Concomitant Use of Multiple Nephrotoxins including Renal Hypoperfusion Medications Causes Vancomycin-Associated Nephrotoxicity: Combined Retrospective Analyses of Two Real-World Databases.

There is a growing concern about the relationship between vancomycin-associated nephrotoxicity (VAN) and concomitant use of nephrotoxins. We examined this relationship by combined retrospective analyses of two real-world databases. Initially, the FDA Adverse Event Reporting System (FAERS) was analyzed for the effects of concomitant use of one or more nephrotoxins on VAN and the types of combinations of nephrotoxins that exacerbate VAN. Next, electronic medical records (EMRs) of patients who received vancomycin (VCM) at Tokushima University Hospital between January 2006 and March 2019 were examined to confirm the FAERS analysis. An elevated reporting odds ratio (ROR) was observed with increases in the number of nephrotoxins administered (VCM + one nephrotoxin, adjusted ROR (95% confidence interval [CI]) 1.67 [1.51-1.85]; VCM + ≥2 nephrotoxins, adjusted ROR [95% CI] 1.54 [1.37-1.73]) in FAERS. EMRs analysis showed that the number of nephrotoxins was associated with higher incidences of VAN [odds ratio: 1.99; 95% CI: 1.42-2.78]. Overall, concomitant use of nephrotoxins was associated with an increased incidence of VAN, especially when at least one of those nephrotoxins was a renal hypoperfusion medication (furosemide, non-steroidal anti-inflammatory drugs, and vasopressors). The concomitant use of multiple nephrotoxins, especially including renal hypoperfusion medication, should be avoided to prevent VAN.

Non-recovery of vancomycin-associated nephrotoxicity is related to worsening survival outcomes: Combined retrospective analyses of two real-world databases.

There has been growing concern in worsening survival and renal outcomes following vancomycin-associated nephrotoxicity (VAN) onset, but the factors associated with these phenomena remain unclear. To examine these factors, we performed a retrospective study combining the analysis of two real-world databases. Initially, the FDA Adverse Event Reporting System (FAERS) was used to evaluate the relationship between VAN and mortality using odds ratios (ORs) and 95% confidence intervals (CIs). Next, electronic medical records (EMRs) were examined in a more robust cohort for evaluation of the association between renal outcomes and worsening survival using Cox proportional hazards regression models. FAERS analysis revealed a significant correlation between VAN occurrence and increased mortality (OR: 1.30; 95% CI: 1.17-1.46). EMR analysis showed that non-recovery of VAN was associated with increased hospital mortality (hazard ratio [HR]: 4.05; 95% CI: 2.42-6.77) and 1-year mortality (HR: 3.03, 95% CI: 1.98-4.64). The HR for VAN recovery was lower for patients with acute kidney injury (AKI) stage ≥2 (HR: 0.09; 95% CI: 0.02-0.40). Thus, worsening survival outcomes were associated with non-recovery of VAN, whereby AKI stage ≥2 was a significant risk factor. Progression to severe VAN should be prevented for better survival outcomes.

Association Between Statin Use and Daptomycin-related Musculoskeletal Adverse Events: A Mixed Approach Combining a Meta-analysis and a Disproportionality Analysis.

BACKGROUND: There is a growing concern about the association between the combined use of daptomycin (DAP) and statins and the occurrence of musculoskeletal adverse events (MAEs), but this remains controversial. This study aimed to clarify the association between statin use and DAP-related MAEs. METHODS: We used a mixed approach that combines 2 methodologies. First, we conducted a meta-analysis to examine the effects of statin use on DAP-related MAEs. Second, we conducted a disproportionality analysis using the US Food and Drug Administration Adverse Events Reporting System (FAERS) to further confirm the results of the meta-analysis and to examine the effect of each type of statin on DAP-related MAEs in a large population. RESULTS: In the meta-analysis, statin use significantly increased the incidence of DAP-related rhabdomyolysis (odds ratio [OR]: 3.83; 95% confidence interval [CI]: 1.43-10.26) but not DAP-related myopathy (OR: 1.72; 95% CI: .95-3.12). In the disproportionality analysis using the FAERS, the use of statin significantly increased the reporting OR (ROR) for DAP-related myopathy (ROR: 5.69; 95% CI: 4.31-7.51) and rhabdomyolysis (ROR: 5.77; 95% CI: 4.33-7.68). Atorvastatin, rosuvastatin, and simvastatin all increased the incidence of DAP-related myopathy and rhabdomyolysis. CONCLUSION: The mixed approach combining a meta-analysis and disproportionality analysis showed that statin use was associated with the occurrence of DAP-related rhabdomyolysis. The appropriate use of statins and DAP should be performed with careful consideration of its safety.

