Radiomics-based nomogram guides adaptive de-intensification in locoregionally advanced nasopharyngeal carcinoma following induction chemotherapy.

OBJECTIVES: This study aimed to construct a radiomics-based model for prognosis and benefit prediction of concurrent chemoradiotherapy (CCRT) versus intensity-modulated radiotherapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (LANPC) following induction chemotherapy (IC). MATERIALS AND METHODS: A cohort of 718 LANPC patients treated with IC + IMRT or IC + CCRT were retrospectively enrolled and assigned to a training set (n = 503) and a validation set (n = 215). Radiomic features were extracted from pre-IC and post-IC MRI. After feature selection, a delta-radiomics signature was built with LASSO-Cox regression. A nomogram incorporating independent clinical indicators and the delta-radiomics signature was then developed and evaluated for calibration and discrimination. Risk stratification by the nomogram was evaluated with Kaplan-Meier methods. RESULTS: The delta-radiomics signature, which comprised 19 selected features, was independently associated with prognosis. The nomogram, composed of the delta-radiomics signature, age, T category, N category, treatment, and pre-treatment EBV DNA, showed great calibration and discrimination with an area under the receiver operator characteristic curve of 0.80 (95% CI 0.75-0.85) and 0.75 (95% CI 0.64-0.85) in the training and validation sets. Risk stratification by the nomogram, excluding the treatment factor, resulted in two groups with distinct overall survival. Significantly better outcomes were observed in the high-risk patients with IC + CCRT compared to those with IC + IMRT, while comparable outcomes between IC + IMRT and IC + CCRT were shown for low-risk patients. CONCLUSION: The radiomics-based nomogram can predict prognosis and survival benefits from concurrent chemotherapy for LANPC following IC. Low-risk patients determined by the nomogram may be potential candidates for omitting concurrent chemotherapy during IMRT. CLINICAL RELEVANCE STATEMENT: The radiomics-based nomogram was constructed for risk stratification and patient selection. It can help guide clinical decision-making for patients with locoregionally advanced nasopharyngeal carcinoma following induction chemotherapy, and avoid unnecessary toxicity caused by overtreatment. KEY POINTS: • The benefits from concurrent chemotherapy remained controversial for locoregionally advanced nasopharyngeal carcinoma following induction chemotherapy. • Radiomics-based nomogram achieved prognosis and benefits prediction of concurrent chemotherapy. • Low-risk patients defined by the nomogram were candidates for de-intensification.

Asarinin attenuates bleomycin-induced pulmonary fibrosis by activating PPARγ.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that lacks effective treatment modalities. Once patients are diagnosed with IPF, their median survival is approximately 3-5 years. PPARγ is an important target for the prevention and treatment of pulmonary fibrosis. Asarinin is a lignan compound that can be extracted from food plant Asarum heterotropoides. In this study, we investigated the therapeutic effects of asarinin in a pulmonary fibrosis model constructed using bleomycin in mice and explored the underlying mechanisms. Intraperitoneal administration of asarinin to mice with pulmonary fibrosis showed that asarinin effectively attenuated pulmonary fibrosis, and this effect was significantly inhibited by the PPARγ inhibitor GW9662. Asarinin inhibited TGF-ß1-induced fibroblast-to-myofibroblast transition in vitro, while GW9662 and PPARγ gene silencing significantly inhibited this effect. In addition, asarinin inhibited not only the canonical Smad pathway of TGF-ß but also the non-canonical AKT and MAPK pathways by activating PPARγ. Our study demonstrates that asarinin can be used as a therapeutic agent for pulmonary fibrosis, and that PPARγ is its key target.

Prognostic Value of Lymph Node Necrosis at Different N Stages in Patients with Nasopharyngeal Carcinoma.

