tbuckley/cabot-search huggingface dataset:
Insulin-like Growth Factor–1 Levels Contribute to the Development of Bacterial Translocation in Sepsis
Authors: Gary W. Hunninghake, Kevin C. Doerschug, Amanda B. Nymon, Gregory A. Schmidt, David K. Meyerholz, Alix Ashare
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Rationale: Many lines of evidence point toward the gastrointestinal (GI) tract in the pathophysiology of organ dysfunction in sepsis. Splanchnic hypoperfusion during sepsis leads to enterocyte apoptosis, diminished barrier function, and release of bacterial products. Sepsis lowers levels of insulin-like growth factor (IGF)–1, a known antiapoptotic factor. We recently demonstrated that treatment with IGF-1 is protective in murine sepsis.Objectives: We hypothesize that decreased IGF-1 levels in sepsis contributes to the development of bacterial translocation.Methods: Sepsis was induced in C57BL/6 mice via intratracheal instillation of Pseudomonas aeruginosa. Human subjects with sepsis were enrolled if they had a documented positive blood culture with a nonenteric organism. Bacterial translocation was measured in serum by quantitative real-time polymerase chain reaction with primers specific for enteric bacteria. Serum IGF-1 was measured by ELISA. Apoptosis of the GI epithelium was assessed via immunohistochemistry.Measurements and Main Results: We found that mice with severe sepsis had evidence of bacterial translocation by 24 hours. Enteric bacterial load correlated inversely with levels of serum IGF-1. If we treated mice with IGF-1, bacterial translocation was significantly decreased. In addition, we found increased GI epithelial cell apoptosis after sepsis, which was significantly decreased after IGF-1 treatment. Human subjects with nonenteric sepsis developed progressive enteric bacteremia over 3 days. The degree of enteric bacteremia correlated inversely with serum IGF-1 levels.Conclusions: These data support the hypothesis that sepsis-induced reductions in IGF-1 levels contribute to the development of bacterial translocation in both a murine model and human subjects.
Glutathione S-transferase M1 and T1 polymorphisms may predict adverse effects after therapy in children with medulloblastoma
Authors: Nadia Barahmani, Sarah Carpentieri, Xio-Nan Li, Tao Wang, Yumei Cao, Laura Howe, Lindsay Kilburn, Murali Chintagumpala, Ching Lau, M. Fatih Okcu
Journal: Neuro-Oncology (2008)

