Down-regulation of the Smad signaling by circZBTB46 via the Smad2-PDLIM5 axis to inhibit type I collagen expression

BACKGROUND Abnormal type I collagen(COL1)expression is associated with the development of many cardiovascular diseases.The TGF-beta/Smad signaling pathway and circRNAs have been shown to regulate COL1 gene expression,but the underlying molecular mechanisms are still not fully understood.METHODS Gain-and loss-of-function experiments were prformed to study the effect of circZBTB46 on the expression of alpha 2 chain of type I collagen(COL1A2).Co-immunoprecipitation assay was performed to observe the interaction between two proteins.RNA immunoprecipitation assay and biotin pull-down assay were performed to observe the interaction of circZBTB46 with PDLIM5.RESULTS In this study,we investigated the role of circZBTB46 in regulating COL1A2 expression in human vascular smooth muscle cells(VSMCs).We found that circZBTB46 is expressed in VSMCs and that TGF-beta inhibits circZBTB46 formation by downregulating KLF4 expression through activation of the Smad signaling pathway.CircZBTB46 inhibits the expression of COL1A2 induced by TGF-beta.Mechanistically,circZBTB46 mediates the interaction between Smad2 and PDLIM5,resulting in the inhibition of Smad signaling and the subsequent downregulation of COL1A2 expression.Furthermore,we found that the expression of TGFbeta and COL1A2 is decreased,while circZBTB46 expression is increased in human abdominal aortic aneurysm tissues,indicating that circZBTB46-mediated regulation of TGF-beta/Smad signaling and COL1A2 synthesis in VSMCs plays a crucial role in vascular homeostasis and aneurysm development.CONCLUSIONS CircZBTB46 was identified as a novel inhibitor of COL1 synthesis in VSMCs,highlighting the importance of circZBTB46 and PDLIM5 in regulating TGF-beta/Smad signaling and COL1A2 expression.

Neural differentiation of human Wharton＇s jelly-derived mesenchymal stem cells improves the recovery of neurological function after transplantation in ischemic stroke rats

Human Wharton＇s jelly-derived mesenchymal stem cells（h WJ-MSCs）have excellent proliferative ability,differentiation ability,low immunogenicity,and can be easily obtained.However,there are few studies on their application in the treatment of ischemic stroke,therefore their therapeutic effect requires further verification.In this study,h WJ-MSCs were transplanted into an ischemic stroke rat model via the tail vein 48 hours after transient middle cerebral artery occlusion.After 4 weeks,neurological functions of the rats implanted with h WJ-MSCs were significantly recovered.Furthermore,many h WJ-MSCs homed to the ischemic frontal cortex whereby they differentiated into neuron-like cells at this region.These results confirm that h WJ-MSCs transplanted into the ischemic stroke rat can differentiate into neuron-like cells to improve rat neurological function and behavior.

Chinese consensus on management of tyrosine kinase inhibitor-associated side effects in gastrointestinal stromal tumors

Tyrosine kinase inhibitors(TKIs) have improved the overall survival of patients with gastrointestinal stromal tumors(GISTs), but their side effects can impact dose intensity and, consequently, the clinical benefit. To date, no guideline or consensus has been published on the TKI-associated adverse reactions. Therefore, the Chinese Society of Surgeons for Gastrointestinal Stromal Tumor of the Chinese Medical Doctor Association organized an expert panel discussion involving representatives from gastrointestinal surgery, medical oncology, cardiology, dermatology, nephrology, endocrinology, and ophthalmology to consider the systemic clinical symptoms, molecular and cellular mechanisms, and treatment recommendations of GISTs. Here, we present the resultant evidence-and experience-based consensus to guide the management of TKI-associated side events in clinical practice.

Parameter identification and global sensitivity analysis of Xin'anjiang model using meta-modeling approach

Parameter identification, model calibration, and uncertainty quantification are important steps in the model-building process, and are necessary for obtaining credible results and valuable information. Sensitivity analysis of hydrological model is a key step in model uncertainty quantification, which can identify the dominant parameters, reduce the model calibration uncertainty, and enhance the model optimization efficiency. There are, however, some shortcomings in classical approaches, including the long duration of time and high computation cost required to quantitatively assess the sensitivity of a multiple-parameter hydrological model. For this reason, a two-step statistical evaluation framework using global techniques is presented. It is based on （1） a screening method （Morris） for qualitative ranking of parameters, and （2） a variance-based method integrated with a meta-model for quantitative sensitivity analysis, i.e., the Sobol method integrated with the response surface model （RSMSobol）. First, the Morris screening method was used to qualitatively identify the parameters＇ sensitivity, and then ten parameters were selected to quantify the sensitivity indices. Subsequently, the RSMSobol method was used to quantify the sensitivity, i.e., the first-order and total sensitivity indices based on the response surface model （RSM） were calculated. The RSMSobol method can not only quantify the sensitivity, but also reduce the computational cost, with good accuracy compared to the classical approaches. This approach will be effective and reliable in the global sensitivity analysis of a complex large-scale distributed hydrological model.

