VEGFR2 blockade inhibits glioblastoma cell proliferation by enhancing mitochondrial biogenesis.

BACKGROUND: Glioblastoma is an aggressive brain tumor linked to significant angiogenesis and poor prognosis. Anti-angiogenic therapies with vascular endothelial growth factor receptor 2 (VEGFR2) inhibition have been investigated as an alternative glioblastoma treatment. However, little is known about the effect of VEGFR2 blockade on glioblastoma cells per se. METHODS: VEGFR2 expression data in glioma patients were retrieved from the public database TCGA. VEGFR2 intervention was implemented by using its selective inhibitor Ki8751 or shRNA. Mitochondrial biogenesis of glioblastoma cells was assessed by immunofluorescence imaging, mass spectrometry, and western blot analysis. RESULTS: VEGFR2 expression was higher in glioma patients with higher malignancy (grade III and IV). VEGFR2 inhibition hampered glioblastoma cell proliferation and induced cell apoptosis. Mass spectrometry and immunofluorescence imaging showed that the anti-glioblastoma effects of VEGFR2 blockade involved mitochondrial biogenesis, as evidenced by the increases of mitochondrial protein expression, mitochondria mass, mitochondrial oxidative phosphorylation (OXPHOS), and reactive oxygen species (ROS) production, all of which play important roles in tumor cell apoptosis, growth inhibition, cell cycle arrest and cell senescence. Furthermore, VEGFR2 inhibition exaggerated mitochondrial biogenesis by decreased phosphorylation of AKT and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which mobilized PGC1α into the nucleus, increased mitochondrial transcription factor A (TFAM) expression, and subsequently enhanced mitochondrial biogenesis. CONCLUSIONS: VEGFR2 blockade inhibits glioblastoma progression via AKT-PGC1α-TFAM-mitochondria biogenesis signaling cascade, suggesting that VEGFR2 intervention might bring additive therapeutic values to anti-glioblastoma therapy.

Dynamic genomic changes in methotrexate-resistant human cancer cell lines beyond DHFR amplification suggest potential new targets for preventing drug resistance.

BACKGROUND: Although DHFR gene amplification has long been known as a major mechanism for methotrexate (MTX) resistance in cancer, the early changes and detailed development of the resistance are not yet fully understood. METHODS: We performed genomic, transcriptional and proteomic analyses of human colon cancer cells with sequentially increasing levels of MTX-resistance. RESULTS: The genomic amplification evolved in three phases (pre-amplification, homogenously staining region (HSR) and extrachromosomal DNA (ecDNA)). We confirm that genomic amplification and increased expression of DHFR, with formation of HSRs and especially ecDNAs, is the major driver of resistance. However, DHFR did not play a detectable role in the early phase. In the late phase (ecDNA), increase in FAM151B protein level may also have an important role by decreasing sensitivity to MTX. In addition, although MSH3 and ZFYVE16 may be subject to different posttranscriptional regulations and therefore protein expressions are decreased in ecDNA stages compared to HSR stages, they still play important roles in MTX resistance. CONCLUSION: The study provides a detailed evolutionary trajectory of MTX-resistance and identifies new targets, especially ecDNAs, which could help to prevent drug resistance. It also presents a proof-of-principal approach which could be applied to other cancer drug resistance studies.

miR-1972 inhibits hepatocellular carcinoma proliferation by targeting GZMH-mediated DNA replication in the cell cycle.

