Gene transfer of GLT-1, a glial glutamate transporter, into the spinal cord by recombinant adenovirus attenuates inflammatory and neuropathic pain in rats

<p>Abstract</p> <p>Background</p> <p>The glial glutamate transporter GLT-1 is abundantly expressed in astrocytes and is crucial for glutamate removal from the synaptic cleft. Decreases in glutamate uptake activity and expression of spinal glutamate transporters are reported in animal models of pathological pain. However, the lack of available specific inhibitors and/or activators for GLT-1 makes it difficult to determine the roles of spinal GLT-1 in inflammatory and neuropathic pain. In this study, we examined the effect of gene transfer of GLT-1 into the spinal cord with recombinant adenoviruses on the inflammatory and neuropathic pain in rats.</p> <p>Results</p> <p>Intraspinal infusion of adenoviral vectors expressing the GLT-1 gene increased GLT-1 expression in the spinal cord 2–21 days after the infusion. Transgene expression was primarily localized to astrocytes. The spinal GLT-1 gene transfer had no effect on acute mechanical and thermal nociceptive responses in naive rats, whereas it significantly reduced the inflammatory mechanical hyperalgesia induced by hindlimb intraplantar injection of carrageenan/kaolin. Spinal GLT-1 gene transfer 7 days before partial sciatic nerve ligation recovered the extent of the spinal GLT-1 expression in the membrane fraction that was decreased following the nerve ligation, and prevented the induction of tactile allodynia. However, the partial sciatic nerve ligation-induced allodynia was not reversed when the adenoviruses were infused 7 or 14 days after the nerve ligation.</p> <p>Conclusion</p> <p>These results suggest that overexpression of GLT-1 on astrocytes in the spinal cord by recombinant adenoviruses attenuates the induction, but not maintenance, of inflammatory and neuropathic pain, probably by preventing the induction of central sensitization, without affecting acute pain sensation. Upregulation or functional enhancement of spinal GLT-1 could be a novel strategy for the prevention of pathological pain.</p

Clinical significance of the expression of connexin26 in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Connexin26 (Cx26) is one of the connexins (Cxs) family members which form gap junction channels. Cx26 is considered to be a tumor suppressor gene. However, recent studies revealed that over expression of Cx26 is associated with a poor prognosis in several human cancers. This study investigated the correlation between Cx26 expression and the clinicopathological features and P53 expression in colorectal cancer.</p> <p>Methods</p> <p>One hundred and fifty-three patients who underwent a curative resection were studied. Tissue samples were investigated by immunohistochemical staining using antibodies for Cx26 and P53. Moreover, apoptotic cells were detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining.</p> <p>Results</p> <p>Cx26 expression was found in 83 cases (54.2%) and P53 expression in 71 cases (46.4%). A correlation was observed between the Cx26 expression and recurrence, histology, and p53 expression (P < 0.05). Cx26 positive tumors had significantly longer survival than Cx26 negative tumors (P < 0.05). A multivariate Cox analysis demonstrated that Cx26 expression was an independent prognostic factor (P < 0.05). However, no significant correlation was observed between Cx26 and AI.</p> <p>Conclusion</p> <p>This study suggests that Cx26 expression is an independent prognostic factor in patients that undergo a curative resection of colorectal cancer.</p

Comparison of muscle quality and functional capacity between Japanese and Brazilian older individuals

Muscle quality is well-known to decrease with aging and is a risk factor for metabolic abnormalities. However, there is a lack of information on race-associated differences in muscle quality and other neuromuscular features related to functional performance. This study aimed to compare muscle quality, function, and morphological characteristics in Japanese and Brazilian older individuals. Eighty-four participants aged 65–87 years were enrolled in the study (42 Japanese: 23 men, 19 women, mean age 70.4 years; 42 Brazilians: 23 men, 19 women, mean age 70.8 years). Echo intensity (EI) and muscle thickness (MT) of the quadriceps femoris were measured using B-mode ultrasonography. A stepwise multiple linear regression analysis with EI as a dependent variable revealed that MT was a significant variable for Japanese participants (R2 = 0.424, P = 0.001), while MT and subcutaneous adipose tissue (SCAT) thickness were significant variables for Brazilian participants (R2 = 0.490, P = 0.001). A second stepwise multiple linear regression analysis was performed after excluding MT and SCAT thickness from the independent variables. Sex and age for Japanese participants (R2 = 0.381, P = 0.001) and lean body mass and body mass index for Brazilian participants (R2 = 0.385, P = 0.001) were identified as significant independent variables. The present results suggest that MT is closely correlated with muscle quality in Japanese and Brazilian older individuals. Increases in muscle size may induce decreases in intramuscular adipose tissue and/or connective tissues, which are beneficial for reducing the risks of metabolic impairments in Japanese and Brazilian older individuals

Two Cases of Long-Term Control of Metastatic Colorectal Cancer via FTD/TPI plus Bevacizumab in Elderly Patients

With advances in new cytotoxic drugs and molecular-targeted drugs, the prognosis of patients with metastatic colorectal cancer (mCRC) has improved. However, physicians often hesitate to administer intensive standard regimens to elderly patients with mCRC. Recently, first-line regimens that are effective in and well-tolerated by patients who are not eligible for intensive chemotherapy have been established. However, the therapeutic strategies to adopt after the failure of first-line treatment for patients who are not eligible for intensive chemotherapy remain unclear. We herein report two cases of long-term control of mCRC via FTD/TPI+bevacizumab (Bmab) as second- or third-line treatment in elderly patients without severe adverse events. In case 1, first-line treatment with Tegafur-Uracil, which is a prodrug of 5-FU, caused disease progression in a short period after the initiation of chemotherapy. In case 2, intensive first-line treatment caused severe adverse events, and treatment was discontinued. However, in both cases, disease control was obtained for a long time without severe adverse events by subsequent treatment with FTD/TPI+Bmab. The success in these present cases indicates that FTD/TPI+Bmab as a second- or third-line treatment is a therapeutic option for elderly patients with mCRC who are not eligible for intensive chemotherapy, even after failure of treatment with 5-FU

