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Mitochondrial membrane protein Bcl-xL, a regulator of adult neuronal growth and synaptic plasticity: multiple functions beyond apoptosis

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Neural Regeneration Research 2014年第19期9卷 1706-1707页

作者： Han-A Park Elizabeth A.Jonas Department of internal medicine Section of EndocrinologyYale University

The B-cell lymphoma 2 （Bcl2） family of proteins participates in cell death or survival through a mitochondrial pathway. The pro-apoptotic members of the Bcl2 family such as Bim, Bid, Bax and Bak trigger cell death by contributing to the enhancement of mitochondrial outer membrane permeabil- ity to pro-apoptotic factors such as cytochrome c, with the subsequent activation of caspases. The anti-apoptotic mem- bers, such as B-cell lymphoma-extra large （Bd-xL）, block the pro-apoptotic Bcl2 members and prevent cell death. Bcl-xL is abundantly expressed during development and in mature neurons, suggesting that it plays a role in protection from death from untoward events occurring in adult life such as ischemia, inflammation or trauma. When these neurotoxic in- sults occur, Bcl-xL translocates to mitochondria and prevents activation and homo-oligomerization of pro-apoptotic family members such Bax and Bak. Numerous studies have shown pro-survival roles for Bcl-xL in adult neurons using various models; nevertheless, the role of Bcl-xL outside of the field of neuronal death, i.e., in adult neuronal growth, excitability or synaptic plasticity, has not been studied in depth.

关键词： Mitochondrial membrane protein Bcl-xL a regulator of adult neuronal growth and synaptic plasticity RNAi Bax

Update on acute myeloid leukemia stem cells:New discoveries and therapeutic opportunities

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World Journal of Stem Cells 2016年第10期8卷 316-331页

作者： Maximilian Stahl Tae Kon Kim Amer M Zeidan section of Hematology Department of Internal MedicineYale School of Medicine

The existence of cancer stem cells has been wellestablished in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells(LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells(HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the selfrenewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.

关键词： Leukemia stem cells Cancer stem cells Acute myeloid leukemia Stem cell niche Xenotransplantation Plerixafor NF-κ B C-X-C chemokine receptor type 4

Impaired gallbladder motility and delayed orocecal transit contribute to pigment gallstone and biliary sludge formation in β-thalassemia major adults

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World Journal of Gastroenterology 2004年第16期10卷 2383-2390页

作者： PieroPortincasa AntonioMoschetta MassimoBerardino Agostino Di Ciaula Michele Vacca Giuseppe Baldassarre AnnaPietrapertosa RosarioCammarota NunziaTannoia Giuseppe Palasciano section of internal medicine Department of Internal Medicine and Public Medicine (DIMIMP)University Medical SchoolBariItaly Division of internal medicine Hospital of BisceglieItaly Division Chair

AIM: Gallbladder and gastrointestinal motility defects exist in gallstones patients and to a lesser extent in pigment gallstone patients. To investigated the role of gallbladder and gastrointestinal motility disorders in pigment gallstoneformation in β-thalassemia ***: Twenty-three patients with β-thalassemia major (16 females; age range 18-37 years) and 70 controls (47 females, age range 18-40 years) were studied for gallbladder and gastric emptying (functional ultrasonography),orocecal transit (OCTT, H2-breath test), autonomic dysfunction (sweat-spot, cardiorespiratory reflex tests),bowel habits, gastrointestinal symptoms and quality of life (all with questionnaires). Gallbladder content (ultrasonography) was examined before and during 8-12 mo ***: Gallstones and/or biliary sludge were found in 13 (56%) patients. β-thalassemia major patients had increased fasting (38.04-4.8 mL vs 20.3±0.7 mL, P= 0.0001) and residual (7.94-1.3 mL vs 5.1±0.3 mL, P= 0.002) volumeb and slightly slower emptying (24.94±2.7 min vs20.2±0.7 min,P = 0.04) of the gallbladder, together with longer OCTT(232.24±7.8 rain vs99.7±2.3 rain, P= 0.00003) than *** differences in gastric emptying and bowel habits were found. Also, patients had higher dyspepsia (score: 6.74-1.2vs 4.94-0.2, P = 0.027), greater appetite (P = 0.000004) and lower health perception (P = 0.00002) than *** dysfunction was diagnosed in 52% of patients (positive tests: 76.2% and 66.7% for parasympathetic and sympathetic involvement, respectively). Patients developing sludge during follow-up (38%, 2 with prior stones) had increased fasting and residual gallbladder ***: Adult β-thalassemia major patients have gallbladder dysmotility associated with delayed small intestinal transit and autonomic dysfunction. These abnormalities apparently contribute together with haemolytic hyperbilirubinemia to the pathogenesis of pigment gallstones/sludge in β-thalassemia major.

