tbuckley/cabot-search huggingface dataset:
Antipsychotic-Induced Weight Gain: A Comprehensive Research Synthesis
Authors: David B. Allison, Janet L. Mentore, Moonseong Heo, Linda P. Chandler, Joseph C. Cappelleri, Ming C. Infante, Peter J. Weiden
Journal: American Journal of Psychiatry (1999)

The purpose of this study was to estimate and compare the effects of antipsychotics-both the newer ones and the conventional ones-on body weight.A comprehensive literature search identified 81 English- and non-English-language articles that included data on weight change in antipsychotic-treated patients. For each agent, a meta-analysis and random effects metaregression estimated the weight change after 10 weeks of treatment at a standard dose. A comprehensive narrative review was also conducted on all articles that did not yield quantitative information but did yield important qualitative information.Placebo was associated with a mean weight reduction of 0.74 kg. Among conventional agents, mean weight change ranged from a reduction of 0.39 kg with molindone to an increase of 3.19 kg with thioridazine. Among newer antipsychotic agents, mean increases were as follows: clozapine, 4.45 kg; olanzapine, 4.15 kg; sertindole, 2.92 kg; risperidone, 2.10 kg; and ziprasidone, 0.04 kg. Insufficient data were available to evaluate quetiapine at 10 weeks.Both conventional and newer antipsychotics are associated with weight gain. Among the newer agents, clozapine appears to have the greatest potential to induce weight gain, and ziprasidone the least. The differences among newer agents may affect compliance with medication and health risk.
IκBα and IκBβ possess injury context-specific functions that uniquely influence hepatic NF-κB induction and inflammation
Authors: Chenguang Fan, Qiang Li, Yulong Zhang, Xiaoming Liu, Meihui Luo, Duane Abbott, Weihong Zhou, John F. Engelhardt
Journal: Journal of Clinical Investigation (2004)

IκB proteins play an important role in regulating NF-κB induction following a diverse range of environmental injuries. Studies evaluating IκBβ knock-in mice (AKBI), in which the IκBα gene is replaced by the IκBβ cDNA, have uncovered divergent properties of IκBα and IκBβ that influence their ability to activate hepatic NF-κB and subsequent downstream proinflammatory processes in a stimulus-specific manner. While AKBI mice demonstrated identical levels of hepatic NF-κB activation in response to endotoxin, a significantly reduced level of hepatic NF-κB activation was observed in AKBI mice after liver ischemia/reperfusion (I/R) injury. This reduced level of NF-κB activation in AKBI mice after liver I/R also correlated with decreased induction of serum TNF-α, reduced hepatic inflammation, and increased survival. In contrast, no differences in any of these indicators were observed between AKBI mice and WT littermates after a lethal injection of LPS. Molecular studies suggest that the specificity of IκBα, but not IκBβ, to properly regulate NF-κB induction during the acute phase of I/R injury is due to injury context–specific activation of c-Src and subsequent tyrosine phosphorylation of IκBα on Tyr42. These results demonstrate that IκBα and IκBβ play unique injury context–specific roles in activating NF-κB–mediated proinflammatory responses and suggest that strategies aimed at inhibiting IκBα gene expression may be of potential therapeutic benefit in hepatic I/R injury.
Bimolecular Interaction of Insulin-Like Growth Factor (IGF) Binding Protein-2 with αvβ3 Negatively Modulates IGF-I-Mediated Migration and Tumor Growth
Authors: Joseph J. Pereira, Tim Meyer, Susan E. Docherty, Hugh H. Reid, John Marshall, Erik W. Thompson, Jamie Rossjohn, John T. Price
Journal: Cancer Research (2004)

Both the integrin and insulin-like growth factor binding protein (IGFBP) families independently play important roles in modulating tumor cell growth and progression. We present evidence for a specific cell surface localization and a bimolecular interaction between the alpha v beta 3 integrin and IGFBP-2. The interaction, which could be specifically perturbed using vitronectin and alpha v beta 3 blocking antibodies, was shown to modulate IGF-mediated cellular migration responses. Moreover, this interaction was observed in vivo and correlated with reduced tumor size of the human breast cancer cells, MCF-7 beta 3, which overexpressed the alpha v beta 3 integrin. Collectively, these results indicate that alpha v beta 3 and IGFBP-2 act cooperatively in a negative regulatory manner to reduce tumor growth and the migratory potential of breast cancer cells.
Infection Genomics:<i>Nramp1</i>as a Major Determinant of Natural Resistance to Intracellular Infections
Authors: Emil Skamene, MD, PhD, Erwin Schurr, PhD, Philippe Gros, PhD
Journal: Annual Review of Medicine (1998)

