Background: The occurrence and development of solid tumors depend on the blood supply in the tumor microenvironment (TME). Blocking angiogenesis is a new therapeutic strategy to inhibit tumor growth. The anti-angiogenic drug bevacizumab has been approved for gynecological malignancies, especially for advanced recurring cervical cancers and recurring ovarian cancers (OC). Studies in OC have shown a limited effect of bevacizumab in the general population, with a slight improvement in progression-free survival (PFS) and no effect on overall survival (OS). This might be related to the bevacizumab’s role in aggravating the hypoxia in the TME, which helps maintain the stemness of ovarian cancer stem cells (CSCs) and promotes the invasion and metastasis of cancer cells. Drugs that target CSCs, such as metformin, may enhance the efficacy of anti-vascular therapies. Therefore, this study aimed to evaluate the effect of metformin combined with bevacizumab on the proliferation of OC cells both in vitro and in vivo, as well as on tumor hypoxia and tumor stem cell markers of human ovarian cancer SKOV3 cells.Methods: The OC cell model SKOV3 was treated with metformin, bevacizumab, and cisplatin alone or in combinations. Cell Counting Kit-8 (CCK-8) was used to measure the rate of cell proliferation. Metformin and bevacizumab were studied in vivo in nude mice. SKOV3 cells were transplanted subcutaneously in nude mice, and different drug interventions were performed after tumor formation, including blank control, bevacizumab alone, metformin alone, cisplatin alone, bevacizumab + metformin, bevacizumab + cisplatin, metformin + cisplatin, and bevacizumab + metformin + cisplatin treatments. The growth of transplanted tumors was routinely monitored and visualized by the tumor growth curve. We used flow cytometry to examine the proportion of CD44+/CD117+ CSCs in each group. The immunohistochemistry (IHC) method was applied to detect expressions of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), and microvascular density-associated factor CD34 in tumor cells. The limit dilution method was used to re-inject tumor cells in nude mice to examine the tumor recurrence rate.Results: Combination therapy of metformin and bevacizumab significantly reduced the proliferation rate of SKOV3 cells and the growth rate of transplanted tumors in nude mice compared with the monotherapy effects. In vivo results showed that metformin significantly reduced the proportion of CD44+/CD117+ CSCs (p < 0.01). Although bevacizumab increased the proportion of CD44+/CD117+ CSCs, the addition of metformin did offset this fluctuating trend. The combination of bevacizumab, metformin, and cisplatin efficiently decreased the proportion of CSCs in the OC animal model. IHC results exhibited that expressions of VEGF, CD34, and HIF-1α in transplanted tumors were decreased by metformin alone compared with the control (p < 0.05). In the bevacizumab treatment, VEGF, and CD34 expressions were decreased, while that of HIF-1α was increased, suggesting that the degree of hypoxia was differentially aggravated after the bevacizumab treatment. The VEGF, CD34, and HIF-1α expressions in the bevacizumab + metformin + cisplatin group were the lowest among all other treatment groups (p < 0.05). Subcutaneous statistics of nude mice reseeded by the limit dilution method showed that the tumor recurrence rate in the bevacizumab + metformin + cisplatin group was relatively lower.Conclusion: Metformin, bevacizumab combined with platinum-based chemotherapy can significantly inhibit the growth of ovarian cancer cells and transplanted tumors, which is due to the reduction of the proportion of CD44+/CD117+ CSCs and the alleviation of hypoxia in the tumor microenvironment. Therefore, this may be a reasonable and promising treatment regimen.

To date, slicing algorithms for additive manufacturing is the most effective for favourable triangular mesh topologies; worst-case models, where a large percentage of triangles intersect each slice plane, take significantly longer to slice than a like-for-like file. In larger files, this results in a significant slicing duration, when models are both worst cases and contain more than 100,000 triangles. The research presented here introduces a slicing algorithm which can slice worst-case large models effectively. A new algorithm is implemented utilising an efficient contour construction method, with further adaptations, which make the algorithm suitable for all model topologies. Edge matching, which is an advanced sorting method, decreases the number of sorts per edge from n total number of intersections to two, alongside additional micro-optimisations that deliver the enhanced efficient contour construction algorithm. The algorithm was able to slice a worst-case model of 2.5 million triangles in the 1025s. Maximum improvement was measured as 9400% over the standard efficient contour construction method. Improvements were also observed in all parts in excess of 1000 triangles. The slicing algorithm presented offers novel methods that address the failings of other algorithms described in literature to slice worst-case models effectively.

The association of high mobility group box 1(HMGB1) expression with clinicopathological significance and prognosis in colorectal carcinoma (CRC) remains controversial. The purpose of this study is to conduct a meta-analysis and literature review to identify the role of HMGB1 in the development of CRC and as a potential target for therapy. Materials/Methods: All eligible studies about the association between HMGB1 protein expression in tissue with clinicopathological significance and prognosis in CRC published up to January 2015 were identified by searching PubMed, Web of Science, CNKI and WanFang database. Analysis of pooled data was performed, odds ratio (OR) with 95% confidence interval (CI) was calculated and summarized to evaluate the strength of this association in fixed-or random-effects model. Results: The expression level of HMGB1 protein in CRC tissues was much higher than in normal colorectal tissues (ORZ 26.57, 95% CI 9.07e77.79, p< 0.00001). There was no relation between the HMGB1 expression and sex, age, tumor size and location (colon or rectum cancer). However, a significant relation was detected between the HMGB1 expression and clinical stage (AJCC7), lymph node metastasis, distant metastasis, tumor invasion depth, differentiation rate (pZ 0.01, pZ 0.0006, p< 0.0001, p< 0.00001, pZ 0.02, respectively). Conclusion: In this meta-analysis, our results illustrated significant relationships of HMGB1 protein overexpression in tissues with clinicopathological characteristics and prognosis of CRC. Thus, HMGB1 may be a promising marker in predicting the clinical outcome of patients with CRC. However, more well-designed studies of large sample size are warranted to validate the findings of current study.

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