Background: Lymph node necrosis (LNN), including retropharyngeal nodal necrosis and cervical nodal necrosis, which is related to radiotherapy/ chemotherapy resistance, is a common phenomenon in nasopharyngeal carcinoma (NPC). This study was to assess the prognostic value of LNN at different N stages in NPC patients. Materials and Methods: In total, 1,665 newly diagnosed NPC patients at stage TxN1-3M0 from two centers were enrolled. Univariate and multivariate models were constructed to assess the association between LNN and long-term survival outcomes. The propensity score matching method was performed to balance treatment groups for baseline characteristics. Results: Of the 1,665, 540 patients (540/1665, 32.4%) were diagnosed with LNN, of which 54.1% (292/540) patients were at stage N1, 31.3% (169/540) at stage N2, and 14.6% (79/540) at stage N3. Univariate and multivariate analyses indicated LNN as an independent predictor for progression­free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) in stage N1-3 patients (all P<0.001). When patients were analyzed according to stage, similar findings were observed for N1 patients (all P<0.001); for N2 patients, LNN independently predicted PFS (P=0.003), OS (P=0.011), and DMFS (P=0.004), and for stage N3, LNN only independently predicted LRRFS (P=0.019). 123 pairs of patients who received induction chemotherapy plus concurrent chemoradiotherapy or only concurrent chemoradiotherapy were matched, adding induction chemotherapy improved 5-year OS, PFS and LRFFS, but the results were not statistically significant. Conclusions: In NPC patients, LNN could independently predict poor prognosis at all N1-3 stages and at each N stage (N1 to N3). The value of adding induction chemotherapy to concurrent chemoradiotherapy in patients with LNN still requires further prospective studies.

Evolutionary route of nasopharyngeal carcinoma metastasis and its clinical significance.

It is critical to understand factors associated with nasopharyngeal carcinoma (NPC) metastasis. To track the evolutionary route of metastasis, here we perform an integrative genomic analysis of 163 matched blood and primary, regional lymph node metastasis and distant metastasis tumour samples, combined with single-cell RNA-seq on 11 samples from two patients. The mutation burden, gene mutation frequency, mutation signature, and copy number frequency are similar between metastatic tumours and primary and regional lymph node tumours. There are two distinct evolutionary routes of metastasis, including metastases evolved from regional lymph nodes (lymphatic route, 61.5%, 8/13) and from primary tumours (hematogenous route, 38.5%, 5/13). The hematogenous route is characterised by higher IFN-γ response gene expression and a higher fraction of exhausted CD8+ T cells. Based on a radiomics model, we find that the hematogenous group has significantly better progression-free survival and PD-1 immunotherapy response, while the lymphatic group has a better response to locoregional radiotherapy.

[Research progress on penis cavernosa fibrosis].

Penis cavernosa fibrosis is an important cause of refractory erectile dysfunction.Its exact pathogenesis remains incompletely elucidated, and conventional treatment is not effective, seriously affecting the quality of life, physical and mental health of men. With the deepening of research, the progress of two-dimensional shear wave elastography (2D-SWE) and molecular imaging provides the possibility for the early diagnosis, grading and staging of cavernous fibrosis. Studies on stem cell therapy, energy-based treatments, targeted therapy, and traditional Chinese medicine show promising applications in the anti-penile cavernous fibrosis. This article reviews the research progress in the diagnosis and treatment of penile cavernosis fibrosis.

High expression of CFTR in cumulus cells from mature oocytes is associated with high-quality of oocyte and subsequent embryonic development.

OBJECTIVE: The purpose of this study was to explore the association of expression of cystic fibrosis transmembrane conductance regulator (CFTR) in cumulus cells (CCs) from mature oocytes with oocyte quality and embryonic development. METHODS: A total of 338 infertile women who underwent ovarian stimulation cycle of oocyte retrieval in Zhejiang University School of Medicine were retrospectively enrolled in this study. The relative mRNA expression levels of CFTR, bone morphogenetic protein 15 (BMP15), and growth differentiation factor 9 (GDF9) in CCs were detected by qPCR technology. ROC curve was applied for the diagnosis of oocyte maturation. The serum levels of anti-Müllerian hormone (AMH), E2, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and androstenedione were measured. Oocyte maturation rate, fertilization rate, cleavage rate, high-quality embryo formation rate, and implantation rate after embryo transfer were also determined. RESULTS: The mRNA expression levels of CFTR in CCs were significantly increased in metaphase II (MII) oocytes compared to that in metaphase I (MI) or germinal vesicle (GV) oocytes. The ROC curve analysis illustrated that CFTR mRNA expression could efficiently discriminate MII oocytes from MI or GV oocytes (AUC = 0.954), and revealed that 0.695 RQU is the optimal cut-off value for diagnosis. So the cut-off value of 2-ΔΔCT = 0.70 was used to divide the patients into two groups: low- (n = 114) and high-CFTR group (n = 224). The mRNA expression of CFTR in CCs was positively correlated with the antral follicular count (AFC), number of oocytes retrieved, number of MII oocytes, serum E2 level on hCG day, and BMP15 and GDF9 expression in CCs. Under continuous stimulation with the same dose of recombinant follicle-stimulating hormone (rFSH), the number of follicles, average recovered oocytes, recovered oocytes, MII oocytes, as well as the oocyte recovery rate, fertilization rate, oocyte cleavage rate, high-quality embryo formation rate, and implantation rate were decreased in patients with lower CFTR. CONCLUSIONS: This study suggests that CFTR expression in CCs is associated with the developmental potential of human oocytes.

