Aortic Stress Activates an Adaptive Program in Thoracic Aortic Smooth Muscle Cells That Maintains Aortic Strength and Protects Against Aneurysm and Dissection in Mice.

BACKGROUND: When aortic cells are under stress, such as increased hemodynamic pressure, they adapt to the environment by modifying their functions, allowing the aorta to maintain its strength. To understand the regulation of this adaptive response, we examined transcriptomic and epigenomic programs in aortic smooth muscle cells (SMCs) during the adaptive response to AngII (angiotensin II) infusion and determined its importance in protecting against aortic aneurysm and dissection (AAD). METHODS: We performed single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) analyses in a mouse model of sporadic AAD induced by AngII infusion. We also examined the direct effects of YAP (yes-associated protein) on the SMC adaptive response in vitro. The role of YAP in AAD development was further evaluated in AngII-infused mice with SMC-specific Yap deletion. RESULTS: In wild-type mice, AngII infusion increased medial thickness in the thoracic aorta. Single-cell RNA sequencing analysis revealed an adaptive response in thoracic SMCs characterized by upregulated genes with roles in wound healing, elastin and collagen production, proliferation, migration, cytoskeleton organization, cell-matrix focal adhesion, and PI3K-PKB/Akt (phosphoinositide-3-kinase-protein kinase B/Akt) and TGF-ß (transforming growth factor beta) signaling. ScATAC-seq analysis showed increased chromatin accessibility at regulatory regions of adaptive genes and revealed the mechanical sensor YAP/transcriptional enhanced associate domains as a top candidate transcription complex driving the expression of these genes (eg, Lox, Col5a2, Tgfb2). In cultured human aortic SMCs, cyclic stretch activated YAP, which directly bound to adaptive gene regulatory regions (eg, Lox) and increased their transcript abundance. SMC-specific Yap deletion in mice compromised this adaptive response in SMCs, leading to an increased AAD incidence. CONCLUSIONS: Aortic stress triggers the systemic epigenetic induction of an adaptive response (eg, wound healing, proliferation, matrix organization) in thoracic aortic SMCs that depends on functional biomechanical signal transduction (eg, YAP signaling). Our study highlights the importance of the adaptive response in maintaining aortic homeostasis and preventing AAD in mice.

HO-1-induced autophagy establishes a HO-1-p62-Nrf2 positive feedback loop to reduce gut permeability in cholestatic liver disease.

OBJECTIVES: The gut-liver axis disruption is a unified pathogenetic principle of cholestatic liver disease (CSLD). Increased gut permeability is the leading cause of gut-liver axis disruption. HO-1 is capable of protecting against gut-liver axis injury. However, it has rarely been reported whether autophagy is involved in HO-1 protecting gut-liver barrier integrity and the underlying mechanism. MATERIALS AND METHODS: Mice underwent bile duct ligation (BDL) was established as CSLD model in vivo. Caco-2 cells with LPS treatment was established as in vitro cell model. Immunofluorescence, western blot and transepithelial electrical resistance (TER) assay were used to observe epithelial tight junction (TJ) and autophagy. Liver injury and fibrosis were evaluated as well through H&E staining, masson staining, sirius red staining and ELISA. RESULTS AND CONCLUSIONS: Our study demonstrated that the epithelial TJ and TER were notably reduced both in BDL mice and in LPS treated intestinal epithelial cells. Increased HO-1 expression could significantly induce intestinal epithelial cell autophagy. Additionally, this increased autophagy level reversed the reduction effects of BDL or LPS on epithelial TJ and TER in vivo and in vitro, therefore decreased transaminase level in serum and relieved liver fibrosis in BDL mice. Besides, increased autophagy level in turn upregulated the expression of HO-1 by p62 degradation of Keap1 and subsequent activation of Nrf2 pathway. Collectively, these results indicate that HO-1 reduces gut permeability by enhancing autophagy level in CSLD, the increased autophagy establishes a HO-1-p62-Nrf2 positive feedback loop to further improve gut-liver axis disruption. Therefore, our study confirms the critical role of autophagy in HO-1 ameliorating gut-liver axis injury during CSLD, highlighting HO-1 as a promising therapeutic target.

