In Vivo Evaluation of 68Ga-Labeled NOTA-EGFRvIII Aptamer in EGFRvIII-Positive Glioblastoma Xenografted Model.

EGFRvIII is expressed only in tumor cells and strongly in glioblastoma and is considered a promising target in cancer diagnosis and therapy. Aptamers are synthetic single-stranded oligonucleotides that bind to biochemical target molecules with high binding affinity and specificity. This study examined the potential of the 68Ga-NOTA-EGFRvIII aptamer as a nuclear imaging probe for visualizing EGFRvIII-expressing glioblastoma by positron emission tomography (PET). EGFRvIII aptamer was selected using the SELEX technology, and flow cytometry and fluorescence microscopy verified the high binding affinity to EGFRvIII positive U87MG vIII 4.12 glioma cells but not to EGFRvIII negative U87MG cells. The EGFRvIII aptamer was conjugated with a chelator (1,4,7-triazanonane-1,4,7-triyl)triacetic acid (NOTA) for 68Ga-labeling. The 68Ga-NOTA-EGFRvIII aptamer was prepared using the preconcentration-based labeling method with a high radiolabeling yield at room temperature. Ex vivo biodistribution analyses confirmed the significantly higher tumor uptake of the 68Ga-NOTA-EGFRvIII aptamer in EGFRvIII-expressing xenograft tumors than that in EGFRvIII negative tumors, confirming the specific tumor uptake of the 68Ga-NOTA-EGFRvIII aptamer in vivo. PET imaging studies revealed a high retention rate of the 68Ga-NOTA-EGFRvIII aptamer in U87MG vIII 4.12 tumors but only low uptake levels in U87-MG tumors, suggesting that the 68Ga-NOTA-EGFRvIII aptamer may be used as a PET imaging agent for EGFRvIII-expressing glioblastoma.

Antioxidant, Enzyme, and H2O2-Triggered Melanoma Targeted Mesoporous Organo-Silica Nanocomposites for Synergistic Cancer Therapy.

The multi-stimuli responsive drug delivery system has recently attracted attention in cancer treatments, since it can reduce several side effects and enhance cancer therapeutic efficacy. Herein, we present the intracellular antioxidant (glutathione, GSH), enzyme (hyaluronidase, HAase), and hydrogen peroxide (H2O2) triggered mesoporous organo-silica (MOS) nanocomposites for multi-modal treatments via chemo-, photothermal, and photodynamic cancer therapies. A MOS nanoparticle was synthesized by two-types of precursors, tetraethyl orthosilicate (TEOS) and bis[3-(triethoxysilyl)propyl] tetrasulfide (BTES), providing large-sized mesopores and disulfide bonds cleavable by GSH. Additionally, we introduced a new ß-cyclodextrin-hyaluronic acid (CDHA) gatekeeper system, enabling nanocomposites to form the specific interaction with the ferrocene (Fc) molecule, control the drug release by the HAase and H2O2 environment, as well as provide the targeting ability against the CD44-overexpressing melanoma (B16F10) cells. Indocyanine green (ICG) and doxorubicin (Dox) were loaded in the MOS-Fc-CDHA (ID@MOS-Fc-CDHA) nanocomposites, allowing for hyperthermia and cytotoxic reactive oxygen species (ROS) under an 808 nm NIR laser irradiation. Therefore, we demonstrated that the ID@MOS-Fc-CDHA nanocomposites were internalized to the B16F10 cells via the CD44 receptor-mediated endocytosis, showing the controlled drug release by GSH, HAase, and H2O2 to enhance the cancer therapeutic efficacy via the synergistic chemo-, photothermal, and photodynamic therapy effect.

Near-Infrared Light-Triggered Generation of Reactive Oxygen Species and Induction of Local Hyperthermia from Indocyanine Green Encapsulated Mesoporous Silica-Coated Graphene Oxide for Colorectal Cancer Therapy.

