Feasibility and Safety of Intravenous Sotalol Loading in Adult Patients With Atrial Fibrillation (DASH-AF).

BACKGROUND: Inpatient initiation of sotalol is recommended owing to its proarrhythmic effects. OBJECTIVES: The DASH-AF (Feasibility and Safety of Intravenous Sotalol Administered as a Loading Dose to Initiate Oral Sotalol Therapy in Adult Patients With Atrial Fibrillation) trial evaluates the safety and feasibility of intravenous (IV) sotalol, achieving a steady state with maximum QTc prolongation within 6 hours instead of the traditional 5-dose inpatient oral (PO) titration. METHODS: DASH-AF is a prospective, nonrandomized, multicenter, open-label trial consisting of patients who underwent IV sotalol loading dose to initiate rapid oral therapy for atrial arrhythmias. IV dose was calculated based on the target oral dose as indicated by baseline QTc and renal function. Patients' QTc (in sinus) was measured via electrocardiography at 15-minute intervals and after IV loading completion. Patients were discharged 4 hours after first oral dose. All patients were monitored via mobile cardiac outpatient telemetry for 72 hours. The control group was composed of patients admitted for the traditional 5 PO doses. Safety outcomes were assessed in both groups. RESULTS: A total of 120 patients from 3 centers were enrolled from 2021 to 2022 in the IV loading group (compared with type of AF- and renal function-matched patients in the conventional PO loading cohort). This study demonstrated no significant change in ΔQTc in both groups, with a significantly lower number of patients requiring dose adjustment in the IV arm compared with the PO arm (4.1% vs 16.6%; P = 0.003). This led to potential cost savings of up to $3,500.68 per admission. CONCLUSIONS: The DASH-AF trial shows that rapid IV sotalol loading in atrial fibrillation/flutter patients for rhythm control is feasible and safe compared with conventional oral loading with significant cost reduction. (Feasibility and Safety of Intravenous Sotalol Administered as a Loading Dose to Initiate Oral Sotalol Therapy in Adult Patients With Atrial Fibrillation [DASH-AF]; NCT04473807).

Anti-inflammatory therapy enables robot-actuated regeneration of aged muscle.

Robot-actuated mechanical loading (ML)-based therapies ("mechanotherapies") can promote regeneration after severe skeletal muscle injury, but the effectiveness of such approaches during aging is unknown and may be influenced by age-associated decline in the healing capacity of skeletal muscle. To address this knowledge gap, this work used a noninvasive, load-controlled robotic device to impose highly defined tissue stresses to evaluate the age dependence of ML on muscle repair after injury. The response of injured muscle to robot-actuated cyclic compressive loading was found to be age sensitive, revealing not only a lack of reparative benefit of ML on injured aged muscles but also exacerbation of tissue inflammation. ML alone also disrupted the normal regenerative processes of aged muscle stem cells. However, these negative effects could be reversed by introducing anti-inflammatory therapy alongside ML application, leading to enhanced skeletal muscle regeneration even in aged mice.

Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety.

