Long acting tariquidar loaded stearic acid-modified hydroxyapatite enhances brain penetration and antitumor effect of temozolomide.

Temozolomide (TMZ) is the first line chemotherapy for glioblastoma (GBM) treatment, but the P-glycoprotein (P-gp) expressed in blood-brain barrier (BBB) will pump out TMZ from the brain leading to decreased TMZ concentration. Tariquidar (TQD), a selective and potent P-gp inhibitor, may be suitable for combination therapy to increase concentration of TMZ in brain. Hydroxyapatite (HAP) is a biodegradable material with sustained release characteristics, and stearic acid surface-modified HAP (SA-HAP) can increase hydrophobicity to facilitate TQD loading. TQD-loaded stearic acid surface-modified HAP (SA-HAP-TQD) was prepared with optimal size and high TQD loading efficiency, and in vitro release and cellular uptake of SA-HAP-TQD showed that SA-HAP-TQD were taken up into lysosome and continuously released TQD from macrophages. In vivo studies have found that over 70% of SA-HAP was degraded and 80% of TQD was released from SA-HAP-TQD 28 days after administration. SA-HAP-TQD could increase brain penetration of TMZ, but it would not enhance adverse effects of TMZ in healthy mice. SA-HAP-TQD and TMZ combination had longer median survival than TMZ single therapy in GL261 orthotopic model. These results suggest that SA-HAP-TQD has sustained release characteristics and are potential for improving antitumor effect with TMZ treatment.

Drug delivery of extracellular vesicles: Preparation, delivery strategies and applications.

Extracellular vesicles (EV) are cell-originated vesicles exhibited with characteristics similar to the parent cells. Several studies have suggested the therapeutic potential of EV since they played as an intercellular communicator and modulate disease microenvironment, and thus EV has been widely studied in cancer management and tissue regeneration. However, merely application of EV revealed limited therapeutic outcome in different disease scenario and co-administration of drugs may be necessary to exert proper therapeutic effect. The method of drug loading into EV and efficient delivery of the formulation is therefore important. In this review, the advantages of using EV as drug delivery system compared to traditional synthetic nanoparticles will be emphasized, followed by the method of preparing EV and drug loading. The pharmacokinetic characteristics of EV was discussed, together with the review of reported delivery strategies and related application of EV in different disease management.

Dementia screening for elderly in-patients and its association with nursing care satisfaction-an observational study.

Inappropriate care for patients with cognitive dysfunction in the hospital could worsen quality of care and medical service satisfaction.All elderly participants were recruited from acute wards of 5 departments in an university hospital. They were administered the Chinese version of Ascertain Dementia 8 (AD8) at admission and the Nursing Service Satisfaction Questionnaire before discharge.A total of 345 participants completed the study. There were 91 (26.4%) participants with AD8 ≥ 2, the cut-off value of high risk of dementia. The prevalence was much higher than prior community-based reports. The Nursing Service Satisfaction Score was significantly lower in AD8 ≥ 2 than in AD8 < 2 (56.99 ±â€Š0.94 vs 60.55 ±â€Š0.48, P < .01).Using AD8 in hospital-based screening might be more efficient than in the community in terms of cost-effectiveness due to higher positive rate and easier approach to diagnostic facilities. AD8 ≥ 2 is also an indicator to identify care dissatisfaction among inpatients. By identifying patients with cognitive dysfunction, such as its related communication barriers, care systems could be tailored for more friendly services.

Antiseptic Effect of Conventional Povidone-Iodine Scrub, Chlorhexidine Scrub, and Waterless Hand Rub in a Surgical Room: A Randomized Controlled Trial.

