tbuckley/cabot-search huggingface dataset:
Clearance of NH2-terminal propeptides of types I and III procollagen is a physiological function of the scavenger receptor in liver endothelial cells.
Authors: J Melkko, T Hellevik, L Risteli, J Risteli, B Smedsrød
Journal: The Journal of Experimental Medicine (1994)

This study was undertaken to determine the fate of circulating NH2-terminal propeptide of type I procollagen (PINP) in rats. Radiolabeled PINP showed a biphasic serum decay curve after intravenous injection. 79% of the material disappeared from the blood during the initial alpha-phase (t1/2 alpha = 0.6 min), while the remaining 21% was eliminated with a t1/2 beta of 3.3 min. The major site of uptake was the liver, 78, 1, and 21% of its radioactivity being recovered in isolated liver endothelial cells (LEC), Kupffer cells, and parenchymal cells, respectively. In LEC, fluorescently labeled PINP accumulated in small (0.1 microns) peripheral and larger (&amp;gt; 0.1 microns) perinuclear vesicles within 10 min at 37 degrees C after a binding pulse at 4 degrees C. These grew in size with increasing chasing time, reaching a maximum diameter of 1 microns or more after 30 min, and taking the shape of rings that were stained only along their periphery. At chase intervals exceeding 30 min, the size of the vesicles decreased, and after 60 min the stain appeared in smaller, densely stained perinuclearly located vesicles. Degradation of 125I-PINP to free smaller fragments and 125I- was significant after 30 min. Only formaldehyde-treated albumin, acetylated LDL, polyinosinic acid and NH2-terminal propeptide of type III procollagen (PIIINP) competed with PINP for uptake. These findings indicate that clearance of PINP and PIIINP, which are normal waste products generated in large quantities, is a physiological function of the scavenger receptor in LEC.
Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma
Authors: M.B. Lens, M. Dawes
Journal: British Journal of Dermatology (2004)

Journal Article Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma Get access M.B. Lens, M.B. Lens John Radcliffe Hospital, University of Oxford, Oxford, U.K., and Department of Family Medicine, McGill University, Montreal, Canada Dr Marko B. Lens. E‐mail: markolens@aol.com Search for other works by this author on: Oxford Academic Google Scholar M. Dawes M. Dawes John Radcliffe Hospital, University of Oxford, Oxford, U.K., and Department of Family Medicine, McGill University, Montreal, Canada Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 150, Issue 2, 1 February 2004, Pages 179–185, https://doi.org/10.1111/j.1365-2133.2004.05708.x Published: 01 February 2004 Article history Accepted: 20 July 2003 Published: 01 February 2004
Alcohol Sales and Risk of Serious Assault
Authors: Joel G Ray, Rahim Moineddin, Chaim M Bell, Deva Thiruchelvam, Maria Isabella Creatore, Piotr Gozdyra, Michael Cusimano, Donald A Redelmeier
Journal: PLoS Medicine (2008)

Alcohol is a contributing cause of unintentional injuries, such as motor vehicle crashes. Prior research on the association between alcohol use and violent injury was limited to survey-based data, and the inclusion of cases from a single trauma centre, without adequate controls. Beyond these limitations was the inability of prior researchers to comprehensively capture most alcohol sales. In Ontario, most alcohol is sold through retail outlets run by the provincial government, and hospitals are financed under a provincial health care system. We assessed the risk of being hospitalized due to assault in association with retail alcohol sales across Ontario.
Outcome of gastric carcinoma detected by gastric mass survey in Japan.
Authors: E Kaneko, T Nakamura, N Umeda, M Fujino, H Niwa
Journal: Gut (1977)

The outcome was studied of gastric carcinoma found in six selected mass survey groups. One-hundred-and-thirty-seven cases of gastric carcinoma were detected and followed-up postoperatively for 16 years at the longest. They consisted of 55 cases of early and 74 of advanced carcinoma with eight cases of unknown depth of involvement. Early carcinoma amounted to 42-6% of the cases with known depth of involvement. The relative five-year and 10-year survival rates calculated by the method of Ederer et al. (1961) in the 137 cases were 0-628 and 0-642, respectively, and those for early carcinoma were 0-959 and 1-016. These survival rates are remarkably high. The five-year survival rate in those who were followed-up after operation for more than five years (83 cases) was 0-554, which is much higher than that of the outpatient cases, who presented themselves for medical advice with some symptoms. The good prognosis is largely explained by a high incidence of early gastric carcinoma in the cases detected in the mass survey. Where methods of screening were concerned, the use of the gastrocamera markedly improved the detection rate of gastric carcinoma.
An Early X-ray Picture
Authors: S. C. Shanks
Journal: BMJ (1954)