Enantioselective synthesis of 8-azabicyclo[3.2.1]octanes via asymmetric 1,3-dipolar cycloadditions of cyclic azomethine ylides using a dual catalytic system.

The first example of asymmetric 1,3-dipolar cycloadditions between diazo imine-derived cyclic azomethine ylides and acryloylpyrazolidinone using a rhodium(ii) complex/chiral Lewis acid binary system is reported. The asymmetric cycloadditions afforded optically active 8-oxabicyclo[3.2.1]octanes with high diastereo- and enantioselectivities (up to >99 : 1 dr, 99% ee). A switch of exo/endo-selectivity was observed depending on the diazo substrates.

Human airway trypsin-like protease (HAT) is released into saliva.

We first discovered human airway trypsin-like protease (HAT) in human mucoid sputum. Precursor HAT (47 kDa), a cell surface type Ⅱ transmembrane serine protease, is proteolyzed to mature HAT (27 kDa). Hitherto, HAT has not been detected in other biological fluids except for human sputum. We aimed to clarify whether human saliva contains mature HAT. Trypsin-like protease was isolated from saliva of healthy volunteers by a method adopted for isolation of HAT from sputum using Boc-Phe-Ser-Arg-MCA as the substrate. Biochemical properties of purified protease were similar to those of recombinant HAT (rHAT). HAT concentration in saliva was measured by ELISA, and immunoreactive HAT:total protein ratio (ng/mg) in saliva samples from healthy subjects was similar to that in mucoid sputum. RT-PCR showed that HAT mRNA was expressed in human gingival epithelial cells but not in gingival fibroblasts. Both indirect immunofluorescence and western blotting using monoclonal antibody for α-smooth muscle actin (α-SMA;a myofibroblast marker) showed that HAT enhanced α-SMA fiber expression in gingival fibroblasts. These results indicate that both mucoid sputum and saliva from healthy subjects have similar concentrations of mature HAT, and HAT is related to certain physiological functions and pathological states of myofibroblasts in the oral cavity. J. Med. Invest. 65:258-267, August, 2018.

The KCNQ1 gene polymorphism as a shared genetic risk for rheumatoid arthritis and chronic periodontitis in Japanese adults: A pilot case-control study.

BACKGROUND: A number of studies have suggested a bidirectional relationship of periodontitis with rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). However, the genetic factors that underlie these relationships have not been elucidated. METHODS: We conducted a multicenter case-control study that included 185 patients with RA and chronic periodontitis (CP), 149 patients with T2DM and CP, 251 patients with CP, and 130 systemically and periodontally healthy controls from a cohort of Japanese adults to assess the shared genetic risk factors for RA and CP as well as for T2DM and CP. A total of 17 candidate single nucleotide polymorphisms (SNPs) associated with RA, T2DM, and CP were genotyped. RESULTS: Multiple logistic regression analyses revealed that the KCNQ1 rs2237892 was significantly associated with comorbidity of RA and CP (P = 0.005) after adjustment for age, sex, and smoking status. The carriers of the T allele among patients with RA and CP showed significantly higher disease activity scores including 28 joints using C-reactive protein values than the non-carriers (P = 0.02), although the age, female percentage, and smoking status were comparable. Other SNPs were not associated with comorbidity of RA and CP, T2DM and CP, or susceptibility to CP. CONCLUSION: The results of the present pilot study suggest for the first time that the KCNQ1 rs2237892 may constitute a shared genetic risk factor for RA and CP, but not for T2DM and CP in Japanese adults.

Defect-Repairable Latent Feature Extraction of Driving Behavior via a Deep Sparse Autoencoder.

Data representing driving behavior, as measured by various sensors installed in a vehicle, are collected as multi-dimensional sensor time-series data. These data often include redundant information, e.g., both the speed of wheels and the engine speed represent the velocity of the vehicle. Redundant information can be expected to complicate the data analysis, e.g., more factors need to be analyzed; even varying the levels of redundancy can influence the results of the analysis. We assume that the measured multi-dimensional sensor time-series data of driving behavior are generated from low-dimensional data shared by the many types of one-dimensional data of which multi-dimensional time-series data are composed. Meanwhile, sensor time-series data may be defective because of sensor failure. Therefore, another important function is to reduce the negative effect of defective data when extracting low-dimensional time-series data. This study proposes a defect-repairable feature extraction method based on a deep sparse autoencoder (DSAE) to extract low-dimensional time-series data. In the experiments, we show that DSAE provides high-performance latent feature extraction for driving behavior, even for defective sensor time-series data. In addition, we show that the negative effect of defects on the driving behavior segmentation task could be reduced using the latent features extracted by DSAE.

