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Due to a unique cortical venous drainage pattern without sinus drainage, ethmoidal dural arteriovenous fistula (DAVF) are uncommon cerebral vascular lesions that carry a high risk of brain bleeding and neurologic deficit. Surgical intervention has been found to have a lower complication rate and a more satisfactory obliteration rate than endovascular treatment among the various DAVF treatment options. The supraorbital keyhole subfrontal approach is one of the least invasive and appropriate surgical techniques for addressing the anterior fossa vascular lesion in eDAVFs. We describe two men, ages 60 and 71, who underwent this surgical intervention to treat asymptomatic Cognard type IV eDAVFs. Complete obliteration with a detached fistulous point and skeletonization was accomplished with the aid of intraoperative neuronavigation. Thus, we suggest that a suitable surgical method for the treatment of eDAVFs would be to use a supraorbital keyhole subfrontal approach. [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) and functional fitness (FF) are crucial for promoting independent living and healthy aging in older adults. However, there is a lack of normative values for the Senior Fitness Test (SFT) among older adults (aged 55–90) living in southern rural Taiwan, particularly in the Chiayi region, which has been relatively underserved in terms of health-related resources compared to northern Taiwan. Purpose: This study aimed to determine the age- and gender-specific normative fitness scores for a large representative population of community-dwelling older adults in southern rural Taiwan. Methods: A cross-sectional descriptive study was conducted to obtain normative FF scores for 3332 community-dwelling elderly people (1057 men and 2275 women) in Chiayi, through the implementation of functional fitness tests across 72 Chiayi communities. The developed normative data served as a reference for exercise prescription for the elderly in southern Taiwan. Results: The study showed that the average normative values of all functional fitness tests declined significantly with increasing age (p < 0.05). Sex differences were also found in all measures of FF tests, with elderly women scoring significantly better than men on flexibility (scratch back: −1.34 ± 9.03 vs. −6.54 ± 11.07; chair sit and reach: 6.56 ± 9.44 vs. 0.56 ± 10.40) (p < 0.05), while men scored significantly higher than women on strength (grip strength: 30.83 ± 8.06 vs. 21.82 ± 5.32; bicep curl: 19.25 ± 5.44 vs. 17.64 ± 4.98) (p < 0.05). Furthermore, four FF normative scores in southern rural Taiwan were found to be significantly higher than their counterparts living in northern Taiwan. Conclusion: These findings contribute positively to the evaluation of fitness levels among older adults in southern rural Taiwan and provide a concrete reference for developing sound PA programs for this population. The results suggest that strategies aimed at promoting increased participation in PA among older adults need to consider age-, sex-, and region-specific factors. [ABSTRACT FROM AUTHOR]

Oral infection is a common clinical symptom. While antibiotics are widely employed as the primary treatment for oral diseases, the emergence of drug-resistant bacteria has necessitated the exploration of alternative therapeutic approaches. One such modality is antimicrobial photodynamic therapy (aPDT), which utilizes light and photosensitizers. Indeed, aPDT has been used alone or in combination with other treatment options dealing with periodontal disease for the elimination of biofilms from bacterial community to achieve bone formation and/or tissue regeneration. In this review article, in addition to factors affecting the efficacy of aPDT, various photosensitizers, the latest technology and perspectives on aPDT are discussed in detail. More importantly, the article emphasizes the novel design and clinical applications of photosensitizers, as well as the synergistic effects of chemical and biomolecules with aPDT to achieve the complete eradication of biofilms and even enhance the biological performance of tissues surrounding the treated oral area. [ABSTRACT FROM AUTHOR]

Pediatric traumatic brain injury is a cause of major mortality, and resultant neurological sequelae areassociated with long-term morbidity. Increasing studies have revealed stem cell therapy to be a potential new treatment. However, much work is still required to clarify the mechanism of action of effective stem cell therapy, type of stem cell therapy, optimal timing of therapy initiation, combination of cocurrent medical treatment and patient selection criteria. This paper will focus on stem cell therapy in children with traumatic brain injury. [ABSTRACT FROM AUTHOR]

P2Y12 inhibitor monotherapy is a feasible alternative treatment for patients after percutaneous coronary intervention (PCI) in the modern era. Clinical trials have shown that it could lower the risk of bleeding complications without increased ischemic events as compared to standard dual antiplatelet therapy (DAPT). However, the efficacy and safety of this novel approach among patients with acute coronary syndrome (ACS) are controversial because they have a much higher risk for recurrent ischemic events. The purpose of this study is to evaluate the efficacy and safety of this novel approach among patients with ACS. We conducted a meta-analysis of randomized controlled trials that compared P2Y12 inhibitor monotherapy with 12-month DAPT in ACS patients who underwent PCI with stent implantation. PubMed, Embase, the Cochrane library database, ClinicalTrials.gov, and other three websites were searched for data from the earliest report to July 2022. The primary efficacy outcome was major adverse cardiovascular and cerebrovascular events (MACCE), a composite of all-cause mortality, myocardial infarction, stent thrombosis, or stroke. The primary safety outcome was major or minor bleeding events. The secondary endpoint was net adverse clinical events (NACE), defined as a composite of major bleeding and adverse cardiac and cerebrovascular events. Five randomized controlled trials with a total of 21,034 patients were included in our meta-analysis. The quantitative analysis showed a significant reduction in major or minor bleeding events in patients treated with P2Y12 inhibitor monotherapy as compared with standard DAPT(OR: 0.59, 95% CI: 0.46–0.75, p < 0.0001) without increasing the risk of MACCE (OR: 0.98, 95% CI: 0.86–1.13, p = 0.82). The NACE was favorable in the patients treated with P2Y12 inhibitor monotherapy (OR: 0.82, 95% CI: 0.73–0.93, p = 0.002). Of note, the overall clinical benefit of P2Y12 inhibitor monotherapy was quite different between ticagrelor and clopidogrel. The incidence of NACE was significantly lower in ticagrelor monotherapy as compared with DAPT (OR: 0.79, 95% CI: 0.68–0.91), but not in clopidogrel monotherapy (OR: 1.14, 95% CI: 0.79–1.63). Both clopidogrel and ticagrelor monotherapy showed a similar reduction in bleeding complications (OR: 0.46, 95% CI: 0.22–0.94; OR: 0.60, 95% CI: 0.44–0.83, respectively). Although statistically insignificant, the incidence of MACCE was numerically higher in clopidogrel monotherapy as compared with standard DAPT (OR: 1.50, 95% CI: 0.99–2.28, p = 0.06). Based on these findings, P2Y12 inhibitor monotherapy with ticagrelor would be a better choice of medical treatment for ACS patients after PCI with stent implantation in the current era. [ABSTRACT FROM AUTHOR]

Background: Oncogenic KRAS mutations are prevalent in human cancers, but effective treatment of KRAS-mutant malignancies remains a major challenge in the clinic. Increasing evidence suggests that aberrant metabolism plays a central role in KRAS-driven oncogenic transformation. The aim of this study is to identify selective metabolic dependency induced by mutant KRAS and to exploit it for the treatment of the disease. Method: We performed an integrated analysis of RNAi- and CRISPR-based functional genomic datasets (n = 5) to identify novel genes selectively required for KRAS-mutant cancer. We further screened a customized library of chemical inhibitors for candidates that are synthetic lethal with NOP56 depletion. Functional studies were carried out by genetic knockdown using siRNAs and shRNAs, knockout using CRISPR/Cas9, and/or pharmacological inhibition, followed by cell viability and apoptotic assays. Protein expression was determined by Western blot. Metabolic ROS was measured by flow cytometry-based quantification. Results: We demonstrated that nucleolar protein 5A (NOP56), a core component of small nucleolar ribonucleoprotein complexes (snoRNPs) with an essential role in ribosome biogenesis, confers a metabolic dependency by regulating ROS homeostasis in KRAS-mutant lung cancer cells and that NOP56 depletion causes synthetic lethal susceptibility to inhibition of mTOR. Mechanistically, cancer cells with reduced NOP56 are subjected to higher levels of ROS and rely on mTOR signaling to balance oxidative stress and survive. We also discovered that IRE1α-mediated unfolded protein response (UPR) regulates this process by activating mTOR through p38 MAPK. Consequently, co-targeting of NOP56 and mTOR profoundly enhances KRAS-mutant tumor cell death in vitro and in vivo. Conclusions: Our findings reveal a previously unrecognized mechanism in which NOP56 and mTOR cooperate to play a homeostatic role in the response to oxidative stress and suggest a new rationale for the treatment of KRAS-mutant cancers. [ABSTRACT FROM AUTHOR]

