Double pituitary adenomas: report of two cases and systematic review of the literature.

Objective: Double pituitary adenomas (DPA) are a rare clinical condition, and our knowledge of them is limited. Missing the second lesion leading to incomplete biochemical remission after surgery is an important challenge in DPA management. This study aims to analyze independent prognostic factors in DPA patients and summarize clinical experiences to prevent surgical failure. Methods: Two cases of DPA patients with Cushing's disease diagnosed and surgically treated at Peking Union Medical College Hospital are reported. A literature review was performed on the online database Pubmed, and 57 DPA patients from 22 retrieved articles were included. Demographic characteristics, endocrine manifestations, diagnostic methods, tumor size, and immunohistochemical features of 59 patients were analyzed. Binary logistic regression models were used to identify independent prognostic factors affecting postoperative biochemical remission. Results: Among 59 DPA patients, the mean ± SD age was 43.64 ± 14.42 years, with 61.02% being female (n = 36). The most common endocrine manifestations were Cushing's syndrome (23/59, 38.98%) and acromegaly (20/59, 33.90%). The most prevalent immunohistochemical types were ACTH-immunopositive (31/118, 26.27%) and GH-immunopositive (31/118, 26.27%) tumors. Microadenomas (<1cm) were the most frequent in terms of tumor size (62/92, 67.39%). The detection rate for double lesions on 3.0T MRI was 50.00% (14/28), which significantly higher than 1.5T MRI (P = 0.034). Univariate analysis revealed that female, Cushing's syndrome and only single lesion detected by surgical exploration were associated with significantly worse prognosis (P<0.05). Multivariate analysis identified double lesion detected by surgical exploration (OR = 0.08, P = 0.003) and contiguous type tumor (OR = 0.06, P = 0.017) as independent protective factors for DPA patients. Conclusions: The double lesion detected by surgical exploration is independently associated with a better prognosis for DPA patients. Comprehensive intraoperative exploration are crucial measures to avoid missing causative lesions.

Corrigendum: LncRNA-AC02278.4 is a novel prognostic biomarker that promotes tumor growth and metastasis in lung adenocarcinoma.

[This corrects the article DOI: 10.3389/fonc.2022.860961.].

Survival analysis of PLWHA undergoing combined antiretroviral therapy: exploring long-term prognosis and influencing factors.

Introduction: The survival time of human immunodeficiency virus (HIV)-infected individuals or patients with acquired immunodeficiency syndrome (AIDS) is influenced by multiple factors. Studying survival and influential factors after antiretroviral therapy (ART) contributes to improving treatment protocols, management strategies, and prognosis for people living with HIV/AIDS (PLWHA). Methods: This retrospective cohort study collected case data and follow-up records of PLWHA who received ART in Dazu District, Chongqing City, between 2007 and 2022. Cumulative survival rates were calculated using life tables. Survival curves were plotted using the Kaplan-Meier method. Uni-variable and multivariable Cox proportional hazards models analyzed factors influencing survival. Results: The study included 5,237 PLWHA receiving ART. Within the first year of ART initiation, 146 AIDS-related deaths occurred, accounting for 29.49% (146/495) of total deaths. Cumulative survival rates at 1, 5, 10, and 15 years were 0.97, 0.90, 0.85, and 0.79, respectively. During the observation period, male patients who received ART had a 1.89 times higher risk of death compared to females (aHR, 1.89; 95%; CI, 1.50-2.37). Patients aged ≥60 years had a 3.44-fold higher risk of death than those aged <30 years (aHR, 3.44; 95% CI, 1.22-9.67). Injection drug users (aHR, 4.95; 95% CI, 2.00-12.24) had a higher risk of death than those with heterosexual (aHR, 1.60; 95% CI, 0.69-3.72) and homosexual transmission. Patients with a baseline CD4+ T lymphocyte count <200 cells/µL (aHR, 8.02; 95% CI, 4.74-13.57) and between 200 and 349 cells/µL (aHR, 2.14; 95% CI, 1.26-3.64) had a higher risk of death than those with ≥350 cells/µL. Patients with ART initiation at WHO clinical stage IV had a 2.48-fold higher risk of death than those at stage I (aHR, 2.48; 95% CI, 1.17-5.23). Conclusion: The first year following ART initiation is critical in HIV/AIDS treatment, emphasizing the need for intensified follow-up and monitoring to facilitate successful immune system reconstruction. Older age, male sex, injection drug use, baseline CD4+ T lymphocyte count <200 cells/µL, and WHO clinical stage IV are associated with an increased risk of death. Tailored treatment and management strategies should be implemented for patient populations at higher risk of mortality and with a poorer prognosis.

Bacteria-based drug delivery for treating non-oncological diseases.

