tbuckley/cabot-search huggingface dataset:
Abstract 2480: Discovery and mechanistic characterization of AV220, a novel small molecule targeting cancer cell metabolism.
Authors: Melissa Millard, Nouri Neamati
Journal: Cancer Research (2013)

Abstract Metabolic plasticity is an adaptive mechanism tumors rely upon for growth advantage. Without sufficient energy and biomass, cell replication cannot proceed. Therefore, interrupting cancer-specific metabolic processes presents a novel means to inhibit tumor growth. The clinical benefit of this approach has not yet been fully realized due to a lack of suitable agents targeting cancer cell metabolism. To address this unmet need we screened our in-house compound library for chemical scaffolds with potential metabolic activity. In the course of our studies we identified the small molecule AV220 as a potent metabolic antagonist suitable for preclinical development. In a panel of cancer cell lines, AV220 showed anti-proliferative activity in the low micromolar range. Mechanistic studies indicate a mode of action that involves energy sensing and regulatory pathways. AV220 treatment produced a rapid and sustained phosphorylation of AMPK and its substrate acetyl-CoA carboxylase. Prolonged treatment with AV220 resulted in profound intracellular vacuolation and increased autophagic flux followed by accumulation of Grp78, CHOP and ATF4. Additional early intracellular signaling events associated with AV220 treatment included phosphorylation of p38 and Erk 1/2 and Src and Akt inhibition. A structure-based search of our small molecule library led to the identification of additional analogs, many of which displayed similar cytotoxicities and a shared mechanism of action. Citation Format: Melissa Millard, Nouri Neamati. Discovery and mechanistic characterization of AV220, a novel small molecule targeting cancer cell metabolism. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2480. doi:10.1158/1538-7445.AM2013-2480
Inhibition of M1 macrophage activation in favour of M2 differentiation by liposomal targeting of glucocorticoids to the synovial lining during experimental arthritis
Authors: W. Hofkens, G. Storm, W. van den Berg, P. van Lent
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objective</h3> Experimental antigen-induced arthritis (AIA) is highly driven by pro-inflammatory 'M1' macrophages which express cytokines such as tumour necrosis factor α (TNFα), interleukin 1β (IL-1β), IL-6 and IL-12. However, macrophages can also be differentiated towards an anti-inflammatory 'M2' phenotype in vitro with glucocorticoids, thereby expressing IL-10 and membrane markers IL-1 receptor type II (IL-1RII) and CD163. The authors now explored whether liposomal targeting of synovial lining macrophages with glucocorticoids shifts the M1/M2 macrophage balance. <h3>Materials and methods</h3> Mice with established AIA were treated with a single intravenous injection of 10 mg/kg liposomal prednisolone phosphate (Lip-PLP) or phosphate-buffered saline (PBS). Naïve mice were injected intra-articularly with interferon γ (IFNγ)/LPS to induce M1 phenotype and 24 h thereafter with Lip-PLP or PBS. Mice were killed at day 1 after Lip-PLP treatment and whole knee joints were isolated for histology and synovial biopsies were isolated for RNA analysis. In vitro, murine bone marrow macrophages were differentiated towards M1 phenotype with LPS and IFNγ, treated with Lip-PLP and M1/M2 markers characterised by quantitative RT-PCR. <h3>Results</h3> Lip-PLP strongly suppressed joint inflammation within 1 day from control treated mice during AIA. Liposomes were primarily targeted to the synovial lining macrophages as demonstrated with gold-laden liposomes. One day after treatment, synovial gene expression was strongly downregulated for the M1 cytokines TNFα IL-1β (10.6-fold), IL-6 (5.6-fold) and IL-12p40 (3-, 11-, 6- and 6-fold respectively) by Lip-PLP compared to PBS treated mice. Expression of M2 markers was only slightly downregulated (IL-10: twofold and IL-1RII: onefold) or even upregulated (CD163: twofold). To evaluate whether Lip-PLP had a direct effect on M1 macrophages, these cells were induced in vitro by IFNγ and LPS and subsequently incubated with Lip-PLP for 24 h. Lip-PLP significantly downregulated M1 markers IL-1β, IL-6 and IL-12p40 (40-, 11- and 5-fold) and increased expression of IL-1RII, CD163 and IL-10 (34-, 11- and 5-fold). Next, the synovial lining was activated in vivo towards M1 by local injection of IFNγ/LPS into normal knee joint, followed by local Lip-PLP treatment 24 h thereafter. Strikingly, significant downregulation of M1 markers IL-1β, IL-6 and IL-12p40 (17-, 9- and 36-fold) was found without significant change in M2 markers IL-1RII, CD163 and IL-10 (one-, one- and twofold change), providing cogent evidence for selective skewing of M1 macrophages in favour of the M2 phenotype. <h3>Conclusion</h3> Systemic delivery of liposomal glucocorticoids during experimental arthritis inhibits M1 macrophages in favour of M2 phenotype in the lining layer and may drive their strong suppressive effect.
Depression
Authors: Richard O. Poe
Journal: JAMA (1966)

