Differential NEUROD1, ASCL1, and POU2F3 Expression Defines Molecular Subsets of Bladder Small Cell/Neuroendocrine Carcinoma with Prognostic Implications.

Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and pro-metastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell neuroendocrine carcinomas (LCNEC) assembled in tissue microarrays. Co-expression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified five distinct molecular subtypes in bladder SMC based on expression of ASCL1, NEUROD1 and POU2F3: ASCL1+/NEUROD1- (n=33; 34%), ASCL1-/NEUROD1+ (n=21; 21%), ASCL1+/NEUROD1+ (n=17; 17%), POU2F3+ (n=22, 22%), and ASCL1-/NEUROD1-/POU2F3- (n=5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (p < 0.001). DLL3 expression was high in both SMC (n=72, 82%) and LCNEC (n=11, 85%). YAP1 expression was enriched in non- neuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (p<0.05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1 and POU2F3. POU2F3 expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter recurrence-free and overall survival. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.

Immune checkpoint markers and tumour mutation burden in Wilms tumour: a study of 59 cases.

Wilms tumour (WT) is the most common renal tumour in children, and studies of immune checkpoint inhibitors (ICIs) treatment and markers are limited in number. In this study we investigated the ICIs' related immune landscape by examining the expression of PD-L1, PD-1, CD8 and DNA mismatch repair (MMR) proteins by immunohistochemistry (IHC), tumour mutation burden (TMB), and correlations with histology and clinical outcome. Positive PD-L1 (SP263) expression was defined as modified combined positive score (CPS) ≥1. A total of 59 WTs (from 2000 to 2017), including eight (14.0%) with anaplasia, from 46 patients were analysed (45 primary and 14 metastatic). Thirteen WTs (13/59, 22%) were positive for PD-L1 (8 primary, 5 metastatic; CPS 1.11-3.42). Positive PD-L1 expression was associated with diffuse anaplasia (p<0.05) and significantly shorter progression-free survival (p<0.05) among WTs with favourable histology (n=39). CD8+ lymphocytes were present in all analysed WTs. A subset of CD8+ cells co-expressed PD-1, which was associated with favourable histology and treatment. MMR IHC stains identified two (2/18, 11%) WTs with isolated PMS2 loss. All six WTs analysed for TMB showed low mutation burden. We found CD8+ lymphocytes in all analysed WTs and identified a fraction of WT (17.8% of primary and 35.8% of metastatic) with positive PD-L1 CPS, suggesting potential response to ICIs in some patients.

A Comprehensive Clinicopathologic and Molecular Reappraisal of GLI1-altered Mesenchymal Tumors with Pooled Outcome Analysis Showing Poor Survival in GLI1- amplified Versus GLI1-rearranged Tumors.

GLI1-altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1-altered mesenchymal neoplasms to date, including 23 GLI1-amplified and 15 GLI1-rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1-rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1-amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1-amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1-amplified tumors. GLI1-amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1-amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1-rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1-amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1-rearranged group. Despite comparable progression rates, GLI1-amplified tumors had a shorter median progression-free survival compared with GLI1-rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1-altered mesenchymal tumors.

Glycated Hemoglobin Variability Is Associated With Adverse Outcomes in Patients With Heart Failure Irrespective of Diabetic Status.

