Correlation between magnesium pre-loading and cisplatin-induced nephrotoxicity in 5-fluorouracil/cisplatin combination therapy for esophageal cancer.

The use of cisplatin may cause nephrotoxicity in patients. Hydration solutions supplemented with magnesium could reduce cisplatin-induced nephrotoxicity. In this study, we evaluated the preventive effect of magnesium pre-loading on cisplatin-induced nephrotoxicity in patients with esophageal cancer. We retrospectively evaluated the prevalence of, and risk factors for, nephrotoxicity in 160 patients with esophageal cancer treated with the 5-fluorouracil/cisplatin regimen from 2014 to 2016 with and without magnesium supplementation. Significant differences were observed between the magnesium and non-magnesium groups in terms of frequency of estimated creatinine clearance of grade 2 or higher that was at 4% (n = 3) and 13% (n = 10) (p = 0.027), respectively. The logistic regression analysis revealed that eCcr of grade 2 or higher was significantly associated with the non-magnesium regimen (odds ratio (OR), 4.175; 95% confidence interval (CI) = 1.061-16.430; p = 0.041) and age ≥ 65 years (OR, 13.951; 95% CI = 1.723-112.974; p = 0.014). This study suggests that 20 mEq magnesium pre-loading significantly reduces the prevalence of cisplatin-induced nephrotoxicity. Furthermore, when cisplatin is administered to individuals older than 64 years, a close observation for the onset of cisplatin-induced nephrotoxicity is crucial.

Prevalence of primary open-angle glaucoma among patients with obstructive sleep apnea.

OBJECTIVE: Our objective was to determine primary open-angle glaucoma (POAG) prevalence among obstructive sleep apnea (OSA) patients because the perioperative environment risks further damaging the optic nerve. STUDY DESIGN: We analyzed a "convenience sample" referred by Sleep Medicine for oral appliances because of continuous positive airway pressure intolerance. We determined the aggregate prevalence of the 3 POAG subtypes-"classic" open-angle glaucoma (COAG), normal-tension glaucoma (NTG), and open-angle glaucoma suspect (OAGS)-among the index population and compared it with that of same hospital's general population. Similarly determined were associations between OSA severity levels (apnea-hypopnea index [AHI]) and POAG subtypes. RESULTS: Among the study sample of 225 patients with OSA (96.4% male; mean age 58.5 ± 12.3 years), 47 (20.9%) had POAG, with a subtype distribution of COAG: 12 (25.5%), NTG: 8 (17.0%), and OAGS: 27 (57.4%). The POAG prevalence rate among medical center's general population was 2.5%, which was significantly less (P < .00001) than among those with comorbid OSA. Severity of the breathing disorder (AHI) failed to identify a significant correlation to any POAG subtype (P > .05). CONCLUSION: The significant prevalence of POAG among OSA sufferers suggests need for preoperative consultations from an ophthalmologist to determine eye health and possibly an anesthesiologist to avoid potential vision loss.

Sex-based differences in CD103+ dendritic cells promote female-predominant Th2 cytokine production during allergic asthma.