关键词：胆囊运动性转接色素胆石症胆汁淤积 β-地中海贫血症成年人胃肠运动

Bifunctional chimeric SuperCD suicide gene -YCD: YUPRT fusion is highly effective in a rat hepatoma model

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World Journal of Gastroenterology 2005年第44期11卷 6910-6919页

作者： Florian Graepler Marie-Luise Lemken Wolfgang A Wybranietz Ulrike Schmidt Irina Smirnow Christine D GroB Martin Spiegel Andrea Schenk Schenk Hansj(o|¨)rg Graf Ulrike A Lauer Reinhard Vonthein Michael Gregor Sorin Armeanu Michael Bitzer Ulrich M.Lauer Department of internal medicine Ⅰ section of Experimental Radiology Department of Medical Biometry

AIM： To investigate the effects of catalytically superior gene-directed enzyme prodrug therapy systems on a rat hepatoma model. METHODS： To increase hepatoma cell chemosensitivity for the prodrug 5-fluorocytosine （5-FC）, we generated a chimeric bifunctional SuperCD suicide gene, a fusion of the yeast cytosine deaminase （YCD） and the yeast uracil phosphoribosyltransferase （YUPRT） gene. RESULTS： In vitro stably transduced Morris rat hepatoma cells （MH） expressing the bifunctional SuperCD suicide gene （MH SuperCD） showed a clearly marked enhancement in cell killing when incubated with 5-FC as compared with MH cells stably expressing YCD solely （MH YCD） or the cytosine deaminase gene of bacterial origin （MH BCD）, respectively. In vivo, MH SuperCD tumors implanted both subcutaneously as well as orthotopically into the livers of syngeneic ACI rats demonstrated significant tumor regressions （P〈0.01） under both high dose as well as low dose systemic 5-FC application, whereas MH tumors without transgene expression （MH naive） showed rapid progression. For the first time, an order of in vivo suicide gene effectiveness （SuperCD〉〉 YCD〉〉BCD〉〉〉negative control） was defined as a result of a direct in vivo comparison of all three suicide genes. CONCLUSION： Bifunctional SuperCD suicide gene expression is highly effective in a rat hepatoma model, thereby significantly improving both the therapeutic index and the efficacy of hepatocellular carcinoma killing by fluorocytosine.

关键词： YCD/YUPRT fusion Cytosine deaminase GDEPT Suicide gene therapy Hepatoma therapy

Endoscopic treatment of gastroparesis

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World Journal of Gastroenterology 2015年第22期21卷 6842-6849页

作者： Thomas R McCarty Tarun Rustagi Department of internal medicine Yale University School of Medicine section of Digestive Diseases Department of Internal Medicine Yale University School of Medicine

Gastroparesis has traditionally been a largely medically managed disease with refractory symptoms typically falling under the umbrella of the surgical *** options include, but are not limited to, gastrostomy,jejunostomy, pyloromyotomy, or pyloroplasty,and the Food and Drug Administration approvedgastric electrical stimulation implantation. Endoscopic management of gastroparesis most commonly involves intrapyloric botulinum toxin injection; however, there exists a variety of endoscopic approaches on the horizon that have the potential to radically shift standard of *** management of gastroparesis seeks to treat delayed gastric emptying with a less invasive approach compared to the surgical approach. This review will serve to highlight such innovative and potentially transformative, endoscopic interventions available to gastroenterologists in the management of gastroparesis.

关键词： Botulinum Gastrojejunostomy Transpyloric Pyloromyotomy Gastric stimulator Gastric pacemaker Stenting

Differential diagnosis between functional and organic intestinal disorders:Is there a role for non-invasive tests?

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World Journal of Gastroenterology 2007年第2期13卷 219-223页

作者： Francesco Costa Maria Gloria Mumolo Santino Marchi Massimo Bellini section of Gastroenterology Department of Internal MedicineUniversity of Pisa Pisa Italy

Abdominal pain and bowel habits alterations are common symptoms in the general population. The investigation to differentiate organic from functional bowel disorders represents a considerable burden both for patients and public health service. The selection of patients who should undergo endoscopic and/or radiological procedures is one of the key points of the diagnostic process, which should avoid the abuse of invasive and expensive tests as well as the underestimation of potentially harmful diseases. Over the cominci years,dinidans and researchers will be challenged to develop strategies to increase the patient＇s compliance and to reduce the economic and social costs of the intestinal diseases.

