tbuckley/cabot-search huggingface dataset:
Abstract P6-15-12: Preclinical Evaluation of a STAT3 Inhibitor in Breast Cancer
Authors: SR Walker, EA Nelson, M Chaudhury, F Madoux, P Subramaniam, P Chase, M Koenig, WR Roush, P Hodder, DA. Frank
Journal: Cancer Research (2010)

Abstract Breast cancer often arises from inappropriate activation of transcription factors involved in normal mammary development, such as the signal transducers and activators of transcription (STAT) family of transcription factors. STAT3, which plays an important role in mammary remodeling, is activated (as assessed by tyrosine phosphorylation) in approximately 70% of primary breast cancers, with many of these tumors being highgrade. Furthermore, inhibition of STAT3 leads to a loss of tumorigenicity of breast cancer cells. Therefore, targeting STAT3 in breast cancer would be a potentially beneficial form of therapy. To identify small molecule STAT3 inhibitors, we developed a high throughput cell-based assay to identify compounds that inhibit STAT3- dependent transcriptional activity. We screened approximately 200,000 compounds, and specificity for STAT3 was ensured by eliminating molecules that inhibited either STAT1- or NF-kappaB-dependent transcriptional activity. From this screen, we identified 4-[4-(phenylmethyl) piperidin-1-yl] thieno[2,3-d]pyrimidine (PMPTP) (Probe ID ML116) as a potent inhibitor of STAT3 transcriptional activity, which has no effect on STAT1 or NF-kappaB-dependent transcriptional activity. Treatment with PMPTP of MDA-MB-468 breast cancer cells, which contain constitutively activated STAT3, leads to inhibition of expression of STAT3 target genes including bcl-x and mcl1. Furthermore, PMPTP is a potent inhibitor of viability of MDA-MB-468 breast cancer cells. By contrast, SK-BR-3 cells, which do not contain constitutively active STAT3, were only minimally affected. This suggests that PMPTP reduces the viability of cells that depend on constitutively active STAT3. PMPTP has no effect on STAT3 tyrosine or serine phosphorylation or STAT3 nuclear translocation, suggesting that PMPTP may be inhibiting STAT3 at the level of DNA binding or co-factor recruitment. Importantly, PMPTP lowers the apoptotic potential of breast cancer cells thereby making them more susceptible to other forms of therapy. Building on this observation, we identified a number of beneficial combinations of PMPTP with cytotoxic drugs currently used in breast cancer therapy as well as novel anti-cancer agents. Additionally, we analyzed a number of structural analogues of PMPTP, and we identified two compounds that had approximately 4-fold increased potency in inhibiting the viability of breast cancer cells containing STAT3 activation. Taken together, these findings identify PMPTP as a potential new form of therapy for breast cancers containing activated STAT3, which can be enhanced using conventional and non-conventional chemotherapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-12.
Inhaled fluticasone decreases bronchial but not alveolar nitric oxide output in asthma
Authors: L. Lehtimäki, H. Kankaanranta, S. Saarelainen, V. Turjanmaa, E. Moilanen
Journal: European Respiratory Journal (2001)

Exhaled nitric oxide (NO) concentration is a noninvasive measure of airway inflammation and is increased in asthma. Inhaled glucocorticoids decrease exhaled NO concentration, but the relative contributions of alveolar and bronchial levels to the decrease in exhaled NO concentration are unknown. Alveolar NO concentration and bronchial NO flux can be separately approximated by measuring exhaled NO at several exhalation flow rates. The effect of steroid treatment on alveolar and bronchial NO output in asthma was studied. Alveolar NO concentration and bronchial NO flux were assessed in 16 patients with asthma before and during treatment with inhaled fluticasone for 8 weeks and in 16 healthy controls. Before the treatment, asthmatics had increased bronchial NO flux (mean±sem: 3.6±0.4 versus 0.7±0.1 nL·s −1 , p&lt;0.001) but normal alveolar NO concentration (1.2±0.5 versus 1.0±0.2 parts per billion (ppb), p&gt;0.05) compared with controls. Inhaled fluticasone decreased bronchial NO flux from 3.6±0.4 to 0.7±0.1 nL·s −1 (p&lt;0.01) but had no effect on alveolar NO concentration (before: 1.2±0.5; after: 1.2±0.1 ppb, p&gt;0.05). The forced expiratory volume in one second improved, whereas asthma symptom score and serum levels of eosinophil cationic protein and eosinophil protein X decreased during the treatment. In conclusion, inhaled fluticasone decreases bronchial but not alveolar nitric oxide output simultaneously with clinical improvement in patients with asthma.
Prospective Study of Diabetes and Risk of Hip Fracture
Authors: Mohsen Janghorbani, Diane Feskanich, Walter C. Willett, Frank Hu
Journal: Diabetes Care (2006)

