tbuckley/cabot-search huggingface dataset:
Cell Type Variation in Responses to Antimitotic Drugs that Target Microtubules and Kinesin-5
Authors: Jue Shi, James D. Orth, Tim Mitchison
Journal: Cancer Research (2008)

Abstract To improve cancer chemotherapy, we need to understand the mechanisms that determine drug sensitivity in cancer and normal cells. Here, we investigate this question across a panel of 11 cell lines at a phenotypic and molecular level for three antimitotic drugs: paclitaxel, nocodazole, and an inhibitor of kinesin-5 (also known as KSP, Eg5, Kif11). Using automated microscopy with markers for mitosis and apoptosis (high content screening), we find that the mitotic arrest response shows relatively little variation between cell types, whereas the tendency to undergo apoptosis shows large variation. We found no correlation between levels of mitotic arrest and apoptosis. Apoptosis depended on entry into mitosis and occurred both from within mitosis and after exit. Response to the three drugs strongly correlated, although paclitaxel caused more apoptosis in some cell lines at similar levels of mitotic arrest. Molecular investigations showed that sensitivity to apoptosis correlated with loss of an antiapoptotic protein, XIAP, during the drug response, but not its preresponse levels, and to some extent also correlated with activation of the p38 and c-Jun NH2 kinase pathways. We conclude that variation in sensitivity to antimitotic drugs in drug-naive cell lines is governed more by differences in apoptotic signaling than by differences in mitotic spindle or spindle assembly checkpoint proteins and that antimitotics with different mechanisms trigger very similar, but not identical, responses. [Cancer Res 2008;68(9):3269–76]
Resolving the contradictions of addiction
Authors: Gene M. Heyman
Journal: Behavioral and Brain Sciences (1996)

Abstract Research findings on addiction are contradictory. According to biographical records and widely used diagnostic manuals, addicts use drugs compulsively, meaning that drug use is out of control and independent of its aversive consequences. This account is supported by studies that show significant heritabilities for alcoholism and other addictions and by laboratory experiments in which repeated administration of addictive drugs caused changes in neural substrates associated with reward. Epidemiological and experimental data, however, show that the consequences of drug consumption can significantly modify drug intake in addicts. The disease model can account for the compulsive features of addiction, but not occasions in which price and punishment reduced drug consumption in addicts. Conversely, learning models of addiction can account for the influence of price and punishment, but not compulsive drug taking. The occasion for this target article is that recent developments in behavioral choice theory resolve the apparent contradictions in the addiction literature. The basic argument includes the following four statements: First, repeated consumption of an addictive drug decreases its future value and the future value of competing activities. Second, the frequency of an activity is a function of its relative (not absolute) value. This implies that an activity that reduces the values of competing behaviors can increase in frequency even if its own value also declines. Third, a recent experiment (Heyman &amp; Tanz 1995) shows that the effective reinforcement contingencies are relative to a frame of reference, and this frame of reference can change so as to favor optimal or suboptimal choice. Fourth, if the frame of reference is local, reinforcement contingencies will favor excessive drug use, but if the frame of reference is global, the reinforcement contingencies will favor controlled drug use. The transition from a global to a local frame of reference explains relapse and other compulsive features of addiction.
The Quest for Self-Identity: Not All Cancer Stem Cells Are the Same
Authors: Anita B. Hjelmeland, Jeremy N. Rich
Journal: Clinical Cancer Research (2012)

A central critique of the cancer stem cell (CSC) hypothesis involves the robustness of CSC markers. Zorniak and colleagues suggest that different progenitor marker profiles can classify CSCs, and improved modeling of cellular hierarchies can be achieved by incorporating inter- and intratumoral diversity.
Histamine receptors in human skin: indirect evidence
Authors: M. W. GREAVES, M. G. DAVIES
Journal: British Journal of Dermatology (1982)

