Myeloid-derived growth factor suppresses VSMC dedifferentiation and attenuates postinjury neointimal formation in rats by activating S1PR2 and its downstream signaling.

Restenosis after angioplasty is caused usually by neointima formation characterized by aberrant vascular smooth muscle cell (VSMC) dedifferentiation. Myeloid-derived growth factor (MYDGF), secreted from bone marrow-derived monocytes and macrophages, has been found to have cardioprotective effects. In this study we investigated the effect of MYDGF to postinjury neointimal formation and the underlying mechanisms. Rat carotid arteries balloon-injured model was established. We found that plasma MYDGF content and the level of MYDGF in injured arteries were significantly decreased after balloon injury. Local application of exogenous MYDGF (50 µg/mL) around the injured vessel during balloon injury markedly ameliorated the development of neointimal formation evidenced by relieving the narrow endovascular diameter, improving hemodynamics, and reducing collagen deposition. In addition, local application of MYDGF inhibited VSMC dedifferentiation, which was proved by reversing the elevated levels of osteopontin (OPN) protein and decreased levels of α-smooth muscle actin (α-SMA) in the left carotid arteries. We showed that PDGF-BB (30 ng/mL) stimulated VSMC proliferation, migration and dedifferentiation in vitro; pretreatment with MYDGF (50-200 ng/mL) concentration-dependently eliminated PDGF-BB-induced cell proliferation, migration and dedifferentiation. Molecular docking revealed that MYDGF had the potential to bind with sphingosine-1-phosphate receptor 2 (S1PR2), which was confirmed by SPR assay and Co-IP analysis. Pretreatment with CCG-1423 (Rho signaling inhibitor), JTE-013 (S1PR2 antagonist) or Ripasudil (ROCK inhibitor) circumvented the inhibitory effects of MYDGF on VSMC phenotypic switching through inhibiting S1PR2 or its downstream RhoA-actin monomers (G-actin) /actin filaments (F-actin)-MRTF-A signaling. In summary, this study proves that MYDGF relieves neointimal formation of carotid arteries in response to balloon injury in rats, and suppresses VSMC dedifferentiation induced by PDGF-BB via S1PR2-RhoA-G/F-actin-MRTF-A signaling pathway. In addition, our results provide evidence for cross talk between bone marrow and vasculature.

Inhibition of YAP Sensitizes the Selumetinib Treatment for Neurofibromatosis Type 1 Related Plexiform Neurofibroma.

Background: Targeted therapy of Neurofibromatosis type 1 (NF1) related plexiform neurofibroma (pNF) aiming at MEK molecule has not demonstrated a convincing result for complete disease inhibition, probably due to other signal pathways crosstalk. Our previous study revealed an increased nuclear translocation of YAP molecule in NF1 related pNF. Herein, we decided to further investigate the therapeutic relations of YAP interference during the MEK treatment against NF1 related pNF. Methods: By means of selumetinib (MEK-inhibitor), RNA-sequencing was firstly performed to identify the changes of signal pathways in pNF Schwann cells, which was probably related to YAP regulation. Nuclear-cytoplasmic fractionation and western blotting were performed to show the intracellular YAP changes under selumetinib treatment. Thirdly, a series of in vitro assays were performed including flow cytometry, CCK-8, and colony/sphere formation under dual treatment of selumetinib and verteporfin (YAP-inhibitor). In addition, Chou-Talalay method was adopted to evaluate the synergistic inhibiting effects of such drug combination. Xenograft study was also used to detect the combining effects in vivo. Results: RNA-sequencing revealed that selumetinib treatment might be associated with the undesirable activation of Hippo pathway in NF1 related pNF tumor cells, which might reduce its pharmaceutic effects. Next, nuclear-cytoplasmic fractionation and further studies demonstrated that selumetinib could promote the nuclear translocation and transcriptional activation of YAP in vitro, which might cause the aforementioned resistance to selumetinib treatment. Additionally, when combined treatments were performed based on verteporfin and selumetinib, synergistic effects were observed on cytotoxicity of NF1 related pNF tumor cells in vitro and in vivo xenograft models. Conclusion: YAP inhibition can effectively sensitize NF1 related pNF tumor cells to selumetinib. Dual targeting of YAP and MEK might be a promising therapeutic strategy for treating NF1 related pNF.