The purpose of this study was to determine whether women with type 1 and type 2 diabetes are at higher risk of hip fractures.A total of 109,983 women aged 34-59 years in 1980 were followed through 2002 for the occurrence of hip fracture. At baseline and through biennial follow-up, women were asked about their history and treatment of diabetes and other potential risk factors for hip fracture.During 2.22 million person-years of follow-up, 1,398 women had a hip fracture. Compared with women without diabetes, the age-adjusted relative risk (RRs) of hip fracture was 7.1 (95% CI 4.4-11.4) for women with type 1 diabetes and 1.7 (1.4-2.0) for those with type 2 diabetes. After further adjustment for BMI, smoking, physical activity, menopausal status, daily intake of calcium, vitamin D, protein, and postmenopausal hormone use, the multivariate RR of incident hip fracture in individuals with type 1 diabetes compared with individuals without diabetes was 6.4 (3.9-10.3) and with type 2 diabetes was 2.2 (1.8-2.7). The RRs increased with longer duration of type 2 diabetes (3.1 [2.3-4.0] for >or=12 years compared with no diabetes, P for trend < 0.001) and ever use of insulin.These data indicate that both type 1 and type 2 diabetes are associated with an increased risk of hip fracture. The results of this study highlight the need for fracture-prevention strategies in women with diabetes.
Humanitarian aid corridor fails to materialise
Authors: Owen Dyer, Judy Siegel-Itzkovich
Journal: BMJ (2006)

Despite Israel's announcement last weekend of a 48 hour suspension of aerial bombing in southern Lebanon, fear of air attack continued to hamper humanitarian efforts in the region, according to aid workers. And as Hezbollah rocket attacks continued on Israel, some medical establishments there came under attack.

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A Red Cross worker carries the body of a girl pulled from a house in Qana, Lebanon, which was hit by an Israeli air strike 

Credit: NICHOLAS ASFOURI/GETTY

Israel's air force resumed attacks on “immediate threats” within 12 hours of the announcement. A spokesman for Israel's army said that the attacks were …

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Primary Nondisseminated Herpes-Simplex Infection in a Newborn Infant
Authors: Miriam G. Wilson, Michael Martini
Journal: New England Journal of Medicine (1962)

NEONATAL herpes-simplex infection, first described in 1935,1 has been recognized primarily as a generalized, disseminated disease, occurring from three to seven days after birth and usually terminating in death.1 2 3 4 5 6 7 8 9 The present report describes an unusual form of neonatal herpetic infection in which the lesions, although multiple, appeared to be confined to the skin. The herpetic lesions recurred twice during the six months in which the infant was observed.Case ReportT.W., a Caucasian female infant, was first admitted to the hospital on the 10th day of life with a tentative diagnosis of neonatal impetigo, possibly staphylococcal, and upper respiratory infection. . . .
Lack of Association Between Migraine Headache and Patent Foramen Ovale
Authors: Pallav Garg, Stephen J. Servoss, Justina C. Wu, Zahid H. Bajwa, Magdy H. Selim, Alexis Dineen, Richard E. Kuntz, E. Francis Cook, Laura Mauri
Journal: Circulation (2010)

Background— Clinical observations of migraine headache symptoms in patients with a patent foramen ovale (PFO), both of which conditions are highly prevalent, have raised the question of a possible pathophysiological relationship. We sought to evaluate the assumption of an association between migraine headaches and the presence of PFO by use of a large case-control study. Methods and Results— We conducted a case-control study to assess the prevalence of PFO in subjects with and without migraine. Case subjects were those with a history of migraine (diagnosed by neurologists at a specialty academic headache clinic). Control subjects were healthy volunteers without migraine 1:1 matched on the basis of age and sex with case subjects. Presence of PFO was determined by transthoracic echocardiogram with second harmonic imaging and transcranial Doppler ultrasonography during a standardized procedure of infused agitated saline contrast with or without Valsalva maneuver and a review of the results by experts blinded to case-control status. PFO was considered present if both studies were positive. Odds ratios were calculated with conditional logistic regression in the matched cohort (n=288). In the matched analysis, the prevalence of PFO was similar in case and control subjects (26.4% versus 25.7%; odds ratio 1.04, 95% confidence interval 0.62 to 1.74, P =0.90). There was no difference in PFO prevalence in those with migraine with aura and those without (26.8% versus 26.1%; odds ratio 1.03, 95% confidence interval 0.48 to 2.21, P =0.93). Conclusions— We found no association between migraine headaches and the presence of PFO in this large case-control study.
Transmission of tuberculosis by patients with HIV infection
Authors: G M Scott, J Holton
Journal: BMJ (1994)

