Histone methyltransferase SETD1A interacts with notch and promotes notch transactivation to augment ovarian cancer development.

BACKGROUND: High expression of SETD1A, a histone methyltransferase that specifically methylates H3K4, acted as a key oncogene in several human cancers. However, the function and underlying molecular mechanism of SETD1A in ovarian cancer (OV) remain markedly unknown. METHODS: The expression of SETD1A in OV were detected by Western blot and analyzed online, and the prognosis of STED1A in OV were analyzed online. The protein and mRNA levels were determined by Western blot and RT-qPCR. The cell proliferatin, migration and invasion were measured by CCK-8 and transwell assays. The protein interaction was detected by co-IP assay. The interaction between protein and DNA was performed by ChIP assay. The tumor growth in vivo was performed by xenograft tumor model. RESULTS: SETD1A was overexpressed in OV and a predictor of poor prognosis. Overexpression of SETD1A augmented the abilities of cell proliferation, migration, and invasion in MRG1 and OVCAR5 cells. In comparison, SETD1A knockdown suppressed cell growth, migration, and invasion in SKOV3 and Caov3 cells. Specifically, SETD1A enhanced Notch signaling by promoting the expression of Notch target genes, such as Hes1, Hey1, Hey2, and Heyl. Mechanistically, SETD1A interacted with Notch1 and methylated H3K4me3 at Notch1 targets to enhance Notch signaling. In addition, restoration of Notch1 in SETD1A-knockdown OV cells recovered cell proliferation, migration and invasion, which was inhibited by SETD1A knockdown. Furthermore, reduction of SETD1A suppressed tumorigenesis in vivo. CONCLUSION: In conclusion, our results highlighted the key role of SETD1A in OV development and proved that SETD1A promotes OV development by enhancing Notch1 signaling, indicating that SETD1A may be a novel target for OV treatment.

Preoperative Hepatic and Regional Arterial Chemotherapy in Patients Who Underwent Curative Colorectal Cancer Resection: A Prospective, Multi-center, Randomized Controlled Trial.

OBJECTIVE: To evaluate the effects of the addition of preoperative hepatic and regional arterial chemotherapy (PHRAC) on prognosis of stage II and III colorectal cancer (CRC) in a multicenter setting. SUMMARY OF BACKGROUND DATA: Our previous single-center pilot trial suggested that PHRAC in combination with surgical resection could reduce the occurrence of liver metastasis (LM) and improve survival in CRC patients. METHODS: A prospective multi-center randomized controlled trial was conducted from December 2008 to December 2012 at 5 hospitals in China. Eligible patients with clinical stage II or III CRC who underwent curative resection were randomized to receive PHRAC plus adjuvant therapy (PHRAC arm) or adjuvant therapy alone (control arm). The primary endpoint was DFS. Secondary endpoints were cumulative LM rates, overall survival (OS), and safety (NCT00643877). RESULTS: A total of 688 patients from 5 centers in China were randomly assigned (1:1) to each arm. The five-year DFS rate was 77% in the PHRAC arm and 65% in the control arm (HR = 0.61, 95% CI 0.46-0.81; P = 0.001). The 5-year LM rates were 7% and 16% in the PHRAC and control arms, respectively (HR = 0.37, 95% CI 0.22-0.63; P < 0.001). The 5-year OS rate was 84% in the PHRAC arm and 76% in the control arm (HR = 0.61, 95% CI 0.43-0.86; P = 0.005). There were no significant differences regarding treatment related morbidity or mortality between the two arms. CONCLUSIONS: The addition of PHRAC could improve DFS in patients with stage II and III CRC. It reduced the incidence of LM and improved OS without compromising patient safety. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00643877.

Serum GGT/ALT ratio predicts vascular invasion in HBV-related HCC.

