News Article | November 14, 2016
NEW YORK NY (November 14, 2016)--Columbia University Medical Center (CUMC) researchers have demonstrated that vision loss associated with a form of retinitis pigmentosa (RP) can be slowed dramatically by reprogramming the metabolism of photoreceptors, or light sensors, in the retina. The study, conducted in mice, represents a novel approach to the treatment of RP, in which the therapy aims to correct downstream metabolic aberrations of the disease rather than the underlying genetic defect. The findings were published online today in the Journal of Clinical Investigation. "Although gene therapy has shown promise in RP, it is complicated by the fact that defects in 67 genes have been linked to the disorder, and each genetic defect would require a different therapy," said study leader Stephen H. Tsang, MD, PhD, the László Z. Bitó Associate Professor of Ophthalmology, Pathology and Cell Biology, and the Institute of Human Nutrition. "Our study shows that precision metabolic reprogramming can improve the survival and function of affected rods and cones in at least one type of RP. Since many, if not most, forms of the disorder have the same metabolic error, precision reprogramming could conceivably be applied to a wide range of RP patients." RP, an inherited form of vision loss, is caused by genetic defects that lead to the breakdown and loss of rods, the photoreceptors in the retina that enable peripheral and night vision. Over time, the deterioration of rods compromises the function of cones, the color-sensing photoreceptors. People with RP start to experience vision loss in childhood, and many are blind by the time they reach adulthood. Currently, there is no cure or effective treatment for RP, which affects about 1 in 4,000 people worldwide. Rods are among the most metabolically active cells in the body. They are particularly active during periods of darkness, when they burn glucose to release energy. In an earlier paper, Dr. Tsang and his colleagues theorized that rods deteriorate in RP, in part, because they lose the daytime's ability to use glucose to rebuild the rods' outer segment (the light-absorbing portion of the photoreceptor). "We hypothesized that diseased rods could be rescued by reprogramming sugar metabolism," said Dr. Tsang. Dr. Tsang tested this hypothesis in mice with a mutation in the Pde6 gene that disrupts rod metabolism, leading to an RP-like disorder. The mice were treated so that their rods could not express Sirt6, a gene that inhibits sugar metabolism. Examination of photoreceptors with electroretinography showed that the mice had significantly greater measures of rod and cone health than untreated controls. Overall, the metabolomes (all of the metabolites found in an organism) of the treated mice had accumulated the molecules needed to build the outer segment. In addition, both rods and cones survived longer in the treated mice than in the controls. While the treatment significantly prolonged survival of the diseased rods and cones, it did not prevent their eventual death. "Our next challenge is to figure out how to extend the therapeutic effect of Sirt6 inhibition," said Dr. Tsang. "Although the treatment that was used in the mice cannot be applied directly to humans, several known Sirt6 inhibitors could be evaluated for clinical use," according to Vinit B. Mahajan, MD, PhD, a contributing researcher from the University of Iowa. The inhibitors include enzyme blockers called thiomyristoyl peptides, a common plant pigment known as quercetin, and vitexin, a substance derived from the English Hawthorn tree. Dr. Tsang noted, "Further studies are needed to explore the exciting possibility that precision metabolic reprogramming may be used to treat other forms of RP and retinal degeneration." The study is titled, "Reprogramming Sirtuin-6 Attenuates Retinal Degeneration." The other contributors are: Lijuan Zhang (CUMC, the Edward S Harkness Eye Institute, and the Shanxi Eye Hospital, affiliated with Shanxi Medical University, Xinghualing, Taiyuan, Shanxi, China), Jianhai Du (University of Washington, Seattle, WA), Sally Justus (CUMC and the Edward S Harkness Eye Institute), Chun-Wei Hsu (CUMC and the Edward S Harkness Eye Institute), Luis Bonet-Ponce (National Institutes of Health, Bethesda, MD), Wen-Hsuan Wu (CUMC and the Edward S Harkness Eye Institute), Yi-Ting Tsai (CUMC and the Edward S Harkness Eye Institute), Wei-Pu Wu (CUMC and the Edward S Harkness Eye Institute), Yading Jia (Shanxi Eye Hospital), Jimmy K. Duong (CUMC), Chyuan-Sheng Lin (CUMC), Shuang Wang (CUMC), and James B. Hurley (University of Washington). The study was supported by grants from the National Institutes of Health (5P30EY019007, R01EY018213, R01EY024698, 1R01EY026682, and R21AG050437), The National Cancer Institute Core (5P30CA013696), the Research to Prevent Blindness (RPB) Physician-Scientist Award, unrestricted funds from RPB, the Tistou and Charlotte Kerstan Foundation, the Schneeweiss Stem Cell Fund, New York State (C029572), the Foundation Fighting Blindness New York Regional Research Center Grant (C-NY05-0705-0312), Jonas Family Fund, and the Gebroe Family Foundation. The authors declare no conflicts of interest. Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. The campus that Columbia University Medical Center shares with its hospital partner, NewYork-Presbyterian, is now called the Columbia University Irving Medical Center. For more information, visit cumc.columbia.edu or columbiadoctors.org.
