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Primary autosomal recessive microcephaly 5 (MCPH5) is a rare neurodevelopmental disorder with a relatively high incidence in regions where consanguineous marriage is widely practiced; So far, only a few MCPH5 cases have been reported from China. Here, we report clinical and molecular characteristics of two Chinese MCPH5 patients, a 24-year-old woman proband and her brother, a 19-year-old man, from a nonconsanguineous family. Main manifestations in the proband were small head circumference, premature closure of fontanelles, impaired concentration and moderate intellectual disability. The proband's brother had similar symptoms, but he was hyperactive and had a more severe sloping forehead. Brain imaging revealed global reduction in brain size, especially in the frontal lobes bilaterally and anterior horns of lateral ventricles. Sequencing results revealed that both patients carried a novel nonsense variant p.Tyr2004* (c.6012_6013delTA) and a novel frameshift variant p.Arg2005Serfs*48 (c.6015_6016delGG) in the ASPM gene. These variants were interpreted to be pathogenic in the in-silico analysis. Our findings help to expand the mutation spectrum of ASPM and provide new opportunities for assisting the traditional clinical diagnosis on the cases with atypical characteristics.

In this study, we investigated the mechanisms through which astrocyte-derived exosomes (AS-Exos) alleviate traumatic brain injury (TBI)-induced neuronal defects in TBI model rats and mice. Treatment with AS-Exos alleviated neurobehavioral deficits, cognitive impairment, and brain edema in TBI rats. AS-Exos also significantly reduced neuronal cell loss and atrophy in the TBI rats. AS-Exos significantly reduced oxidative stress and mitochondrial H2O2 levels by increasing the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) in the hippocampal neurons of TBI rats. TUNEL-staining assays showed that AS-Exos significantly reduced TBI-induced neuronal apoptosis. Mechanistically, AS-Exos ameliorated oxidative stress by activating Nrf2/HO-1 signaling in the hippocampus of TBI rats. In addition, the neuroprotective effects of AS-Exos were abrogated in brain-specific Nrf2-knockout mice subjected to TBI. These findings demonstrate that AS-Exos protects against TBI-induced oxidative stress and neuronal apoptosis by activating Nrf2 signaling in both rat and mouse models.

Background. Transcatheter closure of aneurysmal perimembranous ventricular septal defect (pmVSD), pmVSD near the aortic valve, and intracristal VSD (icVSD) with symmetrical or asymmetrical ventricular septal defect occluders still presents significant challenges. We report our experience with transcatheter closure of pmVSD and icVSD using Amplatzer duct occluder II (ADO II) in children. Method. We retrospectively analyzed all children, who presented to our hospital consecutively between March 2014 and June 2020 for attempted transcatheter closure of pmVSD or icVSD with the ADO II device. Standard safety and last-follow-up outcomes were assessed and compared. Results. In total, 41 patients underwent transcatheter closure of VSD with the ADO II (28 in pmVSD and 13 in icVSD groups) with a median age of 3.5 years (total range: 0.9 to 12 years) and median weight of 15.0 kg (total range: 10.0 to 43.0 kg). Implantation was successful in 40/41 patients (97.5%, 27/28 in pmVSD group, 13/13 in icVSD group). One patient with mild aortic valve prolapse in pmVSD group developed new-onset moderate aortic regurgitation after a 4/4 mm ADO II was deployed; however, this resolved after the device was retrieved and successfully replaced with a 5 mm zero eccentric VSD occluder. There was no procedure-related mortality. After a median follow-up of six months (total range: 6 to 72 months), complete closure rates were 85.1% and 76.9% among pmVSD and icVSD groups, respectively. In the pmVSD group, one case of new-onset moderate tricuspid regurgitation was observed at six months, and there was one case of severe tricuspid regurgitation that had progressed from mild tricuspid regurgitation at 12 months. No serious complications were noted in the icVSD group. Conclusion. ADO II provides a safe and reproducible alternative for the closure of perimembranous and intracristal ventricular septal defects with a diameter less than 5 mm in young children.

Traumatic brain injury (TBI) is a highly lethal event with a poor prognosis. Recovering residual neuronal function in the intermediate stage of TBI is important for treatment; however, neuroinflammation and neuronal apoptosis impede residual neuronal repair processes. Considering that hyperglycemia influences inflammatory processes and neuronal survival, we examined the effects of high glucose on neuroinflammation and neuronal death during the intermediate phase of TBI. Rat models of type 2 diabetes mellitus and/or TBI were developed and behaviorally assessed. Neurological function and cognitive abilities were impaired in TBI rats and worsened by type 2 diabetes mellitus. Histopathological staining and analyses of serum and hippocampal mRNA and protein levels indicated that neuroinflammation and apoptosis were induced in TBI rats and exacerbated by hyperglycemia. Hyperglycemia inhibited hippocampal mitogen-activated protein kinase kinase 5 (MEK5) phosphorylation in TBI rats. In vitro assays were used to assess inflammatory factor expression, apoptotic protein levels and neuronal survival after MEK5 activation in TBI- and/or high-glucose-treated neurons. MEK5/extracellular signal-regulated kinase 5 (ERK5) pathway activation reduced the inflammation, cleaved caspase-3 expression, Bax/Bcl-2 ratio and apoptosis of TBI neurons, even under high-glucose conditions. Thus, high glucose exacerbated neuroinflammation and apoptosis in the intermediate stage post-TBI by inhibiting the MEK5/ERK5 pathway.

It has been reported that multiwalled carbon nanotubes (MWCNTs) can reportedly positively affect growth and differentiation of bone-related cells and therefore offer great potential in biomedical applications. To overcome negative immune responses that limit their application, specific doping and functionalization can improve their biocompatibility. Here, we demonstrated that nitrogen-doped carboxylate-functionalized MWCNTs (N-MWCNTs) enhance bone remodeling both in vitro and in vivo with excellent biocompatibility, via stimulation of both bone resorption and formation. We revealed that 0.2 μg/mL N-MWCNTs not only increase the transcription of osteoblastogenic and osteoclastogenic genes but also up-regulate the activities of both TRAP and AKP in the differentiation of bone marrow stromal cells (BMSCs). Additionally, intramuscular administration of N-MWCNTs at a dosage of 1.0 mg/kg body weight enhances bone mineral density and bone mass content in mice, as well as induces potentiated degree of TRAP- and ARS-positive staining in the femur. The positive regulation of N-MWCNTs on bone remodeling is initiated by macrophage phagocytosis, which induces altered production of inflammatory cytokines by immune response pathways, and consequently up-regulates IL1α, IL10, and IL16. These cytokines collectively regulate the central osteoclastogenic transcription factor NFATc1 and osteoblastogenic BMP signaling, the suppression of which confirmed that these factors respectively participate in N-MWCNT-mediated regulation of osteoclastic and osteoblastic bone marrow stem cell activities. These results suggest that N-MWCNTs can be readily generalized for use as biomaterials in bone tissue engineering for metabolic bone disorders.

Background There is a high incidence of venous thromboembolism (VTE) after lung resection, so it is necessary to identify the risk factors for VTE in these patients. It is also important to evaluate whether the modified Caprini score can accurately assess the risk of VTE in patients after lung resection. Methods This retrospective study included 437 patients undergoing lung resection between July 2016 and December 2017. All patients underwent lower extremities ultrasound before and after operation to determine the presence of the newly diagnosed VTE. Results Forty-seven (10.8%) of the 437 patients were diagnosed with VTE after lung surgery. Multivariate logistic regression analysis showed that age (OR, 2.04; 95% CI, 1.40-2.99), duration of operation (OR, 1.51; 95% CI, 1.08-2.12), lymphocyte count (OR, 0.28; 95% CI, 0.11-0.69), and D-dimer concentration (OR, 1.55; 95% CI, 1.22-1.97) were significantly associated with VTE in lung resection patients. The cut-off values for lymphocyte count and D-dimer concentration determined using receiver operating characteristic (ROC) curve were 1.15×109/L and 1.37 µg/mL respectively. The modified Caprini score divided the patients into three groups: low risk (0-4 points), moderate risk (5-8 points) and high risk (≥9 points), and the incidence of VTE was 12.3% (37/300), 7.5% (10/133) and 0% (0/4), respectively (P>0.05). Conclusions In this study, we identified four independent factors for VTE after lung resection patients: age, duration of operation, lymphocyte count, and D-dimer. According to the modified Caprini score, there were fewer patients in the high-risk group, and the incidence of VTE not increased with the increase of risk. Better evaluation of operation time and D-dimer may help the modified Caprini score to better assess VTE risk in these patients.