BACKGROUND: Long-term data evaluating the efficacy and safety of oral testosterone undecanoate (oral TU; JATENZO) in adult hypogonadal men provides important information for healthcare professionals who prescribe testosterone replacement therapy (TRT). AIM: To determine the efficacy and safety of long-term oral TU therapy, including its impact on total testosterone (T) levels and psychosexual functioning. METHODS: Hypogonadal men, between 18 and 75 years old, (mean age 56.2; 87.2% white) who completed a 12-month, open-label, multicenter, randomized, active-controlled trial were given the opportunity to enroll in a 12-month extension study. Among the 129 eligible TU-treated subjects, 86 chose this option, and 69 completed 24 months of uninterrupted oral TU therapy. OUTCOMES: The efficacy of oral TU was documented by measuring total serum T concentrations; sexual function was measured using the Psychosexual Daily Questionnaire (PDQ). For safety, liver function tests, cardiovascular endpoints, and prostate health were measured. RESULTS: Over 2 years, total serum T concentrations for patients treated with oral TU were in the eugonadal range (300-1,000 ng/dL [10-35 nmol/L]; mean ± SD: 617 ± 427 ng/dL [21 ± 15 nmol/L]) and increased significantly from baseline (P < .0001). For sexual function, mean score changes versus baseline for all PDQ domains at all time points were significantly improved (P < .0011 for all). For the sexual activity and sexual desire components, patient scores were consistently greater than validated thresholds for clinically meaningful change. Typical T-induced safety changes were observed, including a 3-6 mm Hg increase in systolic blood pressure (P < .05); a slight increase in hematocrit (P < .0001) that stayed <48% throughout the study; no clinically significant changes in prostate-specific antigen levels; and decreased high-density lipoprotein cholesterol (-9.8 ± 0.9 mg/dL from baseline; P < .0001). There were no clinically significant changes from baseline in liver function tests. CLINICAL IMPLICATIONS: Over 2 years of treatment, this novel oral TU formulation maintained total T concentrations in mideugonadal ranges, with improvements in sexual function and no clinically significant changes in liver function or other safety concerns previously associated with oral TRT. STRENGTHS & LIMITATIONS: These are the first long-term data to evaluate the efficacy and safety of a novel formulation of oral TU; the comparative long-term safety of oral TU would be strengthened by confirmatory studies versus other TRT formulations. CONCLUSION: Oral TU offers a safe and effective long-term treatment option for men with hypogonadism. Honig S, Gittelman M, Kaminetsky J, et al. Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety. J Sex Med 2022;19:1750-1758.

Unfolded protein response is involved in the metabolic and apoptotic regulation of oral squamous cell carcinoma.

Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) have been shown to be crucial in the pathogenesis and response to treatment in various cancers. However, such response has not been profiled in oral squamous cell carcinoma (OSCC), the most frequent form of cancer in the head and neck region. Cell lines derived from OSCC (SCC4, SCC15 and SCC25) and normal oral mucosa (OKF4, OKF6 and OKP7) were subjected to tunicamycin-induced ER stress (2.5 µg/mL for 24 h) after which the differential regulation of 84 key UPR/ER stress genes were assessed using Quantitative real-time reverse transcription polymerase chain reaction. The expression of the transcription factors SREBP1 and CREB3L3, and the activation of SREBP1, were examined using ELISA and a transcription factor assay. The expression of DDIT3 was immunohistochemically verified in OSCC tissue samples. SREBP1 and CREB3L3 were significantly up-regulated in OSCC with and without tunicamycin-induced ER stress. A significantly higher level of SREBP1 transcriptional activation was observed in OSCC. Apoptosis-associated genes (DDIT3, HTRA4 and HSPA1L) were also significantly up-regulated in OSCC upon ER stress induction. The findings demonstrated the involvement of UPR and ER stress in the pathogenesis of OSCC through the identification of apoptosis-associated genes (DDIT3, HSPA1L and HTRA4) and regulators of metabolism (SREBP1 and CREB3L3) as the key factors differentiating between normal and malignant oral keratinocytes.

Pilot study of the Korean national breast implant registry: Experiences and lessons learned.

BACKGROUND: To improve the safety and early detection of unexpected breast implant-related complications, the Korean Breast Implant Registry (K-BIR) was launched in 2020 in cooperation with the Korean Society of Plastic and Reconstructive Surgeons and the Korean Ministry of Food and Drug Safety, and a pilot study was conducted. OBJECTIVE: This article provides an overview of our pilot study and experiences of the K-BIR. METHODS: The dataset to be used in the pilot form of K-BIR was constructed by holding online surveys and meetings focusing on the global breast device registry's minimum dataset. A pilot study was implemented from April 1, 2020, to July 31, 2020, with six university teaching hospitals and four private clinics. RESULTS: During the pilot study period, 325 patients, 451 procedures, and 366 implants were entered into the K-BIR. The most common procedure registered was augmentation mammaplasty (30%) for cosmetic indications, followed by direct-to-implant breast reconstruction (27%). Smooth silicone implant was the most common type (73%) of implant used. A feedback survey after the pilot study included questions about the registration rate compared with an actual procedure, entry time, reasons for difficulty in entry, and additional data needed. CONCLUSIONS: The continuous maintenance and development of K-BIR will require an effective dataset, a strengthened legal system for an opt-out registry and personal data protection, various incentives for increasing participation rates, and an electronic platform that patients, manufacturers, and clinicians can easily access. K-BIR has the potential to provide quality assurance and outcomes for research and post-market surveillance systems for breast implants as well as methods for enhancing patient safety.

