tbuckley/cabot-search huggingface dataset:
Mitosis-Independent <i>Survivin</i> Gene Expression <i>In vivo</i> and Regulation by p53
Authors: Fang Xia, Dario C. Altieri
Journal: Cancer Research (2006)

Abstract Survivin is an essential mitotic gene, and this has been speculated to reflect its primary function in development and cancer. Here, we generated a knock-in transgenic mouse (SVVp-GFP) in which a green fluorescent protein (GFP) reporter gene was placed under the control of the survivin promoter that regulates transcription at mitosis. The expression of endogenous survivin was widespread in mouse tissues during development and shortly after birth. In contrast, GFP reactivity was undetectable in transgenic mouse embryos, and was largely limited postnatally to mitotic cells in the testes. Double transgenic mice generated in the tumor-prone Min/+ background exhibited intestinal adenomas that strongly expressed endogenous survivin, but only isolated GFP-positive cells. Conversely, dysplastic adenomas (16%) stained intensely for GFP, and revealed focal reactivity for mutant, but not wild-type, p53. The expression of GFP was increased by ∼10-fold in p53−/− as opposed to p53+/+ HCT116 colorectal cancer cells, and reintroduction of p53 in p53−/− cells abolished GFP expression. Therefore, the mitotic transcription of the survivin gene is highly restricted in vivo, and unexpectedly negatively regulated by p53. Contrary to a commonly held view, the dominant function(s) of survivin in development and tumor ontogeny are largely cell cycle–independent. (Cancer Res 2006; (66)7: 3392-5)
Genetics of Alzheimer's disease: recent advances
Authors: Dimitrios Avramopoulos
Journal: Genome Medicine (2009)

Alzheimer's disease is a progressive neurodegenerative disorder with high prevalence in old age. It is the most common cause of dementia, with a risk reaching 50% after the age of 85 years, and with the increasing age of the population it is one of the biggest healthcare challenges of the 21st century. Genetic variation is an important contributor to the risk for this disease, underlying an estimated heritability of about 70%. Alzheimer's genetics research in the 1990s was successful in identifying three genes accounting for most cases of early-onset disease with autosomal dominant inheritance, and one gene involved in the more common late-onset disease, which shows complex inheritance patterns. Despite the presence of significant remaining genetic contribution to the risk, the identification of genes since then has been elusive, reminiscent of most other complex disorders. In the past decade there have been significant efforts towards a systematic evaluation of the multiple genetic association studies for Alzheimer's disease, while the first genome-wide association studies are now being reported with promising results. As sample sizes grow through new collections and collaborative efforts, and as new technologies make it possible to test alternative hypotheses, it is expected that new genes involved in the disease will soon be identified and confirmed. The gene discoveries of the 1990s have taught us a lot about Alzheimer's disease pathogenesis, providing many therapeutic targets that are currently at various stages of testing for future clinical use. As new genes become known and the biological pathways leading to disease are further explored, the possibility of prevention and successful personalized treatment is becoming tangible, providing hope for the millions of patients with Alzheimer's disease and their caregivers.
Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma
Authors: Andre Goy, Anas Younes, Peter McLaughlin, Barbara Pro, Jorge E. Romaguera, Frederick Hagemeister, Luis Fayad, Nam H. Dang, Felipe Samaniego, Michael Wang, Kristine Broglio, Barry Samuels, Frederic Gilles, Andreas H. Sarris, Susan Hart, Elizabeth Trehu, David Schenkein, Fernando Cabanillas, Alma M. Rodriguez
Journal: Journal of Clinical Oncology (2004)

Purpose Evaluate efficacy and toxicity of bortezomib in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Patients and Methods Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m 2 ) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles. Results Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenström's macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study. Conclusion Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents.
Wheeze monitoring in children for assessment of nocturnal asthma and response to therapy
Authors: L. Bentur, R. Beck, M. Shinawi, T. Naveh, N. Gavriely
Journal: European Respiratory Journal (2003)