Background: Iodine deficiency (ID) is a global problem in individuals living in an iodine-deficient environment, specifically in mountainous regions. However, data regarding the iodine nutritional ...

Purpose. The study aimed at investigating the effect of local infiltration analgesia (LIA) with ropivacaine on postoperative analgesia for patients undergoing ankle fracture surgery. Methods. Consecutive patients were retrospectively included and analysed according to their medical records from July 2014 to August 2018 in a tertiary hospital. Inclusion criteria were patients undergoing open reduction and internal fixation (ORIF) for ankle fractures under general anaesthesia. Moreover, patients should have received intravenous patient-controlled analgesia (iPCA) or LIA + iPCA for postoperative pain relief. The primary outcome indicator was visual analogue scale (VAS) from 8 hours to 48 hours after surgery. Secondary outcomes included postoperative opioid requirement, need for rescue medication, opioid-related adverse effects, and wound complications. Results. In total, 89 consecutive patients were included in the study. There were 48 males and 41 females. The average age was 44.6 ± 7.0 years, and VAS scores were significantly lower in the LIA + iPCA group at 8 hours after surgery (1.51 ± 0.58 cm vs 4.77 ± 1.83 cm, p<0.001). The time to first tramadol consumption was longer (580 ± 60.9 minutes vs 281 ± 86.4 minutes, p<0.001), and the number of patients who need tramadol was lower in the LIA + iPCA group (18 vs 26, p=0.04). There was a statistically significant reduction in morphine consumption (25.1 ± 6.3 mg vs 73.4 ± 8.2 mg, p<0.001) and opioid-related side effects in the LIA + iPCA group (4 vs 10, p=0.023). No major wound complications were noted in either group. However, there were 2 cases with superficial wound necrosis in group LIA + iPCA and 3 patients with superficial wound necrosis in group iPCA, and all cured by local wound care. Conclusions. The retrospective cohort study indicates that LIA with ropivacaine can provide better early postoperative pain management with a reduction of VAS scores for ankle fracture surgery. Patients receiving wound infiltration also experience decreased opioid consumption, a lower rate of analgesia-related side effects, and comparable wound complication rate.

Human amnion-derived mesenchymal stem cell (hAD-MSC) transplantation can repair ovarian injury and improve ovarian function in rats with chemotherapy-induced primary ovarian insufficiency (POI). However, ensuring that stem cells home to the ovary to improve their effects on ovarian injury is challenging. This research aimed to directly inject ovarian tissue with hAD-MSCs and improve the homing of stem cells to the ovary. The animals were divided into POI, hAD-MSC (tail vein) treatment, hAD-MSC (in situ) treatment, and control groups. POI rat models were established by intraperitoneal injection of cyclophosphamide (CTX) and busulfan (BUS). The hAD-MSCs isolated from the amnion were injected into the tail vein or ovary of POI rats. The estrous cycle, serum sex hormone levels, follicle counts, ovarian pathological changes, and proteome of the ovaries were evaluated. hAD-MSCs were successfully isolated and cultured from the amnion. Both hAD-MSC (tail vein) and hAD-MSC (in situ) transplantation increased body weight, improved the AMH levels and follicle numbers, and reduced reproductive organ injuries in POI rats. Transplantation of hAD-MSCs (in situ) upregulated 24 proteins and downregulated 4 proteins. Both hAD-MSC (tail vein) and hAD-MSC (in situ) transplantations can repair ovarian injury and improve ovarian function in rats with chemotherapy-induced POI. The paracrine proteome of hAD-MSCs in the ovarian microenvironment can protect against chemotherapy-induced damage by reducing apoptosis and promoting angiogenesis, cell proliferation, and gene expression.

Aorto-oesophageal fistula is a rare but fatal disease. Open surgical repair or endotube repair of aorta and oesophagus save patients from circulatory deterioration, major haematemesis and severe infection. Here we present a rare case of an aorto-oesophageal fistula in the right hemi-arch caused by a fish bone treated with an alternative surgical strategy. Total aortic arch repair using the frozen elephant trunk procedure combined with oesophageal repair were performed. No aortic fistula, oesophageal fistula or artificial graft infection occurred in the follow-up.

Background Wiedemann–Steiner syndrome (WSS) is an autosomal dominant disorder characterized by short stature, hypertrichosis, intellectual disability, developmental delay, along with facial dysmorphism. WSS patients exhibit great phenotypic heterogeneities. Some variants in KMT2A (MLL) gene have been identified as the cause of WSS. Methods Whole exome sequencing on the probands followed by Sanger sequencing validations in the family were applied to determine genetic variants. In silico analyses were used for predicting potential effects of the variants. Results We identified three novel de novo heterozygous variants: c.883A>T (p.Lys295*), c.4171C>T (p.Gln1391*), and c.3499T>C (p.Cys1167Arg), in KMT2A gene from three unrelated Chinese WSS patients. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, these three variants were classified as pathogenic, pathogenic and likely pathogenic variant, respectively. By reviewing all the available cases with same mutated KMT2A regions as the three patients had, we found that in addition to the representative symptoms, our patients exhibited some sporadically observed symptoms, such as severe ophthalmological symptoms, endocardial fibroelastosis, cytomegalovirus infection, and feet eversion. We also revealed that variants in different KMT2A regions contribute to the phenotypic heterogeneity of WSS, highlighting challenges in the diagnosis of syndromic disorders spanning a broad phenotypic spectrum. Conclusion Our study would aid in further broadening our knowledge about the genotype–phenotype correlation of WSS., Endocardial fibroelastosis and feet eversion are newly identified features in Wiedemann–Steiner syndrome. Three novel do novo variants identified in this study help to further associate genotype with phenotype in WSS.

The study explored on the effect of dietary compound plant extract supplementation on the growth performance, serum biochemical indicators, liver and intestinal morphological and gene expression levels in the head kidney and spleen of the hybrid grouper (Epinephelus lanceolatus♂× Epinephelus fuscoguttatus♀). The compound plant extracts (BDG) was a mixture of Bupleurum edulis extract, dandelion extract and Ginkgo biloba extract in a ratio of 1:4:1. Basal diets supplemented with BDG at 0, 0.75, 1.5, 3 and 6 g/kg were fed hybrid grouper for 8 weeks. The results showed that dietary 0.75 and 1.5 g/kg BDG supplementation could significantly increase the WGR and SGR of hybrid grouper (P 0.05). And dietary 0.75 g/kg BDG could also significantly decrease serum aspartate aminotransferase, glucose and lactate dehydrogenase in hybrid grouper (P 0.05). Dietary BGD supplementation protected the integrity of liver and intestinal morphological structure, reduced the accumulation of liver fat. Dietary BDG supplementation might enhance the immunity of hybrid grouper by regulating the expression of antioxidant and inflammation-related genes in head kidney and spleen of hybrid grouper. Our study demonstrated that the growth promoting effect of Bupleurum extract, dandelion extract and Ginkgo biloba extract in the ratio of 1:4:1 as a compound feed additive was better than any of them as a feed additive alone, and the dosage was less. The optimal additive dosage of BDG was 0.75 g/kg in hybrid grouper diets.

