tbuckley/cabot-search huggingface dataset:
The negative interplay between Aurora A/B and BRCA1/2 controls cancer cell growth and tumorigenesis via distinct regulation of cell cycle progression, cytokinesis, and tetraploidy
Authors: Yan Wang, Ziliang Wang, Zihao Qi, Sheng Yin, Na Zhang, Yang Liu, Mingming Liu, Jiao Meng, Rongyu Zang, Zhen Zhang, Gong Yang
Journal: Molecular Cancer (2014)

It is well known that the activation of Aurora A/B (Aur A/B) or inactivation of BRCA1/2 induces tumor formation. Others and we have reported that the mutual suppression between Aur A/B and BRCA1/2 may manipulate cancer cell growth and tumorigenesis, however, the interactive regulation and mechanism between these molecules are still elusive. In this study, by consecutive silencing of Aur A/B or/and BRCA1/2 with specific shRNAs, we showed that, in BRCA2-deficient pancreatic cancer cell line Capan-1 and in ovarian cancer cell line OVCA433, Aur A/B and BRCA1/2 inversely regulated the expression of each other likely through proteasome-mediated proteolysis but not through gene transcription. Aur A/B and BRCA1/2 conversely regulated cell cycle progression mainly through control of p53 and cyclin A. Moreover, the disruption of Aur A/B blocked abnormal cytokinesis and decreased cell multinuclearity and chromosome tetraploidy, whereas the deprivation of BRCA1/2 promoted the abnormal cytokinesis and enhanced the cell multinuclearity and tetraploidy. Furthermore, we showed by animal assays that the depletion of Aur A/B inhibited tumor growth of both cell lines, while the knockdown of BRCA1/2 promoted the tumor growth. However, the concurrent silencing of Aur A/B and BRCA1/2 diminished the effects of these molecules on the regulation of cell cycle, cytokinesis, and tetraploidy, leading to the burdened tumor sizes similar to those induced by scrambled shRNA-treated control cells. In summary, our study revealed that the negative interplay between Aur A/B and BRCA1/2 inversely controls the cell proliferation, cell cycle progression, cell multinuclearity, and tetraploidization to modulate tumorigenesis.
Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug-induced osteomalacia
Authors: Changcheng Zhou, Mahfoud Assem, Jessica C. Tay, Paul B. Watkins, Bruce Blumberg, Erin G. Schuetz, Kenneth E. Thummel
Journal: Journal of Clinical Investigation (2006)

The balance between bioactivation and degradation of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] is critical for ensuring appropriate biological effects of vitamin D. Cytochrome P450, family 24–mediated (CYP24-mediated) 24-hydroxylation of 1,25(OH)2D3 is an important step in the catabolism of 1,25(OH)2D3. The enzyme is directly regulated by vitamin D receptor (VDR), and it is expressed mainly in the kidney, where VDR is also abundant. A recent report suggests that activation of steroid and xenobiotic receptor (SXR) also enhances the expression of CYP24, providing a new molecular mechanism of drug-induced osteomalacia. However, here we showed that activation of SXR did not induce CYP24 expression in vitro and in vivo, nor did it transactivate the CYP24 promoter. Instead, SXR inhibited VDR-mediated CYP24 promoter activity, and CYP24 expression was very low in tissues containing high levels of SXR, including the small intestine. Moreover, 1,25(OH)2D3-induced CYP24 expression was enhanced in mice lacking the SXR ortholog pregnane X receptor, and treatment of humans with the SXR agonist rifampicin had no effect on intestinal CYP24 expression, despite demonstration of marked CYP3A4 induction. Combined with our previous findings that CYP3A4, not CYP24, plays the dominant role in hydroxylation of 1,25(OH)2D3 in human liver and intestine, our results indicate that SXR has a dual role in mediating vitamin D catabolism and drug-induced osteomalacia.
Identification of Novel Prognosticators of Outcome in Squamous Cell Carcinoma of the Head and Neck
Authors: Volkert B. Wreesmann, Weiji Shi, Howard T. Thaler, Ashok Poluri, Dennis H. Kraus, David Pfister, Ashok R. Shaha, Jatin P. Shah, Pulivarthi H. Rao, Bhuvanesh Singh
Journal: Journal of Clinical Oncology (2004)