Potential application of immunotherapy for modulation of pulp inflammation: opportunities for vital pulp treatment.

Caries results in the demineralization and destruction of enamel and dentine, and as the disease progresses, irreversible pulpitis can occur. Vital pulp therapy (VPT) is directed towards pulp preservation and the prevention of the progression of inflammation. The outcomes of VPT are not always predictable, and there is often a poor correlation between clinical signs and symptoms, and the events occurring at a molecular level. The inflamed pulp expresses increased levels of cytokines, including tumour necrosis factor (TNF)-α, interleukin (IL)-1α, IL-1ß, IL-4, IL-6, IL-8, IL-17 and IL-23, which recruit and drive a complex cellular immune response. Chronic inflammation and sustained cytokine release can result in irreversible pulp damage and a decreased capacity for tissue healing. Other chronic inflammatory diseases, such as psoriasis, inflammatory bowel diseases and rheumatoid arthritis, are also characterized by an dysregulated immune response composed of relatively high cytokine levels and increased numbers of immune cells along with microbial and hard-soft tissue destructive pathologies. Whilst anti-cytokine therapies have been successfully applied in the treatment of these diseases, this approach is yet to be attempted in cases of pulp inflammation. This review therefore focuses on the similarities in the aetiology between chronic inflammatory diseases and pulpitis, and explores how anti-cytokine therapies could be applied to manage an inflamed pulp and facilitate healing. Further proof-of-concept studies and clinical trials are justified to determine the effectiveness of these treatments to enable more predictable outcomes in VPT.

Human papillomavirus and oral and oropharyngeal carcinoma: the essentials.

There is a global increase in the prevalence of human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinoma (OPSCC) in Australia and New Zealand. Risk factors for HPV-positive OPSCC are male gender, white race, age older than 40 but younger than 59 years old, having multiple lifetime sex partners, having oro-genital and oro-anal sex. High-risk HPV subtypes play a major role in the pathogenesis of OPSCC, however, they play a much lesser role in oral squamous cell carcinoma (OSCC). Among the laboratory tests used to detect oncogenic HPV infection, polymerase chain reaction is a sensitive method but does not reflect the role of HPV in oncogenesis. While widely used, p16 immunohistochemistry is both a sensitive and a specific surrogate marker for oncogenic HPV infection in OPSCC, but not in OSCC. However, it is a useful prognostic marker in OPSCC. The current gold standard to accurately detect oncogenic HPV infection is E6/E7 mRNAin situ hybridization. Because both HPV-positive and p16-positive OPSCC have better short-term prognoses there is current debate and trials on treatment de-escalation in HPV-positive OPSCC. Dental practitioners can play an important role in early diagnosis of HPV-positive OPSCC.

Relationship of Initial Pancreatic Enzyme Replacement Therapy Dose With Weight Gain in Infants With Cystic Fibrosis.

OBJECTIVE: The aim of the study is to test the hypothesis of a positive relationship between initial dose of pancreatic enzyme replacement therapy (PERT) in infants with cystic fibrosis (CF) and optimal weight gain over the first 2 years of life. METHODS: Using the CF Foundation Patient Registry, we identified 502 children born in 2010 and used multivariable models to compare as our primary analysis their 2-year changes in weight-for-age z score (WAZ) and as our secondary analysis weight-for-length percentile (W/L%) by initial PERT dose. We focused on initial dose without reference to subsequent changes in treatment to avoid confounding by indication (severity). RESULTS: Initial PERT dose demonstrated a linear relationship to change in WAZ and W/L% at age 2 years. An initial dose of >1500 lipase units/kg/largest meal resulted in a higher likelihood of attaining WAZ at 2 years at or above the birth WAZ (adjusted odds ratio [aOR] 1.87, 95% confidence interval [CI] 1.22-2.86) and at the top quartile for improvement over 2 years in WAZ (aOR 1.90, 95% CI 1.19-3.05). There was no correlation between initial PERT dose and weight at initial PERT encounter (P = 0.35). Findings were similar for W/L% and when the cohort was restricted to infants who began PERT in the first 3 months of life. CONCLUSIONS: Infants receiving higher initial PERT dose demonstrate better weight-related outcomes, as reflected by attainment of favorable changes in WAZ and W/L%, at age 2 years.