OBJECTIVE Effective perioperative hand antisepsis is crucial for the safety of patients and medical staff in surgical rooms. The antimicrobial effectiveness of different antiseptic methods, including conventional hand scrubs and waterless hand rubs, has not been well evaluated. DESIGN, SETTING, AND PARTICIPANTS A randomized controlled trial was conducted to investigate the effectiveness of the 3 antiseptic methods among surgical staff of Taipei Medical University-Shuang Ho Hospital. For each method used, a group of 80 participants was enrolled. INTERVENTION Surgical hand cleansing with conventional 10% povidone-iodine scrub, conventional 4% chlorhexidine scrub, or waterless hand rub (1% chlorhexidine gluconate and 61% ethyl alcohol). RESULTS Colony-forming unit (CFU) counts were collected using the hand imprinting method before and after disinfection and after surgery. After surgical hand disinfection, the mean CFU counts of the conventional chlorhexidine (0.5±0.2, P<0.01) and waterless hand rub groups (1.4±0.7, P<0.05) were significantly lower than that of the conventional povidone group (4.3±1.3). No significant difference was observed in the mean CFU count among the groups after surgery. Similar results were obtained when preexisting differences before disinfection were considered in the analysis of covariance. Furthermore, multivariate regression indicated that the antiseptic method (P=.0036), but not other variables, predicted the mean CFU count. CONCLUSIONS Conventional chlorhexidine scrub and waterless hand rub were superior to a conventional povidone-iodine product in bacterial inhibition. We recommend using conventional chlorhexidine scrub as a standard method for perioperative hand antisepsis. Waterless hand rub may be used if the higher cost is affordable. Infect Control Hosp Epidemiol 2017;38:417-422.

Continuous passive motion and its effects on knee flexion after total knee arthroplasty in patients with knee osteoarthritis.

PURPOSE: This study evaluated the effects of continuous passive motion (CPM) on accelerated flexion after total knee arthroplasty (TKA) and whether CPM application measures (i.e. initial angle and daily increment) are associated with functional outcomes. METHODS: A retrospective investigation was conducted at the rehabilitation centre of a university-based teaching hospital. Patients who received CPM therapy immediately after TKA surgery were categorized into rapid-, normal-, and slow-progress groups according to their response to CPM during their acute inpatient stay. Knee pain, passive knee flexion, and knee function-measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-were assessed preoperatively at discharge and at 3- and 6-month outpatient follow-up visits. RESULTS: A total of 354 patients were followed for 6 months after inpatient-stay discharge. The patients in the rapid-progress group (n = 119) exhibited significantly greater knee flexions than those in the slow-progress group did (n = 103) at the 3-month follow-up [mean difference (MD) = 10.3°, 95 % confidence interval (CI) 4.3°-16.3°, p < 0.001] and 6-month follow-up (MD = 10.9°, 95 % CI 6.3°-15.6°, p < 0.001). Significant WOMAC score differences between the rapid- and slow-progress groups were observed at the 3-month follow-up (MD = 7.2, 95 % CI 5.4-9.1, p < 0.001) and 6-month follow-up (MD = 16.1, 95 % CI 13.4-18.7, p < 0.001). CPM initial angles and rapid progress significantly predicted short- and long-term outcomes in knee flexion and WOMAC scores (p < 0.001). CONCLUSION: When CPM is used, early application with initial high flexion and rapid progress benefits knee function up to 6 months after TKA. LEVEL OF EVIDENCE: II.

Cationic polystyrene nanospheres induce autophagic cell death through the induction of endoplasmic reticulum stress.

Nanoparticles (NPs) have been used to produce a wide range of products that have applications in imaging and drug delivery in medicine. Due to their chemical stability, well-controlled sizes and surface charges, polystyrene (PS) NPs have been developed as biosensors and drug delivery carriers. However, the possible adverse biological effects and underlying mechanisms are still unclear. Recently, autophagy has been implicated in the regulation of cell death. In this study, we evaluated a library of PS NPs with different surface charges. We found that NH2-labeled polystyrene (NH2-PS) nanospheres were highly toxic with enhanced uptake in macrophage (RAW 264.7) and lung epithelial (BEAS-2B) cells. Furthermore, NH2-PS could induce autophagic cell death. NH2-PS increased autophagic flux due to reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress caused by misfolded protein aggregation. The inhibition of ER stress decreased cytotoxicity and autophagy in the NH2-PS-treated cells. In addition, the Akt/mTOR and AMPK signaling pathways were involved in the regulation of NH2-PS-triggered autophagic cell death. These results suggest an important role of autophagy in cationic NP-induced cell death and provide mechanistic insights into the inhibition of the toxicity and safe material design.

