Global Interest in Oral and Maxillofacial Surgery: Analysis of Google Trends Data.

PURPOSE: Oral and maxillofacial surgery (OMS) has an expansive scope, with myriad diagnoses treated by practicing surgeons. Patients and referring providers are increasingly turning to Web-based sources to find information about clinical conditions before consultations or in conjunction with ongoing care. The purpose of this study was to examine the current trends of public interest of OMS procedures as assessed by online search trends. MATERIALS AND METHODS: A cross-sectional study of Internet search data obtained via Google Trends (GT; Alphabet, Mountain View, CA) was conducted. Data were collected using GT for OMS-related search terms between January 2004 and May 2019. The search terms used in the analysis were "wisdom teeth," "TMJ," "dental implants," "jaw surgery," "jaw fracture," "facial trauma," and "facial cosmetic surgery," defined to be the core surgical aspects of OMS based on public awareness campaigns sponsored by the American Association of Oral and Maxillofacial Surgeons. Relative search volumes, trends over time, geographic trends, and seasonal trends were analyzed. For all analyses, P ≤ .05 was considered significant. RESULTS: Overall search volume trends for OMS procedures showed an increase over time, with seasonal and geographic trends. "Wisdom teeth" was the most searched term and had the greatest increase in search volume over time. "Facial trauma" was the least searched term, with no appreciable trend over time. Geographic search volume was greatest in the United States. Seasonal changes were most apparent with searches for "wisdom teeth" and "jaw surgery." CONCLUSIONS: Analysis of GT data shows substantial interest in core OMS procedures, with seasonal variations noted for certain areas of practice (third molars and jaw surgery) and consistent interest in other areas (facial cosmetic surgery, dental implant reconstruction, and temporomandibular disorders). The use of GT data may be a powerful tool for predicting demand for OMS services and for public education campaigns.

Outcomes and Predictors of Revision Labiaplasty and Clitoroplasty after Gender-Affirming Genital Surgery.

BACKGROUND: Penile inversion vaginoplasty is the most common gender-affirming procedure for transfeminine patients. Patients undergoing this procedure may require revision labiaplasty and clitoroplasty. This study describes complications and outcomes from the largest reported cohort in the United States to undergo penile inversion vaginoplasty with subsequent revision labiaplasty and/or clitoroplasty. METHODS: A retrospective chart review was performed of a single surgeon's experience with penile inversion vaginoplasty with or without revision labiaplasty and/or clitoroplasty between July of 2014 and June of 2016 in a cohort of gender-diverse patients assigned male at birth. Patient demographic data, complications, and quality of life data were collected. Univariate and multivariate comparisons were completed. RESULTS: A total of 117 patients underwent penile inversion vaginoplasty. Of these, 28 patients (23.9 percent) underwent revision labiaplasty and/or clitoroplasty, with nine patients (7.7 percent) undergoing both procedures. Patients who underwent penile inversion vaginoplasty necessitating revision were significantly more likely to have granulation tissue (p = 0.006), intravaginal scarring (p < 0.001), and complete vaginal stenosis (p = 0.008). The majority of patients who underwent revision labiaplasty and/or clitoroplasty reported satisfaction with their final surgical outcome (82.4 percent) and resolution of their genital-related dysphoria (76.5 percent). CONCLUSIONS: Patients who developed minor postoperative complications following penile inversion vaginoplasty were more likely to require revision surgery to address functional and aesthetic concerns. Patients responded with high levels of satisfaction following revision procedures, with the majority of patients reporting resolution of genital-related dysphoria. Transfeminine patients who undergo penile inversion vaginoplasty should be counseled on the possibility of revisions during their postoperative course. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Expression and therapeutic implications of cyclin-dependent kinase 4 (CDK4) in osteosarcoma.

Overexpression and/or hyperactivation of cyclin-dependent kinase 4 (CDK4) has been found in many types of human cancers, and a CDK4 specific inhibitor, palbociclib, has been recently approved by the FDA for the treatment of breast cancer. However, the expression and the therapeutic potential of CDK4 in osteosarcoma remain unclear. In the present study, CDK4 was found to be highly expressed in human osteosarcoma tissues and cell lines as compared with normal human osteoblasts. Elevated CDK4 expression correlated with metastasis potential and poor prognosis in osteosarcoma patients as determined by immunohistochemical analysis in a human osteosarcoma tissue microarray (TMA). CDK4 inhibition by either palbociclib or specific small interference RNA (siRNA) exhibited dose-dependent inhibition of osteosarcoma cell proliferation and growth, accompanied by suppression of the CDK4/6-cyclinD-Rb signaling pathway. Flow cytometry analysis showed that CDK4 knockdown arrested osteosarcoma cells in the G1 phase of the cell cycle and induced cell apoptosis. Furthermore, inhibition of CDK4 significantly decreased osteosarcoma cell migration in vitro determined by the wound healing assay. These data highlight that CDK4 may be a potential promising therapeutic target in the treatment of human osteosarcoma.