Depression was encountered in 52% of 192 patients during routine psychiatric consultations by residents in a general hospital. The records of the first 100 depressed patients seen were reviewed in detail. Half were found to have depressions precipitated by recent events or the vicissitudes of aging, while the other half, predominantly women, had histories of life-long depressive tendencies. Forty-eight percent had concomitant diagnosed organic disease. Seventeen of the 100 had attempted suicide. The manifestations of depression were varied and often misleading, eg, unexplained pain or fatigue. The authors, on the basis of their experience with such patients in the general-hospital setting, propose that the physician who can recognize depression and who appreciates the role which unacceptable anger, guilt, and injured self-esteem play in its etiology can successfully treat many depressed patients by making use of the doctor-patient relationship.
Percutaneous transluminal coronary angioplasty.
Authors: E Rapaport
Journal: Circulation (1979)

described a new tech- nique in which a special dilating catheter was used for transluminal compression of localized arteriosclerotic obstructions.'The procedure has since been applied by other investigators, particularly abroad, for the management of arteriosclerotic peripheral vascular disease and to obstructions in the renal arteries.2In 1977, after a series of experiments in cadaver hearts and in canine hearts after surgical creation of cor- onary arterial constrictions, Dr. Andreas Gruntzig performed the first nonoperative transluminal angioplasty of coronary arteries in man.4To ac- complish this, he devised a special balloon catheter that could be placed fluoroscopically through a guiding catheter across relatively tight proximal cor- onary arterial obstructions.The balloon is inflated with'a half-saline, half-Renografin solution, subject- ing a proximal obstructive lesion to 4-6 atmospheres of pressure.The pressure is applied for a few seconds and can be repeated several times until demonstrable improvement occurs as judged by lessening of the arterial pressure drop across the obstructive segment and by immediate arteriographic evidence of im- proved luminal diameter.Since this pioneering effort the procedure has been performed in more than 200 patients throughout the world.5Most of the procedures have been done either by Dr. Griintzig or by physicians in three other centers that have collaborated closely with him and have followed a common protocol and technique (Dr.
CELL-TO-CELL INTERACTION IN THE IMMUNE RESPONSE
Authors: R. E. Anderson, J. Sprent, J. F. A. P. Miller
Journal: The Journal of Experimental Medicine (1972)

The helper function of carrier-primed T cells was found to be radiosensitive in vivo. The results could not be attributed to interference with the spleen-seeking properties of the irradiated cells. It is suggested that T cell division is essential for the induction of 7S antibody responses in vivo.
Collection of genomic DNA by buccal swabs for polymerase chain reaction-based biomarker assays.
Authors: A H Walker, D Najarian, D L White, J F Jaffe, P A Kanetsky, T R Rebbeck
Journal: Environmental Health Perspectives (1999)

Studies in molecular and genetic epidemiology require a high-throughput, low cost, and reliable means of genomic DNA collection. Buccal (cheek) swabs have been proposed as a means of achieving these goals, but there is little information about the practical application of this approach. From January 1995 to December 1997, we processed 995 buccal swabs for use in polymerase chain reaction (PCR)-based genotype assays in the context of ongoing molecular epidemiologic studies. Six hundred forty-seven of these swabs were processed immediately after collection and 348 were received by mail. We were able to obtain at least one genotype from 99.7% (645 of 647) of fresh-processed and 97.4% (330 of 339) of mailed biosamples. A PCR success rate of 90.3% (2,546 genotypes from 2,819 assays) was achieved. Genotypes were obtained from 96.1% (1, 865 genotypes from 1,941 assays) of fresh-processed biosamples and 77.6% (681 genotypes from 878 assays) of mailed biosamples. PCR success rates at any single locus ranged from 92.6 to 98.8% (fresh-processed) and 75.5 to 79.6% (mailed). The PCR success rate among fresh-processed biosamples was significantly higher than among mailed biosamples (Fisher's exact test p < 0.0001), and more attempts were required to obtain a successful PCR result for mailed biosamples as compared to fresh-processed biosamples. For one locus (CYP3A4), a subset of mailed biosamples was purified if two or more PCR failures occurred. Additional genotypes were obtained in 58.3% of these previously failed biosamples. Time from biosample receipt to DNA extraction had no effect on PCR success. After storage of processed biosamples for as long as 3 years, there was no appreciable decrease in the rate of PCR success. These results suggest that adequate DNA for PCR-based applications can be obtained from buccal swabs, but sampling or processing considerations may be important in obtaining optimal results.
TRAUMATIC PERFORATIONS OF THE MEMBRANA TYMPANI.
Authors: FRANCIS R. PACKARD
Journal: JAMA (1900)

