BACKGROUND:The posterior auricular flap has long been favored for repairing skin defects on the ear's surface. However, achieving optimal esthetic outcomes in ear reconstruction requires a flexible approach to flap transfer methods. While bipedicle advancement flaps are commonly used for body wound coverage, they are rarely used in auricular defect repair. OBJECTIVE:To propose a modified flap transfer approach based on the orientation of the auricular defect's long axis and assess the postoperative esthetic outcomes. METHODS:The authors reported 12 patients treated using 2 distinct flap transfer techniques. Mild to moderate helix soft tissue defects remained after excision of the masses. A direct island flap was created for patients with longitudinal defects to cover the defect. For patients with transverse defects, a combination of bipedicle and island flaps was used for repair. Scar quality and esthetic outcomes were assessed at least 6 months postsurgery using the Scar Cosmesis Assessment and Rating scale. RESULTS:All patients experienced no serious complications and achieved excellent cosmetic results. Patients undergoing combined flap transfer exhibited relatively more favorable esthetic outcomes. CONCLUSION:The authors propose a novel concept for repairing helix soft tissue defects by designing local flaps based on the direction of the defect's long axis. For repairing helix soft tissue defects with a long axis parallel to the auricular edge, the combined utilization of bipedicle advancement flap and island rotation flap transfer should be consideration more.

BACKGROUND:Based on the knowledge of facial vascularity, facial artery perforator flaps could be used as potent tools for facial defect reconstruction. However, lack of experience and misconception of this technique limits the broad application in the clinical background. Here, we discussed surgical techniques based on our previous experience with facial artery perforator (FAP)-based facial defect reconstruction.METHODS:A retrospective review of 12 patients undergoing facial defect reconstruction using an FAP flap was performed, including 8 defects in the mid-facial part and 4 defects in the nasal area generally resulted from basal cell carcinoma (8 patients), squamous cell carcinoma (3 patients), and actinic keratosis (one patient).RESULTS:All patients received one-stage FAP flap reconstruction. The overall follow-up period was 6 to 12 months. All reconstructions were successful with satisfactory patient-reported outcome and no local recurrence. No significant complications were observed in most cases, except for one instance of partial flap loss.CONCLUSIONS:Overall, taking advantage of FAP flaps will contribute to a good functional and esthetic outcome of facial defect reconstructions.

Circular RNAs (circRNAs) have been recently identified as important regulators of various diseases, especially cancer. However, the roles of circRNAs in hematologic malignancies have been rarely reported. This study aimed to identify a specific circRNA expression profile in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and to evaluate the biological roles of circRNA in MDS and AML for understanding their clinical significance. Reverse transcription-quantitative PCR was performed to validate the expression of circZBTB46. Kruskal–Wallis test, Kaplan–Meier curves, and the Cox regression model were employed to analyze the clinical significance of circZBTB46. Two specific shRNAs as well as an expression lentiviral vector of circZBTB46 were constructed to identify the biological function of circZBTB46. The impact of circZBTB46 on leukemia cell proliferation, cell cycle distribution, and apoptosis was confirmed using cell viability assay and flow cytometry analysis. The expression of circZBTB46 gradually increased in patients with higher-risk MDS and AML, as compared to controls. CircZBTB46 expression was significantly correlated with important clinical parameters of MDS, including WHO classification, absolute neutrophil count (ANC), marrow blast, IPSS karyotype, IPSS/IPSS-R risk groups, and AML transformation. CircZBTB46 expression was also associated with ANC, marrow blast, cytogenetic risk groups, FLT3-ITD mutation, and treatment response in AML patients. Furthermore, circZBTB46 overexpression was significantly correlated with shorter overall survival (OS, P = 0.0342, median survival time 18.5 vs. 45.4 months) and leukemia-free survival (LFS, P = 0.0421) in MDS, also with the shorter OS in AML ( P = 0.0293, median survival time 11.6 vs. 16.9 months). Functional studies revealed that silencing circZBTB46 expression significantly inhibited proliferation and induced apoptosis in SKM-1, THP-1, and K562 cell lines, while rescue experiments alleviated the siRNA-mediated growth inhibition and apoptosis in these leukemic cells. The present data suggested the essential oncogenic role of circZBTB46, as a progression and survival indicator in both MDS and AML.

Free tissue transfer is a great method for the reconstruction of craniofacial defects, especially in complicated situations such as calvarial defects and dura exposure. Latissimus dorsi muscle flap, anterolateral thigh flap, and radial forearm flap are 3 commonly used flaps that have distinct characteristics. The objective of the present study is to share our experiences with microvascular free flap reconstruction of cranium exposure or defects and to compare distinct microvascular free flap options. The authors reviewed 8 cases that received resection and reconstruction of craniofacial tumors. Perioperative and reconstructive techniques employed to improve flap survival, esthetic outcome, and prevent complications in these patients were retrospectively detailed. In addition, the advantages and disadvantages of latissimus dorsi muscle flap, anterolateral thigh flap, and radial forearm flap were illustrated in this study. The authors believe that taking advantage of these flaps according to the characteristics of defects and flaps will contribute to a good functional and esthetic outcome.