Near-infrared (NIR) light-mediated photothermal therapy (PTT) and photodynamic therapy (PDT) have widely been used for cancer treatment applications. However, a number of limitations (e.g., low NIR absorption capacity of photothermal agents, insufficient loading efficiency of photosensitive molecules) have hindered the widespread use of NIR-mediated cancer therapy. Therefore, we developed a mesoporous silica-coated reduced graphene oxide (rGO) nanocomposite that could provide a high encapsulation rate of indocyanine green (ICG) and enhance PTT/PDT efficiency in vitro and in vivo. The ICG-encapsulated nanocomposite not only enhances the photothermal effect but also generates a large number of tumor toxic reactive oxygen species (ROS). By conjugation of polyethylene glycol (PEG) with folic acid (FA) as a tumor targeting moiety, we confirmed that ICG-encapsulated mesoporous silica (MS)-coated rGO nanocomposite (ICG@MS-rGO-FA) exhibited high colloidal stability and intracellular uptake in folate receptor-expressing CT-26 colorectal cancer cells. Upon NIR laser irradiation, this ICG@MS-rGO-FA nanocomposite induced the apoptosis of only CT-26 cells via enhanced PTT and PDT effects without any damage to normal cells. Furthermore, the ICG@MS-rGO-FA nanocomposite revealed satisfactory tumor targeting and biocompatibility in CT-26 tumor-bearing mice, thereby enhancing the therapeutic effects of PTT and PDT in vivo. Therefore, this tumor-targeted ICG@MS-rGO-FA nanocomposite shows a great potential for phototherapy applications.

Risk of Atrial Fibrillation According to Cancer Type: A Nationwide Population-Based Study.

BACKGROUND: Patients with cancer have an increased risk of atrial fibrillation (AF). However, there is a paucity of information regarding the association between cancer type and risk of AF. OBJECTIVES: This study sought to evaluate the risk of AF according to the type of cancer. METHODS: We enrolled 816,811 patients who were diagnosed with cancer from the Korean National Health Insurance Service database between 2009 and 2016. Age- and sex-matched noncancer control subjects (1:2; n = 1,633,663) were also selected. Newly diagnosed AF was identified based on the type of cancer. RESULTS: During a median follow-up of 4.5 years, AF was newly diagnosed in 25,356 patients with cancer (6.6 per 1,000 person-years). In multivariable Fine and Gray's regression analysis, cancer was an independent risk factor for incident AF (adjusted subdistribution hazard ratio [aHR]: 1.63; 95% confidence interval [CI]: 1.61 to 1.66). Multiple myeloma showed a higher association with incident AF (aHR: 3.34; 95% CI: 2.98 to 3.75). Esophageal cancer showed the highest risk among solid cancers (aHR: 2.69; 95% CI: 2.45 to 2.95), and stomach cancer showed the lowest association with AF risk (aHR: 1.27; 95% CI 1.23 to 1.32). CONCLUSIONS: Although patients with cancer were found to have a higher risk of AF, the impact on AF development varied by cancer type.

Near-Infrared Light-Triggered Thermo-responsive Poly(N-Isopropylacrylamide)-Pyrrole Nanocomposites for Chemo-photothermal Cancer Therapy.

The combination therapy based on multifunctional nanocomposites has been considered as a promising approach to improve cancer therapeutic efficacy. Herein, we report targeted multi-functional poly(N-isopropylacrylamide) (PNIPAM)-based nanocomposites for synergistic chemo-photothermal therapy toward breast cancer cells. To increase the transition temperature, acrylic acid (AAc) was added in synthetic process of PNIPAM, showing that the intrinsic lower critical solution temperature was changed to 42 °C . To generate the photothermal effect under near-infrared (NIR) laser irradiation (808 nm), polypyrrole (ppy) nanoparticles were uniformly decorated in PNIPAM-AAc. Folic acid (FA), as a cancer targeting ligand, was successfully conjugated on the surplus carboxyl groups in PNIPAM network. The drug release of PNIPAM-ppy-FA nanocomposites was efficiently triggered in response to the temperature change by NIR laser irradiation. We also confirmed that PNIPAM-ppy-FA was internalized to MDA-MB-231 breast cancer cells by folate-receptor-mediated endocytosis and significantly enhanced cancer therapeutic efficacy with combination treatment of chemo-photothermal effects. Therefore, our work encourages further exploration of multi-functional nanocarrier agents for synergistic therapeutic approaches to different types of cancer cells.