Synaptotagmin-1 (Syt1) is a vesicular calcium sensor required for synchronous neurotransmitter release, composed of a single-pass transmembrane domain linked to two C2 domains (C2A and C2B) that bind calcium, acidic lipids, and SNARE proteins that drive fusion of the synaptic vesicle with the plasma membrane. Despite its essential role, how Syt1 couples calcium entry to synchronous release is poorly understood. Calcium binding to C2B is critical for synchronous release, and C2B additionally binds the SNARE complex. The C2A domain is also required for Syt1 function, but it is not clear why. Here, we asked what critical feature of C2A may be responsible for its functional role and compared this to the analogous feature in C2B. We focused on highly conserved poly-lysine patches located on the sides of C2A (K189-192) and C2B (K324-327). We tested effects of charge-neutralization mutations in either region (Syt1<sup>K189-192A</sup> and Syt1<sup>K326-327A</sup>) side by side to determine their relative contributions to Syt1 function in cultured cortical neurons from mice of either sex and in single-molecule experiments. Combining electrophysiological recordings and optical tweezers measurements to probe dynamic single C2 domain–membrane interactions, we show that both C2A and C2B polybasic patches contribute to membrane binding, and both are required for evoked release. The size of the readily releasable vesicle pool and the rate of spontaneous release were unaffected, so both patches are likely required specifically for synchronization of release. We suggest these patches contribute to cooperative membrane binding, increasing the overall affinity of Syt1 for negatively charged membranes and facilitating evoked release. <b>SIGNIFICANCE STATEMENT</b> Synaptotagmin-1 is a vesicular calcium sensor required for synchronous neurotransmitter release. Its tandem cytosolic C2 domains (C2A and C2B) bind calcium, acidic lipids, and SNARE proteins that drive fusion of the synaptic vesicle with the plasma membrane. How calcium binding to Synaptotagmin-1 leads to release and the relative contributions of the C2 domains are unclear. Combining electrophysiological recordings from cultured neurons and optical tweezers measurements of single C2 domain–membrane interactions, we show that conserved polybasic regions in both domains contribute to membrane binding cooperatively, and both are required for evoked release, likely by increasing the overall affinity of Synaptotagmin-1 for acidic membranes.
Carfilzomib and ONX 0912 Inhibit Cell Survival and Tumor Growth of Head and Neck Cancer and Their Activities Are Enhanced by Suppression of Mcl-1 or Autophagy
Authors: Yan Zang, Sufi M. Thomas, Elena T. Chan, Christopher J. Kirk, Maria L. Freilino, Hannah M. DeLancey, Jennifer R. Grandis, Changyou Li, Daniel E. Johnson
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Carfilzomib is a selective, irreversible inhibitor of the chymotrypsin-like activity of the proteasome and is undergoing clinical evaluation in myeloma. ONX 0912 (oprozomib) is an orally bioavailable derivative. The activities of carfilzomib and ONX 0912 against solid tumor malignancies are less well understood. We investigated the impact and mechanisms of action of carfilzomib and ONX 0912 in preclinical models of head and neck squamous cell carcinoma (HNSCC). Experimental Design: The effects of carfilzomib and ONX 0912 on HNSCC cell survival and xenograft tumor growth were evaluated. The impact and mechanisms of both agents on apoptosis and autophagy induction were also investigated. The contribution of the unfolded protein response (UPR) to autophagy induction and the role of autophagy in attenuating HNSCC cell death were determined. Results: Carfilzomib and ONX 0912 potently induced apoptosis in HNSCC cell lines via upregulation of pro-apoptotic Bik. Upregulation of Mcl-1 by these agents served to dampen their efficacies. Carfilzomib and ONX 0912 also induced autophagy, mediated, in part, by activation of the UPR pathway involving upregulation of ATF4 transcription factor. Autophagy induction served a prosurvival role. Oral administration of ONX 0912 inhibited the growth of HNSCC xenograft tumors in a dose-dependent manner. Conclusions: These results show that carfilzomib and ONX 0912 are potently active against HNSCC cells, and the activities of these agents can be enhanced via suppression of Mcl-1 or inhibition of autophagy. Oral ONX 0912 exhibits in vivo activity against HNSCC tumors and may represent a useful therapeutic agent for this malignancy. Clin Cancer Res; 18(20); 5639–49. ©2012 AACR.
Blood Glutathione Levels in Rheumatoid Arthritis
Authors: D. Watson, D. S. Bidmead, G. D. Kersley
Journal: Annals of the Rheumatic Diseases (1952)