Background: Cerebral vasospasm still results in high morbidity and mortality rates in patients after aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to establish a protocol for the management of vasospasm and demonstrate our experience of angioplasty using the Scepter XC balloon catheter.Methods: In this retrospective study, a computed tomography angiography and perfusion image was arranged if early symptoms occurred or on the 7th day following aneurysmal SAH. In patients with clear consciousness, balloon angioplasties were performed for symptomatic vasospasms, which were not improved within 6-12 h after maximal medical treatments. In unconscious patients, balloon angioplasties were performed for all patients with angiographic vasospasms.Results: Fifty patients underwent Scepter XC balloon angioplasty among 396 consecutive patients who accepted endovascular or surgical treatments for ruptured aneurysms. All angioplasty procedures were successful without complications. 100% angiographic improvement and 94% clinical improvement were reached immediately after the angioplasties. A favorable functional outcome (modified Rankin Score of ≤2) could be achieved in 82% of patients. Even in patients with poor clinical grading (Hunt-Hess grade 4-5), a clinical improvement rate of 87.5% and favorable outcome rate was 70.8% could be achieved.Conclusion: Balloon angioplasty with Scepter XC balloon catheter is safe and effective for post-SAH vasospasm. This device's extra-compliant characteristics could considerably improve the quality of angioplasty procedures. For all patients, even those with poor neurological status, early treatment with combined protocol of nimodipine and angioplasty can have good clinical outcomes. [ABSTRACT FROM AUTHOR]

Daily urine protein (UP) loss is a cumbersome but important measurement to guide diagnosis and treatment of renal disease. Spot urine protein-creatinine ratio (UPCR) can been applied to estimate daily proteinuria. However, the correlations between spot and 24h proteinuria remain controversial. In this cross-sectional study, simultaneous collection of 24h and spot urines were performed from 1,039 (derivation cohort) and 204 CKD patients (validation cohort) of Chang Gung Memorial Hospital, from 2007 to 2017. The correlations between spot UPCR and 24h proteinuria were compared. The mean age of patients of derivation and validation cohort was 63 and 55 years and the mean estimated glomerular filtration rate was 62 ± 35 and 59 ± 36 mL/min/m2, respectively. The correlation coefficient was 0.819 between UPCR and 24hUP. Prediction equation was derived as: Log1024hUP (g) = 0.814 x Log10UPCR (mg/mg) + 0.110 x Gender– 0.004 x Age + 0.004 x Body weight (kg) + 0.002 x CKD stage coefficient– 0.018, where CKD stage coefficient: CKD stage G1 = 1, G2 = 2, G3a = 3.1, G3b = 3.2, G4 = 4, G5 = 5. Correlation coefficient between measured and predicted 24hUP among derivation group and validation group is 0.866 and 0.915, respectively. However, the agreement of spot and daily estimates was less pronounced with proteinuria > 3g than lower values in Bland-Altman analysis. Spot UPCR can accurately predict 24hUP in patients with daily proteinuria below 3g. The development of this equation may facilitate estimation of 24hUP in the clinical practice. [ABSTRACT FROM AUTHOR]

The globo-series glycosphingolipids (GSLs) SSEA3, SSEA4, and Globo-H specifically expressed on cancer cells are found to correlate with tumor progression and metastasis, but the functional roles of these GSLs and the key enzyme β1,3-galactosyltransferase V (β3GalT5) that converts Gb4 to SSEA3 remain largely unclear. Here we show that the expression of β3GalT5 significantly correlates with tumor progression and poor survival in patients, and the globo-series GSLs in breast cancer cells form a complex in membrane lipid raft with caveolin-1 (CAV1) and focal adhesion kinase (FAK) which then interact with AKT and receptor-interacting protein kinase (RIP), respectively. Knockdown of β3GalT5 disrupts the complex and induces apoptosis through dissociation of RIP from the complex to interact with the Fas death domain (FADD) and trigger the Fas-dependent pathway. This finding provides a link between SSEA3/SSEA4/Globo-H and the FAK/CAV1/AKT/RIP complex in tumor progression and apoptosis and suggests a direction for the treatment of breast cancer, as demonstrated by the combined use of antibodies against Globo-H and SSEA4. [ABSTRACT FROM AUTHOR]

Introduction: Cardiac implantable electronic devices (CIEDs) can measure atrial fibrillation (AF) early; however, the timing for administering antiarrhythmic drugs (AADs) to suppress AF remains unclear. This study aimed to investigate the association between baseline values and changes after AAD in terms of relative reduction of AF burden (RRAB) and maximum AF duration (RRMD). Methods: This multicenter retrospective study screened all patients with nonpermanent AF who had dual‐chamber pacemakers and only enrolled those receiving a naive AAD between September 2009 and December 2014. AF burden and maximum duration were calculated using CIED at 0 and 3 to 6 months after starting rhythm control. All the enrolled patients were divided into four groups according to baseline AF burden. RRAB and RRMD were monitored using CIEDs. Results: Overall, 145 eligible subjects received a naive AAD for nonpermanent AF. The mean RRAB in the four groups (AF burden <1%, 1%‐4%, 4%‐18%, and ≥18%) were −65.3%, −46.4%, −34.7%, and −27.9% (P = 0.005), respectively. Mean RRMD were −26.8%, −12.4%, 4.2%, and 6.0%, respectively (P = 0.006). Multivariate analysis revealed that the lowest baseline AF burden (<1%) was significantly associated with greater RRAB, which was not observed in the RRMD model. Conclusions: Lower baseline AF burden was associated with greater RRAB by AADs. Our finding suggests that rhythm control should be started in the early stage to achieve better responses to AADs. [ABSTRACT FROM AUTHOR]

Background. Encapsulating peritoneal sclerosis (EPS) is a rare but serious clinical complication of long-term peritoneal dialysis (PD) patients with high mortality. The purpose of this study was to assess the clinical characteristics of patients with EPS and to search for possible factors useful for EPS prevention and early diagnosis. Method. This retrospective study was performed in a single dialysis center in Taiwan between August 1990 and April 2014. Overall, a total of 565 patients were included and the medical records of those patients who had developed EPS (EPS group) and those who had not developed EPS (control group) were collected. We compared several factors between these two groups. Result. In the univariate analysis, EPS was significantly associated with a change of transport state (Delta 2) (p = 0.007), duration of PD (p < 0.001), duration of peritonitis treatment (p = 0.001), number of peritonitis episodes (p = 0.002), and fungus related peritonitis (p = 0.031). After multivariate logistic model analysis, we found that only the duration of PD was independently significantly associated with EPS (p = 0.034). In addition, we used the ROC curve and found that a duration of peritoneal dialysis of about 8.4 years is the best cut-off point to predict EPS occurrence. Conclusion. In this study, long-termed PD duration is the only strong independent risk factor for EPS development. Total peritonitis times, total peritonitis treatment duration, and marked increased peritoneal D/Pcr ratio were also significantly associated with the duration of PD. [ABSTRACT FROM AUTHOR]

Highlights • Recurrent erythema multiforme major (EMM), mostly triggered by herpes infection, can be a clinical challenge. • A vicious circle of recurrence may be developed due to herpes reactivation and prolonged use of systemic corticosteroids. • Add-on treatment of recurrent EMM by levamisole showed effectively reducing the frequency and severity of recurrent EMM. • As an immunomodulator, levamisole potentially achieved a long term remission of recurrent EMM. Abstract Background Erythema multiforme major (EMM) is an immune-mediated mucocutaneous eruption mostly triggered by herpes simplex virus (HSV) infection. A vicious circle of recurrence may be developed due to HSV reactivation and prolonged use of systemic corticosteroids to control EMM. Levamisole is an immunomodulator and has been applied to prevent relapses of recurrent HSV infection. Objective To evaluate the clinical efficacy and safety of levamisole in patients with recalcitrant recurrent EMM. Methods We enrolled 23 patients with recurrent EMM treated with levamisole and 24 controls, and analyzed the demographics, treatments and outcomes. Results Patients with recurrent EMM for years (mean 3.99 ± 2.71) showed significantly reduced recurrences after various durations of levamisole treatment (recurrences after and before treatment: 3.98 ± 1.04 vs 6.75 ± 1.45 times per year, p = 1.33x10−8). The recurrences of EMM also significantly reduced after levamisole treatment comparing to that of patients without levamisole treatment (p = 3.77x10−9). No patient was reported to have severe side effects during or after levamisole treatment. Conclusions Levamisole was effective in reducing recurrences of recalcitrant recurrent EMM and can thus be considered an alternative or add-on therapy for this disorder. [ABSTRACT FROM AUTHOR]

