Abstract
The neutron lifetime has been measured by comparing the decay rate with the reaction rate of $^3$He nuclei of a pulsed neutron beam from the spallation neutron source at the Japan Proton ...Accelerator Research Complex (J-PARC). The decay rate and the reaction rate were determined by simultaneously detecting electrons from the neutron decay and protons from the $^3$He(n,p)$^3$H reaction using a gas chamber, the working gas of which contains diluted $^3$He. The measured neutron lifetime was $898\,\pm\,10\,_{\rm stat}\,^{+15}_{-18}\,_{\rm sys}\,$s.
Cancer stem cells have been proposed to be responsible for tumorigenesis and recurrence in various neoplastic diseases, including multiple myeloma (MM). We have previously reported that MM cells ...specifically express HLA class I at high levels and that single-chain Fv diabody against this molecule markedly induces MM cell death. Here we investigated the effect of a new diabody (C3B3) on cancer stem cell-like side population (SP) cells. SP fraction of MM cells highly expressed ABCG2 and exhibited resistance to chemotherapeutic agents; however, C3B3 induced cytotoxicity in both SP cells and main population (MP) cells to a similar extent. Moreover, C3B3 suppressed colony formation and tumorigenesis of SP cells in vitro and in vivo. Crosslinking of HLA class I by C3B3 mediated disruption of lipid rafts and actin aggregation, which led to inhibition of gene expression of β-catenin and pluripotency-associated transcription factors such as Sox2, Oct3/4 and Nanog. Conversely, knockdown of Sox2 and Oct3/4 mRNA reduced the proportion of SP cells, suggesting that these factors are essential in maintenance of SP fraction in MM cells. Thus, our findings reveal that immunotherapeutic approach by engineered antibodies can overcome drug resistance, and provide a new basis for development of cancer stem cell-targeted therapy.
Lung adenocarcinoma (LADCA) patients with epidermal growth factor receptor (EGFR) mutations are in general associated with relatively high clinical response rate to EGFR-tyrosine kinase inhibitors ...(TKIs) but not all responded to TKI. It has therefore become important to identify the additional surrogate markers regarding EGFR-TKI sensitivity.
We first examined the effects of EGFR-TKIs, gefitinib and erlotinib, upon cell proliferation of lung adenocarcinoma cell lines. We then evaluated the gene profiles related to EGFR-TKI sensitivity using a microarray analysis. Results of microarray analysis led us to focus on carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, CEACAM 3, 5, 6, 7, and 19, as potential further surrogate markers of EGFR-TKI sensitivity. We then examined the correlation between the status of CEACAM 3, 5, 6, 7, and 19 immunoreactivity in LADCA and clinicopathological parameters of individual cases.
In the cases with EGFR mutations, the status of all CEACAMs examined was significantly higher than that in EGFR wild-type patients, but there were no significant differences in the status of CEACAMs between TKI responder and nonresponder among 22 patients who received gefitinib therapy. However, among 115 EGFR mutation-negative LADCA patients, both CEACAM6 and CEACAM3 were significantly associated with adverse clinical outcome (CEACAM6) and better clinical outcome (CEACAM3).
CEACAMs examined in this study could be related to the presence of EGFR mutation in adenocarcinoma cells but not represent the effective surrogate marker of EGFR-TKI in LADCA patients. However, immunohistochemical evaluation of CEACAM3/6 in LADCA patients could provide important information on their clinical outcome.
Using oligonucleotide microarray data of 45 hepatocellular carcinoma (HCC) samples, we evaluated gene expression in hepatitis B virus-positive and hepatitis C virus-positive HCCs (HBV- and HCV-HCCs) ...for an association with liver cirrhosis (LC). In all, 89 genes were expressed differentially between HBV-HCCs associated with LC and those not associated with LC. Among them, tumors from LC patients showed significantly lower expression levels of 72 genes and significantly higher levels of 17 genes than the levels found in tumors from non-LC patients. The former included genes responsible for signal transduction, transcription, metabolism, and cell growth. The latter included a tumor suppressor gene and a cell-growth-related gene. Only eight genes were expressed differentially between HCV-HCCs associated with and without LC. Our findings provide as a framework for clarifying the role of LC in HBV- and HCV-related hepatocarcinogenesis.