CDK4 expression in chordoma: A potential therapeutic target.

Chordomas are rare bone tumors and treatment is commonly based on a combination of surgery and radiotherapy. There is no standard chemotherapy treatment for chordoma. The aim of this study was to determine the expression of cyclin-dependent kinase 4 (CDK4) in chordoma and its therapeutic implications. We evaluated CDK4 expression both in chordoma cell lines and in chordoma tissues. Also, we investigated the functional roles of CDK4 in chordoma cell growth and proliferation. Furthermore, the therapeutic implications of targeting CDK4 in chordoma were evaluated. We found CDK4 highly expressed in chordoma cell lines and in a majority (97.7%) of chordoma tissues. Higher CDK4 expression correlated with metastasis and recurrence of chordoma. Treatment of chordoma cells using CDK4 inhibitor palbociclib could efficiently inhibit chordoma cells growth and proliferation. These data demonstrate that targeting CDK4 may be useful as a novel strategy in the treatment of chordoma. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1581-1589, 2018.

Noncoding RNA in drug resistant sarcoma.

Sarcomas are a group of malignant tumors that arise from mesenchymal origin. Despite significant development of multidisciplinary treatments for sarcoma, survival rates have reached a plateau. Chemotherapy has been extensively used for sarcoma treatment; however, the development of drug resistance is a major obstacle limiting the success of many anticancer agents. Sarcoma biology has traditionally focused on genomic and epigenomic deregulation of protein-coding genes to identify the therapeutic potential for reversing drug resistance. New and more creative approaches have found the involvement of noncoding RNAs, including microRNAs and long noncoding RNAs in drug resistant sarcoma. In this review, we discuss the current knowledge of noncoding RNAs characteristics and the regulated genes involved in drug resistant sarcoma, and focus on their therapeutic potential in the future.

Wnt inhibitory factor 1 (WIF1) methylation and its association with clinical prognosis in patients with chondrosarcoma.

Chondrosarcoma (CS) is a rare cancer, but it is the second most common primary malignant bone tumor and highly resistant to conventional chemotherapy and radiotherapy. Aberrant DNA methylation in the promoter CpG island of Wnt inhibitory factor 1 (WIF1) has been observed in different cancers. However, no studies have shown the relationship between WIF1 methylation and CS. In this study, we found promoter methylated WIF1 in both CS cell lines (CS-1 and SW1353) and tumor tissues. Western blot analysis confirmed loss WIF1 expression and activation of Wnt pathway proteins (Wnt5a/b, LRP6, and Dvl2). We subsequently examined the correlation between levels of WIF1 methylation and overall survival (OS) and progression-free survival (PFS) in CS patient samples with a follow-up spanning 234 months (mean: 57.6 months). Kaplan-Meier survival curves and log-rank tests revealed that high levels of WIF1 methylation were associated with lower OS and PFS rates (p < 0.05). Multivariate Cox hazard analysis suggested that detection of high level methylation of WIF1 could be an independent prognostic factor in OS and PFS. In conclusion, we found that WIF1 is epigenetically silenced via promoter DNA methylation in CS and propose that WIF1 methylation may serve as a potential prognostic marker for patients with CS.

Facial Layer-by-Layer Engineering of Upconversion Nanoparticles for Gene Delivery: Near-Infrared-Initiated Fluorescence Resonance Energy Transfer Tracking and Overcoming Drug Resistance in Ovarian Cancer.