上消化道异物41例胃镜下治疗分析

目的总结上消化道异物的内镜治疗方法及效果。方法对该院2014年10月-2016年5月41例上消化道异物内镜下治疗病例临床资料进行分析。结果上消化道异物中老年患者多见,异物潴留部位多见于食管(53.6%),异物类型以枣核为主(56.1%),41例患者异物均成功取出,合并穿孔1例。结论内镜治疗上消化道异物是一种安全、有效的方法。

miR-103-3p targets Ndel1 to regulate neural stem cell proliferation and differentiation

The regulation of adult neural stem cells(NSCs) is critical for lifelong neurogenesis. MicroRNAs(miRNAs) are a type of small, endogenous RNAs that regulate gene expression post-transcriptionally and influence signaling networks responsible for several cellular processes. In this study, mi R-103-3 p was transfected into neural stem cells derived from embryonic hippocampal neural stem cells. The results showed that mi R-103-3 p suppressed neural stem cell proliferation and differentiation, and promoted apoptosis. In addition, mi R-103-3 p negatively regulated Nud E neurodevelopment protein 1-like 1(Ndel1) expression by binding to the 3′ untranslated region of Ndel1. Transduction of neural stem cells with a lentiviral vector overexpressing Ndel1 significantly increased cell proliferation and differentiation, decreased neural stem cell apoptosis, and decreased protein expression levels of Wnt3 a, β-catenin, phosphor-GSK-3β, LEF1, c-myc, c-Jun, and cyclin D1, all members of the Wnt/β-catenin signaling pathway. These findings suggest that Ndel1 is a novel mi R-103-3 p target and that mi R-103-3 p acts by suppressing neural stem cell proliferation and promoting apoptosis and differentiation. This study was approved by the Animal Ethics Committee of Nantong University, China(approval No. 20200826-003) on August 26, 2020.

Effect of somatostatin in advanced gastric cancer after D2 radical gastrectomy

AIM:To study the effect of somatostatin in patients with advanced gastric cancer who received D2 lymphadenectomy and vagina vasorum dissection.METHODS:Using a prospective,single-blind,placebocontrolled design,patients with advanced gastric cancer were randomized into a study group(n=61)and a control group(n=59).Patients in the study group were given somatostatin for 5-7 d starting 6 h after the operation,and patients in the control group were given normal saline.Preoperative and nonoperative complications in the perioperative period,as well as differenttypes of postoperative drainage in the two groups were compared.RESULTS:There was no significant difference between the study group and the control group for preoperative clinicopathological indicators.We found no significant difference between the two groups for the overall incidence of complications,but a lower percentage of peritoneal effusion was observed in the treatment group(1.6%vs 10.2%,P<0.05).There were no significant differences between the two groups in the incidence of postoperative pancreatic dysfunction and chylous fistula.However,there were significant differences in the amylase concentration in drainage fluid,volume and duration of drainage,volume and duration of chylous fistula and peritoneal drainage,and volume and duration of gastric tube drainage.The study group did not show any increase in mean hospitalization cost and the cost reduced when the postoperative complications occurred.CONCLUSION:Postoperative somatostatin reduces volume and duration of surgical drainage and related complications.Somatostatin may improve safety of gastric cancer surgery,reducing postoperative complications and promoting recovery.

Pathological diagnosis is maybe non-essential for special gastric cancer: Case reports and review

Histopathological results are critical for the diagnosis and surgical decision regarding gastric cancer. How-ever, opposite opinions from radiology and pathology can sometimes affect clinical decisions. The two cases reported in this article were both highly suspected as gastric cancer by clinical manifestations and radiologic findings, although both showed negative results in the first biopsy examination. One was confirmed as gastric cancer by the time of the 6 th biopsy, while the other was still negative even after 8 biopsies. With a definite pathologic result and the agreement of the patient for the latter case, both of them finally received surgery. Postoperative pathological examination revealed find-ings that were the same as Borrmann type Ⅳ gastric cancer. We believed that duplicate biopsies under ra-diologic guidance were necessary for highly suspected gastric cancer cases in the absence of a definite pathol-ogy result, and patients should be under close follow-up. We propose that, if gastric cancer is highly sus-pected when typical radiology changes of widely diffuse gastric parietal lesions suffice to exclude lymphoma and other similar situations, and even in absence of a posi-tive biopsy result, a diagnostic laparotomy under lapa-roscopy and even radical gastrectomy may be reason-ably performed by an experienced gastric cancer center with the agreement of the patient after being decided by a multidisciplinary discussion team.