Pancreatic cancer is a lethal, extremely aggressive gastrointestinal tumor with a poor prognosis and limited treatment alternatives. Disulfidptosis is a newly defined type of cell death with potential influence on cancer. Research on the association between disulfidptosis and pancreatic cancer is scarce. The expression data of disulfidptosis-related genes were downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Disulfidptosis-related lncRNA signature (DRLS) was developed through the Cox and the least absolute shrinkage and selection operator (LASSO) analysis. Differences in enrichment functions, mutational landscape, immune microenvironment, and predicted therapeutic efficacy between high- and low-risk groups were assessed. Consensus clustering analysis was applied to identify the DRLS-related subtypes. Among 98 disulfidptosis-related lncRNAs, 5 lncRNAs were screened thus constructing a prognostic DRLS. DRLS showed high predictive accuracy and was an independent prognostic factor for pancreatic cancer. According to the risk scores calculated from the signature, samples were categorized into high- and low- risk groups. Overall, low-risk patients had a better prognosis, lower mutational occurrences, higher immune cell infiltration and more sensitivity to anti-tumor agents. The DRLS performed well in predicting prognosis and revealed intimate correlation with biological function, mutation status and immune infiltration landscape of pancreatic cancer, providing some insights for future research on the relationship between disulfidptosis and pancreatic cancer.

The factors that affect hypomethylating agents (HMAs) sensitivity in myelodysplastic syndrome (MDS) are complex and multifaceted. They include DNA methylation, gene expression, mutation, etc. However, the underlying mechanisms are still not clearly illustrated. In the present work, ABAT gene expression was associated with HMAs sensitivity. It was found that ABAT gene interference increased the sensitivity of HL-60 and THP-1 cells to HMAs treatment, while ABAT overexpression decreased its sensitivity. RNA-sequencing analysis showed that ABAT knockdown activated both interferon I and interferon-gamma signaling while inhibiting the secondary metabolic synthesis and arginine metabolic process. Gas chromatography-mass spectrometry (GC-MS) based metabolic profiling also demonstrated that ABAT gene knockdown affected arginine, alanine, aspartate, and glutamate metabolism, in addition to the biosynthesis of valine, leucine, and isoleucine, and the metabolism of beta-alanine. The ABAT gene expression downregulation could activate the CXCR4/mTOR signaling pathway, which was related to HMAs sensitivity. CXCR4 expression was regulated by mTOR activity and vice versa. In vivo, mice injected with ABAT gene knockdown cells lived longer than control mice after HMAs treatment. Overall, this study elucidates the novel regulatory mechanisms of HMAs sensitivity and provides a potential therapeutic target in MDS.

Abstract Triple-negative breast cancer (TNBC) or Basal-like breast cancer is characterized by worse prognosis than other breast cancer subtypes due to the rapid-arising therapeutic resistance accompanied by aggressive metastasis. The therapy-resistant tumor cells, including cancer stem-like cells (CSCs) with intrinsic resistance or tumor cells acquired resistance during treatments, could repopulate the primary tumors and serve as seeds for recurrent metastatic lesions. However, the molecular events orchestrating the innate and acquired therapeutic resistance are not completely understood. We found that the linear ubiquitin-specific deubiquitinase OTULIN is overexpressed in breast tumors, especially in the basal-like subtype, compared with normal breast tissues. Moreover, OTULIN overexpression significantly increased TNBC cells resistance to chemotherapy and is associated with shorter DFS in breast cancer patients. Mechanistically, we found genotoxic treatments activate OTLULIN, which promotes epithelial-to-mesenchymal transition (EMT) in TNBC cells through increased activity of Wnt/β-Catenin signaling. OTULIN overexpression significantly enhanced TNBC cells resistance to chemodrugs while inhibiting Wnt/β-Catenin signaling or OTULIN sensitized TNBC xenografts to Doxorubicin treatment in vivo. Our findings suggest that OTULIN-mediated Wnt/β-Catenin activation may increase TNBC therapeutic resistance and aggressiveness by promoting EMT. Targeting OTULIN and the chemotherapy-induced Wnt/β-Catenin activation may serves as promising strategy to mitigate drug resistance and reduce metastasis in TNBC patients receiving chemotherapy. Citation Format: Wei Wang, Jixiao Niu, Bo Zhang, Zhaohui Wu. OTULIN promotes resistance and metastasis upon chemotherapy in TNBC by activating Wnt/β-Catenin signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 533.