The goal of this study was to identify chromosomal aberrations associated with poor outcome in patients with head and neck squamous cell carcinoma (HNSCC).We assessed the global genomic composition of 82 HNSCCs from previously untreated patients with comparative genomic hybridization (CGH). The CGH data were subcategorized into individual cytogenetic bands. Only genomic aberrations occurring in more than 5% of cases were analyzed, and redundancies were eliminated. Each aberration was submitted to univariate analysis to assess its relationship with disease-specific survival (DSS). We used Monte Carlo simulations (MCS) to adjust P values for the log-rank approximate chi(2) statistics for each abnormality and further applied the Hochberg-Benjamini procedure to adjust the P values for multiple testing of the large number of abnormalities. We then submitted abnormalities whose univariate tests resulted in an adjusted P value of less than.15 together with significant demographic/clinical variables to stepwise Cox proportional hazards regression. We again verified and adjusted P values for the chi(2) approximation of the final model by MCS.CGH analysis revealed a recurrent pattern of chromosomal aberrations typical for HNSCC. Univariate analysis revealed 38 abnormalities that were correlated with DSS. After controlling for multiple comparisons and confounding effects of stage, five chromosomal aberrations were significantly associated with outcome, including amplification at 11q13, gain of 12q24, and losses at 5q11, 6q14, and 21q11 (MCS adjusted P =.0009 to P =.01).HNSCC contains a complex pattern of chromosomal aberrations. A sequential approach to control for multiple comparisons and effect of confounding variables allows the identification of clinically relevant aberrations. The significance of each individual abnormality merits further consideration.
Preventing Fungal Infection in Neutropenic Patients with Acute Leukemia: Fluconazole Compared with Oral Amphotericin B
Authors: Francesco Menichetti
Journal: Annals of Internal Medicine (1994)

Objective: To compare the efficacy and tolerability of fluconazole and oral amphotericin B in preventing fungal infection in neutropenic patients with acute leukemia. Design: A randomized, controlled, multicenter trial. Setting: 30 hematologic units in tertiary care or university hospitals. Patients: 820 consecutive, afebrile, adult patients with acute leukemia and chemotherapy-induced neutropenia. Intervention: Patients were randomly assigned to receive fluconazole, 150 mg, as a once-daily capsule, or amphotericin B suspension, 500 mg every 6 hours. Measurements: An intention-to-treat analysis was done for 820 patients: 420 treated with fluconazole and 400 treated with oral amphotericin B. Results: Definite systemic fungal infection occurred in 2.6% of fluconazole recipients and 2.5% of amphotericin B recipients; suspected systemic fungal infection requiring the empiric use of intravenous amphotericin B occurred in 16% of fluconazole recipients and 21% of oral amphotericin B recipients, a difference of 5 percentage points (95% CI for difference, −0.02% to 10%; P = 0.07). Superficial fungal infection was documented in 1.7% of fluconazole recipients compared with 2.7% of amphotericin B recipients, a difference of one percentage point (CI of difference, −0.9% to 3%; P > 0.2). The distribution of fungal isolates in systemic and superficial fungal infection was similar in both groups. The overall mortality rate accounted for 10% in both groups. An excellent compliance was documented for 90% of patients treated with fluconazole compared with 72% of those treated with amphotericin B suspension, a difference of 18 percentage points (CI for difference, 13% to 23%). Side effects were documented less frequently in fluconazole than in amphotericin B recipients (1.4% compared with 7%, a difference of 5.6 percentage points; CI for difference, 2% to 8%; P < 0.01). Conclusion: Fluconazole was at least as effective as oral amphotericin B in preventing systemic and superficial fungal infection and the empiric use of amphotericin B in neutropenic patients with acute leukemia but was better tolerated. *Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. See Appendix for additional investigators in the study and end of text for participating institutions and current author addresses.
Prevalence of Neuroleptic-Induced Movement Disorders in Chronic Schizophrenia Inpatients
Authors: Sven Janno, Matti Holi, Katinka Tuisku, Kristian Wahlbeck
Journal: American Journal of Psychiatry (2004)