The efficacy of rituximab plus belimumab or telitacicept in refractory lupus nephritis.

OBJECTIVE: Lupus nephritis is a severe and common complication of systemic lupus erythematosus (SLE). The pathogenesis of lupus nephritis is characterized by B-cell activation and autoantibody formation. Rituximab and belimumab, as well as telitacicept, target B cells through different mechanisms, potentially exerting a synergistic effect in the treatment of lupus nephritis. This study aims to investigate the efficacy and safety of treatment with rituximab followed by belimumab or telitacicept in the management of refractory lupus nephritis. METHODS: We conducted a single-center, open-label, retrospective study, including 25 patients with refractory lupus nephritis. All patients received combination therapy with rituximab in individualized dosages to achieve peripheral B-cell depletion, and then followed by belimumab or telitacicept. The follow-up period was at least 12 months, and the primary end point was renal remission rate at the last follow-up. RESULTS: During a median follow-up of 19 (13, 29) months, 20 of 25 (80%) patients achieved objective remission (OR), including 19 (76%) patients achieved complete renal response (CRR). After rituximab (712 ± 416mg in average), 18 patients received belimumab and seven patients received telitacicept. In the rituximab plus telitacicept group, all patients achieved CRR; while in the rituximab plus belimumab group, 12 (66.7%) patients achieved CRR and 13 (72.2%) patients achieved OR. The mean SLEDAI-2K score decreased from 15 ± 6 to 6 ± 6, representing an average reduction of 60%. At the last follow-up, 18/25 (72%) had prednisone ≤ 5 mg/d or even discontinued prednisone use. Adverse effects were mainly immunoglobulin deficiency, respiratory tract infection, urinary tract infections, and rash. No death occurred. CONCLUSIONS: Rituximab followed by belimumab or telitacicept may be effective in inducing remission in refractory lupus nephritis, with tolerable adverse effects.

Early Detection of Aortic Degeneration in a Mouse Model of Sporadic Aortic Aneurysm and Dissection Using Nanoparticle Contrast-Enhanced Computed Tomography.

[Figure: see text].

The survival nomograms for anti-neutrophil cytoplasmic antibody-associated glomerulonephritis patients with a follow-up of more than one year.

OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis with kidney injury, manifested as ANCA-associated glomerulonephritis (AAGN), often portends a poor prognosis of renal function and life survival in long term. METHODS: A cohort of 339 AAGN patients were enrolled retrospectively. These patients survived and were followed up for at least 12 months after diagnosis in our centre. Multivariate Cox regression analysis and nomogram models were performed to determine the risk factors associated with renal survival and patient survival. RESULTS: The median follow-up time of all 339 patients was 65.2 (IQR 45.1, 91.3) months and the median age was 61(IQR 53, 69) years. In order to analyse the impact of the factors on renal survival, we divided the patients into 2 groups: non-dialysis group (204 patients without dialysis at the final visit) and dialysis group (135 patients with maintaining dialysis). The patients in dialysis group had lower haemoglobin level, lower eGFR level, lower platelets count, more daily urine protein, and higher Birmingham Vasculitis Activity Score (BVAS) at admission than those in non-dialysis group. Multivariate Cox regression revealed that low haemoglobin (HR=0.977, 95%CI 0.965-0.990, p<0.001), low eGFR (HR=0.957, 95%CI 0.941-0.973, p<0.001) and high proteinuria (HR=1.139, 95%CI 1.055-1.230, p=0.001) at admission were independent risk factors for developing maintaining dialysis. A nomogram was established based on the results of multivariate Cox analysis and the internal bootstrap resampling approach showed the C-index of the nomogram was 0.83. Then we divided all patients into death group (n=99) and survival group (n=240). The patients in death group had older age, more hypertension, more chronic lung disease, lower platelets count, lower serum albumin, higher BVAS and lower eGFR at admission than those in survival group. Multivariate Cox regression revealed that the status of maintaining dialysis (HR 3.51, 95% CI 1.91-6.47, p<0.001) and old age (HR 1.07, 95% CI 1.04-1.09, p<0.001) were independent risk factors for all-cause mortality. Again, a nomogram was established and the C-index was 0.74. CONCLUSIONS: We analysed the independent risk factors for maintaining dialysis and all-cause mortality in AAGN patients with a follow-up of more than 12 months. The two proposed nomograms were of predictive value.