Abstract: Aim: A sustained proportion of advanced hepatocellular carcinoma (HCC) patients worldwide received either chemotherapy or sorafenib. However, to date, effective and convenient biomarkers to predict their therapeutic outcomes remained elusive. Hypothyroidism was associated with favorable anticancer treatment outcomes in several advanced cancers. Here, we aimed to investigate the potential of using thyroid‐stimulating hormone (TSH) and free T4 (FT4) levels as biomarkers to predict clinical outcomes in HCC patients receiving chemotherapy or sorafenib. Methods: Total 123 advanced HCC patients at Barcelona Clinical Liver Cancer Stage C were included. They were separated into two cohorts, one treated by sorafenib (n = 62) and the other by chemotherapy (n = 61). Clinical data including TSH and FT4 were retrieved and correlated with treatment outcomes. Results: Because of restriction in local insurance policy, the baseline liver function reserve was better in patients receiving sorafenib. Therefore, the two cohorts were analyzed separately. The results showed that a higher (> median) TSH × FT4 value was independently associated with favorable time‐to‐tumor progression (P = 0.006) and overall survival (P = 0.002) if chemotherapy was provided; whereas it was associated with unfavorable time‐to‐tumor progression (P = 0.017) and overall survival (P = 0.001) if sorafenib was administrated. These opposite associations remained valid when patients with Child–Pugh class A liver function from either cohort were included for analysis. Conclusion: A novel thyroid function index, TSH × FT4, significantly predicted opposite clinical outcomes in advanced HCC patients receiving sorafenib or chemotherapy treatment. [ABSTRACT FROM AUTHOR]

Background The bedside fiber bronchoscope has been widely used in the diagnosis and treatment of respiratory disease. This study aims to assess the effect of using bedside fiber bronchoscope in sputum suction and alveolar lavage for treatment of stroke-associated pneumonia (SAP), compared with the use of conventional suction catheter. Methods One hundred and six patients with SAP were randomly divided into control group (n = 53) and experimental group (n = 53) for a controlled study. Patients in the two groups were conventionally treated with phlegm-resolving and anti-infective therapy. The conventional suction catheter was used for sputum suction for patients in the control group, while bedside fiber bronchoscope was used for sputum suction and alveolar lavage in the experimental group. Clinical pulmonary infection score (CPIS) of the two groups was carried out. The heart rate, blood gas, levels of inflammatory factors in serum, and CPIS were contrastively analyzed between the two groups. Results The blood gas (including pH, PaCO2, PaO2) levels of inflammatory factors in serum such as C-reactive protein, procalcitonin, interleukin-6 and tumor necrosis factor, and CPIS (including the third day and seventh day) in the experimental group (n = 53) were all superior to those of the control group (n = 53) (p < 0.05). The results suggested that the pulmonary ventilation condition and inflammatory response of patients with SAP were significantly improved with the use of bedside fiber bronchoscope. Conclusion The use of bedside fiber bronchoscope is beneficial in modifying the pulmonary ventilation and relieving systemic inflammatory response of patients with SAP, exhibiting a great value in clinical application. [ABSTRACT FROM AUTHOR]

With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morbidity and sequela. As a treatment guideline for this devastating condition is still unavailable, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we outline distinct types of SCARs caused by targeted anticancer therapies and immunotherapies. Also, we discuss the clinical course, latency, concomitant medication, tolerability of rechallenge or alternatives, tumor response, and mortality associated with these devastating conditions. Imatinib, vemurafenib, and rituximab were the top three offending medications that most commonly caused SJS/TEN, while EGFR inhibitors were the group of drugs that most frequently induced SJS/TEN. For drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis, imatinib was also the most common offending drug. Additionally, we delineated 10 SCAR cases related to innovative immunotherapies, including PD1 and CTLA4 inhibitors. There was a wide range of latency periods: 5.5–91 days (median). Only eight of 16 reported patients with SCAR showed clinical responses. Targeted anticancer drugs and immunotherapies can lead to lethal SCAR (14 deceased patients were identified as suffering from SJS/TEN). The mortality rate of TEN was high: up to 52.4%. The information compiled herein will serve as a solid foundation to formulate ideas for early recognition of SCAR and to discontinue offending drugs for better management. [ABSTRACT FROM AUTHOR]

Platelet-rich plasma (PRP) is prepared by centrifuging fresh blood in an anticoagulant state, and harvesting the platelet-rich portion or condensing platelets. Studies have consistently demonstrated that PRP concentrates are an abundant source of growth factors, such as platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), and epithelial growth factor (EGF). The complex mechanisms underlying spinal cord injury (SCI) diminish intrinsic repair and neuronal regeneration. Several studies have suggested that growth factor-promoted axonal regeneration can occur for an extended period after injury. More importantly, the delivery of exogenous growth factors contained in PRP, such as EGF, IGF-1, and TGF-β, has neurotrophic effects on central nervous system (CNS) injuries and neurodegenerative diseases. However, only a few studies have investigated the effects of PRP on CNS injuries or neurodegenerative diseases. According to our review of relevant literature, no study has investigated the effect of intrathecal (i.t.) PRP injection into the injured spinal cord and activation of intrinsic mechanisms. In the present study, we directly injected i.t. PRP into rat spinal cords and examined the effects of PRP on normal and injured spinal cords. In rats with normal spinal cords, PRP induced microglia and astrocyte activation and PDGF-B and ICAM-1 expression. In rats with SCIs, i.t. PRP enhanced the locomotor recovery and spared white matter, promoted angiogenesis and neuronal regeneration, and modulated blood vessel size. Furthermore, a sustained treatment (a bolus of PRP followed by a 1/3 dose of initial PRP concentration) exerted more favorable therapeutic effects than a single dose of PRP. Our findings suggest by i.t. PRP stimulate angiogenesis, enhancing neuronal regeneration after SCI in rats. Although PRP induces minor inflammation in normal and injured spinal cords, it has many advantages. It is an autologous, biocompatible, nontoxic material that does not result in a major immune response. In addition, based on its safety and ease of preparation, we hypothesize that PRP is a promising therapeutic agent for SCI. [ABSTRACT FROM AUTHOR]

The dopamine receptor D3 (DRD3) gene, one of the candidate genes for amphetamine dependence (AD), is involved in the mesolimbic dopaminergic system, implicated as the underlying mechanism of addiction. Our case-control study aimed to investigate whether the DRD3 gene is associated with the susceptibility to AD and specific personality traits in AD patients. A total of 1060 unrelated Han Chinese subjects (559 AD patients and 501 controls) were screened using the same assessment tool and genotyped for eight DRD3 polymorphisms. All patients met the DSM-IV-TR criteria for AD, and personality traits of 539 were assessed using a Tridimensional Personality Questionnaire. Furthermore, AD individuals were divided into four clinical subgroups based on gender and psychosis status, to reduce the clinical heterogeneity. We found that the ATA haplotype combination for SNPs rs324029, rs6280, and rs9825563, respectively, was significantly associated with total AD patients (p = 0.0003 after 10,000 permutations). Similar results were observed in the both male and non-psychosis subgroup but not in other subgroups. In addition, DRD3 rs9825563 may influence onset age of drug use, partially mediated by novelty seeking in the non-psychosis AD group. In conclusion, DRD3 is a potential genetic factor in the susceptibility to AD and is associated with onset age of drug use through interaction with novelty seeking in a specific patient group in the Han Chinese population. [ABSTRACT FROM AUTHOR]

High Mobility Group Box 1 (HMGB1) is a multifunctional protein that plays various roles in the processes of inflammation, cancer, and other diseases. Many reports document abundant HMGB1 release following infection with oncolytic viruses (OVs). Further, other groups including previous reports from our laboratory highlight the synergistic effects of OVs with chemotherapy drugs. Here, we show that virus-free supernatants have varying cytotoxic potential, and HMGB1 is actively secreted by two established fibroblast cell lines (NIH 3T3 and 3T6-Swiss albino) following HSV1716 infection in vitro. Further, pharmacologic inhibition or genetic knock-down of HMGB1 reveals a role for HMGB1 in viral restriction, the ability to modulate bystander cell proliferation, and drug sensitivity in 3T6 cells. These data further support the multifactorial role of HMGB1, and suggest it could be a target for modulating the efficacy of oncolytic virus therapies alone or in combination with other frontline cancer treatments. [ABSTRACT FROM AUTHOR]

Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop PEGylated phosphatidylcholine (PC)-rich nanovesicles (phosphatiosomes) carrying ciprofloxacin (CIPX) for lung targeting to eradicate extracellular and intracellular methicillin-resistant Staphylococcus aureus (MRSA). Soyaethyl morphonium ethosulfate (SME) was intercalated in the nanovesicle surface with the dual goals of achieving strengthened bactericidal activity of CIPX-loaded phosphatiosomes and delivery to the lungs. The isothermal titration calorimetry (ITC) results proved the strong association of SME phosphatiosomes with pulmonary surfactant. We demonstrated a superior anti-MRSA activity of SME phosphatiosomes compared to plain phosphatiosomes and to free CIPX. A synergistic effect of CIPX and SME nanocarriers was found in the biofilm eradication. SME phosphatiosomes were readily engulfed by the macrophages, restricting the intracellular MRSA count by 1-2 log units. SME phosphatiosomes efficiently accumulated in the lungs after intravenous injection. In a rat model of lung infection, the MRSA burden in the lungs could be decreased by 8-fold after SME nanosystem application. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most common type of primary and malignant tumor occurring in the adult central nervous system. Temozolomide (TMZ) has been considered to be one of the most effective chemotherapeutic agents to prolong the survival of patients with glioblastoma. Many glioma cells develop drug-resistance against TMZ that is mediated by increasing O-6-methylguanine-DNA methyltransferase (MGMT) levels. The expression of connexin 43 was increased in the resistant U251 subline compared with the parental U251 cells. The expression of epithelial-mesenchymal transition (EMT)-associated regulators, including vimentin, N-cadherin, and β-catenin, was reduced in the resistant U251 subline. In addition, the resistant U251 subline exhibited decreased cell migratory activity and monocyte adhesion ability compared to the parental U251 cells. Furthermore, the resistant U251 subline also expressed lower levels of vascular cell adhesion molecule (VCAM)-1 after treatment with recombinant tumor necrosis factor (TNF)-α. These findings suggest differential characteristics in the drug-resistant GBM from the parental glioma cells. [ABSTRACT FROM AUTHOR]

Background: Kawasaki disease (KD) is an acute systemic vasculitis that occurs in children and may lead to cardiovascular morbidity and mortality. Progressive coronary dilatation for at least 2 months is associated with worse late coronary outcomes in patients with KD having medium or giant aneurysms. However, the risk factors and occurrence of progressive coronary dilatation in patients with KD but without medium or giant aneurysms have been insufficiently explored.Methods: We retrospectively enrolled 169 patients with KD from a tertiary medical center in Taiwan during 2009-2013. Medical records of all patients were reviewed. Echocardiography was performed during the acute KD phase and at 3-4 weeks, 6-8 weeks, 6 months, and 12 months after KD onset. Progressive coronary dilatation was defined as the progressive enlargement of coronary arteries on three consecutive echocardiograms. Logistic regression analysis was conducted to evaluate the potential risk factors for coronary aneurysms and progressive coronary dilatation.Results: Of a total of 169 patients with KD, 31 (18.3%) had maximal coronary Z-scores of ≥ + 2.5 during the acute KD phase, 16 (9.5%; male/female: 9/7) had coronary aneurysms at 1 month after KD onset, and 5 (3.0%) satisfied the definition of progressive coronary dilatation. Multivariate logistic regression analysis revealed that an initial maximal coronary Z-score of ≥ + 2.5 [odds ratio (OR): 5.24, 95% confidence interval (CI): 1.31-21.3, P = 0.020] and hypoalbuminemia (OR: 4.83, 95% CI: 1.11-20.9, P = 0.035) were independent risk factors for coronary aneurysms and were significantly associated with progressive coronary dilatation. However, the association between intravenous immunoglobulin unresponsiveness and the development of coronary aneurysms at 1 month after KD onset didn't reach the level of significance (P = 0.058).Conclusions: In the present study, 3% (5/169) of patients with KD had progressive coronary dilatation, which was associated with persistent coronary aneurysms at 1 year after KD onset. Initial coronary dilatation and hypoalbuminemia were independently associated with the occurrence of progressive coronary dilatation. Therefore, such patients may require intensive cardiac monitoring and adjuvant therapies apart from immunoglobulin therapies. [ABSTRACT FROM AUTHOR]

Background: Combination therapy using acetylcholinesterase inhibitors (AChEIs) and cilostazol is of unknown efficacy for patients with Alzheimer's disease (AD).Methods: We explored the therapeutic responses by using a case-control study, which was conducted in Taiwan. We enrolled 30 participants with stable AD who were receiving cilostazol (50 mg) twice per day as an add-on therapy combined with AChEIs, and 30 participants as controls who were not receiving cilostazol as an add-on therapy. The therapeutic responses were measured using neuropsychological assessments and analyzed in relation to cilostazol use, apolipoprotein E genotype, and demographic characteristics. Mini-mental state examination (MMSE) and clinical dementia rating sum of boxes (CDR-SB) were administered at the outset of the study and 12 months later. Multiple logistic regression analysis was used to estimate the association between the therapeutic response and cilostazol use.Results: For the therapeutic indicator of cognition, Cilostazol use (adjusted odds ratio (aOR) = 0.17, 95% confidence interval (CI) = 0.03-0.80), initial CDR-SB score (aOR = 2.06, 95% CI = 1.31-3.72), and initial MMSE score (aOR = 1.41, 95% CI = 1.11-1.90), but not age, sex, education, or ApoE ε4 status, were significantly associated with poor therapeutic outcomes. For the therapeutic indicator of global status, no significant association was observed between the covariates and poor therapeutic outcomes.Conclusions: Cilostazol may reduce the decline of cognitive function in stable AD patients when applied as an add-on therapy. [ABSTRACT FROM AUTHOR]

Parameters from cardiopulmonary exercise test (CPET) are useful prognostic factors for patients with repaired tetralogy of fallot (TOF). Its application in exercise prescription remains unclear. This study sought to define its role. We made current exercise recommendations in repaired TOF patients according to European Society of Cardiology (ESC) guideline, which were based on ventricular function, pressure/volume load, pulmonary artery pressure, hypoxemia and arrhythmic burden both at rest and during exercise. CPET parameters (peak oxygen consumption, oxygen uptake efficiency plateau, and E/CO slope), along with cardiothoracic ratio, ventricular arrhythmia, QRS duration and NYHA functional status, were used to calculate 'score to exercise'. 112 repaired TOF adolescent and adult aged 32.6 ± 10.8 (14.05- to 56.99-year-old, median 30.1) years received exercise recommendations by ESC guideline, which suggested high, moderate and low intensity sports for 45 (40.2 %), 45 (40.2 %), and 22 (19.6 %) patients, respectively. The optimal cut-off values were 67 and 77 % for peak VO, 86 and 100 % for OUEP, 22 and 28 for E/CO slope to correlate to the exercise intensity recommendation. But, individual CPET parameter had low consistency (41-46 %) in making decisions of exercise intensity compared to ESC recommendations. Using the 'score to exercise', the consistency rate could be increased to 74.1 %. With 'score to exercise' recommended exercise intensity, follow-up result revealed no adverse event related to sports. Individual CPET parameter did not correlate well to the exercise recommendation from ESC. We proposed a scoring system, 'score to exercise', which incorporates three CPET parameters with cardiothoracic ratio, ventricular arrhythmia, QRS duration and NYHA functional status. Score to exercise is easy to be assessed and provides useful information for exercise recommendation in patients with repaired TOF. [ABSTRACT FROM AUTHOR]

