tbuckley/cabot-search huggingface dataset:
THE BACTERICIDAL PROPERTIES OF ULTRAVIOLET IRRADIATED LIPIDS OF THE SKIN
Authors: Franklin A. Stevens
Journal: The Journal of Experimental Medicine (1937)

The lipids of the skin after exposure to ultraviolet light are bactericidal. Since other fats and oils which have been irradiated are bactericidal on account of the active oxygen released on contact with bacteria, the mechanism of the bactericidal action of irradiated lipids of the skin must be similar because the lipids have the properties of other irradiated fats and oils. Irradiation increases the active oxygen content of dried skin markedly but little increase occurs if the lipids have been extracted. Although the normal lipids extracted from the skin contain some active oxygen, the active oxygen content is much increased by irradiation. The vapor from lipids exposed to ultraviolet light fogs photographic plates intensely and retards the growth of hemolytic streptococcus. When emulsified in salt solution, the irradiated lipids kill hemolytic streptococcus promptly in comparison with emulsions of lipid which have not been irradiated. The addition of neutralized cysteine HCl to the emulsions of the lipid, normal or irradiated, prolongs the life of bacteria suspended in the emulsions. This protective effect is due to the reducing action of the cysteine, Normal non-irradiated lipid, extracted from the skin under conditions which permit oxidation, kills bacteria more quickly than that used in these experiments, where precautions were taken to prevent oxidation (unpublished data). Even though these precautions were taken some oxidation occurred, because lipid so extracted contained some active oxygen, and bacteria lived longer in emulsions of this normal lipid if cysteine were added.
Miniprobe confocal laser microscopy for the detection of invisible neoplasia in patients with Barrett's oesophagus
Authors: H Pohl, T Rosch, M Vieth, M Koch, V Becker, M Anders, A C Khalifa, A Meining
Journal: Gut (2008)

The biggest challenge in endoscopic surveillance of Barrett's oesophagus is better detection of neoplasia in mucosa of normal macroscopic appearance. We evaluated in vivo miniprobe confocal laser microscopy (CLM) for the detection of invisible Barrett's neoplasia.Prospective two-centre trial in two phases: phase I to establish criteria of Barrett's neoplasia and phase II to test these criteria.296 biopsy sites in 38 consecutive patients with Barrett's oesophagus (mean age 62.1 years, 89.5% men, median length of the Barrett's oesophagus, 3 cm) were examined with standard high-resolution endoscopy and by miniprobe CLM, with precise matching of CLM recordings to biopsy sites. CLM image criteria for normal versus neoplastic Barrett's oesophagus were established from 95 biopsies of 15 patients (phase I); these criteria were then prospectively tested on 201 biopsies from the remaining patients without visible focal changes (phase II). All 201 CLM video recordings from phase II cases were randomised and blindly evaluated by two gastroenterologists.The primary endpoints were accuracy values in diagnosing HGIN or early carcinoma (EC) on a per-biopsy basis. Secondary endpoints included inter-observer agreement.All initially defined miniprobe CLM criteria (phase I) were significantly more frequently detected in HGIN/EC sites compared with sites with no or low grade neoplasia (phase II). In a per-biopsy analysis, sensitivity and specificity for two independent investigators were 75.0% and 88.8%, and 75.0% and 91.0%, respectively, translating at best into a positive predictive value of 44.4% and a negative predictive value of 98.8%. Inter-observer agreement was good (kappa 0.6).Miniprobe CLM showed a high negative predictive value for the diagnosis of endoscopically invisible neoplasia in Barrett's oesophagus; sensitivity, however, has still to be improved.
CD24 Is an Effector of HIF-1–Driven Primary Tumor Growth and Metastasis
Authors: Shibu Thomas, Michael A. Harding, Steven C. Smith, Jonathan B. Overdevest, Matthew D. Nitz, Henry F. Frierson, Scott A. Tomlins, Glen Kristiansen, Dan Theodorescu
Journal: Cancer Research (2012)