Critical Role of Cytosolic DNA and Its Sensing Adaptor STING in Aortic Degeneration, Dissection, and Rupture.

BACKGROUND: Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation. METHODS: The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in Sting-deficient (Stinggt/gt) mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro. RESULTS: In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model, Stinggt/gt mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challenged Stinggt/gt mice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development. CONCLUSIONS: Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.

Single-Cell Transcriptome Analysis Reveals Dynamic Cell Populations and Differential Gene Expression Patterns in Control and Aneurysmal Human Aortic Tissue.

BACKGROUND: Ascending thoracic aortic aneurysm (ATAA) is caused by the progressive weakening and dilatation of the aortic wall and can lead to aortic dissection, rupture, and other life-threatening complications. To improve our understanding of ATAA pathogenesis, we aimed to comprehensively characterize the cellular composition of the ascending aortic wall and to identify molecular alterations in each cell population of human ATAA tissues. METHODS: We performed single-cell RNA sequencing analysis of ascending aortic tissues from 11 study participants, including 8 patients with ATAA (4 women and 4 men) and 3 control subjects (2 women and 1 man). Cells extracted from aortic tissue were analyzed and categorized with single-cell RNA sequencing data to perform cluster identification. ATAA-related changes were then examined by comparing the proportions of each cell type and the gene expression profiles between ATAA and control tissues. We also examined which genes may be critical for ATAA by performing the integrative analysis of our single-cell RNA sequencing data with publicly available data from genome-wide association studies. RESULTS: We identified 11 major cell types in human ascending aortic tissue; the high-resolution reclustering of these cells further divided them into 40 subtypes. Multiple subtypes were observed for smooth muscle cells, macrophages, and T lymphocytes, suggesting that these cells have multiple functional populations in the aortic wall. In general, ATAA tissues had fewer nonimmune cells and more immune cells, especially T lymphocytes, than control tissues did. Differential gene expression data suggested the presence of extensive mitochondrial dysfunction in ATAA tissues. In addition, integrative analysis of our single-cell RNA sequencing data with public genome-wide association study data and promoter capture Hi-C data suggested that the erythroblast transformation-specific related gene(ERG) exerts an important role in maintaining normal aortic wall function. CONCLUSIONS: Our study provides a comprehensive evaluation of the cellular composition of the ascending aortic wall and reveals how the gene expression landscape is altered in human ATAA tissue. The information from this study makes important contributions to our understanding of ATAA formation and progression.

Activation of Bone Marrow-Derived Cells and Resident Aortic Cells During Aortic Injury.

BACKGROUND: The process of aortic injury, repair, and remodeling during aortic aneurysm and dissection is poorly understood. We examined the activation of bone marrow (BM)-derived and resident aortic cells in response to aortic injury in a mouse model of sporadic aortic aneurysm and dissection. MATERIALS AND METHODS: Wild-type C57BL/6 mice were transplanted with green fluorescent protein (GFP)+ BM cells. For 4 wk, these mice were either unchallenged with chow diet and saline infusion or challenged with high-fat diet and angiotensin II infusion. We then examined the aortic recruitment of GFP+ BM-derived cells, growth factor production, and the differentiation potential of GFP+ BM-derived and GFP- resident aortic cells. RESULTS: Aortic challenge induced recruitment of GFP+ BM cells and activation of GFP- resident aortic cells, both of which produced growth factors. Although BM cells and resident aortic cells equally contributed to the fibroblast populations, we did not detect the differentiation of BM cells into smooth muscle cells. Interestingly, aortic macrophages were both of BM-derived (45%) and of non-BM-derived (55%) origin. We also observed a significant increase in stem cell antigen-1 (Sca-1)+ stem/progenitor cells and neural/glial antigen 2 (NG2+) cells in the aortic wall of challenged mice. Although some of the Sca-1+ cells and NG2+ cells were BM derived, most of these cells were resident aortic cells. Sca-1+ cells produced growth factors and differentiated into fibroblasts and NG2+ cells. CONCLUSIONS: BM-derived and resident aortic cells are activated in response to aortic injury and contribute to aortic inflammation, repair, and remodeling by producing growth factors and differentiating into fibroblasts and inflammatory cells.

