We recently reported that shikonin and its analogs were a class of necroptotic inducers that could bypass cancer drug resistance. However, the molecular targets of shikonin are not known. Here, we showed that shikonin and its analogs are inhibitors of tumor-specific pyruvate kinase-M2 (PKM2), among which shikonin and its enantiomeric isomer alkannin were the most potent and showed promising selectivity, that is, shikonin and alkannin at concentrations that resulted in over 50% inhibition of PKM2 activity did not inhibit PKM1 and pyruvate kinase-L (PKL). Shikonin and alkannin significantly inhibited the glycolytic rate, as manifested by cellular lactate production and glucose consumption in drug-sensitive and resistant cancer cell lines (MCF-7, MCF-7/Adr, MCF-7/Bcl-2, MCF-7/Bcl-x L and A549) that primarily express PKM2. HeLa cells transfected with PKM1 showed reduced sensitivity to shikonin-or alkannin-induced cell death. To the best of our knowledge, shikonin and alkannin are the most potent and specific inhibitors to PKM2 reported so far. As PKM2 universally expresses in cancer cells and dictates the last rate-limiting step of glycolysis vital for cancer cell proliferation and survival, enantiomeric shikonin and alkannin may have potential in future clinical application.

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Chemotherapy is the major choice for the cancer treatment of early and advanced stages. However, intrinsic or acquired drug resistance significantly restricts the clinical efficacy of chemotherapy. It is critical to develop novel approaches to detect and overcome drug resistance. In this study, we demonstrated that accelerated glycolysis played a pivotal role in both intrinsic and acquired cisplatin-resistance of gastric cancer cells. The metabolic reprogramming of cisplatin-resistant cells was characterized by increased glycolysis dependence. Inhibition of glycolysis with glucose starvation or 2-Deoxy-D-glucose (2-DG) treatment significantly reversed drug resistance. By proteomic screening, we found the increased expression of the glycolytic enzyme Enolase 1 (ENO1) in cisplatin-resistant gastric cancer cells. Depletion of ENO1 by siRNA significantly reduced glycolysis and reversed drug resistance. Moreover, the increased expression of ENO1 was attributed to the down-regulation of ENO1-targeting miR-22, rather than activated gene transcriptional or prolonged protein stability. Finally, the elevated levels of ENO1 proteins were associated with the shorter overall survival of gastric cancer patients. In conclusion, ENO1 is a novel biomarker to predict drug resistance and overall prognosis in gastric cancer. Targeting ENO1 by chemical inhibitors or up-regulating miR-22 could be valuable to overcome drug resistance.

Our results indicated that ERalpha and ERbeta were expressed in both gastric cancer and corresponding normal tissues. ERalpha expression and the absence of ERbeta expression are associated with poor survival.

Primary hepatic angiosarcoma (PHA) is a rare malignancy that carries a poor prognosis. Of 1500 patients who underwent hepatectomy for primary hepatic tumors between 1994 and 2013 at our center, two patients were pathologically diagnosed with PHA. Clinical characteristics, treatment modalities, and outcomes of the two patients were collected and analyzed. Both patients underwent hepatectomy and had a postoperative survival time of 8 and 16 mo, respectively. A search of PubMed yielded eight references reporting 35 cases of PHA published between 2004 and 2013. On the basis of the presented cases and review of the literature, we endorse complete surgical resection as the mainstay definitive treatment of PHA, with adjuvant postoperative chemotherapy potentially improving survival. Palliative chemotherapy is an option in advanced hepatic angiosarcoma.

Small intestinal hemolymphangioma is a very rare benign tumor. There was only one report of a hemolymphangioma of the pancreas invading to the duodenum until March 2011. Here we describe the first case of small intestinal hemolymphangioma with bleeding in a 57-year-old woman. She presented with persistent gastrointestinal bleeding and endoscopy revealed a small intestinal tumor. Partial resection of the small intestine was thus performed and the final pathological diagnosis was hemolymphangioma. We also highlight the difficultly in making an accurate preoperative diagnosis in spite of modern imaging techniques. To arrive at a definitive diagnosis and exclude malignancy, partial resection of the small intestine was considered to be the required treatment.

2E) and F4/80 + macrophages (Figure 2F) after DSS treatment for 5 days compared with expression in the colons of healthy mice. These results suggest that increased FBXW7 expression in monocytes and macrophages was correlated with local colonic inflammation in both humans and mice. Fbxw7 deficiency attenuates experimental colitis. To investigate the role of Fbxw7 in macrophages in colitis, LysM-Cre + Fbxw7 fl/fl (LysM + Fbxw7 fl/fl) mice and their control littermates (Fbxw7 fl/fl) were subjected to acute colitis induction using 3% DSS. Colitisinduced macroscopic changes (body weight loss, diarrhea, and rectal bleeding) were significantly alleviated in the LysM + Fbxw7 fl/fl mice compared with Fbxw7 fl/fl littermates (Figure 3A). LysM + Fbxw7 fl/fl mice sacrificed on day 9 displayed significantly longer colons (Figure 3B), milder epithelial damage, and deceased areas of mucosal ulceration (Figure 3C and Supplemental Figure 2A) compared with Fbxw7 fl/fl littermates. Moreover, expression levels of the tight junction genes Cldn1, Cldn2, Ocln, and Tjp1 (Supplemental Figure 2B) and of TJP1 protein (Supplemental Figure 2C) were significantly higher in the epithelia of LysM + Fbxw7 fl/fl mice compared with Fbxw7 fl/fl littermates after DSS treatment, which indicated that the epithelial barrier integrity was less disrupted in mice with myeloid-specific Fbxw7 deficiency. At the same time, LysM + Fbxw7 fl/fl mice showed significantly improved survival rates compared with Fbxw7 fl/fl littermates after 4% DSS treatment (Figure 3D), indicating that Fbxw7 deficiency protects mice from DSS-induced colitis. During the recovery period of intestinal inflammation, the rate of body weight gain was more rapid in LysM + Fbxw7 fl/fl mice than in Fbxw7 fl/fl littermates (Figure 3E). Moreover, LysM + Fbxw7 fl/fl mice had longer colon lengths than did their Fbxw7 fl/fl littermates (Figure 3F) on day 15. Similarly, TNBS-induced colon shortening, the disease activity index (DAI), body weight loss, and epithelial damage were also alleviated in LysM + Fbxw7 fl/fl mice compared with Fbxw7 fl/fl littermates (Supplemental Figure 3, AD). These findings indicate that myeloid Fbxw7 deficiency attenuates experimental colitis. Fbxw7 deficiency decreases proinflammatory MPh accumulation. Microbiota-induced inflammation is critical for the regulation of intestinal homeostasis. To determine whether the decreased DSS colitis susceptibility in LysM + Fbxw7 fl/fl mice was mediated by shifts in gut microbiota, we analyzed the fecal microbiota composition in LysM + Fbxw7 fl/fl mice and Fbxw7 fl/fl littermates. The relative abundance of bacteria at the phylum level and the species composition cluster according to operational taxonomic units (OTUs) among LysM + Fbxw7 fl/fl mice and Fbxw7 fl/fl littermates are shown in Supplemental Figure 4A and Figure 4A, respectively. Moreover, microbial community diversity (Figure 4B) and microbial community composition (Supplemental Figure 4B) were not significantly different between LysM + Fbxw7 fl/fl mice and Fbxw7 fl/fl li...

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