Hypoxia drives malignant progression in part by promoting accumulation of the oncogenic transcription factor hypoxia inducible factor-1α (HIF-1α) in tumor cells. Tumor aggressiveness also relates to elevation of the cancer stem cell-associated membrane protein CD24, which has been causally implicated in tumor formation and metastasis in experimental models. Here, we link these two elements by showing that hypoxia induces CD24 expression through a functional hypoxia responsive element in the CD24 promoter. HIF-1α overexpression induced CD24 mRNA and protein under normoxic conditions, with this effect traced to a recruitment of endogenous HIF-1α to the CD24 promoter. Short hairpin RNA-mediated attenuation of HIF-1α or CD24 expression reduced cancer cell survival in vitro and in vivo at the levels of primary and metastatic tumor growth. CD24 overexpression in HIF-1α-depleted cancer cells rescued this decrease, whereas HIF-1α overexpression in CD24-depleted cells did not. Analysis of clinical tumor specimens revealed a correlation between HIF-1α and CD24 levels and an association of their coexpression to decreased patient survival. Our results establish a mechanistic linkage between 2 critically important molecules in cancer, identifying CD24 as a critical HIF-1α transcriptional target and biologic effector, strengthening the rationale to target CD24 for cancer therapy.
Single Eubacterial Origin of Eukaryotic Sulfide:Quinone Oxidoreductase, a Mitochondrial Enzyme Conserved from the Early Evolution of Eukaryotes During Anoxic and Sulfidic Times
Authors: U. Theissen
Journal: Molecular Biology and Evolution (2003)

Mitochondria occur as aerobic, facultatively anaerobic, and, in the case of hydrogenosomes, strictly anaerobic forms. This physiological diversity of mitochondrial oxygen requirement is paralleled by that of free-living α-proteobacteria, the group of eubacteria from which mitochondria arose, many of which are facultative anaerobes. Although ATP synthesis in mitochondria usually involves the oxidation of reduced carbon compounds, many α-proteobacteria and some mitochondria are known to use sulfide (H2S) as an electron donor for the respiratory chain and its associated ATP synthesis. In many eubacteria, the oxidation of sulfide involves the enzyme sulfide:quinone oxidoreductase (SQR). Nuclear-encoded homologs of SQR are found in several eukaryotic genomes. Here we show that eukaryotic SQR genes characterized to date can be traced to a single acquisition from a eubacterial donor in the common ancestor of animals and fungi. Yet, SQR is not a well-conserved protein, and our analyses suggest that the SQR gene has furthermore undergone some lateral transfer among prokaryotes during evolution, leaving the precise eubacterial lineage from which eukaryotes obtained their SQR difficult to discern with phylogenetic methods. Newer geochemical data and microfossil evidence indicate that major phases of early eukaryotic diversification occurred during a period of the Earth's history from 1 to 2 billion years before present in which the subsurface ocean waters contained almost no oxygen but contained high concentrations of sulfide, suggesting that the ability to deal with sulfide was essential for prokaryotes and eukaryotes during that time. Notwithstanding poor resolution in deep SQR phylogeny and lack of a specifically α-protebacterial branch for the eukaryotic enzyme on the basis of current lineage sampling, a single eubacterial origin of eukaryotic SQR and the evident need of ancient eukaryotes to deal with sulfide, a process today germane to mitochondrial quinone reduction, are compatible with the view that eukaryotic SQR was an acquisition from the mitochondrial endosymbiont.
How the FDA forgot the evidence: the case of donepezil 23 mg
Authors: L. M. Schwartz, S. Woloshin
Journal: BMJ (2012)

In the first of a new occasional series highlighting the exaggerations, distortions, and selective reporting that make some news stories, advertising, and medical journal articles "not so," <b>Lisa M Schwartz</b> and <b>Steven Woloshin</b> challenge the claims made for the new 23 mg dose of donepezil
Antiphospholipid antibodies promote leukocyte–endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via β2GPI and apoER2
Authors: Sangeetha Ramesh, Craig N. Morrell, Cristina Tarango, Gail D. Thomas, Ivan S. Yuhanna, Guillermina Girardi, Joachim Herz, Rolf T. Urbanus, Philip G. de Groot, Philip E. Thorpe, Jane E. Salmon, Philip W. Shaul, Chieko Mineo
Journal: Journal of Clinical Investigation (2010)