Effects of BMP-2 on the osteogenic differentiation of bone marrow stem cells in fibrous dysplasia.

OBJECTIVES: The purpose of this study was to evaluate the effects of BMP-2 on bone-grafting procedures for the treatment of fibrous dysplasia based on in vitro and in vivo experiments. SUBJECTS AND METHODS: Proliferation of stem cells was determined by colony-forming assay, CCK-8 assay and BrdU staining. OCT4 and NANOG expression was analysed by flow cytometry and immunocytochemistry. Osteogenic differentiation was assessed by measuring ALP activity, Alizarin red S staining and in vivo transplantation. Gene expression of the osteogenic markers, osteocalcin and type 1 collagen, was determined by RT-PCR. RESULTS: FD-BMSCs showed few calcium deposits and low ALP activity. Bone formation by transplanted FD-BMSCs was also suppressed relative to that of normal BMSCs. However, BMP-2 treatment enhanced osteogenic differentiation of FD-BMSCs mixed with normal BMSCs in vitro and in vivo. Overall, BMP-2 treatment promoted osteogenic differentiation of FD-BMSCs mixed with normal BMSCs. CONCLUSIONS: In patients with FD, stem cells in affected bone are influenced by the mutation, resulting in weak bone formation with the proliferation of immature osteogenic cells. Current treatment of FD involves surgical removal of excess bulk lesions, which can cause facial disfigurement. Our results suggest that BMP-2 application is a good adjunctive modality to the surgical treatment of patients with FD.

Incidence of cephalosporin-induced anaphylaxis and clinical efficacy of screening intradermal tests with cephalosporins: A large multicenter retrospective cohort study.

BACKGROUND: Few studies have investigated the incidence of anaphylaxis induced by individual or structurally similar cephalosporins. The aims of the study were to assess the incidence of cephalosporin-induced anaphylaxis and evaluate the clinical efficacy of screening skin tests. METHODS: In this retrospective cohort study, we obtained information on total cephalosporin use and cephalosporin-induced anaphylaxis in intravenous cephalosporin recipients in 12 general hospitals between 2013 and 2015. Cephalosporins were divided into 4 groups according to similar side-chain structures. The incidence of cephalosporin-induced anaphylaxis was assessed for each cephalosporin, cephalosporin generation, and side-chain group. To verify the efficacy of screening intradermal tests (IDT) with cephalosporin, the 12 hospitals were assigned to the intervention or control group depending on whether they performed screening IDT before the administration of cephalosporins. RESULTS: We identified 76 cases of cephalosporin-induced anaphylaxis with 1 123 345 exposures to intravenous cephalosporins (6.8 per 100 000 exposures), and the incidence of fatal anaphylaxis by cephalosporin was 0.1 cases per 100 000 exposures. The highest incidences of anaphylaxis occurred in the ceftizoxime (13.0 cases per 100 000 exposures) and side-chain group 1 (cefepime, cefotaxime, ceftizoxime, ceftriaxone, and cefuroxime; 9.3 per 100 000). There was no case of anaphylaxis induced by cefoxitin, cefmetazole, cefminox, and cefotiam. The clinical effectiveness of routine screening IDT was not significant (P = .06). CONCLUSIONS: The incidence of cephalosporin-induced anaphylaxis differed according to individual drugs and side-chain structure. Screening IDT showed no clinical efficacy at a population level.

Fate of mandibular canals displaced by enlarged cystic lesions: does the inferior alveolar neurovascular bundle relocate to its original position?