Excessive self-reactive and inadequate affinity-matured antigen-specific antibody responses have been reported to coexist in lupus, with elusive cellular and molecular mechanisms. Here, we report that the antigen-specific germinal center (GC) response―a process critical for antibody affinity maturation―is compromised in murine lupus models. Importantly, this defect can be triggered by excessive autoimmunity-relevant CD11c + Tbet + age-associated B cells (ABCs). In B cell-intrinsic Ship-deficient (ShipΔB) lupus mice, excessive CD11c + Tbet + ABCs induce deregulated follicular T-helper (T FH ) cell differentiation through their potent antigen-presenting function and consequently compromise affinity-based GC selection. Excessive CD11c + Tbet + ABCs and deregulated T FH cell are also present in other lupus models and patients. Further, over-activated Toll-like receptor signaling in Ship-deficient B cells is critical for CD11c + Tbet + ABC differentiation, and blocking CD11c + Tbet + ABC differentiation in ShipΔB mice by ablating MyD88 normalizes T FH cell differentiation and rescues antigen-specific GC responses, as well as prevents autoantibody production. Our study suggests that excessive CD11c + Tbet + ABCs not only contribute significantly to autoantibody production but also compromise antigen-specific GC B-cell responses and antibody-affinity maturation, providing a cellular link between the coexisting autoantibodies and inadequate affinity-matured antigen-specific antibodies in lupus models and a potential target for treating lupus.

Angiosarcomas are rare but aggressive tumors with poor prognosis. The treatment of angiosarcomas with vascular endothelial growth factor receptor inhibitors is still in the stage of clinical exploration. Herein we reported a patient of skin angiosarcoma with multiple organ metastasis. She was resistance to multiline chemotherapy and pazopanib but achieved remarkable shrinkage of the lesion after apatinib treatment combined with chemotherapy or alone. The progression-free survival of the primary lesion with KRAS V14I and RBM10 E119D mutations (10 months) was shorter than that of the brain without the mutation ( ≥ 12 months). Although it is not clear whether the KRAS V14I and RBM10 E119D mutations are the main factors that impact the effect of apatinib treatment or not, the results of this study will provide valuable clues for relevant follow-up basic and clinical studies.

Ataxia-telangiectasia (A-T) is an autosomal recessive chromosome breakage disorder caused by mutations in the ATM serine/threonine kinase (ATM) gene. Typically, it presents in early childhood with progressive cerebellar dysfunction, accompanied by immunodeficiency and oculocutaneous telangiectasia. In the present study, the clinical and genetic findings of a Chinese family affected with A-T in two live siblings, the proband (II-2) and his elder brother (II-1), as well as a fetus (II-3) were reported. General health, clinical neurological, electrophysiological (motor and sensory nerve conduction) and magnetic resonance imaging evaluations revealed that patients II-1 and II-2 had similar symptoms of ataxia, dysarthria, conjunctival hyperemia and elevated serum α-fetoprotein, whereas patient II-1 had earlier A-T onset at 2 years old and more serious problems with movement and intelligence. Targeted sequencing followed by Sanger sequencing revealed that these two patients carried the compound heterozygotes of a novel nonsense mutation c.5170G>T (p.Glu1724Ter) and a known nonsense mutation c.748C>T (p.Arg250Ter) in the ATM gene. Each mutation was inherited from an asymptomatic parent, which therefore confirmed the diagnosis of A-T. Given this, proband's mother performed prenatal diagnosis in her third pregnancy. Unfortunately, the fetus had the same causal mutations as its siblings and the pregnancy was terminated. The findings of the present study expanded the mutation spectrum of the ATM gene and may help in understanding the genetic basis of A-T, in order to guide genetic counseling and prenatal diagnosis.

Proper control of B cell growth and metabolism is crucial for B-cell-mediated immunity, but the underlying molecular mechanisms remain incompletely understood. In this study, Sin1, a key component of mTOR complex 2 (mTORC2), specifically regulates B cell growth and metabolism. Genetic ablation of Sin1 in B cells reduces the cell size at either the transitional stage or upon antigen stimulation and severely impairs metabolism. Sin1 deficiency also severely impairs B-cell proliferation, antibody responses, and anti-viral immunity. At the molecular level, Sin1 controls the expression and stability of the c-Myc protein and maintains the activity of mTORC1 through the Akt-dependent inactivation of GSK3 and TSC1/2, respectively. Therefore, our study reveals a novel and specific role for Sin1 in coordinating the activation of mTORC2 and mTORC1 to control B cell growth and metabolism.

An hourglass cup-shape pattern of regulation at the molecular level was detected during the development of the primate brain. Specifically, a peak of temporally differentially expressed genes around the time of birth has been observed in the human brain. However, to what extend this peak of regulation exists among species has not been investigated in great detail. Here, by integrating multiple large-scale transcriptome data from rhesus macaques, we confirmed that a similar differential expression peak exists during the development of the macaque brain. We also found that a similar peak exists during the development of other organs, such as liver, testis, kidney and heart. Furthermore, we found that distinct pathways are regulated in the peak period of those organs. Our results highlight the importance of co-evolution of diverse organs during critical periods of perinatal development in primates.

Ulcers are a lower-extremity complication of diabetes with high recurrence rates. Oxidative stress has been identified as a key factor in impaired diabetic wound healing. Hyperglycemia induces an accumulation of intracellular reactive oxygen species (ROS) and advanced glycation end products, activation of intracellular metabolic pathways, such as the polyol pathway, and PKC signaling leading to suppression of antioxidant enzymes and compounds. Excessive and uncontrolled oxidative stress impairs the function of cells involved in the wound healing process, resulting in chronic non-healing wounds. Given the central role of oxidative stress in the pathology of diabetic ulcers, we performed a comprehensive review on the mechanism of oxidative stress in diabetic wound healing, focusing on the progress of antioxidant therapeutics. We summarize the antioxidant therapies proposed in the past 5 years for use in diabetic wound healing, including Nrf2- and NFκB-pathway-related antioxidant therapy, vitamins, enzymes, hormones, medicinal plants, and biological materials.

Objectives The frozen elephant trunk (FET) technique has become an important tool in the treatment of acute type A aortic dissection. The aim of this study was to evaluate the effect of long FET on spinal cord injury (SCI) and distal aortic remodeling after acute type A aortic dissection based on clinical and radiological outcomes. Methods From January 2018 to November 2019, 158 patients (mean age 51.8 years [range: 32-78 years], 88.6% male) with acute type A aortic dissection were treated by FET with 100 mm (n = 113) or 150 mm (n = 45) open hybrid stent graft prosthesis. Patients were divided into two groups according to the length of FET. The clinical and radiological outcomes of the patients were reviewed retrospectively. Results Postoperative outcomes did not differ significantly: in-hospital mortality (9.7% vs. 6.7%, p = .758) and SCI (5.3% vs. 2.2%, p = .674). Aortic remodeling, which was evaluated by aortic diameter, true lumen diameter, false lumen (FL) diameter and the rate of FL complete thrombosis, was more positive in long FET group in the descending thoracic aorta during the follow-up period. At the abdominal level, there was no statistically significant difference between the two groups. Conclusions The long version of FET does not increase the risk of SCI in patients with acute type A aortic dissection. The application of long FET can achieve better results in terms of remodeling of the thoracic aorta in the short- and medium-term follow-up.

