tbuckley/cabot-search huggingface dataset:
Abstract 5472: Loss of TSC2 function predicts optimal therapeutic response to combinations of MEK and mTOR inhibitors
Authors: Beth A. Conlon, Marie-Emmanuelle Legrier, Alicia G. Rodriguez Gabin, Susan Band Horwitz, Hayley M. McDaid
Journal: Cancer Research (2011)

Abstract The MAPK-RAS-PI3K signaling network is oncogenic in many human malignancies. The plasticity of cancer cell ‘circuitry’ is an important consideration in the rational design of drug combinations, particularly those targeting this signaling network. Therapies directed at MEK, a downstream RAS effector, have been in various stages of clinical development and shown to exhibit single-agent activity in RAF-mutant tumors. However, there is significant redundancy in the MAPK-PI3K pathway that mediates acute resistance to drugs that target either axis of this network, therefore the optimal use for MEK inhibitors will be in combination. We have previously demonstrated that the combination of MEK and mTOR inhibitors is synergistic in a broad range of tumor cell lines and xenofrafts and mechanistically this is mediated via potent suppression of cap-dependent translation. To better define which cohort of patients would best benefit from this combination modality, we have evaluated the efficacy of MEK and rapalog combinations in TSC2 defective cells. The TSC1/2 complex integrates AKT/mTOR and MAPK circuitry and normally inhibits mTOR via Rheb. However disruption of the TSC complex occurs by mutational inactivation, LOH and inactivating phosphorylation via various kinases, including ERK. Loss of TSC2 function hyperactivates mTOR signaling and confers increased sensitivity to mTOR-directed therapies, including rapalogs. In spite of the known participation of MAPK signaling in TSC function, pharmacological inhibitors of MAPK or other components have not been evaluated in TSC2 null tumors. Cells defective in TSC2 had increased sensitivity to both single agent MEK or rapalog therapies, relative to TSC2 WT cells, and had a much more synergistic interaction that was associated with potent dephosphorylation of the translational repressor, 4E-BP1. Synergy was associated with autophagy induction in TSC2 null cells followed by profound growth arrest that did not respond to growth factor stimulation. Cells with intact TSC2 function did not undergo autophagy after combined MEK and rapalog-inhibitor treatment and did not exhibit the same degree of growth arrest. Bioenergetic profiling indicated that TSC2 null cells had increased levels of oxygen consumption relative to WT cells, indicating changes in metabolic output associated with mTOR activation. In conclusion, these data support the use of combined MEK and rapalog-inhibitor therapy in tumors with defective TSC2 signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5472. doi:10.1158/1538-7445.AM2011-5472
CONTRIBUTION TO THE CULTIVATION OF THE PARASITE OF RABIES
Authors: Hideyo Noguchi
Journal: The Journal of Experimental Medicine (1913)

Galtier 1 and Pasteur 2 demonstrated the infectiousness of rabies.Negri ~ next described the characteristic inclusions in the ganglion cells, and Babes, 4 J. Koch, 5 Volpino, 6 Proescher, 7 and others found minute granular or pleomorphic particles in the central nervous system of animals infected with ra~bies.Remlinger, s Poor and St einhardt, 9 Bertarelli and Volpino ~° demonstrated the filterability of the rabic virus; but the nature of the virus itself had remained u
Bone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factor
Authors: Helena Stabile, Stefania Mitola, Emanuela Moroni, Mirella Belleri, Stefania Nicoli, Daniela Coltrini, Francesco Peri, Antonello Pessi, Laura Orsatti, Fabio Talamo, Vincent Castronovo, David Waltregny, Franco Cotelli, Domenico Ribatti, Marco Presta
Journal: Blood (2006)
Cellular Manipulation of Human Embryonic Stem Cells by TAT-PDX1 Protein Transduction
Authors: Young Do Kwon, Sun Kyung Oh, Hee Sun Kim, Seung-Yup Ku, Seok Hyun Kim, Young Min Choi, Shin Yong Moon
Journal: Molecular Therapy (2005)