Zhang J.,Shanxi Medical University
Cancer Research and Clinic | Year: 2014
Objective: To evaluate the clinical value of gemstone spectral imaging (GSI) in preliminary assessment of esophageal carcinoma pathology features. Methods: 58 patients were analyzed which were diagnosed with histological pathology as esophageal carcinoma underwent GSI enhanced scans before surgery. The iodine concentrations (IC) in the lesions were measured on the iodine-water based material-decomposition images. The results of IC value were evaluated retrospectively with different pathological grading, locations and pathological morphology according to the final pathologic findings. Results: 52 cases patients were squamous cell carcinoma and 6 patients were adenocarcinoma. The IC values were (14.75±4.24) mg/ml and (12.86±5.09) mg/ml. The IC value between the two different pathological types had not statistically difference (P = 0.35). The IC of different pathological grading: Well differentiation was (20.08±4.66)mg/ml, n = 19. Medium was (14.13±3.39) mg/ml, n = 25. Poor was(11.73±3.21) mg/ml, n = 14. The IC values between pathological grading had significant difference(P = 0.00). There were four different pathological morphology including medullar (n = 16), mushroom type (n = 21), ulcer (n = 13) and narrow type (n = 8). Their IC values respectively were (16.34±2.56) mg/ml, (18.70±3.03) mg/ml, (14.31±4.60) mg/ml and (11.18±2.09) mg/ml. The IC value between mushroom and narrow type had statistical difference (P = 0.04). The Other types had no statistically difference (P = 0.19). Conclusions: The results of this study demonstrate that GSI has a certain ability of pathologic stage of esophageal cancer. The GSI has a certain clinical value in guiding treatment and judging prognosis of esophageal carcinoma.
An N.,Shanxi Medical University
Cancer Research and Clinic | Year: 2015
Objective: To compare the synchronous primary endometrial and ovarian carcinomas with primary endometrial cancer with ovarian metastasis through analysis the general condition, clinical features, pathologic result, treatment and the prognosis of the two diseases. Methods:24 patients with synchronous primary endometrial and ovarian carcinomas and 27 patients with primary endometrial cancer with ovarian metastasis in Shanxi Cancer Hospital from January 2000 to January 2015 were collected. Results: There were statistical significance among age, menopause or not, clinical symptoms, ascites, vascular tumor emboli, tumor differentiation, lymph node metastasis and the prognosis between the two groups (all P < 0.05). The patients with synchronous primary endometrial and ovarian carcinomas were younger, had pelvic mass and stomachache, less ascites, no vascular tumor emboli, well tumor differentiation, no lymph node metastasis. They had better prognosis compared with patients with primary endometrial cancer with ovarian metastasis. Conclusions: Patients with synchronous primary endometrial and ovarian carcinomas are younger than patients with primary endometrial cancer with ovarian metastasis, and more early stage, the excessive treatment should be prevented. They have better prognosis compared with patients with primary endometrial cancer with ovarian metastasis.
Wang J.,Shanxi Medical University
PloS one | Year: 2013
Autophagy is important in cells for removing damaged organelles, such as mitochondria. Insufficient autophagy plays a critical role in tissue injury and organ dysfunction under a variety of pathological conditions. However, the role of autophagy in nonlethal traumatic cardiac damage remains unclear. The aims of the present study were to investigate whether nonlethal mechanical trauma may result in the change of cardiomyocyte autophagy, and if so, to determine whether the changed myocardial autophagy may contribute to delayed cardiac dysfunction. Male adult rats were subjected to nonlethal traumatic injury, and cardiomyocyte autophagy, cardiac mitochondrial function, and cardiac function in isolated perfused hearts were detected. Direct mechanical traumatic injury was not observed in the heart within 24 h after trauma. However, cardiomyocyte autophagy gradually decreased and reached a minimal level 6 h after trauma. Cardiac mitochondrial dysfunction was observed by cardiac radionuclide imaging 6 h after trauma, and cardiac dysfunction was observed 24 h after trauma in the isolated perfused heart. These were reversed when autophagy was induced by administration of the autophagy inducer rapamycin 30 min before trauma. Our present study demonstrated for the first time that nonlethal traumatic injury caused decreased autophagy, and decreased autophagy may contribute to post-traumatic organ dysfunction. Though our study has some limitations, it strongly suggests that cardiac damage induced by nonlethal mechanical trauma can be detected by noninvasive radionuclide imaging, and induction of autophagy may be a novel strategy for reducing posttrauma multiple organ failure.