Bacteria inhabit all over the human body, especially the skin, gastrointestinal tract, respiratory tract, urogenital tract, as well as specific lesion sites, such as wound and tumor. By leveraging their distinctive attributes including rapid proliferation, inherent abilities to colonize various biointerfaces in vivo and produce diverse biomolecules, and the flexibility to be functionalized via genetic engineering or surface modification, bacteria have been widely developed as living therapeutic agents, showing promising potential to make a great impact on the exploration of advanced drug delivery systems. In this review, we present an overview of bacteria-based drug delivery and its applications in treating non-oncological diseases. We systematically summarize the physiological positions where living bacterial therapeutic agents can be delivered to, including the skin, gastrointestinal tract, respiratory tract, and female genital tract. We discuss the success of using bacteria-based drug delivery systems in the treatment of diseases that occur in specific locations, such as skin wound healing/infection, inflammatory bowel disease, respiratory diseases, and vaginitis. We also discuss the advantages as well as the limitations of these living therapeutics and bacteria-based drug delivery, highlighting the key points that need to be considered for further translation. This review article may provide unique insights for designing next-generation bacteria-based therapeutics and developing advanced drug delivery systems.

Basigin Deficiency Induces Spontaneous Polycystic Kidney in Mice.

BACKGROUND: Polycystic kidney disease is the most common hereditary kidney disorder with early and frequent hypertension symptoms. The mechanisms of cyst progression in polycystic kidney disease remain incompletely understood. METHODS: Bsg (basigin) heterozygous and homozygous knockout mice were generated using cas9 system, and Bsg overexpression was achieved by adeno-associated virus serotype 9 injection. Renal morphology was investigated through histological and imaging analysis. Molecular analysis was performed through transcriptomic profiling and biochemical approaches. RESULTS: Bsg-deficient mice exhibited significantly elevated arterial blood pressure. Further investigation demonstrated that Bsg deficiency triggers spontaneous cystic formation in mouse kidneys, which shares similar cyst pathological features and common transcriptional regulatory pathways with human polycystic kidney disease. Moreover, Bsg disruption promoted polycystin-1 ubiquitination and degradation, leading to activation of polycystic kidney disease associated cAMP and AMPK signaling pathways in Bsg knockout mouse kidneys. Finally, adeno-associated virus serotype 9 mediated Bsg reexpression reversed cystic progression in Bsg knockout mice in vivo, and Bsg overexpression inhibited the expansion of Madin-Darby canine kidney cysts in vitro. CONCLUSIONS: Our findings show that Bsg deficiency leads to an early-onset spontaneous polycystic kidney phenotype, suggesting that dysregulated Bsg signaling may be a contributing factor in cystogenesis.

Angioplasty Guidewire-Assisted vs. Conventional Transseptal Puncture for Left Atrial Appendage Occlusion: a multicentre randomized controlled trial.

AIMS: This study was performed to compare the usability, efficiency, and safety of a modified angioplasty guidewire-assisted transseptal puncture (TSP) technique vs. the conventional approach in facilitating access into the left atrium during left atrial appendage occlusion (LAAO) procedures for the treatment of atrial fibrillation. METHODS AND RESULTS: The ADVANCE-LAAO trial (Angioplasty Guidewire-Assisted vs. Conventional Transseptal Puncture for Left Atrial Appendage Occlusion) was an investigator-initiated, prospective, multicentre, randomized controlled trial (NCT05125159). Patients with atrial fibrillation who underwent LAAO were prospectively enrolled from four centres and randomly assigned to an angioplasty guidewire-assisted TSP group (n = 131) or to a conventional Brockenbrough needle TSP group (n = 132). The primary endpoint was the one-time success rate of TSP. We also analysed the TSP procedure time, failure rate of the assigned TSP type, radiation dose, contrast dose, and procedural complications in both groups. All patients in the guidewire-assisted group underwent successful TSP, whereas five in the standard conventional group switched to the guidewire-assisted approach. The guidewire-assisted puncture improved the one-time success rate (92.4 vs. 77.3%, P = 0.001), shortened the TSP procedure time (109.2 ± 48.2 vs. 120.5 ± 57.6 s, P = 0.023), and tended to have a higher rate of good coaxial orientation of the sheath with the left atrial appendage during the LAAO procedure (66.4 vs. 54.5%, P = 0.059). No TSP-related complications occurred in the guidewire-assisted TSP group, whereas two complications occurred in the conventional TSP group. There was no significant difference in the failure rate of the assigned TSP type, the total procedure time, the total radiation dose, the rate of successful LAAO implantation, or the procedural complication rate between the two groups (all P > 0.05). CONCLUSION: This study confirmed that angioplasty guidewire-assisted puncture can effectively improve the success rate of TSP during LAAO procedures. This novel technique has high potential for application in interventional therapies requiring TSP.