BACKGROUND: Gender disparities in adult patients with asthma regarding its prevalence and severity are mainly due to enhanced type 2 T-helper (Th2) cytokine production in female patients compared to that in male patients. However, the pathways mediating this effect remain unclear. OBJECTIVE: We aimed to determine the roles of two major subsets of dendritic cells (DCs) in females, specifically those displaying CD11b or CD103, during enhanced Th2 priming after allergen exposure, using an ovalbumin-induced asthma mouse model. METHODS: Sex-based differences in the number of DCs at inflamed sites, costimulatory molecule expression on DCs, and the ability of DCs to differentiate naïve CD4+ T cells into Th2 population were evaluated after allergen exposure in asthmatic mice. In addition, we assessed the role of 17ß-oestradiol in CD103+ DC function during Th2 priming in vitro. RESULTS: The number of CD11bhigh DCs and CD103+ DCs in the lung and bronchial lymph node (BLN) was increased to a greater extent in female mice than in male mice at 16 to 20 hours after ovalbumin (OVA) inhalation. In BLNs, CD86 and I-A/I-E expression levels and antigen uptake ability in CD103+ DCs, but not in CD11bhigh DCs, were greater in female mice than in male mice. Furthermore, CD4+ T cells cultured with CD103+ DCs from female mice produced higher levels of interleukin (IL)-4, IL-5, and IL-13, compared with CD4+ T cells cultured with CD103+ DCs from male mice. The 17ß-oestradiol-oriented enhancement of CD86 expression on CD103+ DCs after allergen exposure induced the enhanced IL-5 production from CD4+ T cells. CONCLUSIONS AND CLINICAL RELEVANCE: These findings suggest that with regard to asthma, enhanced Th2 cytokine production in females might be attributed to 17ß-oestradiol-mediated Th2-oriented CD103+ DCs in the BLN.

Atp1a3-deficient heterozygous mice show lower rank in the hierarchy and altered social behavior.

Atp1a3 is the Na-pump alpha3 subunit gene expressed mainly in neurons of the brain. Atp1a3-deficient heterozygous mice (Atp1a3+/- ) show altered neurotransmission and deficits of motor function after stress loading. To understand the function of Atp1a3 in a social hierarchy, we evaluated social behaviors (social interaction, aggression, social approach and social dominance) of Atp1a3+/- and compared the rank and hierarchy structure between Atp1a3+/- and wild-type mice within a housing cage using the round-robin tube test and barbering observations. Formation of a hierarchy decreases social conflict and promote social stability within the group. The hierarchical rank is a reflection of social dominance within a cage, which is heritable and can be regulated by specific genes in mice. Here we report: (1) The degree of social interaction but not aggression was lower in Atp1a3+/- than wild-type mice, and Atp1a3+/- approached Atp1a3+/- mice more frequently than wild type. (2) The frequency of barbering was lower in the Atp1a3+/- group than in the wild-type group, while no difference was observed in the mixed-genotype housing condition. (3) Hierarchy formation was not different between Atp1a3+/- and wild type. (4) Atp1a3+/- showed a lower rank in the mixed-genotype housing condition than that in the wild type, indicating that Atp1a3 regulates social dominance. In sum, Atp1a3+/- showed unique social behavior characteristics of lower social interaction and preference to approach the same genotype mice and a lower ranking in the hierarchy.

Diabetes mellitus and risk of early-onset Alzheimer's disease: a population-based case-control study.

BACKGROUND AND PURPOSE: Previous studies have reported that diabetes is a risk factor for both all-cause and vascular dementia; however, diabetes as a risk factor for Alzheimer's disease (AD) remains controversial. Therefore, the aim was to elucidate the association between diabetes and early-onset AD. METHODS: A case-control study was conducted using a population-based database that included medical and pharmacy claims and insurance eligibility data, from beneficiaries of corporate employees and their dependent family members. Cases were aged 40-64 years and were first prescribed medications for AD between 2005 and 2016. Up to four controls matched for age, sex and hospital type were included for each case. Data were analyzed using conditional logistic regression and compared between the sexes. RESULTS: Data from 371 patients with AD (mean age 56.3 ± 5.3 years; 48% female) and 1484 controls were analyzed. Use of antidepressants, antipsychotics and antithrombotics during the index month was higher amongst patients with AD (19.4%, 34.5% and 11.3%, respectively) than amongst controls (2.9%, 10.3% and 7.3%, respectively). Our findings suggest no evidence for an association between diabetes and risk of early-onset AD (adjusted odds ratio 1.31; 95% confidence interval 0.90-1.92). In the subgroup analyses, adjusted odds ratios in patients with diabetes were 0.73 (95% confidence interval 0.38-1.39) and 1.68 (95% confidence interval 1.06-2.67) for female and male patients, respectively. CONCLUSIONS: There is no apparent association between diabetes and risk of early-onset AD in the total study population, although a weak association was observed amongst male patients.