Development of multidrug resistance (MDR) contributes to the majority of treatment failures in clinical chemotherapy. We report facial layer-by-layer engineered upconversion nanoparticles (UCNPs) for near-infrared (NIR)-initiated tracking and delivery of small interfering RNA (siRNA) to enhance chemotherapy efficacy by silencing the MDR1 gene and resensitizing resistant ovarian cancer cells to drug. Layer-by-layer engineered UCNPs were loaded with MDR1 gene-silencing siRNA (MDR1-siRNA) by electrostatic interaction. The delivery vehicle enhances MDR1-siRNA cellular uptake, protects MDR1-siRNA from nuclease degradation, and promotes endosomal escape for silencing the MDR gene. The intrinsic photon upconversion of UCNPs provides an unprecedented opportunity for monitoring intracellular attachment and release of MDR1-siRNA by NIR-initiated fluorescence resonance energy transfer occurs between donor UCNPs and acceptor fluorescence dye-labeled MDR1-siRNA. Enhanced chemotherapeutic efficacy in vitro was demonstrated by cell viability assay. The developed delivery vehicle holds great potential in delivery and imaging-guided tracking of therapeutic gene targets for effective treatment of drug-resistant cancers.

Regulation of microRNA-1 (miR-1) expression in human cancer.

MicroRNAs (miRs) have been found to play important roles in tumorigenesis, apoptosis, metastasis, and drug resistance in cancer. Among a number of miRs, miR-1 was shown to be predominantly downregulated in almost all examined human cancers. As a tumor suppressor miR involved in post-transcriptional regulation of crucial tumor associated gene expression, miR-1 represents a promising target for anticancer therapy. Re-expression of miR-1 can suppress cancer cell proliferation, promote apoptosis, and reverse drug resistance in cancers both in vitro and in vivo. Recently, the regulatory mechanisms of miR-1 expression have been studied in various cancers in different model systems. In this review, we summarize the mechanisms of miR-1 expression through epigenetic, transcriptional, and post-transcriptional regulation. These regulatory mechanisms of miR-1 expression could help us to understand the functions of altered miR-1 expression and provide valuable insights for further investigations into miR-1 based cancer therapy.

Aberrant DNA methylations in chondrosarcoma.

Chondrosarcoma (CS) is the second most common primary malignant bone tumor. Unlike other bone tumors, CS is highly resistant to conventional chemotherapy and radiotherapy, thus resulting in poor patient outcomes. There is an urgent need to establish alternative therapies for CS. However, the etiology and pathogenesis of CS still remain elusive. Recently, DNA methylation-associated epigenetic changes have been found to play a pivotal role in the initiation and development of human cancers, including CS, by regulating target gene expression in different cellular pathways. Elucidating the mechanisms of DNA methylation alteration may provide biomarkers for diagnosis and prognosis, as well as novel treatment options for CS. We have conducted a critical review to summarize the evidence regarding aberrant DNA methylation patterns as diagnostic biomarkers, predictors of progression and potential treatment strategies in CS.

Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats.

Overexpression of P-glycoprotein (Pgp) increases multidrug resistance (MDR) in cancer, which greatly impedes satisfactory clinical treatment and outcomes of cancer patients. Due to unknown pharmacokinetics, the use of Pgp inhibitors to overcome MDR in the clinical setting remains elusive despite promising in vitro results. The purpose of our current preclinical study is to investigate the pharmacokinetics and tolerability of NSC23925b, a novel and potent P-glycoprotein inhibitor, in rodents. Plasma pharmacokinetic studies of single-dose NSC23925b alone or in combination with paclitaxel or doxorubicin were conducted in male BALB/c mice and Sprague-Dawley rats. Additionally, inhibition of human cytochrome P450 (CYP450) by NSC23925b was examined in vitro. Finally, the maximum tolerated dose (MTD) of NSC23925b was determined. NSC23925b displayed favorable pharmacokinetic profiles after intraperitoneal/intravenous (I.P./I.V.) injection alone or combined with chemotherapeutic drugs. The plasma pharmacokinetic characteristics of the chemotherapy drugs were not affected when co-administered with NSC23925b. All the animals tolerated the I.P./I.V. administration of NSC23925b. Moreover, the enzymatic activity of human CYP450 was not inhibited by NSC23925b. Our results demonstrated that Pgp inhibitor NSC23925b exhibits encouraging preclinical pharmacokinetic characteristics and limited toxicity in vivo. NSC23925b has the potential to treat cancer patients with MDR in the future.

The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer.

