A predictive nomogram for intracerebral hematoma expansion based on non-contrast computed tomography and clinical features.

PURPOSE: To develop and validate a new nomogram utilizing non-contrast computed tomography (NCCT) signs and clinical factors for predicting hematoma expansion (HE) in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: HE was defined as > 6 mL or 33% increase in baseline hematoma volume. Multivariable logistic regression analysis was performed to identify the predictors of HE. The discriminatory performance of the proposed model was evaluated via receiver operation characteristic (ROC) analysis, and the predictive accuracy was assessed by a calibration curve. The nomogram was established by R programming language. The decision curve analysis and clinical impact curve were drawn according to the related risk factors. RESULTS: A total of 506 patients with spontaneous ICH were recruited in the development cohort, and 103 patients were registered as the external validation cohort. Among the development cohort, 132 (26.09%) experienced HE. Glasgow coma scale (GCS) (P < 0.001), neutrophil to lymphocyte ratio (NLR) (P < 0.001), blend sign (P < 0.001), swirl sign (P < 0.001), and hypodensities (P = 0.003) were significant predictors of HE, by which were used to establish the nomogram. The model demonstrated good performance with high area under the curve both in the development (AUC = 0.908; 95% confidence interval, 0.880-0.936) and the external validation (AUC = 0.844; 95% confidence interval, 0.760-0.908) cohort. The calibration curve illustrated a high accuracy for HE prediction. CONCLUSION: The nomogram derived from NCCT markers and clinical factors outperformed the NCCT signs-only model in predicting HE for patients with ICH, thus providing an effective and noninvasive tool for the risk stratification of HE.

Uterus Allo-Transplantation in a Swine Model: Long-Term Graft Survival and Reproductive Function.

BACKGROUND The present study examined the feasibility and safety of allogeneic uterus transplantation (UTx) from a living donor and assessed long-term graft survival and the resumption of reproductive function in a swine model. MATERIAL AND METHODS Ten female miniature swine with regular menstrual cycles were used; the animals were either donors or recipients (n=5) depending on the sibling. Retrieval surgery included uterus and uterine arteries together with the anterior branches of the internal iliacs from the living donor; the vaginal canal was cut. After the back-table had been prepared, bilateral internal iliac arteries were anastomosed end-to-side with the external iliac arteries. The transplanted uterus was evaluated based on the arterial blood flow by transabdominal ultrasonography and observed by secondary laparotomy after surgery; estrus recovery was stimulated by mating with a male, and artificial embryo transfer was performed in healing swine. RESULTS All 5 pigs revealed successful surgery without any surgical complications, injuries to other organs, or unanticipated vascular injury. All recipients survived for >3 months after the surgery, except pig 5, which died due to uterus necrosis 3 days post-surgery. A 100% surgical success rate and 80% long-term survival rate of the receptor were observed. Pig 2 had temporary estrus resumed, and the artificial embryo was transplanted 3 months after surgery; however, apparent gestation was not found by ultrasonography. CONCLUSIONS This study evaluated the safety and feasibility of the technology of allogeneic UTx, which was performed only by transplant uterine artery system from living-donor surgery in a swine model. Laboratory animals can show long-term survival and resumed estrous after UTx, which can be monitored by ultrasonography to assess the arterial blood flow of the grafted uterus.

[Corrigendum] The role of IGFBP­5 in mediating the anti­proliferation effect of tetrandrine in human colon cancer cells.

Following the publication of the above article, a concerned reader drew to the authors' attention that, among Figs. 1D, 2A and 4B, certain of the control western blots had been re­used in different blots. The authors have retrieved and re­examined their original data, and were able to identify the correct control western blots where the data had been inadvertently duplicated in the affected original figures. The revised versions of Figs. 2 and 4, now featuring the correct control western blots, are shown in the subsequent two pages. The authors regret that the data in question featured in the original article had been re­used, and thank the Editor of International Journal of Oncology for granting them the opportunity to publish this corrigendum. All the authors agree with the publication of this corrigendum; furthermore, they apologize to the readership of the journal for any inconvenience caused. [International Journal of Oncology 46: 1205­1213, 2015; DOI: 10.3892/ijo.2014.2800].