In antiphospholipid syndrome (APS), antiphospholipid antibodies (aPL) binding to β2 glycoprotein I (β2GPI) induce endothelial cell-leukocyte adhesion and thrombus formation via unknown mechanisms. Here we show that in mice both of these processes are caused by the inhibition of eNOS. In studies of cultured human, bovine, and mouse endothelial cells, the promotion of monocyte adhesion by aPL entailed decreased bioavailable NO, and aPL fully antagonized eNOS activation by diverse agonists. Similarly, NO-dependent, acetylcholine-induced increases in carotid vascular conductance were impaired in aPL-treated mice. The inhibition of eNOS was caused by antibody recognition of domain I of β2GPI and β2GPI dimerization, and it was due to attenuated eNOS S1179 phosphorylation mediated by protein phosphatase 2A (PP2A). Furthermore, LDL receptor family member antagonism with receptor-associated protein (RAP) prevented aPL inhibition of eNOS in cell culture, and ApoER2-/- mice were protected from aPL inhibition of eNOS in vivo. Moreover, both aPL-induced increases in leukocyte-endothelial cell adhesion and thrombus formation were absent in eNOS-/- and in ApoER2-/- mice. Thus, aPL-induced leukocyte-endothelial cell adhesion and thrombosis are caused by eNOS antagonism, which is due to impaired S1179 phosphorylation mediated by β2GPI, apoER2, and PP2A. Our results suggest that novel therapies for APS can now be developed targeting these mechanisms.
The growth of adipose tissue in children and adolescents. Cross-sectional and longitudinal studies of adipose cell number and size.
Authors: J L Knittle, K Timmers, F Ginsberg-Fellner, R E Brown, D P Katz
Journal: Journal of Clinical Investigation (1979)

Adipocyte size and number were determined in 288 subjects ranging in age from 4 mo to 19 yr. The study was performed in 110 obese and 178 non-obese subjects. 4-yr, longitudinal, follow-up studies were also performed in 132 subjects. The results demonstrate that the contribution of cell number and size to the growth of the fat depot in nonobese children varies with age. Deviations from this normal development were observed in obese children shortly after 1 yr of age. By 11 yr of age obese children exceeded the mean cell number found in nonobese adults. Indeed, obese subjects displayed more rapid and earlier elevations in both cell number and size, which were maintained throughout the study. Thus obese children display both quantitative and qualitative differences in fat tissue development when compared to nonobese children. The data indicate that the rate and type of adipose tissue cellular development one encounters in children may play a role in the development of the enlarged fat depots found in obese subjects.
Prostaglandin E2 inhibits sodium transport in rabbit cortical collecting duct by increasing intracellular calcium.
Authors: R L Hébert, H R Jacobson, M D Breyer
Journal: Journal of Clinical Investigation (1991)

The mechanism by which prostaglandin E2 (PGE2) inhibits sodium absorption (JNa) in the rabbit cortical collecting duct (CCD) was explored. PGE2 activates at least three signaling mechanisms in the CCD: (a) by itself PGE2 increases cAMP generation (b) PGE2 also inhibits vasopressin-stimulated cAMP accumulation, and (c) PGE2 raises intracellular calcium([Ca++]i). We tested the contribution of these signaling pathways to PGE2's effect on Na+ absorption, measuring 22Na flux (JNa) and [Ca++]i (using fura-2) in microperfused rabbit CCDs. In control studies PGE2 reduced JNa from 28.2 +/- 3.4 to 15.6 +/- 2.6 pmol.mm-1.min-1. Lowering bath calcium from 2.4 to 45 nM did not by itself alter JNa but in this setting PGE2 failed to inhibit JNa (28.6 +/- 5.4 to 38.5 +/- 4.0). In separate tubules, PGE2 raised [Ca++]i in a spike-like fashion followed by a sustained elevation. However, in 45 nM bath Ca++, PGE2 failed to produce a sustained [Ca++]i elevation. While pretreatment of CCDs with pertussis toxin blocked PGE2 inhibition of vasopressin-stimulated water permeability, it did not block the effect of PGE2 on JNa. To see if cAMP generation contributes to the effect of PGE2 on JNa, we tested the effect of exogenous cAMP, (8-chlorophenylthio(CPT)cAMP) on JNa. 0.1 mM 8-CPTcAMP reduced JNa from 35.75 +/- 2.3 to 21.6 +/- 2.2. However, the addition of PGE2 further blunted JNa to 15.9 +/- 1.3. In CCDs pretreated with indomethacin, 8-CPTcAMP did not significantly decrease JNa 33.6 +/- 2.8 vs. 28.4 +/- 2. However, superimposed PGE2 reduced JNa to 19.0 +/- 3.0. We conclude that PGE2 inhibits sodium transport predominantly by increasing intracellular calcium. This action is not mediated by a pertussis toxin-sensitive G protein. Finally, cAMP, through a cyclooxygenase-dependent mechanism, also inhibits CCD JNa and may contribute to the effects of PGE2 on JNa in the rabbit CCD.
Cardiac microcirculatory effects of beta-adrenergic blockade during sympathetic stimulation.
Authors: D F Cousineau, C A Goresky, C P Rose, A J Schwab
Journal: Circulation Research (1991)

