Deficiency of endothelial FGFR1 signaling via upregulation of ROCK2 activity aggravated ALI/ARDS.

Vascular leakage and inflammation are pathological hallmarks of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Endothelial cells (ECs) serve as a semipermeable barrier and play a key role in disease progression. It is well known that fibroblast growth factor receptor 1 (FGFR1) is required for maintaining vascular integrity. However, how endothelial FGFR1 functions in ALI/ARDS remains obscure. Here, we revealed that conditional deletion of endothelial FGFR1 aggravated LPS-induced lung injury, including inflammation and vascular leakage. Inhibition of its downstream Rho-associated coiled-coil-forming protein kinase 2 (ROCK2) by AAV Vec-tie-shROCK2 or its selective inhibitor TDI01 effectively attenuated inflammation and vascular leakage in a mouse model. In vitro, TNFα-stimulated human umbilical vein endothelial cells (HUVECs) showed decreased FGFR1 expression and increased ROCK2 activity. Furthermore, knockdown of FGFR1 activated ROCK2 and thus promoted higher adhesive properties to inflammatory cells and higher permeability in HUVECs. TDI01 effectively suppressed ROCK2 activity and rescued the endothelial dysfunction. These data demonstrated that the loss of endothelial FGFR1 signaling mediated an increase in ROCK2 activity, which led to an inflammatory response and vascular leakage in vivo and in vitro. Moreover, inhibition of ROCK2 activity by TDI01 provided great value and shed light on clinical translation.

Targeting epigenetically maladapted vascular niche alleviates liver fibrosis in nonalcoholic steatohepatitis.

Chronic hepatic diseases such as nonalcoholic steatohepatitis (NASH) suppress liver regeneration and lead to fibrosis and cirrhosis. Decoding the cellular and molecular network underlying this fibrotic maladaptation might aid in combatting NASH, a growing health challenge with no approved therapies. Here, we used multiomics analysis of human cirrhotic liver, a Western diet­ and carbon tetrachloride (CCl4)­induced minipig NASH model, and genetically modified mice to unravel the landscape of the vascular adaptome at the single-cell level, in which endothelial cells (ECs) and TH17 cells jointly contribute to liver cirrhosis. We found that epigenetics-dependent hepatic vascular maladaptation enriches fibrogenic TH17 cells to promote liver fibrosis in mice, minipigs, and human patients with cirrhosis. Further analysis of humans, minipigs, and mice suggested that cross-talk between histone deacetylase 2 (HDAC2) and DNA methyltransferase 1 (DNMT1) promoted liver EC maladaptation to promote production of angiocrine IGFBP7 and ADAMTS1 in extracellular vesicles, recruiting fibrogenic TH17 cells to the liver. Pharmacological targeting of HDAC2 and DNMT1 alleviated fibrosis in a minipig NASH model. We conclude that epigenetically reprogrammed vascular adaptation contributes to liver fibrosis. Targeting of a vascular adaptation node might block maladaptive vascularization to promote liver regeneration in NASH.

Association between interleukin-32 polymorphisms and ovarian cancer in the Chinese Han population.

Interleukin-32 (IL-32) as a pro-inflammatory cytokine participates in the progression of inflammation and cancer. Ovarian cancer (OC) accounts for a considerable mortality rate, but research on IL-32 and OC is almost nil. Our study aims to explore the association between IL-32 and the progression as well as prognosis of OC initially. This hospital-based case-control study enrolled 147 OC patients and 337 healthy controls, and we used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to distribute the genotypes. The results showed that the homozygous genotype (TT) of rs28372698 SNP was significantly higher in patients compared to controls (12.9% vs. 6.2%, P = 0.018, OR (95% CI) = 2.23 (1.16-4.29)). This revealed that TT genotype might be a risk factor in OC progression. This present study indicates that IL-32 gene polymorphism relates to an increased OC susceptibility, and IL-32 may be a marker for OC progression.

Single-Crystal SnSe Thermoelectric Fibers via Laser-Induced Directional Crystallization: From 1D Fibers to Multidimensional Fabrics.