BACKGROUND: The effect of glycated hemoglobin (HbA1c) variability on adverse outcomes in patients with heart failure (HF) is unclear. We aim to investigate the predictive value of HbA1c variability on the risks of all-cause death and HF rehospitalization in patients with HF irrespective of their diabetic status. METHODS AND RESULTS: Using a previously validated territory-wide clinical data registry, HbA1c variability was assessed by average successive variability (ASV) or SD of all HbA1c measurements after HF diagnosis. Multivariable Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) and its corresponding 95% CI. A total of 65 950 patients with HF were included in the study. Over a median follow-up of 6.7 (interquartile range, 4.0-10.6) years, 34 508 patients died and 52 446 required HF rehospitalization. Every unit increment of variability in HbA1c was significantly associated with higher HF rehospitalization (HR ASV, 1.20 [95% CI, 1.18-1.23]) and all-cause death (HR ASV, 1.50 [95% CI, 1.47-1.53]). Diabetes significantly modified the association between HbA1c variability and outcomes (Pinteraction<0.001). HbA1c variability in patients with HF without diabetes conferred a higher risk of rehospitalization (HR ASV, 1.92 [95% CI, 1.70-2.17] versus HR ASV, 1.19 [95% CI, 1.17-1.21]), and all-cause death (HR ASV, 3.90 [95% CI, 3.31-4.61] versus HR ASV, 1.47 [95% CI, 1.43-1.50] compared with patients with diabetes). CONCLUSIONS: HbA1c variability is significantly associated with greater risk of rehospitalization and all-cause death in patients with HF, irrespective of their diabetic status. These observations were more pronounced in patients with HF without diabetes.

Effect of supervised exercise training on cardiovascular function in patients with intermittent claudication: a systematic review and meta-analysis of randomized controlled trials.

This study aimed to determine the effect of supervised exercise training (SET) on cardiovascular function in patients with intermittent claudication (IC). A systematic search in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases was conducted. Primary outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), rate pressure product (RPP), cardiac output (CO), peak oxygen consumption (VO2peak), and heart rate variability (HRV). Secondary outcomes were maximum walking distance (MWD) and pain-free walking distance (PFWD). Outcomes were reported as weighted mean difference (WMD) between the SET group and the control group and synthesized by using the random-effects model. Seventeen RCTs with a total of 936 patients were included in this review. SET resulted in significant improvements of SBP (WMD = - 7.40, 95% CI - 10.69 ~ - 4.11, p < 0.001, I2 = 15.2%), DBP (WMD = - 1.92, 95% CI - 3.82 ~ - 0.02, p = 0.048, I2 = 0.0%), HR (WMD = - 3.38, 95% CI - 6.30 ~ - 0.46, p = 0.023, I2 = 0.0%), RPP (WMD = - 1072.82, 95% CI - 1977.05 ~ - 168.59, p = 0.020, I2 = 42.7%), and VO2peak with plantar flexion ergometer exercise (WMD = 5.57, 95% CI 1.66 ~ 9.49, p = 0.005, I2 = 62.4%), whereas CO and HRV remained statistically unaltered. SET also improved MWD (WMD = 139.04, 95% CI 48.64 ~ 229.44, p = 0.003, I2 = 79.3%) and PFWD (WMD = 40.02, 95% CI 23.85 ~ 56.18, p < 0.001, I2 = 0.0%). In conclusion, SET is effective in improving cardiovascular function in patients with IC, which was confirmed on outcomes of cardiovascular function associated with exercise ability. The findings hold out that the standard therapy of SET can improve not only walking distance but also cardiovascular function in patients with IC.

Role of deubiquitinase JOSD2 in the pathogenesis of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a deadly malignancy with limited treatment options. Deubiquitinases (DUBs) have been confirmed to play a crucial role in the development of malignant tumors. JOSD2 is a DUB involved in controlling protein deubiquitination and influencing critical cellular processes in cancer. AIM: To investigate the impact of JOSD2 on the progression of ESCC. METHODS: Bioinformatic analyses were employed to explore the expression, prognosis, and enriched pathways associated with JOSD2 in ESCC. Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines (KYSE30 and KYSE150). Functional assays, including cell proliferation, colony formation, drug sensitivity, migration, and invasion, were performed, revealing the impact of JOSD2 on ESCC cell lines. JOSD2's role in xenograft tumor growth and drug sensitivity in vivo was also assessed. The proteins that interacted with JOSD2 were identified using mass spectrometry. RESULTS: Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues, which was associated with poor prognosis. Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells. JOSD2 knockdown inhibited ESCC cell activity, including proliferation and colony-forming ability. Moreover, JOSD2 knockdown decreased the drug resistance and migration of ESCC cells, while JOSD2 overexpression enhanced these phenotypes. In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC. Mechanistically, JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways. Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2, which identified the four primary proteins that bind to JOSD2, namely USP47, IGKV2D-29, HSP90AB1, and PRMT5. CONCLUSION: JOSD2 plays a crucial role in enhancing the proliferation, migration, and drug resistance of ESCC, suggesting that JOSD2 is a potential therapeutic target in ESCC.