BACKGROUND: The gamma-glutamyl transferase (GGT) to alanine aminotransferase (ALT) ratio has been reported as an effective predictor of the severity of hepatitis and HCC. The purpose of this study was to determine the role of the GGT/ALT ratio in the prediction of vascular invasion and survival outcomes in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). METHODS: The risk factors for vascular invasion were determined by univariate/multivariate logistic analysis. The cut-off value of GGT/ALT in predicting vascular invasion was calculated using the receiver operating characteristic (ROC) curve. The prognostic value of GGT/ALT was examined by Cox analysis and Kaplan-Meier curves. Sensitivity analysis, such as subgroup analysis and propensity score matching (PSM), was performed to reduce potential confounding bias. RESULTS: A high GGT/ALT ratio was identified as an independent risk factor for vascular invasion (P = 0.03). The correlation analysis suggested that higher GGT/ALT was associated with more severe tumour burdens, including vascular invasion (P < 0.001), tumour volume > 5 cm (P < 0.001), poor pathological differentiation (P = 0.042), more severe BCLC (P < 0.001) and ALBI grade (P = 0.007). In the survival analysis, a high GGT/ALT ratio was associated with poor overall survival (OS) (HR: 1.38; 95% CI 1.03, 1.87; P < 0.0001) and disease-free survival (DFS) (HR: 1.32; 95% CI 1.03, 1.87; P < 0.0001). In the subgroup analysis, similar results were consistently observed across most subgroups. In PSM analysis, GGT/ALT remained independently associated with vascular invasion (OR, 186; 95% CI 1.23, 3.33). CONCLUSION: The GGT/ALT ratio was a potential effective factor in the prediction of vascular invasion and prognosis in patients with HBV-related HCC.

Dramatic suppression of colorectal cancer cell growth by the dual mTORC1 and mTORC2 inhibitor AZD-2014.

Colorectal cancer is a major contributor of cancer-related mortality. The mammalian target or rapamycin (mTOR) signaling is frequently hyper-activated in colorectal cancers, promoting cancer progression and chemo-resistance. In the current study, we investigated the anti-colorectal cancer effect of a novel mTOR complex 1 (mTORC1) and mTORC2 dual inhibitor: AZD-2014. In cultured colorectal cancer cell lines, AZD-2014 significantly inhibited cancer cell growth without inducing significant cell apoptosis. AZD-2014 blocked activation of both mTORC1 (S6K and S6 phosphorylation) and mTORC2 (Akt Ser 473 phosphorylation), and activated autophagy in colorectal cancer cells. Meanwhile, autophagy inhibition by 3-methyaldenine (3-MA) and hydroxychloroquine, as well as by siRNA knocking down of Beclin-1 or ATG-7, inhibited AZD-2014-induced cytotoxicity, while the apoptosis inhibitor had no rescue effect. In vivo, AZD-2014 oral administration significantly inhibited the growth of HT-29 cell xenograft in SCID mice, and the mice survival was dramatically improved. At the same time, in xenografted tumors administrated with AZD-2014, the activation of mTORC1 and mTORC2 were largely inhibited, and autophagic markers were significantly increased. Thus, AZD-2014 inhibits colorectal cancer cell growth both in vivo and in vitro. Our results suggest that AZD-2014 may be further investigated for colorectal cancer therapy in clinical trials.

Gastritis cystica profunda recurrence after surgical resection: 2-year follow-up.

BACKGROUND: Gastritis cystica profunda (GCP) is an uncommon disease characterized by multiple cystic gastric glands within the submucosa of the stomach. CASE DESCRIPTION: Here, we present a case of a 63-year-old man with intermittent epigastric discomfort in whom gastroscopy revealed multiple irregular elevated nodular lesions with smooth surfaces at the anterior of the antrum. Surgical resection of the nodular lesions was performed, and the diagnosis of gastritis cystica profunda (GCP) was confirmed by histological examination. Another elevated nodular lesion approximately 10 mm in diameter with an ulcer was found on the gastric side of the remnant stomach near the resection side from 6 to 24 months after the surgical resection. Endoscopic ultrasonography (EUS) and repeated biopsies of the new elevated lesion were performed. Homogeneous, anechoic masses originating from the submucosa without gastric adenocarcinoma in histological examination showed GCP recurrence may occur. CONCLUSIONS: We report a case of GCP recurrence within 6 months after surgical resection. GCP should be considered in the differential diagnosis of elevated lesions in the stomach.