Development of Taiwan's strategies for regulating nanotechnology-based pharmaceuticals harmonized with international considerations.

Nanotechnology offers potential in pharmaceuticals and biomedical developments for improving drug delivery systems, medical imaging, diagnosis, cancer therapy, and regenerative medicine. Although there is no international regulation or legislation specifically for nanomedicine, it is agreed worldwide that considerably more attention should be paid to the quality, safety, and efficacy of nanotechnology-based drugs. The US Food and Drug Administration and the European Medicines Agency have provided several draft regulatory guidance and reflection papers to assist the development of nanomedicines. To cope with the impact of nanotechnology and to foster its pharmaceutical applications and development in Taiwan, this article reviews the trends of regulating nanotechnology-based pharmaceuticals in the international community and proposes strategies for Taiwan's regulation harmonized with international considerations. The draft regulatory measures include a chemistry, manufacturing, and controls (CMC) review checklist and guidance for CMC review of liposomal products. These have been submitted for discussion among an expert committee, with membership comprised of multidisciplinary academia, research institutions, the pharmaceutical industry, and regulators, and are currently approaching final consensus. Once a consensus is reached, these mechanisms will be recommended to the Taiwan Food and Drug Administration for jurisdiction and may be initiated as the starting point for regulating nanotechnology-based pharmaceuticals in Taiwan.

N-acetylcysteine attenuates hexavalent chromium-induced hypersensitivity through inhibition of cell death, ROS-related signaling and cytokine expression.

Chromium hypersensitivity (chromium-induced allergic contact dermatitis) is an important issue in occupational skin disease. Hexavalent chromium (Cr (VI)) can activate the Akt, Nuclear factor κB (NF-κB), and Mitogen-activated protein kinase (MAPK) pathways and induce cell death, via the effects of reactive oxygen species (ROS). Recently, cell death stimuli have been proposed to regulate the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). However, the exact effects of ROS on the signaling molecules and cytotoxicity involved in Cr(VI)-induced hypersensitivity have not yet been fully demonstrated. N-acetylcysteine (NAC) could increase glutathione levels in the skin and act as an antioxidant. In this study, we investigated the effects of NAC on attenuating the Cr(VI)-triggered ROS signaling in both normal keratinocyte cells (HaCaT cells) and a guinea pig (GP) model. The results showed the induction of apoptosis, autophagy and ROS were observed after different concentrations of Cr(VI) treatment. HaCaT cells pretreated with NAC exhibited a decrease in apoptosis and autophagy, which could affect cell viability. In addition, Cr (VI) activated the Akt, NF-κB and MAPK pathways thereby increasing IL-1α and TNF-α production. However, all of these stimulation phenomena could be inhibited by NAC in both of in vitro and in vivo studies. These novel findings indicate that NAC may prevent the development of chromium hypersensitivity by inhibiting of ROS-induced cell death and cytokine expression.

Overcoming multidrug resistance using liposomal epirubicin and antisense oligonucleotides targeting pump and nonpump resistances in vitro and in vivo.

