Circular RNA hsa_circ_0001846 facilitates the malignant behaviors of pancreatic cancer by sponging miR-204-3p and upregulating KRAS expression.

Pancreatic cancer (PC) is mainly derived from the exocrine pancreatic ductal epithelial cells, and it is strongly aggressive malignant tumor. Due to its insidious onset and the lack of effective diagnostic biomarkers, PC currently remains one of the main causes of cancer-related mortality worldwide. Recent studies have found that hsa_circ_0001846 is involved in the progression of multiple cancers and has the potential to become biomarkers, but its function and mechanism in PC remains unclear. We found by qRT-PCR experiments that hsa_circ_0001846 was upregulated in PC cells and tissues, while circBase, Sanger sequencing, agarose gel electrophoresis and FISH experiments identified the splicing site, ring structure and cellular localization of hsa_circ_0001846. Various functional experiments by using the construction of small interfering RNA targeting hsa_circ_0001846 and overexpression plasmid demonstrated that hsa_circ_0001846 promoted the proliferation, migration and invasion of PC cells. Moreover, the tumor weight and volume of nude mice were significantly reduced after the stable knockdown of hsa_circ_0001846. In the mechanism exploration, RNA pull-down experiments and dual-luciferase experiments helped us to determine that hsa_circ_0001846 regulated the KRAS expression by sponging miR-204-3p in PC, thus playing a pro-cancer role. In this study, the effect of miR-204-3p on PC was also explored for the first time, and we found that knockdown of miR-204-3p reversed the tumor suppressive effect caused by silencing hsa_circ_0001846, and silencing KRAS also rescued the pro-cancer effect caused by overexpression of hsa_circ_0001846. In conclusion, our study revealed the pro-cancer role of hsa_circ_0001846 in PC, and for the first time identified the mechanism that hsa_circ_0001846 regulated KRAS by sponging miR-204-3p to promote PC progression and had the potential to become a cancer biomarker.

Natriuretic Peptides-New Targets for Neurocontrol of Blood Pressure via Baroreflex Afferent Pathway.

Natriuretic peptides (NPs) induce vasodilation, natriuresis, and diuresis, counteract the renin-angiotensin-aldosterone system and autonomic nervous system, and are key regulators of cardiovascular volume and pressure homeostasis. Baroreflex afferent pathway is an important reflex loop in the neuroregulation of blood pressure (BP), including nodose ganglion (NG) and nucleus tractus solitarius (NTS). Dysfunction of baroreflex would lead to various hypertensions. Here, we carried out functional experiments to explore the effects of NPs on baroreflex afferent function. Under physiological and hypertensive condition (high-fructose drinking-induced hypertension, HFD), BP was reduced by NPs through NG microinjection and baroreflex sensitivity (BRS) was enhanced via acute intravenous NPs injection. These anti-hypertensive effects were more obvious in female rats with the higher expression of NPs and its receptor A/B (NPRA/NPRB) and lower expression of its receptor C (NPRC). However, these effects were not as obvious as those in HFD rats compared with the same gender control group, which is likely to be explained by the abnormal expression of NPs and NPRs in the hypertensive condition. Our data provide additional evidence showing that NPs play a crucial role in neurocontrol of BP regulation via baroreflex afferent function and may be potential targets for clinical management of metabolic-related hypertension.

Prognostic analysis of hepatocellular carcinoma with macrovascular invasion after liver resection and a successful case of conversion therapy.