Imperatorin attenuates CCl4-induced cirrhosis and portal hypertension by improving vascular remodeling and profibrogenic pathways.

BACKGROUND: Cirrhosis leads to portal hypertension (PHT), affecting survival with limited treatment options. This study investigated Imperatorin (IMP), a furanocoumarin with anti-inflammatory and hypotensive properties, for its therapeutic role and mechanisms in cirrhotic PHT. METHODS: Hepatic stellate cells (HSCs) inhibition by IMP was evaluated using LX-2 cell line. Rat cirrhosis was induced via CCl4 for 16 weeks. Experimental group were orally administered IMP (15/25 mg/kg/day) for 4 weeks. We subsequently examined portal pressure (PP), cirrhosis, inflammation, angiogenesis, and vascular remodeling. Network pharmacology was employed for mechanistic insights. RESULTS: IMP significantly inhibited the fibrogenesis in HSCs and suppressed cell viability. CCl4 exposure induced cirrhosis, inflammation, angiogenesis, vascular remodeling and PHT. IMP significantly reduced PP from 22.85 ± 3.88 mmHg to 6.67 ± 0.6 mmHg, diminished collagen deposition and pro-fibrotic factor expression, alleviated inflammation, and improved liver function. Vessel wall thickness in superior mesenteric arteries was restored, and intra-/extrahepatic angiogenesis was inhibited via VEGF and vWF. Furthermore, IMP induced sinusoidal vasodilation by upregulating eNOS and GCH1. Enrichment analysis indicated that IMP was involved in various biological processes associated with cirrhosis, such as the regulation of blood pressure, tissue remodeling, response to inflammation, and regulation of angiogenesis, etc. Additionally, IMP suppressed hepatic expression of TGF-ß both in vitro and in vivo, which was further supported by KEGG analysis. CONCLUSION: Our research demonstrated that IMP significantly mitigated cirrhosis PHT by reducing hepatic fibrosis and inflammation, curbing angiogenesis and vascular remodeling, and promoting vasodilation. This protective mechanism appears to be facilitated through the downregulation of TGF-ß.

Cediranib ameliorates portal hypertensive syndrome via inhibition of VEGFR-2 signaling in cirrhotic rats.

Portal hypertension (PHT) is a syndrome caused by systemic and portal hemodynamic disturbances with the progression of cirrhosis. However, the exact mechanisms regulating angiogenesis-related responses in PHT remain unclear. Cediranib is a potent inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, exhibiting a greater affinity for VEGFR-2. Liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague-Dawley rats. Sham-operated rats were controls. BDL and sham rats were randomly allocated to receive Cediranib or vehicle after BDL. On the 28th day, portal hypertension related parameters were surveyed. Cediranib treatment could significantly reduce the portal pressure (PP) in BDL rats, while it did not affect the mean arterial pressure (MAP) in sham groups and BDL groups. Cediranib treatment could significantly affect the stroke volume (SV), cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), superior mesenteric artery (SMA) flow and SMA resistance in BDL groups and BDL with Cediranib groups. Cediranib treatment could improve the mesenteric vascular remodeling and contractility. Cediranib treatment significantly reduced mesenteric vascular density. And phospho-VEGFR-2 was significantly downregulated by Cediranib. On the other hand, phospho-endothelial Nitric Oxide Synthases (phospho-eNOS) expressions were upregulated. Cediranib not only improved splanchnic hemodynamics, extrahepatic vascular remodeling and vasodilation, but also alleviated intrahepatic fibrosis and collagen deposition significantly. Cediranib treatment could reduce intrahepatic angiogenesis between BDL-vehicle and BDL-Cediranib rats. In conclusion, Cediranib could improve extrahepatic hyperdynamic circulation by inhibiting extrahepatic angiogenesis through inhibition of the VEGFR-2 signaling pathway, portal collateral circulation formation, as well as eNOS-mediated vasodilatation and vascular remodeling, and at the same time, Cediranib improved intrahepatic fibrogenesis and angiogenesis, which together alleviate cirrhotic PHT syndrome.