Cardiogenic shock (CS) is uncommon in patients suffering from acute myocardial infarction (AMI). Long-term outcome and adverse predictors for outcomes in AMI patients with CS receiving percutaneous coronary interventions (PCI) are unclear. A total of 482 AMI patients who received PCI were collected, including 53 CS and 429 non-CS. Predictors for AMI patients with CS including recurrent MI, cardiovascular (CV) mortality, all-cause mortality, and repeated-PCI were analyzed. The CS group had a lower central systolic pressure and central diastolic pressure (both P<0.001). AMI patients with hypertension history were less prone to develop CS (P<0.001). Calcium channel blockers and statins were less frequently used by the CS group than the non-CS group (both P<0.05) after discharge. Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score, CV mortality, and all-cause mortality were higher in the CS group than the non-CS group (all P<0.005). For patients with CS, stroke history was a predictor of recurrent MI (P=0.036). CS, age, SYNTAX score, and diabetes were predictors of CV mortality (all P<0.05). CS, age, SYNTAX score, and stroke history were predictors for all-cause mortality (all P<0.05). CS, age, and current smoking were predictors for repeated-PCI (all P<0.05). [ABSTRACT FROM AUTHOR]

Food allergy is a harmful immune reaction driven by uncontrolled type 2 immune responses. Considerable evidence demonstrates the key roles of mast cells, IgE, and TH2 cytokines in mediating food allergy. However, this evidence provides limited insight into why only some, rather than all, food allergic individuals are prone to develop life-threatening anaphylaxis. Clinical observations suggest that patients sensitized to food through the skin early in life may later develop severe food allergies. Aberrant epidermal thymic stromal lymphopoietin and interleukin (IL) 33 production and genetic predisposition can initiate an allergic immune response mediated by dendritic cells and CD4TH2 cells in inflamed skin. After allergic sensitization, intestinal IL-25 and food ingestion enhance concerted interactions between type 2 innate lymphoid cells (ILC2s) and CD4TH2 cells, which perpetuate allergic reactions from the skin to the gut. IL-4 and cross-linking of antigen/IgE/FcεR complexes induce emigrated mast cell progenitors to develop into the multi-functional IL-9-producing mucosal mast cells, which produce prodigious amounts of IL-9 and mast cell mediators to drive intestinal mastocytosis in an autocrine loop. ILC2s and TH9 cells may also serve as alternative cellular sources of IL-9 to augment the amplification of intestinal mastocytosis, which is the key cellular checkpoint in developing systemic anaphylaxis. These findings provide a plausible view of how food allergy develops and progresses in a stepwise manner and that atopic signals, dietary allergen ingestion, and inflammatory cues are fundamental in promoting life-threatening anaphylaxis. This information will aid in improving diagnosis and developing more effective therapies for food allergy-triggered anaphylaxis. [ABSTRACT FROM AUTHOR]

Background: Metformin has been used for alleviating metabolic abnormalities in patients with schizophrenia. The lowest dose of metformin to treat metabolic abnormalities in clozapine-treated patients is 1000 mg/d. This study was designed to determine whether metformin at 500 mg/d and 1000 mg/d is effective in improving the metabolic profiles of clozapine-treated patients with pre-existing metabolic abnormalities, and whether its effectiveness depends on metformin dosage. Methods: In this 12-week, randomized, double-blind, placebo-controlled trial, metformin at 500 mg/d or 1000 mg/d was prescribed to clozapine-treated patients with schizophrenia who had pre-existing metabolic abnormalities. The recruited patients underwent physical and laboratory evaluations at weeks 4, 8, and 12. The outcomes were any changes in metabolic traits. Results: Among the 96 clozapine-treated patients with schizophrenia screened for the trial, 55 patients with pre-existing metabolic abnormalities were randomly assigned to placebo (n = 18), metformin dosage at 500 mg/d (n = 18), and metformin dosage at 1000 mg/d (n = 19) groups. The body weight (BW) of patients in the metformin 1000 mg/d group significantly decreased, by a mean of 0.97 kg over the 12 week trial period. Moreover, patients in the metformin at 500 mg/d and 1000 mg/d groups had a significant decrease in body mass index (BMI) after 12 weeks, with the mean decrease being 0.70 and 0.50 kg/m2, respectively. No significant changes were observed in the other metabolic parameters of patients in the three groups. Conclusions: Our results demonstrated that a low metformin dosage of either 500 mg/d or 1000 mg/d for 12 weeks slightly reduced the BW and BMI of clozapine-treated patients with pre-existing metabolic abnormalities. A longer period of treatment with a larger sample is warranted to determine the factors that influence the metformin treatment response. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

ABSTRACT Up to date, the morbidity and mortality rates of acute lung injury (ALI) still rank high among clinical illnesses. Endotoxin, also called lipopolysaccharide (LPS), induced sepsis is the major cause for ALI. Beneficial biological effects, such as antioxidation, anti-inflammation, and neuroprotection was found to express by 5,7-dihydroxy-8-methoxyflavone (DHMF). The purpose of present study was to investigate the potential protective effects of DHMF and the possibile mechanisms involved in LPS-induced ALI. In our experimental model, ALI was induced in mice by intratracheal injection of LPS, and DHMF at various concentrations was injected intraperitoneally for 30 min prior to LPS administration. Pretreatment with DHMF inhibited not only the histolopatholgical changes occurred in lungs but also leukocytes infiltration in LPS-induced ALI. Decreased activity of antioxidative enzymes (AOE) such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) caused by LPS was reversed by DHMF. LPS-induced lipid peroxidation HIF-1α accumulation, NF-κB phosphorylation, and IκBα degradation were all inhibited by DHMF. In addition, LPS-induced expression of proinflammatory mediators such as TNF-α and IL-1β were also inhibited by 5,7-dihydroxy-8-methoxyflavone. These results suggested that the protective mechanisms of DHMF on endotoxin-induced ALI might be via up-regulation of antioxidative enzymes, inhibition of NFκB phosphorylation, and HIF-1α accumulation. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1700-1709, 2016. [ABSTRACT FROM AUTHOR]

Melanin contributes to skin color, and tyrosinase is the enzyme that catalyzes the initial steps of melanin formation. Therefore, tyrosinase inhibitors may contribute to the control of skin hyperpigmentation. The inhibition of tyrosinase activity by Cinnamomum zeylanicum extracts was previously reported. In this report, we test the hypothesis that Cinnamomum osmophloeum Kanehira, an endemic plant to Taiwan, contains compounds that inhibit tyrosinase activity, similar to C. zeylanicum . The cytotoxicity of three sources of C. osmophloeum Kanehira ethanol extracts was measured in B16-F10 cells using a methyl thiazolyl tetrazolium bromide (MTT) assay. At concentrations greater than 21.25 μg/mL, the ethanol extracts were toxic to the cells; therefore, 21.25 μg/mL was selected to test the tyrosinase activities. At this concentration, all three ethanol extracts decreased the melanin content by 50% in IBMX-induced B16-F10 cells. In addition to the melanin content, greater than 20% of the tyrosinase activity was inhibited by these ethanol extracts. The RT-PCR results showed that tyrosinase and transcription factor MITF mRNAs expression were down-regulated. Consistent with the mRNA results, greater than 40% of the human tyrosinase promoter activity was inhibited based on the reporter assay. Furthermore, our results demonstrate that the ethanol extracts protect cells from UV exposure. C. osmophloeum Kanehira neutralized the IBMX-induced increase in melanin content in B16-F10 cells by inhibiting tyrosinase gene expression at the level of transcription. Moreover, the ethanol extracts also partially inhibited UV-induced cell damage and prevented cell death. Taken together, we conclude that C. osmophloeum Kanehira is a potential skin-whitening and protective agent. [ABSTRACT FROM AUTHOR]

Background It is uncertain whether adjuvant chemotherapy (CMT) improves survival in patients with low-risk Stage II colon cancer. We aimed to determine the disease-free survival (DFS) and 5-year overall survival (OS) of low-risk Stage II colon cancer patients treated with adjuvant tegafur/uracil (UFUR). Methods From January 2004 to December 2011, the follow-up status of 278 low-risk Stage II colon cancer patients who underwent surgery in a single medical center was retrospectively analyzed. These patients were divided into three groups based on whether they received adjuvant CMT with UFUR, adjuvant CMT with 5-fluorouracil, or surgery alone. DFS and 5-year OS curves were calculated using Kaplan–Meier survival analysis and Cox proportional hazards regression. Results In the study population, including 278 low-risk Stage II colon cancer patients with a mean age of 68.28 ± 13.01 years, 132 (47.5%) received adjuvant CMT with UFUR, 49 (17.6%) received adjuvant CMT with 5-fluorouracil, and 97 (34.9%) underwent radical surgery alone. At 5 years, the adjusted DFS and OS of low-risk Stage II colon cancer patients were 85.5% and 81.8%, respectively, in the surgery alone group and 97.9% and 96.2%, respectively, in the surgery plus UFUR > 12 months group ( p = 0.004 and p = 0.098, respectively). In multivariate analysis, CMT with UFUR for more than 12 months increased DFS over surgery alone. There was no statistical difference in the 5-year OS. Conclusion Adjuvant CMT treatment of low-risk Stage II colon cancer patients with UFUR for more than 12 months following surgery improves DFS over surgery alone. [ABSTRACT FROM AUTHOR]

