tbuckley/cabot-search huggingface dataset:
TRF1 Mediates Mitotic Abnormalities Induced by Aurora-A Overexpression
Authors: Tomokazu Ohishi, Toru Hirota, Takashi Tsuruo, Hiroyuki Seimiya
Journal: Cancer Research (2010)

Abstract Aurora-A, a conserved serine-threonine kinase, plays essential roles in mitosis. Aberrant upregulation of Aurora-A perturbs proper mitotic progression and results in a generation of multinucleated cells with centrosome amplification. The molecular mechanisms for these mitotic defects remain elusive. Here, we show that the overexpressed Aurora-A–induced mitotic defects depend on the telomeric protein TRF1. Live and fixed cell analyses revealed that Aurora-A overexpression in HeLa cells compromises chromosome biorientation, which leads to cytokinetic failure and tetraploidization with increased centrosome numbers. TRF1 depletion by small interfering RNAs or by tankyrase-1 overexpression suppresses Aurora-A–induced occurrence of unaligned chromosomes in metaphase, thus preventing the subsequent abnormalities. We found that Aurora-A binds and phosphorylates TRF1. When TRF1 knockdown cells are complemented with wild-type TRF1, Aurora-A–induced mitotic defects recur. By contrast, a TRF1 mutant that is not phosphorylatable by Aurora-A does not restore such Aurora-A–induced phenotype. We propose that TRF1 phosphorylation by excessive Aurora-A may provoke abnormal mitosis and chromosomal instability. Cancer Res; 70(5); 2041–52
Effects of <i>BRCA1</i>- and <i>BRCA2</i>-Related Mutations on Ovarian and Breast Cancer Survival: A Meta-analysis
Authors: Qian Zhong, Hong-Ling Peng, Xia Zhao, Lin Zhang, Wei-Ting Hwang
Journal: Clinical Cancer Research (2014)

Abstract Purpose: To estimate the effects of BRCA1 and BRCA2 mutations on ovarian cancer and breast cancer survival. Experimental Design: We searched PubMed and EMBASE for studies that evaluated the associations between BRCA mutations and ovarian or breast cancer survival. Meta-analysis was conducted to generate combined HRs with 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS). Results: From 1,201 unique citations, we identified 27 articles that compared prognosis between BRCA mutation carriers and noncarriers in patients with ovarian or breast cancer. Fourteen studies examined ovarian cancer survival and 13 studies examined breast cancer survival. For ovarian cancer, meta-analysis demonstrated that both BRCA1 and BRCA2 mutation carriers had better OS (HR, 0.76; 95% CI, 0.70–0.83 for BRCA1 mutation carriers; HR, 0.58; 95% CI, 0.50–0.66 for BRCA2 mutation carriers) and PFS (HR, 0.65; 95% CI, 0.52–0.81 for BRCA1 mutation carriers; HR, 0.61; 95% CI, 0.47–0.80 for BRCA2 mutation carriers) than noncarriers, regardless of tumor stage, grade, or histologic subtype. Among patients with breast cancer, BRCA1 mutation carriers had worse OS (HR, 1.50; 95% CI, 1.11–2.04) than noncarriers but were not significantly different from noncarriers in PFS. BRCA2 mutation was not associated with breast cancer prognosis. Conclusions: Our analyses suggest that BRCA mutations are robust predictors of outcomes in both ovarian and breast cancers and these mutations should be taken into account when devising appropriate therapeutic strategies. Clin Cancer Res; 21(1); 211–20. ©2014 AACR.
Patient-Specific Dose and Radiation Risk Estimation in Pediatric Cardiac Catheterization
Authors: Klaus Bacher, Evelien Bogaert, Régine Lapere, Daniël De Wolf, Hubert Thierens
Journal: Circulation (2004)