BTN2A2, a new biomarker and therapeutic target for glioma.

BACKGROUND: Protein casein 2A2 (BTN2A2) is a costimulatory molecule first identified in antigen-presenting cells. Studies have shown the involvement of BTN2A2 in immunity. However, the exact role and the mechanism of BTN2A2 in tumors are still unclear. METHODS: First, we performed real-time PCR to measure BTN2A2 expression in glioma cell lines. Next, we performed Genes Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to understand the mechanism of BTN2A2 in glioma. Next, we used the "ESTIMATE", "ssGSEA" and "CIBERSORT" algorithms to analyze the correlation between BTN2A2 and immune cell infiltration (ICI). Finally, we performed immunohistochemistry, growth curve, transwell, and colony formation assays to determine the functions of BTN2A2 in glioma. RESULTS: Our results showed an increase in BTN2A2 expression levels in glioma tissues and cells. Next, we determined that BTN2A2 was correlated with the prognosis of patients with glioma. Then, using the ESTIMATE, ssGSEA, and CIBERSORT algorithms, we discovered that BTN2A2 was significantly associated with immune cell infiltration (ICI) in glioma. We observed an increase in BTN2A2 expression levels with an increase in the patient's tumor grade. Furthermore, BTN2A2 significantly enhanced the proliferative and migratory abilities of glioma cells. CONCLUSIONS: Our results showed a significant increase in BTN2A2 expression levels in glioma cells and tissues. Furthermore, the prognosis of patients expressing high BTN2A2 levels was poor. Moreover, BTN2A2 was correlated with progression and ICI in patients with glioma. Together, this indicates that BTN2A2 could be a therapeutic target for patients with glioma.

CCDC103 as a Prognostic Biomarker Correlated with Tumor Progression and Immune Infiltration in Glioma.

Background: The Coiled-coil domain-containing proteins (CCDCs) are expressed in many cancers, but the role of Coiled-coil domain-containing protein 103 (CCDC103) in cancers remains unclear. Further investigations are necessary to ascertain its diagnostic significance and understand its biological function in cancers. This study aims to elucidate the biological functionalities of CCDC103 in glioma and evaluate the correlation between CCDC103 expression with glioma progression. Methods: Clinical data on glioma patients were acquired from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and the Gene Expression Omnibus (GEO). The evaluation encompassed the examination of correlations between CCDC103 expression, pathological characteristics, and clinical outcomes. Furthermore, the analysis included the assessment of the correlations between CCDC103 expression and immune cell infiltration as well as glioma progression. Results: Gliomas have higher levels of CCDC103 expression than the para-carcinoma tissues. Poorer prognosis, unfavorable histological characteristics, the absence of IDH gene mutations, and the absence of chromosome 1p and 19q deletions were all associated with higher expression of CCDC103 in gliomas. In addition to patient age, tumor grade, the absence of IDH mutations, and the absence of chromosome 1p and 19q deletions, univariate and multivariate Cox analyses showed that CCDC103 expression was independently prognostic of overall survival, disease-free survival, and progression-free survival in patients with glioma. Furthermore, tumor infiltration of B cells, neutrophils, macrophages, and dendritic cells were all linked with elevated expression of CCDC103. High CCDC103 expression was linked to immune response-related signaling pathways and cell proliferation, according to gene set enrichment analysis (GSEA). Notably, the knockdown of CCDC103 in glioma cell lines resulted in a significant reduction in cell proliferation and migration. Conclusion: The correlation between CCDC103 expression and both glioma progression and immune cell infiltration implies that CCDC103 expression holds promise as a valuable prognostic biomarker for glioma.

Long-term outcomes of microsurgery and stereotactic radiosurgery as the first-line treatment for arteriovenous malformations: a propensity score-matched analysis using nationwide multicenter prospective registry data.