Establishment and evaluation of a risk-scoring system for lymph node metastasis in early-stage endometrial carcinoma: Achieving preoperative risk stratification.

AIM: To establish a risk-scoring system for lymph node metastasis (LNM) of early-stage endometrial carcinoma (EC), and to stratify the preoperative risk of LNM. METHODS: We retrospectively analyzed the clinical data of 507 patients diagnosed with the early-stage EC (i.e., confined to the uterine corpus). We determined the risk factors for LNM by logistic regression analysis; then constructed a simple logistic scoring system, and an additive scoring system based on the regression coefficient (ß), and odds ratio, of each variable, respectively. RESULTS: The overall rate of LNM was 9.1% (46/507). Multivariate analysis showed that preoperative serum cancer antigen 125 (CA125) ≥35 U/mL, histopathology of grade 3 and/or type II, depth of myometrial invasion ≥1/2 and positive immunostaining for Ki-67 ≥50%, were independent risk factors for LNM (P < 0.05). The simple logistic and additive scoring systems exhibited good predictive ability (area under the curve [AUC] >0.8). Based on the additive scoring system, the risk of LNM in patients with early-stage EC was classified into three groups: a low-risk group (total score: <5), an intermediate-risk group (total score: 5-10) and a high-risk group (total score: >10). The incidence of LNM differed significantly across these three groups (P < 0.05). CONCLUSION: The risk-scoring system constructed in this study can effectively predict the risk of LNM in patients with early-stage EC, achieve preoperative risk stratification and provide a reference guideline for the use of lymphadenectomy.

NLRP3 (Nucleotide Oligomerization Domain-Like Receptor Family, Pyrin Domain Containing 3)-Caspase-1 Inflammasome Degrades Contractile Proteins: Implications for Aortic Biomechanical Dysfunction and Aneurysm and Dissection Formation.

OBJECTIVE: Increasing evidence suggests that contractile dysfunction in smooth muscle cells (SMCs) plays a critical role in aortic biomechanical dysfunction and aortic aneurysm and dissection (AAD) development. However, the mechanisms underlying SMC contractile dysfunction in sporadic AAD are poorly understood. In this study, we examined the role of the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3)-caspase-1 inflammasome, a key inflammatory cascade, in SMC contractile dysfunction in AAD. APPROACH AND RESULTS: We observed significant SMC contractile protein degradation in aortas from patients with sporadic thoracic AAD. The contractile protein degradation was associated with activation of the NLRP3-caspase-1 inflammasome cascade. In SMCs, caspase-1 bound and directly cleaved and degraded contractile proteins, leading to contractile dysfunction. Furthermore, Nlrp3 or caspase-1 deficiency in mice significantly reduced angiotensin II-induced contractile protein degradation, biomechanical dysfunction, and AAD formation in both thoracic and abdominal aortas. Finally, blocking this cascade with the inflammasome inhibitor, glyburide (an antidiabetic medication), reduced angiotensin II-induced AAD formation. CONCLUSIONS: Inflammasome-caspase-1-mediated degradation of SMC contractile proteins may contribute to aortic biomechanical dysfunction and AAD development. This cascade may be a therapeutic target in AAD formation. In addition, glyburide may have protective effects against AAD development.

[Expression of g6pd gene in wild type zebrafish embryos of early development].