In 1500 consecutive cases taken from the out-patient record books of the Pennsylvania Hospital there were eleven in which the membrana tympani was ruptured by traumatism. The cases were as follows:  Case 1.  —An Irishman, aged 46 years, a longshoreman, was struck on the head by a hammer weighing 3 pounds, which had fallen forty feet. He sustained a severe lacerated wound of the scalp and was rendered unconscious for some minutes. On recovering consciousness, he was deaf in the left ear and suffered from much roaring noise in it. The left auditory canal contained considerable blood. There was a large laceration in the anterior lower segment of the left membrana tympani. At the end of three weeks' treatment his hearing was normal and he had no tinnitus.  Case 2.  —A longshoreman, five days previous to presenting himself at the dispensary, had fallen thirty feet, sustaining severe contusions of the
Individual Prognosis for Changes in Sperm Quality on the Basis of Perceived Stress
Authors: Martin Pook, Bernd Röhrle, Walter Krause
Journal: Psychotherapy and Psychosomatics (1999)

&lt;i&gt;Background:&lt;/i&gt; In this study we examined whether stress has a negative influence on sperm quality. To investigate this issue we developed a scale assessing perceived stress resulting from infertility. &lt;i&gt;Methods and Results:&lt;/i&gt; The Infertility Distress Scale was constructed based on the data of 158 infertility patients contacting an andrological clinic for the first time. The Infertility Distress Scale consists of items assessing self-reported stress, different appraisals of infertility and cognitive involvement in infertility. The scale was shown to have good psychometric properties. Changes in sperm quality were predicted by this scale for 69 patients. Changes in sperm concentration and sperm motility were predicted correctly 75.4 and 65.6% of the time, respectively. While these prediction accuracies were significantly better than chance prediction, the Infertility Distress Scale had no predictive value for changes in morphology. &lt;i&gt;Conclusion:&lt;/i&gt; Results indicate that distress caused by infertility is a risk factor for a decrease in sperm quality.
Public Engagement in Health Priority Setting in Low- and Middle-Income Countries: Current Trends and Considerations for Policy
Authors: Katarzyna Bolsewicz Alderman, David Hipgrave, Eliana Jimenez-Soto
Journal: PLoS Medicine (2013)

David Hipgrave and colleagues argue that we must find more effective, equitable, feasible and affordable ways to engage the public in health priority setting in developing countries. Please see later in the article for the Editors' Summary
Genomic and transcriptional aberrations linked to breast cancer pathophysiologies
Authors: Koei Chin, Sandy DeVries, Jane Fridlyand, Paul T. Spellman, Ritu Roydasgupta, Wen-Lin Kuo, Anna Lapuk, Richard M. Neve, Zuwei Qian, Tom Ryder, Fanqing Chen, Heidi Feiler, Taku Tokuyasu, Chris Kingsley, Shanaz Dairkee, Zhenhang Meng, Karen Chew, Daniel Pinkel, Ajay Jain, Britt Marie Ljung, Laura Esserman, Donna G. Albertson, Frederic M. Waldman, Joe W. Gray
Journal: Cancer Cell (2006)
Persistent hyperparathyroidism in renal allograft recipients: Vitamin D receptor, calcium-sensing receptor, and apoptosis
Authors: M. Taniguchi, M. Tokumoto, D. Matsuo, K. Motoyama, A. Sugitani, S. Kuroki, H. Yotsueda, K. Tsuruya, H. Hirakata, M. Iida
Journal: Kidney International (2006)
Plasma Triglyceride Levels and Coronary Disease
Authors: John D. Brunzell, Melissa A. Austin
Journal: New England Journal of Medicine (1989)