Head-and-neck dermatofibrosarcoma protuberans: Survival analysis and Clinically relevant immunohistochemical indicators.

BACKGROUND: Head and neck dermatofibrosarcoma protuberans (HNDFSP) is extremely rare and not entirely understood. OBJECTIVE: To investigate the clinicopathological features of HNDFSP and identify the expression of its clinically relevant indicators, with the expectation of improving the existing treatment strategies. METHODS: A long-term follow-up of patients with HNDFSP who received treatment between 2000 and 2021 at Shanghai Ninth People's Hospital was conducted. The clinical, histological, and immunohistochemical data of the patients were retrieved and analyzed. The endpoint of the study was the incidence of significant disease-related clinical events (recurrences or metastasis). RESULTS: A total of 49 patients with HNDFSP were included in the study, with males (92.7%) predominating than females (7.3%). Eighteen patients developed recurrent disease (36.8%) after surgery, and the median time of recurrence was 48 months (interquartile, 20-74 months). Metastasis occurred in two cases (4.1%). Two patients died during follow-up, both with local recurrence, and one of them with intestinal metastasis. Post-operation radiotherapy was administered to eight patients (16.3%) and the effect in local control was remarkable. Age, tumor size, and negative margins with sufficient safety width were the main independent factors affecting the disease-free survival. Several potential targeted therapeutic indicators, including EZH2 (80.0%), EGFR (91.4%), PDGF (97.1%), PD-L1 (77.1%), and VEGF (77.1%), were positively expressed in most tumor samples. CONCLUSION: HNDFSP is rare, significantly challenging to control locally, and has a worse prognosis with current treatment strategies. Wide local excision and long-term follow-up are needed. Radiotherapy could improve the prognosis of patients with HNDFSP.

Level IV neck dissection in cN0 HPV-negative oropharyngeal squamous cell carcinoma: a retrospective cohort study.

BACKGROUND: As opposed to observation of the neck, elective neck dissection has a survival benefit for cN0 oropharyngeal squamous cell carcinoma (OPSCC). However, there are limited date on level IV neck dissection in human papillomavirus (HPV)-negative OPSCC because most earlier studies did not stratify by P16 or HPV status. Thus, whether to exclude level IV from selective dissection (SND) of cN0 HPV-negative OPSCC remains controversial. METHODS: In this single-center retrospective cohort study, disease-free survival (DFS) was estimated as the primary endpoint for 124 cN0 HPV-negative OPSCC patients who received SND of levels I-III (Group A) and I-IV (Group B). Overall survival (OS) and disease-specific survival (DSS) were considered secondary endpoints. RESULTS: For the entire cohort, the 5-year DFS rates of Groups A and B were 55.0% and 60.1%, respectively. Five-year OS rates were 58.9% and 61.5%, and 5-year DSS rates were 74.0% and 64.8%, respectively. Group B did not show higher 5-year DFS, OS, or DSS than Group A. CONCLUSIONS: This retrospective cohort study validated that in cN0 HPV-negative OPSCC, SND including level IV does not have substantial benefits regarding DFS, OS or DSS.

Salvage surgery for patients with residual/persistent diseases after improper or insufficient treatment of oral squamous cell carcinoma: can we rectify these mistakes?