Background: The median effective dose (ED50) for motor blockade of spinal plain bupivacaine in adults was previously reported; however, that of ropivacaine is unknown. This study aimed to determine the ED50 for motor blockade of spinal plain ropivacaine in adults, evaluating the effect of age on this parameter.Methods: 133 patients in need of combined spinal and epidural anesthesia were enrolled in this sequential allocation study. They were divided into 6 groups according to age: 20-30, 31-40, 41-50, 51-60, 61-70, and 71-80 years. Using the up-and-down method of Dixon, the ropivacaine dose was varied according to the preceding patient's reaction. The modified Bromage and hip motor function score was used to evaluate the degree of motor block after administration of ropivacaine. ED50 values were estimated by the method of Dixon and Massey. Other indexes, including the onset of motor block, the analgesia level, and the duration of motor block were also assessed.Results: the ED50 for motor block of intrathecal ropivacaine was 20.96 mg (95 % CI: 19.83-22.16 mg) in 20-30, 19.05 mg (95 % CI: 18.43-19.70 mg) in 31-40, 17.91 mg (95 % CI: 17.10-18.76 mg) in 41-50, 17.91 mg (95 % CI: 16.49-19.44 mg) in 51-60, 16.11 mg (95 % CI: 14.50-17.90 mg) in 61-70, and 15.75 mg (95 % CI: 13.98-17.73 mg) in 71-80 year-old patients. Maximum cephalic analgesic effects were obtained at the L4-T6 and L4-T2 levels, at 5 and 10 min, respectively, after intrathecal administration of ropivacaine in all groups.Conclusion: the ED50 for motor block in spinal plain ropivacaine decreases with advancing age, indicating that age has an influence on the potency of spinal ropivacaine. [ABSTRACT FROM AUTHOR]

Background/purpose: Kawasaki disease (KD) is the most common pediatric vasculitis. The study aimed to identify the risk factors of intravenous immunoglobulin (IVIG) unresponsiveness from the initial clinical parameters of the Taiwanese KD patients.Methods: We enrolled 248 KD (development dataset: 181, validation: 67) patients who received IVIG within 10 days after fever onset. IVIG unresponsiveness was defined by persistent fever beyond 24 hours after IVIG or recrudescent fever with KD symptoms.Results: From the development dataset (181 patients), IVIG unresponsiveness was noted in 22 patients (12.1%). The preIVIG levels of albumin, percentage of neutrophils, and positive lymphadenopathy were identified with highest risk for IVIG unresponsiveness. These three variables were used to construct a three-variable logistic regression model, which yielded an area under the receiver-operating-characteristics curve of 0.87. These three variables were further used to generate a composite scoring model (Formosa score) which yielded a sensitivity of 90.9% and specificity of 81.3% for a cut-off point of three or more. Validation in an independent cohort (67 KD patients) yielded sensitivity and specificity of 71.4% and 81.0%, respectively.Conclusion: We have established a simple three-variable Formosa score for KD patients to identify early those at risk of IVIG unresponsiveness for timely aggressive immunomodulation initially. [ABSTRACT FROM AUTHOR]

Objective: For laparoscopic low anterior resection of the rectum, a small additional incision is needed to extract the specimen. We describe an adjustment technique, which inserted the anvil and extracted the specimen through transanal pathway.Methods: Between July 2010 and July 2012, 23 patients underwent laparoscopic rectal surgery with transanal anvil insertion and transanal prolapsing specimen extraction. All perioperative data and short-term outcomes were recorded in a database.Results: The mean patient age was 61.3 years (range 47-68 years). Of the 23 patients, 17 underwent resection for rectal carcinoma and 6 had tubulovillous adenomas. No intraoperative complications occurred. The mean operative time was 137 minutes (range 118-170 minutes). The distal margins, circumferential resection margins, and lymph node dissections were oncologically adequate for all malignancies. One patient experienced anastomotic leakage (4.3%), treated conservatively. One male patient with benign prostatic hyperplasia suffered from postoperative urinary retention. The average postoperative hospital stay was 11.3 days (range 7-21 days). No patients experienced anal dysfunction. At a median follow-up of 26 months, there were no tumor recurrences.Conclusion: The technique of transanal prolapsing specimen extraction for laparoscopic low anterior resection of the rectum is feasible and safe for selected patients. [ABSTRACT FROM AUTHOR]

Objective: This paper evaluates the effectiveness of motivational enhancement therapy plus cognitive behavioural therapy on depressive symptoms, glycosylated haemoglobin, fasting glucose, body mass index (BMI), and health-related quality of life in type II diabetes patients.Methods: A controlled trial was conducted to compare patients who received the behavioural intervention with untreated controls on measures of health outcomes. A total of 31 intervention group participants and 30 controls were selected from patients that met the inclusion criteria from a hospital-based endocrinology outpatient department. The outcome measures including depressive symptoms, glycosylated haemoglobin, fasting glucose, BMI, and both physical and mental quality of life were collected before (T1), after (T2), and after 90 days (T3) following the intervention.Results: The experimental group showed a significant reduction in glycosylated haemoglobin, fasting glucose, and depressive symptoms and a significant increase in physical quality of life and mental quality of life at T2 and T3, while patients in the control group with usual care showed no changes over time.Conclusion: The behavioural intervention facilitated a significant improvement in psychological adjustment and glycemic control, thus strengthening diabetes control skills and leading to healthy outcomes. It is feasible that nurses and psychiatrists can deliver the behavioural intervention for diabetes patients to decrease their depressive symptoms. Sharing discussion and problem-solving experiences is particularly helpful method for self-control, and these will be beneficially influential on further research. [ABSTRACT FROM AUTHOR]

The novel compounds NSC745885 and NSC757963 developed at our laboratory were tested against a panel of 60 cancer cell lines at the National Cancer Institute, USA, and a panel of 39 cancer cell lines at the Japanese Foundation of Cancer Research. Both compounds demonstrated selective unique multi-log differential patterns of activity, with GI50 values in the sub-micro molar range against cancer cells rather than normal cardiac cells. NSC757963 showed high selectivity towards the leukemia subpanel. Activities of both compounds strongly correlated to expression of NFKB1 and CSNK2B genes, implying that they may inhibit the NF-κB pathway. Immunocytochemical microscopy of OVCAR-3 cells showed clear cytosolic accumulation of the NF-κB p65 subunit following treatment. Western blotting showed dose dependent inhibition of the nuclear expression of the NF-κB p65 subunit with subsequent accumulation in the cytosol following treatment. Docking experiments showed binding of both compounds to the NF-κB activator IKKβ subunit preventing its translocation to the nucleus. Collectively, these results confirm the ability of our compounds to inhibit the constitutively active NF-κB pathway of OVCAR-3 cells. Furthermore, COMPARE analysis indicated that the activity of NSC757963 is similar to the antituberculosis agent rifamycin SV, this was confirmed by testing the antimycobacterial activity of NSC757963 against Mycobacterium tuberculosis, results revealed potent activity suitable for use in clinical practice. Molecular properties and Lipinski’s parameters predicted acceptable bioavailability properties with no indication of mutagenicity, tumorigenicity, irritability and reproductive effects. Oral absorption experiments using the human Caco-2 model showed high intestinal absorption of NSC745885 by passive transport mechanism with no intestinal efflux or active transport mechanisms. The unique molecular characterization as well as the illustrated anticancer spectra of activity and bioavailability properties warrant further development of our compounds and present a foundation brick in the pre-clinical investigations to implement such compounds in clinical practice. [ABSTRACT FROM AUTHOR]