reviews are simply uninformed, for there are none to disseminate.It takes up to five years to prepare a valid, clinically useful systematic review, and we are barely one year old.Even when our reviews start coming out next year their number will be small because they have to meet the high standards our members have created.None the less, the prospects for their wide dissemination look good.The current use of their forerunner (the pilot Cochrane Pregnancy and Childbirth Database) is dramatically greater than that of its predecessor (TMe Oxford Database of Perinatal Trials),3 and our arrangements with journals such as the BM7, the Lancet, and Annals of Internal Medicine to avoid restrictive copyright, plus our development of versions of Cochrane reviews on the internet, will lead to unprecedented availability ofthe reviews.We feel anything but complacent and welcome suggestions from supporters and inforned critics alike about how we can do better.
Lung function and the response to exercise in systemic sclerosis
Authors: S. Godfrey, R. Bluestone, B. E. Higgs
Journal: Thorax (1969)

Cardiopulmonary function has been studied at rest and during graded exercise in 11 patients with systemic sclerosis. All patients had multi-system disease, five complained of breathlessness, and four had radiographic evidence of pulmonary fibrosis. All patients had gross effort intolerance. Lung volumes were reduced in half the patients, as was the transfer factor for CO when corrected for lung volume. Airway resistance was normal. Four patients hyperventilated on exercise, but the tidal volume was normal; three developed arterial desaturation during exercise. Six patients had an excessive elevation of blood lactate on exercise and three of these had evidence of muscle disease. Analysis of the exercise data suggested that in seven patients cardiac output and dead space were normal. In four patients there was a pattern of normal cardiac output, increased dead space, and increased venous admixture, suggesting ventilation/perfusion imbalance. There was no correlation between the results of the physiological tests and the extent of clinical involvement with the disease. The possible reasons for this and for the effort intolerance are reviewed.
Declines in Mortality From Acute Myocardial Infarction in Successive Incidence and Birth Cohorts of Patients With Rheumatoid Arthritis
Authors: Eswar Krishnan, Vijaya Bharathi Lingala, Gurkirpal Singh
Journal: Circulation (2004)

Patients with rheumatoid arthritis are at high risk for acute myocardial infarction (AMI). The treatment of rheumatoid arthritis has become more intensive over the past 2 decades, resulting in tighter control of inflammation and lower levels of disability. The impact of this on atherosclerotic cardiovascular diseases is not known.Death rates from AMI in a cohort of 3862 patients with rheumatoid arthritis followed up from 1980 to 1997 were studied. Time trends in AMI mortality among successive incidence and birth cohorts were examined by use of multivariable Poisson regression models and by comparing standardized mortality ratios. The mean age was 56 years in this predominantly female cohort (76%), and median disease duration was 6.5 years. During the period of observation, the use of methotrexate increased substantially, whereas that of prednisone was relatively stable. Over the 22,209 person-years of observation, there were 157 deaths as a result of AMI, with a death rate of 7.06 per 1000 person-years. Mortality rates were higher in older age groups and in men. After adjustment for age, sex, race, and disease duration, the risk of AMI declined in successive incidence years (relative risk, 0.94; 95% CI, 0.92 to 0.96). Patients with rheumatoid arthritis incident after 1990 did not have excess AMI mortality compared with general population. Declines in mortality trends were observed in successive birth cohorts as well.Mortality as a result of AMI among patients with rheumatoid arthritis has declined over time.
Pseudomonas aeruginosa Rash Associated With a Whirlpool
Authors: John Washburn
Journal: JAMA (1976)

A generalized pruritic pustular rash was reported by 32 of 61 (53%) persons who had used the swimming pool and whirlpool at a Minnesota motel in March 1975. A questionnaire survey indicated that attack rates were highest in periods of heaviest bather load. The rash appeared 8 to 48 hours after exposure and resolved within seven days. No rash was reported by 37 motel guests who did not use the pool. Pseudomonas aeruginosa, serogroup 11, was isolated from the skin lesions of two patients and from the water from both pools. Circumstantial evidence implicated the whirlpool as the most probable source of infection. Deficiencies in disinfecting equipment and technique were identified and corrected.
TREATMENT OF SNAKE VENOM POISONING WITH CORTISONE AND CORTICOTROPIN
Authors: William W. Hoback
Journal: JAMA (1953)