L1 Cell Adhesion Molecule (L1CAM) Expression and Molecular Alterations Distinguish Low-Grade Oncocytic Tumor From Eosinophilic Chromophobe Renal Cell Carcinoma.

Renal low-grade oncocytic tumor (LOT) is a recently recognized renal cell neoplasm designated within the "other oncocytic tumors" category in the 2022 World Health Organization classification system. Although the clinicopathologic, immunohistochemical, and molecular features reported for LOT have been largely consistent, the data are relatively limited. The morphologic overlap between LOT and other low-grade oncocytic neoplasms, particularly eosinophilic chromophobe renal cell carcinoma (E-chRCC), remains a controversial area in renal tumor classification. To address this uncertainty, we characterized and compared large cohorts of LOT (n = 67) and E-chRCC (n = 69) and revealed notable differences between the 2 entities. Clinically, LOT predominantly affected women, whereas E-chRCC showed a male predilection. Histologically, although almost all LOTs were dominated by a small-nested pattern, E-chRCC mainly showed solid and tubular architectures. Molecular analysis revealed that 87% of LOT cases harbored mutations in the tuberous sclerosis complex (TSC)-mTOR complex 1 (mTORC1) pathway, most frequently in MTOR and RHEB genes; a subset of LOT cases had chromosomal 7 and 19q gains. In contrast, E-chRCC lacked mTORC1 mutations, and 60% of cases displayed chromosomal losses characteristic of chRCC. We also explored the cell of origin for LOT and identified L1 cell adhesion molecule (L1CAM), a collecting duct and connecting tubule principal cell marker, as a highly sensitive and specific ancillary test for differentiating LOT from E-chRCC. This distinctive L1CAM immunohistochemical labeling suggests the principal cells as the cell of origin for LOT, unlike the intercalated cell origin of E-chRCC and oncocytoma. The ultrastructural analysis of LOT showed normal-appearing mitochondria and intracytoplasmic lumina with microvilli, different from what has been described for chRCC. Our study further supports LOT as a unique entity with a benign clinical course. Based on the likely cell of origin and its clinicopathologic characteristics, we propose that changing the nomenclature of LOT to "Oncocytic Principal Cell Adenoma of the Kidney" may be a better way to define and describe this entity.

[Clinical outcomes and bone resection analysis of unilateral double-channel endoscopic technique in treating lumbar disc herniation].