Since most of the world's schizophrenia patients are treated with conventional antipsychotics, the authors evaluated various methods for establishing the prevalence of neuroleptic-induced movement disorders in these patients.DSM-IV criteria and established score thresholds on a movement disorder rating scale were used to identify cases of neuroleptic-induced movement disorder in a representative Estonian patient sample of 99 chronic institutionalized schizophrenia patients, 18-65 years old, treated with conventional neuroleptics (79.8%) or clozapine (20.2%).Neuroleptic-induced movement disorders according to DSM-IV criteria were found in 61.6% of the group: 31.3% had neuroleptic-induced akathisia, 23.2% had neuroleptic-induced parkinsonism, and 32.3% had neuroleptic-induced tardive dyskinesia. Prevalence rates for akathisia and tardive dyskinesia were similar when either DSM-IV criteria or rating scale scores were used, but the prevalence rate for parkinsonism was much lower per DSM-IV criteria than according to rating scale score.Nearly two-thirds of chronic schizophrenia patients suffered from a neuroleptic-induced movement disorder. Globally, extrapyramidal adverse effects still impose a huge burden on the majority of neuroleptic-treated individuals with schizophrenia. The discrepancy between the standard identification methods for neuroleptic-induced movement disorder indicate the need for further research.
Clinicopathologic Significance of the Mutations of the<i>Epidermal Growth Factor Receptor</i>Gene in Patients with Non–Small Cell Lung Cancer
Authors: Yoshio Tomizawa, Hironobu Iijima, Noriaki Sunaga, Koji Sato, Atsushi Takise, Yoshimi Otani, Shigefumi Tanaka, Tatsuo Suga, Ryusei Saito, Tamotsu Ishizuka, Kunio Dobashi, John D. Minna, Takashi Nakajima, Masatomo Mori
Journal: Clinical Cancer Research (2005)

Abstract Purpose: It has been reported that the mutations of epidermal growth factor receptor (EGFR) are detected in lung cancers. Studies of EGFR mutations in large numbers of patients' tumors with clinical data including response to EGFR tyrosine kinase directed therapy are needed to develop a robust database for clinical use. The purpose of the present study is to gain further insights into the significance of EGFR mutation in non–small cell lung cancer (NSCLC). Experimental Design: We investigated the clinicopathologic significance of tyrosine kinase domain (exons 18-21) EGFR mutations in 120 patients with primary NSCLC and the correlation between EGFR mutation and sensitivity to gefitinib in an additional 20 NSCLC patients treated with gefitinib. In addition, onocogenic KRAS mutations and RASSF1A promoter methylation were determined in the same samples. Results: EGFR mutation was detected in 29 of 120 (24%) tumors. All of the 29 (40%) mutations occurred in 72 adenocarcinomas. EGFR mutation was significantly more frequent in females (47%) than males (12%, P &amp;lt; 0.0001), in younger patients (38%) than older patients (10%, P = 0.0005), in nonsmokers (47%) than smokers (13%, P &amp;lt; 0.0001), and in well-differentiated tumors (39%) than moderately and poorly differentiated tumors (7%, P &amp;lt; 0.0001). Mutation of the EGFR gene was preferentially observed in advanced disease. Furthermore, EGFR mutations were detected in 11 of 14 (79%) responders, whereas none of six (0%) nonresponders had the mutation (P = 0.0022). Conclusions: These results in Japanese (East Asian) patients indicated that EGFR mutation plays an important role in pathogenesis of lung adenocarcinoma.
<i>bax</i>, but not<i>bcl-2</i>, influences the prognosis of human pancreatic cancer
Authors: H Friess, Z Lu, H U Graber, A Zimmermann, G Adler, M Korc, R M Schmid, M W Büchler
Journal: Gut (1998)

