The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

mTOR Signaling in Growth, Metabolism, and Disease

Importance Although cognitive behavioral therapy (CBT) represents the criterion standard for treatment of binge eating disorder (BED), most individuals do not have access to this specialized treatment. Objective To evaluate the efficacy of internet-based guided self-help (GSH-I) compared with traditional, individual face-to-face CBT. Design, Setting, and Participants The Internet and Binge Eating Disorder (INTERBED) study is a prospective, multicenter, randomized, noninferiority clinical trial (treatment duration, 4 months; follow-ups, 6 months and 1.5 years). A volunteer sample of 178 adult outpatients with full or subsyndromal BED were recruited from 7 university-based outpatient clinics from August 1, 2010, through December 31, 2011; final follow-up assessment was in April 2014. Data analysis was performed from November 30, 2014, to May 27, 2015. Interventions Participants received 20 individual face-to-face CBT sessions of 50 minutes each or sequentially completed 11 internet modules and had weekly email contacts. Main Outcomes and Measures The primary outcome was the difference in the number of days with objective binge eating episodes (OBEs) during the previous 28 days between baseline and end of treatment. Secondary outcomes included OBEs at follow-ups, eating disorder and general psychopathologic findings, body mass index, and quality of life. Results A total of 586 patients were screened, 178 were randomized, and 169 had at least one postbaseline assessment and constituted the modified intention-to-treat analysis group (mean [SD] age, 43.2 [12.3] years; 148 [87.6%] female); the 1.5-year follow-up was available in 116 patients. The confirmatory analysis using the per-protocol sample (n = 153) failed to show noninferiority of GSH-I (adjusted effect, 1.47; 95% CI, −0.01 to 2.91; P  = .05). Using the modified intention-to-treat sample, GSH-I was inferior to CBT in reducing OBE days at the end of treatment (adjusted effect, 1.63; 95% CI, 0.17-3.05; P  = .03). Exploratory longitudinal analyses also showed the superiority of CBT over GSH-I by the 6-month (adjusted effect, 0.36; 95% CI, 0.23-0.55; P P  = .70). Reductions in eating disorder psychopathologic findings were significantly higher in the CBT group than in the GSH-I group at 6-month follow-up (adjusted effect, −0.4; 95% CI, −0.68 to −0.13; P  = .005). No group differences were found for body mass index, general psychopathologic findings, and quality of life. Conclusions and Relevance Face-to-face CBT leads to quicker and greater reductions in the number of OBE days, abstinence rates, and eating disorder psychopathologic findings and may be a better initial treatment option than GSH-I. Internet-based guided self-help remains a viable, slower-acting, low-threshold treatment alternative compared with CBT for adults with BED. Trial Registration isrctn.org Identifier:ISRCTN40484777and germanctr.de Identifier:DRKS00000409

/pdf/effect-of-internet-based-guided-self-help-vs-individual-face-33p7lpkycv.pdf

Effect of Internet-Based Guided Self-help vs Individual Face-to-Face Treatment on Full or Subsyndromal Binge Eating Disorder in Overweight or Obese Patients: The INTERBED Randomized Clinical Trial