Our aim was to identify the positional changes of the inferior alveolar neurovascular bundle and evaluate the relocation of the displaced mandibular canal after enucleation of a cyst. Seventy patients (72 sites) who had had cysts enucleated were divided into three groups based on the degree of encroachment of the cystic lesion into the mandibular canal and whether a bone graft had been inserted after the cyst had been enucleated. The mean (range) of patients' ages was 45 (18-75) years, and there were 29 male and 41 female patients. Group A comprised cysts with encroachment on the mandibular canal that were enucleated without a bone graft; Group B consisted of cysts with no encroachment of the mandibular canal, but were enucleated without a bone graft; and Group C comprised cysts with encroachment of the mandibular canal that were enucleated with a bone graft. The displacement of the mandibular canal was identified from analysis of computed tomographic (CT) images. Changes in the position of the mandibular canal were measured on panoramic radiographs. The mandibular canal was repositioned superiorly by a mean (SD) of 2.4 (1.65)mm after enucleation of the cyst, which was significant in Group A (p<0.001), but not in Groups B and C. These results indicate that the displaced inferior alveolar neurovascular bundles that were not surrounded by bony canal tended to relocate towards a supposedly normal position, and after enucleation of the cyst the mandibular canal was remodelled in this new location. This tendency to relocate was blocked by bone grafting. Bone grafts are therefore recommended in cases where enough bony height is required for future insertion of implants.

The utility of ultrasound superb microvascular imaging for evaluation of breast tumour vascularity: comparison with colour and power Doppler imaging regarding diagnostic performance.

AIM: To investigate the utility of superb microvascular imaging (SMI) for evaluating the vascularity of breast masses in comparison with colour or power Doppler ultrasound (US) and the effect on diagnostic performance. MATERIALS AND METHODS: A total of 191 biopsy-proven masses (99 benign and 92 malignant) in 166 women with greyscale, colour Doppler, power Doppler, and SMI images were enrolled in this retrospective study. Three radiologists analysed the vascular images using a three-factor scoring system to evaluate the number, morphology, and distribution of tumour vessels. They assessed the Breast Imaging-Reporting and Data System categories for greyscale US alone and combinations of greyscale US and each type of vascular US. The Kruskal-Wallis test was performed and the area under the receiver-operating characteristic curve (AUC) measured. On SMI, vascular scores were compared between benign and malignant masses and the optimal cut-off value for the overall score was determined. RESULTS: SMI showed higher vascular scores than colour or power Doppler US and malignant masses had higher scores than benign masses (p<0.001). The diagnostic performance of the combination of greyscale US and SMI was higher than those of greyscale US alone and greyscale and colour or power Doppler US (AUC, 0.815 versus 0.774, 0.789, 0.791; p<0.001). The optimal cut-off value of the overall vascular score was 5 with a sensitivity of 82.3% and a specificity of 65.3% (AUC, 0.808). CONCLUSION: SMI is superior to colour or power Doppler US for characterising the vascularity in breast masses and improving diagnostic performance.

Upregulation of angiogenesis in oral lichen planus.

OBJECTIVES: As angiogenesis is fundamental to the pathogenesis of many chronic inflammatory disorders, this study investigated the expression of various vascular markers in oral lichen planus and non-specific oral mucosal inflammatory tissues. METHODS: Archival specimens of oral lichen planus (n = 15) and inflamed tissues (n = 13) were stained using immunohistochemistry with antibodies to CD34, vascular endothelial growth factor, vascular endothelial growth factor receptor and vasohibin. Nine representative sites at the epithelial-connective tissue junction and through the fibrous connective tissue were selected, and automated analysis techniques were used to determine the extent of positivity expressed as the percentage of positive cells. Significance was denoted when P < .05. RESULTS: The expression of pro-angiogenic factors was higher in lichen planus samples compared with inflamed controls. A higher level of CD34 was observed in the deeper parts of the connective tissue of Oral lichen planus (OLP) (P = .04), whereas VEGF and VEGFR2 expressions were higher all through the tissues (respectively, P < .02 and P < .01). The expression of the anti-angiogenic VASH1 was higher in inflamed tissue compared with lichen planus in all sites evaluated (P < .01). CONCLUSIONS: The findings indicate that angiogenic factors are differentially expressed in oral lichen planus compared with inflamed controls, with increased expression of pro-angiogenic factors and decreased anti-angiogenic expression.