Glutathione S-transferases (GSTs) are polymorphic enzymes that catalyze the glutathione conjugation of alkylating agents, platinum compounds, and free radicals formed by radiation used to treat medulloblastoma. We hypothesized that GST polymorphisms may be responsible, in part, for individual differences in toxicity and responses in pediatric medulloblastoma. We investigated the relationship between GSTM1 and GSTT1 polymorphisms and survival and toxicity in 42 children with medulloblastoma diagnosed and treated at the Texas Children's Cancer Center. We conducted Kaplan-Meier analyses to determine if the GST polymorphisms were related to progression-free survival (PFS) and performed logistic regression to explore associations between GST polymorphisms and occurrence of grade 3 or greater (> or =Gr 3) myelosuppression, ototoxicity, nephrotoxicity, neurotoxicity, and intellectual impairment. Patients with at least one null genotype had a 4.3 (95% confidence interval, 1.1-16.8), 3.7 (1-13.6), and 6.4 (1.2-34) times increased risk for any > or =Gr 3 toxicity, any > or =Gr 3 toxicity excluding peripheral neuropathy, and any > or =Gr 3 toxicity requiring omission or cessation of chemotherapy, respectively. Compared with all others, patients with at least one null genotype had, on average, 27.2 (p x= 0.0002), 29 (p = 0.0004), and 21.7 (p = 0.002) lower full-scale, performance, and verbal intelligence quotient (IQ) scores, respectively. GSTM1 and GSTT1 polymorphisms may predict adverse events, including cognitive impairment after therapy, in patients with medulloblastoma. A larger study to validate these findings is under way.
Treatment With Ibritumomab Tiuxetan Radioimmunotherapy in Patients With Rituximab-Refractory Follicular Non-Hodgkin’s Lymphoma
Authors: Thomas E. Witzig, Ian W. Flinn, Leo I. Gordon, Christos Emmanouilides, Myron S. Czuczman, Mansoor N. Saleh, Larry Cripe, Gregory Wiseman, Teresa Olejnik, Pratik S. Multani, Christine A. White
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Rituximab is commonly used as a single agent or in combination therapy for non-Hodgkin’s lymphoma (NHL). Ibritumomab tiuxetan radioimmunotherapy targets the same antigen as rituximab and has demonstrated efficacy in rituximab-naïve NHL. This study evaluated ibritumomab tiuxetan in the treatment of rituximab-refractory follicular NHL. PATIENTS AND METHODS: Eligible patients were refractory to rituximab; this was defined as no objective response to rituximab (375 mg/m 2 weekly for 4 weeks) or time to progression (TTP) of ≤ 6 months. The ibritumomab tiuxetan treatment regimen consisted of pretreatment with rituximab (250 mg/m 2 intravenously on days 1 and 8) to deplete peripheral blood B cells, then yttrium-90 ibritumomab tiuxetan (0.4 mCi/kg; maximum, 32 mCi) intravenously on day 8, administered on an outpatient basis. An imaging/dosimetry dose of indium-111 ibritumomab tiuxetan (5 mCi) was injected after rituximab (day 1) in 28 patients. RESULTS: Fifty-seven patients were treated. The median age was 54 years, 74% had tumors ≥ 5 cm, and all were extensively pretreated (median, four prior therapies; range, one to nine). The estimated radiation-absorbed doses to healthy organs were below the study-defined limit in all patients studied with dosimetry. The overall response rate for the 54 patients with follicular NHL was 74% (15% complete responses and 59% partial responses). The Kaplan-Meier–estimated TTP was 6.8 months (range, 1.1 to ≥ 25.9 months) for all patients and 8.7 months for responders. Adverse events were primarily hematologic; the incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 35%, 9%, and 4%, respectively. CONCLUSION: Ibritumomab tiuxetan radioimmunotherapy is effective in rituximab-refractory patients. The only significant toxicity is hematologic.
Takayasu's arteritis characterised by disturbances of B cell homeostasis responds to B cell depletion with rituximab
Authors: B F Hoyer, K Loddenkemper, I M Mumtaz, A Bruns, C Sengler, K-G Hermann, S Maza, R Keitzer, G-R Burmester, F Buttgereit, A Radbruch, F Hiepe
Journal: Annals of the Rheumatic Diseases (2010)

Takayasu's arteritis (TA) is a large vessel vasculitis of unknown origin involving the aorta and its major branches. T cell mediated autoimmunity …
Randomized Trial of <sup>90</sup> Sr/ <sup>90</sup> Y β-Radiation Versus Placebo Control for Treatment of In-Stent Restenosis
Authors: Jeffrey J. Popma, Mohan Suntharalingam, Alexandra J. Lansky, Richard R. Heuser, Burton Speiser, Paul S. Teirstein, Vincent Massullo, Theodore Bass, Randall Henderson, Sigmund Silber, Peter von Rottkay, Raoul Bonan, Kalon K.L. Ho, Alison Osattin, MPH, Richard E. Kuntz
Journal: Circulation (2002)