Use of differential effects of agonists and antagonists has provided an experimental basis for subdivision of histamine receptors into H1 and H2. This has enabled classification of the responses to histamine in a wide range of organs and tissues. In human skin the vascular and sensory effects of histamine have been studied, and the influence of histamine on epidermal cell growth has been evaluated in vitro. The direct vasodilator and vascular permeability actions of histamine appear to involve both H1 and H1 receptors. However, the axon reflex flare due to histamine appears to be predominantly an H1 effect. Histamine itch involves H1 receptors. These findings have prompted clinical evaluation of combined therapy with H1 and H2 antagonists in patients with urticaria. Initial results have been encouraging in patients with factitious urticaria. Histamine exerts an inhibitory action on epidermopoiesis in vitro in a number of mammalian epidermal cell outgrowth systems including human explants. The pathophysiological relevance of this effect, which involves epidermal H2 receptors and which may be cyclic AMP dependent, is unknown.
Mammalian Target of Rapamycin Inhibition Halts the Progression of Proteinuria in a Rat Model of Reduced Renal Mass
Authors: Fritz Diekmann, Jordi Rovira, Joaquim Carreras, Edgar M Arellano, Elisenda Bañón-Maneus, María José Ramírez-Bajo, Alex Gutiérrez-Dalmau, Mercè Brunet, Josep M Campistol
Journal: Journal of the American Society of Nephrology (2007)

Many kidney transplant patients experience an increase in proteinuria when converted from a calcineurin inhibitor–based regimen to one based on a mammalian target of rapamycin (mTOR) inhibitor, and preexisting proteinuria and poor renal function have been identified as risk factors for this increase. Our aim was to evaluate the effect of sirolimus, an mTOR inhibitor, on renal function and histology in a proteinuric model of reduced renal mass. Sirolimus-treated animals had approximately half as much proteinuria as vehicle-treated animals (<i>P</i> &lt; 0.05), and had less glomerulosclerosis, tubular atrophy, interstitial fibrosis, and inflammation. Immunohistochemistry showed that sirolimus attenuated the increased expression of renal vascular endothelial growth factor (VEGF), as well as the expression of VEGF receptors 1 and 2. In conclusion, sirolimus halted the progression of proteinuria and structural damage in a rat model of reduced renal mass, possibly through a reduction in renal VEGF activity.
Associations of Insulin Resistance and Adiponectin With Mortality in Women With Breast Cancer
Authors: Catherine Duggan, Melinda L. Irwin, Liren Xiao, Katherine D. Henderson, Ashley Wilder Smith, Richard N. Baumgartner, Kathy B. Baumgartner, Leslie Bernstein, Rachel Ballard-Barbash, Anne McTiernan
Journal: Journal of Clinical Oncology (2010)

Purpose Overweight or obese breast cancer patients have a worse prognosis compared with normal-weight patients. This may be attributed to hyperinsulinemia and dysregulation of adipokine levels associated with overweight and obesity. Here, we evaluate whether low levels of adiponectin and a greater level of insulin resistance are associated with breast cancer mortality and all-cause mortality. Patients and Methods We measured glucose, insulin, and adiponectin levels in fasting serum samples from 527 women enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between adiponectin and insulin and glucose levels (expressed as the Homeostatic Model Assessment [HOMA] score) represented as continuous measures and median split categories, along with breast cancer mortality and all-cause mortality, using Cox proportional hazards models. Results Increasing HOMA scores were associated with reduced breast cancer survival (hazard ratio [HR], 1.12; 95% CI, 1.05 to 1.20) and reduced all-cause survival (HR, 1.09; 95% CI, 1.02 to 1.15) after adjustment for possible confounders. Higher levels of adiponectin (above the median: 15.5 μg/mL) were associated with longer breast cancer survival (HR, 0.39; 95% CI, 0.15 to 0.95) after adjustment for covariates. A continuous measure of adiponectin was not associated with either breast cancer–specific or all-cause mortality. Conclusion Elevated HOMA scores and low levels of adiponectin, both associated with obesity, were associated with increased breast cancer mortality. To the best of our knowledge, this is the first demonstration of the association between low levels of adiponectin and increased breast cancer mortality in breast cancer survivors.
A Genome Scan for Loci Shared by Autism Spectrum Disorder and Language Impairment
Authors: Christopher W. Bartlett, Liping Hou, Judy F. Flax, Abby Hare, Soo Yeon Cheong, Zena Fermano, Barbie Zimmerman-Bier, Charles Cartwright, Marco A. Azaro, Steven Buyske, Linda M. Brzustowicz
Journal: American Journal of Psychiatry (2013)