Electro-responsive hydrogel-based microfluidic actuator platform for photothermal therapy.

Electrical stimuli play an important role in regulating the delivery of plasmonic nanomaterials with cancer targeting peptides. Here, we developed an electro-responsive hydrogel-based microfluidic actuator platform for brain tumor targeting and photothermal therapy (PTT) applications. The electro-responsive hydrogels consisted of highly conductive silver nanowires (AgNWs) and biocompatible collagen I gels. We confirmed that an electrically conductive hydrogel could be used as an effective actuator by applying an electrical signal in the microfluidic platform. Furthermore, we successfully demonstrated PTT efficacy for brain tumor cells using targetable Arg-Gly-Asp (RGD) peptide-conjugated gold nanorods (GNRs). Therefore, our electro-responsive hydrogel-based microfluidic actuator platform could be useful for electro-responsive intelligent nanomaterial delivery and PTT applications.

rGO nanomaterial-mediated cancer targeting and photothermal therapy in a microfluidic co-culture platform.

We developed the microfluidic co-culture platform to study photothermal therapy applications. We conjugated folic acid (FA) to target breast cancer cells using reduced graphene oxide (rGO)-based functional nanomaterials. To characterize the structure of rGO-based nanomaterials, we analyzed the molecular spectrum using UV-visible and Fourier-transform infrared spectroscopy (FT-IR). We demonstrated the effect of rGO-FA-based nanomaterials on photothermal therapy of breast cancer cells in the microfluidic co-culture platform. From the microfluidic co-culture platform with breast cancer cells and human umbilical vein endothelial cells (HUVECs), we observed that the viability of breast cancer cells treated with rGO-FA-based functional nanomaterials was significantly decreased after near-infrared (NIR) laser irradiation. Therefore, this microfluidic co-culture platform could be a potentially powerful tool for studying cancer cell targeting and photothermal therapy.

Principal Clinical Factors Predicting Therapeutic Outcomes After Surgical Drainage of Postoperative Cheek Cysts: Experience From a Single Center.

OBJECTIVES: Postoperative cheek cyst (POCC) is a late postoperative complication of radical maxillary sinus surgery including the Caldwell-Luc (C-L) operation. The present study aimed to evaluate the therapeutic outcomes of surgical treatment for POCC and to assess the clinical factors correlated to these outcomes. METHODS: This study included 57 patients (67 nostrils) diagnosed with POCC who underwent surgical drainage. The medical records of the patients were retrospectively reviewed for radiological findings, treatment modalities, residual symptoms, and recurrences. RESULTS: In total, 30 patients were male and 27 patients were female with a mean age of 55 years, and the patients were usually diagnosed with POCC 28.2 years after radical surgery. Endonasal endoscopic marsupialization was performed via inferior meatal antrostomy, and if possible, middle meatal antrostomy was performed at the same time. In patients with cysts that were difficult to reach using an endonasal endoscopic approach, additional open C-L approaches were performed. The median follow-up period was 19.4 months. Overall, adequate drainage and symptomatic relief were achieved in 91% (61/67) of the patients. The recurrence rate was significantly higher in patients who had anterolateral POCC. Failure to achieve symptomatic relief was correlated to a smaller cyst and the use of the open C-L approach for drainage. CONCLUSION: The location and size of the cyst as well as the use of the open surgical approach were important factors in predicting the therapeutic outcome of POCC. The time point of treatment and surgical approaches should be based on the above-mentioned findings.

Gene expression profile of human lung in a relatively early stage of COPD with emphysema.