The scope of the tuberculosis (TB) epidemic in the world today is enormous, with about 30 million active cases. Current research into preventing the spread of TB is focused on development of new drugs to inactivate Mycobacterium tuberculosis, the causative agent of TB, as well as on identifying the critical steps of host defense to infection with Mycobacteria, which might also yield therapeutic targets. Our infection genomics approach toward the latter strategy has been to isolate and characterize a mouse gene, Bcg (Nramp1), which controls natural susceptibility to infection with Mycobacteria, as well as Salmonella and Leishmania. Through comparative genomics, we have identified the homologous human NRAMP1 gene, alleles of which are now being used for tests of linkage with TB and leprosy.
Detection of Bladder Cancer in Urine by a Tumor Suppressor Gene Hypermethylation Panel
Authors: Essel Dulaimi, Robert G. Uzzo, Richard E. Greenberg, Tahseen Al-Saleem, Paul Cairns
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Bladder cancer is potentially curable in the majority of cases; however, the prognosis for patients with advanced disease at presentation remains poor. Current noninvasive tests such as cytology lack sufficient sensitivity to detect low-grade, low-stage tumors. Silencing of tumor suppressor genes, such as p16INK4a, VHL, and the mismatch repair gene hMLH1, has established promoter hypermethylation as a common mechanism for tumor suppressor inactivation in human cancers. It is also a promising new target for molecular detection in bodily fluids including urine, a readily accessible fluid known to contain bladder cancer cells. Methylation-specific PCR (MSP) can determine the presence or absence of methylation of a gene locus at a sensitivity level of up to 1 methylated allele in 1000 unmethylated alleles, appropriate for identifying cancer cell DNA in a bodily fluid. Experimental Design: We first determined the frequency of hypermethylation of the Rb tumor suppressor gene by bisulfite sequencing and of the p16INK4a, p14ARF, APC, and RASSF1A tumor suppressor genes by MSP in 45 bladder cancers. We then designed a panel optimal for diagnostic coverage composed of the APC, RASSF1A, and p14ARF tumor suppressor genes. This panel was tested for detection of hypermethylation in matched sediment DNA from urine specimens obtained before surgery from the same 45 bladder cancer patients (2 Tis, 16 Ta, 10 T1, and 17 T2–4) as well as normal and benign control DNAs. Results: Hypermethylation of at least one of three suppressor genes (APC, RASSF1A, and p14ARF) was found in all 45 tumor DNAs (100% diagnostic coverage). We detected gene hypermethylation in the matched urine DNA from 39 of 45 patients (87% sensitivity), including 16 cases that had negative cytology. No hypermethylation of APC, RASSF1A, or p14ARF was observed in normal transitional cell DNAs or in urine DNAs from normal healthy individuals and patients with inflammatory urinary disease (cystitis). Furthermore, an unmethylated gene in the tumor DNA was always found to be unmethylated in the matched urine DNA (100% specificity). Conclusions: Promoter hypermethylation of tumor suppressor genes is common in bladder cancer and was found in all grades and stages of tumors examined. Hypermethylation was detected in the urine DNA from 39 of 45 (87%) patients, including cases of early-stage disease amenable to cure. MSP may enhance early detection of bladder cancer using a noninvasive urine test.
Pediatric Melanoma: Risk Factor and Survival Analysis of the Surveillance, Epidemiology and End Results Database
Authors: John J. Strouse, Thomas R. Fears, Margaret A. Tucker, Alan S. Wayne
Journal: Journal of Clinical Oncology (2005)