BACKGROUND: This study aimed to compare the risk and benefit profile of microsurgery (MS) and stereotactic radiosurgery (SRS) as the first-line treatment for unruptured and ruptured arteriovenous malformations (AVMs). MATERIALS AND METHODS: The authors included AVMs underwent MS or SRS as the first-line treatment from a nationwide prospective multicenter registry in mainland China. The authors used propensity score-matched methods to balance baseline characteristics between the MS and SRS groups. The primary outcomes were long-term hemorrhagic stroke or death, and the secondary outcomes were long-term obliteration and neurological outcomes. Subgroup analyses and sensitivity analyses with different study designs were performed to confirm the stability of our findings. RESULTS: Of the 4286 consecutive AVMs in the registry from August 2011 to December 2021; 1604 patients were eligible. After matching, 244 unruptured and 442 ruptured AVMs remained for the final analysis. The mean follow-up duration was 7.0 years in the unruptured group and 6.1 years in the ruptured group. In the comparison of primary outcomes, SRS was associated with a higher risk of hemorrhagic stroke or death both in the unruptured and ruptured AVMs (unruptured: hazard ratio 4.06, 95% CI: 1.15-14.41; ruptured: hazard ratio 4.19, 95% CI: 1.58-11.15). In terms of the secondary outcomes, SRS was also observed to have a significant disadvantage in long-term obliteration [unruptured: odds ratio (OR) 0.01, 95% CI: 0.00-0.04; ruptured: OR 0.09, 95% CI: 0.05-0.15]. However, it should be noted that SRS may have advantages in preventing neurofunctional decline (unruptured: OR 0.56, 95% CI: 0.27-1.14; ruptured: OR 0.41, 95% CI: 0.23-0.76). The results of subgroup analyses and sensitivity analyses were consistent in trend but with slightly varied powers. CONCLUSIONS: This clinical practice-based real-world study comprehensively compared MS and SRS for AVMs with long-term outcomes. MS is more effective in preventing future hemorrhage or death and achieving obliteration, while the risk of neurofunctional decline should not be ignored.

Influence and mechanism of sodium-glucose cotransporter-2 inhibitors on the cardiac function: study protocol for a prospective cohort study.

Background: Acute myocardial infarction (AMI) poses a significant threat to cardiovascular diseases (CVDs), leading to a high risk of heart failure (HF) and cardiovascular death. Growing evidence has unveiled the potential of sodium-glucose cotransporter-2 (SGLT2) inhibitors to improve cardiovascular outcomes in patients with CVD regardless of diabetes, but there is limited evidence in AMI patients. Furthermore, it is controversial whether the effects can be ascribed to the amelioration of left ventricular (LV) function, which further complicates the understanding of their underlying mechanism. Methods: This study is a prospective, phase IV, open-label, parallel group, single-center trial conducted in a large tertiary teaching hospital in China. A total of 120 patients with AMI and type 2 diabetes mellitus (T2DM) will be included. Those who received SGLT2 inhibitors are considered as the experimental group, and those taking other antidiabetic agents are considered as the control group. The primary outcome is change in LV end-systolic volume index (LVESVi) measured by cardiac magnetic resonance (CMR) imaging from baseline during 1-year follow-up period. Secondary outcomes include other LV parameters such as LV mass, LV volume, and LV ejection fraction (EF); quality of life and functional capacity such as Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OS) and EuroQol-5 dimension (EQ-5D); biomarkers associated with diagnostic parameters of AMI and possible mechanisms on cardiovascular protection, such as creatine kinase, troponin T (TnT) level, troponin I (TnI) level, soluble suppression of tumorigenicity-2 (sST2), galectin-3 (Gal-3), fibroblast growth factor 21 (FGF21), and microRNA (miRNA) level. Discussion: This study aims to investigate whether SGLT2 inhibitors could improve LV function by measuring CMR, quality of life, and functional capacity in patients with AMI in real-world settings, providing evidence on the underlying mechanism of SGLT2 inhibitors on cardioprotection. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=173672, identifier ChiCTR2200065792.

Peak early diastolic strain rate improves prediction of adverse cardiovascular outcomes in patients with ST-elevation myocardial infarction.

BACKGROUND: The prognostic role of diastolic dysfunction measured by the circumferential peak early diastolic strain rate (PEDSR) on ST-elevation myocardial infarction (STEMI) is not completely established. OBJECTIVES: We aimed to investigate the prognostic value of diastolic function by measuring PEDSR within 1 week after STEMI. METHODS: The cardiac magnetic resonance (CMR) pictures of 420 subjects from a clinical registry study (NCT03768453) were analyzed and the composite major adverse cardiac events (MACEs) were followed up. RESULTS: The PEDSR of patients was significantly lower compared with that of control subjects (P < 0.001). Within the median follow-up period of 52 months, PEDSR of patients who experienced MACEs deceased more significantly than that of patients without MACEs (P < 0.001). After adjusting with clinical or CMR indexes, per 0.1/s reduction of PEDSR increased the risks of MACEs to 1.402 or 1.376 fold and the risk of left ventricular (LV) remodeling to 1.503 or 1.369 fold. When PEDSR divided by best cutoff point, significantly higher risk of MACEs (P < 0.001) and more remarkable LV remodeling (P < 0.001) occurred in patients with PEDSR ≤ 0.485/s. Moreover, when adding the PEDSR to the conventional prognostic factors such as LV ejection fraction and infarction size, better prognostic risk classification models were created. Finally, aging, tobacco use, remarkable LV remodeling, and a low LV ejection fraction were factors related with the reduction of PEDSR. CONCLUSIONS: Diastolic dysfunction has an important prognostic effect on patients with STEMI. Measurement of the PEDSR in the acute phase could serve as an effective index to predict the long-term risk of MACEs and cardiac remodeling.