Importance Biomarkers that reflect prognosis and cellular immunity in patients with head and neck squamous cell carcinoma (HNSCC) are a prerequisite for improving individualized treatment that limits the intensity and morbidity of conventional treatment and may be useful in the introduction of new immunotherapy regimens. Objective To determine if specific classes of tumor-infiltrating lymphocytes (TILs) in pretreatment biopsy specimens have prognostic value for outcomes in a large training and validation cohort of patients with HNSCC. Design, Setting, and Participants In this prospective, epidemiologic study with a median follow-up of 47.5 months, in 464 previously untreated patients with available tissue for construction of tissue microarray, HNSCC disease sites included oral cavity (228), oropharynx (147), larynx (74), and hypopharynx (15). The training cohort consisted of 241 patients and the validation cohort consisted of 223 patients. Overall tumor stage was I (55), II (69), III (71), or IV (269). Patients were enrolled between November 2008 to October 2014. Data were analyzed between October 2018 to April 2019. Main Outcomes and Measures Semiquantitative levels of CD4, CD8, and FoxP3 lymphocytes were assessed by immunohistologic analysis and correlations with clinical prognostic factors, initial treatment modality, and overall survival (OS) and disease-specific (DSS) survival were determined. A principal component analysis was performed to generate a combined TIL-weighted sum score (TILws). Results Of the 464 participants, 135 (29%) were women; mean (SD) age was 61.1 (11.8) years. Higher CD8 counts were associated with improved OS in both training and validation sets (HR, 0.94; 95% CI, 0.90-0.98; and HR, 0.97; 95% CI, 0.95-0.99, respectively). Higher TILwslevels were associated with improved OS and DSS in both the training set (HR, 0.91; 95% CI, 0.86-0.96; and HR, 0.93; 95% CI, 0.87-0.99, respectively) and validation set (HR, 0.96; 95% CI, 0.93-0.99; and HR, 0.94; 95% CI, 0.89-0.99, respectively). A multivariable Cox model controlling for batch, age, clinical stage, disease site, comorbidities, HPV status, and smoking, showed that higher TILwslevels were associated with improved OS and DSS (HR, 0.94; 95% CI, 0.92-0.97; and HR, 0.94; 95% CI, 0.90-0.98, respectively). When grouped by treatment (surgery vs chemoradiation) and tested for interaction, treatment was found to be an effect modifier for CD4 levels and OS. Low CD4 levels were showed greater association with decreased survival in the chemoradiation cohort than the surgery cohort. Conclusions and Relevance The findings from this large cohort study suggest that levels of TILs are an independent prognostic factor in patients with HNSCC. Subsets of TILs and combined TIL scores may be clinically useful predictive and prognostic factors.

/pdf/prognostic-value-of-tumor-infiltrating-lymphocytes-in-head-jq7gxewl5m.pdf

Prognostic Value of Tumor-Infiltrating Lymphocytes in Head and Neck Squamous Cell Carcinoma.

Third molar surgery is the most common ambulatory procedure done by oral and maxillofacial surgeons. Surgical approaches for the removal of third molars have been published since the 20th century. This article reviews the history and development of extraction techniques through a literature review. The literature was selected through a search of an electronic database. Key words for the Medline search were "mandibular/maxillary third molar," "impacted mandibular/maxillary third molar," "mandibular/maxillary third molar flap design," and "mandibular/maxillary third molar incision." The search was restricted to English-language articles. Additionally, a manual search in the major oral surgery journals and books was performed. The aim of this article is to examine the evolution of third molar surgery, recognize pioneering techniques, and compare these techniques to current approaches. Common approaches employed today are discussed and treatment philosophies with thoughts for future therapies are provided.

Third molar surgery: Past, present, and the future.

Purpose of reviewThe objective of this review article is to discuss the current role of surgery as the primary treatment modality in patients with head and neck squamous cell carcinoma (HNSCC).Recent findingsHNSCC represents one of the cancer locations where the primary treatment modality is the mos

Current role of primary surgical treatment in patients with head and neck squamous cell carcinoma.

Objectives The purpose of the retrospective study was to compare the differences of quality of life (QOL) outcomes 2 or more years postoperatively between the free radial forearm flap (FRFF) and anterolateral thigh flap (ALTF) in reconstruction of defects of a hemiglossectomy. Methods Ninety patients who had a lapse ≥2 years since the reconstructive flap surgery were evaluated by the University of Washington quality of life scale (UW-QOL), and Performance Status Scale for Head and Neck (PSS-HN). Results Patients in the FRFF group reported statistically and clinically significantly better scores in the recreation, swallowing, chewing and speech domains of the UW-QOL compared with those in the ALTF group (P  Conclusions FRFF had the advantage of oral functions, such as chewing, speech and swallowing, over the ALTF for reconstruction of defect of half of the tongue. These results may provide useful information for surgeons to select a suitable free flap for tongue reconstruction.

Free radial forearm flap and anterolateral thigh flap for reconstruction of hemiglossectomy defects: A comparison of quality of life.

Background Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis that has not significantly improved in the past several decades. A prognostic-related signature was needed. Methods The Cancer Genome Atlas and GSE41613 databases were downloaded as a training and validation set, respectively. We identified 12 genes that demonstrated progression and prognostic value, and then, a gene signature was constructed. Results This classification could reflect distinct characteristics, phenotypically and molecularly, among HNSCC tumors. It could stratify patients with significantly different survival rates (median survival: 2083 days vs 927 days; P = 3.85E-08) in the training cohort and validation cohort (P = 0.007) and was significantly involved in immune/inflammatory response and tumor progression processes. Conclusions This bioinformatics-based signature suggested the presence of two distinct populations of patients with HNSCC with distinguishable phenotypic characteristics and clinical outcomes and might provide insight for new types of immune therapy.