The Saccharomyces cerevisiae gene,YFL017C, for a putative acetyltransferase was characterized. Disruption of YFL017C was lethal, leading to a morphology similar to those caused by the depletion ...ofAGM1 or UAP1, the genes encoding phospho-N-acetylglucosamine mutase and UDP-N-acetylglucosamine pyrophosphorylase, respectively. This implies the involvement of YFL017C in UDP-N-acetylglucosamine synthesis. The recombinant protein for YFL017C displayed phosphoglucosamine acetyltransferase activities in vitro and utilized glucosamine 6-phosphate as the substrate. When incubated with Agm1p and Uap1p, the Yfl017c protein produced UDP-N-acetylglucosamine from glucosamine 6-phosphate. These results indicate that YFL017C specifies glucosamine-6-phosphate acetyltransferase; therefore, the gene was designated GNA1(glucosamine-6-phosphateacetyltransferase). In addition, whereas bacterial phosphoglucosamine acetyltransferase and UDP-N-acetylglucosamine pyrophosphorylase activities are intrinsic in a single polypeptide, they are encoded by distinct essential genes in yeast. When the sequence of ScGna1p was compared with those of other acetyltransferases, Ile97, Glu98, Val102, Gly112, Leu115, Ile116, Phe142, Tyr143, and Gly147 were found to be highly conserved. When alanine was substituted for these amino acids, the enzyme activity for the substituted Phe142 or Tyr143 enzymes was severely diminished. Although the activity of Y143A was too low to perform kinetics, F142A displayed a significantly increased Km value for acetyl-CoA, suggesting that the Phe142 and Tyr143 residues are essential for the catalysis.
Hepatocellular carcinoma has a poor prognosis because of the high intrahepatic recurrence rate. There are technological limitations to traditional methods such as TNM staging for accurate prediction ...of recurrence, suggesting that new techniques are needed.
We investigated mRNA expression profiles in tissue specimens from a training set, comprising 33 patients with hepatocellular carcinoma, with high-density oligonucleotide microarrays representing about 6000 genes. We used this training set in a supervised learning manner to construct a predictive system, consisting of 12 genes, with the Fisher linear classifier. We then compared the predictive performance of our system with that of a predictive system with a support vector machine (SVM-based system) on a blinded set of samples from 27 newly enrolled patients.
Early intrahepatic recurrence within 1 year after curative surgery occurred in 12 (36%) and eight (30%) patients in the training and blinded sets, respectively. Our system correctly predicted early intrahepatic recurrence or non-recurrence in 25 (93%) of 27 samples in the blinded set and had a positive predictive value of 88% and a negative predictive value of 95%. By contrast, the SVM-based system predicted early intrahepatic recurrence or non-recurrence correctly in only 16 (60%) individuals in the blinded set, and the result yielded a positive predictive value of only 38% and a negative predictive value of 79%.
Our system predicted early intrahepatic recurrence or non-recurrence for patients with hepatocellular carcinoma much more accurately than the SVM-based system, suggesting that our system could serve as a new method for characterising the metastatic potential of hepatocellular carcinoma.
Abstract
Background
Relative apical sparing pattern (RASP) is thought to be associated with prognosis in patients with cardiac amyloidosis or left ventricular hypertrophy (LVH). Although almost all ...patients with severe aortic stenosis (AS) have LVH, little is known about the effect of transcatheter aortic valve implantation (TAVI) in patients with severe AS exhibiting a RASP.
Purpose
This study aimed to elucidate the effect of TAVI on left ventricular global longitudinal strain (LS; LVGLS) in patients with severe AS exhibiting a RASP.