Ultrasound-guided,direct suprainguinal injection for fascia iliaca block for total hip arthroplasty:A retrospective study

BACKGROUND Peripheral regional block combined with general anesthesia might be a preferable anesthetic regimen for elderly patients undergoing total hip arthroplasty.AIM To investigate whether ultrasound-guided,direct suprainguinal injection for fascia iliaca block accelerated recovery after general anesthesia and relieved postoperative pain after total hip arthroplasty.METHODS Patients who underwent total hip arthroplasty under general anesthesia in 2015 or 2019 at The Second Affiliated Hospital of Xuzhou Medical University were retrospectively analyzed.The patients were grouped based on whether preoperative suprainguinal fascia iliaca block was performed or not.The time to tracheal extubation and time spent in the post-anesthesia care unit(PACU),intraoperative remifentanil dosage,fentanyl consumption in the PACU,postoperative cumulative fentanyl consumption within 48 h after operation,visual analogue scale at rest and during movement on the first and second days after surgery,and adverse reactions were compared.RESULTS Thirty-one elderly patients who underwent total hip arthroplasty were included in the study(block group,n=16;no-block group,n=15).The visual analog scale scores at rest and during movement on the first and second days were significantly lower in the block group than in the no-block group(all P<0.05).Compared with the no-block group,the intraoperative remifentanil dosage was lower,the time to tracheal extubation and the time spent in the PACU were shorter in the block group(all P<0.01).Fentanyl consumption in the PACU and postoperative cumulative fentanyl consumption in 48 h after operation were lower in the block group(all P<0.01).The incidence of dizziness was higher in the no-block group than in the block group(P=0.037).CONCLUSION Ultrasound-guided,direct suprainguinal injection for fascia iliaca block led to faster recovery after general anesthesia and early postoperative pain relief in elderly patients undergoing total hip arthroplasty.

Regeneration of neuronal nitric oxide synthase (nNOS)-containing nerve fibers in rat corpus cavernosum

Aim: To investigate the effect of cavernous nerve injury on the nNOS-containing nerve fibers in rat corpus cavernosum.Methods: Thirty-three male SD rats were randomized into 3 groups: 5 rats underwent pelvic exploration without tran-section of cavernous nerve as the sham-operated controls, the unilateral injury group (14 rats) had the cavernous nerve cuton one side, and the bilateral injury group (14 rats) had the nerves cut on both sides. Corpora cavernosa were harvestedat the 3rd week and 6th month after surgery, nNOS-positive nerve fibers were examined with strepavidin peroxidase im-munohistochemistry techniques (SP method). Results: After bilateral ablation, the nNOS-positive nerve fibers weresignificantly decreased at both the 3rd week ( 17 ± 4) and the 6th month (16 ± 4). For the unilateral injury group, thenNOS-positive nerve fibers were similarly decreased on the side of the neurotomy at the 3rd week (18 ± 6), but by the 6thmonth, the number increased significantly (61±9) and approximated the level on the contralateral side (81 ± 13). Con-clusion: In rats after unilateral cavernous nerve ablation, nNOS-containing nerve fibers might regenerate 6 months afteroperation, but regeneration did not occur in animals with bilateral cavernous nerve injury. Results suggest that duringpelvic radical surgery, the cavernous nerve should be preserved at least on one side in order to accomplish adequate regen-eration. (Asian J Androl 1999 Sep ; 1: 135 - 138)

Denervated hippocampus provides a favorable microenvironment for neuronal differentiation of endogenous neural stem cells

Fimbria-fornix transection induces both exogenous and endogenous neural stem cells to differentiate into neurons in the hippocampus.This indicates that the denervated hippocampus provides an environment for neuronal differentiation of neural stem cells.However,the pathways and mechanisms in this process are still unclear.Seven days after fimbria fornix transection,our reverse transcription polymerase chain reaction,western blot assay,and enzyme linked immunosorbent assay results show a significant increase in ciliary neurotrophic factor m RNA and protein expression in the denervated hippocampus.Moreover,neural stem cells derived from hippocampi of fetal（embryonic day 17） Sprague-Dawley rats were treated with ciliary neurotrophic factor for 7 days,with an increased number of microtubule associated protein-2-positive cells and decreased number of glial fibrillary acidic protein-positive cells detected.Our results show that ciliary neurotrophic factor expression is up-regulated in the denervated hippocampus,which may promote neuronal differentiation of neural stem cells in the denervated hippocampus.