AMP-activated protein kinase (AMPK)/Ulk1-dependent autophagic pathway contributes to C6 ceramide-induced cytotoxic effects in cultured colorectal cancer HT-29 cells.

Colorectal cancer is the second leading cause of cancer-related deaths. Drug resistance and/or off-target toxicity against normal cells limit the effectiveness of current chemotherapies for the treatment of colorectal cancer. In the current study, we studied the potential cytotoxic effects of short-chain and cell-permeable C6 ceramide in cultured colorectal cancer HT-29 cells and focused on the underlying mechanisms. We observed that C6 ceramide-induced HT-29 cell death and growth inhibition in a dose- and time-dependent manner. However, no significant apoptosis was observed in C6 ceramide-treated HT-29 cells. Our data support that autophagy contributed to C6 ceramide-induced cytotoxic effects, as autophagy inhibitors, 3-methyladenine (3-MA) and hydroxychloroquine, inhibited C6 ceramide's effect; however, autophagy activators, everolimus (RAD001) and temsirolimus, mimicked C6 ceramide effects and induced HT-29 cell death. Further, we indentified that AMP-activated protein kinase (AMPK)/Ulk1 signaling was required for autophagy induction by C6 ceramide, and AMPK silencing by a specific short hairpin RNA suppressed C6 ceramide-induced autophagy and cytotoxic effects. Reversely, forced activation of AMPK by its activator AICAR or by genetic manipulation caused autophagic death in HT-29 cells, which was inhibited by 3-MA. Our results suggest that autophagy, but not apoptosis, is a major contributor for C6 ceramide-induced cytotoxic effects in HT-29 cells, and activation of AMPK/Ulk1 is required for the process.

Discovery of ANO1 Inhibitors based on Machine learning and molecule docking simulation approaches.

Calcium-activated chloride channels (CaCCs) are chloride channels that are regulated according to intracellular calcium ion concentrations. The channel protein ANO1 is widely present in cells and is involved in physiological activities including cellular secretion, signaling, cell proliferation and vasoconstriction and diastole. In this study, the ANO1 inhibitors were investigated with machine learning and molecular simulation. Two-dimensional structure-activity relationship (2D-SAR) and three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for the qualitative and quantitative prediction of ANO1 inhibitors. The results showed that the prediction accuracies of the model were 85.9% and 87.8% for the training and test sets, respectively, and 85.9% and 87.8% for the rotating forest (RF) in the 2D-SAR model. The CoMFA and CoMSIA methods were then used for 3D QSAR modeling of ANO1 inhibitors, respectively. The q2 coefficients for model cross-validation were all greater than 0.5, implying that we were able to obtain a stable model for drug activity prediction. Molecular docking was further used to simulate the interactions between the five most promising compounds predicted by the model and the ANO1 protein. The total score for the docking results between all five compounds and the target protein was greater than 6, indicating that they interacted strongly in the form of hydrogen bonds. Finally, simulations of amino acid mutations around the docking cavity of the target proteins showed that each molecule had two or more sites of reduced affinity following a single mutation, indicating outstanding specificity of the screened drug molecules and their protein ligands.

Papillary thyroid carcinoma occurring with undifferentiated pleomorphic sarcoma: A case report.

BACKGROUND: Papillary thyroid cancer (PTC) is the most common malignant tumor of the thyroid. However, the coexistence of PTC and sarcoma in one patient is rare. In this article, we report the case of a patient who presented with both PTC and undifferentiated pleomorphic sarcoma (UPS), which has not been previously reported in the online Medline database (PubMed). CASE SUMMARY: A 71-year-old man was admitted to our hospital for a mass on the right side of his neck for one month, which rapidly enlarged within 2 wk with distending pain. The patient was diagnosed with a thyroid malignancy by fine-needle aspiration and underwent total thyroidectomy and bilateral central lymph node dissection. Histology and immunohistochemistry revealed features of both PTC and UPS. The thyroid cancer 8 gene detection kit results showed BRAF and telomerase reverse transcriptase mutations. The disease progressed rapidly, and the patient died four months after surgery from extensive lung metastasis. CONCLUSION: Our report highlights the patient's pathological characteristics and related genetic mutations. Due to the rapid development and poor prognosis of cooccurring PTC and sarcoma, it is important for clinical physicians and pathologists to raise awareness of this type of tumor.