关键词： Intestinal diseases Intestinal inflammation Functional bowel disorders Faecal markers

Ovarian carcinoma in two patients with chronic liver disease

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World Journal of Gastroenterology 2005年第28期11卷 4445-4446页

作者： Mehlika Lsildak Murat Kekilli Yavuz Beyazit Gulay Sain Guven Mustafa Erman Gulay Sain Guverl Mustafa Ermall Department of internal medicine Faculty of Medicine Ha cettepe University Sihhiye Ankara 06100 Turkey Department of internal medicine Section of General Internal Medicine Faculty of Medicine Hacettepe University. Sihhiye Ankara 06100 Turkey Department of internal medicine Section of Medical Oncology Faculty of Medicine Hacettepe UniversitySihhiye Ankara 06100 Turkey

Ascites is a common and debilitating complication of cirrhosis. However, patients with chronic liver disease are not spared from other causes of ascites and physicians should be careful not to miss an underlying malignancy. Ovarian cancer is an insidious disease, which is difficult to diagnose and it ranks first in mortality among all gynecological cancers. Here, we present two cases of patients with chronic liver disease that developed ascites not： simply because of drrhosis but as a manifestation of ovarian cancer. We would like to emphasize that the causes of ascites, other than the liver itself, should not be overlooked in patients with chronic liver disease.

关键词： Ovarian carcinoma Ascites Chronic liver disease

Colon adenoma features and their impact on risk of future advanced adenomas and colorectal cancer

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World Journal of Gastrointestinal Oncology 2016年第12期8卷 826-834页

作者： Audrey H Calderwood Karen E Lasser Hemant K Roy section of Gastroenterology Depart-ment of MedicineDartmouth-Hitchcock Medical Center section of General internal medicine Depart-ment of MedicineBoston University School of Medicine section of Gastroenterology Department of MedicineBoston University School of Medicine

AIMTo review the evidence on the association between specific colon adenoma features and the risk of future colonic neoplasia [adenomas and colorectal cancer (CRC)]. METHODSWe performed a literature search using the National Library of medicine through PubMed from 1/1/2003 to 5/30/2015. Specific Medical Subject Headings terms (colon, colon polyps, adenomatous polyps, epidemiology, natural history, growth, cancer screening, colonoscopy, CRC) were used in conjunction with subject headings/key words (surveillance, adenoma surveillance, polypectomy surveillance, and serrated adenoma). We defined non-advanced adenomas as 1-2 adenomas each 25% villous histology or high-grade dysplasia. A combined endpoint of advanced neoplasia included advanced adenomas and invasive CRC. RESULTSOur search strategy identified 592 candidate articles of which 8 met inclusion criteria and were relevant for assessment of histology (low grade vs high grade dysplasia, villous features) and adenoma size. Six of these studies met the accepted quality indicator threshold for overall adenoma detection rate > 25% among study patients. We found 254 articles of which 7 met inclusion criteria for the evaluation of multiple adenomas. Lastly, our search revealed 222 candidate articles of which 6 met inclusion criteria for evaluation of serrated polyps. Our review found that villous features, high grade dysplasia, larger adenoma size, and having ≥ 3 adenomas at baseline are associated with an increased risk of future colonic neoplasia in some but not all studies. Serrated polyps in the proximal colon are associated with an increased risk of future colonic neoplasia, comparable to having a baseline advanced adenoma. CONCLUSIONData on adenoma features and risk of future adenomas and CRC are compelling yet modest in absolute effect size. Future research should refine this risk stratification.

关键词： Colon adenoma Colorectal cancer screening Surveillance Colonoscopy

Mitral peak early diastolic filling velocity to deceleration time ratio as a predictor of prognosis in patients with chronic heart failure and preserved or reduced ejection fraction

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Journal of Geriatric Cardiology 2015年第4期12卷 346-352页

作者： Flora Pirozzi AntoneUa Paglia Laura Sasso Pasquale Abete Angelo Carlomagno Carlo G Tocchetti Domenico Bonaduce Mario Petretta Department of Translational Medical Sciences Section of Internal Medicine Federico Ⅱ University Naples ltaly

Objective Doppler derived mitral peak early diastolic filling velocity to deceleration time ratio （E/DT） has been proposed as parameter for predicting prognosis in general population. This study prospectively investigates the incremental prognostic value of E/DT over clinical, conven- tional eehocardiographic and mitral-Doppler variables in patients hospitalized for decompensated heart failure （HF）. Methods We analyzed 95 HF patients （mean age 64.8 ± 12.2 years） hospitalized at our institution from January 2010 to March 2012. The primary end-point was cardiac death or hospitalization, whichever occurred first. Cox regression analysis was performed to identify significant predictors of outcomes. Results During follow-up （median 37.7 months） 13 patients died and 44 were hospitalized for a cardiac event. At univariable analysis, New York Heart Association （NYHA） functional class, furosemide dosage, lateral tricuspidal annular plane systolic excursion, deceleration lime and E/DT were predictive of outcome. At multivariable analysis, E/DT was the only predictor of prognosis （hazard ratio = 1.02, P = 0.018）, giving incremental prognostic information to clinical and other echocardio-graphic measures （global chi-square from 15.4 to 25.2; P = 0.032）. Conclusions FJDT gives independent and incremental prognostic information in HF patients.

关键词： Echocardiographic evaluation Left venlricular function Risk stratification