tbuckley/cabot-search huggingface dataset:
Fluticasone furoate restores leptin/leptin receptor pathway in nasal epithelial cells
Authors: Andreina Bruno, Maria Ferraro, Stefania Gerbino, Angela Bonura, Paolo Colombo, Stefania La Grutta, Mark Gjomarkaj, Elisabetta Pace
Journal: European Respiratory Journal (2011)

Leptin/leptin receptor pathway has been shown to be involved in the epithelial homeostasis and in tissue repair. Allergic rhinitis (AR) is characterized by a IgE-mediated inflammation induced by the allergen exposure, leading to a chronic inflammation with consequential structural abnormalities in the nasal epithelium. Topical corticosteroids are recommended as first-line therapy in AR. The role of the leptin/leptin receptor pathway and the specific effect of fluticasone furoate (FF), a new topical corticosteroid, in the homeostasis of nasal epithelial cells are largely unknown. We aimed to determine whether a nasal epithelial dysfunction of leptin/leptin receptor pathway contributes to AR pathogenesis and to investigate the effect of FF on this pathway. The human nasal epithelial cell line RPMI 2650 was first examined for leptin/leptin receptor expression by immunocytochemistry and by flow-cytometry. Then, the RPMI 2650 cells were cultured in the presence or absence of the allergen extract parietaria judaica (PARJ1), of the fibrogenic cytokine TGF-β1 and of FF and analyzed for leptin receptor by flow-citometry and for cell proliferation by clonogenic assay. The RPMI 2650 cells express leptin and leptin receptor. PARJ1 and TGF-β1 significantly decreases the leptin receptor expression and cell proliferation and FF completely abolishes and reverts the effects of both PARJ1 and TGF-β1. In conclusion, allergen exposure and TGF-β1 alter the homeostasis of nasal epithelium by down-regulating leptin/leptin receptor pathway whereas FF is able to restore both this pathway and nasal epithelial homeostasis.
Frederick Treve's first surgical operation for appendicitis
Authors: Manoj Ramachandran, Jeffrey K Aronson
Journal: Journal of the Royal Society of Medicine (2011)

Sir Frederick Treves, baronet (1853–1923), surgeon and author, was born at 108 Cornhill, Dorchester, Dorset, on 15 February 1853, the youngest son of William Treves, an upholsterer, and his wife, Jane (1814–1892). He attended Dorchester Grammar School and then Merchant Taylors' School in the City of London. He read medicine at the London Hospital, where, among others, John Hughlings Jackson and Jonathan Hutchinson taught him. In 1875 he qualified as a Member of the Royal College of Surgeons, having in the previous year become a Licentiate of the Society of Apothecaries. After a job as House Surgeon at the London Hospital, he became Resident Medical Officer at the Royal National Hospital for Scrofula (later the Royal Sea Bathing Hospital) at Margate in 1876, to which his brother William (Frederick's senior by 10 years) was Honorary Surgeon. His research on scrofula, the origin of which puzzled him, would be published as a book entitled Scrofula and its Gland Diseases in 1882, the very same year that Robert Koch demonstrated that it was due to a bacillus.
Increased Expression of Leptin and the Leptin Receptor as a Marker of Breast Cancer Progression: Possible Role of Obesity-Related Stimuli
Authors: Cecilia Garofalo, Mariusz Koda, Sandra Cascio, Mariola Sulkowska, Luiza Kanczuga-Koda, Jolanta Golaszewska, Antonio Russo, Stanislaw Sulkowski, Eva Surmacz
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Recent in vitro studies suggested that the autocrine leptin loop might contribute to breast cancer development by enhancing cell growth and survival. To evaluate whether the leptin system could become a target in breast cancer therapy, we examined the expression of leptin and its receptor (ObR) in primary and metastatic breast cancer and noncancer mammary epithelium. We also studied whether the expression of leptin/ObR in breast cancer can be induced by obesity-related stimuli, such as elevated levels of insulin, insulin-like growth factor-I (IGF-I), estradiol, or hypoxic conditions. Experimental Design: The expression of leptin and ObR was examined by immunohistochemistry in 148 primary breast cancers and 66 breast cancer metastases as well as in 90 benign mammary lesions. The effects of insulin, IGF-I, estradiol, and hypoxia on leptin and ObR mRNA expression were assessed by reverse transcription-PCR in MCF-7 and MDA-MB-231 breast cancer cell lines. Results: Leptin and ObR were significantly overexpressed in primary and metastatic breast cancer relative to noncancer tissues. In primary tumors, leptin positively correlated with ObR, and both biomarkers were most abundant in G3 tumors. The expression of leptin mRNA was enhanced by insulin and hypoxia in MCF-7 and MDA-MB-231 cells, whereas IGF-I and estradiol stimulated leptin mRNA only in MCF-7 cells. ObR mRNA was induced by insulin, IGF-I, and estradiol in MCF-7 cells and by insulin and hypoxia in MDA-MB-231 cells. Conclusions: Leptin and ObR are overexpressed in breast cancer, possibly due to hypoxia and/or overexposure of cells to insulin, IGF-I, and/or estradiol.
Simultaneous development of acute phase response and autoantibodies in preclinical rheumatoid arthritis
Authors: M M J Nielen
Journal: Annals of the Rheumatic Diseases (2005)