OBJECTIVE: To explore clinical outcomes and bone resection of interlaminar fenestration decompression and unilateral biportal endoscopic (UBE) technique in treating lumbar disc herniation(LDH). METHODS: A retrospective study was performed on 105 patients with single-level LDH treated from December 2019 to December 2021. Fifty-four patients in UBE group,including 32 males and 22 females,aged from 18 to 50 years old with an average of(38.7±9.3) years old,were treated with UBE,29 patients with L4,5 and 25 patients with L5S1. There were 51 patients in small fenestration group,including 27 males and 24 females,aged from 18 to 50 years old with an average of (39.9±10.0) years old,were treated with small fenestration,25 patients with L4,5 and 26 patients with L5S1. Perioperative indexes,such as operation time,postoperative time of getting out of bed and hospital stay were observed and compared between two groups. Visual analogue scale (VAS) and Oswestry disability index (ODI) were compared between two groups before operation and 1,3,6 and 12 months after operation,respectively;and modified MacNab evaluation criteria was used to evaluate clinical efficacy. Amount of bone resection and retention rate of inferior articular process laminoid complex were compared between two groups. RESULTS: All 105 patients were successfully completed operation. Both of two groups were followed up from 6 to 12 months with an average of (10.69±2.49) months. Operation time,postoperative time of getting out of bed and hospital stay were (58.20±5.54) min,(2.40±0.57) d and (3.80±0.61) d in UBE group,and (62.90±7.14) min,(4.40±0.64) d and (4.40±0.64) d in small fenestrum group,respectively;and had statistically difference between two groups(P<0.05). Postoperative VAS of low back and leg pain and ODI in both groups were significantly lower than those before surgery (P<0.05). VAS of lumbar pain in UBE group (1.37±0.49) score was lower than that of small fenestration group (2.45±0.64) score,and had statistically difference (t=9.745,P<0.05). Postoperative ODI in UBE group at 1 and 3 months were (28.54±3.31) % and (22.87±3.23) %,respectively,which were lower than those in small fenestra group (36.31±9.08) % and (29.90±8.36) %,and the difference was statistically significant (P<0.05). There were no significant difference in VAS and ODI between two groups at other time points (P>0.05). According to the modified MacNab evaluation criteria at the latest follow-up,49 patients got excellent result,3 good,and 2 fair in UBE group. In small fenestration group,35 patients got excellent,12 good,and 4 fair. In UBE group,amount of bone resection on L4,5 segment was (0.45±0.08) cm3 and (0.31±0.08) cm3 on the segment of L5S1. In small fenestration group,amount of bone resection on L4,5 segment was (0.57±0.07) cm3 and (0.49±0.04) cm3 on the segment of L5S1,and amount of bone resection of lower articular process laminar complex on the same segment in UBE group was less than that in small fenestration group (P<0.05). In UBE group,retention rate of laminoid complex on L4,5 segment was (0.73±0.04) and L5S1 segment was (0.83±0.03),while L4,5 segment was(0.68±0.06) and L5S1 segment was (0.74±0.04) in small fenestration group,the lower articular process laminar complex retention rate in UBE group was higher than that in small fenestration group(P<0.05). CONCLUSION: Both unilateral double-channel endoscopy and small fenestration of laminae could achieve good clinical results in treating LDH,but UBE has advantages of less trauma,higher efficiency,faster postoperative recovery and less damage to bone structure.

Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data.

Tumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor-type classifiers trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole-genome sequencing (WGS), or predicting across limited cancer types. We use genomic features from a data set of 39,787 solid tumors sequenced using a clinically targeted cancer gene panel to develop Genome-Derived-Diagnosis Ensemble (GDD-ENS): a hyperparameter ensemble for classifying tumor type using deep neural networks. GDD-ENS achieves 93% accuracy for high-confidence predictions across 38 cancer types, rivaling the performance of WGS-based methods. GDD-ENS can also guide diagnoses of rare type and cancers of unknown primary and incorporate patient-specific clinical information for improved predictions. Overall, integrating GDD-ENS into prospective clinical sequencing workflows could provide clinically relevant tumor-type predictions to guide treatment decisions in real time. SIGNIFICANCE: We describe a highly accurate tumor-type prediction model, designed specifically for clinical implementation. Our model relies only on widely used cancer gene panel sequencing data, predicts across 38 distinct cancer types, and supports integration of patient-specific nongenomic information for enhanced decision support in challenging diagnostic situations. See related commentary by Garg, p. 906. This article is featured in Selected Articles from This Issue, p. 897.

Deep Learning Model for Tumor Type Prediction using Targeted Clinical Genomic Sequencing Data.

Tumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor type classifiers trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole genome sequencing (WGS), or predicting across limited cancer types. We use genomic features from a dataset of 39,787 solid tumors sequenced using a clinical targeted cancer gene panel to develop Genome-Derived-Diagnosis Ensemble (GDD-ENS): a hyperparameter ensemble for classifying tumor type using deep neural networks. GDD-ENS achieves 93% accuracy for high-confidence predictions across 38 cancer types, rivalling performance of WGS-based methods. GDD-ENS can also guide diagnoses on rare type and cancers of unknown primary, and incorporate patient-specific clinical information for improved predictions. Overall, integrating GDD-ENS into prospective clinical sequencing workflows has enabled clinically-relevant tumor type predictions to guide treatment decisions in real time.