Follicle stimulating hormone promotes production of renin through its receptor in juxtaglomerular cells of kidney.

BACKGROUND: Post-menopausal hypertension has been attributed solely to declining estrogen levels. The purpose of the research is to elucidate the mechanism by which follicle stimulating hormone(FSH) increases renin production involved in the regulation of blood pressure. METHODS: The expression of follicle stimulating hormone receptors (FSHRs) in renal juxtaglomerular cells and a As4.1 juxtaglomerular mouse cell line was evaluated. We established a mouse model by ovariectomy (OVX). Ovariectomized mice were treated with gonadotropin-releasing hormone agonist (GnRHa) (OVX + GnRHa). Ovariectomized mice initially received physiological doses of estrogen and were then injected with recombinant FSH (OVX + E + FSH). RESULTS: We found that FSHR was expressed in mouse renal juxtaglomerular cells labeled by renin antibody and in As4.1 cells. FSH promoted renin synthesis via Gsα-coupled FSHRs that activated protein kinase A, cyclic adenosine monophosphate(cAMP) response element-binding protein, extracellular signal-regulated kinase (Erk1/2), Protein kinase B(AKT), and c-Jun N-terminal kinase signaling pathways in As4.1 cells. We found increased serum FSH levels in the ovariectomized mouse with concurrent increases in renin, angiotensin II, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial blood pressure (MAP). Additionally, increases in serum renin, angiotensin II, HR, SBP, DBP, and MAP were reduced by the additional injection of GnRHa. Exogenous FSH administration completely reversed decreases in renin, angiotensin II, HR, SBP, DBP, and MAP even in mice that received physiological doses of estrogen to maintain normal estradiol levels. CONCLUSIONS: Elevated FSH stimulates renin production involving a mechanism that may be relevant to the expression of FSH receptors in renal juxtaglomerular cells.

Integrin-ß4 regulates the dynamic changes of phenotypic characteristics in association with epithelial-mesenchymal transition (EMT) and RhoA activity in airway epithelial cells during injury and repair.

Background: In airway disease such as asthma a hyperactive cellular event of epithelial-mesenchymal transition (EMT) is considered as the mechanism of pathological airway tissue remodeling after injury to the airway epithelium. And the initiation of EMT in the airways depends on the epithelial disruption involving dissolution and/or destabilization of the adhesive structures between the cells and ECM. Previously, we have shown that integrin-ß4, an epithelial adhesion molecule in bronchial epithelium is an important regulator of cell proliferation and wound repair in human airway epithelial cells. Therefore, in this study we aimed to investigate whether integrin-ß4 also regulates EMT phenotypes during injury and repair in airway epithelial cells of both wild type/integrin-ß4-/- mice in vivo and cultured cells treated with integrin-ß4/nonsense siRNA in vitro. Methods: We induced injury to the airway epithelial cells by either repeated exposure to ozone and mechanical scratch wound, and subsequently examined the EMT-related phenotypic features in the airway epithelial cells including biomarkers expression, adhesion and cytoskeleton reorganization and cell stiffness. Results: The results show that in response to injury (ozone exposure/scratch wound) and subsequent spontaneous repair (ozone withdrawal/wound healing) both in vivo and in vitro, the airway epithelial cells underwent dynamic changes in the epithelial and mesenchymal biomarkers expression, adhesion and cytoskeleton structures as well as cell stiffness, all together exhibiting enhanced EMT phenotypic features after injury and reversal of the injury-induced effects during repair. Importantly, these injury/repair-associated EMT phenotypic changes in airway epithelial cells appeared to be dependent on integrin-ß4 expression. More specifically, when integrin-ß4 was deficient in mice (integrin-ß4-/-) the repair of ozone-injured airway epithelium was impaired and the recovery of ozone-enhanced EMT biomarkers expression in the airway epithelium was delayed. Similarly, in the scratch wounded airway epithelial cells with integrin-ß4 knockdown, the cells were impaired in all aspects related to EMT during wound and repair including cell proliferation, wound closure rate, adhesion and cytoskeleton protein expression (vinculin and vimentin), mesenchymal-like F-actin reorganization, cell stiffness and RhoA activation. Conclusion: Taken together, these results suggested that integrin-ß4 may be essential in regulating the effects of injury and repair on EMT in airway epithelial cells via influencing both the cell adhesion to ECM and cells' physical phenotypes through RhoA signaling pathway.