Background: Seizure control (SC) is often poor in cases of magnetic resonance imaging- negative epilepsy after resection surgery. Objective: This study aimed to evaluate the therapeutic efficacy of depth-electrode-guided stereotactic radiofrequency thermocoagulation (RFTC) applied to the amygdalohippocampal complex (AHC) for the treatment of patients with MRI-negative medial temporal lobe epilepsy. Methods: A total of 62 cases with magnetic resonance imaging-negative medial temporal lobe epilepsy were retrospectively studied after the application of depth-electrode-guided RFTC to the AHC. Single-target coagulations were applied to all patients, and multi-target coagulations were applied to those patients who did not experience significant reductions in discharges after the first target ablation. Bilateral-target coagulations were applied to bilateral medial temporal lobe epilepsy patients, using single target ablation applied to each side. Results: After 24-83 months of follow-up, 32/62 (51.61%) patients became seizure-free, and 35/62 (56.45%) patients reported significant reductions in seizure episodes. The total effective rate was 69.35% (43/62). No significant differences were observed for SC among the single-target, multi-target, and bilateral-target groups. However, a significant difference was observed for the reduction in epileptic discharges after coagulations between those patients who became seizure-free and those who did not. Magnetic resonance imaging-negative medial temporal lobe epilepsy patients can benefit from RFTC applied to the AHC. A significant reduction in epileptic discharges observed during operations after RFTC is applied may predict good SC. Conclusion: RFTC applied to the AHC could be considered a promising method for the treatment of magnetic resonance imaging-negative medial temporal lobe epilepsy patients.

Background. With the rapid development of transcatheter techniques and instruments, transcatheter occlusion for patients with perimembranous ventricular septal defect (pVSD) and aortic valve prolapse (AVP) was constantly being tried, while the efficacy and safety of pVSD with AVP remain controversial. Objective. The aim of this study was to evaluate long-term efficacy and safety of transcatheter occlusion of pVSD with AVP. Methods. We retrospectively analyzed 164 children with pVSD and AVP who underwent transcatheter occlusion between January 2013 and November 2014. AVP was divided into 3 degrees according to right coronary leaflet morphology at end-diastole during aortic root angiography. Patient demographic and clinical data were collected. Results. There were 97 males and 67 females (median age, 40.0 (30.0–62.7) months; average weight, 16.94 ± 9.02 kg). Mild (n = 63), moderate (n = 89), and severe (n = 12) AVP success rates were 93.7%, 89.9%, and 58.3%, respectively. Immediately after procedure, there was no new-onset aortic regurgitation (AR) above trivial degree, residual shunt above mild degree, or complications requiring medication or operation, except for 1 patient who developed transient complete atrioventricular block. During follow-up, 1 mild AVP patient aggravated from mild to moderate AR and 1 moderate AVP patient aggravated from trivial to moderate AR. The new-onset AR in mild, moderate, and severe AVP was 2%, 1.8%, and 20%, respectively. AR disappeared in 17 patients. Residual shunt occurred in 9 patients after procedure, 4 of which disappeared during the follow-up period. No serious complications occurred in any patient during follow-up. Five-year cardiovascular event-free survival rates for mild, moderate, and severe AVP were 89.6%, 94.5%, and 80.0%, respectively. Conclusion. Transcatheter occlusion of pVSD with mild and moderate AVP has a high success rate and few complications, which is safe and effective in long-term follow-up. Transcatheter occlusion of pVSD with severe AVP has low success rates and high AR incidence. Therefore, transcatheter occlusion of pVSD with AVP is recommended for mild to moderate, but not severe, AVP.

Objective PCOS is a heterogeneous endocrine disorder with both reproductive and metabolic abnormalities. At present, PCOS has been confirmed to have a certain genetic background. Compared with healthy women, the vast majority of PCOS patients have hyperandrogenemia, and this excessive androgen exposure during pregnancy may affect the development of female fetuses. The aim of the current study was to investigate the effect of adiponectin intervention during early pregnancy of obese mice with PCOS on the metabolic phenotype of adult female offspring. Methods After the PCOS model was established, C57BL/6J mice were divided into maternal-control, maternal-PCOS, and maternal-PCOS + APN groups. DHEA-induced PCOS mice were supplemented with adiponectin (10 mg/kg/day) in the early pregnancy in order to eliminate adverse hormone exposure and then traced for endocrine indicators in their adult female offspring, which were observed for metabolism syndrome or endocrine disturbance and exhibited the main effects of APN. To further explore the underlying mechanism, the relative expressions of phosphorylated AMPK, PI3K, and Akt were detected in the ovaries of offspring mice. Results The serum testosterone level of the maternal-PCOS + APN group in early pregnancy was significantly lower than that of the maternal-PCOS group (p p <0.05), the diestrus time characterized by massive granulocyte aggregation in the estrus cycle was significantly shorter than in the offspring-PCOS group (pp < 0.05). Compared with the control group, the expression levels of phosphorylated AMPK, PI3K, and Akt in the offspring-PCOS group were significantly decreased (p < 0.05), while those in the offspring-PCOS + APN group were significantly increased (p < 0.05). Conclusions APN intervention in early pregnancy significantly reduced the adverse effects of maternal obesity and high androgen levels during pregnancy on female offspring and corrected the PCOS-like endocrine phenotype and metabolic disorders of adult female offspring. This effect may be caused by the activation of the AMPK/PI3K-Akt signaling pathway in PCOS offspring mice.

Summary Background & aims A large number of clinical studies have shown that intravenous vitamin C supplementation is beneficial for critically ill patients, but current research conclusions are controversial. This meta-analysis included high-quality randomized controlled trials (RCTs) to evaluate the efficacy of intravenous vitamin C in critically ill patients. Methods We searched PubMed, EMBASE and the Cochrane Library from inception to August 15, 2020 to identify published reports of RCTs evaluating the role of intravenous vitamin C in critically ill patients. Risk ratios values (RRs) and 95% confidence intervals (CIs) were calculated by random-effects meta-analysis. Trial sequential analysis (TSA), meta-regression, subgroup analyses and sensitivity analyses were also performed. Results Our meta-analysis included 18 RCTs involving 2001 patients (1005 with vitamin C treatment and 996 control treatment). Intravenous vitamin C administration reduced the intensive care unit (ICU) length of stay (LOS) (MD = −0.36, 95% CI: −0.60 to −0.11, P = 0.004) and hospital LOS (MD = −1.50, 95% CI: −2.64 to −0.35, P = 0.01) but had no significant effect on the longest follow-up mortality, hospital or ICU mortality and change in Sequential Organ Failure Assessment (SOFA) score. TSAs for mortality, ICU and hospital LOS were inconclusive. Conclusions Intravenous vitamin C administration may shorten ICU LOS and hospital LOS. It had no effect on mortality and organ failure. All TSAs were inconclusive, and the value of vitamin C for critically ill patients needs to be demonstrated in more high-quality RCTs.

Objective: This study aimed to explore PLEK2 expression profile, its prognostic value, and the potential genomic alterations associated with its dysregulation in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Materials and methods: Data from The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and Kaplan-Meier plotter were used in combination for bioinformatic analysis. Results: PLEK2 mRNA was significantly upregulated in both LUAD and LUSC compared with their respective normal controls. PLEK2 upregulation showed independent prognostic value in progression-free survival (PFS) (HR: 1.169, 95%CI: 1.033 -1.322, p = 0.014). PLEK2 mRNA expression was positively correlated with invasion, cell cycle, DNA damage, and DNA repair of LUAD cells at the single-cell level. Genomic analysis showed that gene-level amplification might not directly lead to increased PLEK2 expression. Methylation profile analysis found 4 CpG sites (cg12199376, cg14437634, cg17641252, and cg06724236) had at least a weakly negative correlation with PLEK2 expression, among which cg12199376, cg14437634 and cg17641252 locate around the first exon of the gene. Conclusions: Increased PLEK2 expression might be a specific prognostic biomarker of poor PFS in LUAD patients. Its expression had significant positive correlations with invasion, cell cycle, DNA damage, and DNA repair of LUAD cells at the single-cell level. Promoter hypomethylation might be a potential mechanism leading to its upregulation.