BACKGROUND: Patterns of failure after treatment of oral and squamous cell carcinomas (OSCC) are diversified, with recurrences being one of the common causes. A special group of patients are sometimes encountered in the outpatient clinic for improper or insufficient initial treatment with reports of positive margins, implying residual/persistent diseases. The question of whether these patients can be surgically salvaged remain unanswered. METHODS: A retrospective study was performed between January 2013 and December 2017 for patients with residual or rapid recurrent (within 3 months) OSCCs, who received salvage surgeries in our institution. The patients with residual/persistent OSCCs were those with microscopic or macroscopic positive surgical margins, while those with rapid recurrent OSCCs were those with close or negative margins, but unabated painful symptoms right after treatment. Both clinicopathological and prognostic variables were analyzed. The focus was also directed towards lessons for possible initial mistakes, resulting in these residual/persistent diseases. RESULTS: Of 103 patients, 68 (66%) were men, with mean age of 56.3 years. The overall survival reached 60.2%. Regarding the primary OSCC status, most of our patients (n = 75, 72.8%) were diagnosed with ycT2-3 stages. Besides, most patients were found with macroscopic residual diseases (52.4%) before our salvage surgery. The sizes of the residual/persistent OSCCs were generally under 4 cm (87.3%) with minimally residual in 21 (20.4%). Among all the variables, primary T stage (p = 0.003), and residual lesion size (p < 0.001) were significantly associated with the prognosis in multivariate analysis. Though the causes for the initial surgical failure were multifactorial, most were stemmed from poor planning and unstandardized execution. CONCLUSIONS: Cases with residual/persistent OSCCs were mostly due to mistakes which could have been avoided under well-round treatment plans and careful surgical practice. Salvage surgery for cases with smaller residual/persistent OSCCs is still feasible with acceptable outcomes.

Standardize routine angiography assessment of leg vasculatures before fibular flap harvest: lessons of congenital and acquired vascular anomalies undetected by color Doppler and physical examinations.

BACKGROUND: Fibular flaps have been widely used for mandibular and maxillary reconstructions. On occasion, anatomical variants of fibular arteries (FA) will be encountered. PURPOSE: Although anatomical variants of FA during fibular harvest have been reported, controversy exists regarding whether simple color Doppler ultrasonography (CDU) and physical examinations (PE) are sufficient for early preoperative detection. MATERIAL AND METHODS: A 10-year retrospective analysis in our department was performed to find the patients with various FA anomalies confirmed by computed tomography angiography (CTA) or intraoperative findings. RESULTS: A total number of 19 FA anomalies were found either pre- or intraoperatively in 16 patients, in whom three cases were with bilateral FA variants. Type IIIC variants, also called arteria peronea magna (great peroneal artery), were confirmed in two legs, while the majority (13 legs) had type IIIA hypoplastic/aplastic posterior tibialis arteries (PTA). Four legs had new type IIID (low FA and PTA bifurcations). Preoperative CDU and PE only suspected anomalies in two legs. Six cases proceeded with using the affected fibulas, within whom vascular grafts were used in half of them for lengthening the FA pedicle. Local ischemia, partial soleus muscle necrosis, and claudication were reported in one. CONCLUSIONS: Routine CTA before every fibular harvest, rather than simple PE and CDU, should be added for screening contraindications and ensuring safety for fibular flap harvest.

Salvage Surgery for Recurrent Tongue Cancer With Contralateral Neck Metastasis.

PURPOSE: Treatment recommendations have been widely reported for primary tongue squamous cell carcinoma (TSCC) with contralateral neck metastases (CNMs), but little is known concerning recurrent TSCCs with CNMs, especially in patients who have undergone ipsilateral neck dissection. The aim of this study was to estimate overall survival (OS) and to identify prognostic factors associated with OS in patients treated for recurrent TSCCs. PATIENTS AND METHODS: We performed a retrospective cohort study of patients who underwent salvage surgery (SS) for recurrent TSCC in our institution between January 2010 and December 2014. Before SS, all patients had been surgically treated for primary TSCC with ipsilateral neck dissection. The primary outcome variable was OS, and the patients were grouped by the primary predictor variable of CNM status for comparison. Other heterogeneous variables of interest included demographics, medical histories, clinicopathologic characteristics, surgical data, and adjuvant treatment modalities. In addition, the midline involvement and anatomic subsites of local recurrences were evaluated. Univariate log-rank and Cox regression tests were used for statistical analyses. RESULTS: The study sample included 177 subjects with a mean age of 55.4 years, and 44.6% were males. The median OS was 18 months. Within the entire cohort, the incidence of CNM was 23.7% (n = 42), with an inclination (n = 30) for contralateral level I or II. Factors associated with improved survival included CNM (hazard ratio [HR], 2.108; 95% confidence interval [95% CI], 1.341 to 3.315; P = .001), disease-free interval (HR, 0.601; 95% CI, 0.387 to 0.934; P = .023), and local recurrence subsite score (HR, 3.276; 95% CI, 0.924 to 11.623; P = .001). CONCLUSIONS: Patients with both recurrent TSCCs and CNMs had a dismal prognosis (OS rate, 16.2%) compared with those without CNMs (OS rate, 52.7%). SS for TSCC patients with collateral failures should be used cautiously because of the very unfavorable outcomes.