Background— After conventional treatment of in-stent restenosis, the incidence of recurrent clinical restenosis may approach 40%. We report the first multicenter, blinded, and randomized trial of intracoronary radiation with the use of a 90 Sr/ 90 Y β-source for the treatment of in-stent restenosis. Methods and Results— After successful catheter-based treatment of in-stent restenosis, 476 patients were randomly assigned to receive an intracoronary catheter containing either 90 Sr/ 90 Y (n=244) or placebo (n=232) sources. The prescribed dose 2 mm from the center of the source was 18.4 Gy for vessels between 2.70 and 3.35 mm in diameter and 23.0 Gy for vessels between 3.36 and 4.0 mm. The primary end point, ie, clinically driven target-vessel revascularization by 8 months, was observed in 56 (26.8%) of the patients assigned to placebo and 39 (17.0%) of the patients assigned to radiation ( P =0.015). The incidence of the composite including death, myocardial infarction, and target-vessel revascularization was observed in 60 (28.7%) of the patients assigned to placebo and 44 (19.1%) of the patients assigned to radiation ( P =0.024). Binary 8-month angiographic restenosis (≥50% diameter stenosis) within the entire segment treated with radiation was reduced from 45.2% in the placebo-treated patients to 28.8% in the 90 Sr/ 90 Y-treated patients ( P =0.001). Stent thromboses occurred in 1 patient assigned to placebo &lt;24 hours after the procedure and in 1 patient assigned to 90 Sr/ 90 Y at day 244. Conclusions— The results of this study demonstrated that β-radiation using 90 Sr/ 90 Y is both safe and effective for preventing recurrence in patients with in-stent restenosis.
Regulation of rDNA Transcription During Endothelin-1Induced Hypertrophy of Neonatal Cardiomyocytes
Authors: Joachim Luyken, Ross D. Hannan, Joseph Y. Cheung, Lawrence I. Rothblum
Journal: Circulation Research (1996)

Abstract Treatment of cultured neonatal cardiomyocytes with endothelin-1 and phorbol 12-myristate 13-acetate (PMA) results in cardiomyocyte hypertrophy. However, the signal transduction pathways involved in this process are poorly understood. Because increased ribosome biogenesis is a requisite for hypertrophy, we sought to (1) confirm the hypothesis that these two hypertrophic agents did indeed induce rRNA synthesis and (2) examine the mechanism through which this induction was accomplished. In this study, hypertrophy of contraction-arrested neonatal cardiomyocytes induced by treatment with either endothelin-1 or PMA was associated with increased rDNA transcription. Western blots demonstrated that the enhanced rates of rDNA transcription were not mediated by increased amounts of either RNA polymerase I or upstream binding factor (UBF), an rDNA transcription factor. However, immunoprecipitation of [ 32 P]orthophosphate-labeled UBF from hypertrophying neonatal cardiomyocytes suggested that the increased rate of rDNA transcription may be due to the hyperphosphorylation of UBF, which would increase the activity of UBF. The increase in UBF phosphorylation occurred within 3 to 6 hours after exposure to either agent, was maximal at 12 hours, and was sustained for at least the first 24 hours of exposure. Phosphoamino acid analysis of UBF immunoprecipitated from control and treated cardiomyocytes demonstrated that UBF was phosphorylated exclusively on serine residues. Our previous studies have shown that the cellular UBF content increased in adrenergic- and contraction-induced models of cardiac hypertrophy. This study with endothelin-1 and PMA demonstrates that the modulation of UBF phosphorylation is an additional pathway by which ribosome biogenesis may be regulated in neonatal cardiomyocytes. These results support the hypothesis that UBF is an important regulatory factor during the initiation and maintenance of the accelerated rate of rDNA transcription observed during neonatal cardiomyocyte hypertrophy mediated by both phorbol esters and endothelin-1.
Molecular Biology of the 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4 Isomerase Gene Family
Authors: Jacques Simard, Marie-Louise Ricketts, Sébastien Gingras, Penny Soucy, F. Alex Feltus, Michael H. Melner
Journal: Endocrine Reviews (2005)