Background Hypertensive myocardial fibrosis (MF) is characterized by excessive deposition of extracellular matrix and cardiac fibroblast proliferation, which can lead to heart failure, malignant arrhythmia, and sudden death. In recent years, with the deepening of research, microRNAs have been found to have an important role in blood pressure control and maintaining normal ventricular structure and function. Methods and Results In this study, we first documented the downregulation of microRNA‐26a (miR‐26a) in the plasma and myocardium of spontaneously hypertensive rats; more importantly, miR‐26a–deficient mice showed MF, whereas overexpression of miR‐26a significantly prevented elevated blood pressure and inhibited MF in vivo and angiotensin II‐induced fibrogenesis in cardiac fibroblasts by directly targeting connective tissue growth factor and Smad4. miR‐26a inhibited cardiac fibroblast proliferation by the enhancer of zeste homolog 2/p21 pathway. Conclusions Our study identified a novel role for miR‐26a in blood pressure control and hypertensive MF and provides a possible treatment strategy for miR‐26a to alleviate and reverse hypertensive MF.

BACKGROUND AND PURPOSE Hypertensive vascular remodelling is responsible for end-organ damage and is the result of increased extracellular matrix accumulation and excessive vascular smooth muscle cell (VSMC) proliferation. MicroRNA-26a (miR-26a), a non-coding small RNA, is involved in several cardiovascular diseases. We aimed to validate the effect and mechanisms of miR-26a in hypertensive vascular remodelling. EXPERIMENTAL APPROACH Male spontaneously hypertensive rats (SHRs) were injected intravenously with recombinant adeno-associated virus-miR-26a. Samples of thoracic aorta were examined histologically with H&E staining. In vitro, angiotensin II (AngII)-induced VSMCs cultured from thoracic aortae of female Sprague-Dawley rats, were transfected with miR-26a mimic or inhibitor. Western blots, qRT-PCR and immunohistological methods were used, along with chromatin-immunoprecipitation and luciferase reporter assays. Specific siRNAs were used to silence Smad production in VSMCs KEY RESULTS: Levels of miR-26a were lower in the thoracic aorta and plasma of SHRs than in WKY rats. Overexpression of miR-26a inhibited extracellular matrix deposition by targeting connective tissue growth factor (CTGF) and decreased VSMC proliferation by regulating the enhancer of zeste homologue 2 (EZH2)/p21 pathway both in vitro and in vivo. AngII-mediated Smad3 activation suppressed miR-26a expression, which in turn promoted Smad3 activation via targeted regulation of Smad4, leading to further down-regulation of miR-26a. CONCLUSION AND IMPLICATIONS Our data show that AngII stimulated a Smads/miR-26a positive feedback loop, which further reduced expression of miR-26a, leading to collagen production and VSMC proliferation and consequently vascular remodelling. MiR-26a has an antagonistic effect on hypertensive vascular remodelling and can be a strategy for treating hypertensive vascular remodelling.

People with visual impairment cannot easily obtain external information through vision and thus they face more challenges when traveling than sighted people. The travel environment for people with visual impairment includes pedestrian safety concerns, especially when crossing roads at intersections. Tactile paving can be used as a guidance cue for street-crossing purposes but its use is not yet widespread globally (except at some test sites in Japan). This study investigated the effectiveness of tactile paving on crosswalks based on a field trial conducted in China. A drone and three-axis accelerometer were used to collect participants' behavioral data. Several quantitative indices for street-crossing behavior, including trajectory, maximum distance of the directional deviation, crossing speed, crossing time, and gait regularity and symmetry, were investigated to measure the participants' street-crossing performance. Before-after comparative analysis of the quantitative index results was conducted to compare the participants' use of crosswalks with and without tactile paving. The results reveal that tactile paving helps people with visual impairment to maintain a straight crossing path, avoid directional deviation, reduce their crossing time, and improve their gait regularity and symmetry. Study participants reported positive impressions of the effectiveness of crosswalk tactile paving based on one-to-one interviews conducted after the crosswalk tests. The results also indicate that crosswalk tactile paving is more effective for people with blindness than for those with low vision. This study's findings could serve as a theoretical basis for the deployment of various barrier-free traffic facilities (especially street-crossing facilities) for people with visual impairment.

Objective: To compare and analyze the clinical efficacy of brain radiotherapy combined with targeted therapy and concurrent radiotherapy and chemotherapy in the treatment of non-small cell lung cancer (NSCLC) with brain metastasis. Methods: Fifty-eight patients with NSCLC with brain metastasis who were admitted to our hospital between October 2016 and October 2017 were randomly divided into a control group and an observation group, 29 cases in each group. The control group was treated with concurrent radiotherapy and chemotherapy, while the observation group was treated with whole brain radiotherapy plus targeted therapy. The disease control rate, adverse reactions and survival condition were compared between the two groups. Results: The disease control rate of the observation group was 68.97%, significantly higher than 41.38% of the control group (P

BACKGROUND: The purpose of this study was to investigate the incidence of venous thromboembolism (VTE) in epidermal growth factor receptor (EGFR) mutations patients with lung adenocarcinoma, to provide clinical basis for the perioperative prevention and treatment of VTE in patients with lung cancer. METHODS: This study included patients with invasive lung adenocarcinoma confirmed by pathology from July 2016 to March 2018 after surgical pulmonectomy in Thoracic Surgery Department of Beijing Chaoyang Hospital. All enrolled patients were tested for relevant gene mutations. All patients were classified as adenocarcinoma subtypes by the 2011 International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS). Patients were divided into the VTE group and the control group according to whether VTE occurred postoperatively. Baseline data, gene test results, operative data and tumor pathology data between the two groups were compared. RESULTS: According to the inclusion criteria, a total of 323 patients underwent lung cancer surgery were analyzed in this study, including 148 males and 175 females, aged from 25 to 82 years old. Postoperative VTE occurred in 33 patients, with an incidence of 10.2%. Compared the baseline data, there were significant differences in age and BMI between the two groups, but no significant differences in other indicators. Comparing the results of postoperative genetic tests, the cases of exon 18, 19, 20, 21, 30, 31 mutation, exon 18 and 20 mixed mutation and exon 20 and 21 mixed mutation were 5, 42, 6, 57, 1, 3, 1 and 1. The total EGFR mutation rate in the enrolled patients was 36.2% (117/323). Among them, the proportion of EGFR mutation in the VTE group was significantly higher than that in the non-VTE group (60.6% vs. 33.4%, P=0.002). Exon mutations in specific regions and mixed region of EGFR were not statistically significant between them; there was no statistical difference in the concomitant KRAS and ALK gene mutations between them. Comparing the pathological conditions, the proportion of acinar dominant lung adenocarcinoma in the VTE group was higher than that in the non-VTE group (57.6% vs. 30.7%, P=0.002); other histologic subtypes showed no statistical difference. The D-dimer difference before and 1 day after surgery, preoperative FEV1, surgical method, duration of surgery and blood loss were statistically significant differences between the two groups. The results of univariate analysis showed that there were significant differences between the VTE group and the control group in proportion of EGFR mutant lung adenocarcinoma, age, BMI, D-dimer difference before and 1 day after surgery, preoperative FEV1, surgical method, duration of surgery, blood loss and proportion of acinar dominant lung adenocarcinoma (P

This study was designed to demonstrate that prenatal ethanol exposure (PEE) can induce low functional expression of the hypothalamus in male offspring rats and explore the underlying mechanism. Pregnant rats were administered 4 g/kg ethanol or normal saline by oral gavage each day from gestational day (GD) 9 to GD20. Male GD20 foetuses and postnatal day 120 adult offspring rats were sacrificed under anaesthesia. Hypothalamic cells from male GD20~postnatal day (PD) 7 rats were treated with different doses of corticosterone and the glucocorticoid receptor (GR) antagonist mifepristone for 5 days. In this study, we found that PEE-induced overexposure of maternal glucocorticoids enhanced the expression of L-glutamic acid decarboxylase (GAD) 67 in the hypothalamic paraventricular nucleus (PVN) by activating the glucocorticoid metabolic activation system, further inducing the conversion of glutamate to L-gamma-aminobutyric acid (GABA) and developmental imbalance of glutamatergic/GABAergic projections to the PVN. The imbalance change was maintained until after birth, resulting in the inhibition of parvocellular neurons and low functional expression of the hypothalamus in PEE offspring rats. Our study indicated that low functional expression of the hypothalamus in male PEE offspring rats was associated with developmental programming of an imbalance of glutamatergic/GABAergic projections to the PVN.