Transumbilical Single-incision Laparoscopic Surgery for Harvesting Rib and Costal Cartilage.

The study aimed to introduce a rib and costal cartilage harvesting surgery by transumbilical single-incision laparoscopy and evaluate its efficiency and safety. Methods: Patients who underwent rib and costal cartilage harvest under different approaches (direct open approach and transumbilical) were collected in this retrospective study. The differences in the pain scores [visual analog scale (VAS)], postoperative appearance, and complications were compared between the two groups at 1, 2, 3, and 7 days after surgery. In addition, based on the minimal clinically important difference and the generalized estimating equation, the differences were compared between the two groups in terms of the VAS score. Results: On postoperative day 1, the VAS scores of the direct open approach group and the transumbilical group were significantly different, that is, 7.29 and 6.10, respectively (P < 0.001). Also, the generalized estimating equation results were different (P < 0.001). An interaction was observed between different groups and days, that is, a statistical difference was observed in the VAS score between the two groups (P < 0.001). In terms of aesthetics and complications, patients from the transumbilical group had no scars on the chest wall and no obvious postoperative complications. Conclusions: Transumbilical single-incision laparoscopic surgery is an innovative surgical approach for harvesting ribs and costal cartilage, which leaves no scars on the skin of the chest wall and has the advantages of slight postoperative pain, quick recovery, and fewer complications. This novel surgery is beneficial to patients with higher aesthetic requirements.

Construction and comprehensive analysis of a lncRNA-mRNA interactive network to reveal a potential lncRNA for hepatic encephalopathy development.

Little is known about the role of lncRNA-mRNA regulatory relationships in hepatic encephalopathy (HE). Here, we aimed to construct the potential lncRNA and mRNA interactive network in forecasting HE development in patients with liver cirrhosis using different bioinformatic analysis method. Through analyses, we found that AL137857.1 had the most connections with other mRNAs and was deemed as a hub lncRNA. It was obviously upregulated in HE patients, which was also validated by another independent dataset. GO and KEGG analyses suggested that AL137857.1 was involved in microglial cell activation, phagocytosis, cytokine biosynthetic process, interleukin-6 production and tumor necrosis factor production. In vitro experiments suggested LPS could stimulate microglia to generate AL137857.1. In addition, we found that inhibition of AL137857.1 suppressed the expression of a series of inflammatory cytokines, including IL-1, IL-6, TNF-α, Cox2 and iNOS. Conversely, AL137857.1 over-expression induced a marked increase in these factors. Finally, AL137857.1 was demonstrated to be highly associated with the ability of microglial phagocytosis. Taken together, we have constructed a lncRNA-mRNA regulatory network associated with HE and explored the biological significance of mRNAs in the network, then discovered a novel lncRNA AL137857.1 in HE that might act as a potential regulator of the downstream inflammatory cytokines.

Telmisartan relieves liver fibrosis and portal hypertension by improving vascular remodeling and sinusoidal dysfunction.