Factors associated with regular dental visits among hemodialysis patients.

AIM: To investigate awareness and attitudes about preventive dental visits among dialysis patients; to clarify the barriers to visiting the dentist. METHODS: Subjects included 141 dentate outpatients receiving hemodialysis treatment at two facilities, one with a dental department and the other without a dental department. We used a structured questionnaire to interview participants about their awareness of oral health management issues for dialysis patients, perceived oral symptoms and attitudes about dental visits. Bivariate analysis using the χ(2) test was conducted to determine associations between study variables and regular dental check-ups. Binominal logistic regression analysis was used to determine factors associated with regular dental check-ups. RESULTS: There were no significant differences in patient demographics between the two participating facilities, including attitudes about dental visits. Therefore, we included all patients in the following analyses. Few patients (4.3%) had been referred to a dentist by a medical doctor or nurse. Although 80.9% of subjects had a primary dentist, only 34.0% of subjects received regular dental check-ups. The most common reasons cited for not seeking dental care were that visits are burdensome and a lack of perceived need. Patients with gum swelling or bleeding were much more likely to be in the group of those not receiving routine dental check-ups (χ(2) test, P < 0.01). Logistic regression analysis demonstrated that receiving dental check-ups was associated with awareness that oral health management is more important for dialysis patients than for others and with having a primary dentist (P < 0.05). CONCLUSION: Dialysis patients should be educated about the importance of preventive dental care. Medical providers are expected to participate in promoting dental visits among dialysis patients.

Immunochemoradiotherapy for patients with oral squamous cell carcinoma: augmentation of OK-432-induced helper T cell 1 response by 5-FU and X-ray irradiation.

Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-ß but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-ß. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression.

[A case of oral squamous cell carcinoma responding to S-1].

A 76-year-old patient with oral squamous cell carcinoma was treated by chemotherapy with S-1. S-1 (100 mg/body/day) was orally administered for 4 weeks followed by a 2-week rest period as one course. The primary lesion markedly decreased at 7 days after the beginning of S-1 treatment, and disappeared after one course of S-1. After two courses, the primary lesion was assessed to show a complete response (CR),and no tumor cells were identified as a result of biopsy. In addition, the value of tumor marker SCC decreased from 2.13 ng/mL before treatment to 0.68 ng/mL after two courses of S-1. Although the patient is still taking UFT, she is well with no signs of recurrence 50 months from the initial treatment.

Cepharanthin-enhanced radiosensitivity through the inhibition of radiation-induced nuclear factor-kappaB activity in human oral squamous cell carcinoma cells.

We have already demonstrated that human head and neck cancer cells have significantly enhanced levels of transcription factor nuclear factor (NF)-kappaB activity compared to their normal counterparts, suggesting that NF-kappaB plays an important role in the development of head and neck cancer. However, it has been reported that chemotherapeutic agents and radiation activate NF-kappaB activity in cancer cells, thus making the cells radioresistant and chemoresistant. In addition, we have shown that the suppression of NF-kappaB activity enhanced apoptosis in oral squamous cell carcinoma cells. In this study, we examined whether cepharanthin-induced inhibition of NF-kappaB activity enhances radiosensitivity in human oral carcinoma cells. Cepharanthin is a biscoclaurine alkaloid extracted from the roots of Stephania cepharantha hayata, and is widely used in Japan for the treatment of patients with leucopenia, nasal allergy, and venomous snakebites. gamma-irradiation (IR) induces NF-kappaB activity in oral carcinoma cells through the activation of upstream molecules, including Akt and IkappaB kinase. However, a luciferase assay revealed that cepharanthin suppresses IR-induced NF-kappaB activity in oral squamous cell carcinoma cells, thereby enhancing the radio-sensitivity. Western blot analysis showed an enhanced cleavage of poly-(ADP-ribose) polymerase protein in carcinoma cells by both cepharanthin treatment and IR exposure compared to IR or cepharanthin alone. In an in vivo study, B88 cells were s.c. inoculated into the backs of nude mice. Tumor-bearing nude mice received either cepharanthin, IR alone, or a combination of cepharanthin and IR. The combined treatment suppressed tumor growth significantly more than either cepharanthin or IR alone. Cepharanthin inhibited the production of IR-induced IL-6 and IL-8, which are downstream targets of NF-kappaB. In quantitative real-time RT-PCR, IR also induced the expression of anti-apoptotic proteins [cellular inhibitor of apoptosis protein (cIAP)-1 and -2] in carcinoma cells. Treatment of cancer cells with cepharanthin combined with exposure to IR decreased cIAP-1 and -2 mRNA expression. These findings suggested that the combination of radiotherapy and cepharanthin could enhance radiosensitivity in the treatment of human oral cancer.