AIM: To understand the regulatory roles of miR-1972 and GZMH in hepatocellular carcinoma (HCC) and explore their potential as therapeutic biomarkers. METHODS: In vitro verification of the regulation of malignant cell behavior by differential expression of miR-1972 in HCC cells. The GSE113996 dataset was studied using weighted gene co-expression network analysis (WGCNA) and differential expressed genes respectively to identify the key prognostic gene GZMH and assess the effect of its differential expression on the prognosis of the patient. Finally, the regulation of GZMH expression by miR-1972 was verified, and the effect of their combination on HCC cell behavior was analyzed. RESULTS: Inhibition of miR-1972 can reduce cell proliferation, migration, and invasion, while overexpression of miR-1972 has the opposite effect in HCC cells. According to the data, a positive prognosis for HCC was linked with higher GZMH expression. Interestingly, miR-1972 was observed to reverse-regulate the expression of GZMH. Besides, the combined regulation of GZMH and miR-1972 has been discovered to affect the cell growth, invasive capacity, and migratory potential of HCC cells, especially the cell cycle arrest in the G2 phase. CONCLUSIONS: miR-1972 regulates the malignant behavior of HCC cells, especially cell proliferation, by regulating GZMH expression.

Single-cell analysis revealing the metabolic landscape of prostate cancer.

Tumor metabolic reprogramming is a hallmark of cancer development, and targeting metabolic vulnerabilities has been proven to be an effective approach for castration-resistant prostate cancer (CRPC) treatment. Nevertheless, treatment failure inevitably occurs, largely due to cellular heterogeneity, which cannot be deciphered by traditional bulk sequencing techniques. By employing computational pipelines for single-cell RNA sequencing, we demonstrated that epithelial cells within the prostate are more metabolically active and plastic than stromal cells. Moreover, we identified that neuroendocrine (NE) cells tend to have high metabolic rates, which might explain the high demand for nutrients and energy exhibited by neuroendocrine prostate cancer (NEPC), one of the most lethal variants of prostate cancer (PCa). Additionally, we demonstrated through computational and experimental approaches that variation in mitochondrial activity is the greatest contributor to metabolic heterogeneity among both tumor cells and nontumor cells. These results establish a detailed metabolic landscape of PCa, highlight a potential mechanism of disease progression, and emphasize the importance of future studies on tumor heterogeneity and the tumor microenvironment from a metabolic perspective.

Prospective observational study of surgery alone for locally advanced oral squamous cell carcinoma: a real-world study.

INTRODUCTION: A prospective observational study was modified to assess the efficacy of surgery alone for the treatment of locally advanced oral squamous cell carcinoma. (LA-OSCC) MATERIALS AND METHODS: This prospective, single-institution, single-arm study involved 174 patients who underwent major surgery for LA-OSCC. Participating patients did not receive postoperative radiation. After initial curative treatment, patients were routinely monitored via clinical examination and imaging. The follow-up period was 3-70 months. Tumour recurrence and death were considered as the Clinical End Point in Research. RESULTS: The 5-year overall survival (OS), disease-free survival (DFS), and locoregional control rates for 174 patients were 66.7% (95% confidence interval [CI], 59.8 to 73.6), 66.1% (95% CI, 59.2 to 73.0), and 82.4% (95% CI, 76.5 to 88.3), respectively. CONCLUSION: A study of patients with LA-OSCC treated with surgery alone may have the optimal therapeutic impact for LA-OSCC, as evidenced by solid data for our next RCT trial. This conclusion still needs to be validated in higher-level RCTs.

Application of anatomy unit resection surgery for lateral basicranial surgical approach in oral squamous carcinoma.