Within the last five months we have had the opportunity to observe the effects of cortisone or corticotropin in treatment of three patients bitten by poisonous snakes. All received, in addition, standard treatment consisting of the application of a tourniquet and incision and suction of fang wounds, antivenom, tetanus antitoxin, antibiotics, and other symptomatic and supportive therapy. We have been impressed by the pronounced decrease in morbidity in these patients as compared with 11 others seen in the last three years who did not receive cortisone or corticotropin. We have been able to find no other reports of cortisone therapy for this disorder and only one report of the use of corticotropin.<sup>1</sup> <h3>REPORT OF CASES</h3><h3>Case 1.—</h3> A 4-year-old white girl was admitted to the Clinch Valley Clinic Hospital on Aug. 29, 1952, because of a snake bite of the left foot. She had been bitten by an unknown
Changes in Mitochondrial DNA as a Marker of Nucleoside Toxicity in HIV-Infected Patients
Authors: Hélène C.F. Côté, Zabrina L. Brumme, Kevin J.P. Craib, Christopher S. Alexander, Brian Wynhoven, Lillian Ting, Hubert Wong, Marianne Harris, P. Richard Harrigan, Michael V. O'Shaughnessy, Julio S.G. Montaner
Journal: New England Journal of Medicine (2002)

Nucleoside analogues can induce toxic effects on mitochondria by inhibiting the human DNA polymerase γ. The toxic effects can range from increased serum lactate levels to potentially fatal lactic acidosis. We studied changes in mitochondrial DNA relative to nuclear DNA in the peripheral-blood cells of patients with symptomatic, nucleoside-induced hyperlactatemia.
Desoxycorticosterone in Addison's Disease
Authors: D. M. Dunlop
Journal: BMJ (1943)

It is well established that desoxycorticosterone acetate (D.O.C.A.) is highly effective in the treatment of Addison's disease when given intramuscularly or implanted in pellets under the skin.The drug is ineffective when swallowed.The repeated injection of an oily solution, however, is inconvenient, especially for thin patients with poor muscles, who form the majority of those suffering from Addison's, disease; in addition such an injection usually involves a visit to the doctor, and for the uninsured this may add considerably to the already high cost of the drug.The implantation of a big single dose of D.O.C.A. practically eliminates these drawbacks, since such -an implantation may suffice for many months.Once implantation has been made, however, there is no means of controlling dosage.Thus dangerous toxic effects such as massive oedema and hypertension are theoretically possible from the excessive absorption of the active principle, and these have been noted by Loeb (1940).
Lamina-Specific Reductions in Dendritic Spine Density in the Prefrontal Cortex of Subjects With Schizophrenia
Authors: Nutan Kolluri, Zhuoxin Sun, Allan R. Sampson, David A. Lewis
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: In a previous study the authors found that dendritic spine density was reduced on prefrontal pyramidal neurons in layer 3 of subjects with schizophrenia. From a neural circuitry perspective, understanding the pathophysiological significance of this finding requires knowledge of whether pyramidal neurons in other cortical layers are similarly affected. The authors’ goal was to determine whether their finding in layer 3 was also present in other cortical layers in the same group of subjects with schizophrenia. METHOD: Spine density and other dendritic measures were made for pyramidal neurons in layers 5 and 6 of prefrontal area 46 in the brains of deceased subjects with schizophrenia, subjects with other psychiatric disorders, and normal comparison subjects. RESULTS: None of the dendritic measures for layer 5 or 6 pyramidal neurons differed across the subject groups, but the within-subject differences in spine density between deep layer 3 and layer 5 or 6 pyramidal neurons were significantly greater in the patients with schizophrenia than in the comparison subjects. CONCLUSIONS: These findings are consistent with the idea that prefrontal pyramidal neurons involved in corticocortical and/or thalamocortical connections are preferentially affected in schizophrenia.
Coexistence of IgA antibodies to desmogleins 1 and 3 in pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus
Authors: L.F. Mentink, M.C.J.M. de Jong, G.J. Kloosterhuis, J. Zuiderveen, M.F. Jonkman, H.H. Pas
Journal: British Journal of Dermatology (2007)