Human embryonic stem cells (hESCs) are an in vitro model system for the study of human early development and a potential source for cell-based therapies. An efficient strategy for cellular manipulation of hESCs may be highly valuable for the analysis of gene function involved in human embryogenesis and the development of cell-based therapies via induced differentiation into particular cell types. However, plasmid transfection of hESCs has low efficiency and viral transduction may not be the method of choice for cell-based therapies due to genome integration. To overcome these limitations, we applied protein transduction technology that can transfer proteins into cells via direct penetration across the lipid bilayer. Here, we show that the FITC dye fused to the TAT protein transduction domain (PTD) was efficiently transferred into hESCs. In addition, the PDX1 transcription factor, which plays a central role in pancreatic development, was transferred into hESCs as a fusion form of TAT PTD. The transduced TAT-PDX1 activated its downstream target genes and induced insulin protein production in hESCs. These results demonstrate that protein transduction could be used in the cellular manipulation of hESCs and would provide a significant breakthrough for basic and therapeutic research in hESCs.
Relation between soluble interleukin 2 receptor and clinical findings in patients with systemic lupus erythematosus.
Authors: Y Tokano, A Murashima, Y Takasaki, H Hashimoto, K Okumura, S Hirose
Journal: Annals of the Rheumatic Diseases (1989)

The concentration of soluble interleukin 2 receptor (IL-2R) was determined in the serum of 54 patients with systemic lupus erythematosus (SLE) by an enzyme linked immunosorbent assay (ELISA) using two monoclonal antibodies with the IL-2R. Concentrations of soluble IL-2R in the serum of the patients with SLE (study group) were significantly higher than in 20 normal subjects (control group). The relation between concentrations of soluble IL-2R and clinical findings was investigated. The concentration of soluble IL-2R showed no particular relation with the clinical manifestations and did not correlate with the level of anti-DNA antibody or CH50. Significant correlation between the concentration of soluble IL-2R and disease activity did exist, however. Furthermore, the concentration of soluble IL-2R in some cases changed simultaneously with the disease activity. Thus the concentration of soluble IL-2R may serve as a new clinical indicator of disease activity in patients with SLE.
Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis
Authors: D. Caldeira, J. Alarcao, A. Vaz-Carneiro, J. Costa
Journal: BMJ (2012)

<b>Objective</b> To systematically review longitudinal studies evaluating use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and risk of pneumonia. <b>Design</b> Systematic review and meta-analysis. <b>Data sources</b> Medline through PubMed, Web of Science with conference proceedings (inception to June 2011), and US Food and Drug Administration website (June 2011). Systematic reviews and references of retrieved articles were also searched. <b>Study selection</b> Two reviewers independently selected randomised controlled trials and cohort and case-control studies evaluating the use of ACE inhibitors or ARBs and risk of pneumonia and retrieved characteristics of the studies and data estimates. <b>Data synthesis</b> The primary outcome was incidence of pneumonia and the secondary outcome was pneumonia related mortality. Subgroup analyses were carried according to baseline morbidities (stroke, heart failure, and chronic kidney disease) and patients’ characteristics (Asian and non-Asian). Pooled estimates of odds ratios and 95% confidence intervals were derived by random effects meta-analysis. Adjusted frequentist indirect comparisons between ACE inhibitors and ARBs were estimated and combined with direct evidence whenever available. Heterogeneity was assessed using the I<sup>2</sup> test. <b>Results</b> 37 eligible studies were included. ACE inhibitors were associated with a significantly reduced risk of pneumonia compared with control treatment (19 studies: odds ratio 0.66, 95% confidence interval 0.55 to 0.80; I<sup>2</sup>=79%) and ARBs (combined direct and indirect odds ratio estimate 0.69, 0.56 to 0.85). In patients with stroke, the risk of pneumonia was also lower in those treated with ACE inhibitors compared with control treatment (odds ratio 0.46, 0.34 to 0.62) and ARBs (0.42, 0.22 to 0.80). ACE inhibitors were associated with a significantly reduced risk of pneumonia among Asian patients (0.43, 0.34 to 0.54) compared with non-Asian patients (0.82, 0.67 to 1.00; P&lt;0.001). Compared with control treatments, both ACE inhibitors (seven studies: odds ratio 0.73, 0.58 to 0.92; I<sup>2</sup>=51%) and ARBs (one randomised controlled trial: 0.63, 0.40 to 1.00) were associated with a decrease in pneumonia related mortality, without differences between interventions. <b>Conclusions</b> The best evidence available points towards a putative protective role of ACE inhibitors but not ARBs in risk of pneumonia. Patient populations that may benefit most are those with previous stroke and Asian patients. ACE inhibitors were also associated with a decrease in pneumonia related mortality, but the data lacked strength.
Measurement of Blood-pressure: Comparison of Intra-arterial and Cuff Values
Authors: W. W. Holland, S. Humerfelt
Journal: BMJ (1964)