Comparison of wall removal type versus wall retaining type of decompression for treating large mandibular odontogenic cysts.

OBJECTIVE: To evaluate the differences between two types of decompression for treating large mandibular odontogenic cysts. MATERIALS AND METHODS: This retrospective, cohort study included patients who were diagnosed for large mandibular odontogenic cysts from January 2015 to April 2018 and underwent two different types of decompression based on removal or retention of the cyst wall. The primary outcome was the percentage of the residual cyst area within 1 year after surgery. We used the propensity score matching (PSM) to balance the covariates of the two groups, and the primary outcome was analyzed by the non-inferiority test. RESULTS: A total of 93 cases were included in our study. After 1 year, the wall removal group was non-inferior to the wall retaining group in terms of cyst area, cyst volume, and the difference between the HU values of the original cyst region and the normal mandible. In subgroup analysis, we found there were no differences between two groups in the percentage of patients in whom the cystic area was reduced by 90% after 1 year. CONCLUSION: Our findings suggest that the wall removal group showed better results than the cyst wall retaining group in large mandibular odontogenic cysts.

Regional metastasis to anatomies beyond traditional neck dissection boundaries: a multi-institutional analysis focused on unconventional metastases in oral cancer patients.

BACKGROUND: Regional metastasis sometimes occurs in anatomies that are not included in traditional neck dissections. The purpose of this study was to evaluate the treatment outcomes of squamous cell carcinoma of oral cavity (SCCOC) patients with unconventional metastatic lymph nodes (UMLNs) in sublingual, buccinator, and parotid anatomies. METHODS: This retrospective multi-institutional analysis of squamous cell carcinoma of oral cavity patients with unconventional metastatic lymph nodes was performed from January 2008 to December 2015. All the included patients received surgical treatment for unconventional metastatic lymph nodes. The end point of the study was to determine the factors influencing these patients' survival and the corresponding solutions to improve survival. Pathological grade, contralateral metastasis, extranodal extension, and other factors were collected and analyzed by logistic regression and the Cox model. RESULTS: A total of 89 patients were identified. Among these patients, 25 (28.1%) received primary treatment, 28 (31.5%) received staged (therapeutic) neck dissections, and 36 (40.4%) had recurrent or residual diseases. Altogether, 45 patients (51%) had buccinator node metastases, 31 (35%) had sublingual metastases, 12 (14%) had parotid metastases, and 1 had both buccinator and parotid metastases. Regarding regional metastases, 31 patients (34.8%) had isolated unconventional metastatic lymph nodes. Adjuvant therapies were administered to 72 (80.9%) patients, 25 (28.1%) of whom were treated with radio-chemotherapies. The overall survival rate was 38.2%. Multivariate analysis found that the subsites of unconventional metastatic lymph nodes (P = 0.029), extranodal extension in both unconventional metastatic lymph nodes (P = 0.025) and cervical lymph nodes (P = 0.015), sites of primary or recurrent squamous cell carcinoma of oral cavity (P = 0.035), and types of neck dissections (P = 0.025) were significantly associated with overall survival. CONCLUSIONS: Unconventional metastatic lymph nodes are uncommon, yet awareness of potential unconventional metastatic lymph nodes should be heightened. Early surgical interventions are warranted in patients with sublingual or buccinator metastases, while caution should be given to those with parotid metastases. Aggressive en bloc (in-continuity) resections may be mandatory in advanced oral cancer cases for close anatomic locations with possible buccal or sublingual metastases.

Is There a Role for Craniofacial Surgery in the Treatment of Extensive or Recurrent Head and Neck Tumors Involving the Cranial Base?