The 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (3β-HSD) isoenzymes are responsible for the oxidation and isomerization of Δ5-3β-hydroxysteroid precursors into Δ4-ketosteroids, thus catalyzing an essential step in the formation of all classes of active steroid hormones. In humans, expression of the type I isoenzyme accounts for the 3β-HSD activity found in placenta and peripheral tissues, whereas the type II 3β-HSD isoenzyme is predominantly expressed in the adrenal gland, ovary, and testis, and its deficiency is responsible for a rare form of congenital adrenal hyperplasia. Phylogeny analyses of the 3β-HSD gene family strongly suggest that the need for different 3β-HSD genes occurred very late in mammals, with subsequent evolution in a similar manner in other lineages. Therefore, to a large extent, the 3β-HSD gene family should have evolved to facilitate differential patterns of tissue- and cell-specific expression and regulation involving multiple signal transduction pathways, which are activated by several growth factors, steroids, and cytokines. Recent studies indicate that HSD3B2 gene regulation involves the orphan nuclear receptors steroidogenic factor-1 and dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1 (DAX-1). Other findings suggest a potential regulatory role for STAT5 and STAT6 in transcriptional activation of HSD3B2 promoter. It was shown that epidermal growth factor (EGF) requires intact STAT5; on the other hand IL-4 induces HSD3B1 gene expression, along with IL-13, through STAT 6 activation. However, evidence suggests that multiple signal transduction pathways are involved in IL-4 mediated HSD3B1 gene expression. Indeed, a better understanding of the transcriptional factors responsible for the fine control of 3β-HSD gene expression may provide insight into mechanisms involved in the functional cooperation between STATs and nuclear receptors as well as their potential interaction with other signaling transduction pathways such as GATA proteins. Finally, the elucidation of the molecular basis of 3β-HSD deficiency has highlighted the fact that mutations in the HSD3B2 gene can result in a wide spectrum of molecular repercussions, which are associated with the different phenotypic manifestations of classical 3β-HSD deficiency and also provide valuable information concerning the structure-function relationships of the 3β-HSD superfamily. Furthermore, several recent studies using type I and type II purified enzymes have elegantly further characterized structure-function relationships responsible for kinetic differences and coenzyme specificity.
Electrophysiological remodeling in hypertrophy and heart failure
Authors: G Tomaselli
Journal: Cardiovascular Research (1999)

Time for primary review 28 days. 

Over 2 million Americans suffer from heart failure and more than 200 000 die annually. The incidence is estimated to be 400 000 per year with a prevalence of over 4.5 million, numbers that will increase with the aging of the US population [1]. Despite remarkable improvements in medical therapy the prognosis of patients with myocardial failure remains poor with over 15% of patients dying within 1 year of initial diagnosis and greater than 80% 6 year mortality [2]. Of the deaths in patients with heart failure, up to 50% are sudden and unexpected.

The failing heart undergoes a complex series of changes in both myocyte and non-myocyte elements. In an attempt to compensate for the reduction in cardiac function the sympathetic nervous (SNS), renin–angiotensin–aldosterone (RAAS) systems and other neurohumoral mechanisms are activated. The altered signal transduction in heart failure initiates changes in gene expression that produce myocyte hypertrophy. Ultimately the changes in gene expression that initially maintain tissue perfusion prove to be maladaptive, predisposing to further myocyte loss, ventricular chamber remodeling and interstitial hyperplasia resulting in a progressive reduction in force development and impairment of ventricular relaxation.

The intrinsic cardiac and peripheral responses to myocardial failure adversely alter the electrophysiology of the heart predisposing patients with heart failure to an increase in arrhythmic death. With progression of heart failure there is an increase in the frequency and complexity of ventricular ectopy [3,4]. Total mortality in heart failure patients correlates with LV function and the presence of complex ventricular ectopy [5–7]. However, there is no clear correlation between SCD and LV function or ventricular ectopy. In fact, data from VHeFT (Veteran’s Administration Heart Failure Trial) and other trials suggest that death is disproportionately sudden in patients with more modest myocardial dysfunction [8] … 