Pemphigus is a bullous mucocutaneous autoimmune disease characterized by IgG autoantibodies to desmoglein (Dsg) 1 and/or Dsg3. Occasionally direct immunofluorescence of pemphigus skin reveals IgA depositions with an intraepidermal intercellular pattern in addition to the IgG deposition.To investigate if pemphigus patients, in addition to having IgG autoantibodies, also generate IgA antibodies to Dsg1 and/or Dsg3.Sera of 100 pemphigus patients and 36 bullous pemphigoid controls were tested by IgA enzyme-linked immunosorbent assay (ELISA) to the recombinant extracellular domains of Dsg1 and Dsg3. The patients were selected on clinical grounds and positive IgG ELISA index values for Dsg1 and/or Dsg3. They were divided into four groups: patients having IgG to only Dsg1 (n=34), patients having IgG to both Dsg1 and Dsg3 (n=31), patients having IgG to only Dsg3 (n=27) and patients who had paraneoplastic pemphigus (PNP) (n=8).IgA antibodies to Dsg1 were found in 13 (38%) of the patients with IgG to Dsg1, in five (16%) of the patients with IgG to both Dsg1 and Dsg3, in four (15%) of the patients with IgG to Dsg3 and in none of the PNP patients. IgA antibodies to Dsg3 were found in one (3%) of the patients with IgG to Dsg1, in 18 (58%) of the patients with IgG to both Dsg1 and 3, in 18 (67%) of the patients with IgG to Dsg3, and in four (50%) of the PNP patients. Immunofluorescence analysis demonstrated intraepidermal intercellular staining IgA antibodies in serum and intercellular IgA deposits in skin of IgA ELISA-positive patients, although to a lesser extent than by ELISA.This study shows that in a considerable number of supposedly IgG-mediated pemphigus patients IgA to Dsg1 and Dsg3 is also present. In most cases the antigen specificity of the IgA follows the antigen specificity of the IgG, although in a small number of cases IgA is present against the Dsg not recognized by IgG.
Isolation of human eosinophil phospholipase D.
Authors: L A Kater, E J Goetzl, K F Austen
Journal: Journal of Clinical Investigation (1976)

Phospholipase D preferentially contained in human eosinophil polymorphonuclear leukocytes as compared to other leukocytes was isolated by sequential asion and cation exchange chromatography and gel filtration. The purified eosinophil enzyme specifically liberated choline from I-alpha-phosphatidyl choline with a pH optimum of 4.5-6.0 and exhibited a pI of 5.8-6.2 on polyacrylamide-gel isoelectric focusing, which are properties shared by phospholipase D from plant sources; however, its apparent mol wt of 60,000 is approximately one-half that of the plant enzymes. Eosinophil and cabbage phospholipase D inactivated a partially purified rat platelet-activating factor (PAF) in a time- and dose-dependent reaction. The cleavage of this PAF activity was attributed to the inherent phospholipase D activity of the eosinophil enzyme since the two activities chromatographed together at each purification step, and there was apparent reciprocal inhibition of choline-generating activity by PAF and of PAF-inactivating activity by phosphatidyl choline. Thus, possible regulatory functions of the eosinophil in immediate hypersensitivity reactions include inactivation of a PAF by phospholipase D as well as degradation of slow-reacting substance of anaphylaxis by arylsulfatase B.
Glucocorticoids exacerbate obesity and insulin resistance in neuron-specific proopiomelanocortin-deficient mice
Authors: James L. Smart, Virginie Tolle, Malcolm J. Low
Journal: Journal of Clinical Investigation (2006)

Null mutations of the proopiomelanocortin gene (Pomc–/–) cause obesity in humans and rodents, but the contributions of central versus pituitary POMC deficiency are not fully established. To elucidate these roles, we introduced a POMC transgene (Tg) that selectively restored peripheral melanocortin and corticosterone secretion in Pomc–/– mice. Rather than improving energy balance, the genetic replacement of pituitary POMC in Pomc–/–Tg+ mice aggravated their metabolic syndrome with increased caloric intake and feed efficiency, reduced oxygen consumption, increased subcutaneous, visceral, and hepatic fat, and severe insulin resistance. Pair-feeding of Pomc–/–Tg+ mice to the daily intake of lean controls normalized their rate of weight gain but did not abolish obesity, indicating that hyperphagia is a major but not sole determinant of the phenotype. Replacement of corticosterone in the drinking water of Pomc–/– mice recapitulated the hyperphagia, excess weight gain and fat accumulation, and hyperleptinemia characteristic of genetically rescued Pomc–/–Tg+ mice. These data demonstrate that CNS POMC peptides play a critical role in energy homeostasis that is not substituted by peripheral POMC. Restoration of pituitary POMC expression to create a de facto neuronal POMC deficiency exacerbated the development of obesity, largely via glucocorticoid modulation of appetite, metabolism, and energy partitioning.