Mutual relationships between structural and functional changes in a PsbM-deletion mutant of photosystem II.

Photosystem II (PSII) is a membrane protein complex that performs light-induced electron transfer and oxygen evolution from water. PSII consists of 19 or 20 subunits in its crystal form and binds various cofactors such as chlorophyll a, plastoquinone, carotenoid, and lipids. After initial light excitation, the charge separation produces an electron, which is transferred to a plastoquinone molecule (QA) and then to another plastoquinone (QB). PsbM is a low-molecular-weight subunit with one transmembrane helix, and is located in the monomer-monomer interface of the PSII dimer. The function of PsbM has been reported to be stabilization of the PSII dimer and maintenance of electron transfer efficiency of PSII based on previous X-ray crystal structure analysis at a resolution of 4.2 Å. In order to elucidate the structure-function relationships of PsbM in detail, we improved the quality of PSII crystals from a PsbM-deleted mutant (ΔPsbM-PSII) of Thermosynechococcus elongatus, and succeeded in improving the diffraction quality to a resolution of 2.2 Å. X-ray crystal structure analysis of ΔPsbM-PSII showed that electron densities for the PsbM subunit and neighboring carotenoid and detergent molecules were absent in the monomer-monomer interface. The overall structure of ΔPsbM-PSII was similar to wild-type PSII, but the arrangement of the hydrophobic transmembrane subunits was significantly changed by the deletion of PsbM, resulting in a slight widening of the lipid hole involving QB. The lipid hole-widening further induced structural changes of the bicarbonate ion coordinated to the non-heme Fe(ii) atom and destabilized the polypeptide chains around the QB binding site located far from the position of PsbM. The fluorescence decay measurement indicated that the electron transfer rate from QA to QB was decreased in ΔPsbM-PSII compared with wild-type PSII. The functional change in electron transfer efficiency was fully interpreted based on structural changes caused by the deletion of the PsbM subunit.

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

Comparison of the multidetector-row computed tomography findings of IgG4-related sclerosing cholangitis and extrahepatic cholangiocarcinoma.

AIM: To compare the multidetector-row computed tomography (MDCT) findings of IgG4-related sclerosing cholangitis (IgG4-SC) and extrahepatic cholangiocarcinoma (EH-CCA). MATERIALS AND METHODS: Two radiologists who had no knowledge of the patients' clinical information retrospectively evaluated the CT findings of patients with IgG4-SC (n=33) and EH-CCA (n=39) on a consensus basis. Another radiologist measured the biliary lesions. IgG4-SC was diagnosed using the Japan Biliary Association criteria (2012) or the Mayo Clinic's HISORt criteria. EH-CCA was diagnosed based on surgical findings. RESULTS: Compared with EH-CCA, IgG4-SC exhibited the following findings significantly more frequently: (a) wall thickening alone, (b) concentric wall thickening, (c) smooth inner margins, (d) homogeneous attenuation in the arterial phase, (e) a lesion involving the intrapancreatic bile duct, (f) smooth outer margins, (g) fully visible lumen, (h) a funnel-shaped proximal bile duct, (i) skip lesions, and (j) abnormal pancreatic findings. Conversely, (k) dual-layered attenuation in all phases was significantly more common in EH-CCA. The specificity values of parameters (e-k) were >80%. Regarding dimensions, (l) the biliary lesions were longer in IgG4-SC than in EH-CCA. (m) The diameters of the dilated proximal common bile duct and (n) the dilated proximal intrahepatic bile duct were smaller in IgG4-SC than in EH-CCA. CONCLUSION: A number of CT findings are useful for differentiating between IgG4-SC and EH-CCA. CT findings (e-k) are particularly useful for this purpose.

WT1 immunoenzyme staining using SurePath(™) processed urine cytology helps to detect kidney disease.