Objective: Macrovascular invasion (MVI) is an important factor leading to poor prognosis in hepatocellular carcinoma (HCC). Liver resection may offer favorable prognosis for selected patients with HCC. This study aimed to analyze the prognostic factors of HCC with MVI after liver resection as well as demonstrate a case of conversion therapy in an HCC patient with portal vein tumor thrombus (PVTT). Methods: A total of 168 HCC patients with MVI who underwent primary liver resection at the Affiliated Hospital of Qingdao University between January 2013 and October 2021 were enrolled in the study. Clinicopathological data were collected retrospectively. Univariate and multivariate regression analyses were used to investigate the risk factors influencing recurrence and overall survival. Additionally, conversion therapy with drug-eluting bead transarterial chemoembolization (D-TACE), and sorafenib plus sintilimab treatment was performed in an HCC patient with PVTT. Results: Among the 168 patients with HCC, 11 were diagnosed with hepatic vein tumor thrombosis, and the rest were diagnosed with PVTT. The 1-year disease-free survival rate was 37.5%, and the 3-year overall survival rate was 52.7%. Univariate and multivariate regression analyses revealed that HBsAg positivity, alpha-fetoprotein (AFP) level ≥400 ng/ml, liver capsule invasion, and tumor number ≥2 were independent prognostic factors for tumor recurrence, whereas HBsAg positivity was an independent risk factor for overall survival. Postoperative prophylactic medication did not significantly prolong the recurrence time. The median survival time (MST) after tumor recurrence was 13.4 months. In the patient treated with conversion therapy, the tumor gradually shrank and was eventually surgically resected. Conclusions: This study identified the independent prognostic and risk factors associated with recurrence and overall survival in HCC patients with MVI. Additionally, we successfully performed conversion therapy in an HCC patient with PVTT. The findings would help identify patients at high risk of recurrence and indicate that combined therapy may prolong the survival of HCC patients with PVTT.

Circular RNA hsa_circ_0007367 promotes the progression of pancreatic ductal adenocarcinoma by sponging miR-6820-3p and upregulating YAP1 expression.

Circular RNAs (circRNAs) play critical regulatory roles in cancer biological processes. Nevertheless, the contributions and underlying mechanisms of circRNAs to pancreatic ductal adenocarcinoma (PDAC) remain largely unexplored. Dysregulated circRNAs between cancerous tissues and matched adjacent normal tissues were identified by circRNA microarray in PDAC. The biological effect of hsa_circ_007367 both in vitro and in vivo was demonstrated by gain- and loss-of-function experiments. Further, dual-luciferase reporter and RNA pull-down assays were performed to confirm the interaction among hsa_circ_007367, miR-6820-3p, and Yes-associated protein 1 (YAP1). The expression of hsa_circ_007367 and YAP1 were detected by in situ hybridization (ISH) and immunohistochemistry (IHC) using tissue microarray (TMA) in 128 PDAC samples. We first identified that a novel circRNA, hsa_circ_0007367, was markedly upregulated in PDAC tissues and cells. Functionally, in vivo and in vitro data indicated that hsa_circ_0007367 promotes the proliferation and metastasis of PDAC. Mechanistically, we confirmed that hsa_circ_0007367 could facilitate the expression of YAP1, a well-known oncogene, by sponging miR-6820-3p, which function as a tumor suppresser in PDAC cells. The results of ISH and IHC demonstrated that hsa_circ_0007367 and YAP1 were upregulated in PDAC tissues. Furthermore, clinical data showed that higher hsa_circ_0007367 expression was correlated with advanced histological grade and lymph node metastasis in PDAC patients. In conclusion, our findings reveal that hsa_circ_0007367 acts as an oncogene via modulating miR-6820-3p/YAP1 axis to promote the progression of PDAC, and suggest that hsa_circ_0007367 may serve as a potential therapeutic target for treatment of PDAC.

Clinical evaluation of a real-time optoelectronic device in cervical cancer screening.

