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Super‐selective adrenal venous sampling (ssAVS) can collect the adrenal tributary venous blood in the aldosterone (ALD)‐hypersecreting segments in primary aldosteronism. The concentrations of the C18‐oxygenated steroids, especially 18‐oxocortisol (18‐oxoF), in the lesion segments might be more useful indices than those in the peripheral or adrenal central veins (current candidate indexes) for the differential diagnosis of unilateral ALD‐producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). To verify this hypothesis, we developed a liquid chromatography/electrospray ionization‐tandem mass spectrometry (LC/ESI–MS/MS) method for simultaneously quantifying ALD, 18‐oxoF and 18‐hydroxycortisol in the adrenal tributary venous serum sample collected by ssAVS (ssAVS serum) and compared their concentrations between APA and BAH patients. Only deproteinization was required for a 10 μl sample prior to the LC/ESI–MS/MS analysis. Endogenous corticoids did not interfere with the quantifications, and the intra‐assay and interassay precisions (≤ 8.3%) and accuracies (94.2–102.7%) were acceptable. The clinical study revealed that the 18‐oxoF concentration was significantly higher in the ALD‐producing tumor tissues (from APA patients) than in the hyperplastic tissues (from BAH patients). However, in conclusion, the 18‐oxoF concentration in the ssAVS serum sample can be a rough indication but cannot be decisive for the differential diagnosis between APA and BAH owing to the significant individual difference. [ABSTRACT FROM AUTHOR]

Glyoxalase I (GLO I), a major enzyme involved in the detoxification of the anaerobic glycolytic byproduct methylglyoxal, is highly expressed in various tumors, and is regarded as a promising target for cancer therapy. We recently reported that piceatannol potently inhibits human GLO I and induces the death of GLO I‐dependent cancer cells. Pyruvate kinase M2 (PKM2) is also a potential therapeutic target for cancer treatment, so we evaluated the combined anticancer efficacy of piceatannol plus low‐dose shikonin, a potent and specific plant‐derived PKM2 inhibitor, in two GLO I‐dependent cancer cell lines, HL‐60 human myeloid leukemia cells and NCI‐H522 human non‐small‐cell lung cancer cells. Combined treatment with piceatannol and low‐dose shikonin for 48 h synergistically reduced cell viability, enhanced apoptosis rate, and increased extracellular methylglyoxal accumulation compared to single‐agent treatment, but did not alter PKM1, PKM2, or GLO I protein expression. Taken together, these results indicate that concomitant use of low‐dose shikonin potentiates piceatannol‐induced apoptosis of GLO I‐dependent cancer cells by augmenting methylglyoxal accumulation. [ABSTRACT FROM AUTHOR]

Background and Aim: In Japan, screening colonoscopy for colorectal cancer is expected to reduce colorectal cancer mortality, although its complication rate has not been sufficiently examined. The aim of this study is to analyze severe complications due to colonoscopy. Methods: As a study population, we retrospectively used commercially anonymized health insurance claims data covering 5.71 million patients from January 2005 to August 2018. We extracted patients who received colonoscopy with lesions resection or without treatment. Main outcomes were rates of hemorrhage, perforation, fatal events, and their risk factors. Results: Among 341 852 colonoscopy without treatment in 260 128 patients (mean age: 49.6 ± 11.7 years), the rates of hemorrhage, perforation, and fatal events were 0.0059% (95% confidence interval [CI] 0.0031–0.0085), 0.0032% (95% CI 0.0011–0.0052), and 0.00029% (95% CI 0–0.0012), respectively. Regarding hemorrhage, compared with the rate for patients <50 years old (0.0050%), the rates for those 50–59, 60–69, and ≥70 years old were 0.0095% (P = 0.17), 0.0031% (P = 0.17), and 0%, respectively. Regarding perforation, compared with patients <50 years old (0.0056%), the rates for those 50–59, 60–69, and ≥70 years old were 0%, 0.0015% (P = 0.99), and 0.0102% (P = 0.99), respectively. A multivariate analysis for risk factors showed no significant findings for hemorrhage and perforation without treatment. Among 123 087 colonoscopy with lesions resection in 102 058 patients (mean age: 53.7 ± 9.3 years), the rates of hemorrhage, perforation, and fatal events were 0.136% (95% CI 0.1157–0.1572), 0.033% (95% CI 0.0228–0.0437), and 0.00081% (95% CI 0–0.0035), respectively. Conclusions: The analysis using health insurance claims data demonstrated the safety of colonoscopy. [ABSTRACT FROM AUTHOR]

Objectives: The combination therapy of phenothrin (PHT) and ivermectin (PI regimen) was effective for pyrethroid‐resistant head lice in Okinawa; however, further investigations have been required to improve the regimen. This study aimed to investigate the efficacy of the modified PI (mPI) regimen, which increased the maximum number of PHT treatments in the PI regimen by one, in Tsukuba, which has a low mutation rate compared to Okinawa. Methods: An open‐label, uncontrolled, exploratory study was conducted at the Department of Dermatology, University of Tsukuba Hospital to investigate the treatment effect of mPI regimen. Genotypes were investigated for the knockdown (kdr) mutations at voltage‐sensitive sodium channel (VSSC) and glutamate‐gated chloride receptor‐encoding loci to identify their correlation with drug resistance. Results: All the 8 patients treated with the mPI regimen resulted in lice free on day 29. Compared to baseline, the number of bodies, eggs, and itching grade significantly decreased on day 29. Mild erythema appeared after the second application of PHT on day 8 in one patient, persisted for 2 days, and recovered on day 15. No other adverse events were reported. Mutation rates were more than double in head lice collected from one patient for whom PHT was ineffective compared to those in lice from patients who responded to PHT. Furthermore, we identified four new haplotypes of VSSC loci in head lice. Conclusions: The mPI regimen is a potential effective treatment for economically combating both PHT‐sensitive and resistant head lice. [ABSTRACT FROM AUTHOR]