Purpose: As only some smokers develop COPD with emphysema, we explored the molecular pathogenesis of early-stage COPD with emphysema using gene expression profiling of human lung tissues. Patients and methods: First, 110 subjects who had smoked more than ten pack-years were classified into three groups: COPD with emphysema, COPD without emphysema, and healthy smokers. COPD and emphysema were confirmed by post-bronchodilator forced expiratory volume in 1 second/forced vital capacity <0.7 and by chest computed tomography. Lung tissues obtained surgically from the 110 subjects were processed and used for RNA-Seq analysis. Results: Among the 110 subjects, 29 had COPD with emphysema, 21 had COPD without emphysema, and 60 were healthy smokers; their mean post-bronchodilator forced expiratory volume in 1 second values were 78%, 80%, and 94%, respectively. Using RNA-Seq, we evaluated 16,676 genes expressed in lung tissues. Among them, 1,226 genes in the COPD with emphysema group and 434 genes in the COPD without emphysema group were differentially expressed genes compared to the expression in healthy smokers. In the COPD with emphysema group, ACER2 and LMAN2L were markedly increased and decreased, respectively. In the COPD without emphysema group, the CHRM3 gene, previously reported to be associated with COPD, and HDAC10 were markedly increased and decreased, respectively. Conclusion: Our study identified differences in gene expression in subjects with COPD according to emphysema status using RNA-Seq transcriptome analysis. These findings may have mechanistic implications in COPD.

Evaluation of the success of obstructive sleep apnea surgery using criteria based on long-term symptoms and incident hypertension.

OBJECTIVE: To identify appropriate success criteria, based on long-term symptoms and incident hypertension, after surgery for obstructive sleep apnea (OSA). METHODS: This observational cohort study included 97 adult OSA patients (90 men) who underwent surgical treatment at our tertiary medical center. Subjective symptoms [witnessed sleep apnea and snoring, and Epworth sleepiness scale (ESS) scores] were evaluated through a telephone survey, and incident hypertension was assessed from medical records. The subjects were divided into success and failure groups according to seven different criteria, and data were analyzed to identify the criteria that could significantly differentiate the success from failure groups. RESULTS: The participants had a mean age of 48.8 ± 11.9 years and a mean preoperative body mass index of 26.5 ± 3.5 kg/m2. The mean preoperative and postoperative apnea-hypopnea index (AHI) values were 36.1/h and 19.4/h, respectively. The mean follow-up duration was 77.0 ± 31.1 months. Postoperative witnessed apnea, snoring, and the ESS scores decreased significantly compared to preoperative scores in both the success and failure groups based on most of the seven criteria. Among the seven criteria, success and failure groups based on a postoperative AHI cutoff of 15 or 20/h differed significantly in witnessed apnea, snoring, or ESS scores. Kaplan-Meier survival analysis based on incident hypertension revealed that no criterion could significantly distinguish between the two groups. CONCLUSIONS: Our results suggest that some of the success criteria analyzed may be more useful in differentiating between success and failure groups after surgery, in terms of long-term improvement of subjective OSA-related symptoms.

Early experience with a patient-specific virtual surgical simulation for rehearsal of endoscopic skull-base surgery.

BACKGROUND: With the help of contemporary computer technology it is possible to create a virtual surgical environment (VSE) for training. This article describes a patient-specific virtual rhinologic surgical simulation platform that supports rehearsal of endoscopic skull-base surgery. We also share our early experience with select cases. METHODS: A rhinologic VSE was developed, featuring a highly efficient direct 3-dimensional (3D) volume renderer with simultaneous stereoscopic feedback during surgical manipulation of the virtual anatomy, as well as high-fidelity haptic feedback. We conducted a retrospective analysis on 10 patients who underwent various forms of sinus and ventral skull-base surgery to assess the ability of the rhinologic VSE to replicate actual intraoperative findings. RESULTS: In all 10 cases, the simulation experience was realistic enough to perform dissections in a similar manner as in the actual surgery. Excellent correlation was found in terms of surgical exposure, anatomical features, and the locations of pathology. CONCLUSION: The current rhinologic VSE shows sufficient realism to allow patient-specific surgical rehearsal of the sinus and ventral skull base. Further validation studies are needed to assess the benefits of performing patient-specific rehearsal.