OBJECTIVE: : To observe the expression of g6pd gene in the early development stage of wild zebrafish embryos. METHODS: : The collinearity of g6pd gene and the sequence similarity of G6pd protein were analyzed with gene database and BLAST software, respectively. Expression of g6pd gene in different development stages of zebrafish embryos was detected by in situ hybridization. The g6pd-EGFP-pCS2+ recombinant plasmids were microinjected into zebrafish embryos, and fluorescence was observed under a fluorescence microscope. The expression of G6pd protein at 24, 48 and 72 hour post fertilization (hpf) zebrafish embryos was detected by Western blotting; the enzyme activity of G6pd at 24, 48 and 72 hpf zebrafish embryos was detected by modified G6pd quantitative ratio method. RESULTS: : The G6pd protein similarity of zebrafish and human was 88%, and that of zebrafish and mouse was 87%. The results of in situ hybridization showed that the g6pd gene was mainly expressed in the hematopoietic tissues of zebrafish; the results observed after microinjection of g6pd-EGFP-pCS2+ recombinant plasmid were consistent with the results of in situ hybridization. At 24, 48 and 72 hpf, the relative expression levels of G6pd protein in zebrafish embryos were 1.44±0.03, 1.47±0.05, and 1.54±0.02, respectively(P>0.05); the G6pd enzyme activity levels were 1.74±0.17, 1.75±0.12, 1.71±0.22, respectively (P>0.05). CONCLUSIONS: : The study has observed the expression of g6pd gene and G6pd protein, and G6pd enzyme activity in zebrafish embryos at different development phases, which provides a reference for the establishment of a zebrafish G6PD deficiency model.

MicroRNA-148a promotes apoptosis and suppresses growth of breast cancer cells by targeting B-cell lymphoma 2.

MicroRNAs (miRNAs) contribute toward tumorigenesis through the modulation of tumor-related genes. MiR-148a has been characterized as a tumor-suppressing miRNA and its downregulation has been reported in tumors of a variety of cancers. However, the functional role of miR-148a in breast cancer is not yet fully understood. Using both in-vitro and in-vivo models, we confirmed that miR-148a acts to inhibit the proliferation of breast cancer cells. Through the use of bioinformatic approaches in miRNA target prediction, we determined that B-cell lymphoma 2 (BCL-2) is a likely target of miR-148a. The overexpression and tumorigenic effects of BCL-2 have already been confirmed in cancerous tumors of the breast. A dual-luciferase assay was performed to confirm that miR-148a targets the 3'-untranslated region of BCL-2. In this study, we first characterized the downregulation of miR-148a in breast cancer tissues. We then found that restoring expression of miR-148a suppressed the expression of BCL-2 at the level of both mRNA and protein. Upregulation of miR-148a caused a subsequent reduction of proliferation and an increase in apoptosis. In conclusion, we have confirmed the role of miR-148a as a pivotal regulator in breast cancer through its targeting of BCL-2. This evidence strongly suggests that miR-148a could prove to be a novel therapeutic target in breast cancer.

Serum Matrix Metalloproteinase-7 Level is Associated with Fibrosis and Renal Survival in Patients with IgA Nephropathy.

BACKGROUND/AIMS: In view of the latest findings that matrix metalloproteinase-7 (MMP-7) acted as a vital marker and pathogenic mediator of renal fibrosis in a murine model, we hypothesized that serum MMP-7 level might serve as a noninvasive prognostic biomarker in IgA nephropathy (IgAN) patients. METHODS: We conducted a retrospective follow-up study of 244 IgAN patients for a median of 81.9 months. Serum MMP-7 was detected at the time of diagnosis, and renal progression was assessed by Cox proportional hazards method. RESULTS: Compared with healthy populations, the serum levels of MMP-7 were significantly elevated in IgAN patients. Besides, serum MMP-7 levels were well correlated with renal scarring lesions characterized by glomerular sclerosis and interstitial fibrosis. Follow-up analyses revealed that increased serum MMP-7 levels were linked with a greater risk of poor renal outcome with a hazard ratio of 1.898 per doubling MMP-7 concentration. By contrast with the first quartile, the risk of deterioration in renal function elevated such that the hazard ratio for the second quartile was 1.805, 3.383 for the third, and 5.173 for the fourth quartile of the MMP-7 level. CONCLUSIONS: This study showed that the higher serum MMP-7 levels were independently associated with renal fibrosis and poor prognosis in IgAN.