Although lithium-sulfur batteries have drawn widespread attentions due to their high energy densities at low costs, the scale-up applications are still hindered by issues such as dissolution of lithium polysulfides (LiPSs) and slow oxidation/reduction kinetics. Herein, we report a novel cathode composite composed of “moss-like” P-doped NiSe2 arrays grown on activated carbon cloth substrates (P-NiSe2/ACC). Experiments and DFT calculations together suggest that P-doping enhances the electron transfers between P-NiSe2 and LiPSs, leading to improved chemical adsorptions and catalytic effects towards the redox conversions of the active sulfur species. This effectively inhibits the shuttling of LiPSs and maximizes the utilization of sulfur towards high specific capacities and stable long-term cycling at high sulfur loadings. The strong interactions and effective catalysis of P-NiSe2 on LiPSs also enables three-dimensional growth of Li2S2/Li2S on the P-NiSe2/ACC cathode, realizing effective accommodation of volume expansions and significant alleviation of cathode passivation. As a result, the P-NiSe2/ACC cathode provides a high specific capacity of 1211 mAh g−1 at 0.2 C and an outstanding high-rate performance of 679 mAh g−1 at 3 C. At the high sulfur loading of 9.9 mg cm−2, an area capacity of 8.42 mAh cm−2 is achieved with stable cycling for 100 charge/discharge cycles.

Background Human amnion-derived mesenchymal stem cells (hAD-MSCs) have the features of mesenchymal stem cells (MSCs). Low-intensity pulsed ultrasound (LIPUS) can promote the expression of various growth factors and anti-inflammatory molecules that are necessary to keep the follicle growing and to reduce granulosa cell (GC) apoptosis in the ovary. This study aims to explore the effects of LIPUS-pretreated hAD-MSC transplantation on chemotherapy-induced primary ovarian insufficiency (POI) in rats. Methods The animals were divided into control, POI, hAD-MSC treatment, and LIPUS-pretreated hAD-MSC treatment groups. POI rat models were established by intraperitoneal injection of cyclophosphamide (CTX). The hAD-MSCs isolated from the amnion were exposed to LIPUS or sham irradiation for 5 consecutive days and injected into the tail vein of POI rats. Expression and secretion of growth factors promoted by LIPUS in hAD-MSCs were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) in vitro. Estrous cycle, serum sex hormone levels, follicle counts, ovarian pathological changes, GC apoptosis, Bcl2 and Bax expression, and pro-inflammatory cytokine levels in ovaries were examined. Results Primary hAD-MSCs were successfully isolated from the amnion. LIPUS promoted the expression and secretion of growth factors in hAD-MSCs in vitro. Both hAD-MSC and LIPUS-pretreated hAD-MSC transplantation increased the body and reproductive organ weights, improved ovarian function, and reduced reproductive organ injuries in POI rats. Transplantation of hAD-MSCs increased the Bcl-2/Bax ratio and reduced GC apoptosis and ovarian inflammation induced by chemotherapy in ovaries. These effects could be improved by pretreatment with LIPUS on hAD-MSCs. Conclusion Both hAD-MSC transplantation and LIPUS-pretreated hAD-MSC transplantation can repair ovarian injury and improve ovarian function in rats with chemotherapy-induced POI. LIPUS-pretreated hAD-MSC transplantation is more advantageous for reducing inflammation, improving the local microenvironment, and inhibiting GC apoptosis induced by chemotherapy in ovarian tissue of POI rats.

Background: The aim of this study was to investigate the diagnostic value of the intravoxel incoherent motion (IVIM) for distinguishing non-metastatic from metastatic mediastinal lymph nodes in lung cancer. Methods: IVIM-diffusion weighted imaging (DWI) exams were performed preoperatively on 66 patients with lung cancer from October 2015 to June 2016 in Beijing Chao-Yang Hospital, Capital Medical University. Fifty patients underwent enhanced chest computed tomography (CT) in our hospital, while the other 16 patients already had enhanced chest CT images when they were admitted. The patients’ complete preoperative examination included chest magnetic resonance imaging (MRI), enhanced chest CT, head MRI, bone scanning and cardiopulmonary function testing. None of the patients were receiving any treatment for their cancer prior to their evaluation and surgery, including neoadjuvant chemotherapy, radiation therapy, immunotherapy or gene targeted therapy. The following IVIM parameters of the mediastinal lymph nodes were measured: the short axis diameter, apparent diffusion coefficient (ADC), diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f). All of the patients underwent lobectomy and lymph node dissection. We compared the CT and MRI results and analysed the IVIM parameters of the pathologically determined non-metastatic and metastatic mediastinal lymph nodes in our 50 patients to generate the ROC curves and determine the best cut-off value for diagnosis. The remaining 16 patients’ IVIM parameters were used to verify the diagnostic cut-off value. This study was approved by the institutional research ethics committee of Beijing Chao-Yang Hospital (2014-S-166), and all the patients signed the MRI informed consent. Results: In this study, MRI was used to measure 140 groups of mediastinal lymph nodes in 50 cases, and the results showed that 19 groups of mediastinal lymph nodes were metastatic, while 121 groups of mediastinal lymph nodes were non-metastatic. The pathological analysis showed that 20 groups of mediastinal lymph nodes were metastatic and 120 groups of mediastinal lymph nodes were non-metastatic. CT was used to measure 273 groups of mediastinal lymph nodes, and the result showed that 34 groups of mediastinal lymph nodes were metastatic, while 239 groups of mediastinal lymph nodes were non-metastatic. The pathological analysis showed that 20 groups of mediastinal lymph nodes were metastatic and 253 groups of mediastinal lymph nodes were non-metastatic. The ADC, D, D*, f values and the short axis diameters of the non-metastatic lymph nodes (n=121) were 2.9370±0.743×10 −3 , 0.533±0.175×10 −3 , 0.384±0.121×10 −3 mm 2 /s, 0.426±0.120, 6.903±1.831 mm, respectively, and 1.863±0.691×10 −3 , 0.454±0.204×10 −3 , 0.358±0.106×10 −3 mm 2 /s, 0.413±0.085, 7.705±2.213 mm, respectively, for the metastatic lymph nodes (n=19). The ADC and D values of the non-metastatic lymph nodes were significantly higher than the values for the metastatic lymph nodes (P −3 mm 2 /s (0.897, 93.3%, 80.0%), Youden index 0.733; and D =0.344×10 −3 mm 2 /s (0.651, 90.8%, 50.0%), Youden index 0.651. When these cut-off values were applied as the diagnostic criteria in the remaining cases and compared with the pathology results, the diagnostic performance was good. Conclusions: IVIM is useful to distinguish metastatic from non-metastatic lymph nodes in lung cancer. The ADC and the D values are significantly lower in metastatic lymph nodes, making these parameters more sensitive than the other parameters (D*, f, and short axis diameter). As a result, IVIM can be used in the N-stage diagnosis of lung cancer.