Angiogenesis has been proven to play an important role in the progression of hepatocellular carcinoma (HCC). However, the molecular mechanism underlying HCC angiogenesis is not well understood. In this study, Prospero‐related homeobox 1 (PROX1) was identified as a novel proangiogenic factor in HCC cell lines and tissues. A strong positive correlation was found between the levels of PROX1 and microvessel density in HCC tissues. Knockdown of PROX1 expression in HCC cells significantly inhibited the in vitro capillary tube formation by human vascular endothelial cells and in vivo angiogenesis of HCC, while overexpression of PROX1 in HCC cells induced the opposite effects. PROX1 and nuclear factor κB p65 expression levels were positively correlated in both HCC tissues and cell lines. PROX1 enhances the nuclear accumulation of p65 and stabilizes p65 by recruiting ubiquitin‐specific protease 7 to prevent p65 ubiquitination. Consequently, PROX1 activated nuclear factor κB signaling and selectively promoted expression of the proangiogenic interleukin‐8 (IL‐8) by epigenetically stimulating the IL‐8 promoter. Finally, progression of high PROX1 expression HCC in tumor xenograft mice could be effectively contained by an anti‐IL‐8 monoclonal antibody. Conclusions: We have identified PROX1 as a crucial promoter of HCC angiogenesis; our study provides an insight into PROX1's function in HCC progression and the potential therapeutic application of anti‐IL‐8 antibody in high PROX1 expression HCC patients. (Hepatology 2017;66:1894–1909)

Melanoma is the most aggressive type of skin cancer. Melanoma has an extremely poor prognosis because of its high potential for vascular invasion, metastasis and recurrence. The mechanism of melanoma metastasis is not well understood. ATP-binding cassette sub-family B member 5 (ABCB5) plays a key role in melanoma growth. However, it is uncertain what function ABCB5 may exert in melanoma metastasis. In this report, we for the first time demonstrate ABCB5 as a crucial factor that promotes melanoma metastasis. ABCB5 positive (ABCB5+) malignant melanoma initiating cells (MMICs) display a higher metastatic potential compared with ABCB5 negative (ABCB5-) melanoma subpopulation. Knockdown of ABCB5 expression reduces melanoma cell migration and invasion in vitro and melanoma pulmonary metastasis in tumor xenograft mice. ABCB5 and NF-κB p65 expression levels are positively correlated in both melanoma tissues and cell lines. Consequently, ABCB5 activates the NF-κB pathway by inhibiting p65 ubiquitination to enhance p65 protein stability. Our finding highlights ABCB5 as a novel pro-metastasis factor and provides a potential therapeutic target for melanoma.

A multi-center study from the French Myelodysplastic Syndrome (MDS) Group confirmed that iron chelation therapy is an independent prognostic factor that can increase the survival rate of patients who are suffering from transfusion-dependent low-risk MDS. In this study, we aimed to explore this clinical phenomena in vitro, by exploring the synergistic effect of the iron chelator Deferasirox (DFX) and the DNA methyl transferase inhibitor Decitabine (DAC) in the leukemia cell lines SKM-1, THP-1, and K-562. Treatment with both DFX or DAC promoted apoptosis, induced cell cycle arrest, and inhibited proliferation in all three of these cell lines. The combination of DFX and DAC was much greater than the effect of using either drug alone. DFX showed a synergistic effect with DAC on cell apoptosis in all three cell lines and on cell cycle arrest at the G0/G1 phase in K-562 cells. DFX decreased the ROS levels to varying degrees. In contrast, DAC increased ROS levels and an increase in ROS was also noted when the two drugs were used in combination. Treatment of cells with DAC induced re-expression of ABAT, APAF-1, FADD, HJV, and SMPD3, presumably through demethylation. However the combination of DAC and DFX just had strong synergistic effect on the re-expression of HJV.

Chromobox protein homolog 7 (CBX7), one of the polycomb group (PcG) proteins, is a transcriptional repressor involved in the regulation of cell proliferation and senescence. In the present study, we showed that CBX7 negatively regulates the proliferation, viability, chemoresistance, and migration of pancreatic cancer cells. Overexpression of CBX7 significantly inhibited the proliferation of pancreatic cancer cells in vitro and in vivo. Depletion of CBX7 facilitated their growth. CBX7 also impaired the viability and chemoresistance of pancreatic cancer cells. Transwell assays showed that CBX7 reduces the migratory capacity of pancreatic cancer cells. Of note, CBX7 reduced PTEN/Akt signaling in pancreatic cancer cells by increasing PTEN transcription, suggesting involvement of PTEN/Akt pathway in the tumor suppressive activity of CBX7. In addition, immunohistochemical analysis the CBX7 and PTEN expression in 74 surgically resected pancreatic ductal adenocarcinoma (PDAC) specimens revealed that CBX7 expression is significantly downregulated in pancreatic ductal adenocarcinoma, compared to normal pancreatic tissues. Reduced expression of CBX7 and PTEN was associated with increased malignancy grade in pancreatic adenocarcinoma, whereas maintenance of CBX7 and PTEN expression showed a trend toward a longer survival. These findings suggest CBX7 is an important tumor suppressor that negatively modulates PTEN/Akt signaling during pancreatic tumorigenesis.