Multidrug resistance (MDR) is a serious obstacle in cancer treatment. In this study, epirubicin (Epi), an anthracycline antineoplastic agent, and/or antisense oligonucleotides (ASOs) targeting MDR1, MDR-associated protein (MRP)1, MRP2, and BCL-2/BCL-xL were incorporated into polyethylene glycol-coated (PEGylated) liposomes to develop a suitable anticancer drug delivery system. We evaluated in vitro cytotoxicity, intracellular accumulation and cell cycle analysis of these formulations. We also assessed in vivo pharmacokinetics and antitumor efficacy of these formulations in Sprague-Dawley (SD) rats and mouse colon adenocarcinoma CT26-bearing Balb/c mice. ASOs in PEGylated liposomes significantly enhanced the cytotoxicity and the intracellular accumulation of Epi in CT26 cells. This combination also intensified Epi-induced apoptosis in CT26 cells. An in vivo pharmacokinetic study using SD rats showed that after intravenous administration of PEGylated liposomal Epi and ASOs, Epi had greater area under the curve and longer half-life than in an Epi solution. The treatment of PEGylated liposomal Epi and ASOs also demonstrated significant improvements in tumor growth inhibition and survival percentage in CT26-bearing Balb/c mice in vivo. The PEGylated liposomal formulation of Epi and ASOs against MDR1, MRP1, MRP2, and BCL-2/BCL-xL exhibited the most pronounced effect among all the formulations used in this study. This study pioneered in demonstrating that PEGylated liposomal ASOs targeting both pump and nonpump resistances increase antitumor efficacy in vivo through the simultaneous inhibition of MDR transporters and apoptosis induction. This approach provides a potential strategy to overcome MDR in cancer chemotherapy.

Solanum incanum extract (SR-T100) induces human cutaneous squamous cell carcinoma apoptosis through modulating tumor necrosis factor receptor signaling pathway.

BACKGROUND: The Solanum species herbs have been used to treat cancer for centuries; however, the underlying mechanisms and effectiveness in vivo remain unclear. OBJECTIVES: SR-T100, extracted from the Solanum incanum, contains solamargine alkaloid as the main active ingredient. Here, we investigated the apoptosis-inducing effects of SR-T100 for targeting squamous cell carcinoma (SCC) in vitro and in vivo. METHODS: We elucidated the mechanism by which SR-T100 induces apoptosis of human SCCs (A431, SCC4, SCC9, and SCC25) cells. The efficacy and safety issues were addressed regarding topical treatment of SR-T100 on UVB-induced cutaneous SCC of hairless mice and actinic keratoses (AKs) of human. RESULTS: SR-T100 induces apoptosis in human SCCs cell lines by up-regulating the expressions of tumor necrosis factor receptors (TNFRs) and Fas, and downstream adaptors FADD/TRADD of the TNF-α and Fas ligand signaling cascades. SR-T100 also triggered the mitochondrial apoptotic pathway, as up-regulated cytochrome c and Bax, down-regulated Bcl-X(L). Animal experiments showed that all papillomas (35/35) and 27 of 30 UVB-induced microinvasive SCCs in hairless mice disappeared within 10 weeks after once-daily application of topical SR-T100. Furthermore, 13 patients, who suffered with 14 AKs, were treated with once-daily topical SR-T100 gel and 10 AKs cured after 16 weeks, showing negligible discomforts. CONCLUSION: Our studies indicate that SR-T100 induces apoptosis of SCC cells via death receptors and the mitochondrial death pathway. The high efficacy of SR-T100 in our preclinical trial suggests that SR-T100 is a highly promising herb for AKs and related disorders.

Effects of topical sesame oil on oxidative stress in rats.

OBJECTIVE: To assess the effects of topical sesame oil on systemic oxidative stress in rats. DESIGN: Oxidative stress was induced with lipopolysaccharide and assessed by determining serum lipid peroxidation, superoxide anion, and hydroxyl radical levels. The levels of 3 circulating antioxidants--superoxide dismutase, catalase, and glutathione--also were determined. RESULTS: Topical sesame oil significantly reduced lipid peroxidation, superoxide anion, and hydroxyl radical levels after lipopolysaccharide administration. However, sesame oil did not affect the 3 circulating antioxidants. Further, sesame oil decreased the activity of xanthine oxidase and nitric oxide production in lipopolysaccharide-treated rats. CONCLUSION: Sesame oil given topically might attenuate oxidative stress by inhibiting the production of xanthine oxidase and nitric oxide in rats.