Purpose To evaluate risk factors for the development of and factors influencing survival in pediatric melanoma. Patients and Methods We evaluated 1,255 children (age &lt; 20 years) and 2,673 young adults (age 20 to 24 years) with melanoma in the 2001 National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) database. We estimated exposure to UV radiation based on Environmental Protection Agency (EPA) measurements. Results The incidence of pediatric melanoma increased 46% (95% CI, 40 to 52) per year of age and 2.9% (95% CI, 2.1 to 3.6) per year from 1973 to 2001. Incidence rates were lower in black patients (−95%; 95% CI, −98 to −90) compared with white patients and in male patients (−39%; 95% CI −46 to −31) compared with females. Increased ambient UV radiation was associated with elevated risk (19% per kJ; 95% CI, 9 to 30). Children with melanoma had a 5-year melanoma-specific survival of 93.6% (95% CI, 91.9 to 94.9), which improved from 1973 to 2001. The hazard ratio of death from melanoma increased with male sex; older age; advanced disease; location of the primary other than extremities or torso; earlier year of diagnosis; and previous cancer. Conclusion The incidence of melanoma in the United States is increasing rapidly in children. Risk factors for pediatric melanoma include being white, being female, increasing age, and environmental UV radiation. Survival is decreased for children and adolescents with unfavorable prognostic factors (male sex, unfavorable site, and/or second primary or regional or distant metastasis). More effective therapeutic strategies are needed for these groups.
Consensus Recommendations for Managing Patients with Nonvariceal Upper Gastrointestinal Bleeding
Authors: Alan Barkun, Marc Bardou, John K. Marshall
Journal: Annals of Internal Medicine (2003)

Background: The management of patients with acute nonvariceal upper gastrointestinal bleeding has evolved substantially over the past 10 years amid a paucity of published consensus guidelines. Purpose: To provide evidence-based management recommendations that address clinically relevant issues. Review and Consensus Processes: A multidisciplinary consensus group of 25 voting participants representing 11 national societies used a 7-step approach to develop recommendation statements according to accepted standards. Sources of data included narrative and systematic reviews as well as published and new meta-analyses. The quality of the evidence, the strength of the recommendation, and the level of consensus were graded according to recognized classifications. Main Findings: Recommendations emphasize appropriate initial resuscitation of the patient and a multidisciplinary approach to clinical risk stratification that determines the need for early endoscopy. Early endoscopy allows safe and prompt discharge of selected patients classified as low risk. Endoscopic hemostasis is reserved for patients with high-risk endoscopic lesions. Although monotherapy with injection or thermal coagulation is effective, the combination is superior to either treatment alone. The placement of endoscopic clips for endoscopic hemostasis appears promising. High-dose intravenous proton-pump inhibition is recommended in patients who have undergone successful endoscopic therapy. Routine second-look endoscopy is not recommended. Patients with upper gastrointestinal bleeding should be tested for Helicobacter pylori infection and receive eradication therapy if infection is present. Future Directions: The efficacy of newer endoscopic therapeutic technologies, the optimal regimen of proton-pump inhibition, and the roles of other pharmacologic agents require further research. *For a list of the voting participants in the Nonvariceal Upper GI Bleeding Consensus Conference Group, see the Appendix.
Time to combination therapy for sildenfail monotherapy in pulmonary artery hypertension (PAH). A comparison with the reported experience with bosentan
Authors: Tanya McWilliams, Kenneth Whyte, Colleen Stewart, Arthur Coverdale, Cara Wasywich
Journal: European Respiratory Journal (2013)