OBJECTIVES: Damage and detachment of podocytes and loss into the urine have been implicated in the progression of kidney diseases. The purpose of this study was to investigate the potential role of urine cytology based on SurePath(™) combined with immunoenzyme staining using Wilms' tumour 1 (WT1) antibody as a podocyte marker in the discrimination of normality and non-renal urinary tract disease from kidney disease. METHODS: Sixty-six patients with kidney disease, 45 patients with lower urinary tract disease and 30 healthy volunteers were examined. Urine cytology slides were prepared using the SurePath method and immunoenzyme stained with WT1 antibody, and the number of WT1-positive cells was counted. RESULTS: In kidney disease, WT1-positive cells were found in 33 (50%) of 66 samples. No WT1-positive cells were found in 45 patients with lower urinary tract disease or in 30 healthy volunteers. The positive rates for WT1 varied with disease type, but not significantly: immunoglobulin A (IgA) nephropathy, (14/23); membranous glomerulonephritis, (4/10); Henoch-Schönlein purpura nephritis, (3/5); diabetic glomerulopathy, (5/5); minor glomerular abnormality/minimal change nephrotic syndrome (0/4). CONCLUSIONS: The results suggest that WT1 immunoenzyme staining of urine cytology can be used to detect some types of kidney disease.

Observation of co-segregation of titanium and boron at the interface between recrystallized and unrecrystallized grains in cold-rolled interstitial-free steel sheets.

It has been reported that the addition of ppm levels of B strongly retarded the growth of recrystallized grain into unrecrystallized grains in the process of cold-rolling and annealing of Ti-added interstitial-free (IF) ferritic steels. This phenomenon was explained by solute drag effect based on the assumption that, during annealing, B atoms segregate at the interface between recrystallized and unrecrystallized grains where they interact with Ti atoms. To verify this, atom probe tomography analysis of the interface was performed in Ti-added IF steels with and without B addition. Needle tips containing the interface identified from electron backscattering diffraction analysis, were produced by focused ion beam milling with the lift-out method. To increase the experiment reliability, the misorientation angle of the aimed interface was compared with that estimated by field ion microscopy analysis. Considerable amount of Ti segregation was observed at the interface in the steel without B addition, which increased with increasing amount of B segregation in the steel with B addition. The results suggest that the retardation of the interface migration was caused by solute drag effect based on the simultaneous co-segregation of Ti and B due to their attractive interaction.

The Tol2 transposon system mediates the genetic engineering of T-cells with CD19-specific chimeric antigen receptors for B-cell malignancies.

Engineered T-cell therapy using a CD19-specific chimeric antigen receptor (CD19-CAR) is a promising strategy for the treatment of advanced B-cell malignancies. Gene transfer of CARs to T-cells has widely relied on retroviral vectors, but transposon-based gene transfer has recently emerged as a suitable nonviral method to mediate stable transgene expression. The advantages of transposon vectors compared with viral vectors include their simplicity and cost-effectiveness. We used the Tol2 transposon system to stably transfer CD19-CAR into human T-cells. Normal human peripheral blood lymphocytes were co-nucleofected with the Tol2 transposon donor plasmid carrying CD19-CAR and the transposase expression plasmid and were selectively propagated on NIH3T3 cells expressing human CD19. Expanded CD3(+) T-cells with stable and high-level transgene expression (~95%) produced interferon-γ upon stimulation with CD19 and specifically lysed Raji cells, a CD19(+) human B-cell lymphoma cell line. Adoptive transfer of these T-cells suppressed tumor progression in Raji tumor-bearing Rag2(-/-)γc(-/-) immunodeficient mice compared with control mice. These results demonstrate that the Tol2 transposon system could be used to express CD19-CAR in genetically engineered T-cells for the treatment of refractory B-cell malignancies.

Effects of ouabain on respiratory rhythm generation in brainstem-spinal cord preparation from newborn rats and in decerebrate and arterially perfused in situ preparation from juvenile rats.