[Male infertility and urologic cancers: Advances in studies].

Male infertility is one of the most common diseases in andrology. Studies show that male infertility is significantly correlated with the incidence and mortality of tumors, especially malignant tumors in the genitourinary system, such as testis cancer and prostate cancer. The relationship of male infertility with genitourinary system tumors involves various aspects, mainly including changes in chromosome mutations, epigenetic marks, hormonal imbalance, and congenital deformity. Besides, some chronic diseases are shown to be significantly associated with male infertility, and semen quality or fertility status may be biomarkers of the overall health of males. In-depth studies of the correlation between male infertility and these factors are very important for an insight into the pathogenesis and prevention of the related diseases.

Ghrelin Affects Gastric Cancer Progression by Activating AMPK Signaling Pathway.

As the endogenous ligand for the GH secretagogue receptor (GHSR), Ghrelin is aberrant expressed in multiple malignant carcinoma, and involved in regulating a number of progression of cancer, especially in metastasis and proliferation. However, the precise role of Ghrelin in tumorigenesis of gastric cancer (GC) is still poorly understood. In this study, we extensively investigated the roles and mechanisms of Ghrelin in human gastric cancer. Ghrelin levels in cancer tissues and cell lines were analyzed by immunohistochemistry, qRT-PCR, and Western blot. Functional studies were performed after Ghrelin overexpressed or knockdown in AGS cell line. Cell proliferation was evaluated in by MTT and clone formation assays. The wound healing and Transwell system were used to assess the cell migration and invasive ability of GC cells. Cell apoptosis was detected by flow cytometry, and metabolic assays were performed to reveal the function of Warburg effect in the process. Ghrelin was lowly expressed in gastric cancer tissues and cell lines. Overexpression of Ghrelin inhibited gastric cancer cell proliferation, migration, invasion, and promoted apoptosis by activating the AMPK pathway, while D-[lys3]-GHRP-6 (a GHSR agonist) treatment relieved the effect, promoting tumorigenesis. Ghrelin knockdown increased the glucose uptake and lactic acid release, suggesting that Ghrelin elicited an anti-Warburg effect via AMPK pathway to inhibit gastric tumorigenesis. Ghrelin inhibits cell proliferation, migration, and invasion by eliciting an anti-Warburg effect via AMPK signaling pathway in gastric cancer cells.

LncRNA NBR2 inhibits tumorigenesis by regulating autophagy in hepatocellular carcinoma.

Long noncoding RNAs (lncRNAs) have been identified to play increasingly important roles in tumorigenesis, and they may serve as novel biomarkers for cancer therapy. LncRNA NBR2 (neighbor of BRCA1 gene 2), a novel identified lncRNA, is demonstrated to decrease in several cancers. However, it is still unknown whether lncRNA NBR2 is involved in hepatocellular carcinoma and autophagy. We found that HCC cases with lower NBR2 expression had significantly worse overall survival than those with higher NBR2 expression in advanced patients. And the expression of NBR2 was negatively correlated with the degree of malignancy of HCC cell lines and differentiation of hepatocellular carcinoma. Besides, NBR2 inhibited the proliferation, invasion, and migration of liver cancer cells. We further found that NBR2 repressed cytoprotective autophagy to restrain HCC cell proliferation. Moreover, NBR2 inhibited Beclin 1-dependent autophagy through ERK and JNK pathways. Taken together, NBR2 suppressed autophagy-induced cell proliferation at least partly through ERK and JNK pathways. These data indicated that NBR2 served as a tumor suppressor gene in hepatocellular carcinoma. The current study provides a novel insight and treatment strategy for hepatocellular carcinoma.