Because of the higher radiosensitivity of infants and children compared with adults, there is a need to evaluate the doses delivered to pediatric patients who undergo interventional cardiac procedures. However, knowledge of the effective dose in pediatric interventional cardiology is very limited.For an accurate risk estimation, a patient-specific Monte Carlo simulation of the effective dose was set up in 60 patients with congenital heart disease who underwent diagnostic (n=28) or therapeutic (n=32) cardiac catheterization procedures. The dose-saving effect of using extra copper filtration in the x-ray beam was also investigated. For diagnostic cardiac catheterizations, a median effective dose of 4.6 mSv was found. Therapeutic procedures resulted in a higher median effective dose of 6.0 mSv because of the prolonged use of fluoroscopy. The overall effect of inserting extra copper filtration into the x-ray beam was a total effective dose reduction of 18% with no detrimental effect on image quality. An excellent correlation between the dose-area product and effective patient dose was found (r=0.95). Hence, dose-area product is suitable for online estimation of the effective dose with good accuracy. With all procedures included, the resulting median lifetime risk for stochastic effects was 0.08%.Because of the high radiation exposure, it is important to monitor patient dose by dose-area product instrumentation and to use additional beam filtration to keep the effective dose as low as possible in view of the sensitivity of the pediatric patients.
THE BRAIN LESION OF GOLDTHIOGLUCOSE OBESITY
Authors: G. Brecher, G. L. Laqueur, E. P. Cronkite, P. M. Edelman, I. L. Schwartz
Journal: The Journal of Experimental Medicine (1965)

The development of hypothalamic lesions due to goldthioglucose are described. The initial extensive necrotic lesion occurs in close to 100 per cent of animals injected with LD(50). Within 2 weeks the necrotic material has been removed and a narrow scar results. After a lapse of several months, the scar is often difficult to visualize, especially in animals that have not developed obesity. The ventromedial nucleus is not the center of the lesion. The nucleus is preserved in some instances, and partially or completely destroyed in others, depending on the extent of the lesion. The more prominent scar in the obese animals correlates with the larger initial lesion necessary for the complete bilateral destruction of the ventromedial nucleus which is known to be a prerequisite for the development of hypothalamic obesity. Thus, contrary to earlier suggestions, goldthioglucose does not localize specifically in the cells of the ventromedial nucleus.
B-Type Natriuretic Peptide and Clinical Judgment in Emergency Diagnosis of Heart Failure
Authors: Peter A. McCullough, Richard M. Nowak, James McCord, Judd E. Hollander, Howard C. Herrmann, Philippe G. Steg, Philippe Duc, Arne Westheim, Torbjørn Omland, Cathrine Wold Knudsen, Alan B. Storrow, William T. Abraham, Sumant Lamba, Alan H.B. Wu, Alberto Perez, Paul Clopton, Padma Krishnaswamy, Radmila Kazanegra, Alan S. Maisel
Journal: Circulation (2002)

Background — We sought to determine the degree to which B-type natriuretic peptide (BNP) adds to clinical judgment in the diagnosis of congestive heart failure (CHF). Methods and Results — The Breathing Not Properly Multinational Study was a prospective diagnostic test evaluation study conducted in 7 centers. Of 1586 participants who presented with acute dyspnea, 1538 (97%) had clinical certainty of CHF determined by the attending physician in the emergency department. Participants underwent routine care and had BNP measured in a blinded fashion. The reference standard for CHF was adjudicated by 2 independent cardiologists, also blinded to BNP results. The final diagnosis was CHF in 722 (47%) participants. At an 80% cutoff level of certainty of CHF, clinical judgment had a sensitivity of 49% and specificity of 96%. At 100 pg/mL, BNP had a sensitivity of 90% and specificity of 73%. In determining the correct diagnosis (CHF versus no CHF), adding BNP to clinical judgment would have enhanced diagnostic accuracy from 74% to 81%. In those participants with an intermediate (21% to 79%) probability of CHF, BNP at a cutoff of 100 pg/mL correctly classified 74% of the cases. The areas under the receiver operating characteristic curve were 0.86 (95% CI 0.84 to 0.88), 0.90 (95% CI 0.88 to 0.91), and 0.93 (95% CI 0.92 to 0.94) for clinical judgment, for BNP at a cutoff of 100 pg/mL, and for the 2 in combination, respectively ( P &lt;0.0001 for all pairwise comparisons). Conclusions — The evaluation of acute dyspnea would be improved with the addition of BNP testing to clinical judgment in the emergency department.
Pulsed dye laser-resistant port-wine stains: mechanisms of resistance and implications for treatment
Authors: J.A. Savas, J.A. Ledon, K. Franca, A. Chacon, K. Nouri
Journal: British Journal of Dermatology (2013)