The hippocampal slice preparation was used to classify cholinergic effects in terms of muscarinic receptor subtypes (M1 or M2) and biochemical effector systems linked to these effects in CA1 pyramidal cells. Based on the action of the M1 antagonist pirenzepine and the M2 antagonist gallamine, the muscarinic-induced membrane depolarization and blockade of the afterhyperpolarization appear to result from activation of an M1 receptor, while the cholinergic depression of the EPSP and the blockade of a potassium current termed the M-current appears to involve the activation of an M2 receptor. All of the muscarinic actions could be observed in pertussis toxin-treated hippocampi, suggesting that a pertussis toxin-sensitive G-protein is not involved in these actions. Cholinergic agents that are weak agonists of phosphoinositide (PI) turnover are fully effective in all of the muscarinic actions except the blockade of the M-current on which they had little agonist activity and actually blocked the action of full agonists. These results strongly suggest that the blockade of the M-current may involve stimulation of PI turnover. In addition, we show that the blockade of the M-current is mimicked by intracellular application of inositol trisphosphate. Our results do not show any obvious relationship between the muscarinic receptor subtypes and the biochemical effector systems.
Distal intestinal obstruction syndrome in cystic fibrosis treated by oral intestinal lavage, and a case of recurrent obstruction despite normal pancreatic function.
Authors: A C Davidson, K Harrison, C L Steinfort, D M Geddes
Journal: Thorax (1987)

An oral intestinal lavage solution has been successfully used in the treatment of six patients with chronic distal intestinal obstruction syndrome (previously referred to as meconium ileus equivalent) complicating cystic fibrosis and a further case of recurrent small bowel obstruction. The patient with recurrent obstruction is unusual in having no evidence of pancreatic maldigestion, which previously has been considered a prerequisite for the syndrome.
Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials
Authors: Antoinette Moran, Brian Bundy, Dorothy J Becker, Linda A DiMeglio, Stephen E Gitelman, Robin Goland, Carla J Greenbaum, Kevan C Herold, Jennifer B Marks, Philip Raskin, Srinath Sanda, Desmond Schatz, Diane K Wherrett, Darrell M Wilson, Jeffrey P Krischer, Jay S Skyler, Linda Pickersgill, Eelco de Koning, Anette-G Ziegler, Bernhard Böehm, Klaus Badenhoop, Nanette Schloot, Jens Friis Bak, Paolo Pozzilli, Didac Mauricio, Marc Y Donath, Luis Castaño, Ana Wägner, Hans Henrik Lervang, Hans Perrild, Thomas Mandrup-Poulsen
Journal: The Lancet (2013)
Innate Stat3-mediated induction of the antimicrobial protein Reg3γ is required for host defense against MRSA pneumonia
Authors: Sun-Mi Choi, Jeremy P. McAleer, Mingquan Zheng, Derek A. Pociask, Mark H. Kaplan, Shulin Qin, Todd A. Reinhart, Jay K. Kolls
Journal: The Journal of Experimental Medicine (2013)