Multidrug Resistance of Gastric Cancer: The Mechanisms and Chinese Medicine Reversal Agents.

Chemotherapy is the main clinical treatment method of gastric cancer. Multidrug resistance (MDR) has become a common phenomenon with the development of tumors, which alleviates the effect of chemotherapy and makes it difficult to break the bottleneck of survival rate of advanced gastric cancer. Therefore, the exploration of MDR reversal agents for gastric cancer is the focus and also the difficulty of current treatment. Currently, the researches on the mechanisms of drug resistance in gastric cancer have been continuously deepened, which reveal different pathways and targets of MDR, laying a solid foundation for studying reversal agents. As a kind of natural medicine, traditional Chinese medicine (TCM) owns the characteristics of low toxicity, high safety and effectiveness. It can inhibit the occurrence, growth and metastasis of tumors, and reverse MDR via multiple pathways and mechanisms, the pathological function of which has become a research hotspot in recent years. TCM reversers are mainly divided into Chinese medicine monomers, Chinese patent medicines, and Chinese herbal compounds. With certain quantity and advantage, TCM reversers for MDR play an important role in the clinical treatment and show great potential in gastric cancer.

Cost-effectiveness analysis of pembrolizumab plus chemotherapy with PD-L1 test for the first-line treatment of NSCLC.

BACKGROUND: Pembrolizumab (Pembro) in combination with chemotherapy has been approved for the treatment of pretreated advanced NSCLC in the United States and China for its significant efficacy. However, the cost-effectiveness is unknown considering Pembro's high price. The impact of programmed death ligand 1 (PD-L1) test on the cost-effectiveness is also unknown. The current study assessed the cost-effectiveness of combination therapy for nonsquamous NSCLC from the United States and China public payers' perspective. MATERIALS AND METHODS: A literature-based Markov model was conducted using KEYNOTE-189 trial data to compare cost and quality-adjusted life years (QALYs) of three treatment strategies for nonsquamous NSCLC: Pembro-chemotherapy combination and chemotherapy strategy without PD-L1 test, and treatment strategy according to their PD-L1 status. RESULTS: In base case analysis, the combination strategy generated an additional 0.78 QALYs and 0.59 QALYs over chemotherapy in the United States and China respectively, resulting in an ICER of $132 392/QALY in the United States and $92 533/QALY in China. In the PD-L1 ≥1% base case, the ICERs were $77 754/QALY and $56 768/QALY respectively in the United States and China for PD-L1 test strategy. In the PD-L1 ≥50% base case, the ICERs were $44 731/QALY and $34 388/QALY respectively in the United States and China for PD-L1 test strategy. Lowering Pembro price can also partly decrease the ICERs. CONCLUSION: Compared with chemotherapy, the combination strategy is not cost-effective for the treatment of NSCLC in the American and Chinese health care system at WTP threshold of $100 000/QALY for the United States and $27 351/QALY for China. Using PD-L1 test for patient selection and price reduction could improve the cost-effective probabilities of immunotherapy for nonsquamous NSCLC.

Urachal remnant with heterotopic sinus in an adult male: A case report.

INTRODUCTION: Urachal remnant with heterotopic sinus is an extremely rare congenital anomaly, and usually coexists with other congenital anomalies. We report the case of a 32-year-old adult male with urachal remnant with heterotopic sinus. PATIENT CONCERNS: A 32-year-old adult male presented with purulent secretion in the heterotopic sinus on the dorsal side of the normal external urethral orifice and pain in the balanus since 5 months. DIAGNOSIS: The computed tomography scan demonstrated a 4 cm cystic mass next to the anterior wall of the urinary bladder. Retrograde urethrography was performed, which demonstrated that this mass communicated with the heterotopic sinus on the dorsal side of the normal external urethral orifice. Cystoscopy showed that there was no communication between the mass and the bladder. Pathology results confirmed that this mass was urachal tissue. INTERVENTIONS: The patient underwent a laparoscopy surgery to undertake the cystic mass, part of the anterior wall of urinary bladder and the epithelium of channel which communicated with the cystic mass. OUTCOMES: The patient was discharged without any complications after 6 months and follow-up was continued in the clinic. CONCLUSIONS: Urachal remnant with heterotopic sinus is rare, and we recommend that urachal remnant should be considered when a patient presents with a mass in the retropubic space.