As part of an effort to profile potential therapeutics for the treatment of inflammation-related diseases, a diversity of amide-linked small molecules was synthesized by using parallel synthesis strategy. Moreover, these new compounds were also evaluated for their inhibitory effects on nitric oxide (NO) by using tumor necrosis factor alpha (TNF-α)-induced inflammatory responses in chondrocytes. Among the tested compounds, N-(3-chloro-4-fluorophenyl)-2-hydroxybenzamide (HS-Ck) was the most potent inhibitor of NO production and inducible nitric oxide synthase (iNOS) expression in TNF-α-stimulated chondrocytes. In addition, our biological results indicated that HS-Ck might suppress the expression levels of iNOS and matrix metalloproteinases-13 (MMP-13) activities through downregulating the activation of nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT-3) transcriptional factors. Therefore, the parallel synthesis was successful used to develop a new class of potential anti-inflammatory agents as chondroprotective candidates for the treatment of osteoarthritis. [ABSTRACT FROM AUTHOR]

ABSTRACT Bisphenol-A-glycidyldimethacrylate (BisGMA) is a frequently used monomer in dental restorative resins. However, BisGMA could leach from dental restorative resins after polymerization leading to inflammation in the peripheral environment. Wogonin, a natural flavone derivative, has several benefits, such as antioxidative, anti-inflammatory and neuroprotective properties. Pretreatment of macrophage RAW264.7 cells with wogonin inhibited cytotoxicity which is induced by BisGMA in a concentration-dependent manner. BisGMA induced apoptotic responses, such as redistribution of phosphatidylserine from the internal to the external membrane and DNA fragmentation, were decreased by wogonin in a concentration-dependent manner. In addition, BisGMA-induced genotoxicity, which detected by cytokinesis-blocked micronucleus and single-cell gel electrophoresis assays, were inhibited by wogonin in a concentration-dependent manner. Furthermore, wogonin suppressed BisGMA-induced activation of intrinsic caspase pathways, such as caspases-3 and −8. Parallel trends were observed in inhibition of caspase-3 and −8 activities, apoptosis, and genotoxicity. These results indicate wogonin suppressed the BisGMA-induced apoptosis and genotoxicity mainly via intrinsic caspase pathway in macrophages. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 176-184, 2016. [ABSTRACT FROM AUTHOR]

Background Oncolytic viral efficacy may be limited by the penetration of the virus into tumors. This may be enhanced by intraoperative application of virus immediately after surgical resection. Methods Oncolytic vaccinia virus GLV-1h68 was delivered in silk-elastin-like protein polymer (SELP) in vitro and in vivo in anaplastic thyroid carcinoma cell line 8505c in nude mice. Results GLV-1h68 in SELP infected and lysed anaplastic thyroid cancer cells in vitro equally as effectively as in phosphate-buffered saline (PBS), and at 1 week retains a thousand fold greater infectious plaque-forming units. In surgical resection models of residual tumor, GLV-1h68 in SELP improves tumor control and shows increased viral β-galactosidase expression as compared to PBS. Conclusion The use of SELP matrix for intraoperative oncolytic viral delivery protects infectious viral particles from degradation, facilitates sustained viral delivery and transgene expression, and improves tumor control. Such optimization of methods of oncolytic viral delivery may enhance therapeutic outcomes. © 2014 Wiley Periodicals, Inc. Head Neck 38: 237-246, 2016 [ABSTRACT FROM AUTHOR]

Single-factor experiment and Box–Behnken design (BBD) were applied to optimize the ultrasound-assisted extraction of mulberry fruits polysaccharides (MFP). Under optimum conditions: ratio of water to raw material 40.25, extraction temperature 69 °C, ultrasonic power 190 W and extraction time 75 min, the MFP yield was 3.13% (±0.07%), in accordance to the predicted value of 3.04%. The mulberry fruits polysaccharides fractions was obtained by deproteinization (MFP-1), followed by decolorization and deionization (MFP-2). Carbohydrate content in MFP, MFP-1 and MFP-2 was 58.61% (±1.47%), 69.98% (±0.91%), 81.18% (±1.29%), as well as proteins was estimated 16.50% (±0.86%), 1.57% (±0.63%), 1.02% (±0.18%), respectively. The FT-IR indicated that MFP, MFP-1 and MFP-2 were acidic polysaccharides. The MFP-1 exhibited the strongest antioxidant activity, while MFP-2 showed the strongest hyperglycemic activity in vitro . This may be caused by their different compositions and physical properties in the different mulberry fruit polysaccharides fractions. [ABSTRACT FROM AUTHOR]

Objectives. Suicide is an important issue in the military service, since it can influence military morale and create dangerous situations for other personnel. The serotonin transporter (SERT) has been suggested to be involved in the pathophysiology of depression and suicidal behaviours. The aims of this study were to examine whether the brain SERT availability differs between military conscripts with depression and control subjects, and whether suicidal ideation is correlated with SERT availability. Methods.We used N,N-dimethyl-2-(2-amino-4-[18F]-fluorophenylthio)benzylamine (4-[18F]-ADAM) as a radioligand for positron emission tomography (PET) imaging. All participants completed the Hamilton Depression Rating Scale and Beck Scale for Suicide Ideation (BSS) prior to PET imaging. Results. The effect of major depression and BSS scores had an interaction on SERT availability. After adjusting for the BSS score, subjects with depression had lower SERT availability than control subjects (F1,17 = 23.85, P < 0.001). A positive correlation between SERT availability and BSS scores was observed in the depression group (F1,8 = 30.67, P = 0.001). The status of depression and intensity of suicidal ideation exert opposite effects on SERT availability. Conclusions. The extent of suicidal ideation may moderate the reduction effect in SERT binding observed in major depression in male military conscripts. [ABSTRACT FROM AUTHOR]

Wogonin is a flavonoid compound which exhibits antioxidation, anti-inflammation, neuroprotection, and antitumorgenesis functions. However, the mechanism of how wogonin reduces proinflammatory cytokine generation in activated microglia is unclear. At present, we found wogonin inhibited lipopolysaccharide (LPS)-/interferon-γ (INF-γ)-induced generation of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Wogonin exhibited parallel inhibition on LPS-/INF-γ-induced expression of IL-6 and TNF-α messenger RNA at the same concentration range. LPS-/INF-γ-induced phosphorylation of signal transduction and transcription 1 and 3 (STAT1/3) were also inhibited by wogonin. Although wogonin expressed only weak inhibitory effect on LPS-/INF-γ-induced phosphorylation of Janus kinase-2 (Jak-2) and tyrosine kinase (Tyk)-2, it significantly attenuated the phosphorylation of Jak-1 and Jak-3. These results indicated that the blockade of IL-6 and TNF-α production by wogonin in LPS-/INF-γ-stimulated BV2 microglial cells was attributed mainly to the interference in Jak-1/-3-STAT1/3 signaling pathway. [ABSTRACT FROM AUTHOR]

The present study demonstrated that intravenous injection of a high dose of compound 48/80 to the rat induced 50 % drop, within a few min, in the mean arterial pressure and pulse pressure as well as systemic inflammatory plasma leakage that might lead to circulatory and respiratory failure. We also investigated whether pretreatment with Evans blue, a stimulator of BK channels, could exert inhibitory effect against compound C48/80-induced allergic circulatory shock and systemic inflammation. Different groups of Sprague-Dawley rats received an intravenous injection of a dose of Evans blue (0, 5, 10, or 50 mg/kg) just 20 s prior to injection of compound 48/80 (200 μg/kg, over 2 min). The present study found that pretreatment with Evans blue in a dose of 10 or 50 mg/kg exerted acute inhibitory effect on compound 48/80-induced sudden drop in mean arterial and pulse pressures. We also showed that pretreatment with Evans blue in a dose of 5, 10, or 50 mg/kg significantly inhibited compound 48/80-induced extensive plasma extravasation, mast cell degranulation, and edema formation in various organs including the airways, esophagus, and skin. Pretreatment with Evans blue 50 mg/kg 1 h earlier exhibited longer-term inhibitory effect on compound 48/80-induced arterial hypotension and systemic inflammation. We concluded that Evans blue pretreatment prevented rats from compound 48/80-triggered allergic shock and systemic inflammation, possibly mainly through inhibition of mast cell degranulation. Evans blue might be potentially useful in elucidating the mechanism and acting as a therapeutic agent of allergic shock and systemic inflammation. [ABSTRACT FROM AUTHOR]