bcl-2 and bax belong to the bcl-2-related gene family, which marks a new class of genes that influence apoptosis. The bcl-2 oncogene acts as a broad antiapoptotic factor and extends both normal and tumour cell survival. In contrast, the bax gene is a promoter of apoptosis.To analyse the expression of bcl-2 and bax in pancreatic cancer and correlate the results with clinical parameters.Pancreatic cancer tissue samples were obtained from 28 female and 32 male patients (median age 63, range 43-79 years) having surgery for pancreatic cancer. Normal pancreatic tissues obtained from 18 previously healthy organ donors served as controls.The levels of bcl-2 and bax mRNA expression were analysed by northern blot and the exact site of mRNA transcription was determined by in situ hybridisation. The presence of the corresponding proteins was determined by immunohistochemistry.Northern blot analysis indicated that, in comparison with the normal pancreas, bcl-2 mRNA was overexpressed in 30% and bax mRNA in 61% of the pancreatic cancer samples. Concomitant overexpression of bcl-2 and bax was present in 26% of the cancer samples. Pancreatic adenocarcinomas exhibited 3.7-fold and 5.4-fold increases (p < 0.001) in bcl-2 and bax mRNA levels respectively. In situ hybridisation showed that both bcl-2 and bax mRNA were expressed in the cancer cells. Immunohistochemical analysis showed positive Bcl-2 and Bax immunostaining in 28 and 83% of the cancer samples respectively. In multivariate analysis (Cox regression model), bax expression was found to be a strong indicator of survival (p < 0.001). Patients whose tumours exhibited Bax immunostaining lived significantly longer (12 months) than those whose tumours were Bax negative (five months) (p < 0.039). In contrast, no relation was found between Bcl-2 and survival time.The data indicate that genes that are involved in the regulation of apoptosis are upregulated in human pancreatic cancer cells. Prolonged survival times in patients in whom apoptosis promoting factors are upregulated indicate that apoptotic pathways are of biological significance in pancreatic cancer.
Smoking is a strong risk factor for rheumatoid nodules in early rheumatoid arthritis
Authors: B-M Nyhall-Wahlin
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To examine whether smoking is a risk factor for rheumatoid nodules in early rheumatoid arthritis, and if so to determine the quantitative effect of smoking. <b>Methods:</b> From a cohort (n = 1589) in a structured programme for follow up of newly diagnosed cases of rheumatoid arthritis (symptoms of swollen joints ⩽12 months), 112 individuals with rheumatoid nodules at inclusion were identified. Nodular patients were each compared with two age and sex matched controls without nodules from the same cohort. A detailed self administered tobacco use questionnaire was answered by 210 patients (63%). <b>Results:</b> Seventy patients were current smokers, 71 former smokers, and 69 had never smoked. Current smoking and former smoking were more common in patients with rheumatoid nodules compared with controls (86% <i>v</i> 59%) in both sexes. Positive rheumatoid factor (RF) was found more often among cases with nodules than controls (78% <i>v</i> 64%). Using detailed information from the questionnaires with conditional logistic regression analyses, ever having smoked was associated with an increased risk of the presence of rheumatoid nodules (odds ratio (OR) = 7.3 (95% confidence interval, 2.3 to 23.6); p = 0.001). The risk of having nodules was not obviously dose dependent when smoking duration as well as smoking amount were examined. A stratified analysis showed that only RF positive smokers had an increased risk of rheumatoid nodules. Smoking was associated with rheumatoid nodules among both men (p = 0.006) and women (p = 0.001). Tobacco use other than smoking (n = 31) was not associated with an increased risk of nodules (OR = 0.8 (0.2 to 3.4); p = 0.813). <b>Conclusions:</b> There is a strong association between smoking and rheumatoid nodules in early seropositive rheumatoid arthritis.
Instrumentation for the Genome Project
Authors: J. M. Jaklevic, H. R. Garner, G. A. Miller
Journal: Annual Review of Biomedical Engineering (1999)

▪ Abstract Much of the recent rapid progress in large-scale genomic sequencing has been driven by the dramatic improvements both in the area of biological protocols and in the availability of improved laboratory instrumentation and automation platforms. We discuss recent developments in the area of bioinstrumentation that are contributing to the current revolution in genetic analysis. Examples of systems for laboratory automation are described together with specific single-purpose instruments. Emphasis is placed on those tools that are contributing significantly to the scale-up of genomic mapping and sequencing efforts. In addition, we present a selection of more advanced measurement techniques and instrumentation developments that are likely to contribute significantly to future advances in sequencing and genome analysis.
Phase I Study of an Oral Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid, in Patients With Advanced Cancer
Authors: William Kevin Kelly, Owen A. O'Connor, Lee M. Krug, Judy H. Chiao, Mark Heaney, Tracy Curley, Barbara MacGregore-Cortelli, William Tong, J. Paul Secrist, Lawrence Schwartz, Stacy Richardson, Elaina Chu, Semra Olgac, Paul A. Marks, Howard Scher, Victoria M. Richon
Journal: Journal of Clinical Oncology (2005)