The effects of beta-adrenergic blockade on cardiac transcapillary exchange were examined at rest and during sympathetic stimulation. Multiple indicator dilution experiments were carried out in closed-chest anesthetized dogs at rest and during carotid occlusion, either under basal conditions or after beta-adrenergic blockade with alprenolol. beta-Adrenergic blockade at rest had no effect on coronary flow or transcapillary exchange in comparison with the control situation, but it abolished the increase in coronary flow and in the permeability/surface area product for labeled sucrose produced by carotid occlusion. High coronary resistance values in beta-blocked animals with carotid occlusion were associated with a high degree of heterogeneity in capillary transit times, but the overall relation between coronary flow and the capillary permeability/surface area product was unchanged. The findings indicate that beta-blockade increases coronary resistance during sympathetic stimulation and, simultaneously, decreases the coronary blood flow and capillary permeability/surface area product while increasing the heterogeneity of capillary transit times.
Sildenafil for Long-Term Treatment of Nonoperable Chronic Thromboembolic Pulmonary Hypertension
Authors: Hossein A. Ghofrani, Ralph T. Schermuly, Frank Rose, Ralph Wiedemann, Markus G. Kohstall, André Kreckel, Horst Olschewski, Norbert Weissmann, Beate Enke, Stefanie Ghofrani, Werner Seeger, Friedrich Grimminger
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Only a small percentage of patients with chronic thromboembolic pulmonary hypertension are eligible for pulmonary thrombendarterectomy. We investigated the effects of oral sildenafil on hemodynamics and exercise capacity in 12 nonoperable chronic thromboembolic pulmonary hypertension patients. All patients were in disease progression despite sufficient long-term anticoagulation and the best supportive care and suffered from severe pulmonary hypertension (pulmonary vascular resistance index 1,935 +/- 228 dyn. s. cm-5. m2, cardiac index 2.0 l. min-1. m-2, 6-minute walking distance 312 +/- 30 m). After approximately 6 months of sildenafil treatment, pulmonary hemodynamics and exercise capacity improved significantly (pulmonary vascular resistance index 1,361 +/- 177 L. min-1. m2, p = 0.004, cardiac index 2.4 +/- 0.2 L. min-1. m-2, p = 0.009, 6-minute walking distance 366 +/- 28 m, p = 0.02). Therefore, oral sildenafil may offer a new option for medical treatment of this devastating disease.
The Potential Impact of Pre-Exposure Prophylaxis for HIV Prevention among Men Who Have Sex with Men and Transwomen in Lima, Peru: A Mathematical Modelling Study
Authors: Gabriela B. Gomez, Annick Borquez, Carlos F. Caceres, Eddy R. Segura, Robert M. Grant, Geoff P. Garnett, Timothy B. Hallett
Journal: PLoS Medicine (2012)

Gabriela Gomez and colleagues developed a mathematical model of the HIV epidemic among men who have sex with men and transwomen in Lima, Peru to explore whether HIV pre-exposure prophylaxis could be a cost-effective addition to existing HIV prevention strategies.
Laparoscopic Partial Nephrectomy With Segmental Renal Artery Clamping: Technique and Clinical Outcomes
Authors: Pengfei Shao, Chao Qin, Changjun Yin, Xiaoxin Meng, Xiaobing Ju, Jie Li, Qiang Lv, Wei Zhang, Zhengquan Xu
Journal: European Urology (2010)
Role of Eotaxin-1 Signaling in Ovarian Cancer
Authors: Vera Levina, Brian M. Nolen, Adele M. Marrangoni, Peng Cheng, Jeffrey R. Marks, Miroslaw J. Szczepanski, Marta E. Szajnik, Elieser Gorelik, Anna E. Lokshin
Journal: Clinical Cancer Research (2009)

Tumor cell growth and migration can be directly regulated by chemokines. In the present study, the association of CCL11 with ovarian cancer has been investigated.Circulating levels of CCL11 in sera of patients with ovarian cancer were significantly lower than those in healthy women or women with breast, lung, liver, pancreatic, or colon cancer. Cultured ovarian carcinoma cells absorbed soluble CCL11, indicating that absorption by tumor cells could be responsible for the observed reduction of serum level of CCL11 in ovarian cancer. Postoperative CCL11 levels in women with ovarian cancer negatively correlated with relapse-free survival. Ovarian tumors overexpressed three known cognate receptors of CCL11, CC chemokine receptors (CCR) 2, 3, and 5. Strong positive correlation was observed between expression of individual receptors and tumor grade. CCL11 potently stimulated proliferation and migration/invasion of ovarian carcinoma cell lines, and these effects were inhibited by neutralizing antibodies against CCR2, CCR3, and CCR5. The growth-stimulatory effects of CCL11 were likely associated with activation of extracellular signal-regulated kinase 1/2, MEK1, and STAT3 phosphoproteins and with increased production of multiple cytokines, growth factors, and angiogenic factors. Inhibition of CCL11 signaling by the combination of neutralizing antibodies against the ligand and its receptors significantly increased sensitivity to cisplatin in ovarian carcinoma cells.We conclude that CCL11 signaling plays an important role in proliferation and invasion of ovarian carcinoma cells and CCL11 pathway could be targeted for therapy in ovarian cancer. Furthermore, CCL11 could be used as a biomarker and a prognostic factor of relapse-free survival in ovarian cancer.
Cytokines induce airway smooth muscle cell hyperresponsiveness to contractile agonists
Authors: Y. Amrani, R. A Panettieri
Journal: Thorax (1998)