Effect of angiotensin II on irradiation exacerbated decompression sickness.

In some complicated situations, decompression sickness (DCS) combined with other injuries, such as irradiation, will seriously endanger life safety. However, it is still unclear whether irradiation will increase the incidence of DCS. This study was designed to investigate the damage effects of irradiation on decompression injury and the underlying mechanism. Sprague-Dawley rats were exposed to irradiation followed by hyperbaric decompressing and the mortality and decompression symptoms were observed. Lung tissue and bronchoalveolar lavage fluid were collected to detect the lung lesion, inflammation response, activity of the angiotensin system, oxidative stress, and relative signal pathway by multiple methods, including Q-PCR, western blot, and ELISA. As a result, pre-exposure to radiation significantly exacerbated disease outcomes and lung lesions of DCS. Mechanically, the up-regulation of angiotensin-converting enzyme expression and angiotensin II levels was responsible for the exacerbated DCS and lung lesions caused by predisposing irradiation exposure. Oxidative stress and PI3K/AKT signal pathway activation in pulmonary tissue were enhanced after irradiation plus decompression treatment. In conclusion, our results suggested that irradiation could exacerbate lung injury and the outcomes of DCS by activating the angiotensin system, which included eliciting oxidative stress and activation of the PI3K/AKT signal pathway.

The safety and immunogenicity of a recombinant five-antigen Staphylococcus aureus vaccine among patients undergoing elective surgery for closed fractures: A randomized, double-blind, placebo-controlled, multicenter phase 2 clinical trial.

BACKGROUND: Vaccines are urgently required to control Staphylococcus aureus hospital and community infections and reduce the use of antibiotics. Here, we report the safety and immunogenicity of a recombinant five-antigen Staphylococcus aureus vaccine (rFSAV) in patients undergoing elective surgery for closed fractures. METHODS: A randomized, double-blind, placebo-controlled, multicenter phase 2 clinical trial was carried out in 10 clinical research centers in China. Patients undergoing elective surgery for closed fractures, aged 18-70 years, were randomly allocated at a ratio of 1:1 to receive the rFSAV or placebo at a regimen of two doses on day 0 and another dose on day 7. All participants and investigators remained blinded during the study period. The safety endpoint was the incidence of adverse events within 180 days. The immunogenicity endpoints included the level of specific antibodies to five antigens after vaccination, as well as opsonophagocytic antibodies. RESULTS: A total of 348 eligible participants were randomized to the rFSAV (n = 174) and placebo (n = 174) groups. No grade 3 local adverse events occurred. There was no significant difference in the incidence of overall systemic adverse events between the experimental (40.24 %) and control groups (33.72 %) within 180 days after the first immunization. The antigen-specific binding antibodies started to increase at days 7 and reached their peaks at 10-14 days after the first immunization. The rapid and potent opsonophagocytic antibodies were also substantially above the background levels. CONCLUSIONS: rFSAV is safe and well-tolerated in patients undergoing elective surgery for closed fractures. It elicited rapid and robust specific humoral immune responses using the perioperative immunization procedure. These results provide evidence for further clinical trials to confirm the vaccine efficacy. China's Drug Clinical Trials Registration and Information Publicity Platform registration number: CTR20181788. WHO International Clinical Trial Registry Platform identifier: ChiCTR2200066259.

Engineering Escherichia coli to produce aromatic chemicals from ethylene glycol.