AKT2 confers protection against aortic aneurysms and dissections.

RATIONALE: Aortic aneurysm and dissection (AAD) are major diseases of the adult aorta caused by progressive medial degeneration of the aortic wall. Although the overproduction of destructive factors promotes tissue damage and disease progression, the role of protective pathways is unknown. OBJECTIVE: In this study, we examined the role of AKT2 in protecting the aorta from developing AAD. METHODS AND RESULTS: AKT2 and phospho-AKT levels were significantly downregulated in human thoracic AAD tissues, especially within the degenerative medial layer. Akt2-deficient mice showed abnormal elastic fibers and reduced medial thickness in the aortic wall. When challenged with angiotensin II, these mice developed aortic aneurysm, dissection, and rupture with features similar to those in humans, in both thoracic and abdominal segments. Aortas from Akt2-deficient mice displayed profound tissue destruction, apoptotic cell death, and inflammatory cell infiltration that were not observed in aortas from wild-type mice. In addition, angiotensin II-infused Akt2-deficient mice showed significantly elevated expression of matrix metalloproteinase-9 (MMP-9) and reduced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). In cultured human aortic vascular smooth muscle cells, AKT2 inhibited the expression of MMP-9 and stimulated the expression of TIMP-1 by preventing the binding of transcription factor forkhead box protein O1 to the MMP-9 and TIMP-1 promoters. CONCLUSIONS: Impaired AKT2 signaling may contribute to increased susceptibility to the development of AAD. Our findings provide evidence of a mechanism that underlies the protective effects of AKT2 on the aortic wall and that may serve as a therapeutic target in the prevention of AAD.

Impaired right and left ventricular function in asymptomatic children with repaired tetralogy of Fallot by two-dimensional speckle tracking echocardiography study.

BACKGROUND: Early detection of right ventricular (RV) and left ventricular (LV) dysfunction in patients with repaired tetralogy of Fallot (TOF) is essential because dysfunction is correlated with a poor clinical outcome. The aim of this study was to assess RV and LV function in asymptomatic children with repaired TOF by two-dimensional ultrasound speckle tracking echocardiography (STE). METHODS: Fifty-six asymptomatic children with a preserved biventricular ejection fraction (EF) after repair of TOF and 35 healthy control subjects were studied. RV and LV strain and strain rate were measured by STE. RVEF and pulmonary regurgitation (PR) were assessed using cardiac magnetic resonance imaging. RESULTS: Compared with the control subjects, RV regional longitudinal strain and strain rate and global longitudinal strain (GLS) and strain rate (GLSR) were impaired in children with repaired TOF. Likewise, LV circumferential and radial strain and strain rate were reduced in patients with TOF. In contrast, longitudinal strain and strain rate did not differ between the groups. RV and LV GLSR were correlated with postoperative follow-up period (r1 = -0.44; r2 = -0.48). RV GLS and GLSR were associated with RVEF (r1 = 0.64; r2 = 0.60) and PR (r1 = -0.48; r2 = -0.49). LV circumferential strain rate was related to PR (r = -0.45). CONCLUSIONS: STE can identify abnormalities that may represent early impairment of RV and LV systolic function in postoperative TOF patients with a preserved EF. PR is associated with decreased biventricular performance in repaired patients. STE-derived strain and strain rate may be useful indices for detecting the early deterioration of biventricular performance in patients with TOF.

Fetal echocardiographic characteristics of fused heart in thoracopagus conjoined twins.

Conjoined twins (CT) are rare with possible serious malformations in which soft tissue, bone, or some organs are joined in utero. The extent of cardiac fusion and intracardiac anatomy of CT determine the viability, natural history, and outcome of potential surgical intervention. Early prenatal diagnosis and assessment may provide a window of opportunity to counsel the family for their informed decision on the pregnancy and to plan for prenatal and perinatal care. In this report, we describe a case of thoracopagus twins diagnosed by fetal echocardiography at 23-week gestation. The 2 hearts fused at the atrial and ventricular levels. The outcome and review of literature on fetal echocardiographic characteristics of this malformation are discussed.