BACKGROUND: The basicranial region lacks definite boundaries and includes various anatomical units. We developed a novel concept of the posterior oral anatomical complex (POAC) to identify these anatomical units in the basicranial region. OSCC with POAC involvement is termed posterior oral squamous cell carcinoma (POSCC) with poor prognosis. The principal aim of this study was to evaluate the effect of anatomy unit resection surgery (AUSR) on patients with POSCC. METHODS: A total of 120 POSCC patients who underwent radical surgical treatment were recruited for this study. These POSCC patients were treated with conventional surgery or AUSR. According to the extent of primary tumor resection in the AUSR group, the lateral basicranial surgical approach can be subdivided into four types: face-lateral approach I, face-lateral approach II, face-median approach or face-median and face-lateral combined approach. Facial nerve function was evaluated according to the House-Brackmann Facial Nerve Grading System. RESULTS: The overall survival rate was 62.5% and 37.5% in the AURS group and conventional group (hazard ratio: 0.59; p < 0.0001), respectively. The disease-free survival rate was 62.5% and 34.3% in the AURS group and conventional group (hazard ratio: 0.43; p = 0.0008), respectively. The local disease control rate in the AURS group (71.4%) was significantly better than that in the conventional group (34.4%) in present study (p < 0.0001). Compared to the conventional group, all the patients undergoing AURS were classified as T4 stage and presented with more lymph node metastasis (71.4%). A total of 20 patients (face-lateral approach I and face-lateral combined approach) were temporarily disconnected from the temporofacial branch of the facial nerve. Fifteen patients exhibited slight paresis, and five patients presented with moderate or severe paresis. The survival rate of zygomatic arch disconnection was 94.6% (54 of 56 patients). CONCLUSION: This lateral basicranial surgical approach based on AUSR improves the survival rate and enhances the local control rate while also preserving a good prognosis without damaging the nerve and zygomatic bone. This surgical approach based on AUSR provides a novel and effective surgical treatment to address POSCC with better prognosis, especially for patients without metastatic lymph nodes.

Postoperative radiotherapy may not be necessary for locally advanced head and neck squamous cell carcinoma: a case-match multicentre study.

BACKGROUND: Some head and neck cancer surgeons found that many patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) without postoperative radiotherapy (PORT) also have a good prognosis. The purpose of this study was to determine the effect of PORT on survival in patients with LA-HNSCC. METHODS: A case-match cohort analysis was performed at two institutions on patients with LA-HNSCC. Patients who received surgery alone were case-matched 1: 1 with patients treated by surgery plus PORT based on pT, pN, tumor subsite etc. RESULTS: 114 patients were matched into 57 pairs, with a median follow-up period of 40.2 months. No difference in overall survival (OS, HR 0.88; 95% CI 0.50-1.58; P = 0.79) or disease-specific survival (DFS, 0.86; 95% CI 0.50-1.50; P = 0.76) was observed with no PORT. CONCLUSIONS: PORT isn't necessary for patients with LA-HNSCC who are treated for the first time as long as the head and neck cancer surgeon adhere to appropriate surgical concepts. The indications of PORT for patients with LA-HNSCC need to be further discussed.

Enhanced Anti-Tumor Effect of Folate-Targeted FA-AMA-hyd-DOX Conjugate in a Xenograft Model of Human Breast Cancer.

Folate-aminocaproic acid-doxorubicin (FA-AMA-hyd-DOX) was firstly synthesized by our group. It was indicated that FA-AMA-hyd-DOX was pH-responsive, and had strong cytotoxicity on a folate receptor overexpressing cell line (KB cells) in vitro. The aim of our study was to further explore the potential use of FA-AMA-hyd-DOX as a new therapeutic drug for breast cancer. The cellular uptake and the antiproliferative activity of the FA-AMA-hyd-DOX in MDA-MB-231 cells were measured. Compared with DOX, FA-AMA-hyd-DOX exhibited higher targeting ability and cytotoxicity to FR-positive tumor cells. Subsequently, the tissue distribution of FA-AMA-hyd-DOX was studied, and the result confirmed that DOX modified by FA can effectively increase the selectivity of drugs in vivo. After determining the maximum tolerated dose (MTD) of FA-AMA-hyd-DOX in MDA-MB-231 tumor-bearing nude mice, the antitumor effects and the in vivo safety of FA-AMA-hyd-DOX were systematically evaluated. The data showed that FA-AMA-hyd-DOX could effectively increase the dose of DOX tolerated by tumor-bearing nude mice and significantly inhibit MDA-MB-231 tumor growth in vivo. Furthermore, FA-AMA-hyd-DOX treatment resulted in almost no obvious damage to the mice. All the positive data suggest that FA-targeted FA-AMA-hyd-DOX is a promising tumor-targeted compound for breast cancer therapy.

Hypoxia-induced ROS promotes mitochondrial fission and cisplatin chemosensitivity via HIF-1α/Mff regulation in head and neck squamous cell carcinoma.