* Corresponding author. Tel.: +1-410-955-2774; fax: +1-410-955-7953
Iron-Dependent Regulation of Ferritin and Transferrin Receptor Expression by the Iron-Responsive Element Binding Protein
Authors: E A Leibold, B Guo
Journal: Annual Review of Nutrition (1992)

INTRODUCTION  345 STRUCTURE AND FUNCTION OF FERRITIN AND TRANSFERRIN RECEPTOR  348 THE IRON-RESPONSE ELEMENT ........ ..... . . . . . . . . ... . . . ... . . . . . . . . . . . . . . . . . . . . . . .. .. .. . . . . 349 STRUCTURE AND FUNCTION OF THE IRON-RESPONSIVE ELEMENT BINDING PROTEINS (IRE-BPs)   35 1 Conservation of IRE-BPs.. . .. . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . .. . . . . ... . . . . . . . . . . . .. . . . . .. . . 35 1 Purification, Cloning, and Characterization of IRE-BPs .. ..... ........ ...... . . . . . . . . . . . . 351 IRON-DEPENDENT POSTTRANSCRIPTIONAL REGULATION BY IRE-BPs . . ..... , 353 Translational Regulation by IRE-BPs . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . .. . . . . . . .. . . . 353 Stabilization of TjR mRNA by IRE-BPs.... .. .... . . . .. . . . .. . . . . . .. . . . . . . . . . . . ... . . .. . . . . . . . .. 357 A Model for the Coordinate Regulation of Ferritin and TjR by IRE-BPs   .. 358 MECHANISM OF ACTIVATION OF IRE-BPs BY IRON   360 RELATED FAMILIES OF IRE-BPs   363 CONCLUDING REMARKS   363
Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages
Authors: Amir Kol, Todd Bourcier, Andrew H. Lichtman, Peter Libby
Journal: Journal of Clinical Investigation (1999)

Both chlamydial and human heat shock protein 60s (HSP 60), which colocalize in human atheroma, may contribute to inflammation during atherogenesis. We tested the hypothesis that chlamydial or human HSP 60 activates human endothelial cells (ECs), smooth muscle cells (SMCs), and monocyte-derived macrophages. We examined the expression of adhesion molecules such as endothelial-leukocyte adhesion molecule-1 (E-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), and the production of the proinflammatory cytokine interleukin-6 (IL-6). We also tested whether either HSP 60 induces nuclear factor-κB (NF-κB), which contributes to the gene expression of these molecules. Either chlamydial or human HSP 60 induced E-selectin, ICAM-1, and VCAM-1 expression on ECs similar to levels induced by Escherichia coli lipopolysaccharide (LPS). Each HSP 60 also significantly induced IL-6 production by ECs, SMCs, and macrophages to an extent similar to that induced by E. coli LPS, as assessed by enzyme-linked immunosorbent assay (ELISA). In ECs, either HSP 60 triggered activation of NF-κB complexes containing p65 and p50 Rel proteins. Heat treatment abolished all these effects, but did not alter the ability of E. coli LPS to induce these functions. Chlamydial and human HSP 60s therefore activate human vascular cell functions relevant to atherogenesis and lesional complications. These findings help to elucidate the mechanisms by which a chronic asymptomatic chlamydial infection might contribute to the pathophysiology of atheroma.
Granulocytic colonies on macrophage‐coated membranes
Authors: A. R. Turner, W. J. Pfrimmer, B. J. Torok‐Storb, D. R. Boggs
Journal: American Journal of Hematology (1978)