Background  In New Zealand sildenafil is first line therapy for Class I, IV and V PAH with WHO Class III and IV symptoms. Combination therapy (CT) with an endothelin receptor antagonist (ERA) or inhaled iloprost is approved by a national panel, for worsening symptoms and a decline in 6MW and RHC hemodynamics.  Objectives  To analyze time between start of sildenafil monotherapy (MT) and addition of a second agent to treat PAH in a cohort of patients on sildenafil 50mg tds monotherapy. To report 6MW results, WHO class and RHC hemodynamic profiles from baseline and prior to initiation of CT.  Results  107 patients with PAH were included: 82 (76.6% were female). Diagnosis: IPAH 40 (37.4%), CTD 31 (29%) CHD 7 (6.5%) CTEPH 15 (14%) and PoPH 8 (7.5%) Mean age at diagnosis 48 years. The median time to diagnosis 38.43 weeks (range: 1-613 weeks). 46 patients required additional therapy. Median time to CT was 73.21 weeks (range: 4-327) weeks. 33/46 were on sildenafil + ERA and 13/46 sildenafil + iloprost.  The 6MW and RHC hemodynamics are summarized below, these differences were not significant. There was a significant decline in WHO class p=0.016 prior to initiation of CT.  Conclusion  This unique group of patients includes Class I, IV and V PH commenced on sildenafil MT had a similar time to CT (73.2 weeks/18.2 months) as reported with bosentan in other studies (18-20 months).
Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity
Authors: Cai-Hong Yun, Titus J. Boggon, Yiqun Li, Michele S. Woo, Heidi Greulich, Matthew Meyerson, Michael J. Eck
Journal: Cancer Cell (2007)
Relation between rectal sensation and anal function in normal subjects and patients with faecal incontinence.
Authors: W M Sun, N W Read, P B Miner
Journal: Gut (1990)

The relation between sensory perception of rapid balloon distension of the rectum and the motor responses of the rectum and external and internal anal sphincters in 27 normal subjects and 16 patients with faecal incontinence who had impaired rectal sensation but normal sphincter pressures was studied. In both patients and normal subjects, the onset and duration of rectal sensation correlated closely with the external anal sphincter electrical activity (r = 0.8, p less than 0.0001) and with rectal contraction (r = 0.51, p less than 0.001), but not with internal sphincter relaxation. All normal subjects perceived a rectal sensation within one second of rapid inflation of a rectal balloon with volumes of 20 ml or less air. Six patients did not perceive any rectal sensation until 60 ml had been introduced, while in the remaining nine patients the sensation was delayed by at least two seconds. Internal sphincter relaxation occurred before the sensation was perceived in three of 27 normal subjects and 11 of 16 patients (p less than 0.001), and could be associated with anal leakage, which stopped as soon as sensation was perceived. The lowest rectal volumes required to induce anal relaxation, to cause sustained relaxation, or to elicit sensations of a desire to defecate or pain were similar in patients and normal subjects. In conclusion, these results show the close association between rectal sensation and external anal sphincter contraction, and show that faecal incontinence may occur as a result of delayed or absent external anal sphincter contraction when the internal anal sphincter is relaxed.
Pivotal Role of the Cell Death Factor BNIP3 in Ceramide-Induced Autophagic Cell Death in Malignant Glioma Cells
Authors: Shigeru Daido, Takao Kanzawa, Akitsugu Yamamoto, Hayato Takeuchi, Yasuko Kondo, Seiji Kondo
Journal: Cancer Research (2004)

Abstract The sphingolipid ceramide has been recognized as an important second messenger implicated in regulating diverse signaling pathways especially for apoptosis. Very little is known, however, about the molecular mechanisms underlying nonapoptotic cell death induced by ceramide. In the present study, we first demonstrate that ceramide induces nonapoptotic cell death in malignant glioma cells. The cell death was accompanied by several specific features characteristic of autophagy: presence of numerous autophagic vacuoles in the cytoplasm, development of the acidic vesicular organelles, autophagosome membrane association of microtubule-associated protein light chain 3 (LC3), and a marked increase in expression levels of two forms of LC3 protein (LC3-I and LC3-II). We additionally demonstrate that ceramide decreases mitochondrial membrane potential and activates the transcription of death-inducing mitochondrial protein, BNIP3, resulting in increased expression levels of its mRNA and protein in malignant glioma cells. Moreover, tumor cells transfected with BNIP3 gene undergo autophagy in the absence of ceramide. These results suggest that ceramide induces autophagic cell death in malignant glioma cells via activation of BNIP3. This study adds a new concept to characterize the pathways by which ceramide acts to induce nonapoptotic autophagic cell death in malignant gliomas.
Enhanced sensitivity of celecoxib in human glioblastoma cells: Induction of DNA damage leading to p53-dependent G1 cell cycle arrest and autophagy
Authors: Khong Kang, Congju Zhu, Sook Yong, Qiuhan Gao, Meng Wong
Journal: Molecular Cancer (2009)