Tough adhesives for diverse wet surfaces.

Adhesion to wet and dynamic surfaces, including biological tissues, is important in many fields but has proven to be extremely challenging. Existing adhesives are cytotoxic, adhere weakly to tissues, or cannot be used in wet environments. We report a bioinspired design for adhesives consisting of two layers: an adhesive surface and a dissipative matrix. The former adheres to the substrate by electrostatic interactions, covalent bonds, and physical interpenetration. The latter amplifies energy dissipation through hysteresis. The two layers synergistically lead to higher adhesion energies on wet surfaces as compared with those of existing adhesives. Adhesion occurs within minutes, independent of blood exposure and compatible with in vivo dynamic movements. This family of adhesives may be useful in many areas of application, including tissue adhesives, wound dressings, and tissue repair.

Second opinion oral pathology referrals in New Zealand.

Referral for a second opinion is an important aspect of pathology practice, which reduces the rate of diagnostic error and ensures consistency with diagnoses. The Oral Pathology Centre (OPC) is the only specialist oral diagnostic centre in New Zealand. OPC provides diagnostic services to dentists and dental specialists throughout New Zealand and acts as a referral centre for second opinions for oral pathology specimens that have been sent to anatomical pathologists. The aim of this study was to review second opinion referral cases sent to the OPC over a 15-year period and to assess the levels of concordance between the original and final diagnoses. The findings indicated that the majority of referred cases were odontogenic lesions, followed by connective tissue, epithelial and salivary lesions. The most prevalent diagnoses were ameloblastoma and keratocystic odontogenic tumour, followed by oral squamous cell carcinoma. Discordant diagnoses were recorded in 24% of cases. Diagnostic discrepancies were higher in odontogenic and salivary gland lesions, resulting in the change of diagnoses. Second opinion of oral pathology cases should be encouraged in view of the relative rarity of these lesions in general pathology laboratories and the rates of diagnostic discrepancy, particularly for odontogenic and salivary gland lesions.

Effect of decompression on cystic lesions of the mandible: 3-dimensional volumetric analysis.

Decompression is effective in reducing both the size of cystic lesions on jaws and the associated morbidity of resection. However, quantitative measurement of reduced volume after decompression among different cystic diseases has not been fully investigated. We have retrospectively investigated the difference in reduction in volume among keratocystic odontogenic tumours (n=17), unicystic ameloblastomas (n=10), and dentigerous cysts (n=10) of the posterior mandible using 3-dimensional computed tomography (CT). Various other influential factors such as age, sex, the presence of impacted teeth, and the number of drains were also recorded. There was no significant difference in the speed of shrinkage among the 3 groups, but there was a significant correlation (p<0.01) between the initial detected volume of the lesion and the absolute speed of shrinkage in each type of cyst. Initial volume was also significantly associated (p<0.01) with reduction of total volume in each type of cyst. Age may correlate negatively with the rate of reduction in dentigerous cysts, which means that the older the patient is, the less the reduction. Treatment seemed to last longer as the speed of shrinkage lessened in the keratocystic tumours and dentigerous cysts (p<0.05) as multiple regression has shown. The relative speed of shrinkage of unicystic ameloblastomas seemed to be slower when an impacted tooth was involved in the lesion (p=0.019). However, the sample size was too small to make any definite statistical statement. These results suggest that the rate of reduction of volume was related to the original size of the lesion. Despite the need for a second operation and longer duration of treatment compared with excision alone, decompression is a valuable way of reducing the size of large cystic lesions, with low morbidity and recurrence rate. There was no difference in the rate of reduction according to the underlying histopathological picture.

Cafestol overcomes ABT-737 resistance in Mcl-1-overexpressed renal carcinoma Caki cells through downregulation of Mcl-1 expression and upregulation of Bim expression.