Pulmonary Staphylococcus aureus (SA) infections are a public health concern and a major complication of hyper-IgE syndrome, caused by mutations in STAT3. In contrast to previous findings of skin infection, we observed that clearance of SA from the lung did not require T, B, or NK cells but did require Stat3 activation. Immunohistochemistry showed robust Stat3 phosphorylation in the lung epithelium. We identified that a critical Stat3 target gene in lung epithelium is Reg3g (regenerating islet-derived 3 γ), a gene which is highly expressed in gastrointestinal epithelium but whose role in pulmonary host defense is uncharacterized. Stat3 regulated Reg3g transcription through direct binding at the Reg3g promoter region. Recombinant Reg3γ bound to SA and had both bacteriostatic and bactericidal activity in a dose-dependent fashion. Stat3 inhibition in vivo reduced Reg3g transcripts in the lung, and more importantly, recombinant Reg3γ rescued mice from defective SA clearance. These findings reveal an antibacterial function for lung epithelium through Stat3-mediated induction of Reg3γ.
The Question of Operation upon Fistula in Phthisis
Authors: H. Wm. Allingham
Journal: BMJ (1890)

1.It is most exceptional to find a cerebral aneurysm which is not associated with fungating endocarditis.2. The lodging of a septic embolus is the starting point of the changes which take place in the vessel.3. The clot inflames and in most cases disappears, the vessel dilating from the inflammatory changes in its coats.4. An aneurysm may form and rupture in three weeks.5.The onset of the embolism may not be marked by any sym- ptoms, and the rupture of the aneurysm may be the first indication that there is danger.CASE CLXXVII.-Aman brought in dead, ill one hour.Aneurysm on middle cerebral had ruptured into lateral ventricle.The clot weighed 4 ounces.Fungating endocarditis.The aneurysms are usually on the surface of the brain, and when they rupture they are more rapidly fatal than other forms of cerebral heemorrhage.As the aneurysm increases in size it tends to spread inwards, ploughing up the cerebral tissue, and may rupture into the lateral ventricle, although it has originated on or near the surface.Cases of cerebral ha.morrhage in young people will generally be found to have originated in aneurysm.' 1 It would have occupied too much space to publish here even the briefest abstract of all the cases with which these lectures deal.The lectures will be reubMlished with the eases in et.enso.
Lung function in school-aged asthmatic children with inhaled cromoglycate, nedocromil and corticosteroid therapy
Authors: K. Korhonen, M. Korppi, S.T. Remes, T.M. Reijonen, K. Remes
Journal: European Respiratory Journal (1999)

Inhaled steroids are frequently used in childhood asthma, but concerns based on limited objective evidence remain, regarding long-term side-effects. In this study the systemic effects of standard doses of inhaled steroids in childhood asthma were assessed, comparing beclomethasone dipropionate (BDP) with fluticasone propionate (FP). The study was prospective, randomized and double-blind. Twenty-three steroid-naive children with moderately severe asthma, aged 5-10 yrs, were allocated either BDP (400 microg x day(-1) or FP (200 microg x day(-1)) using a metered-dose inhaler with a spacer. Asthma control was assessed at regular intervals over 20 months. Fasting morning blood and overnight urine samples were collected for estimation of serum cortisol, serum 1-carboxyterminal telopeptide (ICTP), serum osteocalcin and urine deoxypyridinoline (DPD). Bone mineral density (BMD) was measured at each visit. None of the markers of bone turnover showed any change during the study period. BMD increased at normal rates with age. Serum cortisol significantly decreased on BDP, but not on FP. A significant difference in growth rates was found between the groups, with a slower rate of growth towards the end of the observation period in the BDP group. In conclusion when taken in a relatively modest dose over a period of time, beclomethasone dipropionate had significant effects on the hypothalamic-pituitary-adrenal axis and statural growth in childhood asthma. These systemic effects were not seen with an equipotent dose of fluticasone propionate.
Tuberculin Skin Testing of Hospital Workers
Authors: John E. Beck
Journal: JAMA (1996)

<b>Q</b>A local hospital requires all volunteers to have annual tuberculin skin tests. There is no screening for other communicable diseases. With the scarcity of active tuberculosis and its transmission by casual contact being minimal, is it reasonable to continue this requirement? <b>A</b>In 1995, a total of 22 860 cases of tuberculosis (TB) were reported in the United States, yielding a case rate of 8.7 cases per 100 000 population.<sup>1</sup>Rates at the state and local levels vary widely. For example, state TB case rates ranged from 0.7 per 100 000 population in Vermont to 16.9 per 100 000 in New York State. Although 45% of US counties reported no cases of TB in 1995, case rates in the New York metropolitan area were 30.1 per 100 000.<sup>1</sup>Thus, the approach to TB control in each community must be individualized. Periodic tuberculin skin testing of hospital employees
Is the Relationship between Prenatal Exposure to PCB-153 and Decreased Birth Weight Attributable to Pharmacokinetics?
Authors: Marc-André Verner, Robin McDougall, Anders Glynn, Melvin E. Andersen, Harvey J. Clewell, Matthew P. Longnecker
Journal: Environmental Health Perspectives (2013)