BACKGROUNDS: Telmisartan(TEL) has demonstrated anti-fibrotic and blood pressure lowering effect in various diseases. In this study, we aimed to explore the beneficial effects of TEL on portal hypertension(PHT). METHODS: Two models of cirrhosis-induced PHT were involved including carbon tetrachloride injection(CCl4) and bile duct ligation(BDL). Rats were orally gavaged with TEL for 4 weeks. After that, the portal pressure(PP) was determined, and liver and mesenteric tissue specimens were collected to evaluate inflammatory response, liver fibrosis, vascular remodeling, angiogenesis, etc. RESULTS: In CCl4 PHT models, TEL decreased PP significantly from 12.79 ± 2.92 to 6.91 ± 1.19 mmHg(p < 0.05). In inflammatory response, hepatic expressions of interleukin(IL)-6, lipopolysaccharide(LPS), and tumor necrosis factor-α(TNF-α) were significantly decreased after TEL treatment. Moreover, in the liver fibrotic area, the expressions of α-smooth muscle actin(α-SMA), collagen1a1(Col1a1), desmin, transforming growth factor-ß(TGF-ß), and hydroxyproline, and serum hyaluronic acid were significantly decreased after TEL treatment. Additionally, the expressions of von Willebrand factor(vWF), vascular endothelial growth factor(VEGF) and platelet-derived growth factor-ß(PDGF-ß), matrix metallopeptidase(MMP)-2, and MMP-9 were ameliorated in liver sinusoid, while the expressions of MMP-2 and vWF were reduced in mesenteric arteries after TEL treatment. Meanwhile, TEL treatment up-regulated the hepatic expressions of an anti-fibrotic factor Krüppel-like factor-4(KLF-4) and its downstream endothelial nitric oxide synthase(eNOS) in rats with PHT. The performance of TEL in BDL model was similar but slightly weaker. CONCLUSIONS: TEL ameliorated the cirrhosis-induced PHT by reducing liver fibrosis, inflammation responses, angiogenesis, and vascular remodeling. Collectively, KLF-4 and eNOS were the possible molecular targets for the management of cirrhosis-associated PHT.

Salivary biomarkers-assisted ultrasound-based differentiation of malignant and benign thyroid nodules.

BACKGROUND: The incidence of papillary thyroid cancer (PTC) is increasing annually. ultrasonography (US) is the current primary method for evaluating thyroid nodules; however, there have been persisting challenges in diagnosing borderline malignancies. This paper aimed to establish the differential diagnostic value of salivary biomarkers for thyroid nodules geared towards improving the efficacy of US. METHODS: We recruited a total of 44 PTC patients and 42 benign thyroid tumor (BTT) patients to this study. The distribution of tumor markers and thyroid hormones in saliva and serum were compared between groups; then, uni-/multi-variate logistic analyses were used to determine the risk factors of PTC. Further, we estimated the differential diagnostic value of biomarkers in thyroid nodules, especially in borderline scenarios. Finally, a multi-index diagnostic model was constructed constituting biomarkers and US. RESULTS: The distributions of serum thyroglobulin (TG), salivary triiodothyronine (T3), free-triiodothyronine (FT3), and free-thyroxine (FT4) were significantly different in BTT and PTC (P<0.05); salivary FT3 was identified as an independent risk factor for PTC. By analyzing the diagnostic accuracy of various Thyroid Imaging Reporting and Data System (TI-RADS) categories, category 4A was shown to have the lowest diagnostic accuracy (48.39%) with the largest proportion (31 people, 36.05%). In 4A patients, the K-nearest neighbor (KNN) algorithm attained the highest sensitivity of 87.50% and specificity of 100.00% among the machine learning-based multi-biomarkers models. Eventually, by combing the US with the KNN-based biomarkers model, the sensitivity and specificity reached 90.91% and 83.33%, respectively. CONCLUSIONS: Salivary biomarkers exhibit good potential in the differential diagnosis of borderline thyroid nodules and they significantly improve the prediction accuracy of the US. Additionally, we found that salivary FT3 is an independent risk factor for PTC and may be used as a key marker for PTC diagnosis.

Residual tumor and central lymph node metastasis after thermal ablation of papillary thyroid carcinoma: A case report and review of literature.

BACKGROUND: Debate exists regarding the use of thermal ablation (TA) to treat papillary thyroid carcinoma (PTC). Some studies have recommended TA as a new, efficient and safe technology for PTC. In this article, we report one case of a residual tumor and central lymph node metastasis (CLNM) after TA for PTC. CASE SUMMARY: A 63-year-old female underwent bilateral ultrasound (US)-guided radiofrequency ablation for PTC. Three months later, she was diagnosed as thyroid cancer with suspected CLNM by US and contrast-enhanced computed tomography. The subsequent fine-needle aspiration (FNA) biopsies were negative. Due to her strong personal preference, she underwent total thyroidectomy and central lymph node dissection. Local tissue adhesion and a difficult dissection were noted during the operation. The pathology of the frozen sections during the operation was still negative. The final pathology results of paraffin-embedded sections revealed residual tumor cells at the edge of the PTC and CLNM. CONCLUSION: TA may lead to a residual tumor in patients with PTC. Follow-up using US and FNA biopsy may not be adequate to evaluate the residual tumor. TA should be carefully considered in PTC treatment.