Human papillomavirus and p53 protein immunoreactivity in condylomata acuminatum and squamous cell carcinoma of penis

Aim: To determine the immunoreactive pattern of human papillomavirus (HPV) antigen and p53 protein in condylo-mata acuminatum (CA) and squamous cell carcinoma (SCC) of penis. Methods: Immunohistochemistry for HPVand p53 were performed in 40 specimens of formalin fixed, paraffin embedded tissues using a polyclonal (rabbit) anti-body against HPV and a monoclonal (mouse) antibody against human p53 protein. Twenty one cases of CA and nine-teen cases of SCC were examined. Results: HPV antigen was detected in all 21 CA and 2 penile SCC. p53 proteinoverexpression was observed in 12 of 19 (63%) SCC in which 6 cases were strong positive. Five of 21 CA (24%)showed low-grade p53 protein overexpression. Conclusion; CA is related to HPV infection and some cases showp53 protein low-grade overexpression. In contrast, p53 protein overexpression is common in penile SCC, which is sel-dom related to HPV infection. (Asian J Androl 2001 Mar; 3: 75-77)

Association of polymorphisms of A260G and A386G in DAZL gene with male infertility： a meta-analysis and systemic review

To investigate the association of single nucleotide polymorphism 260 and 386 （SNP260 and SNP386） gene with male infertility, an electronic search was performed to identify case-control studies evaluating the relationship of SNP260 or SNP386 of deleted in azoospermia-like （DAZL） and male infertility. Review Manager 5 was used to process the meta-analysis and other statistical analysis. A total of 139 records were retrieved, of which 13 case-control studies with total 2715 patients and 1835 normozoospermic men were included. SNP260 was found not to play a functional role in male oligo/azoospermia either for Caucasians or for Asians. But for SNP386, models of allele （A/G）, dominant （AA/AG ＋ GG）, co-dominant （AA/AG） and super-dominant （AA ＋ GG/AG） had a strong correlation to spermatogenic failure with related odds ratio being 0.15 （95% confidence interval [95% CI] 0.07 to 0.34, P〈 0.00001）, 0.16 （95% CI 0.07 to 0.35, P〈 0.00001）, 0.15 （95% CI 0.06 to 0.33, P〈 0.00001） and 0.15 （95% CI 0.06 to 0.33, P 〈 0.00001）, respectively. Moreover, this correlation was only found in the Chinese Han population （decreasing around 85% risk of oligo/azoospermia infertility） and not found in India, Japan, and Caucasian countries. Our analysis demonstrated that SNP260 of DAZL did not contribute to oligo/azoospermia while SNP386 was correlated to male infertility. However, this correlation was only found in China with a country-specific and ethnicity-specific manner.

Clinical and preclinical treatment of urologic diseases with phosphodiesterase isoenzymes 5 inhibitors： an update

Phosphodiesterase isoenzymes 5 inhibitors （PDE5-1s） are the first-line therapy for erectile dysfunction （ED）. The constant discoveries of nitric oxide （NO）/cyclic guanosine monophosphate （cGMP） cell-signaling pathway for smooth muscle （SM） control in other urogenital tracts （UGTs） make PDE5-1s promising pharmacologic agents against other benign urological diseases. This article reviews the literature and contains some previously unpublished data about characterizations and activities of PDE5 and its inhibitors in treating urological disorders. Scientific discoveries have improved our understanding of cell-signaling pathway in NO/cGMP-mediated SM relaxation in UGTs. Moreover, the clinical applications of PDE5-1s have been widely recognized. On-demand PDE5-1s are efficacious for most cases of ED, while daily-dosing and combination with testosterone are recommended for refractory cases. Soluble guanylate cyclase （sGC） stimulators also have promising role in the management of severe ED conditions. PDE5-1s are also the first rehabilitation strategy for postoperation or postradiotherapy ED for prostate cancer patients. PDE5-1s, especially combined with （z-adrenoceptor antagonists, are very effective for benign prostatic hyperplasia （BPH） except on maximum urinary flow rate （Qmax） with tadalafil recently proved for BPH with/without ED. Furthermore, PDE5-1s are currently under various phases of clinical or preclinical researches with promising potential for other urinary and genital illnesses, such as priapism, premature ejaculation, urinary tract calculi, overactive bladder, Peyronie＇s disease, and female sexual dysfunction. Inhibition of PDE5 is expected to be an effective strategy in treating benign urological diseases. However, further clinical studies and basic researches investigating mechanisms of PDE5-1s in disorders of UGTs are required.