Single-crystal tin selenide (SnSe), a record holder of high-performance thermoelectric materials, enables high-efficient interconversion between heat and electricity for power generation or refrigeration. However, the rigid bulky SnSe cannot satisfy the applications for flexible and wearable devices. Here, a method is demonstrated to achieve ultralong single-crystal SnSe wire with rock-salt structure and high thermoelectric performance with diameters from micro- to nanoscale. This method starts from thermally drawing SnSe into a flexible fiber-like substrate, which is polycrystalline, highly flexible, ultralong, and mechanically stable. Then a CO2 laser is employed to recrystallize the SnSe core to single-crystal over the entire fiber. Both theoretical and experimental studies demonstrate that the single-crystal rock-salt SnSe fibers possess high thermoelectric properties, significantly enhancing the ZT value to 2 at 862 K. This simple and low-cost approach offers a promising path to engage the fiber-shaped single-crystal materials in applications from 1D fiber devices to multidimensional wearable fabrics.

Associations between TAB2 gene polymorphisms and dilated cardiomyopathy in a Chinese population.

Aim: The present study aimed to investigate the role of TAB2 gene polymorphisms in dilated cardiomyopathy (DCM) susceptibility and prognosis in a Chinese population. Materials & methods: A total of 343 DCM patients and 451 controls were enrolled and had their blood genotyped. Survival analysis was evaluated with Kaplan-Meier curves and Cox regression analysis. Results: G carriers (AG/GG) and AG genotype of rs237028 had a higher DCM susceptibility as well as a worse DCM prognosis. Additionally, C carriers (CT/CC) of rs652921 and G carriers (TG/GG) of rs521845 had a higher DCM risk and CC homozygote of rs652921 had a worse DCM prognosis. These associations were still significant after adjustment for the Bonferroni correction. Conclusion:TAB2 gene polymorphisms were associated with DCM susceptibility and prognosis in the Chinese population.

Mixed adenoneuroendocrine carcinoma of the liver: A rare case report.

A 55-year-old woman presented with chest and back pain of unknown cause. Contrast-enhanced computed tomography revealed two low-density tumors, sized 4.6 and 4.4 cm, in the hepatic caudate and left inner lobes, respectively. There are multiple enlarged lymph nodes around the abdominal aorta, hepatogastric ligament and gastrosplenic ligament. At the same time, there were multiple enlarged lymph nodes between the portal vein and the vena cava. Upper gastrointestinal endoscopy revealed chronic non-atrophic gastritis and esophagitis (grade B). Endoscopic examination of the lower digestive tract revealed polyps of the colon, diagnosed as tubular adenomas following biopsy and histopathological examination. The patient underwent left three hepatic resection (including left inner lobe, left outer lobe and right anterior lobe resection), abdominal lymph node dissection, right liver tumor radiofrequency ablation, hepatic caudate lobe resection, intestinal adhesion release, vena cava formation, portal vein repair and hilar cholangioplasty. The pathological examination of the resected specimens revealed intrahepatic bile duct carcinoma and hepatic parenchymal neuroendocrine tumor (NET). In addition, liver solid portions consisted of tumor cells with characteristic salt-and-pepper nuclei. Immunohistochemical examination revealed expression of the neuroendocrine marker synaptophysin in this solid component, confirming the diagnosis of NET. Furthermore, the MIB-1 proliferation index of the NET was higher compared with that of the adenocarcinoma, and lymph node invasion by the NET component was detected, indicating a neuroendocrine carcinoma (NEC, or NET G3). The diagnosis of mixed adenoneuroendocrine carcinoma of the liver was confirmed based on the World Health Organization 2010 criteria. Taking into consideration the patient's poor general condition, only symptomatic supportive treatment was administered postoperatively, without chemotherapy. Contrast-enhanced computed tomography at 45 days postoperatively revealed disease progression, with metastases in the liver stump, abdominal lymph nodes, spine and pelvis. The patient remained on symptomatic supportive treatment and succumbed to disease progression 3 months after surgery.

Associations between TAB2 Gene Polymorphisms and Epithelial Ovarian Cancer in a Chinese Population.