Port-wine stains (PWS) are among the most common congenital vascular malformations. Unlike capillary haemangiomas, these lesions do not involute spontaneously but rather become progressively more disfiguring as the patient ages. While benign in nature, the cosmetic deformity and attendant psychological and emotional distress prompt the majority of those afflicted to seek treatment. The pulsed dye laser (PDL) has long been considered the treatment of choice for these vascular lesions; however, very few patients achieve total clearance with PDL therapy and a significant number of lesions fail to respond at all. In order to address these recalcitrant cases, the mechanisms that contribute to treatment resistance must be understood and novel laser and light therapies must be employed. This review will address what is currently known about lesion-specific characteristics of PDL-resistant PWS as well as discuss current and future treatment options.
Analysis of the Immunoglobulin Light Chain Genes in Zebra Finch: Evolutionary Implications
Authors: Sabyasachi Das, Uzra Mohamedy, Masayuki Hirano, Masatoshi Nei, Nikolas Nikolaidis
Journal: Molecular Biology and Evolution (2009)

All jawed vertebrates produce immunoglobulins (IGs) as a defense mechanism against pathogens. Typically, IGs are composed of two identical heavy chains (IGH) and two identical light chains (IGL). Most tetrapod species encode more than one isotype of light chains. Chicken is the only representative of birds for which genomic information is currently available and is an exception to the above rule because it encodes only a single IGL isotype (i.e., lambda). Here, we show that the genome of zebra finch, another bird species, encodes a single IGL isotype, that is, lambda, like the chicken. These results strongly suggest that the second isotype (i.e., kappa) present in both reptiles and mammals was lost in a very early stage of bird evolution. Furthermore, we show that both chicken and zebra finch contain a single set of functional variable, joining, and constant region genes and multiple variable region pseudogenes. The latter finding suggests that this type of genomic organization was already present in the common ancestor of these bird species and remained unchanged over a long evolutionary time. This conservation is in contrast with the high levels of variation observed in the mammalian IGL loci. The presence of a single functional variable region gene followed by multiple variable pseudogenes in zebra finch suggest that this species may be generating antibody diversity by a gene conversion-like mechanism like the chicken.
Involvement of Rac in Fenretinide-Induced Apoptosis
Authors: Humam Kadara, Eiji Tahara, Hyun-Jung Kim, Dafna Lotan, Jeffrey Myers, Reuben Lotan
Journal: Cancer Research (2008)