The important pathophysiological features of the airways in asthma include exaggerated narrowing to bronchoconstrictor agonists and attenuated relaxation to beta adrenoceptor stimulation. These physiological perturbations are associated with inflammation and remodelling of the airways, the latter including an increase in airway smooth muscle cell mass, disruption of the airway epithelium, and changes in the airway tissue extracellular matrix. Recent evidence suggests that cytokines, important molecules modulating airway inflammation, also directly decrease airway smooth muscle responsiveness to beta adrenergic agents, stimulate cytokine secretion, inhibit or promote airway smooth muscle proliferation, and "prime" airway smooth muscle to become hyperresponsive to bronchoconstrictors. Characterisation of the cellular and biochemical events that are involved in activation of airway smooth muscle is likely to be the major consideration in the design of future therapies for asthma. Because calcium is an essential regulatory element for cell growth and cell contraction, it is likely that alterations in calcium mobilisation may, in part, play a role in creating an airway smooth muscle phenotype that is hyperresponsive to contractile agonists. Further studies will be required to determine the precise mechanisms involved in cytokine modulation of calcium homeostasis in airway smooth muscle.
Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles.
Authors: G Tancini, G Bonadonna, P Valagussa, S Marchini, U Veronesi
Journal: Journal of Clinical Oncology (1983)

We report the 5-yr results of a prospective randomized study comparing 12 versus 6 cycles of CMF (cyclophosphamide, methotrexate, fluorouracil) with the aim to evaluate the possibility of reducing the duration of adjuvant treatment without compromising the therapeutic effect of the multimodal approach. At 5-yr from mastectomy, both relapse-free survival (CMF 12: 59%; CMF 6: 65.6%) and total survival (CMF 12: 72.7%; CMF 6: 76.9%) were not significantly different in the two treatment groups. Within the two series, no difference was detected between pre- and postmenopausal patients (CMF 12: 59.3% versus 57.6%; CMF 6: 66.5% versus 63.1%), while findings were inversely related to the number of involved axillary nodes. The analysis of relapse-free survival confirmed that in both menopausal groups, relapse-free survival was not significantly affected by estrogen receptor status. Acute toxic manifestations were moderate and reversible. In particular, no drug-induced leukemia nor increased incidence of solid tumors other than breast cancer were documented in this series. Present results after 12 CMF cycles are almost identical to those of our first CMF adjuvant study. Current findings are sufficiently mature to indicate that the maximum tumor cytoreduction with CMF occurs within a relatively short period of time. To improve the results achieved with a single multidrug regimen, more intensive forms of treatment, i.e., utilizing non-cross-resistant combinations, warrant careful evaluation.
Methotrexate in rheumatoid arthritis.
Authors: G R Hughes
Journal: Annals of the Rheumatic Diseases (1990)

Leaders Methotrexate in rheumatoid arthritisIt is unusual in the conservative world of rheumatology for a treatment to be widely hailed as a therapeutic 'advance'.Examples might include the introduction of non-steroidal anti-inflammatory drugs and, more recently, the use of pulse intravenous cyclophosphamide regimens in vasculitis.One that must surely qualify for consideration, however, is the use of low dose methotrexate in inflammatory arthritis-a treatment being assessed world wide.Although methotrexate has been in use in psoriasis for many years, its success in rheumatoid arthritis has only recently been emphasised.Perhaps rheumatologists are making up for lost time-in 1980 there was one paper on the subject, in 1988 over 120 were published-surprisingly few from the United Kingdom.In October 1989 a symposium held at St Thomas's Hospital in London sought to redress the balance and brought together many with extensive experience of the drug, including Dr Michael Weinblatt, who reviewed his own and other large series, and Dr Andrew Griffiths, who presented a dermatologist's viewpoint.