Anatomy of the Platysma Muscle.

The aim of this paper was to review the anatomy the platysma systematically.The term "platysma AND anatomy" was used to search PubMed and Scopus, producing 394 and 214 papers, respectively. After excluding 95 duplicate titles, 513 abstracts and 98 full papers were reviewed. Among these 98 papers, 83 were excluded and 5 were added. Ultimately, 20 papers were analyzed.The most common aging-related change of the platysma was shortening (70.7%), followed by thinning (25.2%). The platysma most commonly originated from the upper portion of thorax anterior to clavicle (67.7%), followed by the subcutaneous tissue of the subclavicular and acromial regions (22.6%) and pectoralis (9.7%). The platysma ascended upward and medially (68.5%) or ascended from the clavicle to the face (31.5%). The platysma most commonly inserted on the cheek skin (57.5%), followed by the cutaneous muscles around the mouth (18.6%), the mandibulocutaneous ligament or zygoma (18.6%), and the parotid fascia or periosteum of the mandible (5.3%). The platysma was most commonly innervated by the cervical branch of the facial nerve (38.2%) or the cervical branch and mandibular branch of the facial nerve (60.5%), followed by the cervical plexus (0.6%), the cervical motor nucleus (0.6%), and the glossopharyngeal nerve (0.1%). The most common action of the platysma was drawing the lips inferiorly (83.3%) or posteriorly (12.9%). Four papers classified the platysma into subtypes; however, these classification strategies used arbitrary standards.Further studies will be necessary to establish the thickness of the platysma and to characterize age-related changes of the platysma.

Acute fatal pericardial effusion induced by accidental ingestion of cigarette butts in a dog.

A dog was referred for collapse and tachypnea after ingesting cigarette butts. Thoracic radiography and echocardiography indicated pericardial effusion, and an electrocardiogram showed tachycardia, variable QRS complexes, and ventricular premature complexes. This is the first description of fatal pericardial effusion associated with cigarette butt ingestion in a veterinary patient.

Effusion péricardique aiguë mortelle induite par l'ingestion accidentelle de mégots de cigarette chez un chien. Un chien a été recommandé pour un collapsus et une tachypnée après l'ingestion de mégots de cigarette. Une radiographie thoracique et une échocardiographie ont indiqué une effusion péricardique et un électrocardiogramme a montré la tachycardie, des complexes QRS variables et des complexes ventriculaires prématurés. Il s'agit de la première description d'une effusion péricardique mortelle associée à l'ingestion de mégots de cigarettes chez un patient vétérinaire.(Traduit par Isabelle Vallières).

Effect of Celecoxib on Survival of Mobile Tongue Cancer.

AIM: The goal of the present study was to evaluate the effects of celecoxib on treatment outcomes of squamous cell carcinoma of the mobile tongue. PATIENTS AND METHODS: Among 158 patients who were diagnosed with mobile tongue cancer, 19 received celecoxib during the preoperative, postoperative, or post-recurrence phase. Differences in disease-specific survival (DSS) and recurrence-free survival (RFS) between patients who received celecoxib (study group) and those who did not (control group) were analyzed. RESULTS: For the entire cohort, DSS and RFS were not significantly different according to duration of celecoxib treatment (p=0.293 and 0.703, respectively). Among patients who received chemotherapy, DSS was significantly higher in the study group than in the control group (p=0.048), but RFS was not different between the two groups (p=0.117). CONCLUSION: When combined with chemotherapy, celecoxib may have a beneficial effect on the survival of patients with mobile tongue cancer.

Comparison of anterior cervical foraminotomy vs arthroplasty for unilateral cervical radiculopathy.