The authors conducted a genetic linkage study of families that have both autism spectrum disorder (ASD) and language-impaired probands to find common communication impairment loci. The hypothesis was that these families have a high genetic loading for impairments in language ability, thus influencing the language and communication deficits of the family members with ASD. Comprehensive behavioral phenotyping of the families also enabled linkage analysis of quantitative measures, including normal, subclinical, and disordered variation in all family members for the three general autism symptom domains: social, communication, and compulsive behaviors.The primary linkage analysis coded persons with either ASD or specific language impairment as "affected." The secondary linkage analysis consisted of quantitative metrics of autism-associated behaviors capturing normal to clinically severe variation, measured in all family members.Linkage to language phenotypes was established at two novel chromosomal loci, 15q23-26 and 16p12. The secondary analysis of normal and disordered quantitative variation in social and compulsive behaviors established linkage to two loci for social behaviors (at 14q and 15q) and one locus for repetitive behaviors (at 13q).These data indicate shared etiology of ASD and specific language impairment at two novel loci. Additionally, nonlanguage phenotypes based on social aloofness and rigid personality traits showed compelling evidence for linkage in this study group. Further genetic mapping is warranted at these loci.
Magnetic resonance enterography in adolescents and young adults with crohn's disease
Authors: P. Kumar, A. Razack, D. Ashok, N. Rao, J. Cast, A. Azaz, S. Sebastian
Journal: Gut (2011)

<h3>Introduction</h3> MRE has been increasingly used for evaluation of known and suspected Crohn9s disease patients but variable availability and high cost remains a problem in some areas. Young patients with Crohn9s disease are reported to be particularly at higher risk of receiving high doses of radiation. There is limited data on the use of MRE in this group. The authors aimed to asses the effectiveness of use of MRE in adolescents and young adults based on select criteria used in our institution. <h3>Methods</h3> Patients with known Crohn9s disease diagnosed between 10 and 30 years undergoing MRE during a 2-year period were included. All had full endoscopic assessment and were classified based on Montreal classification. Demographics and clinical parameters were recorded. Actual radiation exposure in DAP (Dose Area Product) and milliseverts (mSv) recorded in <i>RadCentre</i> during procedure of all relevant radiological investigations procedures before and after MRE was calculated. Clinician recorded Montreal classification 3 months before MRE and post-MRE was recorded in relation to changes to classification in extent (L) and disease behaviour (B). Any change to management within 3 months following MRE was noted. <h3>Results</h3> 31 patients were included in analysis. Male to female ratio was 1:2. Mean age at diagnosis of Crohn9s disease was 17.9 years and at the point of MRE scan was 21.25 years. The mean duration of Crohn9s disease follow-up pre-MRE was 2.6 years and post-MRE was 1.28 years. The indications included obstructive symptoms (n=14, 45.1%), assessment of extent (n=15, 48.3%), suspicion of internal fistula (n=1, 3.2%) and non-responsiveness to therapy (n=1, 3.2%). The findings included small bowel stricture (20), stricture with associated abscess (3), colonic stricture (n=2), thickening (3), fistula (1) and gastric outlet obstruction (1). In 6 patients the MRE was normal. Following MRE 16 patients (51.6%) had upgrading of disease behaviour (B) and 3 of them also had additional disease location (L). In 4 patients the MRE identified longer length of small bowel involvement than recorded before. The average radiation exposure pre-MRE was 7.47 mSv and post-MRE was 1.56 mSv. In 4 patients the planned management was modified due to additional findings in MRE result. <h3>Conclusion</h3> This study describes our experience in the use of MRE in a high risk group of adolescent and young adults with Crohn9s disease. Application of specific referral criteria and patient selection may increase pick up rate, improve clinical utility by altering disease classification and extent, reduce radiation exposure and potentially reduce costs. Longer follow-up of a larger cohort of patients following introduction of MRE in a hospital is needed to confirm reduction in radiation exposure in this group.
Postoperative Nomogram for Disease-Specific Survival After an R0 Resection for Gastric Carcinoma
Authors: Michael W. Kattan, Martin S. Karpeh, Madhu Mazumdar, Murray F. Brennan
Journal: Journal of Clinical Oncology (2003)