To investigate the temporal relationship between onset of inflammation (as measured by secretory phospholipase A2 (sPLA2) and C reactive protein (CRP)) and the presence of autoantibodies (IgM rheumatoid factor (IgM RF) and antibodies against citrullinated peptides (anti-CCP)) in the preclinical phase of rheumatoid arthritis (RA).For 79 patients with RA who had been blood donors before the onset of disease, a median of 13 serum samples per patient was available. sPLA2 was measured in patient and matched control samples and related to previous CRP, IgM RF, and anti-CCP measurements. The temporal relationship between the increased markers of inflammation and autoantibodies was analysed with time lag analysis.IgM RF and anti-CCP concentrations were significantly associated (p<0.001) with concentrations of sPLA2, CRP, and the combination of sPLA2 and CRP at the same time point. However, we found no stronger association between the two autoantibody tests and the three inflammation measures 1, 2, and 3 years before or after a time point than for measurements at the same time, in the whole group or in subgroups of IgM RF and anti-CCP positive patients.Both the acute phase response and autoantibody formation often develop years before the first symptoms of RA occur, and these phenomena are probably closely connected in time.
A Phase I and Pharmacokinetic Study of the Oral Histone Deacetylase Inhibitor, MS-275, in Patients with Refractory Solid Tumors and Lymphomas
Authors: Lia Gore, Mace L. Rothenberg, Cindy L. O'Bryant, Mary Kay Schultz, Alan B. Sandler, Denise Coffin, Candice McCoy, Astrid Schott, Catherine Scholz, S. Gail Eckhardt
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To evaluate the toxicity profile, pharmacologic, and biological properties of 3-pyridylmethyl N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate (MS-275), a histone deacetylase inhibitor, when administered orally on three different dosing schedules. Experimental Design: Patients with advanced solid malignancies and lymphomas were treated on three dose schedules: once every other week, twice weekly for 3 weeks every 28 days, and once weekly for 3 weeks every 28 days. First-cycle plasma pharmacokinetics and peripheral blood mononuclear cell histone acetylation were determined. Results: Twenty-seven patients received ≥149 courses of treatment. Hypophosphatemia and asthenia were dose limiting on the weekly and twice-weekly dosing schedules; there was no dose-limiting toxicity on the every other week schedule. Pharmacokinetic variables revealed dose-dependent and dose-proportional increases. Two of 27 patients showed partial remissions, including one patient with metastatic melanoma who had a partial response and has remained on study for &amp;gt;5 years. Six patients showed prolonged disease stabilization. Levels of histone H3 and H4 acetylation in peripheral blood mononuclear cells increased qualitatively but with a high degree of interpatient variation. Conclusions: MS-275 is well tolerated at doses up to 6 mg/m2 every other week or 4 mg/m2 weekly for 3 weeks followed by 1 week of rest and results in biologically relevant plasma concentrations and antitumor activity. Twice-weekly dosing was not tolerable due to asthenia, and further evaluation of this schedule was halted. The recommended dose for further disease-focused studies is 4 mg/m2 given weekly for 3 weeks every 28 days or 2 to 6 mg/m2 given once every other week.
Differential response of hamster cheek pouch microvessels to vasoactive stimuli during the early development of hypertension.
Authors: R L Click, J P Gilmore, W L Joyner
Journal: Circulation Research (1979)