Treatment of leiomyomatosis peritonealis disseminata with goserelin acetate: A case report and review of the literature.

BACKGROUND: Leiomyomatosis peritonealis disseminata (LPD) is a rare condition characterized by multiple pelvic and abdominal nodules, which are composed of smooth-muscle cells. To date, no more than 200 cases have been reported. The diagnosis of LPD is difficult and there are no guidelines on the treatment of LPD. Currently, surgical excision is the mainstay. However, hormone blockade therapy can be an alternative choice. CASE SUMMARY: A 33-year-old female patient with abdominal discomfort and palpable abdominal masses was admitted to our hospital. She had undergone four surgeries related to uterine leiomyoma in the past 8 years. Computed tomography revealed multiple nodules scattered within the abdominal wall and peritoneal cavity. Her symptoms and the result of the core-needle biopsy were consistent with LPD. The patient refused surgery and was then treated with tamoxifen, ulipristal acetate (a selective progesterone receptor modulator), and goserelin acetate (a gonadotropin-releasing hormone agonist). Both tamoxifen and ulipristal acetate were not effective in controlling the disease progression. However, the patient achieved an excellent response when goserelin acetate was attempted with relieved syndromes and obvious shrinkage of nodules. The largest nodule showed a 25% decrease in the sum of the longest diameters from pretreatment to posttreatment. Up to now, 2 years have elapsed and the patient remains asymptomatic and there is no development of further nodules. CONCLUSION: Goserelin acetate is effective for the management of LPD. The long-term use of goserelin acetate is thought to be safe and effective. Hormone blockade therapy can replace repeated surgical excision in recurrent patients.

Prognostic Value of Serum Osteoprotegerin Level in Patients With Hepatocellular Carcinoma Following Surgical Resection.

BACKGROUND: Multiple studies have reported that tissue or serum osteoprotegerin (OPG) level is a prognostic factor for patients with cancer. However, little is known about the role of serum OPG in hepatocellular carcinoma (HCC). In this study, we aimed to investigate whether serum OPG concentration has an effect on HCC patients' prognosis. METHODS: A total of 386 eligible HCC patients undergoing radical hepatectomy were enrolled from Shanghai Ninth People's Hospital and Zhongshan Hospital between 2010 and 2018. Kaplan-Meier curves, Cox regression model, and the restricted mean survival time (RMST) were used to estimate the association of OPG and HCC patients' survival outcome. In addition, sensitivity analyses were carried out including subgroup analysis and propensity score matching (PSM). RESULTS: Patients were separated into two groups according to the cut-off value of OPG calculated by X-tile. Multivariate Cox analysis showed that patients with high OPG level had worse overall survival (OS) (HR: 1.93; 95% CI: 1.40-2.66, p<0.001) and disease-free survival (DFS) (HR: 1.85; 95% CI: 1.39-2.47, p<0.001) before matching. On average, RMST ratio between high and low OPG turned out to be 0.797 (95% CI: 0.716-0.887, p<0.001). In the matched population, we found that OPG level was negatively associated with OS (HR: 1.85; 95% CI: 1.25-2.74, p=0.002) and DFS (HR: 1.71; 95% CI: 1.20-2.44, p=0.003). In addition, a similar trend was further confirmed by subgroup analyses. CONCLUSION: In a word, HCC patients with high OPG level had poorer survival rates compared with HCC patients with low OPG level. This factor could act as a potential prognostic predictor for HCC patients who underwent radical resection in the future.

COX-2/sEH Dual Inhibitor PTUPB Alleviates CCl 4 -Induced Liver Fibrosis and Portal Hypertension.