Few published studies have addressed individual patient risk after R0 resection for gastric cancer. We developed and internally validated a nomogram that combines these factors to predict the probability of 5-year gastric cancer-specific survival on the basis of 1,039 patients treated at a single institution.Nomogram predictor variables included age, sex, primary site (distal one-third, middle one-third, gastroesophageal junction, and proximal one-third), Lauren histotype (diffuse, intestinal, mixed), number of positive lymph nodes resected, number of negative lymph nodes resected, and depth of invasion. Death as a result of gastric cancer was the predicted end point. The concordance index was used as an accuracy measure, with bootstrapping to correct for optimistic bias. Calibration plots were constructed.Gastric cancer-specific survival at 5 years was 50%. A nomogram was constructed on the basis of a Cox regression model. The bootstrap-corrected concordance index was 0.80. When compared with the predictive ability of American Joint Committee on Cancer stage, the nomogram discrimination was superior (P <.001). Nomogram calibration appeared to be excellent.A nomogram was developed to predict 5-year disease-specific survival after R0 resection for gastric cancer. This tool should be useful for patient counseling, follow-up scheduling, and clinical trial eligibility determination.
Immunotherapy with a candidate extract of natural rubber latex (NRL)
Authors: S.L. Limb, R.G. Hamilton, K.C. Brown, J. Choi, N.F. Adkinson
Journal: Journal of Allergy and Clinical Immunology (2005)

RATIONALE: We conducted a Phase I dose-escalation study to evaluate the safety and immune responses associated with natural rubber latex (NRL) immunotherapy. METHODS: Two female subjects (ages 53, 57) with NRL allergy established by history, NRL-specific IgE (>0.35 kIU/L; Pharmacia CAP system), and positive airway challenge (Hood Exposure Chamber (HEC)) were enrolled in a weekly, dose-escalation protocol of immunotherapy with a candidate extract of non-ammoniated NRL. Endpoints included frequency and severity of adverse reactions and dose-related changes in skin-test titration, HEC challenge threshold, and NRL-specific serum IgE and IgG levels. RESULTS: Both subjects experienced mild, self-limited nasal (40% visits), bronchial (20%), and skin (16%) allergic reactions during dose escalation. Because of repeated doses due to systemic reactions, both subjects reached the target maintenance dose (50mcg protein) after 71 and 91 weeks respectively. The airway challenge threshold increased from pre-treatment dilutions of 1:64 to 1:8 (Subject 1) and 1:2048 to 1:128 (Subject 2). These changes in airway challenge threshold roughly correlated with reduction in skin-test sensitivity. Serum IgE anti-latex rose slightly after treatment initiation, then declined to concentrations still above pre-treatment levels. IgG antibodies after weeks of maintenance injections were 4.2 and 2.0 mcg/ml respectively. CONCLUSIONS: In this limited trial, NRL immunotherapy produced frequent, mild, systemic reactions which retarded dose escalation. Substantial improvement in the airway challenge threshold dose was achieved with a 50mcg maintenance dose, which resulted in only modest IgG anti-latex responses. Pre-treatment with antihistamines or anti-IgE may facilitate faster dose escalation that may be required for acceptable efficacy.
Conjugated Equine Estrogen and Risk of Benign Proliferative Breast Disease: A Randomized Controlled Trial
Authors: T. E. Rohan, A. Negassa, R. T. Chlebowski, L. Habel, A. McTiernan, M. Ginsberg, S. Wassertheil-Smoller, D. L. Page
Journal: JNCI Journal of the National Cancer Institute (2008)