Efficacy and safety analysis of angiotensin receptor neprilysin inhibition(ARNI)in patients with heart failure: a real-world retrospective study.

BACKGROUND: In a large randomized controlled trial (PARADIGM-HF), ARNI has been shown to significantly reduce cardiovascular mortality and hospitalization for patients with reduced ejection fraction in heart failure. This study analyzed the efficacy and safety of ARNI on the basis of various types of heart failure patients in southwestern Sichuan Province. METHODS: This study included patients with heart failure who were treated at the Affiliated Hospital of North Sichuan Medical College from July 2017 to June 2021. This study analyzed the efficacy and safety of ARNI in the treatment of heart failure, and analyzed the risk factors for readmission after ARNI treatment. RESULTS: After propensity score matching, a total of 778 patients were included in the study. The readmission rate for heart failure in patients treated with ARNI (8.7%) was significantly lower than that in the standard treatment group (14.5%) (P = 0.023). Both the proportion of patients with increased LVEF and with decreased LVEF were higher in the ARNI treatment group than in the conventional therapy group. Compared with receiving standard medical treatment, combined ARNI treatment resulted in a greater reduction in SBP (-10.00, 95%CI: -24.00-1.50 vs. -7.00, 95%CI: -20.00-4.14; P = 0.016) in HF patients. Combination ARNI therapy did not increase the risk of adverse events. The study found that age (> 65 vs. ≤65 years) (OR = 4.038, 95%CI: 1.360-13.641, P = 0.013) and HFrEF (OR = 3.162, 95%CI: 1.028-9.724, P = 0.045) were independent predictors of readmission in HF patients treated with ARNI. CONCLUSION: Patients with heart failure treated with ARNI can improve clinical symptoms and reduce the risk of readmitted hospital admission. Age > ~ 65 years and HFrEF were independent predictors of readmission in HF patients treated in ARNI group.

Ascorbic acid induces MLC2v protein expression and promotes ventricular-like cardiomyocyte subtype in human induced pluripotent stem cells derived cardiomyocytes.

Introduction: The potentially unlimited number of cardiomyocyte (CMs) derived from human induced pluripotent stem cells (hiPSCs) in vitro facilitates high throughput applications like cell transplantation for myocardial repair, disease modelling, and cardiotoxicity testing during drug development. Despite promising progress in these areas, a major disadvantage that limits the use of hiPSC derived CMs (hiPSC-CMs) is their immaturity. Methods: Three hiPSC lines (PCBC-hiPSC, DP3-hiPSCs, and MLC2v-mEGFP hiPSC) were differentiated into CMs (PCBC-CMs, DP3-CMs, and MLC2v-CMs, respectively) with or without retinoic acid (RA). hiPSC-CMs were either maintained up to day 30 of contraction (D30C), or D60C, or purified using lactate acid and used for experiments. Purified hiPSC-CMs were cultured in basal maturation medium (BMM) or BMM supplemented with ascorbic acid (AA) for 14 days. The AA treated and non-treated hiPSC-CMs were characterized for sarcomeric proteins (MLC2v, TNNI3, and MYH7), ion channel proteins (Kir2.1, Nav1.5, Cav1.2, SERCA2a, and RyR), mitochondrial membrane potential, metabolomics, and action potential. Bobcat339, a selective and potent inhibitor of DNA demethylation, was used to determine whether AA promoted hiPSC-CM maturation through modulating DNA demethylation. Results: AA significantly increased MLC2v expression in PCBC-CMs, DP3-CMs, MLC2v-CMs, and RA induced atrial-like PCBC-CMs. AA treatment significantly increased mitochondrial mass, membrane potential, and amino acid and fatty acid metabolism in PCBC-CMs. Patch clamp studies showed that AA treatment induced PCBC-CMs and DP3-CMs adaptation to a ventricular-like phenotype. Bobcat339 inhibited MLC2v protein expression in AA treated PCBC-CMs and DP3-CMs. DNA demethylation inhibition was also associated with reduced TET1 and TET2 protein expressions and reduced accumulation of the oxidative product, 5 hmC, in both PCBC-CMs and DP3-CMs, in the presence of AA. Conclusions: Ascorbic acid induced MLC2v protein expression and promoted ventricular-like CM subtype in hiPSC-CMs. The effect of AA on hiPSC-CM was attenuated with inhibition of TET1/TET2 mediated DNA demethylation.