Arteriolar responses in the hamster cheek pouch to direct microapplications of norepinephrine (NE), angiotensin n (A II), and potassium chloride (KC1) were investigated during the early developmental phase of hypertension.After determination of arterial pressure in 12 hamsters, control luminal and wall diameters and the response of arterioles (second order branching, 28-60 jun diameters) to microapplications of NE (0.5, 1.0, 5.0 ng), A II (0.5 ng), KC1 (22.2 min) and the vehicle (Tris-buffered Ringer's solution) were determined.Then using a figure-eight ligature around each kidney hypertension was induced in nine animals, and three were sham-operated.Measurements were repeated on the same hamsters 4, 8, and 13 days later.Four of the nine animals developed a sustained hypertension (HT-S) and the remaining five developed a transient hypertension (HT-T), only on day 4.The sham-operated hamsters remained normotensive.The arteriolar response to KC1 was increased significantly in the HT-S group on days 4 and 8 whereas the arteriolar response to NE and A II was increased significantly on days 8 and 13.There were no significant differences in the arteriolar responses of either the HT-T or normotensive group to any agent at any time.Futhennore, there were no significant changes in arteriolar wall/lumen ratios for any group at any time.Thus, the transient nature of the arteriolar response to potassium combined with the delayed Increase in the arteriolar response to NE and A II implies that there are two vascular phases associated with the early development of hypertension in this model.The first phase may be an ionic alteration which in turn may initiate the second or humoral phase.Ore Res 44: 512-517, 1979ALTERATIONS that can result in an increased peripheral resistance in hypertension may involve various components: (1) neurogenic, an altered autonomic output to the peripheral circulation, (2) hormonal, increased levels of vasoconstrictor or decreased levels of vasodilator substances, (3) local, changes in the vascular smooth muscle-receptor complex which lead to increased sensitivity of the blood vessels, and (4) structural, hypertrophy of the vascular smooth muscle concomitant with a decrease in luminal diameter of the arterioles.All of these factors may contribute to an increase in peripheral resistance, but the local and structural
Killing of gram-negative bacteria by polymorphonuclear leukocytes: role of an O2-independent bactericidal system.
Authors: J Weiss, M Victor, O Stendhal, P Elsbach
Journal: Journal of Clinical Investigation (1982)

Previous studies have suggested that a cationic bactericidal/permeability-increasing protein (BPI) present in both rabbit and human polymorphonuclear leukocytes is the principal O2-independent bactericidal agent of these cells toward several strains of Escherichia coli and Salmonella typhimurium (1978. J. Biol. Chem. 253: 2664--2672; 1979. J. Biol. Chem. 254: 11000--11009). To further evaluate the possible role of this protein in the killing of gram-negative bacteria by polymorphonuclear leukocytes, we have measured the bactericidal activity of intact rabbit peritoneal exudate leukocytes under aerobic or anaerobic conditions and of intact human leukocytes from a patient with chronic granulomatous disease. Anaerobic conditions were created by flushing the cells under a nitrogen stream. Effective removal of oxygen was demonstrated by the inability of nitrogen-flushed leukocytes to mount a respiratory burst (measured as increased conversion of 1-[14C]glucose leads to 14CO2 or by superoxide production) during bacterial ingestion. At a bacteria/leukocyte ratio of 10:1, killing of gram-positive, BPI-resistant, Staphylococcus epidermidis is markedly impaired in the absence of oxygen (76.4 +/- 3.3% killing in room air, 29.2 +/- 8.2% killing in nitrogen). Essentially all increased bacterial survival is intracellular. In contrast, both a nonopsonized rough strain (MR-10) and an opsonized smooth strain (MS) of S. typhimurium 395 are killed equally well in room air and nitrogen. A maximum of 70--80 MR-10 and 30--40 MS are killed per leukocyte either in the presence or absence of oxygen. There is no intracellular bacterial survival in either condition indicating that intracellular O2-independent bactericidal system(s) of rabbit polymorphonuclear leukocytes can at least match the leukocyte's ingestive capacity. Whole homogenates and crude acid extracts manifest similar bactericidal capacity toward S. typhimurium 395. This activity can be accounted for by the BPI content of these cell fractions and is virtually eliminated by immune (anti-BPI), but not by preimmune goat IgG-rich fractions. Opsonization of smooth MS, required for bacterial killing by intact leukocytes, does not alter bacterial sensitivity to BPI in crude or purified form. Leukocytes of a patient with chronic granulomatous disease killed ingested S. typhimurium 396 MS nearly as well as did normal leukocytes. The bactericidal activity toward E. coli (J5) of crude acid extracts of the CGD and normal human leukocytes was virtually the same and was nearly completely inhibited by anti-BPI IgG-rich fractions, but not by preimmune IgG-rich fractions. These findings suggest that the killing of gram-negative bacteria such as S. typhimurium by intact polymorphonuclear leukocytes may also be attributed to the action of BPI.
Liver Transplantation for Hepatocellular Carcinoma
Authors: See Ching Chan
Journal: Liver Cancer (2013)