The utilisation of nocturnal wheeze monitoring and quantification for assessment of asthma activity was studied in symptomatic school-aged children before and during treatment. Twelve children 6-14 yrs of age with mild or moderate untreated asthma were studied at home three times: before, 48 h and 6 weeks into treatment with 5 mg montelukast daily. Lung sounds were recorded overnight by an automatic wheeze detection device (PulmoTrack). Per cent wheezing within each respiratory cycle was calculated every 30 s throughout the night and a Nocturnal Wheeze Index (NWI) was calculated for the total night. The results were compared with spirometric indices (forced expiratory volume in one second (FEV1), forced vital capacity), bronchial reactivity (provocative concentration causing a 20% fall in FEV1 by adenosine 5'-monophosphate (PC20)) and daily symptom scores, performed in parallel at each stage of the study. The pretreatment NWI was 814+/-898 (mean+/-SD), which declined to 318+/-199 2 days after onset, and to 137+/-101 after 6 weeks of treatment. The NWI in seven healthy children was 47+/-43. The FEV1, PC20 and symptom scores improved in parallel. Wheeze monitoring provides quantitative and noninvasive information about the extent of nocturnal wheezing in children, correlates well with conventional indices of asthma activity and can assist in assessing efficacy of treatment.
Alcoholism Among Methadone Patients: A Specific Treatment Method
Authors: IRA LIEBSON, GEORGE BIGELOW, RONALD FLAMER
Journal: American Journal of Psychiatry (1973)

Alcoholism is a frequent complication of methadone treatment. In this study, the reinforcing properties of methadone were employed therapeutically to maintain patients on disulfiram. In the experimental condition, alcoholic methadone patients were given methadone only if they also ingested disulfiram. In the control situation, patients with the same addictions were given disulfiram but were not required to ingest it as a condition of receiving methadone. The results indicated that alcoholism was effectively arrested only while patients were treated under the experimental condition.
Renal Cell Carcinoma: A Priority Malignancy for Development and Study of Novel Therapies
Authors: Robert J. Motzer
Journal: Journal of Clinical Oncology (2003)