Complete Response of Pulmonary Metastases from Rectal Cancer to Tegafur-Uracil/Leucovorin plus Bevacizumab in an Elderly Patient: A Case Report

As a result of recent major advances in chemotherapy for metastatic colorectal cancer, the prognosis for patients with metastatic colorectal cancer has improved. However, elderly patients often cannot receive intensive therapy. There are still many problems to solve regarding treatment for elderly patients with metastatic colorectal cancer. We herein report a case of complete response of pulmonary metastases from rectal cancer to tegafur-uracil (UFT)/leucovorin (LV) + bevacizumab (Bmab) in an elderly patient. An 80-year-old woman who had undergone curative surgery for rectal cancer 5 years ago was diagnosed with pulmonary metastases. Taking into account her advanced age and low renal function (creatinine clearance: 41.2 mL/min), UFT/LV + Bmab therapy was selected. The patient received UFT (300 mg/m2/day) and LV (75 mg/day) on days 1–5, 8–12, and 15–19 and Bmab (7.5 mg/kg) on day 1. The treatment cycle was repeated every 21 days. Following 17 courses of treatment without adverse events, a complete response was observed. Furthermore, there was no recurrence within 6 months after the final course of therapy. This case indicates that UFT/LV + Bmab is suitable for the treatment of elderly patients with metastatic colorectal cancer

Association of serum gamma-glutamyltransferase (GGT) and diabetes with triglycerides-to-HDL cholesterol ratio in Japanese subjects: The Nagasaki Study

Background: Although we reported in a previous study that diabetes with a high serum triglycerides to high-density lipoproteincholesterol (TG-HDL) ratio constitutes a risk for atherosclerosis, associations in terms of TG-HDL ratio between diabetes and gamma-glutamyltransferase (GGT), which is also known as an independent risk factor for atherosclerosis, have not yet been clarified. The purpose of this study was to test the hypothesis that a positive association between GGT and diabetes may be confined to high TG-HDL. Methods: This was a cross-sectional study of 2,302 Japanese subjects who were undergoing a general health check in 2014. All subjects were divided into TG-HDL level tertiles and serum GGT and diabetes status were investigated. Results: Of 207 diabetes patients identified in this study, 94 had high TG-HDL, 63 intermediate TG-HDL, and 50 low TG-HDL. Independent of classical cardiovascular risk factors, serum GGT showed a positive association with diabetes in patients with high TG-HDL, but not in patients with intermediate and low TG-HDL diabetes. The multivariable adjusted odds ratios (OR) and 95% coincidence intervals (95%CI) of diabetes for 1 standard deviation (SD) increment of GGT were 1.64 (95%CI: 1.16-2.31) for high TG-HDL, 1.46 (95%CI: 0.95-2.26) for intermediate TG-HDL, and 1.04 (95%CI: 0.60-1.79) for low TG-HDL diabetes. Conclusion: Serum GGT is positively associated with diabetes in patients with high TG-HDL but not with intermediate or low TG-HDL diabetes. This finding may prove to be an efficient tool for estimating atherosclerotic risk in diabetes patients

Allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with t(6;9)(p23;q34) dramatically improves the patient prognosis: A matched-pair analysis

Acute myeloid leukemia (AML) with t(6;9)(p23;q34) is well known to have a poor prognosis treated with chemotherapy and autotransplantation. The presence of this karyotype is an indicator for allogeneic hematopoietic stem cell transplantation (HSCT); however, the impact of t(6;9)(p23;q34) on the HSCT outcome remains unclear. We conducted a matched-pair analysis of de novo AML patients with and without t(6;9)(p23;q34) using data obtained from the Japanese HSCT data registry. A total of 57 patients with t(6;9)(p23;q34) received transplants between 1996 and 2007, and 171 of 2056 normal karyotype patients matched for age, disease status at HSCT and graft source were selected. The overall survival, disease-free survival, cumulative incidence of relapse and the non-relapse mortality in t(6;9)(p23;q34) patients were comparable to those for normal karyotype patients. A univariate analysis showed that t(6;9)(p23;q34) had no significant impact on the overall survival. These findings suggest that allogeneic HSCT may overcome the unfavorable impact of t(6;9)(p23;q34) as an independent prognostic factor. © 2012 Macmillan Publishers Limited All rights reserved

Prognostic factors for acute myeloid leukemia patients with t(6;9)(p23;q34) who underwent an allogeneic hematopoietic stem cell transplant

We have recently reported that the outcome of acute myeloid leukemia (AML) patients with t(6;9)(p23;q34) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) was comparable to that of patients with a normal karyotype. We performed a further analysis regarding the prognostic factors for t(6;9)(p23;q34) AML patients who underwent a HSCT. Seven pediatric patients and 57 adult patients, transplanted between 1996 and 2007, were assessed in this study. The overall survival (OS) of the pediatric patients tended to be better than the OS of the adults, although there were no statistically significant differences. The present study focused on the adult patients revealed that the disease status at HSCT was the sole prognostic factor affecting the OS identified in the univariate analysis. A multivariate analysis showed that the disease status at HSCT and M2 in the FAB classification were extracted as the significant variables affecting the OS. The patients who were not in remission at HSCT and had non-FAB-M2 showed a poorer outcome; 6 deaths in the 9 patients were due to a relapse of the AML. These findings suggest that novel therapeutic approaches might be needed for patients with these poor prognostic factors.発行後6か月より全文公開