OBJECTIVE: Early screening and intervention are crucial for the prevention and treatment of cervical cancer. TruScreen is a real-time, intelligent, pathological diagnostic technology designed for cervical cancer screening. The aim of this study was to evaluate the clinical value of TruScreen in screening for cervical lesions. STUDY DESIGN: A total of 458 women aged between 25 and 65 years were recruited to receive cervical cancer screening, including human papillomavirus (HPV) testing, cytological testing using the ThinPrep cytology test (TCT), and TruScreen from December 2018 to January 2020. The clinical performance of TruScreen, alone and in combination with HPV testing, was evaluated to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+ or CIN3+). RESULTS: For detection of CIN2+, the sensitivity and specificity of TruScreen were 83.78% and 78.86%, respectively. The specificity of TruScreen was significantly higher than those of HPV testing (50.59%, P < 0.001) and TCT (55.58%, P < 0.001). In high-risk HPV-positive women, the specificity of HPV testing combined with TruScreen was significantly higher than that of HPV testing combined with TCT (50% vs 39.9%, P = 0.004). The sensitivity of HPV testing combined with TruScreen was comparable to that of HPV testing combined with TCT (93.94% vs 87.88%, P = 0.625). Similar patterns were also observed for CIN3+ cases. CONCLUSION: TruScreen has the potential for screening high-grade cervical precancerous lesions and may replace cytological tests as a cervical cancer screening method in China to avoid subjectivity in the interpretation of cytological tests and requirements by pathologists.

The effect of 5-Aminolaevulinic Acid Photodynamic Therapy versus CO2 laser in the Treatment of Cervical Low-grade Squamous Intraepithelial Lesions with High-Risk HPV Infection: A non-randomized, controlled pilot study.

BACKGROUND: There are insufficient studies comparing the efficacy of 5-aminolaevulinic acid (ALA) photodynamic therapy (PDT) against CO2 laser therapy in the treatment of cervical low-grade squamous intraepithelial lesion (LSIL) with high-risk human papillomavirus (HR-HPV), especially for long-term efficacy. METHODS: Patients with cervical LSIL and HR-HPV infection were divided into two treatment groups based on their own choice. All patients had a follow-up test including HPV testing, cytology and colposcopy at 4-6 months and 12 months after the treatment. RESULTS: (1) Among 277 patients, 176 patients received 5-ALA PDT and 101 patients received CO2 laser therapy. (2) 4-6 months after treatment, there was no significant difference between two groups in the complete remission (CR) rates of cervical LSIL and the clearance rate of HR-HPV infection. (3) 12 months after treatment, compared with the CO2 laser group, the CR rates of cervical LSIL in the 5-ALA PDT group was significantly higher than the CO2 laser group. There was no statistical difference in the clearance rate of HR-HPV infection between the two groups. (4) 12 months after treatment, the recurrence rate of cervical lesions and the reinfection rate of HR-HPV infection in 5-ALA PDT group were significantly lower than those in CO2 laser group. CONCLUSION: The effect of 5-ALA PDT is similar to CO2 laser at 4-6 months. The long-term efficacy of 5-ALA PDT appears better than CO2 laser. As a non-invasive treatment, 5-ALA PDT is a highly effective therapeutic procedure for cervical LSIL with HR-HPV infection.

The effect of local photodynamic therapy with 5-aminolevulinic acid for the treatment of cervical low-grade squamous intraepithelial lesions with high-risk HPV infection: A retrospective study.