Asymmetric epoxidation of alpha-olefins having neighboring sugar chiral templates and alternating copolymerization with dicarboxylic anhydrides.

Sugar-substituted epoxides 5-8 were synthesized by asymmetric epoxidation (in CH(2)Cl(2)/water) of alpha-olefins having neighboring sugars (1-4) by use of an achiral oxidant (MCPBA), in which the sugar moiety acted as a chiral template. The diastereoselectivities depend on the methylene spacer between vinyl group and carbohydrate derivatives. The methylene spacer between sugar and vinyl groups influenced the diastereoselectvity. In the case of epoxidation of 4 at 27 degrees C for 24 h, the diastereoselectivity was the highest (99/1). Copolymerizations of 5-8 with succinic anhydride were attained at 100 degrees C for 72 h to give poly(ethylene succinate) having pendant carbohydrate [poly(SAn-alt-5), M(n) = 1.4 x 10(3); poly(SAn-alt-6), M(n) = 2.2 x10(3); poly(SAn-alt-7), M(n) = 2.9 x 10(3); poly(SAn-alt-8), M(n) = 1.8 x 10(3)]. The methylene spacer between sugar and epoxide has an effect on the reactivity of epoxide in copolymerization as well as the diastereoselectivity. Alternating copolymerization of 7 and glutaric anhydride gave a polyester of M(n) 4.2 x10(3).

Acquisition of lymph node, but not distant metastatic potentials, by the overexpression of CXCR4 in human oral squamous cell carcinoma.

Recently, it has been suggested that chemokine/receptor interactions determine the destination of the invasive tumor cells in several types of cancer. It has also been proposed that the stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system might be involved lymph node metastasis in oral squamous cell carcinoma (SCC). In order to further clarify the role of the SDF-1/CXCR4 system in oral SCC, we generated CXCR4 stable transfectants (IH-CXCR4) using oral SCC cells, and compared them to IH, which did not express CXCR4 and which did not have lymph node metastatic potentials in vivo. We introduced enhanced green fluorescent protein (GFP) fused-CXCR4 into IH cells, and detected the GFP fluorescence in the cytoplasm and cell membrane in approximately 60% of the G418-resistant cells. This bulk-transfectant expressed a high level of CXCR4 mRNA and protein, and exhibited the characteristic calcium fluxes and chemotactic activity observed in treatment with SDF-1. SDF-1 biphasically activated extracellular signal-regulated kinase (ERK)1/2, but continuously activated Akt/protein kinase B (PKB) in IH-CXCR4 cells. Most importantly, IH-CXCR4 cells frequently metastasized to the cervical lymph node, but not to the distant organs in the orthotopic inoculation of nude mice. Furthermore, these lymph node metastases were inhibited by the treatment of a mitogen-activated protein kinase/ERK kinase inhibitor, U0126, or a phosphatidylinositol 3 kinase inhibitor, wortmannin. These results indicate that SDF-1/CXCR4 signaling mediates the establishment of lymph node metastasis in oral SCC via ERK1/2 or Akt/PKB pathway.

Overexpression of p27(Kip1) induces growth arrest and apoptosis in an oral cancer cell line.

p27(Kip1) is a cyclin-dependent kinase inhibitor which regulates progression of cells from G1 into S phase in a cell cycle. Loss of p27(Kip1) has been associated with disease progression and an unfavorable outcome in several malignancies. In the present study, we conducted to examine whether up-regulation or down-regulation of p27(KiP1) can affect the growth of oral cancer cell (B88 cell) in vitro and in vivo. We constructed an expression vector containing sense- or antisense-oriented human p27(Kip1) cDNA with pcDNA3.1(Invitrogen). We transfected B88 cells with the sense or antisense expression vector to regulate the expression of p27(Kip1) gene in each transfectant. The expression of p27(Kip1) protein was up-regulated in the sense transfectants and down-regulated in the antisense transfectants. Moreover, up-regulation of p27(Kip1) protein exerted the growth inhibitory effect, and down-regulation of p27(Kip1) protein enhanced the growth of B88 cells in vitro and in vivo. Furthermore, we detected the G1 arrest and sub-G1 peak in the sense transfectants by flow cytometry analysis. These results suggest that up-regulation of p27(Kip1) protein may exert the growth inhibitory effects through induction of G1 arrest and apoptosis on oral cancer cell line.