Despite development of markers for identification of cancer stem cells, the mechanism underlying the survival and division of cancer stem cells in breast cancer remains unclear. Here we report that PKCλ expression was enriched in basal-like breast cancer, among breast cancer subtypes, and was correlated with ALDH1A3 expression (p = 0.016, χ2-test). Late stage breast cancer patients expressing PKCλhigh and ALDH1A3high had poorer disease-specific survival than those expressing PKCλlow and ALDH1A3low (p = 0.018, log rank test for Kaplan-Meier survival curves: hazard ratio 2.58, 95% CI 1.24–5.37, p = 0.011, multivariate Cox regression analysis). Functional inhibition of PKCλ through siRNA-mediated knockdown or CRISPR-Cas9-mediated knockout in ALDH1high MDA-MB 157 and MDA-MB 468 basal-like breast cancer cells led to increases in the numbers of trypan blue-positive and active-caspase 3-positive cells, as well as suppression of tumor-sphere formation and cell migration. Furthermore, the amount of CASP3 and PARP mRNA and the level of cleaved caspase-3 protein were enhanced in PKCλ-deficient ALDH1high cells. An Apoptosis inhibitor (z-VAD-FMK) suppressed the enhancement of cell death as well as the levels of cleaved caspase-3 protein in PKCλ deficient ALDH1high cells. It also altered the asymmetric/symmetric distribution ratio of ALDH1A3 protein. In addition, PKCλ knockdown led to increases in cellular ROS levels in ALDH1high cells. These results suggest that PKCλ is essential for cancer cell survival and migration, tumorigenesis, the asymmetric distribution of ALDH1A3 protein among cancer cells, and the maintenance of low ROS levels in ALDH1-positive breast cancer stem cells. This makes it a key contributor to the poorer prognosis seen in late-stage breast cancer patients. [ABSTRACT FROM AUTHOR]

Cancer cells upregulate the expression levels of glycolytic enzymes in order to reach the increased glycolysis required. One such upregulated glycolytic enzyme is glyoxalase 1 (GLO 1), which catalyzes the conversion of toxic methylglyoxal to nontoxic S-D-lactoylglutathione. Protein kinase Cλ (PKCλ) is also upregulated in various types of cancer and is involved in cancer progression. In the present study, the association between enhanced glycolysis and PKCλ in breast cancer was investigated. In human breast cancer, high GLO 1 expression was associated with high PKCλ expression at the protein (P<0.01) and mRNA levels (P<0.01). Furthermore, Wilcoxon and Cox regression model analysis revealed that patients with stage III–IV tumors with high GLO 1 and PKCλ expression had poor overall survival compared with patients expressing lower levels of these genes [P=0.040 (Gehan-Breslow generalized Wilcoxon test) and P=0.031 (hazard ratio, 2.36; 95% confidence interval, 1.08–5.16), respectively]. Treatment of MDA-MB-157 and MDA-MB-468 human basal-like breast cancer cells with TLSC702 (a GLO 1 inhibitor) and/or aurothiomalate (a PKCλ inhibitor) reduced both cell viability and tumor-sphere formation. These results suggested that GLO 1 and PKCλ were cooperatively involved in cancer progression and contributed to a poor prognosis in breast cancer. In conclusion, GLO 1 and PKCλ serve as potentially effective therapeutic targets for treatment of late-stage human breast cancer. [ABSTRACT FROM AUTHOR]

[Display omitted] • The carboxyl group in the TLSC702 molecule is critical for binding to GLO I. • Lipophilicity of TLSC702 derivatives is correlated with antiproliferative effects. • Addition of hydrophobic groups at phenyl position increases apoptosis inducibility. Glyoxalase I (GLO I) is a known therapeutic target in cancer. Even though TLSC702, a GLO I inhibitor that we discovered, induces apoptosis in tumor cells, exceptionally higher doses are required compared with those needed to inhibit GLO I activity in vitro. In this work, structure–activity optimization studies were conducted on four sections of the TLSC702 molecule to determine the partial structural features necessary for the inhibition of GLO I. Herein, we found that the carboxy group in TLSC702 was critical for binding with the divalent zinc at the active site of GLO I. In contrast, the side chain substituents in the meta- and para- positions of the benzene ring had little influence on the in vitro inhibition of GLO I. The CLogP values of the TLSC702 derivatives showed a positive correlation with the antiproliferative effects on NCI-H522 cells. Thus, two derivatives of TLSC702, which displayed either high or low lipophilicity due to the types of substituents at the phenyl position, were selected. Even though both derivatives showed comparable inhibitory effects as that of their parent compound, the derivative with the high CLogP value was distinctly more antiproliferative than TLSC702. In contrast, the derivative with the low CLogP value did not decrease cell viability in NCI-H522 and HL-60 cells. These findings suggested that structural improvements, such as the addition of hydrophobic moieties to the phenyl group, enhanced the ability of TLSC702 to induce apoptosis by increasing cell membrane permeability. [ABSTRACT FROM AUTHOR]