Novel autoregulatory function of hepatitis B virus M protein on surface gene expression.

The hepatitis B virus surface gene consists of a single open reading frame divided into three coding regions: pre-S1, pre-S2, and S. By alternate translation at each of the three initiation codons, L, M, and S proteins can be synthesized. Studies have shown that M protein is not essential for viral replication, virion morphogenesis, or in vitro infectivity. In this study, we show that native M protein can regulate surface gene expression at the transcriptional level. The regulatory effect of M protein is mediated through the CCAAT box within the S promoter. Deletion mapping analysis indicated that the transactivating effect of M protein is mediated through amino acids 1-57 of M protein (the MHBs(au) domain), although its maximal transactivation activity coincides with that of the pre-S2 domain. This conclusion is supported by the fact that disruption of the putative V8 protease site at the pre-S2/S domain junction not only rendered M protein incapable of transactivating the S promoter but also inactivated its nuclear translocation potential. Immunoprecipitation and immunoblot experiments demonstrated that pre-S2 interacts with the three subunits of the CCAAT box-binding factor/nuclear factor Y, the cognate binding protein of the CCAAT box. These results demonstrate and define a novel regulatory role of M protein, which, under natural conditions, may undergo a proteolytic process to generate an MHBs(au) species that will be translocated inside the nucleus, where it will interact with the CCAAT box-binding factor to regulate surface gene expression. Because the CCAAT box is located at a fixed position within numerous promoters, these observations might provide a plausible explanation for hepatitis B virus-associated hepatocarcinogenesis.

Nasopharyngeal carcinoma-susceptibility locus is localized to a 132 kb segment containing HLA-A using high-resolution microsatellite mapping.

Nasopharyngeal carcinoma (NPC) is an epithelial tumor uniquely prevalent in southern Chinese. HLA-A2 is associated with NPC. In a previous study, we showed that the genes associated with susceptibility to NPC are primarily located within the HLA-A locus in Taiwanese NPC patients. However, the pathogenic genes causing NPC susceptibility remain unknown. Here, 8 polymorphic microsatellite markers distributed over a 1 megabase region surrounding the HLA-A locus were subjected to genetic analysis for the NPC-susceptibility locus. Statistical studies of associated alleles detected on each microsatellite locus showed that the NPC- susceptibility genes are most likely located between the D6S510 and D6S211 markers within a 132 kb segment containing the HLA-A locus. These results undoubtedly would facilitate the further positional cloning of the NPC-susceptibility locus, which has been elusive for the past 30 years.

Effect of occupational exposure to rayon manufacturing chemicals on skin barrier to evaporative water loss.

To evaluate the effects of the occupational exposure to rayon manufacturing chemicals (RMC, containing predominantly carbon disulfide (CS(2)) and minor sulfuric acid) in a rayon factory on the basal transepidermal water loss (TEWL), barrier integrity (BI), and sequential increasing TEWL profiles. Six Thais and five Chinese workers in the spinning department of a rayon manufacturing plant and five healthy unexposed controls were recruited as the test subjects. An area of 4.5 x 5.5 cm on the mid-side of the volar forearm on the right hand was stripped by means of moderate pressure with commercially available adhesive tape by the same technician throughout the experiment. The skin was progressively stripped until glistening. TEWL was measured at every three and five tape strips on the right hand. The corresponding site on the left hand was measured parallel as the self-control. We found significant differences in basal TEWL and in BI between Chinese workers and Chinese controls, and between Thai workers and Chinese workers, respectively. Two-stage patterns of progressive TEWL profiles were found in such a chronic and repeated occupational exposure to RMC containing CS(2). The occupational exposure to RMC could result in the perturbation of the skin barrier function. Basal TEWL might be more sensitive to chronic skin irritant exposure. The TEWL profile achieved to the glistening stage might be necessary to avoid erroneous pattern estimation. Due to the lack of Thais control in this study, the racial difference in response to the RMC warrants further study.