Association between antihypertensive drugs and oral cancer: a drug target Mendelian randomization study.

Background: Recent reports have suggested that antihypertensive drugs may play an oncogenic role in common cancers, but it is still uncertain whether this could influence the risk of oral cancer. Through two-sample Mendelian randomization (MR), we sought to assess the causal effect of antihypertensive drugs on oral cancer outcomes. Methods: To proxy the exposure of antihypertensive drugs, we utilized two genetic instruments, including expression quantitative trait loci of drug target genes and genetic variants within or around drug target genes related to blood pressure from genome-wide association studies. Inverse-variance-weighted MR (IVW-MR) and summary-data-based MR (SMR) were employed to compute the instrument effect estimates. Results: It was observed through IVW-MR analysis that there is a positive relationship between KCNH2 (target of beta-adrenoceptor blockers)-mediated blood pressure and oral cancer (odds ratio [OR] = 1.197, 95% confidence interval [CI] = 1.028-1.394). Similarly, SMR analysis demonstrated that a higher expression of KCNH2 (target of beta-adrenoceptor blockers) was linked to a greater risk of oral cancer (OR = 2.223, 95% CI = 1.094-4.516). Both analyses yielded no consistent evidence of other associations. Conclusion: This two-sample MR study proposed a latent causal association between KCNH2 (target of beta-adrenoceptor blockers) inhibition and diminished risk of oral cancer.

Predicting major adverse cardiac events based on multi-parameter coronary computed tomography angiography.

OBJECTIVE: To build a nomogram model to improve the prediction of major adverse cardiac events (MACE) using multi-parameter coronary computed tomography angiography (CCTA). METHODS: All patients underwent CCTA. Those who developed MACE 90 days later but within 2 years between January 2008 and December 2018 were retrospectively enrolled as MACE group, while those without MACE were 1:1 propensity score matched in the control group. CCTA stenosis, plaque qualitative-quantitative characteristics, and fractional flow reserve derived from computed tomography angiography (FFRct) were analyzed and compared between the two groups. The independent risk factors for predicting MACE were obtained through univariate and multivariate regression analysis, after which multi-parameter models were built to predict MACE. Finally, the nomogram for predicting MACE was created using the independent risk factors from multivariate regression analysis. RESULTS: A total of 483 vessels in 260 patients were successfully analyzed. The combination of CCTA stenosis, plaque qualitative-quantitative characteristics, and FFRct (AUC = 0.922, P < 0.001) showed a higher predictive value compared to CCTA stenosis alone, FFRct alone, plaque qualitative-quantitative characteristics alone, CCTA stenosis combined with plaque qualitative-quantitative characteristics, and CCTA stenosis combined with FFRct (all P < 0.001). Independent risk factors were CCTA stenosis ≥50%, low attenuation plaque, positive remodeling, napkin ring sign, lipid plaque volume proportion, and FFRct. Subsequently, a nomogram was created using these independent risk factors. CONCLUSIONS: The multi-parameter CCTA model has improved performance in predicting MACE. Nomogram for predicting MACE, which includes these factors, represents a practical and easy-to-use method in the clinical setting.

Oridonin upregulates PTEN through activating p38 MAPK and inhibits proliferation in human colon cancer cells.

Oridonin (ORI) has been reported as an antiproliferation and apoptosis-inducing natural product in various cancer cells. However, the exact molecular mechanism underlying these effects remains unclear. In the present study, we demonstrated the antiproliferation effect of ORI in HCT116 cells, and analyzed the possible molecular mechanism which mediates this effect. We found that ORI inhibits proliferation, induces cell cycle arrest and apoptosis in HCT116 cells, thus also tumor growth. Mechanically, we found that ORI has no substantial effect on mRNA expression of phosphatase and tensin homologue (PTEN), but increases the total protein level of PTEN and markedly reduces the phosphorylation of PTEN; Exogenous expression of PTEN potentiates the anticancer effect of ORI, while knockdown of PTEN attenuates it. ORI also increases the phosphorylation of p38 MAPK, and p38 MAPK-specific inhibitor reduces the antiproliferation effect ORI in HCT116 cells. Moreover, inhibition of p38 MAPK increases the phosphorylation of PTEN, and reverses ORI-induced decrease of PTEN phosphorylation. Our findings suggested that ORI may be a potential anticancer drug for colon cancer, this effect may be mediated by enhancing the function of PTEN through reducing its phosphorylation, which may be resulted from the ORI-induced activation of p38 MAPK.