Overexpression and/or hyperactivation of cyclin-dependent kinases (CDKs) are common features of most cancer types. CDKs have been shown to play important roles in tumor cell proliferation and growth by controlling cell cycle, transcription, and RNA splicing. CDK4/6 inhibitor palbociclib has been recently approved by the FDA for the treatment of breast cancer. CDK11 is a serine/threonine protein kinase in the CDK family and recent studies have shown that CDK11 also plays critical roles in cancer cell growth and proliferation. A variety of genetic and epigenetic events may cause universal overexpression of CDK11 in human cancers. Inhibition of CDK11 has been shown to lead to cancer cell death and apoptosis. Significant evidence has suggested that CDK11 may be a novel and promising therapeutic target for the treatment of cancers. This review will focus on the emerging roles of CDK11 in human cancers, and provide a proof-of-principle for continued efforts toward targeting CDK11 for effective cancer treatment.

Targeting EZH2-mediated methylation of H3K27 inhibits proliferation and migration of Synovial Sarcoma in vitro.

Synovial sarcoma is an aggressive soft tissue sarcoma genetically defined by the fusion oncogene SS18-SSX. It is hypothesized that either SS18-SSX disrupts SWI/SNF complex inhibition of the polycomb complex 2 (PRC2) methyltransferase Enhancer of Zeste Homologue 2 (EZH2), or that SS18-SSX is able to directly recruit PRC2 to aberrantly silence target genes. This is of potential therapeutic value as several EZH2 small molecule inhibitors are entering early phase clinical trials. In this study, we first confirmed EZH2 expression in the 76% of human synovial sarcoma samples. We subsequently investigated EZH2 as a therapeutic target in synovial sarcoma in vitro. Knockdown of EZH2 by shRNA or siRNA resulted in inhibition of cell growth and migration across a series of synovial sarcoma cell lines. The EZH2 selective small-molecule inhibitor EPZ005687 similarly suppressed cell proliferation and migration. These data support the hypothesis that targeting EZH2 may be a promising therapeutic strategy in the treatment of synovial sarcoma; clinical trials are initiating enrollment currently.

MiR-708 promotes steroid-induced osteonecrosis of femoral head, suppresses osteogenic differentiation by targeting SMAD3.

Steroid-induced osteonecrosis of femoral head (ONFH) is a serious complication of glucocorticoid (GC) use. We investigated the differential expression of miRs in the mesenchymal stem cells (MSCs) of patients with ONFH, and aimed to explain the relationship between GC use and the development of MSC dysfunction in ONFH. Cells were collected from bone marrow of patients with ONFH. Samples were assigned to either GCs Group or Control Group at 1:1 matched with control. We then used miRNA microarray analysis and real-time PCR to identify the differentially expressed miRs. We also induced normal MSCs with GCs to verify the differential expression above. Subsequently, we selected some of the miRs for further studies, including miRNA target and pathway prediction, and functional analysis. We discovered that miR-708 was upregulated in ONFH patients and GC-treated MSCs. SMAD3 was identified as a direct target gene of miR-708, and functional analysis demonstrated that miR-708 could markedly suppress osteogenic differentiation and adipogenesis differentiation of MSCs. Inhibition of miR-708 rescued the suppressive effect of GC on osteonecrosis. Therefore, we determined that GC use resulted in overexpression of miR-708 in MSCs, and thus, targeting miR-708 may serve as a novel therapeutic biomarker for the prevention and treatment of ONFH.

Evaluation of P-glycoprotein (Pgp) expression in human osteosarcoma by high-throughput tissue microarray.

Survival of osteosarcoma patients is currently limited by the development of metastases and multidrug resistance (MDR). A well-established cause of MDR involves overexpression of P-glycoprotein (Pgp) in tumor cells. However, some discrepancies still exist as to the clinical significance of Pgp in osteosarcoma. We sought to elucidate further whether the Pgp expression correlated with clinical behavior in a series of patients with osteosarcoma via high-throughput tissue microarray (TMA) analysis. Immunohistochemical analysis of Pgp expression in a TMA of 114 specimens with a retrospective review of 70 osteosarcoma patients admitted to the Massachusetts General Hospital (MGH) was performed. High Pgp expression was correlated with metastasis development and poor response to pre-operative chemotherapy in osteosarcoma patients. Eighteen of the fifty-seven patients initially admitted with primary osteosarcoma showed high Pgp expression. Among these 18 patients with high Pgp expression, 13 of 18 (72%) patients eventually developed metastases. There was no significant clinical relevance between Pgp expression and osteosarcoma survival. These results support that high expression of Pgp is important, but cannot be assigned as, an individual predictor in the development of human osteosarcoma. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1606-1612, 2016.

Development and potential applications of CRISPR-Cas9 genome editing technology in sarcoma.