In situ crosslinked thermo-responsive hydrogel applied for minimally invasive treatment of intervertebral disc degeneration (IVDD) may not prevent extrusion of cell suspension from injection site due to high internal pressure of intervertebral disc (IVD), causing treatment failure or osteophyte formation. In this study, mesenchymal stromal cells (MSCs) were encapsulated in alginate precursor and loaded into previously developed macroporous PGEDA-derived microcryogels (PMs) to form three-dimensional (3D) microscale cellular niches, enabling non-thermo-responsive alginate hydrogel to be injectable. The PMs reinforced alginate hydrogel showed superior elasticity compared to alginate hydrogel alone and could well protect encapsulated cells through injection. Chondrogenic committed MSCs in the injectable microniches expressed higher level of nucleus pulposus (NP) cell markers compared to 2D cultured cells. In an ex vivo organ culture model, injection of MSCs-laden PMs into NP tissue prevented cell leakage, improved cell retention and survival compared to free cell injection. In canine IVDD models, alleviated degeneration was observed in MSCs-laden PMs treated group after six months which was superior to other treated groups. Our results provide in-depth demonstration of injectable alginate hydrogel reinforced by PMs as a leak-proof cell delivery system for augmented regenerative therapy of IVDD in canine models. [ABSTRACT FROM AUTHOR]

Background Management of diseases of the descending thoracic aorta is trending from open surgery toward thoracic endovascular aortic repair (TEVAR), because TEVAR is reportedly associated with less perioperative mortality. However, comparisons between TEVAR and open surgery, adjusting for patient comorbidities, have not been well studied. In this nationwide population-based study, we compared the outcomes between TEVAR and open surgery in type B aortic dissection. Methods From 2003 to 2009, data on patients with type B aortic dissection who underwent either open surgery or TEVAR were obtained from the National Health Insurance Research Database. Survival, length of stay, and complications were compared between TEVAR and open repair. To minimize possible bias, we performed an additional analysis after matching patients by age, sex, and propensity score. Results A total of 1661 patients were identified, of whom 1542 underwent open repair and 119 TEVAR. Patients in the TEVAR group were older (63.0 ± 15.4 years vs. 58.1 ± 13.1 years; p = 0.001), included more males, and had more preoperative comorbidities. Thirty-day mortality in the TEVAR group was significantly lower than that in the open repair group (4.2% vs. 17.8%; p < 0.001). The midterm survival rates in the unmatched cohort between the open surgery and TEVAR groups at 1 year, 2 years, 3 years, and 4 years were 76%, 73%, 71%, and 68% vs. 92%, 86%, 82%, and 79%, respectively. The length of stay in the TEVAR group was shorter than that in the open repair group ( p = 0.001). The TEVAR group had less respiratory failure ( p = 0.022) and fewer wound complications than the open repair group ( p = 0.008). The matched cohort showed similar results. Conclusion TEVAR for type B aortic dissection repair has less perioperative mortality, a shorter length of hospitalization, a higher midterm survival rate, less postoperative respiratory failure, and fewer wound complications than open surgery. [ABSTRACT FROM AUTHOR]

Tamiflu , the ethyl ester form of oseltamivir carboxylic acid (OC), is the first orally available anti-influenza drug for the front-line therapeutic option. In this study, the OC-hydroxamates, OC-sulfonamides and their guanidino congeners (GOC) were synthesized. Among them, an OC-hydroxamate 7d bearing an O -(2-indolyl)propyl substituent showed potent NA inhibition (IC 50 = 6.4 nM) and good anti-influenza activity (EC 50 = 60.1 nM) against the wild-type H1N1 virus. Two GOC-hydroxamates ( 9b and 9d ) and one GOC-sulfonamide ( 12a ) were active to the tamiflu-resistant H275Y virus (EC 50 = 2.3–6.9 μM). [ABSTRACT FROM AUTHOR]

Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease. [ABSTRACT FROM AUTHOR]

Background The purpose of this study was to investigate the prophylactic irradiation volume to neck drainage areas for patients with N0 classification nasopharyngeal carcinoma (NPC) treated by intensity-modulated radiotherapy (IMRT). Methods From January 2003 to October 2008, 270 patients with N0 classification (American Joint Committee on Cancer [AJCC] 2002 staging system) NPC who had undergone IMRT were retrospectively analyzed. Among all the patients, 171 patients received prophylactic upper-neck irradiation, and 99 patients received prophylactic whole-neck irradiation. Results At a median follow-up of 65.1 months (range, 4-106 months). The 5-year overall survival (OS), nodal recurrence-free survival (NRFS), and distant metastasis-free survival (DMFS) rates of the upper neck group and the whole neck group were 93.6% vs 90.9% ( p = .553), 99.4% vs 99.0% ( p = .278), and 98.8% vs 94.9% ( p = .128), respectively. A total of 3 neck recurrences were found, including 2 from the whole neck group and 1 from the upper neck group. The latter (0.6%) was an out-of-field recurrence. Conclusion Prophylactic irradiation to the upper neck (levels II, III, and VA) may be feasible for patients with neck lymph node-negative NPC. © 2013 Wiley Periodicals, Inc. Head Neck 36: 687-693, 2014 [ABSTRACT FROM AUTHOR]

Colon cancer is one of the most common malignant cancers worldwide but the current therapeutic approaches for advanced colon cancer are less efficient. This study investigated associations between the expression of nuclear transcription factor SOX4 and various clinicopathologic parameters as well as patients’ survival. Expression levels of nuclear SOX4 were analyzed by immunohistochemistry; the data comprised colon tissues from 263 patients with colon cancer. Paired t tests were used to analyze the differences in nuclear SOX4 expression between tumor and non-tumor tissues from each patient. Two-tailed Χ2 tests were performed to determine whether the differences in nuclear SOX4 expression and clinicopathologic parameters were significant. Time-to-event endpoints for clinicopathologic parameters were plotted using the Kaplan-Meier method, and statistical significance was determined using univariate log-rank tests. Cox proportional hazard model was used for multivariate analysis to determine the independence of prognostic effects of nuclear SOX4 expression. Overexpression of nuclear SOX4 was significantly correlated with depth of invasion (P = 0.0041), distant metastasis (P<0.0001), and stage (P = 0.0001). Patients who displayed high expression levels of nuclear SOX4 achieved a significantly poorer disease-free survival rate, compared with patients with low SOX4 expression levels (P<0.001). Univariate Cox regression analysis showed that overexpression of nuclear SOX4 was a clear prognostic marker for colon cancer (P = 0.001). Overexpression of nuclear SOX4 may be used as a marker to predict the outcome of patients with colon cancer. [ABSTRACT FROM AUTHOR]

Background: The morbidity and mortality associated with bacterial peritonitis remain high. Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a potent intestinal cytoprotective agent. The aim of this study was to evaluate the effect of HB-EGF in a model of murine peritonitis. Methods: HB-EGF(−/−) knockout (KO) mice and their HB-EGF(+/+) wild-type (WT) counterparts were subjected to sham operation, cecal ligation and puncture (CLP), or CLP with HB-EGF treatment (800 μg/kg IP daily). Villous length, intestinal permeability, intestinal epithelial cell (IEC) apoptosis, bacterial load in peritoneal fluid (PF) and mesenteric lymph nodes (MLN), inflammatory cytokine levels, and survival were determined. Results: After exposure to CLP, HB-EGF KO mice had significantly shorter villi (1.37 ± 0.13 vs 1.96 ± 0.4 relative units; P < .03), increased intestinal permeability (17.01 ± 5.18 vs 11.50 ± 4.67 nL/min/cm2; P < .03), increased IEC apoptotic indices (0.0093 ± 0.0033 vs 0.0016 ± 0.0014; P < .01), and increased bacterial counts in PF (25,313 ± 17,558 vs 11,955 ± 6,653 colony forming units [CFU]/mL; P < .05) and MLN (19,009 ± 11,200 vs 5,948 ± 2,988 CFU/mL/g; P < .01) compared with WT mice. Administration of HB-EGF to WT and HB-EGF KO mice exposed to CLP led to significantly increased villous length and decreased intestinal permeability, IEC apoptosis and bacterial counts in MLN (P < .05). Survival of HB-EGF KO mice subjected to CLP was significantly improved with administration of HB-EGF (P < .05). Conclusion: HB-EGF gene KO increases susceptibility to peritonitis-induced intestinal injury, which can be reversed by administration of HB-EGF. These results support a protective role of HB-EGF in peritonitis-induced sepsis. [ABSTRACT FROM AUTHOR]