Although ABT-737, a small-molecule Bcl-2/Bcl-xL inhibitor, has recently emerged as a novel cancer therapeutic agent, ABT-737-induced apoptosis is often blocked in several types of cancer cells with elevated expression of Mcl-1. Cafestol, one of the major compounds in coffee beans, has been reported to have anti-carcinogenic activity and tumor cell growth-inhibitory activity, and we examined whether cafestol could overcome resistance against ABT-737 in Mcl-1-overexpressed human renal carcinoma Caki cells. ABT-737 alone had no effect on apoptosis, but cafestol markedly enhanced ABT-737-mediated apoptosis in Mcl-1-overexpressed Caki cells, human glioma U251MG cells, and human breast carcinoma MDA-MB231 cells. By contrast, co-treatment with ABT-737 and cafestol did not induce apoptosis in normal human skin fibroblast. Furthermore, combined treatment with cafestol and ABT-737 markedly reduced tumor growth compared with either drug alone in xenograft models. We found that cafestol inhibited Mcl-1 protein expression, which is important for ABT-737 resistance, through promotion of protein degradation. Moreover, cafestol increased Bim expression, and siRNA-mediated suppression of Bim expression reduced the apoptosis induced by cafestol plus ABT-737. Taken together, cafestol may be effectively used to enhance ABT-737 sensitivity in cancer therapy via downregulation of Mcl-1 expression and upregulation of Bim expression.

Antipsychotic agent thioridazine sensitizes renal carcinoma Caki cells to TRAIL-induced apoptosis through reactive oxygen species-mediated inhibition of Akt signaling and downregulation of Mcl-1 and c-FLIP(L).

Thioridazine has been known as an antipsychotic agent, but it also has anticancer activity. However, the effect of thioridazine on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitization has not yet been studied. Here, we investigated the ability of thioridazine to sensitize TRAIL-mediated apoptosis. Combined treatment with thioridazine and TRAIL markedly induced apoptosis in various human carcinoma cells, including renal carcinoma (Caki, ACHN, and A498), breast carcinoma (MDA-MB231), and glioma (U251MG) cells, but not in normal mouse kidney cells (TMCK-1) and human normal mesangial cells. We found that thioridazine downregulated c-FLIP(L) and Mcl-1 expression at the post-translational level via an increase in proteasome activity. The overexpression of c-FLIP(L) and Mcl-1 overcame thioridazine plus TRAIL-induced apoptosis. We further observed that thioridazine inhibited the Akt signaling pathway. In contrast, although other phosphatidylinositol-3-kinase/Akt inhibitors (LY294002 and wortmannin) sensitized TRAIL-mediated apoptosis, c-FLIP(L) and Mcl-1 expressions were not altered. Furthermore, thioridazine increased the production of reactive oxygen species (ROS) in Caki cells, and ROS scavengers (N-acetylcysteine, glutathione ethyl ester, and trolox) inhibited thioridazine plus TRAIL-induced apoptosis, as well as Akt inhibition and the downregulation of c-FLIP(L) and Mcl-1. Collectively, our study demonstrates that thioridazine enhances TRAIL-mediated apoptosis via the ROS-mediated inhibition of Akt signaling and the downregulation of c-FLIP(L) and Mcl-1 at the post-translational level.

Prospective RCT comparing two hydrocolloid dressings in acute trauma wounds in South Korea.

OBJECTIVE: To compare the efficacy of two hydrocolloid dressings (Medifoam H; Genewel Co. Ltd. and DuoDERM; ConvaTec Inc.) for the management of lacerations, abrasions, and minor operation incisions. METHOD: Patients with lacerations, abrasions, and minor operation incisions were randomly allocated to receive either Medifoam H or DuoDERM. Data collected included wound assessment (amount of exudate, wound infection, rate of wound closure, and the percentage of necrotic, sloughy, fibrous,granulation, and epithelial tissue present in the wound bed) and patient evaluation of itching, burning,leakage of exudate, pain and discomfort incurred from dressing and dressing change. RESULTS: In total, 66 patients were included in the study. No significant difference in wound assessment or in patient evaluation was detected between two groups. CONCLUSION: The data collected from this study gave no evidence for any difference in efficacy between Medifoam H and DuoDERM for minor, acute trauma wound management.