PURPOSE: Chemotherapy based on cisplatin (CDDP) has been established as the treatment of choice for head and neck squamous cell carcinoma (HNSCC). Malignant tumors respond to microenvironmental alterations through a dynamic balance between mitochondrial fission and fusion. HNSCCs are known to exhibit hypoxic conditions, yet the respective effects and underlying mechanisms of hypoxia on chemosensitivity and mitochondrial dynamics remain to be resolved. METHODS: The effect of hypoxia on the chemosensitivity of HNCC cells was determined by flow cytometry. Mitochondrial fission factor (Mff) expression was assessed by RT-PCR and Western blotting in hypoxic HNSCC cells, and further verified in primary CDDP-sensitive and CDDP-resistant HSNCC samples. The biological function of Mff was evaluated by loss of function and gain of function analyses, both in vitro and in vivo. RESULTS: We found that hypoxia promoted mitochondrial fission and CDDP sensitivity in HNSCC cells. Importantly, Mff was found to be correlated with chemosensitivity in primary clinical samples under hypoxic conditions. Hypoxia-inducible factor 1α (HIF-1α) was found to markedly increase Mff transcription and to directly bind to Mff. Hypoxia enhanced the release of reactive oxygen species (ROS) and upregulated the expression of Mff via HIF-1α in HNSCC cells. ROS depletion in HNSCC cells attenuated HIF-1α expression, Mff expression and mitochondrial fission. Moreover, Mff knockdown led to suppression of hypoxia-induced mitochondrial fission and to decreased CDDP chemosensitivity in vivo and in vitro. CONCLUSIONS: Our findings indicate that hypoxia-induced release of ROS can promote mitochondrial fission and CDDP chemosensitivity via HIF1α/Mff regulation in HNSCC cells, indicating that Mff may serve as a biomarker to predict neoadjuvant chemosensitivity in HNSCC patients and as a target for overcoming chemoresistance.

Platinum-Based Neoadjuvant Chemotherapy for Breast Cancer With BRCA Mutations: A Meta-Analysis.

BACKGROUND: Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer and the major phenotype of BRCA related hereditary breast cancer. Platinum is a promising chemotherapeutic agent for TNBC. However, its efficacy for breast cancer with BRCA germline mutation remains inconclusive. Here we present a meta-analysis to evaluate the effect of platinum agents for breast cancer patients with BRCA mutation in neoadjuvant setting. MATERIALS AND METHODS: Pubmed, Embase, and Cochrane Central Register of Controlled Trials databases were searched for relevant studies on neoadjuvant platinum treatment and BRCA related breast cancer. Fixed- and random-effect models were adopted for meta-analyses. Heterogeneity investigation was conducted by sensitivity and subgroup analyses. Publication bias was evaluated by funnel plot and Begg's test. RESULTS: In all, five studies with 363 patients were included for meta-analysis. The pooled pathological complete response (pCR) rates were 43.4% (59/136) and 33.9% (77/227) for platinum and control groups, respectively. Adding platinum to neoadjuvant regimen did not significantly improved pCR rate (odds ratio [OR]: 1.340, 95% confidence interval [CI] = 0.677-2.653, p = 0.400). Sensitivity analyses also revealed platinum did not significantly increase pCR rate in either TNBC or HER2- patients (TNBC subgroup: OR: 1.028, 95% CI = 0.779-1.356, p = 0.846; HER2- subgroup: OR: 0.935, 95% CI = 0.716-1.221, p = 0.622). CONCLUSIONS: Our meta-analysis suggested that the addition of platinum to neoadjuvant chemotherapy did not significantly improve pCR rate for patients with BRCA mutations. Further large-scale randomized control trial with survival data may provide more robust evidence on therapeutic value of platinum for breast cancer neoadjuvant treatment.

"Sushi roll" technique for precise total tongue functional reconstruction using a pre-sutured femoral anterolateral myocutaneous flap.