Mitochondrial GSNOR Alleviates Cardiac Dysfunction via ANT1 Denitrosylation.

BACKGROUND: The cardiac-protective role of GSNOR (S-nitrosoglutathione reductase) in the cytoplasm, as a denitrosylase enzyme of S-nitrosylation, has been reported in cardiac remodeling, but whether GSNOR is localized in other organelles and exerts novel effects remains unknown. We aimed to elucidate the effects of mitochondrial GSNOR, a novel subcellular localization of GSNOR, on cardiac remodeling and heart failure (HF). METHODS: GSNOR subcellular localization was observed by cellular fractionation assay, immunofluorescent staining, and colloidal gold particle staining. Overexpression of GSNOR in mitochondria was achieved by mitochondria-targeting sequence-directed adeno-associated virus 9. Cardiac-specific knockout of GSNOR mice was used to examine the role of GSNOR in HF. S-nitrosylation sites of ANT1 (adenine nucleotide translocase 1) were identified using biotin-switch and liquid chromatography-tandem mass spectrometry. RESULTS: GSNOR expression was suppressed in cardiac tissues of patients with HF. Consistently, cardiac-specific knockout mice showed aggravated pathological remodeling induced by transverse aortic constriction. We found that GSNOR is also localized in mitochondria. In the angiotensin II-induced hypertrophic cardiomyocytes, mitochondrial GSNOR levels significantly decreased along with mitochondrial functional impairment. Restoration of mitochondrial GSNOR levels in cardiac-specific knockout mice significantly improved mitochondrial function and cardiac performance in transverse aortic constriction-induced HF mice. Mechanistically, we identified ANT1 as a direct target of GSNOR. A decrease in mitochondrial GSNOR under HF leads to an elevation of S-nitrosylation ANT1 at cysteine 160 (C160). In accordance with these findings, overexpression of either mitochondrial GSNOR or ANT1 C160A, non-nitrosylated mutant, significantly improved mitochondrial function, maintained the mitochondrial membrane potential, and upregulated mitophagy. CONCLUSIONS: We identified a novel species of GSNOR localized in mitochondria and found mitochondrial GSNOR plays an essential role in maintaining mitochondrial homeostasis through ANT1 denitrosylation, which provides a potential novel therapeutic target for HF.

Association of embolization with long-term outcomes in brain arteriovenous malformations: a propensity score-matched analysis using nationwide multicenter prospective registry data.

BACKGROUND: Brain arteriovenous malformations (AVMs) account for 25% of hemorrhagic strokes in young adults. Although embolization has been widely performed as a stand-alone procedure to cure brain AVM, it is undermined whether patients benefit from this treatment. This study aimed to compare the long-term outcome of hemorrhagic stroke or death in patients with either conservative management or stand-alone embolization for AVM. METHODS: The study population was derived from a nationwide multicenter prospective collaboration registry (the MATCH registry) between August 2011 and August 2021. The propensity score-matched survival analysis was performed in the overall and stratified AVM cases (unruptured and ruptured), respectively, to compare the long-term outcome of hemorrhagic stroke or death, and neurological status. The efficacy of distinct embolization strategies was also evaluated. Hazard ratios (HRs) with 95% CI were calculated using Fine-Gray competing risk models. RESULTS: Of the 3682 consecutive AVMs, 906 underwent either conservative management or embolization as the stand-alone management strategy. After propensity score matching, a total of 622 (311 pairs) patients constituted an overall cohort. The unruptured and ruptured subgroups were composed of 288 cases (144 pairs) and 252 cases (126 pairs), respectively. In the overall cohort, embolization did not prevent long-term hemorrhagic stroke or death compared with conservative management [2.07 vs. 1.57 per 100 patient-years; HR, 1.28 (95% CI, 0.81-2.04)]. Similar results were maintained in both unruptured AVMs [1.97 vs. 0.93 per 100 patient-years; HR, 2.09 (95% CI, 0.99-4.41)] and ruptured AVMs [2.36 vs. 2.57 per 100 patient-years; HR, 0.76 (95% CI, 0.39-1.48)]. Stratified analysis showed that the target embolization might be beneficial for unruptured AVMs [HR, 0.42 (95% CI, 0.08-2.29)], while the curative embolization improved the outcome of ruptured AVMs [HR, 0.29 (95% CI, 0.10-0.87)]. The long-term neurological status was similar between these two strategies. CONCLUSIONS: This prospective cohort study did not support a substantial superiority of embolization over conservative management for AVMs in preventing long-term hemorrhagic stroke or death.

LncRNA GSCAR promotes glioma stem cell maintenance via stabilizing SOX2 expression.

