younger ages. Meanwhile, they showed an age-dependent decrease in FC between the right BNST and left amygdala. Furthermore, for SAD patients, FC between the right BNST and left amygdala during movie viewing was positively correlated with separation anxiety scores. CONCLUSIONS: The right BNST plays an essential role in the aberrant brain functioning in children and adolescents with SAD. The atypicality of BNST's FC has remarkable age dependence in SAD, suggesting an association of SAD with neurodevelopmental traits.

Age-dependent alterations in the coordinated development of subcortical regions in adolescents with social anxiety disorder.

Subcortical brain regions play essential roles in the pathology of social anxiety disorder (SAD). While adolescence is the peak period of SAD, the relationships between altered development of the subcortical regions during this period and SAD are still unclear. This study investigated the age-dependent alterations in structural co-variance among subcortical regions and between subcortical and cortical regions, aiming to reflect aberrant coordination during development in the adolescent with SAD. High-resolution T1-weighted images were obtained from 76 adolescents with SAD and 67 healthy controls (HC), ranging from 11 to 17.9 years. Symptom severity was evaluated with the Social Anxiety Scale for Children (SASC) and the Depression Self Rating Scale for Children (DSRS-C). Structural co-variance and sliding age-window analyses were used to detect age-dependent group differences in inter-regional coordination patterns among subcortical regions and between subcortical and cortical regions. The volume of the striatum significantly correlated with SAD symptom severity. The SAD group exhibited significantly enhanced structural co-variance among key regions of the striatum (putamen and caudate). While the co-variance decreased with age in healthy adolescents, the co-variance in SAD adolescents stayed high, leading to more apparent group differences in middle adolescence. Moreover, the striatum's mean structural co-variance with cortical regions decreased with age in HC but increased with age in SAD. Adolescents with SAD suffer aberrant developmental coordination among the key regions of the striatum and between the striatum and cortical regions. The degree of incoordination is age-dependent, which may represent a neurodevelopmental trait of SAD.

Self-assembling small-molecule adjuvants as antigen nano-carriers.

The effective co-delivery of antigens and immune potentiators (adjuvants) and the high degree of antigen presentation have been two major challenges in the development of subunit vaccines. Here, we address these issues by conjugating peptide antigens with cholicamide, a self-assembling small molecule adjuvant. Co-assemblies of the conjugates and cholicamide achieved high levels of both cytokine induction and MHC class II peptide presentation.

Comparison of Effectiveness and Safety between High-Power Short-Duration Ablation and Conventional Ablation for Atrial Fibrillation: A Systematic Review and Meta-Analysis.

Aim: We aimed to evaluate the effectiveness and safety between high-power short-duration (HPSD) radiofrequency ablation (RFA) and conventional RFA in patients with atrial fibrillation (AF). Methods: Studies comparing HPSD and traditional applications in patients undergoing initial catheter ablation for atrial fibrillation from inception through December 2021 were searched on Pubmed, Medline, Cochrane, and Clinicaltrials.gov. Results: The meta-analysis included seventeen studies with a total of 4934 patients. HPSD group decreased procedure duration (mean difference (MD) -38.28 min, P < 0.001), RF duration (MD -20.51 min, P < 0.001), fluoroscopy duration (MD -5.19 min, P < 0.001), and acute pulmonary vein reconnection (Odds ratio (OR) 0.40, P < 0.001), while improving the freedom from atrial arrhythmia at one year (OR 1.48, 95% confidence interval (CI) 1.12-1.94, P=0.005) and rates of first-pass isolation (OR 8.92, P=0.001). Compared with the conventional group, freedom from atrial arrhythmia at one-year follow-up was higher in the HPSD group without the guidance of AI/LSI (OR 1.66, P=0.01) and studies with a power setting of 40-50 W (OR 1.93, P=0.002). Nevertheless, the two groups had similar effectiveness with a power setting of 50 W in the HPSD RFA (OR 1.10, P=0.52). There was no difference in complications between the two groups (P=0.71). Conclusion: HPSD RFA was associated with shorter procedure duration, higher freedom from atrial arrhythmia, and comparable safety compared to conventional RFA.

Comparing the Effectiveness of Brain Structural Imaging, Resting-state fMRI, and Naturalistic fMRI in Recognizing Social Anxiety Disorder in Children and Adolescents.