PURPOSE: Extensive or recurrent head and neck tumors involving the cranial base are extremely difficult to treat from a surgical perspective. The purposes of this study were to estimate and identify factors associated with overall survival after traditional craniofacial resection in these cases and to discuss the specific indications and treatment outcomes. MATERIALS AND METHODS: From January 2005 to December 2014, a retrospective cohort study was performed with the analysis of patients diagnosed with extensive or recurrent head and neck tumors extending to the skull base. The clinical records were reviewed for predictor variables regarding demographic characteristics, prior treatment status, pathologic characteristics, tumor sites and sizes, skull base bone or brain parenchyma invasion, reconstructive approaches, surgical margins, and adjuvant therapies. The outcome variable was overall survival. Overall survival was estimated by Kaplan-Meier methods, and risk factors were identified by use of Cox modeling. RESULTS: The cohort was composed of 119 patients with a mean age of 44.53 years; there were 67 male patients (56.30%). Through-and-through resection of the skull base bones (dural exposure) was performed in 100 patients (84.03%). The overall complication rate for the entire group was 42.86%, and the perioperative mortality rate was 2.52% (n = 3). The mean follow-up period reached 43.88 months. Of the patients without perioperative death (n = 116), 39 had local recurrences. After multivariate analysis, surgical margins (P = .001), pathologic classification (P = .016), and extent of skull base involvement (P = .001) were found to be independent factors affecting overall survival. CONCLUSIONS: Craniofacial surgery for extensive or recurrent skull base lesions is feasible in well-selected patients.

Primary Ectopic Meningioma of the Tongue: Case Report and Review of the Literature.

Primary ectopic (extracranial) meningiomas (PEMs) are very rare and have been reported only sporadically. Histologically speaking, PEMs are similar to their intracranial counterparts in being composed of neoplastic arachnoidal (meningothelial) cells. In addition, several types of microscopic cellular morphologies have been observed in intracranial meningiomas: meningothelial (syncytial), psammomatous, atypical, anaplastic, fibrous, and angioblastic. To the best of the authors' knowledge, PEM presenting as a mass in the tongue has not been reported previously. This report describes a case of lingual PEM in a 17-year-old boy. Special attention is given to the unique clinical presentation and management. The literature was reviewed to provide valuable knowledge to clinicians.

Surgical Management of Giant Cell Tumors in Temporomandibular Joint Region Involving Lateral Skull Base: A Multidisciplinary Approach.

PURPOSE: Giant cell tumors (GCTs) in the temporomandibular joint (TMJ) region invading the lateral skull base are relatively uncommon. The management of these lesions is still controversial because of their proximity to vital neurovascular structures. Although sporadically reported, the clinical outcomes of such disease after surgery are still largely unknown. MATERIALS AND METHODS: We retrospectively reviewed the records of 28 patients with resectable GCTs in the TMJ region involving the lateral skull base treated from 1994 to 2013. A multidisciplinary team, formed by oral and maxillofacial surgeons, neurosurgeons, and otorhinolaryngologists, had surgically treated all these patients by craniomaxillofacial resection. Clinical variables, different treatment modalities, and outcomes are compared. Representative cases also are presented. RESULTS: Our case series consisted of 15 male and 13 female patients with a median age of 41 years. The median follow-up duration for our series was 5.4 years (range, 0.8-18.5 years). The average tumor size measured 8.6 cm. Most of the GCTs (n = 19, 67.9%) extended through the skull base bones into the brain parenchyma and other surrounding soft tissues. Titanium meshes for cranioplasty of skull base bones was used in 9 patients (32.1%), whereas temporalis fascia (n = 5, 17.9%) or free flaps (n = 6, 21.4%) were used more frequently for duraplasty. A postoperative cerebrospinal fluid leak was found in only 1 patient. During follow-up, the local control rate reached 85.7%. Thoroughness of tumor resection (hazard ratio, 15.763; 95% confidence interval, 1.630-152.437; P = .017) was found to be associated with recurrence-free survival. CONCLUSIONS: Craniomaxillofacial surgery for GCTs in the TMJ region invading the skull base is feasible in selected patients. A meticulous plan via a multidisciplinary approach is mandatory for the success of such treatment.

Clinical application of the dorsalis pedis free flap for reconstruction of oral cancer defects.