Background: A recent meta-analysis based on data from > 7,000 pregnancies reported an association between prenatal polychlorinated biphenyl (PCB)–153 exposure and reduced birth weight. Gestational weight gain, which is associated negatively with PCB levels in maternal and cord blood, and positively with birth weight, could substantially confound this association.Objective: We sought to estimate the influence of gestational weight gain on the association between PCB-153 exposure and birth weight using a pharmacokinetic model.Methods: We modified a recently published pharmacokinetic model and ran Monte Carlo simulations accounting for variability in physiologic parameters and their correlations. We evaluated the pharmacokinetic model by comparing simulated plasma PCB-153 levels during pregnancy to serial measurements in 10 pregnant women from another study population. We estimated the association between simulated plasma PCB-153 levels and birth weight using linear regression models.Results: The plasma PCB-153 level profiles generated with the pharmacokinetic model were comparable to measured levels in 10 pregnant women. We estimated a 118-g decrease in birth weight (95% CI: –129, –106 g) for each 1-μg/L increase in simulated cord plasma PCB-153, compared with the 150-g decrease estimated based on the previous meta-analysis. The estimated decrease in birth weight was reduced to –6 g (95% CI: –18, 6 g) when adjusted for simulated gestational weight gain.Conclusion: Our findings suggest that associations previously noted between PCB levels and birth weight may be attributable to confounding by maternal weight gain during pregnancy.Citation: Verner MA, McDougall R, Glynn A, Andersen ME, Clewell HJ III, Longnecker MP. 2013. Is the relationship between prenatal exposure to PCB-153 and decreased birth weight attributable to pharmacokinetics? Environ Health Perspect 121:1219–1224; http://dx.doi.org/10.1289/ehp.1206457
False-Positive Results in Cancer Epidemiology: A Plea for Epistemological Modesty
Authors: P. Boffetta, J. K. McLaughlin, C. La Vecchia, R. E. Tarone, L. Lipworth, W. J. Blot
Journal: JNCI Journal of the National Cancer Institute (2008)

False-positive results are inherent in the scientific process of testing hypotheses concerning the determinants of cancer and other human illnesses. Although much of what is known about the etiology of human cancers has arisen from well-conducted epidemiological studies, epidemiology has been increasingly criticized for producing findings that are often sensationalized in the media and fail to be upheld in subsequent studies. Herein we describe examples from cancer epidemiology of likely false-positive findings and discuss conditions under which such results may occur. We suggest general guidelines or principles, including the endorsement of editorial policies requiring the prominent listing of study caveats, which may help reduce the reporting of misleading results. Increased epistemological humility regarding findings in epidemiology would go a long way to diminishing the detrimental effects of false-positive results on the allocation of limited research resources, on the advancement of knowledge of the causes and prevention of cancer, and on the scientific reputation of epidemiology and would help to prevent oversimplified interpretations of results by the media and the public.
Preclinical Development and Clinical Translation of a PSMA-Targeted Docetaxel Nanoparticle with a Differentiated Pharmacological Profile
Authors: Jeffrey Hrkach, Daniel Von Hoff, Mir Mukkaram Ali, Elizaveta Andrianova, Jason Auer, Tarikh Campbell, David De Witt, Michael Figa, Maria Figueiredo, Allen Horhota, Susan Low, Kevin McDonnell, Erick Peeke, Beadle Retnarajan, Abhimanyu Sabnis, Edward Schnipper, Jeffrey J. Song, Young Ho Song, Jason Summa, Douglas Tompsett, Greg Troiano, Tina Van Geen Hoven, Jim Wright, Patricia LoRusso, Philip W. Kantoff, Neil H. Bander, Christopher Sweeney, Omid C. Farokhzad, Robert Langer, Stephen Zale
Journal: Science Translational Medicine (2012)

A targeted nanoparticle containing docetaxel displays antitumor activity in animals and differentiated pharmacological properties in patients with advanced solid tumors.