The significance of Na/K-ATPase on respiratory rhythm generation is not well understood. We investigated the effects of the Na/K-ATPase blocker, ouabain, on respiratory rhythm. Experiments were performed with brainstem-spinal cord preparation from 0 to 3-day-old Wistar rats and with decerebrate and arterially perfused in situ preparation from juvenile rats (postnatal day 11-13). Newborn rat preparations were superfused at a rate of 3.0 ml/min with artificial cerebrospinal fluid, equilibrated with 95% O2 and 5% CO2, pH 7.4, at 26-27 °C. Inspiratory activity was monitored from the fourth cervical ventral root (C4). Application of ouabain (15-20 min) resulted in a dose-dependent increase in the burst rate of C4 inspiratory activity. After washout, the burst rate further increased to reach quasi-maximum values under each condition (e.g. 183% of control in 1 µM, 253% in 10 µM, and 303% in 20 µM at 30 min washout). Inspiratory or pre-inspiratory neurons in the rostral ventrolateral medulla were depolarized. We obtained similar results (i.e. increased phrenic burst rate) in an in situ perfused preparation of juvenile rats. Genes encoding the Na/K-ATPase α subunit were expressed in the region of the parafacial respiratory group (pFRG) in neonatal rats, suggesting that cells (neurons and/or glias) in the pFRG were one of the targets of ouabain. We concluded that Na/K-ATPase activity could be an important factor in respiratory rhythm modulation.

Outcomes of case-matched injection sclerotherapy with a new agent for hemorrhoids in patients treated with or without blood thinners.

PURPOSE: In Japan, a new type of sclerotherapy termed ALTA (aluminum potassium sulfate and tannic acid) injection therapy has recently been introduced. The objectives of this study were to determine whether the presence or absence of antithrombotic treatment (AT) affected the efficacy rate or the occurrence of complications associated with ALTA injection sclerotherapy. METHODS: This study was a case-matched study of 37 patients who underwent ALTA therapy to treat hemorrhoids between 2007 and 2009. Each AT patient was matched for age and degree of hemorrhoids with a control non-AT patient. In each of the subgroups, the therapeutic efficacy of ALTA therapy was evaluated by comparing an assessment completed before therapy with an assessment completed 6 months after therapy. RESULTS: The efficacy in patients with bleeding did not differ between the two groups (P = 0.074). The efficacy in patients with prolapse was significantly lower in the AT group than in the non-AT group (P = 0.013). The two groups did not differ significantly in the occurrence of complications (P = 0.450). CONCLUSIONS: Among patients with hemorrhoids receiving AT, ALTA injection sclerotherapy is recommended for those in whom it is difficult to discontinue AT.

Can population differences in chemotherapy outcomes be inferred from differences in pharmacogenetic frequencies?

Inter-ethnic differences in drug handling and frequencies of pharmacogenetic variants are increasingly being characterized. In this study, we systematically assessed the feasibility of inferring ethnic trends in chemotherapy outcomes from inter-ethnic differences in pharmacogenetic variant frequencies. Frequencies of 51 variants and chemotherapy outcomes of East Asian and Caucasian colorectal cancer patients on standard chemotherapy regimens were summarized by meta-analyses, and variant frequencies were validated by MassARRAY analysis. Inferences of relative chemotherapy outcomes were made by considering minor allele function and population differences in their frequency. Significant population differences in genotype distributions were observed for 13/23 (60%) and 27/35 (77%) variants in the meta-analyses and validation series, respectively. Across chemotherapy regimens, East Asians had lower rates of grade 3/4 toxicity for diarrhea and stomatitis/mucositis than Caucasians, which was correctly inferred from 13/18 (72%, P=0.018) informative genetic variants. With appropriate variant selection, inferring relative population toxicity rates from population genotype differences may be relevant.

Supramolecular approaches for drug development.