In recent years numerous reports have appeared?for example, Pickering (1955)?of discrepancies between arterial blood pressure measured by an intra-arterial method and by the usual cuff and sphygmomanometer. Part of this discrepancy has been attributed to the effect of arm circumference on arterial pressure measured with a cuff. Corrections based on measurements made by Ragan and Bordley (1941) have been published by Pickering, Roberts and Sowry (1954). While several workers report good agreement between systolic blood-pressure determined by the intra-arterial and that by the cuff method, there is disagreement over which of the two phases (phase 4, muffling, or phase 5, disappearance) represents the true diastolic pressure.
Allelic-Dependent Expression of an Activating Fc Receptor on B Cells Enhances Humoral Immune Responses
Authors: Xinrui Li, Jianming Wu, Travis Ptacek, David T. Redden, Elizabeth E. Brown, Graciela S. Alarcón, Rosalind Ramsey-Goldman, Michelle A. Petri, John D. Reveille, Richard A. Kaslow, Robert P. Kimberly, Jeffrey C. Edberg
Journal: Science Translational Medicine (2013)

Allele-dependent expression of activating FcγRIIc on human B cells enhances humoral immunity.
Incidental Visualization of Cadaveric Kidney Transplant Before Tc-99m MAG3 Evaluation of Transplant Renal Function
Authors: FRANK J. PAPATHEOFANIS, REBECCA SAJDAK
Journal: Clinical Nuclear Medicine (1995)

Tc-99m MAG3 is commonly employed in the postoperative evaluation of renal transplant function. A case of radiotracer uptake in the cadaveric donor kidney transplanted in a 17-year-old recipient demonstrates residual Tc-99m activitiy from a previous Tc-99m brain survival study of the donor.
DIABETIC GANGRENE OF THE FACE AND EAR COMPLICATED BY FIFTH AND SEVENTH NERVE INVOLVEMENT
Authors: A. J. Brier
Journal: JAMA (1934)

This case is presented because (1) of the rarity of the occurrence of diabetic gangrene of the face and (2) because of the unique complications that occurred subsequent to the gangrenous process. H. M., a man, aged 24, a farmer, brought to the hospital, Dec. 16, 1933, noticed a sore lump just in front of his right ear about thirty-six hours before. He was seen by his family physician shortly after its appearance. Local application of heat was then advised. In spite of the treatment, the condition became worse. The surrounding tissue became red, hot and swollen. The pain increased. In a few hours he complained of being short of breath. Because of the rapid progress of the local symptoms and the oncoming dyspnea he was sent to the hospital. Shortly after his admission he became quite stuporous and complained of being unable to breathe on account of "gas in
Genetic study of FGF19 receptor variants in gallstone disease
Authors: Marcin Krawczyk, Monica Acalovschi, Frank Lammert
Journal: Hepatology (2012)

In their relevant study, Zweers et al.1 demonstrate that fibroblast growth factor (FGF19) is secreted by human gallbladder epithelial cells. This novel intestinal hormone is also released by ileal enterocytes into the portal circulation in response to bile salt absorption. In target organs, FGF19 binds to FGF receptor 4 (FGFR4) and its coreceptor Klotho-β (KLB), which results in feedback inhibition of hepatic bile salt synthesis and might also stimulate mucin expression. Zweers et al.1 point out that it is unexplored whether genetic variation within the FGF19-FGFR4-KLB axis contributes to cholelithiasis. Recently, functional FGFR4-KLB variants have been identified.2 To investigate their relevance for gallstone disease, we genotyped common FGFR4 (rs351855, rs376618) and KLB (rs17618244) variants in a cohort of 239 gallstone patients from 107 families (age range, 24-80 years; 86% women) and 248 stone-free controls (age range, 21-78 years; 93% women); patient characteristics of the incipient cohort were reported in Hepatology.3 Table 1 shows that the KLB genotype [AA] is more prevalent in cases than controls. Therefore, we tested for associations between genotypes and gallstone disease using contingency tables (allele frequency difference/positivity, heterozygous/homozygous carriers).3 Individuals who are homozygous for the minor allele [A] are at increased risk of developing gallstones (odds ratio, 3.23; 95% confidence interval, 1.32-7.92; P = 0.007) as compared to carriers of genotype [GG]. Departure of the KLB genotype distribution from Hardy-Weinberg equilibrium in cases (exact test, P < 0.001; Supplementary Fig. 1 rpar; but not in controls supports the association of the KLB polymorphism with gallstones. However, nonparametric linkage analysis in affected sibs3 was negative (P > 0.05). In contrast to the KLB variant, both FGFR4 variants are not associated with gallstones in our cohort (data not shown). In conclusion, this study supports the functional link between KLB and gallstone disease, as suggested by Zweers et al.1 Interestingly, carriers of the KLB risk allele [A] display longer small intestinal transit times as compared to homozygous carriers of the common allele.2 Because slow intestinal transit increases the cholelithogenic state due to hyperabsorption of cholesterol and synthesis of secondary hydrophobic bile salts such as deoxycholate,4 we speculate that intestinal hypomotility contributes to gallstone susceptibility in carriers of the KLB risk variant. Marcin Krawczyk M.D.*, Monica Acalovschi M.D. , Frank Lammert M.D.*, * Department of Medicine II, Saarland University Medical Center, Hamburg, Germany, Department of Medicine III, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
What Is Balance in the Physician Workforce?
Authors: Robert G. Petersdorf
Journal: JAMA (1995)