PURPOSE: The purposes of this study were to evaluate the clinical application and efficacy of the dorsalis pedis fasciocutaneous flap in the reconstruction of oral cavity defects and to assess the associated donor-site morbidity. PATIENTS AND METHODS: From September 2009 to December 2012, 7 patients with associated oral cavity defects resulting from tumor resection underwent reconstruction with a dorsalis pedis fasciocutaneous flap. Surgical anatomy and harvesting procedure of the dorsalis pedis flap are described. Special consideration was given to the associated donor-site morbidity. RESULTS: All flaps survived without any complications. All 7 flaps were based on the dorsalis pedis artery and the greater saphenous vein for perfusion and drainage respectively. In all 7 cases, the donor site was closed with a full-thickness skin graft, with no associated healing complications or functional deficit of the foot. The resulting scar was well hidden in the lower extremity. CONCLUSIONS: The dorsalis pedis fasciocutaneous flap is a thin and pliable flap sharing many similarities with the radial forearm flap, thus making it ideal for intraoral reconstruction. Proper intraoperative and postoperative care of the donor site can result in minimal morbidity, as shown in this study. This flap may provide an ideal alternative to the radial forearm free flap, with the added advantages of a well-hidden scar and a high level of patient satisfaction.

Superficial Circumflex Iliac Artery Perforator Flap: A Promising Candidate for Large Soft Tissue Reconstruction of Retromolar and Lateral Buccal Defects After Oncologic Surgery.

PURPOSE: Surgical reconstruction of extensive retromolar and lateral buccal defects after oncologic resection remains a major challenge because early and aggressive invasion by retromolar malignancies generally entails wider resection of several local anatomic structures to attain tumor-free margins. The superficial circumflex iliac artery perforator (SCIP) flap, which is a promising candidate with multiple advantages, provides a better choice of quality and esthetics for such reconstruction. PATIENTS AND METHODS: Three patients (median age, 44.7 yr; age range, 23 to 63 yr) diagnosed with retromolar or lateral buccal squamous cell carcinoma (or mucoepidermoid carcinoma) underwent ablative surgery and simultaneous SCIP flap reconstruction. Preoperative computed tomographic angiographic (CTA) and color ultrasonographic images were used for confirmation and positioning of the SCIPs. Volumes of defects and corresponding SCIP flaps were recorded and analyzed. In addition, pre- and postoperative functions of speech, swallowing, and mouth opening and donor-site morbidity were compared. RESULTS: The SCIP flaps were raised according to information gathered from CTA and sonographic imaging. The median pedicle length reached 8.2 cm and the flap sizes ranged from 5 × 6 to 6.0 × 8.0 cm. All flaps survived uneventfully during the perioperative period and subsequent follow-up showed no recurrence. Compatible donor-recipient volume, easy harvesting, acceptable postoperative functions, and inconspicuous donor-site scars were regarded as the main advantages of the SCIP flaps. CONCLUSION: For defects after resection of retromolar and lateral buccal tumors, the SCIP flap might play an innovative and supplementary role to traditional soft tissue reconstruction approaches.

Kanglexin counters vascular smooth muscle cell dedifferentiation and associated arteriosclerosis through inhibiting PDGFR.

BACKGROUND: Dysregulation of vascular smooth muscle cell (VSMC) function leads to a variety of diseases such as atherosclerosis and hyperplasia after injury. However, antiproliferative drug targeting VSMC exhibits poor specificity. Therefore, there is an urgent to develop highly specific antiproliferative drugs to prevention and treatment VSMC dedifferentiation associated arteriosclerosis. Kanglexin (KLX), a new anthraquinone compound designed by our team, has potential to regulate VSMC phenotype according to the physicochemical properties. PURPOSE: This project aims to evaluate the therapeutic role of KLX in VSMC dedifferentiation and atherosclerosis, neointimal formation and illustrates the underlying molecular mechanism. METHODS: In vivo, the ApoE-/- mice were fed with high-fat diet (HFD) for a duration of 13 weeks to establish the atherosclerotic model. And rat carotid artery injury model was performed to establish the neointimal formation model. In vitro, PDGF-BB was used to induce VSMC dedifferentiation. RESULTS: We found that KLX ameliorated the atherosclerotic progression including atherosclerotic lesion formation, lipid deposition and collagen deposition in aorta and aortic sinus in atherosclerotic mouse model. In addition, The administration of KLX effectively ameliorated neointimal formation in the carotid artery following balloon injury in SD rats. The findings derived from molecular docking and surface plasmon resonance (SPR) experiments unequivocally demonstrate that KLX had potential to bind PDGFR-ß. Mechanism research work proved that KLX prevented VSMC proliferation, migration and dedifferentiation via activating the PDGFR-ß-MEK -ERK-ELK-1/KLF4 signaling pathway. CONCLUSION: Collectively, we demonstrated that KLX effectively attenuated the progression of atherosclerosis in ApoE-/- mice and carotid arterial neointimal formation in SD rats by inhibiting VSMC phenotypic conversion via PDGFR-ß-MEK-ERK-ELK-1/KLF4 signaling. KLX exhibits promising potential as a viable therapeutic agent for the treatment of VSMC phenotype conversion associated arteriosclerosis.

