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Restoration of W1282X CFTR activity by enhanced expression 总被引:1,自引:0,他引:1
Rowe SM Varga K Rab A Bebok Z Byram K Li Y Sorscher EJ Clancy JP 《American journal of respiratory cell and molecular biology》2007,37(3):347-356
Cystic fibrosis results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Premature termination codons represent a common minority of CFTR mutations, and are caused by base pair substitutions that produce abnormal stop codons in the coding sequence. Select aminoglycosides induce "translational readthrough" of premature stop codons and have been shown to restore full-length functional protein in a number of preclinical and clinical settings. We studied two well-described premature termination codons found in the distal open reading frame of CFTR, W1282X and R1162X, expressed in polarizing and nonpolarizing cells. Our findings indicate that W1282X CFTR-expressing cells demonstrate significantly greater CFTR activity when overexpressed compared with R1162X CFTR cells, even when truncated protein is the predominant form. In addition, our results show that the combination of stimulated expression and stop codon suppression produces additive effects on CFTR-mediated ion transport. These findings provide evidence that W1282X CFTR exhibits membrane localization and retained chloride channel function after enhanced expression, and suggest that patients harboring this mutation may be more susceptible to CFTR rescue. 相似文献
145.
Omar Vergara-Fernandez Rabí Mejía-Ovalle Noel Salgado-Nesme Nathalie Rodríguez-Dennen Javier Pérez-Aguirre Víctor Hugo Guerrero-Guerrero Juan Carlos Sánchez-Robles Miguel Angel Valdovinos-Díaz 《Surgery today》2014,44(1):34-38
Purpose
To assess the functional outcomes and quality of life in patients with laparoscopic total colectomy for slow-transit constipation (STC).Methods
All patients undergoing laparoscopic colectomy with ileorectal anastomosis for colonic inertia at two referral centers were analyzed. Their preoperative, intraoperative and postoperative details were recorded with a one-year follow-up. Their quality of life was assessed using the SF-36 questionnaire.Results
Between 2004 and 2007, 710 patients were evaluated. Eight female patients (1.1 %) fulfilled the criteria for STC without obstructive defecation syndrome. Their mean age was 38 years ± 15 (range from 22 to 62). The conversion rate was 12.5 %. The morbidity rate was 37.5 %, and mortality was nil. The preoperative abdominal pain was 6.6 ± 0.3 and had decreased to 3.6 ± 2.3 postoperatively (P = 0.008). At 1 year, the defecation frequency per week had increased from 0.84 ± 0.24 to 6.75 ± 3.4 (P = 0.001). Three patients developed nocturnal leakage (37.5 %). Eighty-eight percent of the patients recommend the procedure. All parameters of the SF-36 questionnaire had improved at the one-year follow-up examination.Conclusion
Laparoscopic colectomy for slow-transit constipation is safe and increased the number of evacuations per week. Although nocturnal leakage may occur, these patients experience improvements in their quality of life. 相似文献146.
Kinematic analysis of the upper extremity has been conducted using a wide variety of techniques, philosophies, and analytic methods. We describe a simple, marker-based three-dimensional video analytic technique that borrows concepts from lower extremity kinematic analysis. A sequential rotation order about orthogonal axes is described, although alternate methods are examined as well. The method has been verified by application to a mechanical model. In certain positions, gimbal lock may occur, and a different sequence of rotational decomposition may be required. Agreement on standardization of technique would assist in the dissemination of upper extremity scientific data. 相似文献
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Naimi AI Bourbeau J Perrault H Baril J Wright-Paradis C Rossi A Taivassalo T Sheel AW Rabøl R Dela F Boushel R 《Clinical physiology and functional imaging》2011,31(2):124-131
Evidence exists for locomotor muscle impairment in patients with chronic obstructive pulmonary disease (COPD), including fiber type alterations and reduced mitochondrial oxidative capacity. In this study high-resolution respirometry was used to quantify oxygen flux in permeabilized fibres from biopsies of the vastus lateralis muscle in patients with COPD and compared to healthy control subjects. The main findings of this study were that (i) routine state 2 respiration was higher in COPD; (ii) state 3 respiration in the presence of ADP was similar in both groups with substrate supply of electrons to complex I (COPD 38·28 ± 3·58 versus control 42·85 ± 3·10 pmol s(-1) mg tissue(-1) ), but O(2) flux with addition of succinate was lower in COPD patients (COPD 63·72 ± 6·33 versus control 95·73 ± 6·53 pmol s(-1) mg tissue(-1) ); (iii) excess capacity of cytochrome c oxidase in COPD patients was only ~50% that of control subjects. These results indicate that quadriceps muscle mitochondrial function is altered in patients with COPD. The regulatory mechanisms underlying these functional abnormalities remain to be uncovered. 相似文献
150.
Masanori Oshi Tsutomu Kawaguchi Li Yan Xuan Peng Qianya Qi Wanqing Tian Amy Schulze Kerry-Ann McDonald Sumana Narayanan Jessica Young Song Liu Luc GT Morris Timothy A Chan Pawel Kalinski Ryusei Matsuyama Eigo Otsuji Itaru Endo Kazuaki Takabe 《American journal of cancer research》2021,11(7):3628
Evaluation of the functional aspects if the tumor immune microenvironment (TIME), such as the recently introduced cytolytic activity score (CYT) index have been under the spotlight in cancer research; however, clinical relevance of immune cell killing activity in breast cancer has never been analyzed in large patient cohorts. We hypothesized that CYT reflects the immune activity of TIME and can predict patient survival. A total of 7533 breast cancer patients were analyzed as both discovery and validation cohorts. We found that high CYT was associated with advanced histological grade and triple-negative breast cancer (TNBC). High CYT in tumors was significantly associated with better survival in TNBC, but unexpectedly, not in other breast cancer subtypes. High CYT TNBC included both favorable immune-related, as well as unfavorable (suppressive) inflammation-related gene sets, and characterized by high infiltration with T cells and B cells. High CYT TNBC was associated with high homologous recombination deficiency and low somatic copy number alteration score and less mutant allele tumor heterogeneity, but not with tumor mutation burden (TMB). Although CYT was not associated with pathological complete response after neoadjuvant chemotherapy, it was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, CYT of TNBC is associated with enhanced anti-cancer immunity, less intra-tumoral heterogeneity, and with better survival. 相似文献