OBJECTIVES: Reconstruction of the total tongue after cancer resection remains one of the challenges in head and neck surgery. Inadequate reconstruction after subtotal or total glossectomy defects leads to poor quality of life. The aim of this study was to explore an economical, practical and effective flap design for functional tongue reconstruction. MATERIAL AND METHODS: Sixty patients were randomly divided into two groups, namely, a "Sushi roll" technique group (30 patients) and a conventional surgery group (30 patients). Then, the patients underwent total or subtotal tongue reconstruction. Swallowing function, speech intelligibility, cosmetic results, and quality of life were assessed with the appropriate scales. Outcomes were analysed, and a p-value <0.05 was considered significant. RESULTS: The perioperative recovery of the "Sushi roll" group was superior to that of the conventional group. Relative to patients in the conventional group, patients in the "Sushi roll" group showed significantly improved speech intelligibility (p = 0.025), cosmetic results (p < 0.001) and swallowing function (p < 0.001). CONCLUSION: The innovative "Sushi roll" anterolateral thigh myocutaneous flap approach for total tongue reconstruction creates a free neotongue tip with adequate volume and protuberance and causes minimal damage to the donor site, producing acceptable swallowing function and speech intelligibility.

Association between metabolic syndrome and prognosis of breast cancer: a meta-analysis of follow-up studies.

BACKGROUND: Metabolic syndrome (MetS) has been suggested to be a risk factor for many cancers, including breast cancer. However, it remains unclear whether MetS predicts poor prognosis in women with breast cancer. A meta-analysis was performed to summarize the association between MetS and clinical outcome in women with breast cancer. METHODS: Cohort studies were identified by search of PubMed and Embase databases. A random-effect model incorporating the potential heterogeneity was applied to pool the results. Subgroup analyses according to the ethnicity and study design were performed. RESULTS: Nine cohort studies with 17,892 women with breast cancer were included. Pooled results showed that MetS was significantly associated with an increased risk of breast cancer recurrence (adjusted risk ratio [RR] = 1.52, 95%, p = 0.02). Subgroup analyses showed that MetS was independently associated with increased recurrence of breast cancer in Caucasians (adjusted RR = 1.75, p = 0.02), but not in Asians (adjusted RR = 1.07, p = 0.81), and MetS was associated with a trend of increased risk of breast cancer recurrence in both the prospective and retrospective studies. Although we failed to show a significant association between MetS and breast cancer related deaths (adjusted RR = 1.24, p = 0.41), MetS was associated with increased risk of all-cause deaths in these patients (adjusted RR = 1.80, p < 0.001). CONCLUSIONS: MetS may predict the risk of cancer recurrence and mortality in women with breast cancer, particularly in Caucasians.

Nonvascularized Iliac Bone Reconstruction for the Mandible Without Maxillofacial Skin Scarring.

PURPOSE: There are many methods to reconstruct the mandible, but they are often accompanied by trauma, which can lead to scarring of the maxillofacial skin. The purpose of this study was to show the utility of a minimally invasive method for reconstruction of the mandible with nonvascularized iliac bone grafts without a skin scar, as well as to evaluate the success rate and complications. PATIENTS AND METHODS: This was a retrospective case series. We retrospectively analyzed patients who underwent transoral resection of benign mandibular pathologies, followed by nonvascularized iliac bone graft reconstruction. The primary outcome variable was the success rate of the bone grafts. Secondary outcome variables were postoperative complications at the grafted bone recipient and donor sites, the long-term absorptivity of grafted bone, and the type of mandibular defect. We computed descriptive statistics or performed the χ2 test for each variable. RESULTS: Overall, 54 patients were included in the study, including 21 male and 33 female patients, with an age range of 10 to 65 years. The complete survival rate was 87.0% (47 of 54 patients), and the partial survival rate was 98.1% (53 of 54). The average bone absorption rate 3 years after surgery was 1.8 to 30.7%. We propose a new classification method for mandibular defects based on the extent of the tumor, location of the osteotomy, and degree of surgical difficulty. CONCLUSIONS: Intraoral nonvascularized iliac bone grafting is a highly successful minimally invasive method for mandibular reconstruction. It is also one of the best methods for mandibular reconstruction in patients with benign mandibular tumors without soft tissue involvement.