Castration-resistant prostate cancer (CRPC) ultimately occurs after a period of treatment with androgen deprivation therapy. Furthermore, CRPC patients can only derive limited survival benefits from traditional cytotoxic drugs. HSP90, which is a molecular chaperone, plays a vital role in client protein processing and maintaining the function of cells. HSP90 is usually overexpressed in prostate cancer tissues, which makes it a potential target for managing prostate cancer. Geldanamycin (GA), which was recognized as the first natural HSP90 inhibitor, has demonstrated potent anti-tumor efficacy in large-scale pre-clinical studies, but its application in the clinic is not permitted due to its liver toxicity and unstable physical properties. In this study, we report a new GA derivative, 17-PAG (17-(propynylamino)-17-demethoxygeldanamycin), which demonstrates highly effective anti-tumor activity against androgen-independent prostate cancer cells. Treating cells with 17-PAG dose-dependently suppressed proliferation, reduced colony formation and induced apoptosis of DU-145/C4-2B cells. Moreover, 17-PAG suppressed the migration and invasion of DU-145/C4-2B cells by regulating epithelial mesenchymal transition (EMT). 17-PAG also downregulated the HSP90 client proteins, including Her2, EGFR, C-Raf, AKT, p-AKT, and CDK4. Animal assays confirmed that 17-PAG shows strong anti-tumor effects with no obvious organ toxicity in DU-145 cell xenografted nude mice. These results provide us with a potential target for treating androgen-independent prostate cancer in a safe and effective manner.

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death from cancer worldwide. HCC has a very poor prognosis because of tumor invasiveness, frequent intrahepatic spread, and extrahepatic metastasis. The molecular mechanism of HCC invasiveness and metastasis is poorly understood. The homeobox protein PROX1 is required for hepatocyte migration during mouse embryonic liver development. In this study, we show that high PROX1 protein expression in primary HCC tissues is associated with significantly worse survival and early tumor recurrence in postoperative HCC patients. Knockdown of PROX1 expression in HCC cells inhibited cell migration and invasiveness in vitro and HCC metastasis in nude mice while overexpression of PROX1 in HCC cells promoted these processes. PROX1's pro-metastasis activity is most likely attributed to its up-regulation of hypoxia-inducible factor 1α (HIF-1α) transcription and stabilization of HIF-1α protein by recruiting histone deacetylase 1 (HDAC1) to prevent the acetylation of HIF-1α, which subsequently induces an epithelial-mesenchymal transition response in HCC cells. We further demonstrated the prognostic value of using the combination of PROX1 and HDAC1 levels to predict postoperative survival and early recurrence of HCC. Conclusion: PROX1 is a critical factor that promotes HCC metastasis. (Hepatology 2013;58:692-705)

Centrosome duplication is tightly controlled during faithful cell division, and unnecessary reduplication can lead to supernumerary centrosomes and multipolar spindles that are associated with most human cancer cells1,2,3,4,5. In addition to nucleocytoplasmic transport, the Ran–Crm1 network is involved in regulating centrosome duplication to ensure the formation of a bipolar spindle6,7,8. Here, we discover that nucleophosmin (NPM) may be a Ran–Crm1 substrate that controls centrosome duplication. NPM contains a functional nuclear export signal (NES) that is responsible for both its nucleocytoplasmic shuttling and its association with centrosomes, which are Ran–Crm1-dependent as they are sensitive to Crm1-specific nuclear export inhibition, either by leptomycin B (LMB) or by the expression of a Ran-binding protein, RanBP1. Notably, LMB treatment induces premature centrosome duplication in quiescent cells, which coincides with NPM dissociation from centrosomes. Moreover, deficiency of NPM by RNA interference results in supernumerary centrosomes, which can be reversed by reintroducing wild-type but not NES-mutated NPM. Mutation of a potential proline-dependent kinase phosphorylation site at residue 95, from threonine to aspartic acid (T95D) within the NES motif, abolishes NPM association and inhibition of centrosome duplication. Our results are consistent with the hypothesis that the Ran–Crm1 complex may promote a local enrichment of NPM on centrosomes, thereby preventing centrosome reduplication.