Pyroptosis is involved in cryopreservation and auto-transplantation of mouse ovarian tissues and pyroptosis inhibition improves ovarian graft function.

The aim of this study was to investigate the role of pyroptosis in the cryopreservation and transplantation of mouse ovarian tissues; the effects of pyroptosis inhibitior on the ovarian graft function were also explored. ICR (institute of cancer research) mice were randomly divided into control group and experimental groups (n = 10 per group). The experimental groups included fresh graft group (autograft), cryopreserved graft group (cryopreservation + autograft), and pyroptosis inhibition group (cryopreservation + autograft + pyroptosis inhibitor). At the third day after auto-transplantation, caspase-1 and NLRP3 protein expression in grafts were assessed by Western blot; in the meantime, serum concentration of IL-1ß was examined by ELISA. After 28 days of auto-transplantation, estradiol concentrations and follicular densities of grafts were evaluated. The caspase-1 and NLRP3 protein expression in grafts from all the experimental groups were significantly higher than that from control group respectively; moreover, there was a significant increase in serum concentrations of IL-1ß in all experimental groups compared with control group. The concentration of estradiol and follicular densities of grafts in pyroptosis inhibition group were significantly higher than that in cryopreserved graft group. Pyroptosis is involved in cryopreservation and auto-transplantation of mouse ovarian tissues, and pyroptosis inhibition can improve the ovarian graft function.

MicroRNA-34a promotes MICB expression in hepatocytes.

MicroRNA-34a (miR-34a) behaves as a tumor suppressor by decreasing the expression of oncogenes involved in multiple carcinogenic pathways. Intravenous delivery of miR-34a mimics has been investigated in clinical trials as a potential treatment for advanced cancers; however, the effect of miR-34a on cancer immune surveillance is controversial. In the current study, we found that miR-34a plays a dual role in the regulation of major histocompatibility complex class I-related sequence B (MICB) protein, a ligand of the NKG2D receptor. MiR-34a could both induce and reduce MICB expression by upregulating ataxia telangiectasia and Rad3-related (ATR) protein kinase and downregulating the transcription factor E2F1, respectively. The net effect of miR-34a on MICB expression depended on endogenous E2F1 levels. Overexpression of miR-34a promoted MICB expression in hepatocytes and hepatocellular carcinoma (HCC) cells that have low E2F1 levels but not in HCC cells that have high E2F1 levels. In HCC patients, the expression of miR-34a and MICB showed positive correlation in paratumor liver tissues, which have low E2F1 levels, but not in HCC tissues, which have high E2F1 levels. We showed that miR-34a overexpression in non-transformed liver cells enhanced cytolysis and interferon-γ production by NK-92MI cells. Furthermore, higher miR-34a expression in tumor and paratumor tissues was associated with positive and negative outcomes, respectively, in HCC patients. Our findings suggest that miR-34a induces MICB expression in paratumor liver tissues, which may cause liver damage and serious cytokine release syndrome, thus disclosing potential side effects of systemic administration of miR-34a in anticancer therapy.

Silencing circular RNA hsa_circ_0000977 suppresses pancreatic ductal adenocarcinoma progression by stimulating miR-874-3p and inhibiting PLK1 expression.

Circular RNAs (CircRNAs) are a novel type of endogenous noncoding RNAs that regulate target gene expression by interacting with microRNA (miRNA). Emerging evidence shows that dysregulation of circRNAs plays important roles in biological and pathological processes, including cancer development and progression. The functional role of circRNA in PDAC (pancreatic ductal adenocarcinoma) remains to be investigated. In this study, high throughput microarray assay revealed that hsa_circ_0000977 was aberrantly up-regulated in pancreatic cancer tissues; this was also validated by qRT-PCR. Silencing hsa_circ_0000977 suppressed pancreatic cancer cell proliferation and induced cell cycle arrest, which was simulated by hsa-miR-874-3p mimics and blocked by hsa-miR-874-3p inhibitor. Bioinformatics analysis predicted that there is an hsa_circ_0000977/hsa-miR-874-3p/PLK1 (Polo like kinase 1) axis in pancreatic cancer progression. Dual-luciferase reporter system and FISH assay validated the direct interaction of hsa_circ_0000977, hsa-miR-874-3p, and PLK1. Western blot verified that inhibition of hsa_circ_0000977 decreased PLK1 expression. Furthermore, silencing hsa_circ_0000977 suppressed pancreatic cancer growth in vivo. Altogether, silencing hsa_circ_0000977 suppresses progression of pancreatic cancer by interacting with hsa-miR-874-3p and decreasing inhibiting PLK1 expression. Our results may provide a promising strategy for future diagnosis and treatment of pancreatic cancer.