Abstract The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) has shown potential as a chemopreventive and therapeutic agent. The ability of 4HPR to enhance production of reactive oxygen species (ROS) leading to apoptosis has been suggested as a possible mechanism underlying these effects. We explored the possibility that ROS induction by 4HPR involves the small GTPase Ras-related C3 botulinum toxin substrate (Rac), a regulatory subunit of the NADPH oxidase complex. Rac was activated in human head and neck squamous cell carcinoma (HNSCC) cells as early as 5 minutes following 4HPR exposure. Moreover, inhibition of Rac activity or silencing of its expression by RNA interference decreased ROS generation in human head and neck, lung, and cervical cancer cells and murine melanoma cells. In HNSCC UMSCC-22B cells, this decrease correlated with reduction in apoptosis induction by 4HPR. Expression of a constitutive active mutant Rac increased basal and 4HPR-induced ROS generation and poly(ADP-ribose) polymerase cleavage. In addition, the metastatic DM14 cells exhibited higher Rac activation following 4HPR treatment compared with the primary Tu167-C2 cells. Furthermore, the metastatic cancer cells tested exhibited higher ROS generation and growth inhibition due to 4HPR exposure compared with their primary cancer cell counterparts. These findings show a preferential susceptibility of metastatic cells to the proapoptotic retinoid 4HPR through Rac activation and support the use of ROS-inducing agents such as 4HPR against metastatic cancer cells. [Cancer Res 2008;68(11):4416–23]
Management of the Open Abdomen During the Global War on Terror
Authors: Gordon M. Riha, Laszlo N. Kiraly, Brian S. Diggs, S. David Cho, Loic J. Fabricant, Stephen F. Flaherty, Reed Kuehn, Samantha J. Underwood, Martin A. Schreiber
Journal: JAMA Surgery (2012)

To evaluate factors that are predictive of delayed abdominal closure in patients injured during military conflict.Seventy-one patients managed with an open abdomen were identified from records at Landstuhl Regional Medical Center from 2005 and 2006. Follow-up data were available from Walter Reed Army Medical Center. Records were reviewed through all echelons of care. Ordinal logistic regression was used to predict delayed abdominal closure.Patients sustained injury from blunt (n = 2), penetrating (n = 30), and blast (n = 39) mechanisms. The median Injury Severity Score was 25 (interquartile range, 17-34). Abdominal injury was observed in 85% of patients, and 48% underwent a massive transfusion. The median time to transfer to the United States was 5.3 days (interquartile range, 4.3-6.8 days). Abdomens were definitively closed downrange (11%), at Landstuhl Regional Medical Center (33%), or at Walter Reed Army Medical Center (56%). The median time until abdominal closure was 13 days (interquartile range, 4-40 days) in 2005 compared with 4 days (interquartile range, 1-14.5 days) in 2006 (P = .02). The multivariate model identified massive transfusion (odds ratio, 3.9), presence of complications (odds ratio, 5.1), and an injury date in 2005 (odds ratio, 3.4) as independently predictive variables for later abdominal closure.Massive transfusion, occurrence of complications, and earlier injury date were predictive of delayed abdominal closure in casualties managed with an open abdomen. These data suggest an evolving approach to the management of severely injured combat casualties that involves earlier abdominal closure.
Comparison of Cefuroxime With or Without Intranasal Fluticasone for the Treatment of Rhinosinusitis&lt;SUBTITLE&gt;The CAFFS Trial: A Randomized Controlled Trial&lt;/SUBTITLE&gt;
Authors: Rowena J. Dolor
Journal: JAMA (2001)

ContextIt is not known whether intranasal corticosteroids are beneficial to treat acute rhinosinusitis in patients with a history of chronic or recurrent sinus symptoms.ObjectiveTo assess whether the addition of an intranasal corticosteroid to antibiotic therapy affects the speed and rate of recovery of such patients with acute rhinosinusitis.Design, Setting, and PatientsA double-blind, randomized, placebo-controlled multicenter trial of 95 patients (median age, 39 years) with a history of recurrent sinusitis or chronic rhinitis and evidence of acute infection by sinus radiograph or nasal endoscopy, which was conducted from October 1998 through April 2000 at 22 sites (12 primary care and 10 otolaryngology).InterventionTwo puffs (total dose, 200 µg) of fluticasone propionate (n = 47) or placebo nasal spray (n = 48) in each nostril once daily for 21 days; all received 2 puffs of xylometazoline hydrochloride in each nostril twice daily for 3 days and 250 mg of cefuroxime axetil twice daily for 10 days.Main Outcome MeasureTime to clinical success (patient reported cured or much improved) during telephone follow-up at 10, 21, and 56 days.ResultsA total of 88 patients (93%) completed follow-up. Patients recorded their symptoms, work assessment, and compliance during the 3-week treatment phase. Patients receiving fluticasone achieved a significantly higher rate of clinical success than patients receiving placebo (93.5% vs 73.9%; P = .009). Patients treated with fluticasone improved significantly more rapidly (median of 6.0 days to clinical success) vs patients in the placebo group (median of 9.5 days; P = .01).ConclusionsThe addition of fluticasone to xylometazoline and antimicrobial therapy with cefuroxime improves clinical success rates and accelerates recovery of patients with a history of chronic rhinitis or recurrent sinusitis who present for treatment of acute rhinosinusitis.
Response to Comment on: Gruden et al. Severe Hypoglycemia and Cardiovascular Disease Incidence in Type 1 Diabetes: The EURODIAB Prospective Complications Study. Diabetes Care 2012;35:1598–1604
Authors: Gabriella Gruden, Federica Barutta, Paolo Cavallo Perin, Graziella Bruno
Journal: Diabetes Care (2012)