Methods
Eighty-four patients who underwent transfemoral or subclavian TAVI were evaluated. They were divided into the RASP and non-RASP groups. The average apical LS divided by the sum of the average mid and basal LS values of >1.0 was defined as the RASP. We analyzed the difference between pre- and post-TAVI LVGLS (ΔGLS = post-TAVI LVGLS − pre-TAVI LVGLS).
Results
Of the 84 patients (mean age, 84.5±3.9 years; 24 men), 15 (17.9%) exhibited a RASP. No significant difference in mean pre-TAVI LVGLS was found between the RASP and non-RASP groups (−16.6% ± 3.8% vs. −15.8% ± 3.9%). The ΔGLS in the RASP group was significantly higher than that in the non-RASP group (−0.97% ± 2.5% vs. −2.6% ± 3.0%; P<0.05). Multivariate analysis revealed that relative apical longitudinal strain was an independent predictor of ΔGLS (β = 0.35, p=0.002).
Conclusion
Relative apical longitudinal strain was associated with LVGLS recovery. The effect of TAVI on LVGLS in patients with a RASP is inferior to that in patients without a RASP.
Funding Acknowledgement
Type of funding source: None
Introduction
Dry eye disease (DED) is commonly encountered in eye clinics and hospitals, and it is therefore very important to understand DED prevalence in outpatients.
Methods
A multicenter, ...hospital-based cross-sectional study was conducted among outpatients in Japan to ascertain DED prevalence and relationships between DED and patient profiles, including eye disease, DED diagnosis history, and surgical history. DED was diagnosed according to diagnostic criteria of the Asia Dry Eye Society. Patient self-assessment of DED-related subjective symptoms was conducted using the 5-Item Dry Eye Questionnaire (DEQ-5). Tear break-up time was evaluated in subjective symptom-positive patients.
Results
The prevalence of DED was 55.7% in 990 patients (mean age 69.1 ± 13.4 years), DED was commonly experienced in combination with other ocular diseases. In revisiting patients, 15.2% had not previously been diagnosed as DED, and their total DEQ-5 scores were higher than those of patients who had undergone DED treatment.
Conclusion
This study revealed that more than half of the outpatients had DED. Among revisiting patients, there were many “hidden” DED patients who had not been diagnosed with DED in the past. There is a high likelihood of finding DED comorbidity in patients with other eye diseases in eye clinics and hospitals.
Funding
Santen Pharmaceutical Co., Ltd.
Trial Registration
UMIN Clinical Trials Registry Identifier, UMIN000035506.
The human mRNA 5′-capping enzyme cDNA was identified. Three highly related cDNAs, HCE1 (human mRNA capping enzyme 1), HCE1A and HCE1B, were isolated from a HeLa cDNA library. The HCE1 cDNA has the ...longest ORF, which can encode a 69 kDa protein. A short region of 69 bp in the 3′-half of the HCE1 ORF was missing in HCE1A and HCE1B, and, additionally, HCE1B has an early translation termination signal, which suggests that the latter two cDNAs represent alternatively spliced product. When expressed in Escherichia coli as a fusion protein with glutathione S-transferase, Hce1p displayed both mRNA 5′-triphosphatase (TPase) and mRNA 5′-guanylyltransferase (GTase) activities, and it formed a cap structure at the 5′-triphosphate end of RNA, demonstrating that it indeed specifies an active mRNA 5′-capping enzyme. The recombinant proteins derived from HCE1A and HCE1B possessed only TPase activity. When expressed from ADH1 promoter, HCE1 but not HCE1A and HCE1B complemented Saccharomyces cerevisiae CEG1 and CET1, the genes for GTase and TPase, respectively. These results demonstrate that the N-terminal part of Hce1p is responsible for TPase activity and the C-terminal part is essential for GTase activity. In addition, the human TPase domain cannot functionally substitute for the yeast enzyme in vivo.
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