Zhang Q.L.,Shanxi Medical University
International journal of immunopathology and pharmacology | Year: 2011
The rapid development and expanding applications of nanotechnology have led to enhanced exposure of human body to nanoparticles. It is, therefore, necessary to address the safety issue via rigorous toxicological evaluation and to understand the underlying interaction mechanism. However, only a few studies to date have evaluated the safety of nano-sized materials and their potential adverse effects on biological systems. In this study, we sought to investigate the potential toxicity of aluminum oxide (alumina) nanoparticles in ICR strained mice, focusing on potential neurobehavioral defects and the possible mechanisms. The results demonstrated that nano-alumina impaired neurobehavioral functions, including lengthened escape latency, shorter time spent in the target quadrant and reductions in the number of platform crossing. In addition, it induced cell necrosis and apoptosis, which were likely mediated by the reduction of MMP and ROS, and the induction of the caspase-3 gene. Our results implicated that mitochondrial impairment plays a key role in neurotoxicity of nano-alumina, sequent oxidative damage and neural cell loss, especially necrosis, may be direct causes for the neurobehavioral defects. Collectively, nano-alumina presents a strong pro-cell death effect on ICR mice in vivo, suggesting that nano-alumina may serve as an inducer for neural toxicology. Findings in the present study indicating that surface chemical characteristics and nanoscale sizes of nano-alumina could co-contribute significantly to neurotoxicity. The impaired neurobehavioral patterns indicate that nano-alumina particles are more toxic to the cerebrum than those of nano-carbon with the same nanoparticle size and micro-alumina with the same surface chemical characteristics.
Li X.,Shanxi Medical University
PloS one | Year: 2013
Adenylyl cyclases (ACs) play important role in regulating pancreatic beta cell growth, survival and secretion through the synthesis of cyclic AMP (cAMP). MDL-12,330A and SQ 22536 are two AC inhibitors used widely to establish the role of ACs. The goal of this study was to examine the effects of MDL-12,330A and SQ 22536 on insulin secretion and underlying mechanisms. Patch-clamp recording, Ca(2+) fluorescence imaging and radioimmunoassay were used to measure outward K(+) currents, action potentials (APs), intracellular Ca(2+) ([Ca(2+)]i) and insulin secretion from rat pancreatic beta cells. MDL-12,330A (10 μmol/l) potentiated insulin secretion to 1.7 times of control in the presence of 8.3 mmol/l glucose, while SQ 22536 did not show significant effect on insulin secretion. MDL-12,330A prolonged AP durations (APDs) by inhibiting voltage-dependent K(+) (KV) channels, leading to an increase in [Ca(2+)]i levels. It appeared that these effects induced by MDL-12,330A did not result from AC inhibition, since SQ 22536 did not show such effects. Furthermore, inhibition of the downstream effectors of AC/cAMP signaling by PKA inhibitor H89 and Epac inhibitor ESI-09, did not affect KV channels and insulin secretion. The putative AC inhibitor MDL-12,330A enhances [Ca(2+)]i and insulin secretion via inhibition of KV channels rather than AC antagonism in beta cells, suggesting that the non-specific effects is needed to be considered for the right interpretation of the experimental results using this agent in the analyses of the role of AC in cell function.
Zhao Y.,Shanxi Medical University |
Ma L.,Shanxi Medical University
Cornea | Year: 2015
Purpose: Ex vivo cultured limbal epithelial transplantation (CLET) with amniotic membrane (AM) as the substrate is a relatively new type of surgical therapy in treating limbal stem cell deficiency (LSCD). We summarize available evidence for determining the efficiency of this technique by a systematic review and metaanalysis. Methods: Searching the following electronic databases, MEDLINE, EMBASE, and the Cochrane Library, we analyzed the selected articles in 5 main aspects: donor screening, culture methods, evidence of cultivated stem cells, subjective symptoms, and adverse events through systematic review. Specifically, meta-analysis was used in evaluating improvements in ocular surface and visual acuity. Results: A total of 18 articles involving 572 eyes of 562 patients were available. The rate of success and 2-line improvement in bestcorrected visual acuity (BCVA) was 67% [95% confidence interval (CI), 0.59-0.75; I2 = 60%] and 62% (95% CI, 0.57-0.66; I2 = 37.7%), respectively; and no difference was found both in success rate [odds ratio (OR), 1.35; 95% CI, 0.63-2.89; I2 = 46%] and visual acuity outcome (OR, 1.53; 95% CI, 0.67-3.45; I2 = 42.1%) between autograft and allograft. Conclusions: CLET is efficacious in patients with LSCD, and no difference both in success rate and visual acuity outcome between autograft and allograft was found. Overall safety profile was good, with most side effects being transient and amenable to subsequent treatments. The long-term results of autograft and allograft will inform future treatment algorithms and techniques with random control trials and better-designed analysis. © 2015 Wolters Kluwer Health, Inc.