Social anxiety disorder (SAD) is a common anxiety disorder in childhood and adolescence. Studies on SAD in adults have reported both structural and functional aberrancies of the brain at the group level. However, evidence has shown differences in anxiety-related brain abnormalities between adolescents and adults. Since children and adolescents can afford limited scan time, optimizing the scan tasks is essential for SAD research in children and adolescents. Thus, we need to address whether brain structure, resting-state fMRI, and naturalistic imaging enable individualized identification of SAD in children and adolescents, which measurement is more effective, and whether pooling multi-modal features can improve the identification of SAD. We comprehensively addressed these questions by building machine learning models based on parcel-wise brain features. We found that naturalistic fMRI yielded higher classification accuracy (69.17%) than the other modalities and the classification performance showed dependence on the contents of the movie. The classification models also identified contributing brain regions, some of which exhibited correlations with the symptoms scores of SAD. However, pooling brain features from the three modalities did not help enhance the classification accuracy. These results support the application of carefully designed naturalistic imaging in recognizing children and adolescents at risk of SAD.

Discovery of Self-Assembling Small Molecules as Vaccine Adjuvants.

Immune potentiators, termed adjuvants, trigger early innate immune responses to ensure the generation of robust and long-lasting adaptive immune responses of vaccines. Presented here is a study that takes advantage of a self-assembling small-molecule library for the development of a novel vaccine adjuvant. Cell-based screening of the library and subsequent structural optimization led to the discovery of a simple, chemically tractable deoxycholate derivative (molecule 6, also named cholicamide) whose well-defined nanoassembly potently elicits innate immune responses in macrophages and dendritic cells. Functional and mechanistic analyses indicate that the virus-like assembly enters the cells and stimulates the innate immune response through Toll-like receptor 7 (TLR7), an endosomal TLR that detects single-stranded viral RNA. As an influenza vaccine adjuvant in mice, molecule 6 was as potent as Alum, a clinically used adjuvant. The studies described here pave the way for a new approach to discovering and designing self-assembling small-molecule adjuvants against pathogens, including emerging viruses.

Discovery of 4-Aminoquinoline-3-carboxamide Derivatives as Potent Reversible Bruton's Tyrosine Kinase Inhibitors for the Treatment of Rheumatoid Arthritis.

A structure-hopping strategy was applied to discover a series of novel 4-aminoquinoline-3-carboxamide derivatives as potent, reversible BTK inhibitors. Compared to the previously described cinnoline scaffold compounds, the 4-aminoquinoline analogues showed significantly improved drug-like properties, especially in their aqueous solubility. The most potent compound, 25, displayed a stronger inhibitory effect on both BTKWT (IC50 = 5.3 nM) and BTKC481S (IC50 = 39 nM). In a rodent collagen-induced arthritis model, compound 25 efficiently reduced paw swelling without a loss in body weight. On the basis of potency, drug-like properties, stability, and noncovalent mode of inhibition, our representative inhibitors could have a promising profile to be treatments for a wide range of autoimmune diseases.

Design and synthesis of substituted pyrido[3,2-d]-1,2,3-triazines as potential Pim-1 inhibitors.

A novel series of substituted pyrido[3,2-d]-1,2,3-triazines were designed and synthesized as Pim-1 inhibitors through scaffold hopping. Most of the derivatives showed potent in vitro Pim-1 inhibitory activities and anti-proliferative effects toward prostate cancer cells. Among them, 6b, 6h and 6m showed the best Pim-1 inhibitory activity with IC50 values of 0.69, 0.60 and 0.80 µM, respectively. Furthermore, compounds 6b, 6i, 6j and 6m showed strong inhibitory activity to human prostate cancer LNcap and PC-3 cell lines with IC50 values at low micromolar level. Structure-activity relationship analysis revealed that appropriate substitutions at C-6 positions contributed to the kinase inhibition and antiproliferative effects. Moreover, western blot assay suggested that 6j could decrease the levels of p-BAD and p-4E-BP1 in a dose-dependent manner in PC-3 cells. Docking studies showed that 3-N of the scaffold formed a hydrogen bond with Lys67, aromatic 4-aniline formed a key π-π stack with Phe49. Taken together, this study might provide the first sight for developing the pyrido[3,2-d]-1,2,3-triazine scaffold as novel Pim-1 inhibitors.

[Design, synthesis and antiproliferative activity in cancer cells of novel 18ß-glycyrrhetinic acid derivatives].

To investigate the anticancer effects of ring C in 18ß-glycyrrhetinic acid (GA), a series of GA derivatives featured with 9(11)-ene moiety in ring C were designed and synthesized. The structures were confirmed by IR, LC-MS and 1H NMR. Their inhibitory effects towards human prostate cancer PC-3 and leukemia HL-60 cell lines were determined. Most of the derivatives displayed stronger antiproliferative activities than GA. Particularly, compound 14 showed promising anticancer activity with the GI50 values of 4.48 µmol · L(-1) and 1.2 µmol · L(-1) against PC-3 and HL-60 cells respectively, which is worth further study.