Selective cyclooxygenase (COX)-2 inhibitors elicit anti-proliferative responses in various tumours, however the underlying anti-tumour mechanisms are unclear. Mutational inactivation of the tumour suppressor p53 gene is frequent in malignant gliomas. The role of p53 mutation in the anti-tumour responses of the selective COX-2 inhibitor celecoxib in human glioblastoma cells is unknown. In this study, we used human glioblastoma cells with various p53 status; U87MG (with high and low p53 functional levels), LN229 (functional p53) and U373MG (mutant p53) cells. Inhibition of p53 was achieved in U87MG cells transfected with E6 oncoprotein (U87MG-E6) and treated with pifithrin-α, a reversible inhibitor of p53 (U87MG-PFT). We investigated whether the anti-glioblastoma responses of celecoxib were p53-dependent, and whether celecoxib induced DNA damage leading to p53-dependent G1 cell cycle arrest, followed by autophagy or apoptosis. Our findings demonstrated that celecoxib concentration-dependently reduced glioblastoma cell viability, following 24 and 72 hours of treatment. Inhibition of functional p53 in glioblastoma cells significantly reduced the anti-proliferative effect of celecoxib. In U87MG cells, celecoxib (8 and 30 μM) significantly induced DNA damage and inhibited DNA synthesis, corresponding with p53 activation. Celecoxib induced G1-phase cell cycle arrest, accompanied with p21 activation in U87MG cells. Cell cycle progression of U87MG-E6 and U87MG-PFT cells was not affected by celecoxib. In parallel, celecoxib induced G1 cell cycle arrest in LN229 cells, but not in U373MG cells. Autophagy was induced by celecoxib in U87MG and LN229 cells, as shown by the significantly greater population of acridine orange-stained cells and increased levels of LC3-II protein (in comparison with non-treated controls). Celecoxib did not induce significant autophagy in U87MG-PFT, U87MG-E6 and U373MG cells, which lack functional p53. Regardless of p53 status, celecoxib caused no significant difference in apoptosis level of U87MG, U87MG-PFT, U87MG-E6 and U373MG cells. Our findings reveal that p53 increases human glioblastoma sensitivity to celecoxib. Celecoxib inhibits glioblastoma cell viability by induction of DNA damage, leading to p53-dependent G1 cell cycle arrest and p53-dependent autophagy, but not apoptosis.
Pulmonary sequestration with congenital broncho-oesophageal fistula
Authors: WB Evers, R Vissers, JA van Noord
Journal: European Respiratory Journal (1990)

Complaints of older patients due to a congenital broncho-pulmonary foregut malformation are rare. A 53 yr old woman presented with this condition. The diagnosis was made by means of oesophagography, which showed a broncho-oesophageal fistula. Using the supplying vessel, identified by angiography, as a guideline, an operation was carried out to correct the anomaly.
Human skin carcinoma arising from kidney transplant–derived tumor cells
Authors: Laurence Verneuil, Mariana Varna, Philippe Ratajczak, Christophe Leboeuf, Louis-François Plassa, Morad Elbouchtaoui, Pierre Schneider, Wissam Sandid, Celeste Lebbé, Marie-Noelle Peraldi, François Sigaux, Hugues de Thé, Anne Janin
Journal: Journal of Clinical Investigation (2013)

Tumor cells with donor genotype have been identified in human skin cancer after allogeneic transplantation; however, the donor contribution to the malignant epithelium has not been established. Kidney transplant recipients have an increased risk of invasive skin squamous cell carcinoma (SCC), which is associated with accumulation of the tumor suppressor p53 and TP53 mutations. In 21 skin SCCs from kidney transplant recipients, we systematically assessed p53 expression and donor/recipient origin in laser-microdissected p53+ tumor cells. In one patient, molecular analyses demonstrated that skin tumor cells had the donor genotype and harbored a TP53 mutation in codon 175. In a kidney graft biopsy performed 7 years before the skin SCC diagnosis, we found p53+ cells in the renal tubules. We identified the same TP53 mutation in these p53+ epithelial cells from the kidney transplant. These findings provide evidence for a donor epithelial cell contribution to the malignant skin epithelium in the recipient in the setting of allogeneic kidney transplantation. This finding has theoretical implications for cancer initiation and progression and clinical implications in the context of prolonged immunosuppression and longer survival of kidney transplant patients.