We thank Dr. Gimenez and Dr. Conget for their comments (1) on our article, recently published in Diabetes Care (2). We acknowledge that our study has several limitations, as it was stated in the discussion, and that the “null hypothesis” should be accepted with caution. In addition, we agree that further large prospective epidemiological studies in type 1 diabetic patients are needed to offer a definite answer on this relevant topic. On the other hand, we believe that existing clinical/epidemiological data …
Reciprocal changes in vanilloid (TRPV1) and endocannabinoid (CB1) receptors contribute to visceral hyperalgesia in the water avoidance stressed rat
Authors: S Hong, J Fan, E S Kemmerer, S Evans, Y Li, J W Wiley
Journal: Gut (2008)

<h3>Background:</h3> Increasing evidence suggests that chronic stress plays an important role in the pathophysiology of several functional gastrointestinal disorders. We investigated whether cannabinoid receptor 1 (CB1) and vanilloid receptor 1 (TRPV1; transient receptor potential vanilloid 1) are involved in stress-induced visceral hyperalgesia. <h3>Methods:</h3> Male rats were exposed to 1 h water avoidance (WA) stress daily for 10 consecutive days. The visceromotor response (VMR) to colorectal distension (CRD) was measured. Immunofluorescence and western blot analysis were used to assess the expression of CB1 and TRPV1 receptors in dorsal root ganglion (DRG) neurons. <h3>Results:</h3> WA stressed rats demonstrated a significant increase in the serum corticosterone levels and faecal pellet output compared to controls supporting stimulation of the hypothalamic–pituitary–adrenal (HPA) axis. The VMR increased significantly at pressures of 40 and 60 mm Hg in WA stress rats compared with controls, respectively, and was associated with hyperalgesia. The endogenous CB1 agonist anandamide was increased significantly in DRGs from stressed rats. Immunofluorescence and western blot analysis showed a significant decrease in CB1 and a reciprocal increase in TRPV1 expression and phosphorylation in DRG neurons from stressed rats. These reciprocal changes in CB1 and TRPV1 were reproduced by treatment of control DRGs with anandamide in vitro. In contrast, treatment of control DRGs in vitro with the CB1 receptor agonist WIN 55,212-2 decreased the levels of TRPV1 and TRPV1 phosphorylation. Treatment of WA stress rats in situ with WIN 55,212-2 or the TRPV1 antagonist capsazepine prevented the development of visceral hyperalgesia and blocked the upregulation of TRPV1. <h3>Conclusions:</h3> These results suggest that the endocannabinoid (CB1) and TRP (TRPV1) pathways may play a potentially important role in stress-induced visceral hyperalgesia.
Striae and acne following cardiac surgery in a child
Authors: None GOGGIN, None ENRIGHT, None COSTIGAN, None DUFF, None OSLIZLOK, None WOOD, None WATSON
Journal: British Journal of Dermatology (1999)