In this issue of the Journal, Kihara et al. report marked hypertriglyceridemia and pancreatitis in a young woman with autoimmune disease.1 IgA antibodies to lipoprotein lipase appeared to block its function, resulting in marked hypertriglyceridemia. Although the association of autoimmune disease with this degree of hypertriglyceridemia is unusual, Beaumont has been suggesting for 20 years that less severe autoimmune hyperlipidemia may be common.1 Autoimmune disease with antibodies to lipoprotein lipase or hepatic triglyceride lipase may cause mild hypertriglyceridemia and hypercholesterolemia and contribute to the acquired causes of hyperlipidemia induced by abnormalities in lipoprotein lipase, such as untreated diabetes mellitus, . . .
P. A. Downie (Ed.) "Cash's Textbook of Orthopaedics and Rheumatology for Physiotherapists"
Authors: P. Willcock
Journal: British Journal of Sports Medicine (1984)

weeks, but the author does not specify the position of the finger during immobilisation.Two years later he states that the condition is satisfactory.Nathan and Schlein (1973) find that there are no problems with the treatment, and that their patients do well.The described lesions in our patient, with chip fractures at the site of the proximal and distal joints, show the severity of the injury.We find that a double dislocation should be regarded as far more serious than a single dislocation when considering the prognosis.
Diagnostic Significance of Apparent Abnormal Bowel Activity on Ga-67 Scans in AIDS Patients
Authors: WALTER J. SLIZOFSKI, STEVEN J. BROWN, SIMIN DADPARVAR, LAURA B. GLAB
Journal: Clinical Nuclear Medicine (1991)

Twenty-one Ga-67 studies on 19 AIDS patients were analyzed to investigate the relationship between clinically acute gastrointestinal disease and abnormal scintigraphic bowel activity. Whole body images were obtained at times ranging from 4 to 192 hours, with most exams imaged at 48 and 72 hours. Abnormal bowel activity was observed in eight of 21 exams. Patients experienced acute GI disease during seven studies. Gallium scan results and clinical presentation agreed in 14 cases; both were abnormal in four and normal in 10. However, four exams showed abnormal activity in asymptomatic patients, while three normal studies were obtained in patients with clinically evident GI disease. Sensitivity was 57% and specificity 71%. Positive predictive value was .50 and negative predictive value .77. All true-positive cases were associated with Mycobacterium avium intracellulare (MAI) infection. This study implies that gallium imaging is unreliable for diagnosing acute bowel disease in AIDS patients, but may suggest a particular pathogen (MAI) in the symptomatic individual.
Lack of Conventional Dendritic Cells Is Compatible with Normal Development and T Cell Homeostasis, but Causes Myeloid Proliferative Syndrome
Authors: Tal Birnberg, Liat Bar-On, Anita Sapoznikov, Michele L. Caton, Luisa Cervantes-Barragán, Divine Makia, Rita Krauthgamer, Ori Brenner, Burkhard Ludewig, Damian Brockschnieder, Dieter Riethmacher, Boris Reizis, Steffen Jung
Journal: Immunity (2008)
Effect of the Contraceptive Sponge on Chlamydial Infection, Gonorrhea, and Candidiasis
Authors: Michael J. Rosenberg
Journal: JAMA (1987)

To investigate the effect of the nonoxynol 9-impregnated contraceptive sponge on the incidence of chlamydial infection, gonorrhea, and candidiasis, we conducted a randomized comparative study among high-risk women in Bangkok, Thailand. The first (parallel) portion of the study covered 434 woman-weeks among sponge users and 494 woman-weeks among nonusers. As compared with women not using the sponge, sponge users were found to be less likely to become infected with chlamydia (relative rate, 0.67; 95% confidence interval, 0.42 to 1.07) and gonorrhea (relative rate, 0.31 [0.16 to 0.60]) but more likely to become infected with Candida (relative rate, 2.76 [0.96 to 7.98]). Women who continued in the study were crossed over to the alternate group, with former nonusers starting to employ the sponge and vice versa. The results of this second phase were similar to those of the larger parallel study. Overall, these results suggest that women using the sponge are protected against the two most common sexually transmitted pathogens, which are also those with the most serious health consequences. However, women using the sponge should be advised they may have an increased likelihood of a vaginal infection with Candida.
Snuff gives heart rate, blood pressure a kick
Authors: Phil Gunby
Journal: JAMA (1982)