Background: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl) -benzenesulfonamide (PTUPB), a dual cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) inhibitor, was found to alleviate renal, pulmonary fibrosis and liver injury. However, few is known about the effect of PTUPB on liver cirrhosis. In this study, we aimed to explore the role of PTUPB in liver cirrhosis and portal hypertension (PHT). Method: Rat liver cirrhosis model was established via subcutaneous injection of carbon tetrachloride (CCl4) for 16 weeks. The experimental group received oral administration of PTUPB (10 mg/kg) for 4 weeks. We subsequently analyzed portal pressure (PP), liver fibrosis, inflammation, angiogenesis, and intra- or extrahepatic vascular remodeling. Additionally, network pharmacology was used to investigate the possible mechanisms of PTUPB in live fibrosis. Results: CCl4 exposure induced liver fibrosis, inflammation, angiogenesis, vascular remodeling and PHT, and PTUPB alleviated these changes. PTUPB decreased PP from 17.50 ± 4.65 to 6.37 ± 1.40 mmHg, reduced collagen deposition and profibrotic factor. PTUPB alleviated the inflammation and bile duct proliferation, as indicated by decrease in serum interleukin-6 (IL-6), liver cytokeratin 19 (CK-19), transaminase, and macrophage infiltration. PTUPB also restored vessel wall thickness of superior mesenteric arteries (SMA) and inhibited intra- or extrahepatic angiogenesis and vascular remodeling via vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), etc. Moreover, PTUPB induced sinusoidal vasodilation by upregulating endothelial nitric oxide synthase (eNOS) and GTP-cyclohydrolase 1 (GCH1). In enrichment analysis, PTUPB engaged in multiple biological functions related to cirrhosis, including blood pressure, tissue remodeling, immunological inflammation, macrophage activation, and fibroblast proliferation. Additionally, PTUPB suppressed hepatic expression of sEH, COX-2, and transforming growth factor-ß (TGF-ß). Conclusion: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl)- benzenesulfonamide ameliorated liver fibrosis and PHT by inhibiting fibrotic deposition, inflammation, angiogenesis, sinusoidal, and SMA remodeling. The molecular mechanism may be mediated via the downregulation of the sEH/COX-2/TGF-ß.

Reduction of Hip2 suppresses gastric cancer cell proliferation, migration, invasion and tumorigenesis.

BACKGROUND: Hip2, a ubiquitin-conjugating enzyme, has been shown to modulate the stability of cyclin B1, a cell cycle regulator. However, the function of Hip2 in gastric cancer (GC) remains largely elusive. METHODS: The expression of Hip2 in GC cell lines was analyzed by RT-qPCR, Western Blotting and Immunohistochemical Staining. shRNA was utilized to knock down the expression of Hip2. Cell growth, cell cycle, migration, invasion and tumorigenesis were performed by CCK-8, BrdU staining, flow cytometry, wound healing, transwell migration and invasion, and xenograft assay, respectively. RESULTS: Hip2 was highly expressed in GC cell lines and patients. High level of Hip2 indicated poor prognosis. Knockdown of Hip2 suppressed cell growth, lead to G2/M phase arrest, and reduced cell migration and invasion in vitro. Furthermore, downregulation of Hip2 inhibited tumorigenesis in vivo. CONCLUSIONS: Elevated expression of HIP2 in GC patients suggested poor prognosis. Reduction of Hip2 suppressed GC progression, indicating that Hip2 may be a potential target for the management of GC.

Identifying Cancer Targets Based on Machine Learning Methods via Chou's 5-steps Rule and General Pseudo Components.

In recent years, the successful implementation of human genome project has made people realize that genetic, environmental and lifestyle factors should be combined together to study cancer due to the complexity and various forms of the disease. The increasing availability and growth rate of 'big data' derived from various omics, opens a new window for study and therapy of cancer. In this paper, we will introduce the application of machine learning methods in handling cancer big data including the use of artificial neural networks, support vector machines, ensemble learning and naïve Bayes classifiers.