Oridonin inhibits the proliferation of human colon cancer cells by upregulating BMP7 to activate p38 MAPK.

Oridonin (ORI), a diterpenoid purified from Rabdosia rubescens, has been reported as a promising chemotherapy drug for colon cancer treatment; yet, the precise mechanisms underlying this anticancer activity remain unclear. In the present study, we investigated the anticancer effect of ORI in HCT116 cells, and dissected the possible molecular mechanisms underlying this activity. With crystal violet staining, flow cytometry and western blot assay, we found that ORI effectively inhibited the proliferation and induced the apoptosis of HCT116 cells. Further analysis of the results indicated that BMP7 was greatly upregulated by ORI in the HCT116 cells, but its endogenous expression in FHC cells was apparently lower than that in the colon cancer cell lines. Exogenous expression of BMP7 inhibited the proliferation of the HCT116 cells, and substantially potentiated the anticancer effect of ORI. However, the specific antibody of BMP7 nearly abolished this anticancer activity of ORI in the HCT116 cells. Meanwhile, ORI exerted no significant effect on the level of phosphorylated Smad1/5/8 or total p38 MAPK, but greatly increased the level of phosphorylated p38 MAPK in the HCT116 cells. A p38 MAPK-specific inhibitor partly reversed the antiproliferative effect of BMP7 in the HCT116 cells, but prominently promoted the effect of the BMP7 antibody on proliferation. Exogenous expression of BMP7 increased the ORI-induced phosphorylation of p38 MAPK, while the BMP7 antibody almost abolished the ORI-elevated p38 MAPK phosphorylation. Our findings suggest that ORI may be an efficacious drug for colon cancer treatment. This anticancer activity of ORI may be mediated by upregulating BMP7 at least to increase the activation of p38 MAPK.

BMP9/p38 MAPK is essential for the antiproliferative effect of resveratrol on human colon cancer.

Colon cancer is one of the most common malignancies of the digestive system. Although more effective therapeutic strategies have been developed in the last decades, there is still a great clinical need to explore new treatment regimens for colon cancer due to the undesirable prognosis. In the present study, we investigated the anticancer activity of resveratrol (Res) in human colon cancer cells, and the possible mechanism underlying this effect. We employed crystal violet staining, flow cytometry and western blotting to test the antiproliferation- and apoptosis-inducing effects of Res in LoVo cells. A xenograft tumor model was also introduced to confirm the in vivo anticancer effect of Res. Using PCR, western blotting, a recombinant adenovirus and a specific inhibitor of p38 MAPK or bone morphogenetic protein receptor (BMPR) to explore the possible molecular mechanisms. We found that Res markedly inhibited the proliferation and promoted the apoptosis of LoVo cells, and suppressed the in vivo tumor growth of colon cancer. Res substantially upregulated the expression of bone morphogenetic protein 9 (BMP9). Exogenous expression of BMP9 enhanced the anticancer effect of Res in LoVo cells, while BMP9 knockdown partly reduced this activity. Res increased the activation of p38 MAPK, which was enhanced by the exogenous expression of BMP9. The anticancer activity of Res, or Res combined with BMP9, was reduced partly by the p38 MAPK inhibitor. The BMPR inhibitor almost abolished the Res-induced activation of p38 MAPK, and attenuated the antiproliferative effect of Res in the LoVo cells. Our findings strongly suggest that the anticancer effect of Res in human colon cancer cells may be partly mediated by upregulation of BMP9 to activate p38 MAPK in a BMPR-dependent manner.

The role of IGFBP-5 in mediating the anti-proliferation effect of tetrandrine in human colon cancer cells.