Various supramolecular systems can be used as drug carriers to alter physicochemical and pharmacokinetic characteristics of drugs. Representative supramolecular systems that can be used for this purpose include surfactant/polymer micelles, (micro)emulsions, liposomes, layer-by-layer assemblies, and various molecular conjugates. Notably, liposomes are established supramolecular drug carriers, which have already been marketed in formulations including AmBisome(®) (for treatment of fungal infection), Doxil(®) (for Kaposi's sarcoma), and Visudyne(®) (for age-related macular degeneration and choroidal neovascularization). Microemulsions have been used oral drug delivery of poorly soluble drugs due to improvements in bioavailability and predictable of absorption behavior. Neoral(®), an immunosuppressant used after transplant operations, is one of the most famous microemulsion-based drugs. Polymer micelles are being increasingly investigated as novel drug carriers and some formulations have already been tested in clinical trials. Supramolecular systems can be functionalized by designing the constituent molecules to achieve efficient delivery of drugs to desired sites in the body. In this review, representative supramolecular drug delivery systems, that may improve usability of candidate drugs or add value to existing drugs, are introduced.

Diagnostic performance of chromoendoscopy and narrow band imaging for colonic neoplasms: a meta-analysis.

AIM: We conducted a meta-analysis to compare the diagnostic test performance of chromoendoscopy and narrow band imaging (NBI) for colonic neoplasms. METHOD: MEDLINE, EMBASE and the Cochrane Library were searched (1966 to March 2009). Articles were included if: (i) chromoendoscopy or NBI was used, (ii) sensitivity and specificity were reported; (iii) absolute numbers of true-positive, false-positive, true-negative and false-negative results were provided or could be calculated; and (iv) pathology was used as the reference standard. Sensitivity and specificity were pooled using random effects model. Secondary analyses were conducted by limiting the studies in which magnifying endoscopy was used alone as a diagnostic modality, and polyp size and macroscopic appearance of lesions were not considered. RESULTS: Of 1342 screened articles, 27 met the inclusion criteria. Pooled sensitivity for chromoendoscopy and NBI was 0.94 (95% CI, 0.92-0.95) and 0.94 (0.91-0.97), and specificity was 0.82 (0.77-0.88) and 0.86 (0.83-0.89), respectively. There were no differences in sensitivity (P = 0.99) or specificity (P = 0.54) between the two methods. In the secondary analysis, pooled sensitivity for choromoendoscopy and NBI was 0.93 (95% CI, 0.90-0.97) and 0.96 (0.93-0.99) and specificity was 0.80 (0.73-0.87) and 0.85 (0.78-0.92). respectively. Overall, the pooled false-negative rate was 0.057 (95% CI, 0.040-0.73) for chromoendoscopy and 0.057 (95% CI, 0.028-0.085) for NBI. CONCLUSION: Chromoendoscopy and NBI had similar diagnostic test characteristics in the assessment of colonic neoplasms; however, the false-negative rate for both methods of 5.7% is an unacceptably high rate and currently therefore, neither method is ready for general use.

Tumour suppressors miR-1 and miR-133a target the oncogenic function of purine nucleoside phosphorylase (PNP) in prostate cancer.

BACKGROUND: Our recent analyses of miRNA expression signatures showed that miR-1 and miR-133a were significantly reduced in several types of cancer. Interestingly, miR-1 and miR-133a are located on the same chromosomal locus in the human genome. We examined the functional significance of miR-1 and miR-133a in prostate cancer (PCa) cells and identified the novel molecular targets regulated by both miR-1 and miR-133a. METHODS AND RESULTS: The expression levels of miR-1 and miR-133a were significantly downregulated in PCa compared with non-PCa tissues. Restoration of miR-1 or miR-133a in PC3 and DU145 cells revealed significant inhibition of proliferation, migration, and invasion. Molecular target identification by genome-wide gene expression analysis and luciferase reporter assay showed that purine nucleoside phosphorylase (PNP) was directly regulated by both miRNAs. Silencing of the PNP gene inhibited proliferation, migration, and invasion in both PC3 and DU145 cells. Immunohistochemistry detected positive staining of PNP in PCa specimens. CONCLUSIONS: Downregulation of miR-1 and miR-133a was a frequent event in PCa and both function as tumour suppressors. The PNP is a novel target gene of both miRNAs and potentially functions as an oncogene. Therefore, identification of novel molecular networks regulated by miRNAs may provide new insights into the underlying causes of PCa oncogenesis.