<h3>To the Editor.</h3> —A number of organizations, public and private, have called for an increase in the production of primary care physicians to 50% of medical school output.<sup>1-4</sup>Others have cast doubt on this goal. Dr Cooper<sup>5</sup>claims that production of one-third generalists would be more appropriate. That would essentially maintain the current specialist-generalist distribution. Cooper uses selected data to make several arguments against the "50% solution." First, he states that the size of each specialty should depend on technological advances within the specialty rather than on the population to be served. Actually, there is no direct relationship between specialist numbers and expanding technology; the equation is multifactorial, with income potential, training center needs, and academic value systems among the independent variables. Fully developed, rather than "halfway," technologies frequently reduce workforce needs.<sup>6</sup> Elsewhere, Cooper states a preference for market-driven solutions over regulation and legislation. Isn't the market
New Evidence May Expand Indications for Chemotherapy in Breast Cancer
Authors: Beverly Merz
Journal: JAMA (1989)

IT'S TIME TO RETHINK the role of chemotherapy in treating mammary carcinoma. That was the message delivered by Gianni Bonadonna, MD, in the 20th Karnofsky Award lecture at the annual meeting of the American Society of Clinical Oncology in San Francisco, Calif. Bonadonna, who is director, division of medical oncology, Istituto Nazionale Tumori, Milan, Italy, indicated that it may be time to go beyond current guidelines and employ combination chemotherapy as an adjuvant in some additional patient populations and as a primary therapy in others. The guidelines Bonadonna would like to expand were developed in response to the publication in December of a meta-analysis of 61 randomized trials that involved 28 896 women (<i>N Engl J Med</i>. 1988;319:1681-1692). All of the patients underwent surgical tumor resection with or without radiation. The study determined that mortality was lower in patients who also underwent subsequent drug therapy than in those who did
Re: Clinical Factors Associated With Merkel Cell Polyomavirus Infection in Merkel Cell Carcinoma
Authors: Christian Andres, Benedetta Belloni, Ursula Puchta, Christian A. Sander, Michael J. Flaig
Journal: JNCI Journal of the National Cancer Institute (2009)

Polyomavirus Infection in Merkel Cell CarcinomaSihto et al. ( 1) recently analyzed 114 formalinfixed and paraffin-embedded Merkel cell carcinoma (MCC) samples from a Finnish cohort for the presence of Merkel cell polyomavirus (MCPyV) DNA.They reported that the prevalence of MCPyV DNA in MCC was 79.8% and, surprisingly, that MCPyV DNA -positive MCCs were preferentially located on the limbs compared with MCPyV DNA -negative MCCs.Their data also suggested that patients with MCPyV DNA -positive tumors had a better prognosis and fewer regional nodal metastases at time of diagnosis compared with patients with MCPyV DNA -negative tumors.We asked if the fi ndings of Sihto et al. could be replicated in an independent cohort of MCC patients.We previously investigated 35 MCC tissue samples from 31 German patients for the presence of MCPyV DNA.We detected MCPyV DNA by polymerase chain reaction amplifi cation in 22 samples (63%) and in 21 patients (68%) ( 2 ) using two sets of primers.Polymerase chain reaction amplifi cation with these two primer sets resulted in a 138-base pair product (MCV138 forward: 5 ′ -GGTTAGAGAT GCTGGAAATGACC-3 ′ ; reverse:and a 191-base pair product (MCV191 forward: 5 ′ -CCACTTTATT ATCTTAGCCCAT-3 ′ ; reverse: 5 ′ -TCCT TTTGGCTAGAACAGTGTC-3 ′ ) that target the large and small T-antigen regions, respectively.The exact locations for the primer pairs are forward 2185 -2207 and reverse 2301 -2322 (MCV138) and forward 1994 -2015 and reverse 2163 -2184 (MCV191) and are based on reference sequences in the National Center for Biotechnology Information Entrez Nucleotide database (gb|EU375803.1,MCPyV isolate MCC350).All positive polymerase chain reaction results were confi rmed by Southern blot analysis as previously described ( 2 ).Of the 31 primary tumor tissue samples from the German MCC patients, 21 were positive for MCPyV DNA and 10 M. Lackas Foundation.
Coxsackie A16 Infection From Lake Water
Authors: F. A. Denis
Journal: JAMA (1974)