BACKGROUND: Epithelial ovarian cancer (EOC) is highly lethal worldwide. Factors involved in the inflammation and hormone-associated signaling pathway play vital roles in EOC carcinogenesis. The transforming growth factor-ß- (TGF-ß-) activated kinase 1 (MAP3K7) binding protein 2 (TAB2), mediating convergence of inflammatory and estrogen, may be implicated in EOC. The present study is aimed at exploring the association between the TAB2 gene polymorphisms and EOC. METHODS: Three single nucleotide polymorphisms (SNPs) (rs237028, rs521845, and rs652921) of TAB2 were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 221 patients and 252 healthy controls. Associations between SNPs and clinical characteristics were performed either with the χ 2 test or with Fisher's exact test. The Kaplan-Meier method and Cox proportional hazard models were used to detect associations between genotypes and overall survival. RESULTS: The rs237028 polymorphism was significantly associated with an increased risk of EOC with an allelic genetic model (A vs. G; OR = 1.45; 95%CI = 1.07-1.96; P = 0.016), dominant genetic model (AA vs. AG-GG; OR = 1.66; CI 1.14-2.41; P = 0.008), and overdominant genetic model (AA-GG vs. AG; OR = 1.60; CI 1.08-2.36; P = 0.017). However, no significant association was observed between rs237028 polymorphism and overall survival. CONCLUSIONS: Our study indicated that the rs237028 polymorphism in the TAB2 gene was associated with EOC susceptibility and the TAB2 gene might contribute to the initiation of EOC.

Association between AXIN1 gene polymorphisms and epithelial ovarian cancer in Chinese population.

Aim: The study was aimed to explore the association between AXIN1 gene polymorphism and epithelial ovarian cancer (EOC) susceptibility as well as prognosis. Methods: A total of 165 EOC cases and 327 healthy controls were recruited to participate in this study. In total three tag SNPs in AXIN1 gene were genotyped using PCR-restriction fragment length polymorphism. Results: Significantly increased EOC risk was found associated with the A/C heterozygous genotype of rs12921862, the C allele and C/T genotype in the rs1805105 and the T/T genotype of rs370681. Meanwhile, Kaplan-Meier survival curves showed that patients with rs12921862 C/C genotype improved overall survival in the EOC group. Conclusion: Our results suggest that the AXIN1 gene may be related to susceptibility and overall survival in EOC.

Transcription factor FOXP3 gene variants affect epithelial ovarian carcinoma in the Han Chinese population.

BACKGROUND: Epithelial ovarian cancer (EOC) is the most common cause of death among gynecological cancers. FOXP3 gene is the most dependable marker for regulatory T cells (Treg) which play a major role in immune tolerance. The aim of this study was to explore whether the FOXP3 gene polymorphisms (rs3761548 A/C and rs5902434del/ATT) were associated susceptibility and prognosis for EOC. METHODS: A total of 455 ovarian cancer patients and 337 healthy female controls were enrolled. Genotyping of FOXP3 polymorphisms rs3761548 A/C was determined by polymerase chain reaction-restrictive fragment length polymorphism (PCR-RFLP), while rs5902434 del/ATT was directly visualized in a 6% polyacrylamide gel electrophoresis stained after PCR. Kaplan-Meier method and Cox regression analysis were used to find an association between the FOXP3 gene and survival of EOC patients. RESULTS: Data showed that AC genotype of FOXP3 rs3761548 was associated with the high susceptibility of EOC (overdominant model: OR=1.42, 95% CI=1.07-1.89, P=0.015), while AA genotype showed lower risk for ovarian cancer compared with CC/AC genotypes (OR=0.45, 95% CI=0.23-0.90, P=0.022). In contrast, there were no significant differences for rs5902434 polymorphism of FOXP3 in ovarian cancer patients and controls. However, del/ATT genotype might be an independent risk factor for EOC prognosis in the dominant (HR=2.60, 95% CI=1.26-5.38, P=0.010) and overdominant (HR=2.46, 95% CI=1.31-4.61, P=0.005) models. CONCLUSIONS: Our findings suggest that rs3761548 could contribute to EOC risk in a Chinese Han population. Rs5902434 polymorphisms might be a marker to identify high risk patients.