Article Tools EDITORIAL Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2003.12.072 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12663704 Renal Cell Carcinoma: A Priority Malignancy for Development and Study of Novel Therapies Robert J. MotzerxRobert J. MotzerSearch for articles by this author Show More Memorial Sloan-Kettering Cancer Center, New York, NY https://doi.org/10.1200/JCO.2003.12.072 Full Text PDF Figures and Tables "Renal Cell Carcinoma: A Priority Malignancy for Development and Study of Novel Therapies." Journal of Clinical Oncology, 21(7), pp. 1193–1194© 2003 by American Society of Clinical Oncology
How To Fully Protect the Kidney in a Severe Model of Progressive Nephropathy
Authors: Carla Zoja, Daniela Corna, Davide Camozzi, Dario Cattaneo, Daniela Rottoli, Cristian Batani, Cristina Zanchi, Mauro Abbate, Giuseppe Remuzzi
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. The current therapy for chronic proteinuric nephropathies is angiotensin-converting enzyme inhibitors (ACEi), which slow, but may not halt, the progression of disease, and which may be not effective to the same degree in all patients. In accelerated passive Heymann nephritis (PHN), this study assessed the effect of combining ACEi with angiotensin II receptor antagonist (AIIRA) and with statin that, besides lowering cholesterol, influences inflammatory and fibrogenic processes. Uninephrectomized PHN rats were divided into four groups (n = 10 each) and daily given oral doses of the following: vehicle; 40 mg/L lisinopril; 100 mg/L lisinopril plus L-158,809; 0.3 mg/kg lisinopril plus L-158,809 plus cerivastatin. Treatments started at 2 mo when rats had massive proteinuria and signs of renal injury and lasted until 10 mo. Increases in BP were equally lowered by treatments. ACEi kept proteinuria at levels comparable to pretreatment and numerically lower than vehicle. The addition of AIIRA to lisinopril was more effective, being proteinuria reduced below pretreatment values and significantly lower than vehicle. When cerivastatin was added on top of ACE inhibition and AIIR blockade, urinary protein regressed to normal values and renal failure was prevented. Renal ACE activity was increased threefold in PHN, it was inhibited by more than 60% after ACEi, and decreased below control values with triple therapy. Cerivastatin inhibited ACE activity by 30%. Glomerulosclerosis, tubular damage and interstitial inflammation were ameliorated by ACEi alone or combined with AIIRA, and prevented by addition of statin. TGF-β1 mRNA upregulation in PHN kidney was partially reduced after ACEi or combined with AIIRA and almost normalized after adding statin. Cerivastatin inhibited TGF-β1 gene upregulation by 25%. These data suggest a possible future strategy to induce remission of proteinuria, lessen renal injury, and protect from loss of function in those patients who do not fully respond to ACEi therapy.
Effect of p21WAF1/CIP1 Expression on Tumor Progression in Bladder Cancer
Authors: John P. Stein, David A. Ginsberg, Gary D. Grossfeld, Sunanda J. Chatterjee, David Esrig, Ming G. Dickinson, Susan Groshen, Clive R. Taylor, Peter A. Jones, Donald G. Skinner, Richard J. Cote
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: Altered expression of p53 protein is an important predictor of progression in bladder cancer. The action of p53 on cell cycle regulation is mediated, in part, through expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21). Loss of p21 expression may, therefore, contribute to tumor progression. We sought to determine the relationship between p21 expression in bladder cancer and disease progression. Methods: Tumor specimens were obtained from 242 patients who underwent cystectomy for bladder cancer. Median follow-up was 8.5 years (range, 0.1–11.8 years). Nuclear p21 status was determined by immunohistochemistry and was then analyzed in relationship to the probability of tumor recurrence, overall survival, and tumor p53 status. Reported P values are two-sided. Results: Nuclear p21 expression was detected in the tumors of 156 (64%) of the 242 patients. Patients with p21-positive tumors had a decreased probability of tumor recurrence (P<.00001) and an increased probability of overall survival (P<.00001) in comparison with patients with p21-negative tumors. In a multivariable analysis, p21 expression was an independent predictor of tumor recurrence (P = .0017) and of survival (P = .006) when assessed with tumor grade, tumor stage, lymph node status, and p53 status. p21 expression was associated with p53 status (P<.001); 56% of tumors with p53 alterations showed loss of p21 expression, whereas 79% of tumors expressing wildtype p53 were p21 positive. Patients with p53-altered/p21- negative tumors demonstrated a higher rate of recurrence and worse survival compared with those with p53-altered/ p21-positive tumors (P<.0001). Patients with p53-altered/ p21-positive tumors demonstrated a similar rate of recurrence and survival as those with p53-wild type tumors. Conclusion: Loss of p21 expression is a statistically significant and independent predictor of bladder cancer progression. Maintenance of p21 expression appears to abrogate the deleterious effects of p53 alterations on bladder cancer progression. [J Natl Cancer Inst 1998;90:1072–9]
G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation.
Authors: Irmgard Tegeder, Sabine Grösch, Achim Schmidtko, Annett Häussler, Helmut Schmidt, Ellen Niederberger, Klaus Scholich, Gerd Geisslinger
Journal: Cancer Research (2003)