BACKGROUND: Preservation of segmental motion and avoidance of adjacent segment degeneration are common theoretical advantages of cervical arthroplasty and ACF. In patients with unilateral cervical radiculopathy, both procedures have shown good clinical results; but there are currently no proven comparative biomechanical results. This study was designed to compare the biomechanical effect of cervical arthroplasty and ACF and to propose optimal inclusion criteria for each surgery. METHODS: Among the patients with unilateral cervical radiculopathy, 15 patients who underwent arthroplasties using the Bryan disk (Medtronic Sofamor Danek, Memphis, TN) and 13 patients who underwent ACFs were retrospectively analyzed. A radiological assessment and comparative analysis of the biomechanical results (sagittal alignment, ROM, and disk height) between the 2 procedures were performed. RESULTS: Both procedures showed similar but contrary biomechanical results, with the exception of the disk height. Anterior cervical foraminotomy has been shown to restrict motion in the segmental and adjacent segment motion and a tendency toward restoration of lordosis. Anterior cervical foraminotomy caused a significant decrease in disk height after surgery, whereas arthroplasty caused no change in height. The restoration of disk height was achieved by arthroplasty, especially in patients with spondylotic radiculopathy. CONCLUSIONS: In unilateral cervical radiculopathy, arthroplasty and ACF provided favorable clinical and radiological outcomes. However, we should understand the different biomechanical backgrounds resulting in common advantages. To achieve the fundamental goal of the procedures, the patients' biomechanical abnormalities should be elucidated and treated by the optimal procedure.

Depressed interleukin-12 production by peripheral blood mononuclear cells after in vitro stimulation with the 30-kDa antigen in recurrent pulmonary tuberculosis patients.

Some patients develop recurrent tuberculosis (R-TB), even after successfully completing initial anti-tubercular treatment. Although R-TB may be caused by relapse or exogenous reinfection, little is known about the underlying host responses associated with R-TB. This study investigated the profile of cytokines [interferon (IFN)-gamma, interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, IL-6, and IL-10] present in peripheral blood mononuclear cells (PBMCs) of 17 R-TB patients after stimulation with the 30-kDa antigen (Ag) or purified protein derivative (PPD) Ag of Mycobacterium tuberculosis. These data were compared with data obtained from 15 patients with newly diagnosed pulmonary TB (N-TB), 22 patients with treatment failure (TF-TB), and 19 healthy tuberculin reactors (HTR). N-TB and R-TB patients were enrolled in this study within 1 month of beginning anti-tubercular chemotherapy. ELISA results showed that IFN-gamma production following stimulation with the 30-kDa Ag was significantly lower in each group of TB patients than in the HTR controls. In addition, patients with R-TB showed the most significant IL-12 depression among the subject groups after in vitro stimulation with either Ag. Furthermore, a significant decrease in TNF-alpha and IL-10 levels was observed in R-TB patients relative to N-TB patients. However, there was no statistical difference in TNF-alpha and IL-10 production between R-TB patients, TF-TB patients, and HTR controls. Our findings suggest that the underlying mechanisms of cytokine regulation might differ between N-TB and R-TB patients, and that decreased IL-12 production in response to the 30-kDa or PPD Ag might be involved in the immunopathogenesis of human R-TB.

Isolation and partial characterisation of the Triton X-100 solubilised protein antigen from Mycobacterium tuberculosis.

This report describes extraction of a new native antigen fraction from Mycobacterium tuberculosis without massive degradation of proteins by Triton X-100. The Triton X-100 solubilised protein (TSP) antigen showed a characteristic antigen profile and reproducible extraction pattern. To characterise the nature of their composition, the TSP antigen was fractionated by Triton X-114 phase partitioning. The TSP antigen contained a variety of lipids and glycoconjugates as well as diverse proteins. Most proteins were partitioned into the aqueous phase during phase fractionation, whereas non-protein molecules and lipoproteins were recovered in the detergent phase. The lymphoproliferative responses to the TSP aqueous fraction in healthy tuberculin reactors were significantly higher than those to the purified protein derivative (PPD) and unfractionated TSP. In contrast, the antibody responses to TSP aqueous fraction in tuberculosis patients showed weak reactivity. This study suggests that the TSP aqueous fraction can be used as a T-cell antigen associated with protective immunity against tuberculosis.