Association Between Metabolic Syndrome and Breast Cancer Risk: An Updated Meta-Analysis of Follow-Up Studies.

Background: Association between metabolic syndrome (MetS) and incidence of breast cancer remains to be validated. Moreover, whether menopausal status of the women affects this association is unclear. A meta-analysis was performed to summarize the association between MetS and breast cancer risk. Methods: Follow-up studies were identified by search of PubMed and Embase databases published until May 26, 2019. A random-effect model or fixed-effect model was applied to pool the results according to the heterogeneity. Subgroup analyses according to the menopausal status, ethnic groups, cancer histopathological features, and study design characteristics. Results: Overall, 17 follow-up studies with 602,195 women and 15,945 cases of breast cancer were included. Results of meta-analysis showed that MetS defined by the revised National Cholesterol Education Program's Adults Treatment Panel III criteria was associated with significantly increased risk for breast cancer incidence (adjusted risk ratio [RR] = 1.15, p = 0.003). Subgroup analyses showed that MetS was associated with significantly increased risk of breast cancer in postmenopausal women (adjusted RR = 1.25, p < 0.001), but significantly reduced breast cancer risk in premenopausal women (adjusted RR = 0.82, p < 0.001). Further analyses showed that the association between MetS and increased risk of breast cancer were mainly evidenced from studies including Caucasian and Asian women, reporting invasive breast cancer, and of retrospective design. Conclusions: Menopausal status may affect the association between MetS and breast cancer incidence. Postmenopausal women with Mets are associated with increased risk of breast cancer.

HOXC10 promotes migration and invasion via the WNT-EMT signaling pathway in oral squamous cell carcinoma.

As a master regulator of embryonic morphogenesis, homeodomain-containing gene 10 (HOXC10) has been found to promote progression of human cancers and indicate poor survival outcome. Therefore, we concentrate on elucidating the role of HOXC10 in progression of oral squamous cell carcinoma (OSCC). In our study, the expression of HOXC10 was significantly increased in human OSCC samples and was significantly correlated with TNM stage and lymph node metastasis. Upregulation of HOXC10 indicated a poor overall survival of OSCC patients according to the Kaplan-Meier survival curves. Furthermore, HOXC10-knockdown dramatically suppressed migration, invasion, and expression of N-Cadherin, Vimentin and Snail, as well as increased E-cadherin level both in vivo and in vitro. Bioinformatics and cellular study further confirmed that HOXC10 may promote invasion and migration of OSCC cells by regulating the WNT/epithelial-mesenchymal transition (EMT) signaling pathway. These findings suggest that HOXC10 plays a pivotal role in the metastasis of OSCC and highlight its usefulness as a potential prognostic marker or therapeutic target in human OSCC.

Effects of Left Gastric Artery Ligation Versus Sleeve Gastrectomy on Obesity-Induced Adipose Tissue Macrophage Infiltration and Inflammation in Diet-Induced Obese Rats.

BACKGROUND Bariatric procedures such as left gastric artery ligation (LGAL) and sleeve gastrectomy (SG) have emerged as important procedures for treating morbid obesity. In this study, we compared the effects of LGAL vs. SG on obesity-induced adipose tissue macrophage infiltration and inflammation in diet-induced obese rats. MATERIAL AND METHODS Sprague-Dawley (SD) rats were fed a high-fat diet (HFD) for 16 weeks to induce obesity. SG, GLAL, or corresponding sham surgeries were performed in anesthetized rats. Inflammatory factor expression in serum and epididymal and retroperitoneal adipose tissues were analyzed 4 weeks after surgery. Macrophage infiltration and phenotype transformation were also assessed with Western blot analysis and immunofluorescence. RESULTS Both LGAL and SG strongly attenuated high-fat diet (HFD)-induced fat accumulation in retroperitoneal and epididymal tissues. The expressions of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and monocyte chemoattractant protein (MCP)-1 were downregulated after LGAL and after SG by promoting activation of M2 macrophages, despite continued exposure to HFD. Furthermore, both LGAL and SG resulted in increased macrophage infiltration, but did not contribute to phenotype transformation of macrophages to M1. CONCLUSIONS LGAL and SG both reduced fat accumulation caused by HFD feeding. Therapies designed to ameliorate the inflammatory response by promoting activation of M2 macrophages may be valuable.