Opioid effects on tumor growth have been a controversial topic of discussion. In the present study, morphine inhibited tumor cell proliferation at concentrations of >or=10 micro M. This was primarily caused by inhibition of cell cycle progression from G(1) to S phase. At higher concentrations (>or=500 micro M for 24 h), morphine also caused cell death. In nude mice, morphine significantly reduced the growth of MCF-7 and MDA-MB231 tumors but had no effect on HT-29 tumor growth. In these experiments, morphine plasma concentrations were similar to those found in cancer patients receiving chronic morphine treatment for pain relief (0.9-3.4 micro M). In MCF-7 and MDA-MB231 cells, morphine caused a naloxone (Nx)- and pertussis toxin-sensitive, concentration-dependent increase of GTPase activity, indicating that morphine signals could be transduced by opioid receptors via a G protein. However, the antiproliferative effects of morphine were not antagonized by Nx, pertussis toxin, forskolin, and 8-bromo-cAMP, suggesting that the typical opioid receptor-coupled signaling cascade involving the G(i), adenylyl cyclase, and protein kinase A was not involved. Instead, morphine caused an NH(2)-terminal phosphorylation of p53 at Ser(9) and/or Ser(15) and a stabilization of p53 in MCF-7 cells that express wild-type p53. p53 phosphorylation was not antagonized by Nx and resulted in an increase of p53-dependent proteins including p21, Bax, and the death receptor Fas. Blockade of Fas by Fas-fusion protein or inhibition of caspase 8 resulted in a partial inhibition of morphine-induced apoptosis. In addition, Fas ligand only induced apoptosis when administered together with morphine. However, the sensitivity of the tumor cells toward Fas ligand remained low. HT-29 cells, which express dominant negative p53 and show no increase of GTPase activity when treated with morphine, were less sensitive in vitro and were not affected in vivo. Our results suggest that morphine, alone or in combination with Nx, may reduce the growth of certain tumors, apparently in part through activation of p53.
Gliadin activates mucosal cell mediated immunity in cultured rectal mucosa from coeliac patients and a subset of their siblings
Authors: R Troncone, G Mazzarella, N Leone, M Mayer, M De Vincenzi, L Greco, S Auricchio
Journal: Gut (1998)

CD3 and gamma delta cells in the rectal mucosa increase after local instillation of gluten in children with coeliac disease and in half of their siblings. Aim- To establish an in vitro system for assessing immunological changes induced by gluten in the rectum.Rectal biopsy specimens obtained from 13 treated coeliac children, nine of their siblings, and nine controls were cultured in vitro with a peptic-tryptic digest of gliadin or ovalbumin. CD3 and CD25 cells were counted, and the expression of adhesion molecules evaluated.In the lamina propria of coeliac biopsy samples cultured with gliadin, but not in those from controls, the expression of vascular cell adhesion molecule 1 (VCAM-1) was enhanced, and the number of CD25 cells was significantly higher than in those cultured in medium alone; the density of intraepithelial CD3 cells was also significantly higher. No differences were noted in coeliac biopsy specimens cultured with ovalbumin. A discriminant analysis allowed correct classification of all controls and all coeliacs but one, but three of nine siblings were allocated to the coeliac group.Our data confirm that gliadin is able to activate cell mediated immunity in the rectal mucosa in coeliac patients and in a subset of their first degree relatives.
Late Diagnosis Defines a Unique Population of Long-term Survivors of Cystic Fibrosis
Authors: David M. Rodman, Jillian M. Polis, Sonya L. Heltshe, Marci K. Sontag, Cathy Chacon, Rachel V. Rodman, Sara J. Brayshaw, Gwen A. Huitt, Michael D. Iseman, Milene T. Saavedra, Lynn M. Taussig, Jeffrey S. Wagener, Frank J. Accurso, Jerry A. Nick
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Although the median survival for patients with cystic fibrosis (CF) is 32.9 years, a small group of patients live much longer. We analyzed the genotype and phenotype of CF patients 40 years and older seen between 1992 and 2004 at the National Jewish Medical and Research Center (n = 55). These patients were divided into two groups according to age at diagnosis: an early diagnosis (ED) group, median age at diagnosis 2.0 years (range 0.1–15 years, n = 28), and a late diagnosis (LD) group, median age of diagnosis 48.8 years (range 24–72.8 years, n = 27). Consistent with the hypothesis that the CFTR genotype affects the age at diagnosis, CFTR ΔF508 homozygous individuals were more common in the ED group. Although patients in the ED group were predominantly male, the majority of LD patients were female. Patients with CF diagnosed late had a significantly lower prevalence of pancreatic insufficiency and CF-related diabetes, and better lung function. Fewer patients in the LD groups were infected with Pseudomonas aeruginosa, whereas a greater percentage had cultures positive for nontuberculous mycobacteria. This is the largest cohort of older patients with CF described to date, and our findings indicate that patients diagnosed as adults differ distinctly from survivors of long-term CF diagnosed as children.
Assessment of a Combined, Adenovirus-Mediated Oncolytic and Immunostimulatory Tumor Therapy
Authors: Kathrin Maria Bernt, Shaoheng Ni, Anh-Thu Tieu, André Lieber
Journal: Cancer Research (2005)