Profunda Artery Perforator Flaps From the Posteromedial Region of the Thigh for Head and Neck Reconstruction.

OBJECTIVE: Profunda femoris artery perforator flaps (PAPFs) have not been widely used in head and neck reconstructions. The feasibility and outcomes of PAPFs for various head and neck reconstructions need to be investigated. STUDY DESIGN: Retrospective analysis. SETTING: A single-institution review. METHODS: PAPFs were utilized in head and neck reconstructions from 2019 to 2021. Local anatomy, surgical technique, and complications were discussed. Chimeric PAPF applications with muscle components were described for coverage of extensive multiunit defects. Additionally, aesthetic and functional outcomes were compared with anterolateral thigh perforator flaps. RESULTS: A total of 33 cases were included. The average age was 54.2 years (range, 30-74). The most common underlying pathology was oral squamous cell carcinoma (n = 26, 78.8%), while the mean ± SD body mass index was 25.4 ± 2.8 kg/m2 . Middle perforators (n = 14, 42.4%) were the most commonly utilized ones. The perforator-based chimeric/composite applications were used in 9 (27.3%), with the muscular components consisting of gracilis (n = 3, 9.1%), adductor magnus (n = 5, 15.2%), or semimembranosus muscles (n = 1, 3.0%). Venous thromboses of the PAPFs were found in 2 (6.1%), though salvaged. The occurrence of postoperative 90-day morbidity (complication) was related to mandibulectomy/maxillectomy (P = .020). Postoperative validated questionnaires showed a trend of intermediate to high scores, indicating noninferior outcomes in several categories, when compared with the anterolateral thigh perforator flap counterparts. CONCLUSION: PAPFs are a good reconstructive alternative for intermediate to large head and neck reconstructions. Besides, PAPFs can provide sufficient tissue volume and versatility of potentially incorporating adjacent muscle components.

A novel small molecule AdipoR2 agonist ameliorates experimental hepatic steatosis in hamsters and mice.

Adiponectin receptor 2 (AdipoR2) can be activated by its endogenous ligand adiponectin to reduce hepatic steatosis, and is regarded as a therapeutic target for metabolic associated fatty liver disease (MAFLD). This study proposes a novel anthraquinone compound, emodin succinate monoethyl ester (ESME), which activates AdipoR2, inhibits hepatic lipogenesis, promotes fatty acid oxidation, and alleviates experimental hepatic steatosis in hamsters and mice. Molecular docking shows that ESME has strong binding potential with AdipoR2 by forming a arene-arene interaction. AdipoR2 on the cytomembrane of HepG2 cells can be labeled by fluorescent ESME (Cy5-ESME). ESME activates AdipoR2, AMPK and PPARα, and reduces lipid deposition in palmitic acid or oleic acid-induced HepG2 and L02 cells. Suppression of AdipoR2 expression or AMPK activation completely eliminates the effect of ESME on reducing lipid accumulation in hepatocytes. Oral administration of ESME reduces liver lipid production and accumulation, and alleviates hepatic steatosis in hamsters and Apoe-/- mice induced by high-fat diet. Compared with statins and emodin, ESME showed prepotent efficacy and safety in reducing hepatic steatosis and protecting hepatocytes. Furthermore, ESME activates CaMKK2 and LKB1 in liver to activate AMPK and reduce lipogenesis through stimulating AdipoR2. Taken together, ESME reduces hepatic lipid accumulation and alleviates hepatic steatosis by agonizing AdipoR2. ESME is a promising new agent for clinical treatment of MAFLD.