There was no obvious cause for the elevated blood pressure (BP) of the football player at Texas Lutheran College, Seguin. But one fact fascinated William G. Squires, PhD, associate professor of physical education and biology. Since seventh grade, the young man had used oral tobacco. Could that be a factor? Also known as snuff (because once it primarily was sniffed through the nose) or chewing leaf, smokeless oral tobacco (so called because it now is often placed between the lip and gum for absorption through the oral mucosa) may be used by at least one in every 12 to 15 Americans. United States sales are said to be up by more than 25% since 1976, especially at colleges. Squires and colleagues from Baylor College of Medicine, Houston (where he has an adjunct appointment) decided to study 20 male athlete volunteers. Ten were oral tobacco users; ten were not. All volunteers
Preventive care programmes keep people active and independent for longer
Authors: A. J. Tulloch, D. L. Beales
Journal: BMJ (2013)

We contest D’Souza and Guptha’s claim that “no convincing evidence exists that increases in the provision of community services reduce the length of stay for frail older people.”1

There are two commonly used markers of the effectiveness of such programmes in older patients—the number of institutional referrals and time spent in institutional care. The ultimate objective of care in this field is to keep these vulnerable old people active and independent for as long as possible. Thus, the effectiveness of these measures is best reflected by reductions in the number of bed days of institutional care rather than the number of institutional referrals.

The authors …
Combination of antioxidants and iron chelators during ischaemia reduces reperfusion injury. An in vivo experimental study
Authors: L.K. Michalis, D. Nikas, C.S. Katsouras, A. Karahaliou, G. Kolios, E. Sourla, D. Niokou, K. Seferiadis, D. Galaris, D.A. Sideris
Journal: European Journal of Heart Failure (2000)
Autologous Blood Donations Prior to Elective Cardiac Surgery
Authors: Debra V. Owings
Journal: JAMA (1989)

Blood transfusions are frequently necessary for patients having open heart surgery. Although autologous blood is free of such risks as transfusion-transmitted diseases, the safety and effectiveness of autologous donations by cardiac patients are debated. We analyzed the records of 291 consecutive patients undergoing elective open heart surgery. One hundred seven (36.8%) donated between 1 and 6 U of autologous blood (mean, 3.0 +/- 1.5 U) before undergoing surgery. First-time elective coronary artery bypass surgery was the most common indication for autologous donation (90.6% of autologous donors). Problems following donations were infrequent (2 of 326 donations) and without long-term consequences. Among patients having coronary artery bypass surgery who donated autologous blood, 27% required homologous blood transfusions as compared with 82% of other patients undergoing the same procedure. We conclude that autologous blood donations are safe for patients with cardiac disease and effective in significantly reducing homologous blood needs in patients undergoing elective coronary artery bypass surgery.
GMC hearing against GP who ran out of hours was "disastrous," says judge
Authors: C. Dyer
Journal: BMJ (2014)

The High Court has refused an application by the General Medical Council (GMC) to extend a GP’s interim suspension to four and a half years pending the resolution of a misconduct case against him, and criticised the regulator for “unconscionable delay.”

Judge Mark Pelling said that the GMC made the application after a “disastrous” hearing that started last June in the case of Ravi Sondhi, former director of the out of hours service Croydoc. The hearing was scheduled to last for 30 days but only nine days’ worth of evidence was heard in that time.1

The GMC was obliged to relist the rest of the case to be heard in various …
A Lecture ON THE VALUE AND MISUSE OF SPECTACLES IN THE TREATMENT OF HEADACHE, MIGRAINE, AND OTHER FUNCTIONAL TROUBLES OF THE EYES
Authors: R. W. Doyne
Journal: BMJ (1910)

WHLLE I approach the subject of my lecture with the keenest interest, I am not free from a certain amount of trepidation, for I know that I must necessarily tread on the toes of some to whom it has become almost a gospel to inflict on mankind on the smallest pretext the machinery of spectacles.It is in no sense an exaggeration to say that we are at the present time face to face with honourable, high-minded medical practitioners who honestly believe that they are preventing the incidence of tubercle, appendicitis,, and other troubles by correcting minute refractive errors such as probably more than 90 per cent.of the population would be found, if examined, to possess.It appears to me that the word " astigmatism " has pro-*duced in them a mental condition resembling the condition that represents.In addition to these doctors, the country is flooded with opticians, many of them capable men and highly trained in physical optics, who, with no knowledge