Abstract In this study, we identified murine breast cancer cell lines that support DNA replication of E1-deleted adenovirus vectors and which can be killed by an oncolytic adenovirus expressing adenovirus E1A and tumor necrosis factor (TNF)–related apoptosis inducing ligand (TRAIL) in a replication-dependent manner (Ad.IR-E1A/TRAIL). We showed that systemic or intratumoral (i.t.) injection of adenovirus vectors into mice increases plasma levels of proinflammatory cytokines and chemokines, including TNF-α, INF-γ, and MCP-1, which are potent inducers of dendritic cell maturation. Furthermore, we showed that in vivo expression of Flt3L from an adenovirus vector increases the number of CD11b+ and CD11c+ cells (populations that include dendritic cells) in the blood circulation. Based on these findings, we tested whether Ad.IR-E1A/TRAIL induced killing of tumor cells in combination with dendritic cell mobilization by Ad.Flt3L or, for comparison, Ad.GM-CSF would have an additive antitumor effect. As a model, we used immunocompetent C3H mice with syngeneic s.c. tumors derived from C3L5 cells. We found that vaccination of mice with C3L5 cells that underwent viral oncolysis in combination with Flt3L or granulocyte-macrophage colony-stimulating factor (GM-CSF) expression induces a systemic antitumor immune response. I.t. injection of the oncolytic and Flt3L expressing vectors into established tumors delayed tumor growth but did not cause efficient tumor elimination. This study shows the effectiveness of a combined oncolytic/immunostimulatory tumor therapy approach.
Mitochondrial Contagion Induced by Parkin Deficiency in <i>Drosophila</i> Hearts and Its Containment by Suppressing Mitofusin
Authors: Poonam Bhandari, Moshi Song, Yun Chen, Yan Burelle, Gerald W. Dorn
Journal: Circulation Research (2013)

Rationale: Dysfunctional Parkin-mediated mitophagic culling of senescent or damaged mitochondria is a major pathological process underlying Parkinson disease and a potential genetic mechanism of cardiomyopathy. Despite epidemiological associations between Parkinson disease and heart failure, the role of Parkin and mitophagic quality control in maintaining normal cardiac homeostasis is poorly understood. Objective: We used germline mutants and cardiac-specific RNA interference to interrogate Parkin regulation of cardiomyocyte mitochondria and examine functional crosstalk between mitophagy and mitochondrial dynamics in Drosophila heart tubes. Methods and Results: Transcriptional profiling of Parkin knockout mouse hearts revealed compensatory upregulation of multiple related E3 ubiquitin ligases. Because Drosophila lack most of these redundant genes, we examined heart tubes of parkin knockout flies and observed accumulation of enlarged hollow donut mitochondria with dilated cardiomyopathy, which could be rescued by cardiomyocyte-specific Parkin expression. Identical abnormalities were induced by cardiomyocyte-specific Parkin suppression using 2 different inhibitory RNAs. Parkin-deficient cardiomyocyte mitochondria exhibited dysmorphology, depolarization, and reactive oxygen species generation without calcium cycling abnormalities, pointing to a primary mitochondrial defect. Suppressing cardiomyocyte mitochondrial fusion in Parkin-deficient fly heart tubes completely prevented the cardiomyopathy and corrected mitochondrial dysfunction without normalizing mitochondrial dysmorphology, demonstrating a central role for mitochondrial fusion in the cardiomyopathy provoked by impaired mitophagy. Conclusions: Parkin deficiency and resulting mitophagic disruption produces cardiomyopathy in part by contamination of the cardiomyocyte mitochondrial pool through fusion between improperly retained dysfunctional/senescent and normal mitochondria. Limiting mitochondrial contagion by inhibiting organelle fusion shows promise for minimizing organ dysfunction produced by defective mitophagic signaling.