Estrogens stimulate proliferation of breast epithelium and may therefore increase the risk of benign proliferative breast disease, a condition that is associated with increased risk of breast cancer. We tested the effect of conjugated equine estrogen (CEE) on risk of benign proliferative breast disease in the Women's Health Initiative (WHI) randomized controlled trial.In the WHI CEE trial, 10,739 postmenopausal women were randomly assigned to 0.625 mg/d of CEE or to placebo. Baseline and annual breast examinations and mammograms were required. We identified women in the trial who reported breast biopsies that were free of cancer, obtained the associated histological sections, and subjected them to standardized central review. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.A total of 232 incident cases of benign proliferative breast disease were ascertained during follow-up (average duration, 6.9 years), with 155 in the CEE group and 77 in the placebo group. Use of CEE was associated with a more than two-fold increase in the risk of benign proliferative breast disease (HR = 2.11, 95% CI = 1.58 to 2.81). For benign proliferative breast disease without atypia, the HR was 2.34 (95% CI = 1.71 to 3.20), whereas for atypical hyperplasia, it was 1.12 (95% CI = 0.53 to 2.40). Risk varied little by levels of baseline characteristics.Use of 0.625 mg/d of CEE was associated with a statistically significant increased risk of benign proliferative breast disease.
Trans-splicing as a possible molecular mechanism for the multiple isotype expression of the immunoglobulin gene.
Authors: A Shimizu, M C Nussenzweig, H Han, M Sanchez, T Honjo
Journal: The Journal of Experimental Medicine (1991)

We analyzed the molecular mechanism for the immunoglobulin (Ig) multiple isotype expression using a transgenic mouse (TG.SA) model system. Though most of the endogenous mu chain expression was excluded by the expression of the human rearranged mu transgene in the TG.SA mouse, a significant portion of splenic B lymphocytes could express the transgenic human IgM and endogenous mouse IgG simultaneously after stimulation with lipopolysaccharide and interleukin 4. The fluorescence-activated cell sorter-purified population of the human IgM+/mouse IgG+ cells expressed mRNA that consisted of properly spliced sequences of the transgenic VHDJH and the endogenous mouse C gamma genes (trans-mRNA), together with the transgenic human mu mRNA and germline transcripts of the mouse C gamma gene, without apparent rearrangement of the transgene. We also found that a lymphoma tumor, derived from the cross between the TG.SA mouse and another transgenic mouse carrying Ig H chain enhancer-driven c-myc oncogene, expressed about equal levels of the trans-mRNA and the transgenic mu mRNA without DNA rearrangement in either the transgene or the endogenous mouse switch region. These findings strongly support our previous proposal that the trans-splicing can account for the multiple isotype expression in this transgenic model and also suggest that novel molecular mechanism(s) might be involved in this reaction.
Impact of aspiration pneumonia in community-acquired pneumonia and healthcare-associated pneumonia
Authors: Kosaku Komiya, Hiroshi Ishii, Kenji Umeki, Shunji Mizunoe, Jun-ichi Kadota
Journal: European Respiratory Journal (2012)

Background : Aspiration pneumonia is ranked as a considerable etiology in community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP). However, its frequency and role have not been fully evaluated due to difficulties in the diagnosis.

Objective : To determine the frequency of aspiration pneumonia in CAP and HCAP, and to evaluate its impact on the outcome among these patients with acute pneumonias.

Methods : We defined aspiration pneumonia as the following conditions: having risk factors for aspiration pneumonia, including dysphagia due to neurological disorder, mechanical obstruction of the airways and disturbance of consciousness, and also showing lung gravitational opacities in chest CT. Clinical features, microbiology, and outcomes in total 637 patients with CAP (n=417) and HCAP (n=220) were retrospectively analyzed.

Results : Forty-six (11%) patients with CAP and 102 (46%) patients with HCAP met the definition of aspiration pneumonia (p<0.001). The severity score (CURB-65) was higher in HCAP patients (median 3.0, interquartile range; IQR 1.0) than in CAP patients (median 2.0, IQR 1.0; p<0.001). The treatment failure due to resistant pathogens was more frequently seen in HCAP (9.5%) than in CAP (3.4%, p=0.001). In the entire patients with pneumonias, a multivariate analysis indicated that aspiration pneumonia was associated with 30-day mortality (adjusted hazard ratio 4.263, p=0.001) after adjusting for other variables.

Conclusion : Aspiration pneumonia may be a significant predictor of mortality in both patients with CAP and HCAP. Therefore, it would be better for the treatment guidelines for CAP and HCAP to adopt a concept of objectively-defined aspiration pneumonia.