[Early conversion from calcineurin inhibitor to sirolimusto after renal transplantation:a prospective, open-label and non-randomized control study].

OBJECTIVE: To explore the efficacy and safety of designed early conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) as major immunosuppressive therapy in renal transplant recipients with stable renal function. METHODS: A prospective, open-label and non-randomized control study was performed for 112 renal transplant recipients (3-6 months post-operation) with stable renal function between June 2008 and June 2011. The patients in SRL group (n = 57) switched to sirolimus while those in CNI group (n = 55) continued CNI. The dosing of mycophenolate mofetil and steroids had no change. They were followed up for at least 24 months to evaluate the acute rejection, patient and graft survival, renal function, estimated glomerular filtration rate (eGFR), blood lipids, blood glucose, liver function and urinary protein at 1, 6, 12 and 24 months after inclusion. Adverse events were also recorded. RESULTS: The serum creatinine of SRL group decreased significantly after conversion ( (89.2 ± 24.7), (87.6 ± 23.8), (86.1 ± 20.4), (86.7 ± 19.7) vs (117.0 ± 16.3) µmol/L, all P < 0.05). CNI group showed no improvement of renal function.SRL group had a significantly higher eGFR than CNI group (P < 0.05). Among 3 cases of acute rejection, there were 2 in SRL group and 1 in CNI group (P > 0.05). Blood lipids in SRL group increased significantly at 1 month after conversion (P < 0.05) and reverted back to average level after intervention (P > 0.05).SRL group had a drop of hemoglobin level within the normal range. Two patients in SRL group developed hypokalemia and another 2 patients had oral ulcer. They all improved after treatment. During follow-ups, 1 case of mild proteinuria was found in SIR group. Three patients were diagnosed with diabetes (1 in SRL group vs 2 in CNI group). CONCLUSIONS: Early conversion from CNI to SRL as major immunosuppressive therapy in renal transplant recipients with stable renal function further improves renal function. There is no higher rate of acute rejection during follow-up.Elevated blood lipids after conversion may be easily controlled. No other adverse events are found.

P-CAB versus PPI in the eradication of Helicobacter pylori: a systematic review and network meta-analysis.

Background: The efficacy and safety of potassium-competitive acid blockers (P-CABs) in the eradication of Helicobacter pylori (Hp) remains controversial when compared with proton pump inhibitors (PPIs). Objectives: The current study set out to compare the differences in the eradication rate and adverse reactions between eradication regimens based on P-CAB or PPI drugs and the differences between the vonoprazan-based and the tegoprazan-based regimens to explore the efficacy and safety of different Hp eradication regimens. Data sources and methods: Databases including PubMed, EMBASE, Cochrane Library, and WOS were searched from the inception of these databases up to July 2023, and eligible randomized controlled trials (RCTs) were included. The outcome measures were the eradication rate and the incidence of adverse reactions of different regimens in treating Hp. The results were estimated as relative risk (RR) and its 95% confidence interval (CI), and R 4.2.1 software was used to perform the network meta-analysis (NMA). Results: A total of 20 studies were included in the analysis, involving 5815 patients with Hp. In terms of eradication rate, the 2-week vonoprazan-based triple regimen (V-Tri-2w) was the best, which was superior to the 2-week PPI-based quadruple regimen [P-Qua-2w, RR = 0.9, 95% CI: (0.85-0.95)] and the 1-week tegoprazan-based triple regimen [T-Tri-1w, RR = 0.79, 95% CI: (0.64-0.97)]; the 2-week tegoprazan-based quadruple regimen (T-Qua-2w) was superior to the 1-week PPI-based triple regimen [P-Tri-1w, RR = 0.82, 95% CI: (0.67-0.99)], and there was no difference between the remaining tegoprazan-based regimens and the PPI-based or vonoprazan-based regimens. In terms of the incidence of adverse reactions, the 2-week vonoprazan-based binary regimen (V-Bi-2w) was lower than that of the 2-week PPI-based quadruple regimen [P-Qua-2w, RR = 1.98, 95% CI: (1.57-2.52)]; there was no significant difference between 1 and 2 weeks for each regimen, such as the vonoprazan-based triple regimen [RR = 1.11, 95% CI: (0.82-1.52)]. Conclusion: In the eradication treatment of Hp, the efficacy and safety of vonoprazan-based regimens are generally better than those of PPI-based regimens. Among them, the V-Tri-2w regimen has the highest eradication rate and may be the preferred choice for Hp eradication.