A gene signature associated with prognosis and immune processes in head and neck squamous cell carcinoma

OBJECTIVE To investigate the clinical value of occlusal guide plate combined with intermaxillary fixation screw in mandibular defect repair with free fibular flap. METHODS Between August and December 2011, 7 patients with mandibular tumor were treated, including 5 cases of ameloblastoma and 2 cases of gingival cancer. Of 7 patients, 4 were males and 3 were females, aged 32-65 years (median, 50 years). Occlusal guide plate was prepared and the implanted position of intermaxillary fixation screws was determined preoperatively. Hemimandibulectomy was performed in 5 cases, half mandibular segmental resection with condyle reservation in the other 2 cases. The free fibular flaps of 11-13 cm in length were harvested for repairing mandibular defects. When the free fibular flaps were fixed, the occlusal guide plate and intermaxillary fixation screws were utilized to restorate the occlusal relation. The donor site was sutured directly. RESULTS The average operation time was 9.5 hours (range, 7-12 hours). All free fibular flaps survived completely. All incisions at the donor site and recipient site healed by first intention. All patients were followed up 10-14 months with an average of 12.3 months. All patients had symmetrical face, good occlusal relation, normal mouth opening, and normal mandibular lateral movement, and no pain of bilateral temporomandibular joints occurred. Panoramic tomography showed good mandibular contour and the suitable emplacement of fibular flaps postoperatively. No tumor recurrence occurred during follow-up period. CONCLUSION When repairing the mandibular defect with free fibular flap, occlusal guide plate with intermaxillary fixation screw contributes to simplifying operation, accurate recovery of the appearance and occlusal relation, and improving the oral comfort level postoperatively.

Application of occlusal guide plate combined with intermaxillary fixation screw in mandibular defect repair with free fibular flap

The present study investigated and evaluated the efficacy and safety of platelet-rich fibrin (PRF) in patients during bilateral mandibular third molars extraction by systematic review and meta-analysis. The PubMed, Embase, and Cochrane library databases were retrieved, and the effect of PRF on the healing process of the alveolar socket after surgical extraction of the mandibular third molars was evaluated by meta-analysis. The postoperative pain, swelling, trismus, osteoblastic activity, and soft tissue healing were assessed, and the incidence of alveolar osteitis, weighted mean difference (WMD)/standard mean difference (SMD), the risk ratio (RR), and the 95% confidence interval (CI) were calculated. The current results showed that the local application of PRF during lower third molar extraction prevented postoperative complications. Subsequently, the pain (SMD = − 0.53, 95% CI: − 1.02–-0.05, Pheterogeneity = 0.001, I2 = 75.7%) and swelling (WMD = − 0.55, 95% CI: − 1.08–-0.01, Pheterogeneity = 0.573, I2 = 0) were relieved and the incidence of alveolar osteitis was reduced (RR = 0.35, 95% CI: 0.16–0.75, Pheterogeneity = 0.597, I2 = 0%). However, no significant difference was observed in trismus, osteoblastic activity, and soft tissue healing between the PRF and non-PRF groups. The current study confirms that PRF only reduces some of the postoperative complications but does not prevent all the postoperative complications. PRF significantly relieved the pain and swelling and reduced the incidence of alveolar osteitis after the extraction of an impacted lower third molar.

/pdf/impact-of-platelet-rich-fibrin-on-mandibular-third-molar-3nhagnnqcg.pdf

Impact of platelet-rich fibrin on mandibular third molar surgery recovery: a systematic review and meta-analysis.

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Papers

Free radial forearm flap and anterolateral thigh flap for reconstruction of hemiglossectomy defects: A comparison of quality of life.

A gene signature associated with prognosis and immune processes in head and neck squamous cell carcinoma

Application of occlusal guide plate combined with intermaxillary fixation screw in mandibular defect repair with free fibular flap

Impact of platelet-rich fibrin on mandibular third molar surgery recovery: a systematic review and meta-analysis.