Reports in recent years have suggested that adiponectin (APN) improves insulin resistance and inhibits apoptosis by activating the AMP-activated protein kinase (AMPK) pathway and the PI3K/Akt signaling pathway after binding to its receptor. This study aims to explore the mechanism by which APN reduces embryo loss rate and trophoblast apoptosis in early pregnancy of mice with polycystic ovary syndrome (PCOS). PCOS mice were subcutaneously injected with APN (10 μg mg kg−1 day−1) on 11 consecutive days from the 3rd day of pregnancy onwards to observe the change of the embryo loss rate of PCOS mice induced by APN. Quantitative real-time PCR and Western blot were used to determine the relative expressions of mRNA and the proteins AMPK, PI3K, and Akt in mouse uterine tissue. At the same time, primary cultured mouse villous trophoblast cells were used to further explore the underlying mechanisms in vitro. APN significantly reduces the pregnancy loss rate of PCOS mice. At the same time, APN increases phosphorylation and mRNA expression levels of AMPK, PI3K, and Akt in PCOS mouse uterine tissue. In addition, trophoblast cells of model mice were treated with APN and inhibitors, and APN was found to reduce trophoblast cell apoptosis by affecting the phosphorylation levels of AMPK, PI3K, Akt, and FoxO3a proteins. APN reduces the embryo loss rate and ameliorates trophoblast apoptosis in PCOS mice by affecting the AMPK/PI3K/AKT/FoxO3a signaling pathway.

Endometrial carcinoma (EC) is a malignant neoplasm of the endometrial epithelium, which may be diagnosed by pathological investigations. The aim of the current study was to identify new markers for the diagnosis of EC using machine learning. The association between human T cell lymphotropic virus type 1 (HTLV-1) infection and endometrial cancer risk have not been widely reported. It remains ambiguous whether HTLV-1 infection is associated with several types of cancer. The present study investigated the association between HTLV-1 infection-associated genes and EC risk. RNA sequencing uterine cancer expression data were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed genes (DEGs) were identified between normal and matched tumor samples. A total of 41 genes were selected by an overlap between HTLV-1 infection pathway-associated genes and the DEGs. Two-way hierarchical clustering analysis (HCA) and a support vector machine (SVM) classifier were constructed using the 41 genes. The accuracy of the candidate genes in risk-stratifying the samples was 100%. The accuracy of the proposed SVM model was 100%. In addition, the classification power of the SVM model was validated using a merged dataset (TCGA and the Genotype-Tissue Expression project). This predictive feature achieved reliable outcomes with risk-stratifying samples of almost 99% in two-way HCA, and an accuracy yield of 98% of the SVM classifier. In conclusion, the 41 genes identified in the current study may be implicated in the development of EC and may be of prognostic value for the disease. The results obtained the current study suggest that HTLV-1 may be potentially associated with EC and highlight potential disease mechanisms.

Background: Hypertensive ventricular remodeling can lead to heart failure with preserved ejection fraction. Therefore, seeking new therapeutic targets for hypertensive ventricular remodeling at the molecular level has become important. Methods: We examined the expression patterns of circulating and myocardial microRNA-26a (miR-26a) in hypertensive patients, Spontaneously Hypertensive Rats (SHRs) and miR-26a+/− mice. For mechanistic studies, we used recombinant adeno-associated virus (rAAV)-miR-26a to upregulate the expression of miR-26a in SHRs, and we used miR-26a mimic or inhibitor to intervene in angiotensin II-induced cardiofibroblasts. Findings: We found the downregulation of miR-26a in the plasma of both in SHRs and patients with hypertensive left ventricular hypertrophy; myocardial miR26a level was significantly decreased in SHRs as compared with normal control rats. More importantly, miR-26a-deficient mice showed cardiac hypertrophy and fibrosis, whereas overexpression of miR-26a significantly prevented elevated blood pressure and inhibited myocardial fibrosis in vivo and angiotensin II-induced fibrogenesis in cardiofibroblasts by directly targeting connective tissue growth factor and Smad4. miR-26a inhibited cardiofibroblast proliferation and promoted apoptosis by the enhancer of zeste homolog 2/p21 pathway, thereby reducing cardiac hypertrophy. Interpretation: Our study identified a novel role for miR-26a in blood pressure control and hypertensive ventricular remodeling and provides a possible treatment strategy for miR-26a to alleviate and reverse hypertensive ventricular remodeling. Funding Statement: National Natural Science Foundation of China (81570382, 81872563). Declaration of Interests: The authors declared no conflict of interest. Ethics Approval Statement: The study was explained, and informed consent obtained. All procedures were performed in compliance with protocols approved by the Ethics Committee for Human Studies at the Second Affiliated Hospital of Xian Jiaotong University.

With an improvement in the survival rate of cancer patients, chemotherapy-induced premature ovarian insufficiency (POI) is increasingly affecting the quality of life of female patients. Currently, there are many relevant studies using mice as an animal model. However, a large coefficient of variation for weight in mice is not appropriate for endocrine-related studies, compared with rats; therefore, it is necessary to identify an appropriate experimental model in rats. In this study, cyclophosphamide combined with busulfan was used to establish an animal model. We compared several common modeling methods using chemotherapeutic drugs, cisplatin, cyclophosphamide, and 4-vinylcyclohexene diepoxide (VCD), and we found that the combination of cyclophosphamide and busulfan was more effective in establishing a POI model in rats with few side effects by analyzing general physical conditions, pathological tissue sections of heart, liver, lung, spleen, kidney, uterus, and ovary, serum hormone levels, and follicle counts; thus, providing a more reliable model basis for subsequent studies.

Background/Aims: The main purpose of this study was to investigate the effect of exhaustive exercise on L-cysteine uptake and its effect on erythrocyte glutathione (GSH) synthesis and metabolism. Methods: Rats were divided into three groups: sedentary control (C), exhaustive running exercise (ERE) and moderate running exercise (MRE) (n=12 rats/group). We determined the L-cysteine efflux and influx in vitro in rat erythrocytes and its relationship with GSH synthesis. Total anti-oxidant potential of plasma was measured in terms of the ferric reducing ability of plasma (FRAP) values for each exercise group. In addition, the glucose metabolism enzyme activity of erythrocytes was also measured under in vitro incubation conditions. Results: Biochemical studies confirmed that exhaustive running exercise significantly increased oxidative damage parameters in thiobarbituric acid reactive substances (TBARS) and methemoglobin levels. Pearson correlation analysis suggested that L-cysteine influx was positively correlated with erythrocyte GSH synthesis and FRAP values in both the control and exercise groups. In vitro oxidation incubation significantly decreased the level of glucose metabolism enzyme activity in the control group. Conclusion: We presented evidence of the exhaustive exercise-induced inhibition of GSH synthesis due to a dysfunction in L-cysteine transport. In addition, oxidative stress-induced changes in glucose metabolism were the driving force underlying decreased L-cysteine uptake in the exhaustive exercise group.

// Yuyuan Dai 1, * , Shu Liu 1, * , Wen-Qian Zhang 1, 2 , Yi-Lin Yang 1 , Phillip Hang 1 , Hui Wang 1 , Li Cheng 1 , Ping-Chih Hsu 1 , Yu-Chen Wang 1 , Zhidong Xu 1 , David M. Jablons 1 , Liang You 1 1 Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA, USA 2 Department of Thoracic Surgery, Beijing Chao-Yang Hospital, Affiliated with Capital University of Medical Science, Beijing, People’s Republic of China * These authors contributed equally to this work Correspondence to: Liang You, email: Liang.you@ucsfmedctr.org Keywords: ABCG2, YAP1, side population, cancer stem cells, lung cancer Received: June 04, 2016 Accepted: November 21, 2016 Published: November 29, 2016 ABSTRACT A small population of cancer cells called cancer-initiating cells or cancer stem cells (CSCs) are involved in drug resistance, metastasis, and cancer relapse. Finding pathways that regulate CSC is very important for clinical therapy. ATP-binding cassette sub-family G member 2 (ABCG2) plays a role in side population (SP) cell formation and contributes to chemotherapy resistance in common forms of cancer. Yes-associated protein 1 (YAP1) is a major transcriptional effector of the Hippo pathway, which plays important roles in organ size control and tumorigenesis. In this study, we found ABCG2 and YAP1 were both overexpressed in lung cancer SP cells. Disruption of YAP1 expression by siRNA attenuated the expression of ABCG2 transcript and significantly reduced the percentage of SP cells and sphere formation in lung cancer cells. Overexpression of YAP1 in lung cancers led to an increase in ABCG2 expression and increased the percentage of SP cells. However, overexpression of YAP1 in purified non-SP cells did not increase ABCG2 expression and the percentage of SP cells, which may be due to the inhibition of YAP activity through phosphorylation. YAP1 directly transcriptionally regulated ABCG2 by binding to the promoter of ABCG2. Moreover, the YAP1 inhibitor verteporfin and YAP1 siRNA downregulated ABCG2 level through inhibition of YAP1 in lung cancer cells and sensitized them to the chemotherapy drug doxorubicin. Our study adds a new function for YAP1 that may be relevant to drug resistance and cancer therapy through regulation of ABCG2 and side population cell formation in lung cancer.