Abstract A macrophage cell coating covering a cellulose acetate disk was an effective microenvironment for the production of peroxidase‐positive hematopoietic colonies. These developed after intraperitoneal injection of marrow cells with a linear cell relationship of dose to colonies formed. One colony formed for every 2,000 nucleated marrow cells injected. Observation of colony formation daily showed a steady increase in number and size until seven days after cell inoculation. X‐irradiation (400 rads) eliminated intrinsic colony formation in BALB/c mice. Irradiation of the donor of the ip marrow cells resulted in a D o of 95 rads. Treatment of the marrow donor with cytosine arabino‐side had a suppressive effect on colony formation as did treatment of the host animal after receipt of the ip marrow. These results indicate that the precursor of the granulocytic colonies seen in the macrophage layers are more similar to committed granulocytic precursors than to the pluripotential stem cell.
Molecular Epidemiology: On the Path to Prevention?
Authors: F. P. Perera
Journal: JNCI Journal of the National Cancer Institute (2000)

Cancer prevention has been the stated goal of molecular cancer epidemiology for the past 17 years. In this review, progress toward that goal is evaluated by using as examples well-studied environmental exposures—i.e., tobacco smoke, polycyclic aromatic hydrocarbons, aflatoxin B1, benzene, and hepatitis B virus—and their roles in lung, breast, and liver cancers and leukemia. The contributions of molecular epidemiology discussed here include providing evidence that environmental agents pose carcinogenic risks, helping establish the causal roles of environmental factors in cancer, identifying environment–susceptibility interactions and populations at greatest risk, and developing new intervention strategies. Molecular epidemiologic and other data indicate that assessment of carcinogenic risks should address both the range of risk across the population and the risk to subgroups who may be at high risk because of genetic or acquired susceptibilities, including young children. However, for the most part, research results have not yet been effectively translated into risk assessments and preventive health policies. An infrastructure linking scientists, policy makers, and other constituencies is needed to facilitate this process. To extend our knowledge, the second generation of molecular epidemiologic research should include large-scale, collaborative studies incorporating validated biomarkers and automated technologies. An incentive to make the necessary investment is the recognition that prevention of only 20% of cancer in the United States would result in 200000 fewer new cases diagnosed each year and an annual savings of $21.4 billion in direct costs alone.
Prevalence and predictive factors of sleep breathing disorders (SBD) in severe COPD patients
Authors: Abdelbaki Azouzi, Rahma Ben Jazia, Jihene Ayachi, Halima Ben Salem, Sana Aissa, Mouna Ben Khlifa, Imen Gargouri, Mohamed Benzarti, Ahmed Abdelghani, Mohamed Boussarsar
Journal: European Respiratory Journal (2014)

Background : Severe COPD opposes challenges to the clinician for appropriate and rational prescription of ventilatory support at home. Ventilatory and blood gases (ABGs) abnormalities may worsen during sleep while remaining esoteric to the clinician.

Aims and objectives : Evaluate the prevalence and typology of SBD in severe COPD patients.

Identify predictive factors of SBD in severe COPD patients in order to design a predictive score.

Methods : Prospective study. Consecutive patients admitted to ICU or the pulmonology department within a period of 9 months. Clinical and functional data were collected. Epworth and Pittsburgh scales were measured. Respiratory polygraphy was performed at steady state. Univariate then multivariate analyses were performed to identify factors independently associated with SBD in severe COPD patients.

Results : 51 patients were included. They were 62.3±9.6yr aged ; BMI, 33.8±9.9Kg/m2; mMRCII, 52.9% and pCO2, 43.6±6.5mmHg. The prevalence of SBD was 49% (64% overlap syndrome, 36% nocturnal hypoventilation-related desaturation). 18(72) patients demonstrated SBD while their diurnal pCO2 remained below 55mmHg. Multivariate analysis identified snoring, nocturia, mood disorders and excessive daytime sleepiness as only factors independently associated with SBD. The combination of these four symptoms in a so called SBD-C score demonstrated very interesting discriminative properties (AUC=0.92).

Conclusion : This study identified a high prevalence of SBD while ABGs abnormalities remains below thresholds of prescription of home ventilatory support. A predictive novel score, the SBD-C may be a useful tool in an integrative diagnostic strategy of SBD in severe COPD patients.