We report a 13‐year‐old girl with extensive striae and an acneiform eruption following surgery for complex congenital heart disease. These findings were associated with elevated serum and urinary cortisol levels with loss of diurnal rhythm. The resolution of the eruption and the fading of her striae coincided in time with normalization of her blood parameters on day 72 postoperatively. We conclude that the cause of steroid excess in our patient was stress induced by the cardiac surgery and a complicated and protracted postoperative course. To our knowledge, this is the first report in the English language literature of skin changes due to endogenous hypercortisolaemia caused by intense physical and emotional stress.
γδ T cells protect against lung fibrosis via IL-22
Authors: Philip L. Simonian, Fabian Wehrmann, Christina L. Roark, Willi K. Born, Rebecca L. O'Brien, Andrew P. Fontenot
Journal: The Journal of Experimental Medicine (2010)

Inflammation-induced pulmonary fibrosis (PF) leads to irreversible loss of lung function and is a predictor of mortality in numerous lung diseases. Why some subjects with lung inflammation but not others develop PF is unclear. In a mouse model of hypersensitivity pneumonitis that progresses to lung fibrosis upon repeated exposure to the ubiquitous microorganism Bacillus subtilis, γδ T cells expand in the lung and inhibit collagen deposition. We show that a subset of these γδ cells represents the predominant source of the Th17 cytokine IL-22 in this model. Preventing expression of IL-22, either by mutating the aryl hydrocarbon receptor (AhR) or inhibiting AhR signaling, accelerated lung fibrosis. Direct blockade of IL-22 also enhanced collagen deposition in the lung, whereas administration of recombinant IL-22 inhibited lung fibrosis. Moreover, the presence of protective γδ T cells and IL-22 diminished recruitment of CD4+ T cells to lung. These data reveal a protective pathway that involves the inhibition of αβ T cells by regulatory IL-22–secreting γδ T cells.
The Akt/Mammalian Target of Rapamycin Signal Transduction Pathway Is Activated in High-Risk Myelodysplastic Syndromes and Influences Cell Survival and Proliferation
Authors: Matilde Y. Follo, Sara Mongiorgi, Costanza Bosi, Alessandra Cappellini, Carlo Finelli, Francesca Chiarini, Veronica Papa, Massimo Libra, Giovanni Martinelli, Lucio Cocco, Alberto M. Martelli
Journal: Cancer Research (2007)

Abstract The Akt/mammalian target of rapamycin (mTOR) signaling pathway is important for both cell growth and survival. In particular, an impaired regulation of the Akt/mTOR axis has been strongly implicated in mechanisms related to neoplastic transformation, through enhancement of cell proliferation and survival. Myelodysplastic syndromes (MDS) are a group of heterogeneous hematopoietic stem cell disorders characterized by ineffective hematopoiesis and by a high risk of evolution into acute myelogenous leukemia (AML). The pathogenesis of the MDS evolution into AML is still unclear, although some recent studies indicate that aberrant activation of survival signaling pathways could be involved. In this investigation, done by means of immunofluorescent staining, we report an activation of the Akt/mTOR pathway in high-risk MDS patients. Interestingly, not only mTOR was activated but also its downstream targets, 4E-binding protein 1 and p70 ribosomal S6 kinase. Treatment with the selective mTOR inhibitor, rapamycin, significantly increased apoptotic cell death of CD33+ (but not CD33−) cells from high-risk MDS patients. Rapamycin was ineffective in cells from healthy donors or low-risk MDS. Moreover, incubation of high-risk MDS patient CD34+ cells with rapamycin decreased the in vitro clonogenic capability of these cells. In contrast, the phosphoinositide 3-kinase inhibitor, LY294002, did not significantly affect the clonogenic activity of high-risk MDS cells. Taken together, our results indicate that the Akt/mTOR pathway is critical for cell survival and proliferation in high-risk MDS patients. Therefore, this signaling network could become an interesting therapeutic target for treating more advanced MDS cases. [Cancer Res 2007;67(9):4287–94]