Gliomas are the most aggressive type of malignant brain tumors. Recent studies have demonstrated that the existence of glioma stem cells (GSCs) is critical for glioma recurrence, metastasis, and chemo- or radio-therapy resistance. Temozolomide (TMZ) has been used as an initial therapy for gliomas. However, the overall survival time is still limiting due to the lack of effective targets and treatment options. Therefore, identifying novel biomarkers for gliomas, especially for GSCs, is important to improve the clinical outcome in the future. In this study, we identify a human-specific long non-coding RNA (lncRNA, ENSG00000250377), termed GSCAR (glioma stem cell associated lncRNA), which is highly expressed in glioma cancerous tissues and cell lines. We reveal that GSCAR positively correlates with tumor grade. Glioma patients with GSCAR high expression exhibit shortened overall survival time, compared to patients with GSCAR low expression. Furthermore, we show that GSCAR knockdown by shRNAs or antisense oligonucleotide (ASO) reduces tumor cell proliferation, migration and xenograft tumor formation abilities. Mechanistic study shows that GSCAR acts as a ceRNA (competing endogenous RNA) for miR-6760-5p to promote the expression of oncogene SRSF1 (serine and arginine rich splicing factor 1). In addition, GSCAR mediates the protein complex formation between DHX9 (DExH-Box helicase 9) and IGF2BP2 (insulin-like growth factor 2 mRNA-binding protein 2), leading to the stabilization of SOX2 (sex-determining region Y-box 2) mRNA and then the transcriptional activation of GSCAR. Depleting GSCAR reduces SOX2 expression and GSC self-renewal ability, but promotes tumor cell responses to TMZ. These findings uncover that GSCAR/miR-6760-5p/SRSF1 axis and GSCAR/DHX9-IGF2BP2/SOX2 positive feedback loop are critical for glioma progression, which could be used as prognostic biomarkers and therapeutic targets in the future.

High-Dose Ionizing Radiation Accelerates Atherosclerotic Plaque Progression by Regulating P38/NCOA4-Mediated Ferritinophagy/Ferroptosis of Endothelial Cells.

PURPOSE: Radiation therapy (RT) significantly increased the incidence of coronary artery diseases, especially atherosclerosis. Endothelial dysfunction has been the major side effect of RT among tumor patients who received RT. However, the involvement between endothelial dysfunction and radiation-induced atherosclerosis (RIA) remains unclear. Here, we constructed a murine model of RIA, aiming to uncover its underlying mechanisms and identify novel strategies for RIA prevention and treatment. METHODS AND MATERIALS: Eight-week-old ApoE-/- mice that were fed a Western diet were subjected to partial carotid ligation (PCL). Four weeks later, ionizing radiation (IR) of 10 Gy was performed to verify the detrimental role of IR on atherogenesis. Ultrasound imaging, RT quantitative polymerase chain reaction, histopathology and immunofluorescence, and biochemical analysis were performed 4 weeks after IR. To study the involvement of endothelial ferroptosis induced by IR in RIA, mice after IR were administrated with ferroptosis agonist (cisplatin) or antagonist (ferrostatin-1) intraperitoneally. Western blotting, autophagic flux measurement, reactive oxygen species level detection, and coimmunoprecipitation assay were carried out in vitro. Furthermore, to determine the effect of ferritinophagy inhibition on RIA, in vivo knockdown of NCOA4 was carried out by pluronic gel. RESULTS: We verified that accelerated plaque progression was concomitant with endothelial cell (EC) ferroptosis after IR induction, as suggested by a higher level of lipid peroxidation and changes in ferroptosis-associated genes in the PCL + IR group than in the PCL group within vasculature. In vitro experiments further validated the devastating effects of IR on oxidative stress and ferritinophagy in ECs. Mechanistic experiments revealed that IR induced EC ferritinophagy and subsequent ferroptosis in a P38/NCOA4-dependent manner. Both in vitro and in vivo experiments confirmed the therapeutic effect of NCOA4 knockdown in alleviating IR-induced ferritinophagy/ferroptosis of EC and RIA. CONCLUSIONS: Our findings provide novel insights into the regulatory mechanisms of RIA and first prove that IR accelerates atherosclerotic plaque progression by regulating ferritinophagy/ferroptosis of ECs in a P38/NCOA4-dependent manner.

Prognostic significance of non-infarcted myocardium correlated with microvascular impairment evaluated dynamically by native T1 mapping.