Sarcomas include some of the most aggressive tumors and typically respond poorly to chemotherapy. In recent years, specific gene fusion/mutations and gene over-expression/activation have been shown to drive sarcoma pathogenesis and development. These emerging genomic alterations may provide targets for novel therapeutic strategies and have the potential to transform sarcoma patient care. The RNA-guided nuclease CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein-9 nuclease) is a convenient and versatile platform for site-specific genome editing and epigenome targeted modulation. Given that sarcoma is believed to develop as a result of genetic alterations in mesenchymal progenitor/stem cells, CRISPR-Cas9 genome editing technologies hold extensive application potentials in sarcoma models and therapies. We review the development and mechanisms of the CRISPR-Cas9 system in genome editing and introduce its application in sarcoma research and potential therapy in clinic. Additionally, we propose future directions and discuss the challenges faced with these applications, providing concise and enlightening information for readers interested in this area.

The emerging roles and therapeutic potential of microRNAs (miRs) in liposarcoma.

Liposarcoma (LPS) is a common subtype of soft tissue sarcoma and accounts for approximately 20% of adult sarcomas. Despite the progress in diagnosis and treatment of LPS, there is still a high mortality rate due to local recurrence or metastasis. The mechanisms underlying the development of recurrence and metastasis of LPS remain elusive. MicroRNAs (miRNAs or miRs) are non-coding RNAs that regulate target gene expression, influencing many cellular functions, including cell proliferation, apoptosis, differentiation, oncogenesis, and drug resistance in malignant cells. The dysregulation of miRs is involved in the initiation and progression of human cancers, including LPS. Functional studies have shown the potent pro- and anti-tumorigenic activity of specific miRs both in vitro and in vivo. miR signatures that are unique to specific types of LPS have been proposed. Several lines of evidence have shown that miRs can act either as oncogenes or tumor suppressor genes, as well as diagnostic and prognostic biomarkers for LPS. In addition, miRs may be a powerful therapeutic target in LPS, although obstacles such as delivery of miRs in vivo need to be overcome. In this review, we discuss the emerging roles of miRs in different histological subtypes of LPS.

Rhabdomyosarcoma: Advances in Molecular and Cellular Biology.

Rhabdomyosarcoma (RMS) is the most common soft tissue malignancy in childhood and adolescence. The two major histological subtypes of RMS are alveolar RMS, driven by the fusion protein PAX3-FKHR or PAX7-FKHR, and embryonic RMS, which is usually genetically heterogeneous. The prognosis of RMS has improved in the past several decades due to multidisciplinary care. However, in recent years, the treatment of patients with metastatic or refractory RMS has reached a plateau. Thus, to improve the survival rate of RMS patients and their overall well-being, further understanding of the molecular and cellular biology of RMS and identification of novel therapeutic targets are imperative. In this review, we describe the most recent discoveries in the molecular and cellular biology of RMS, including alterations in oncogenic pathways, miRNA (miR), in vivo models, stem cells, and important signal transduction cascades implicated in the development and progression of RMS. Furthermore, we discuss novel potential targeted therapies that may improve the current treatment of RMS.

CD44 is a direct target of miR-199a-3p and contributes to aggressive progression in osteosarcoma.

Osteosarcoma is the most common primary bone malignancy in children and adolescents. Herein, we investigated the role of cluster of differentiation 44 (CD44), a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion, and migration in osteosarcoma. We constructed a human osteosarcoma tissue microarray with 114 patient tumor specimens, including tumor tissues from primary, metastatic, and recurrent stages, and determined the expression of CD44 by immunohistochemistry. Results showed that CD44 was overexpressed in metastatic and recurrent osteosarcoma as compared with primary tumors. Higher expression of CD44 was found in both patients with shorter survival and patients who exhibited unfavorable response to chemotherapy before surgical resection. Additionally, the 3'-untranslated region of CD44 mRNA was the direct target of microRNA-199a-3p (miR-199a-3p). Overexpression of miR-199a-3p significantly inhibited CD44 expression in osteosarcoma cells. miR-199a-3p is one of the most dramatically decreased miRs in osteosarcoma cells and tumor tissues as compared with normal osteoblast cells. Transfection of miR-199a-3p significantly increased the drug sensitivity through down-regulation of CD44 in osteosarcoma cells. Taken together, these results suggest that the CD44-miR-199a-3p axis plays an important role in the development of metastasis, recurrence, and drug resistance of osteosarcoma. Developing strategies to target CD44 may improve the clinical outcome of osteosarcoma.