Surgical site infection in elderly oral cancer patients: is the evaluation of comorbid conditions helpful in the identification of high-risk ones?

PURPOSE: This study was performed to gain some knowledge on the possible relation between surgical site infection (SSI) and geriatric patients who undergo surgical treatment of oral squamous cell carcinoma and to identify the risk factors in this specific population. PATIENTS AND METHODS: A retrospective study from 2004 through 2010 at the Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine was conducted. The primary outcome variable was the presence of SSIs. Twenty-seven variables of the patients concerning general characteristics, comorbidities, disease information, and treatment options were investigated. A multivariate analysis using logistic regression was implemented to find SSI risk factors. RESULTS: The data of 376 patients (183 men, 48.7%; 193 women, 51.3%) older than 65 years with the diagnosis of oral squamous cell carcinoma were included in the present analysis. In multivariate logistic regression analysis, 6 parameters were identified for a significant and independent association with the development of SSI: body mass index (P = .0086); diabetes (P < .0001); American Society of Anesthesiologists score (P = .0127); Adult Comorbidity Evaluation-27 score (P = .0392); operation time (P = .0003); and reconstruction with pectoralis major myocutaneous flaps or free flaps (P < .0001). CONCLUSIONS: Special attention to SSIs should be given to elderly patients with oral squamous cell carcinoma. The authors advocate a preoperative evaluation of comorbidities and the selection of high-risk elderly patients for a more effective prevention of SSIs.

Mutagenic Activation of Glutathione Peroxidase-4: Approaches toward Rational Design of Allosteric Drugs.

Glutathione peroxidase 4 (GPX4) reduces lipid hydroperoxides in lipid membranes, effectively inhibiting iron-dependent cell death or ferroptosis. The upregulation of the enzyme by the mutations at residues D21 and D23 has been suggested to be associated with higher protein activity, which confers more protection against neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Therefore, it has become an attractive target for treating and preventing neurodegenerative diseases. However, identifying means of mimicking the beneficial effects of these mutations distant from the active site constitutes a formidable challenge in moving toward therapeutics. In this study, we explore using molecular dynamics simulations to computationally map the conformational and energetic landscape of the wild-type GPX4 protein and three mutant variants to identify the allosteric networks of the enzyme. We present the conformational dynamic profile providing the desired signature behavior of the enzyme. We also discuss the implications of these findings for drug design efforts.

Anteromedial thigh septocutaneous perforator flap as a first choice for head and neck reconstruction: A clinical algorithm based on perforator-pedicle relationship.

BACKGROUND: Anterolateral thigh perforator flaps (ALTPFs) have long been considered workhorse flaps for head and neck reconstructions. However, in some instances, anteromedial thigh septocutaneous perforator flaps (AMTPFs) are easier to harvest than ALTPFs. This study aimed to determine when and how the AMTPF should be considered the first choice as a reconstructive tool. METHODS: A retrospective cohort study was performed in the Department of Oral and Maxillofacial Surgery-Head & Neck Oncology, Shanghai Ninth People Hospital, from January 2014 to December 2018. Both the perforator-pedicle relationships and postoperative functional outcomes were compared. RESULTS: A total of 168 patients were included in this study, among whom 49 underwent AMTPF reconstructions. The AMTPF perforators in this study were mostly septocutaneous (n = 38, 77.5%). Notably, the AMTPF perforators mainly originated from the medial branch of the descending branches of the lateral circumflex femoral arteries (n = 44, 89.8%), while for the other 5 patients, the perforators were found to originate from the superficial femoral arteries. Additionally, the average pedicle length of the AMTPFs was 8.7 cm (range: 6.0 to 13.0 cm), which was comparable to that of the ALTPFs (8.9 cm) (p = 0.442). The postoperative complication rate and functional outcomes were comparable between the two groups. The algorithm and harvesting approaches are presented. CONCLUSIONS: The role of AMTPF should not be downplayed. After careful preoperative evaluation, we believe that AMTPF should not be considered a second choice in patients with sizable septocutaneous perforators.