<h3>To the Editor.—</h3> Some days after bathing in a lake, five children showed symptoms of a disease with identical clinical characteristics. The most frequent were fever, diarrhea, vomiting, gastrointestinal and articular pain, refusal to eat, malaise, and myalgia. Three families refused to allow sera or specimens to be taken from their children, but two boys, 7 and 9 years old, were examined in the pediatrics ward of the Niort Hospital. The two boys showed a few pulmonary rales and reddish eardrums; one had an exanthem. Neither lesions of the mouth, palms, and soles nor clinical and biological symptoms of meningitis were seen. Stool and throat specimens were cultured immediately after collection, and two sera were collected from each patient. For the detection of enteric viruses in four samples (10 liters each) of lake water, we used a virus concentrator (Sartorius) with 12 membranes (160 × 160 mn, SM 12133). Each sample had
RESTORATION OF ANGIOGENIC ACTIVITY OF HYPERGLYCEMIA-INSULTED BONE MARROW STEM CELLS BY OXYTOCIN VIA KLF2 UP-REGULATION
Authors: Youngkeun Ahn, Yong Sook Kim, Jin Sook Kwon, Myung Ho Jeong, Jeong Gwan Cho, Jong Chun Park, Jung Chaee Kang
Journal: Journal of the American College of Cardiology (2011)
Pemphigus herpetiformis with IgA and IgG antibodies to desmoglein 1 and IgG antibodies to desmocollin 3
Authors: A. Kozlowska, T. Hashimoto, M. Jarzabek-Chorzelska, A. Amagai, Y. Nagata, Z. Strasz, S. Jablonska
Journal: Journal of the American Academy of Dermatology (2003)
THE TRUE AND THE FALSE PRESYSTOLIC MURMURS
Authors: WILLIAM D. REID
Journal: JAMA (1924)

The importance commonly attached to the presystolic murmur, so called, in the diagnosis of cardiac abnormality justifies further discussion as to its causation. In two previous papers I<sup>1</sup>have offered evidence that the crescendo murmur ending in a sharp first sound is in reality early systolic, and due to ventricular systole rather than being presystolic in time and auricular in causation. In a review of one of these papers and that of Henderson,<sup>2</sup>Pepper<sup>3</sup>writes: "This theory is attractive and highly plausible; it does not, however, seem to fit in very satisfactorily with the well known disappearance of the mitral stenotic murmur which occurs with the onset of auricular fibrillation." It is my purpose here to answer Dr. Pepper's objection, to offer some further data concerning the mechanism of the crescendo murmur, and to reemphasize that there are two murmurs, one the so-called presytolic and the other
Clinical Neuroanatomy for Medical Students
Authors: Charles M. Poser
Journal: JAMA (1980)

Many authors have attempted to produce a textbook of clinical neuroanatomy that would successfully compete with "M.A.S.H." for entertainment and educational value. The subject matter invariably strikes terror in the hearts of most medical students, but hardly lends itself to the narrative style of Hemingway, or perhaps more appropriately, to that of Harry Lee Parker in his delightful<i>Clinical Studies in Neurology</i>. The intricacies and intrinsic beauty of clinical neuroanatomy are much more likely to appeal to the experienced clinical neurologist than to the embryonic family physician. Nevertheless, Dr Snell has made a valiant, although not quite successful attempt at rendering neuroanatomy more palatable. The organization of the book follows the classical lines laid down many years ago by teachers of neuroanatomy for reasons that have always been somewhat difficult to understand by a clinician who must apply this knowledge to the patients' problems: The author would have rendered a