The platelet-derived growth factor receptor/STAT3 signaling pathway regulates the phenotypic transition of corpus cavernosum smooth muscle in rats.

Erectile dysfunction (ED) is a common clinical disease that is difficult to treat. We previously found that hypoxia modulates the phenotype of primary corpus cavernosum smooth muscle cells (CCSMCs) in rats, but the underlying molecular mechanism is still unknown. Platelet-derived growth factor receptor (PDGFR)-related signaling pathways are correlated with cell phenotypic transition, but research has been focused more on vascular smooth muscle and tracheal smooth muscle and less on CCSMCs. Here, we investigated the role of PDGFR-related signaling pathways in penile CCSMCs, which were successfully isolated from rats and cultured in vitro. PDGF-BB at 5, 10, or 20 ng/ml altered CCSMC morphology from the original elongated, spindle shape to a broader shape and promoted the synthetic phenotype and expression of the related proteins vimentin and collagen-I, while inhibiting the contractile phenotype and expression of the related proteins smooth muscle (SM) α-actin (α-SMA) and desmin. Inhibition of PDGFR activity via siRNA or the PDGFR inhibitor crenolanib inhibited vimentin and collagen-I expression, increased α-SMA and desmin expression, and considerably inhibited serine-threonine protein kinase (AKT) and signal transducer and activator of transcription 3 (STAT3) phosphorylation. STAT3 knockdown promoted the contractile phenotype, inhibited vimentin and collagen-I expression, and increased α-SMA and desmin expression, whereas AKT knockdown did not affect phenotype-associated proteins. STAT3 overexpression in CCSMC cells weakened the suppressive effect of PDGFR inhibition on the morphology and phenotypic transformation induced by PDGF-BB. Through activation of the PDGFR/STAT3 signaling pathway, PDGF promoted the synthetic phenotype transition; thus, regulation of this pathway might contribute to ED therapy.

[TNFR-Fc prevents lipopolysaccharide-induced acute lung injury in mice via oxidative stress inhibition].

OBJECTIVE: Acute lung injury (ALI) was associated with excessive inflammation caused by high TNF-α concentration. We hypothesized that anti-TNF-α therapy would have beneficial effects in experimental ALI in mice via oxidative stress inhibition. METHODS: BALB/c mice (8 - 10 week old) were randomly assigned to an LPS group, a TNFR-Fc + LPS group and a control group. LPS (5 mg/kg) was intratracheally administered to the mice. For the TNFR-Fc + LPS group, TNFR-Fc was given intraperitoneally once at a dose of 0.4 mg/kg before LPS treatment, at 0 and 2 h after LPS treatment, the mice were sacrificed. Wet to dry ratio of the lung and the protein concentration in BALF were measured. Lung histology was evaluated for lung injury. TNF-α concentration in serum, MDA and total anti-oxidative stability were assayed. Finally, the transcription level of iNOS, Nox1, Nox2, Nox4, XO and SOD were evaluated by qRT-PCR. RESULTS: TNFR-Fc treatment significantly decreased the serum TNF-α concentration (P < 0.001), reduced the score of lung histology and decreased the protein concentration in BALF (P < 0.001), but did not change the wet to dry ratio of the lung. The ALI mice treated with TNFR-Fc had a lower transcription level of Nox1, Nox2, Nox4 and XO (all P < 0.001). The total anti-oxidative stability of mice treated with TNFR-Fc was preserved better than those treated with LPS alone (P < 0.05). CONCLUSION: Treatment with TNFR-Fc significantly reduced LPS-induced ALI. The transcription level of Nox and XO was down-regulated by anti-TNF-α therapy, followed by oxidative stress attenuation.