OBJECTIVES: This study aimed to investigate the influence of microvascular impairment on myocardial characteristic alterations in remote myocardium at multiple time points, and its prognostic significance after acute ST-segment elevation myocardial infarction (STEMI). METHODS: Patients were enrolled prospectively and performed CMR at baseline, 30 days, and 6 months. The primary endpoint was major adverse cardiac events (MACE): death, myocardial reinfarction, malignant arrhythmia, and hospitalization for heart failure. Cox proportional hazards regression modeling was analyzed to estimate the correlation between T1 mapping of remote myocardium and MACE in patients with and without microvascular obstruction (MVO). RESULTS: A total of 135 patients (mean age 60.72 years; 12.70% female, median follow-up 510 days) were included, of whom 86 (63.70%) had MVO and 26 (19.26%) with MACE occurred in patients. Native T1 values of remote myocardium changed dynamically. At 1 week and 30 days, T1 values of remote myocardium in the group with MVO were higher than those without MVO (p = 0.030 and p = 0.001, respectively). In multivariable cox regression analysis of 135 patients, native1w T1 (HR 1.03, 95%CI 1.01-1.04, p = 0.002), native30D T1 (HR 1.05, 95%CI 1.03-1.07, p < 0.001) and LGE (HR 1.10, 95%CI 1.05-1.15, p < 0.001) were joint independent predictors of MACE. In multivariable cox regression analysis of 86 patients with MVO, native30D T1 (HR 1.05, 95%CI 1.04-1.07, p < 0.001) and LGE (HR 1.10, 95%CI 1.05-1.15, p < 0.001) were joint independent predictors of MACE. CONCLUSIONS: The evolution of native T1 in remote myocardium was associated with the extent of microvascular impairment after reperfusion injury. In patients with MVO, native30D T1 and LGE were joint independent predictors of MACE.

Multiple Effects of High Surface Area Hollow Nanospheres Assembled by Nickel Cobaltate Nanosheets on Soluble Lithium Polysulfides.

Inhibiting the shuttle effect of soluble polysulfides and improving slow reaction kinetics are key factors for the future development of Li-S batteries. Herein, edelweiss shaped NiCo2O4 hollow nanospheres with a high surface area were prepared by a simple template method to modify the separator to realize multiple physical constraints and strong chemical anchoring on the polysulfides. On one hand, the good electrolyte wettability of NiCo2O4 promoted the migration of Li-ions and greatly improved the dynamics. On the other hand, mesoporous NiCo2O4 nanomaterials provided many strong chemical binding sites for loading sulfur species. The hollow structure also provided a physical barrier to mitigate the sulfur species diffusion. Therefore, the modified separator realized multiple physical constraints and strong chemical anchoring on sulfur species. As a result, the sulfur cathode based on this composite separator showed significantly enhanced electrochemical performance. Even at 4 C, a high capacity of 505 mAh g-1 was obtained, and about 80.6% could be retained after 300 cycles.

Protocol for pyrotinib cardiac safety in patients with HER2-positive early or locally advanced breast cancer-The EARLY-MYO-BC study.

Background and aim: Cardiotoxicity has become the most common cause of non-cancer death among breast cancer patients. Pyrotinib, a tyrosine kinase inhibitor targeting HER2, has been successfully used to treat breast cancer patients but has also resulted in less well-understood cardiotoxicity. This prospective, controlled, open-label, observational trial was designed to characterize pyrotinib's cardiac impacts in the neoadjuvant setting for patients with HER2-positive early or locally advanced breast cancer. Patients and methods: The EARLY-MYO-BC study will prospectively enroll HER2-positive breast cancer patients who are scheduled to receive four cycles of neoadjuvant therapy with pyrotinib or pertuzumab added to trastuzumab before radical breast cancer surgery. Patients will undergo comprehensive cardiac assessment before and after neoadjuvant therapy, including laboratory measures, electrocardiography, transthoracic echocardiography, cardiopulmonary exercise testing (CPET), and cardiac magnetic resonance (CMR). To test the non-inferiority of pyrotinib plus trastuzumab therapy to pertuzumab plus trastuzumab therapy in terms of cardiac safety, the primary endpoint will be assessed by the relative change in global longitudinal strain from baseline to completion of neoadjuvant therapy by echocardiography. The secondary endpoints include myocardial diffuse fibrosis (by T1-derived extracellular volume), myocardial edema (by T2 mapping), cardiac volumetric assessment by CMR, diastolic function (by left ventricular volume, left atrial volume, E/A, and E/E') by echocardiography, and exercise capacity by CPET. Discussion: This study will comprehensively assess the impacts of pyrotinib on myocardial structural, function, and tissue characteristics, and, furthermore, will determine whether pyrotinib plus trastuzumab is a reasonable dual HER2 blockade regimen with regard to cardiac safety. Results may provide information in selecting an appropriate anti-HER2 treatment for HER2-positive breast cancer. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04510532.