Integrated single-cell sequencing, spatial transcriptome sequencing and bulk RNA sequencing highlights the molecular characteristics of parthanatos in gastric cancer.

BACKGROUND: Parthanatos is a novel programmatic form of cell death based on DNA damage and PARP-1 dependency. Nevertheless, its specific role in the context of gastric cancer (GC) remains uncertain. METHODS: In this study, we integrated multi-omics algorithms to investigate the molecular characteristics of parthanatos in GC. A series of bioinformatics algorithms were utilized to explore clinical heterogeneity of GC and further predict the clinical outcomes. RESULTS: Firstly, we conducted a comprehensive analysis of the omics features of parthanatos in various human tumors, including genomic mutations, transcriptome expression, and prognostic relevance. We successfully identified 7 cell types within the GC microenvironment: myeloid cell, epithelial cell, T cell, stromal cell, proliferative cell, B cell, and NK cell. When compared to adjacent non-tumor tissues, single-cell sequencing results from GC tissues revealed elevated scores for the parthanatos pathway across multiple cell types. Spatial transcriptomics, for the first time, unveiled the spatial distribution characteristics of parthanatos signaling. GC patients with different parthanatos signals often exhibited distinct immune microenvironment and metabolic reprogramming features, leading to different clinical outcomes. The integration of parthanatos signaling and clinical indicators enabled the creation of novel survival curves that accurately assess patients' survival times and statuses. CONCLUSIONS: In this study, the molecular characteristics of parthanatos' unicellular and spatial transcriptomics in GC were revealed for the first time. Our model based on parthanatos signals can be used to distinguish individual heterogeneity and predict clinical outcomes in patients with GC.

Hydroxychloroquine Induces Remission for IgA Nephropathy With Mild to Moderate Proteinuria: A Single-Centered Retrospective Analysis.

BACKGROUND: Hydroxychloroquine (HCQ) influences both toll-like receptor (TLR) signaling and leukocyte activation, which are speculated to play a role in the pathogenesis of IgA nephropathy (IgAN). METHODS: This is a single-centered retrospective study involving 426 IgAN patients diagnosed from May 2016 to August 2020. All patients were matched according to a propensity score matching (PSM) to produce three groups: renin-angiotensin-aldosterone system inhibitors (RAASi) group (RAASi only), corticosteroids group (corticosteroids only or combined with RAASi), and HCQ group (HCQ only or combined with RAASi), consisting of 63 patients for each group. RESULTS: After PSM, the median urine protein/creatinine ratio (UPCR) of overall patients was 0.91 g/g, while their median serum creatinine was 87.00 µmol/L. After the median follow-up period of 11.03 months, the total remission rates of the RAASi group, corticosteroids group, and HCQ groups were 49.21% (n = 31), 74.60% (n = 47), and 52.38% (n = 33), respectively (p = 0.017). Thirteen (6.88%) patients experienced a decline in estimated glomerular filtration rate (eGFR) of more than 25% from baseline, including six (9.52%) patients in the RAASi group, three (4.76%) patients in the corticosteroids group, and four (6.35%) patients in HCQ group (p = 0.677). One (1.59%) patient in the HCQ group had blurred vision and continued to use HCQ after ruling out retinal lesions by ophthalmic examination. CONCLUSION: HCQ is effective in inducing remission and well-tolerated in IgAN patients with mild to moderate proteinuria.