Microbial overproduction of aromatic chemicals has gained considerable industrial interest and various metabolic engineering approaches have been employed in recent years to address the associated challenges. So far, most studies have used sugars (mostly glucose) or glycerol as the primary carbon source. In this study, we used ethylene glycol (EG) as the main carbon substrate. EG could be obtained from the degradation of plastic and cellulosic wastes. As a proof of concept, Escherichia coli was engineered to transform EG into L-tyrosine, a valuable aromatic amino acid. Under the best fermentation condition, the strain produced 2 g/L L-tyrosine from 10 g/L EG, outperforming glucose (the most common sugar feedstock) in the same experimental conditions. To prove the concept that EG can be converted into different aromatic chemicals, E. coli was further engineered with a similar approach to synthesize other valuable aromatic chemicals, L-phenylalanine and p-coumaric acid. Finally, waste polyethylene terephthalate (PET) bottles were degraded using acid hydrolysis and the resulting monomer EG was transformed into L-tyrosine using the engineered E. coli, yielding a comparable titer to that obtained using commercial EG. The strains developed in this study should be valuable to the community for producing valuable aromatics from EG.

The Effects of MicroRNAs in the Development of Heart Failure.

PURPOSE OF REVIEW: Heart failure is a severe clinical syndrome with complex and unclarified mechanisms, and it poses a serious threat to human health. MicroRNA, a non-coding RNA, can directly bind to target genes and regulate their expression. The important role of microRNAs in the development of HF has become a hot topic of research in recent years. This paper summarizes and prospects the mechanisms of microRNAs in regulating cardiac remodeling during heart failure to provide reference ideas for further research and clinical treatment. RECENT FINDINGS: With extensive research, more target genes for microRNAs have been clarified. By modulating various molecules, microRNAs affect the contractile function of the myocardium and alter the process of myocardial hypertrophy, myocyte loss, and fibrosis, thereby interfering with the process of cardiac remodeling and exerting an important effect in the process of heart failure. Based on the above mechanism, microRNAs have promising applications in the diagnosis and treatment of heart failure. MicroRNAs form a complex post-transcriptional control mechanism of gene expression, and the increase or decrease of their content during heart failure largely alters the course of cardiac remodeling. By continuously identifying their target genes, it is expected to achieve more precise diagnosis and treatment of this important topic of heart failure.

A systematic review and meta-analysis of cold exposure and cardiovascular disease outcomes.

Background: Cold exposure has been considered an essential risk factor for the global disease burden, while its role in cardiovascular diseases is still underappreciated. The increase in frequency and duration of extreme cold weather events like cold spells makes it an urgent task to evaluate the effects of ambient cold on different types of cardiovascular disease and to understand the factors contributing to the population's vulnerability. Methods: In the present systematic review and meta-analysis, we searched PubMed, Scopus, and Cochrane. We included original research that explored the association between cold exposure (low temperature and cold spell) and cardiovascular disease outcomes (mortality and morbidity). We did a random-effects meta-analysis to pool the relative risk (RR) of the association between a 1°C decrease in temperature or cold spells and cardiovascular disease outcomes. Results: In total, we included 159 studies in the meta-analysis. As a result, every 1°C decrease in temperature increased cardiovascular disease-related mortality by 1.6% (RR 1.016; [95% CI 1.015-1.018]) and morbidity by 1.2% (RR 1.012; [95% CI 1.010-1.014]). The most pronounced effects of low temperatures were observed in the mortality of coronary heart disease (RR 1.015; [95% CI 1.011-1.019]) and the morbidity of aortic aneurysm and dissection (RR 1.026; [95% CI 1.021-1.031]), while the effects were not significant in hypertensive disease outcomes. Notably, we identified climate zone, country income level and age as crucial influential factors in the impact of ambient cold exposure on cardiovascular disease. Moreover, the impact of cold spells on cardiovascular disease outcomes is significant, which increased mortality by 32.4% (RR 1.324; [95% CI 1.2341.421]) and morbidity by 13.8% (RR 1.138; [95% CI 1.015-1.276]). Conclusion: Cold exposure could be a critical risk factor for cardiovascular diseases, and the cold effect varies between disease types and climate zones. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier: CRD42022347247.