Purpose To determine the safety, dosing schedules, pharmacokinetic profile, and biologic effect of orally administered histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with advanced cancer. Patients and Methods Patients with solid and hematologic malignancies were treated with oral SAHA administered once or twice a day on a continuous basis or twice daily for 3 consecutive days per week. Pharmacokinetic profile and bioavailibity of oral SAHA were determined. Western blots and enzyme-linked immunosorbent assays of histones isolated from peripheral-blood mononuclear cells (PBMNCs) pre and post-therapy were performed to evaluate target inhibition. Results Seventy-three patients were treated with oral SAHA and major dose-limiting toxicities were anorexia, dehydration, diarrhea, and fatigue. The maximum tolerated dose was 400 mg qd and 200 mg bid for continuous daily dosing and 300 mg bid for 3 consecutive days per week dosing. Oral SAHA had linear pharmacokinetics from 200 to 600 mg, with an apparent half-life ranging from 91 to 127 minutes and 43% oral bioavailability. Histones isolated from PBMNCs showed consistent accumulation of acetylated histones post-therapy, and enzyme-linked immunosorbent assay demonstrated a trend towards a dose-dependent accumulation of acetylated histones from 200 to 600 mg of oral SAHA. There was one complete response, three partial responses, two unconfirmed partial responses, and 22 (30%) patients remained on study for 4 to 37+ months. Conclusions Oral SAHA has linear pharmacokinetics and good bioavailability, inhibits histone deacetylase activity in PBMNCs, can be safely administered chronically, and has a broad range of antitumor activity.
Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy
Authors: Alfonso Quintás-Cardama, Hagop Kantarjian, Dan Jones, Jianqin Shan, Gautam Borthakur, Deborah Thomas, Steven Kornblau, Susan O'Brien, Jorge Cortes
Journal: Blood (2009)
GENERALIZED COMMON AND HYPERTROPHIC WARTS.
Authors: S. JABLONSKA, B. MILEWSKI
Journal: British Journal of Dermatology (1957)

Journal Article GENERALIZED COMMON AND HYPERTROPHIC WARTS. Get access S. JABLONSKA, S. JABLONSKA Department of Dermatology, Warsaw Medical School, Poland Search for other works by this author on: Oxford Academic Google Scholar B. MILEWSKI B. MILEWSKI Department of Dermatology, Warsaw Medical School, Poland Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 69, Issue 7-8, 1 July 1957, Pages 273–279, https://doi.org/10.1111/j.1365-2133.1957.tb13267.x Published: 01 July 1957
The cholecystokinin-A receptor mediates inhibition of food intake yet is not essential for the maintenance of body weight
Authors: Alan S. Kopin, Wendy Foulds Mathes, Edward W. McBride, Minh Nguyen, Wisam Al-Haider, Frank Schmitz, Susan Bonner-Weir, Robin Kanarek, Martin Beinborn
Journal: Journal of Clinical Investigation (1999)

Food intake and body weight are determined by a complex interaction of regulatory pathways. To elucidate the contribution of the endogenous peptide cholecystokinin, mice lacking functional cholecystokinin-A receptors were generated by targeted gene disruption. To explore the role of the cholecystokinin-A receptor in mediating satiety, food intake of cholecystokinin-A receptor-/- mice was compared with the corresponding intakes of wild-type animals and mice lacking the other known cholecystokinin receptor subtype, cholecystokinin-B/gastrin. Intraperitoneal administration of cholecystokinin failed to decrease food intake in mice lacking cholecystokinin-A receptors. In contrast, cholecystokinin diminished food intake by up to 90% in wild-type and cholecystokinin-B/gastrin receptor-/- mice. Together, these findings indicate that cholecystokinin-induced inhibition of food intake is mediated by the cholecystokinin-A receptor. To explore the long-term consequences of either cholecystokinin-A or cholecystokinin-B/gastrin receptor absence, body weight as a function of age was compared between freely fed wild-type and mutant animals. Both cholecystokinin-A and cholecystokinin-B/gastrin receptor-/- mice maintained normal body weight well into adult life. In addition, each of the two receptor-/- strains had normal pancreatic morphology and were normoglycemic. Our results suggest that although cholecystokinin plays a role in the short-term inhibition of food intake, this pathway is not essential for the long-term maintenance of body weight.
A Mononuclear Cell‐Derived Histamine Releasing Factor in Asthmatic Patients
Authors: R. Alam, J. Rozniecki
Journal: Allergy (1985)

In an attempt to study the role of lymphokines in asthma, lymphocytes from asthmatic patients were stimulated in vitro with skin test‐positive allergen (dust mite) or with non‐specific mitogen‐phytohaemagglutinin for 4h, then washed carefully and cultured alone for 16h. Cell‐free supernatants were subsequently collected and applied in the basophil histamine release test in vitro and in bronchial provocation test and skin prick test in vivo . Supernatant of non‐stimulated lymphocytes from asthmatic patients released significant amounts of histamine from basophils. Stimulation of lymphocytes with specific allergen or phytohamagglutinin augmented the supernatant‐induced histamine release. Lymphocyte supernatants from the majority of patients also induced bronchoconstriction and elicited skin wheal and flare reaction in vivo .