Tumour suppressive microRNA-874 regulates novel cancer networks in maxillary sinus squamous cell carcinoma.

BACKGROUND: On the basis of the microRNA (miRNA) expression signature of maxillary sinus squamous cell carcinoma (MSSCC), we found that miR-874 was significantly reduced in cancer cells. We focused on the functional significance of miR-874 in cancer cells and identification of miR-874-regulated novel cancer networks in MSSCC. METHODS: We used PCR-based methods to investigate the downregulated miRNAs in clinical specimens of MSSCC. Our signature analyses identified 23 miRNAs that were significantly reduced in cancer cells, such as miR-874, miR-133a, miR-375, miR-204, and miR-1. We focused on miR-874 as the most downregulated novel miRNA in our analysis. RESULTS: We found potential tumour suppressive functions such as inhibition of cancer cell proliferation and invasion. A molecular target search of miR-874 revealed that PPP1CA was directly regulated by miR-874. Overexpression of PPP1CA was observed in MSSCC clinical specimens. Silencing of the PPP1CA gene significantly inhibited cancer cell proliferation and invasion. CONCLUSION: The downregulation of miR-874 was a frequent event in MSSCC, which suggests that miR-874 functions as a tumour suppressive miRNA, directly regulating PPP1CA that has a potential role of an oncogene. The identification of novel miR-874-regulated cancer pathways could provide new insights into potential molecular mechanisms of MSSCC oncogenesis.

Quantitative analysis of carbon content in cementite in steel by atom probe tomography.

Atom probe performance in the quantitative analysis of carbon atoms in steel was investigated through analysis of stoichiometric spherical cementite (Fe(3)C) in steel. The carbon concentration was estimated by determining the mean carbon number of molecular ions having a mass-to-charge ratio of 24. The apparent carbon concentration of cementite increased as the specimen temperature decreased, and it was several at% higher than the stoichiometric value (25 at%) under the preferable condition of low specimen temperature. On the other hand, the apparent carbon concentration was not changed by pulse fraction. These results indicate that the large deviation from the stoichiometric value did not arise from the preferential retention and evaporation between carbon and iron. The other mechanisms explaining the phenomenon have been discussed.

The tumour-suppressive function of miR-1 and miR-133a targeting TAGLN2 in bladder cancer.

BACKGROUND: On the base of the microRNA (miRNA) expression signature of bladder cancer (BC), we found that miR-1 and miR-133a were significantly downregulated in BC. In this study, we focussed on the functional significance of miR-1 and miR-133a in BC cell lines and identified a molecular network of these miRNAs. METHODS AND RESULTS: We investigated the miRNA expression signature of BC clinical specimens and identified several downregulated miRNAs (miR-133a, miR-204, miR-1, miR-139-5p, and miR-370). MiR-1 and miR-133a showed potential role of tumour suppressors by functional analyses of BC cells such as cell proliferation, apoptosis, migration, and invasion assays. Molecular target searches of these miRNAs showed that transgelin 2 (TAGLN2) was directly regulated by both miR-1 and miR-133a. Silencing of TAGLN2 study demonstrated significant inhibitions of cell proliferation and increase of apoptosis in BC cell lines. The immunohistochemistry showed a positive correlation between TAGLN2 expression and tumour grade in clinical BC specimens. CONCLUSIONS: The downregulation of miR-1 and miR-133a was a frequent event in BC, and these miRNAs were recognised as tumour suppressive. TAGLN2 may be a target of both miRNAs and had a potential oncogenic function. Therefore, novel molecular networks provided by miRNAs may provide new insights into the underlying molecular mechanisms of BC.