Hepatitis B is endemic in many regions of Asia, including China, Korea and India. This results in a heavy burden of hepatocellular carcinoma (HCC) because hepatitis B virus is a major risk factor in the development of the disease. In addition, the incidence of hepatitis-C-related HCC is on the rise in the United States. HCC patients with poor liver function reserve are not suitable candidates for resection, and liver transplantation (LT) has emerged as the treatment of choice for small unresectable HCCs. To treat more HCC patients with LT, the standard patient selection criteria have been expanded at a number of centers. Careful and well-considered selection of patients is the key to success in LT for HCC. Although tumor size and tumor number are used to predict whether transplantation is likely to be successful, the weighting that should be attached these two parameters has not been determined. In addition to the size and number of lesions, the morphology of HCC is also predictive of its behavior. Well-circumscribed lesions, in general, are less aggressive than those with poorly defined borders. On the waiting list for LT, HCC patients compete with liver failure patients. It is essential that the criteria used for selecting HCC patients for LT should be easily applicable and fair to other transplant candidates. In the face of the scarcity of deceased-donor livers and the inevitable risks for living liver donors, a predictably low rate of recurrence of HCC after LT is mandatory.
Illness Risk Following Rapid Versus Gradual Discontinuation of Antidepressants
Authors: Ross J Baldessarini, Leonardo Tondo, Carmen Ghiani, Beatrice Lepri
Journal: American Journal of Psychiatry (2010)

Objective Rapid discontinuation of some psychotropic medications is followed by discontinuation symptoms as well as an increased risk of early illness recurrence. Recurrence occurs earlier after rapid than after gradual discontinuation with lithium and antipsychotics. The authors compared illness recurrence after rapid versus gradual discontinuation of antidepressants. Method The authors compared 398 patients with a DSM-IV diagnosis of recurrent major depressive disorder (N=224), panic disorder (N=75), bipolar II disorder (N=62), or bipolar I disorder (N=37). Two-thirds were women, the mean age was 42 years, and patients were treated with antidepressants for a mean of 8.5 months. Antidepressants were discontinued clinically, either rapidly (over 1–7 days; N=188) or gradually (over 14 days or more; N=210), with a mean follow-up duration of 2.8 years; patients who were ill at discontinuation were excluded from the analysis. The authors compared latency to first new illness episodes using survival analysis and Cox multivariate modeling. Results The latency to first illness with rapid discontinuation was 0.4 times that with gradual discontinuation, and the latency after rapid discontinuation was one-fourth the estimated average previous interepisode interval in the same patients. The effect was similar across antidepressant classes and across years; the pace of discontinuation had less effect with drugs of prolonged half-life. The effect also varied by diagnosis (bipolar I ≥ panic > bipolar II ≥ major depressive disorder) but not by episodes per year, duration of index illness, use of concomitant treatment, or antidepressant dose or duration. Conclusions The recurrence risk for depression or panic was much shorter after rapid than after gradual discontinuation of antidepressants. These findings have implications for both clinical management and the design and interpretation of clinical trials.
Toward an Improved Definition of the Tumor Spectrum Associated With <i>BAP1</i> Germline Mutations
Authors: Thomas Wiesner, Isabella Fried, Peter Ulz, Elvira Stacher, Helmut Popper, Rajmohan Murali, Heinz Kutzner, Sigurd Lax, Freya Smolle-Jüttner, Jochen B. Geigl, Michael R. Speicher
Journal: Journal of Clinical Oncology (2012)
STUDIES ON THE RELATIONSHIP OF STREPTOCOCCUS HEMOLYTICUS TO THE RHEUMATIC PROCESS
Authors: Alvin F. Coburn, Ruth H. Pauli
Journal: The Journal of Experimental Medicine (1932)