Li Q.,Shanxi Medical University
Cancer Research and Clinic | Year: 2015
Objective To investigate the expression of the enhancer of zeste homolog 2 (EZH2) gene and its significance in colorectal adenocarcinoma. Methods Immunohistochemistry and Western blot was used to assess the expression of EZH2 in human colorectal adenocarcinoma tissues, colorectal adenoma tissues and non-cancerous adjacent colorectal tissues. The relationships between EZH2 and each clinical pathology parameter were analyzed. Results The results of immunohistochemical trail showed that the expression rates of EZH2 in colorectal adenocarcinoma, colorectal adenoma and non-cancerous adjacent colorectal tissues were 80.56 % (87/108), 62.5 % (25/40) and 5.00 % (2/40), respectively (P < 0.05). Western blot revealed that the expression level of EZH2 in colorectal adenocarcinoma tissues, colorectal adenoma tissues and non-cancerous adjacent colorectal tissues level 0.549±0.145, 0.283 ±0.023 and 0.107±0.022, respectively. The level in colorectal adenocarcinoma tissues (0.549±0.145) and colorectal adenoma (0.283±0.023) was significantly higher than that in non-cancerous adjacent colorectal tissues (0.107 ±0.022). Compared with colorectal adenoma tissues, level in colorectal adenocarcinoma tissues was significantly higher. There were significant differences among the three groups (F = 20.113, P < 0.05). The ratio of high expression level of EZH2 in colorectal adenocarcinoma tissues was closed related with tumorgenesis, differentiation, TNM staging and lymphatic metastsis (all P < 0.05). However, no correlation was revealed between EZH2 expression and the age, gender (both P > 0.05). Conclusion The expression of EZH2 may be associated with the tumorgenesis invasion, metastasis and progression of colorectal adenocarcinoma.
Holscher C.,University of Ulster |
Li L.,Shanxi Medical University
Neurobiology of Aging | Year: 2010
Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD). This is most likely due to the desensitisation of insulin receptors in the brain. Insulin acts as a growth factor and supports neuronal repair, dendritic sprouting, and differentiation. This review discusses the potential role that insulin-like hormones could play in ameliorating the reduced growth factor signalling in the brains of people with AD. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have very similar properties in protecting neurons from toxic effects, and are capable of reversing the detrimental effects that beta-amyloid fragments have on synaptic plasticity. Therefore, incretins show great promise as a novel treatment for reducing degenerative processes in AD. © 2008 Elsevier Inc.
Zhang H.,Shanxi Medical University
Cancer Research and Clinic | Year: 2015
Objective: To analyze the clinical features, prognosis and its influence factors of pharyngeal lymphatic ring diffuse large B-cell lymphoma. Methods: 66 cases diagnosed with pharyngeal lymphatic ring diffuse large B-cell lymphoma were analyzed retrospectively, including 13 nasopharynx cases, 49 tonsil cases and 4 tongue root cases. The patients in I - II phases were mainly treated with chemotherapy plus involvement wild illuminate, and the patients in HI-IV phases were mainly treated with chemotherapy. Results: Most patients with pharyngeal lymphatic ring diffuse large B-cell lymphoma were in phase II, showing that neighboring organs were infiltrated, but rare systemic symptom, spleen were invaded and lactic acid dehydrogenase was increased. The overall survival rates of 3 and 5 years in patients with pharyngeal lymphatic ring diffuse large B-cell lymphoma were 77.9 % and 66.9 % respectively. The single-factor analysis indicated that the lactic acid dehydrogenase ≥ 248 U/L, the international prognostic index (IPI) score ≥1, and ECOG score≥2 were the adverse prognosis influence factors. The multiple-factor analysis showed that the IPI score ≥ 1 was related to poor prognosis of pharyngeal lymphatic ring diffuse large B-cell lymphoma. Conclusion: Pharyngeal lymphatic ring diffuse large B-cell lymphoma has unique clinical characteristics, and IPI score can influence the prognosis.