BACKGROUND: High-risk HPV infection is the main cause of cervical cancer and pre-cancerous lesions. The current principle of clinical management of cervical low-grade squamous intraepithelial lesion is observation for 2 years. Progression to high-grade squamous intraepithelial lesion warrants intervention. Primary treatment option is surgical excision which may have a negative impact on fertility. Topical photodynamic therapy is a non-invasive and targeted therapy. We investigated the clinical efficacy of this therapy for cervical low-grade squamous intraepithelial lesion with high-risk HPV infection. METHODS: A retrospective study consisting of 258 female patients aged 21-69 years with a histologically confirmed cervical low-grade squamous intraepithelial lesion with high-risk HPV infection was carried out. Subjects were treated with three sessions of 20 % 5-aminolevulinic acid photodynamic therapy at intervals of 7-14 days. Three months after treatment, the effect was evaluated through HPV typing, Thinprep cytology and colposcopy directed biopsy. Six months after treatment, the photodynamic therapy effect was evaluated by HPV genotyping and Thinprep cytology first, the pathological examination would be performed at the 6-month follow-up point if the cytological results indicated the risk of high-grade squamous intraepithelial lesions. RESULTS: Three months after treatment, among 258 low-grade squamous intraepithelial lesion with high-risk HPV infection patients, total baseline HPV remission rates was 64.34 % (166/258). The remission rate of HPV16/18 group was not statistically significant compared to the HPV non-16/18 group (73.13 % vs 61.26 %, p = 0.081).The remission rates of the <50 age group was significantly higher than the >50 age group (67.28 %vs46.34 %, p = 0.001). The total lesion regression rate wa treatment, among 258 low-grade squamous intraepithelial lesion with high-risk HPV infection patients, total baseline HPV remission rates was 64.34 % (166/258). The remission rate of HPV16/18 group was not statistically significant compared to the HPV non-16/18 group (73.13 % vs 61.26 %, p = 0.081).The remission rates of the <50 age group was significantly higher than the >50 age group (67.28 %vs46.34 %, p = 0.001). The total lesion regression rate was 84.88 % (219/258). 12.8 % (33/258) of patients did not progress. Only 2.33 % (6/258) patients progressed to high-grade squamous intraepithelial lesion and accepted loop electrosurgical excision procedure. The patients >50 age group had significant higher progression rate than the patients ＜50 age group (p＜0.05). Six months after treatment, except for 6 patients who progressed to high-grade squamous intraepithelial lesion and underwent surgical treatment, the total baseline HPV remission rates was up to 82.54 % (208/252). CONCLUSION: 5-aminolevulinic acid photodynamic therapy was highly effective and did not appear to create cervical damage.. It might be an ideal treatment for cervical low-grade squamous intraepithelial lesion with high-risk HPV infection, but this requires additional clinical trials.

Fn14 overcomes cisplatin resistance of high-grade serous ovarian cancer by promoting Mdm2-mediated p53-R248Q ubiquitination and degradation.

BACKGROUND: High-grade serous ovarian cancer (HGSOC) is the most lethal of all gynecological malignancies. Patients often suffer from chemoresistance. Several studies have reported that Fn14 could regulate migration, invasion, and angiogenesis in cancer cells. However, its functional role in chemoresistance of HGSOC is still unknown. METHODS: The expression of Fn14 in tissue specimens was detected by IHC. CCK-8 assay was performed to determine changes in cell viability. Apoptosis was measured by flow cytometry. The potential molecular mechanism of Fn14-regulated cisplatin resistance in HGSOC was investigated using qRT-PCR, western blotting, and Co-IP assays. The role of Fn14 in HGSOC was also investigated in a xenograft mouse model. RESULTS: In this study, we found that Fn14 was significantly downregulated in patients with cisplatin resistance. Patients with low Fn14 expression were associated with shorter progression-free survival and overall survival. Overexpression of Fn14 suppressed cisplatin resistance in OVCAR-3 cells, whereas knockdown of Fn14 did not affect cisplatin resistance in SKOV-3 cells. Interestingly, Fn14 could exert anti-chemoresistance effect only in OVCAR-3 cells harboring a p53-R248Q mutation, but not in SKOV-3 cells with a p53-null mutation. We isolated and identified primary cells from two patients with the p53-R248Q mutation from HGSOC patients and the anti-chemoresistance effect of Fn14 was observed in both primary cells. Mechanistic studies demonstrated that overexpression of Fn14 could reduce the formation of a Mdm2-p53-R248Q-Hsp90 complex by downregulating Hsp90 expression, indicating that degradation of p53-R248Q was accelerated via Mdm2-mediated ubiquitin-proteasomal pathway. CONCLUSION: Our findings demonstrate for the first time that Fn14 overcomes cisplatin resistance through modulation of the degradation of p53-R248Q and restoration of Fn14 expression might be a novel strategy for the treatment of HGSOC.