In the first two papers findings were presented which point to a close relationship between the incidence of rheumatic fever and the distribution of Streptococcus hemolyticus. The fact was emphasized that in the rheumatic subject a recrudescence of the disease process is usually preceded by pharyngeal infection with hemolytic streptococci. These organisms conspicuous in the throat flora during the period of infection preliminary to an attack of acute rheumatism fell into six antigenic groups and produced toxins which in 70 per cent were neutralized by a monovalent streptococcus antiserum. In the present study, four series of observations have been presented, demonstrating the development of immune bodies to hemolytic streptococcus during the course of rheumatic fever. The agglutination and complement fixation reactions of sera from patients with acute rheumatism suggest recent infection with streptococcus. Precipitin tests indicate that at the time of appearance of the rheumatic attack, individuals develop, in their blood, precipitins to the protein fractions of hemolytic streptococcus. That these precipitins may not be entirely specific is recognized from their cross-reactions with antigens of chemically related organisms. The studies made in association with E. W. Todd of England have demonstrated that at the onset of an attack of acute rheumatism, there occurs in each instance a rise in the antistreptolysin titer of the patient's serum. This titer is much higher than that observed in normal subjects or in patients with bacterial infection other than hemolytic streptococcus. This presence of antistreptolysin with an N.D. of 0.005 cc. is considered strong evidence of recent infection by hemolytic streptococcus. In conclusion, the relationship between the incidence of hemolytic streptococcus and the geographical distribution of rheumatic fever, the relationship between the recrudescence in the rheumatic subject and infection of the throat with hemolytic streptococcus, the development of immune bodies for hemolytic streptococcus at the onset of the rheumatic attack and the apparently specific relationship of antistreptolysin formation to infection with hemolytic streptococcus,—together this combined evidence indicates that the infectious agent initiating the rheumatic process is Streptococcus hemolyticus.
A three year follow up of patients allocated to placebo, or oral or injectable gold therapy for rheumatoid arthritis.
Authors: H A Capell, D Lewis, J Carey
Journal: Annals of the Rheumatic Diseases (1986)

Ninety patients randomly allocated to receive auranofin, matching placebo, or sodium aurothiomalate have been followed up for three years. Inefficacy led to cessation of treatment in 14 patients receiving auranofin, 27 receiving placebo, and one receiving sodium aurothiomalate. Twenty seven of the patients receiving placebo were reallocated within the study and 16 continued therapy at three years. This group showed similar statistically significant improvement in clinical and laboratory parameters at one, two, and three years to those on an active drug from the outset. Patients who discontinued auranofin because of inefficacy were offered sodium aurothiomalate therapy--eight patients in this group completed three years of treatment on sodium aurothiomalate and showed significant improvement in some but not all parameters. A hand radiograph erosion score showed a deterioration in 80% of patients remaining on auranofin, 75% of those on sodium aurothiomalate, and 80% of the original placebo group who continued an active drug for three years. Although more patients discontinued auranofin over the study period because of inefficacy, no difference could be shown between the degree of improvement in the subgroup who remained on auranofin and those receiving sodium aurothiomalate. No disadvantage in outcome could be shown for patients originally assigned to placebo.
Generation of functional human T cell hybrids.
Authors: O Irigoyen, P V Rizzolo, Y Thomas, L Rogozinski, L Chess
Journal: The Journal of Experimental Medicine (1981)

Human T cell hybrids were generated by fusing lectin-activated normal and leukemic human T cells with an aminopterin-sensitive human T cell line. This mutant cell line, designated CEM-T15, was derived from the human T cell line CEM after chemical mutagenesis with ethane methylsulfonate and subsequent culture in medium containing 6-thioguanine. After polyethylene glycol-induced fusion, the cells were cultured in hypoxanthine-aminopterin-thymidine selective medium. More than 5 wk after fusion, evidence for successful hybridization was obtained by three independent criteria: (a) The majority of the cultures contained cells expressing the OKT3 surface antigen: this antigen is expressed on normal T cells but not on CEM-T15 cells. (b) Most of the cultures contained polyploid cells. (c) Some of the cultures provided helper activity in the generation of antibody-forming cells. This functional activity is absent from the CEM-T15 parental cell line. Evidence for functional stability of the hybrids greater than 20 wk after fusion was provided by several clones that not only continue growing exponentially but also maintain expression of OKT3 surface antigen and high levels of helper function. These T cell hybrids constructed using antigen-specific human T cells should be of considerable importance in further studies of the immunobiology of human T cells.