Cobalt iron phosphide nanoparticles embedded within a carbon matrix as highly efficient electrocatalysts for the oxygen evolution reaction.

Co3FePx/C nanocomposites were derived from one-step phosphorization of anthraquinone-2-sulfonate (AQS2) intercalated Co3Fe layered double hydroxides (Co3Fe LDHs). The carbonized AQS2 confines Co3FePx nanoparticles in the amorphous carbon matrix during thermal treatment. Ultra-small and uniformly distributed Co3FePx/C nanoparticles in carbon exhibit excellent durability and outstanding OER catalytic activity.

Retraction Note: Upregulation of the long non-coding RNA AFAP1-AS1 affects the proliferation, invasion and survival of tongue squamous cell carcinoma via the Wnt/ß-catenin signaling pathway.

The authors have retracted this article [1] because there are errors in Figures 4a and 4b.

Vascular regeneration in adult mouse cochlea stimulated by VEGF-A165 and driven by NG2-derived cells ex vivo.

Can damaged or degenerated vessels be regenerated in the ear? The question is clinically important, as disruption of cochlear blood flow is seen in a wide variety of hearing disorders, including in loud sound-induced hearing loss (endothelial injury), ageing-related hearing loss (lost vascular density), and genetic hearing loss (e.g., Norrie disease: strial avascularization). Progression in cochlear blood flow (CBF) pathology can parallel progression in hair cell and hearing loss. However, neither new vessel growth in the ear, nor the role of angiogenesis in hearing, have been investigated. In this study, we used an established ex vivo tissue explant model in conjunction with a matrigel matrix model to demonstrate for the first time that new vessels can be generated by activating a vascular endothelial growth factor (VEGF-A) signal. Most intriguingly, we found that the pattern of the newly formed vessels resembles the natural 'mesh pattern' of in situ strial vessels, with both lumen and expression of tight junctions. Sphigosine-1-phosphate (S1P) in synergy with VEGF-A control new vessel size and growth. Using transgenic neural/glial antigen 2 (NG2) fluorescent reporter mice, we have furthermore discovered that the progenitors of "de novo" strial vessels are NG2-derived cells. Taken together, our data demonstrates that damaged strial microvessels can be regenerated by reprogramming NG2-derived angiogenic cells. Restoration of the functional vasculature may be critical for recovery of vascular dysfunction related hearing loss.

Application of a new classification of chimeric anterolateral thigh free flaps.

BACKGROUND: The anterolateral thigh free flap is one of the most commonly used flaps in reconstructive procedures. The purpose of this study was to assess this new classification of chimeric anterolateral thigh free flaps. METHODS: Sixty-five patients underwent free anterolateral thigh chimeric free flap reconstruction of defects in the head and neck region. We summarized the anatomic features of perforators, including the number and origin of the perforators. RESULTS: Sixty-five cases of femoral anterolateral double island flaps were divided into 3 types: trunk type (type I), 11 cases (16.9%), in which the perforators of two flaps originated in the descending branch and the transverse branch of the lateral femoral circumflex artery; branch type (type II), 45 cases (69.3%), in which both the perforators originated in the descending branch or the transverse branch of the lateral femoral circumflex artery; and bifurcation type (type III), 9 cases (13.8%), in which two perforators originated in the bifurcation of one perforator that originated in the descending branch or the transverse branch of the lateral femoral circumflex artery. All 65 flaps survived and none showed partial necrosis. CONCLUSIONS: The anterolateral thigh chimeric flap can be divided into 3 types: trunk type (I type), branch type (II type) and bifurcation type (III type).