Intervention strategies in familial adenomatous polyposis (FAP) patients and other high-risk colorectal cancer (CRC) populations have highlighted a critical need for endoscopy combined with safe and effective preventive agents. We performed transcriptome profiling of colorectal adenomas from FAP patients and the polyposis in rat colon (Pirc) preclinical model, and prioritized molecular targets for prevention studies in vivo. At clinically relevant doses in the Pirc model, the drug Clotam (tolfenamic acid, TA) was highly effective at suppressing tumorigenesis both in the colon and in the small intestine, when administered alone or in combination with Sulindac. Cell proliferation in the colonic crypts was reduced significantly by TA, coincident with increased cleaved caspase-3 and decreased Survivin, β-catenin, cyclin D1 and matrix metalloproteinase 7. From the list of differentially expressed genes prioritized by transcriptome profiling, Mmp7, S100a9, Nppb and Aldh1a3 were defined as key oncogene candidates downregulated in colon tumors after TA treatment. Monthly colonoscopies revealed the rapid onset of tumor suppression by TA in the Pirc model, and the temporal changes in Mmp7, S100a9, Nppb and Aldh1a3, highlighting their value as potential early biomarkers for prevention in the clinical setting. We conclude that TA, an "old drug" repurposed from migraine, offers an exciting new therapeutic avenue in FAP and other high-risk CRC patient populations.

Diabetic cardiomyopathy (DCM) is characterized by structural and functional changes in the myocardium. Several studies have revealed that myocardial apoptosis and fibrosis occur during DCM. Studies have also indicated that oxidative stress may be a major factor associated with the development of DCM. Protein kinase C (PKC)β2 has been demonstrated to be activated in diabetic rats, and overexpression of PKCβ2 in the myocardium may result in cardiac hypertrophy and fibrosis. The P66shc adaptor protein, which is mediated by PKCβ, serves an important role in apoptosis during oxidative stress. The aim of the present study was to investigate whether the PKCβ2/P66shc oxidative stress pathway is associated with DCM, and to investigate the role and mechanisms of carvedilol in preserving cardiac function. Experimental diabetic rat models were induced by streptozotocin treatment accompanied by high energy intake. Carvedilol was orally administrated at a dose of 1 or 10 mg/kg/day. Cardiac function was evaluated by serum N-terminal pro-B-type natriuretic peptide level and cardiac ultrasound. Myocardial inflammation, oxidative stress, apoptosis and fibrosis were assessed by histopathological and echocardiographic analyses and tests for oxidative markers. Associated proteins and factors were examined by immunohistochemical and western blot analyses. Rats in the diabetes mellitus group exhibited significantly decreased systolic cardiac function along with elevated expression levels of phosphorylated (p)-PKCβ2, phos-P66shc, caspase-3, malondialdehyde, collagen type I, tumor necrosis factor-α and interleukin-1β, which were accompanied by disorder in metabolic processes. Treatment with carvedilol reversed these changes. Thus, the present results suggest that the PKCβ2/P66shc signaling pathway may be associated with diabetic cardiomyopathy; furthermore, carvedilol, as a novel β-receptor blocker, may protect the myocardium from injury by suppressing the myocardial inflammatory response, fibrosis, P66shc-mediated oxidative stress and subsequent apoptosis in myocardial tissue. Consequently, carvedilol may have potential as a therapy for the treatment of DCM.

Background: The high incidence of venous thromboembolism (VTE) has been perceived in post thoracic surgery patients. However, the significance of perioperative coagulation and fibrinolysis related parameters after lung surgery for VTE predicting is not clear. To investigate that, we conducted a prospective single center study. Methods: A total of 111 patients undergoing lung surgery were enrolled in this study, included 52 primary lung cancer patients and 59 benign lung disease patients from July 2016 to March 2017. Preoperative and postoperative days 1, 3, and 5 coagulation and fibrinolysis related parameters were tested, including antithrombin (AT), fibrinogen degradation product (FDP), prothrombin time (PT), prothrombin time activity (PA), prothrombin time ratio (PR), international normalized ratio (INR), activated partial thromboplastin time (APTT), plasma fibrinogen (FBG), thrombin time (TT) and D-Dimer. The Doppler ultrasonography was performed before and after surgery for deep venous thrombosis (DVT) confirmation. Patients with new postoperative DVT, unexplained dyspnea, hemoptysis, chest pain, or high Caprini score (≥9) were received further computer tomography pulmonary angiography (CTPA) for pulmonary embolism (PE). We used the area under receiver-operating-characteristic (ROC) curve to discriminate patients between those who developed VTE and those who did not. Single factor analysis was utilized to define risk factors associated with VTE. Results: The overall incidence of VTE was 16.2% (18/111). The incidence of VTE in primary lung cancer patients was 23.1% (12/52), much higher than that in benign lung diseases 10.2% (6/59), but did not reach statistical significance (P=0.066). Among 18 VTE patients, 83.3% was DVT, 16.7% was DVT + PE and 72.2% was muscular veins of the calf thrombosis. D-Dimer was much higher in VTE group than that in non-VTE group preoperatively and at postoperative days 1, 3 (0.64±0.24 vs . 0.33±0.06, P=0.007; 3.14±0.75 vs . 1.51±0.09, P=0.005, and 1.88±0.53 vs . 0.76±0.05, P=0.001, respectively). And the ROC curve areas of preoperative and postoperative days 1, 3 of D-Dimer were 0.70, 0.71 and 0.74, respectively. And FDP was much higher in VTE group than that in non-VTE group at postoperative day 3 (6.78±1.43 vs . 3.79±0.15, P=0.004). But AT, PT, PA, PR, INR, APTT, FBG and TT there were no significantly difference. Conclusions: The overall incidence of VTE after lung surgery was 16.2%. The patients with preoperative high D-Dimer should receive VTE prophylaxis.

Donor organ rejection remains a significant problem. The present study aimed to assess whether transferring a donor's major histocompatibility complex (MHC) genes to the recipient could mitigate rejection in organ transplantation. Seven loci of MHC genes from donor mice were amplified and ligated into vectors; the vectors either contained one K locus, seven loci or were empty (control). The vectors were subsequently injected into the thymus of recipients (in heterotransplants, recipient rats received the vector containing one K locus), following which donor mouse hearts were transplanted. Following the transplantation of allograft and heterograft, electrocardiosignals were viable for a significantly longer duration in recipient mice and rats receiving the donor histocompatibility-2 complex (H-2)d genes compared with those in controls, and in mice that received seven vectors compared with those receiving one vector. Mixed lymphocyte cultures containing cells from these recipients proliferated significantly less compared with mixed lymphocyte cultures containing controls. Also, hearts from H-2d genes-treated recipients demonstrated less lymphocyte infiltration and necrosis compared with the control recipient. The present study concluded that allograft and heterograft rejection may be mitigated by introducing the donor's MHC into the recipient; transferring seven loci has been demonstrated to be more effective than transferring one locus.