Colon cancer is one of the most common malignancies, causes considerable morbidity and mortality. The current treatment for colon cancer is more modest than had been hoped. There is an urgent clinical need to explore new agents or adjuvants for colon cancer treatment. Natural products and their derivates act as one of the major source for anticancer agent. In the present study, we investigated the anti-proliferation and chemoprevention effects of tetrandrine (Tet) on colon cancer cells to uncover the possible molecular basis of this effect. We found that Tet can inhibit proliferation and induce apoptosis in LoVo cells. With dimethylhydrazine (DMH) and dextran sodium sulfate (DSS) induced colon cancer model, we found that Tet can prevent or inhibit DMH plus DSS induced aberrant crypt foci (ACF) and colon cancer formation, as well as suppress tumor growth in the xenograft colon cancer model. Tet can downregulate the expression of IGFBP-5 in LoVo cells. Exogenous expression of IGFBP-5 can attenuate the anti-cancer activity of Tet, while IGFBP-5 knockdown potentiates this effect of Tet on LoVo cells. Tet can inhibit Wnt/ß-catenin signaling transduction, which can be partly reversed by exogenous expression of IGFBP-5, but is enhanced by IGFBP-5 knockdown. Our results demonstrated that the anticancer activity of Tet in colon cancer cells may be mediated partly by downregulating the expression of IGFBP-5, thus inactivating Wnt/ß-catenin signaling transduction.

Antiproliferation effect of evodiamine in human colon cancer cells is associated with IGF-1/HIF-1α downregulation.

Colon cancer is one of the most common malignancies. Although the current treatment regimes for colon cancer have been well-developed in the past decades, the prognosis remains still undesirable. It is still urgent to explore new treatment strategies for colon cancer. Natural products is one of the most useful sources for anticancer agents, although some of them have serious side-effects. Evodiamine (Evo) is an quinolone alkaloid from the traditional herb medicine Evodia rutaecarpa. In the present study, we investigated the anticancer effect of Evo in human colon cancer cells. We found that Evo exhibits prominent antiproliferation and apoptosis inducing effects in LoVo cells. Evo leads to apparent downregulation of HIF-1α either in vitro or in vivo; exogenous expression of HIF-1α can attenuate the antiproliferation effect of Evo in LoVo cells, while HIF-1α knockdown potentiates this effect greatly. Further analysis indicated that Evo can also inhibit the phosphorylation of Akt1/2/3 and decrease greatly the expression of IGF-1. Thus, our findings strongly suggested that the anticancer effect of Evo in human colon cancer may be partly mediated by downregulating HIF-1α expression, which is initiated by inactivating PI3K/Akt signaling transduction though decreasing the expression of IGF-1 in colon cancer cells. Therefore, Evo may be used alone or in combination as a potential anticancer agent for colon cancer treatment.

The role of COX-2 in mediating the effect of PTEN on BMP9 induced osteogenic differentiation in mouse embryonic fibroblasts.

Mouse embryonic fibroblasts (MEFs) are multi-potent progenitor cells (MPCs), can differentiate into different lineages, such as osteogenic, and adipogenic. PTEN, a tumor suppressor, may be involved in regulating bone development through interacting with COX-2. BMP9, the most potent osteogenic BMPs, can up-regulate COX-2 in MPCs. Whether PTEN is involved in BMP9 induced osteogenic differentiation in MPCs remains unknown. The goal of this investigation is to identify the effect of PTEN on BMP9-induced osteogenic differentiation in MPCs and dissect the possible mechanism underlay this. We found that BMP9 down-regulates PTEN, and PTEN inhibitor (VO) effectively increases different osteogenic markers induced by BMP9 in MEFs. Exogenous expression of PTEN inhibits BMP9 induced ectopic bone formation apparently. Mechanistically, we found that VO can enhance BMP9 induced BMPs/Smads signaling prominently without no substantial effects on cell cycle. Further analysis indicates that VO can promote BMP9-induced expression of COX-2 in MEFs, which can be eliminated by PI3K inhibitor. Additionally, COX-2 knockdown abolishes the effect of VO on BMP9-induced ALP activities in MEFs. Our findings suggest that PTEN plays an important role in regulating BMP9 induced osteogenic differentiation in MPCs, which may be mediated by PTEN/PI3K/Akt signaling to modulate the expression of COX-2.