tbuckley/cabot-search huggingface dataset:
PI3′-Kinase Inhibition Forestalls the Onset of MEK1/2 Inhibitor Resistance in <i>BRAF</i>-Mutated Melanoma
Authors: Marian M. Deuker, Victoria Marsh Durban, Wayne A. Phillips, Martin McMahon
Journal: Cancer Discovery (2014)

Abstract Phosphatidylinositide 3′ (PI3′)-lipid signaling cooperates with oncogenic BRAFV600E to promote melanomagenesis. Sustained PI3′-lipid production commonly occurs via silencing of the PI3′-lipid phosphatase PTEN or, less commonly, through mutational activation of PIK3CA, encoding the 110-kDa catalytic subunit of PI3′-kinase-α (PI3Kα). To define the PI3K catalytic isoform dependency of BRAF-mutated melanoma, we used pharmacologic, isoform-selective PI3K inhibitors in conjunction with melanoma-derived cell lines and genetically engineered mouse (GEM) models. Although BRAFV600E/PIK3CAH1047R melanomas were sensitive to the antiproliferative effects of selective PI3Kα blockade, inhibition of BRAFV600E/PTENNull melanoma proliferation required combined blockade of PI3Kα, PI3Kδ, and PI3Kγ, and was insensitive to PI3Kβ blockade. In GEM models, isoform-selective PI3K inhibition elicited cytostatic effects, but significantly potentiated melanoma regression in response to BRAFV600E pathway–targeted inhibition. Interestingly, PI3K inhibition forestalled the onset of MEK inhibitor resistance in two independent GEM models of BRAFV600E-driven melanoma. These results suggest that combination therapy with PI3K inhibitors may be a useful strategy to extend the duration of clinical response of patients with BRAF-mutated melanoma to BRAFV600E pathway–targeted therapies. Significance: Although BRAFV600E pathway–targeted therapies elicit melanoma regression, the onset of drug resistance limits the durability of response. Here, we show that combined treatment with PI3K inhibitors significantly forestalled the onset of MEK1/2 inhibitor–resistant disease in BRAF-mutated GEM melanoma models. These results provide a conceptual framework for the combined deployment of BRAFV600E plus PI3K pathway–targeted inhibitors in the treatment of a subset of patients with BRAF-mutated melanoma. Cancer Discov; 5(2); 143–53. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 97
Central Body Fat Distribution Associates with Unfavorable Renal Hemodynamics Independent of Body Mass Index
Authors: Arjan J. Kwakernaak, Dorien M. Zelle, Stephan J.L. Bakker, Gerjan Navis
Journal: Journal of the American Society of Nephrology (2013)

Central distribution of body fat is associated with a higher risk of renal disease, but whether it is the distribution pattern or the overall excess weight that underlies this association is not well understood. Here, we studied the association between waist-to-hip ratio (WHR), which reflects central adiposity, and renal hemodynamics in 315 healthy persons with a mean body mass index (BMI) of 24.9 kg/m(2) and a mean (125)I-iothalamate GFR of 109 ml/min per 1.73 m(2). In multivariate analyses, WHR was associated with lower GFR, lower effective renal plasma flow, and higher filtration fraction, even after adjustment for sex, age, mean arterial pressure, and BMI. Multivariate models produced similar results regardless of whether the hemodynamic measures were indexed to body surface area. Thus, these results suggest that central body fat distribution, independent of BMI, is associated with an unfavorable pattern of renal hemodynamic measures that could underlie the increased renal risk reported in observational studies.
Lipopolysaccharide Depresses Cardiac Contractility and β-Adrenergic Contractile Response by Decreasing Myofilament Response to Ca <sup>2+</sup> in Cardiac Myocytes
Authors: Satoshi Yasuda, Wilbur Y. W. Lew
Journal: Circulation Research (1997)

Abstract Lipopolysaccharide (LPS) plays a key role in the pathogenesis of sepsis. Cardiac function and the inotropic response to β-adrenergic stimulation are impaired in sepsis. We hypothesized that LPS, in clinically relevant levels (1 ng/mL), directly depresses contractility and β-adrenergic responses in cardiac myocytes. Cardiac myocytes were isolated from the left ventricle of adult rabbits using digestive enzymes (collagenase and protease). We depyrogenated the enzymes (LPS contamination lowered from 100 to 300 ng/mL to &lt;0.7 ng/mL) to minimize development of LPS tolerance during cell isolation. After 6 hours of incubation with 1 ng/mL LPS, there was a decrease in the extent of active cell shortening with no change in Ca 2+ transients (measured with indo 1 fluorescence), indicating decreased myofilament responsiveness to Ca 2+ . This was related to NO pathways, since cGMP (a second messenger of NO) increased in cardiac myocytes and LPS effects were completely reversed with a 1 mmol/L N G -monomethyl- l -arginine (L-NMMA, a NO synthase inhibitor). LPS did not alter the intracellular Ca 2+ response to β-adrenergic stimulation with isoproterenol but attenuated the contractile response (maximal cell shortening, 15.5±1.0% versus 23.3±1.1% in control myocytes; P &lt;.001). LPS attenuation of the contrac-tile response to isoproterenol was restored completely by L-NMMA and almost completely restored (to 86% of the control response) by an inhibitor of cGMP-dependent protein kinase. We conclude that LPS depresses cardiac contractility and the contractile response to β-adrenergic stimulation by a NO-cGMP–mediated decrease in myofilament responsiveness to Ca 2+ . The direct effects of low levels of LPS on cardiac myocytes may contribute to cardiac depression and hemodynamic decompensation during sepsis.
Intracoronary infusion of dobutamine to patients with and without severe congestive heart failure. Dose-response relationships, correlation with circulating catecholamines, and effect of phosphodiesterase inhibition.
Authors: W S Colucci, A R Denniss, G F Leatherman, R J Quigg, P L Ludmer, J D Marsh, D F Gauthier
Journal: Journal of Clinical Investigation (1988)

We infused dobutamine into the left main coronary artery of 24 patients with severe congestive heart failure (CHF) and 8 normal subjects without hemodynamic dysfunction. The maximal +dP/dt response to intracoronary (IC) dobutamine in CHF patients was only 37% of that in normals. This decrease in maximal response was not associated with a rightshift in the EC50 for dobutamine's effect on +dP/dt, or a decrease in the affinity of myocardial beta adrenergic receptors for dobutamine determined in vitro. In nine of the CHF patients, IC dobutamine infusion was followed by IC infusion of the phosphodiesterase inhibitor milrinone, and subsequently, by a second IC infusion of dobutamine. After IC milrinone, the increase in +dP/dt caused by IC dobutamine (74 +/- 10%) was significantly greater than that caused by the first infusion of dobutamine (52 +/- 11%; P less than 0.003) or milrinone (42 +/- 6%; P less than 0.001). Resting plasma norepinephrine was markedly elevated in CHF patients (837 +/- 208 ng/liter), but not in normal subjects (142 +/- 32 ng/liter); and the increase in +dP/dt caused by IC dobutamine was inversely related to resting plasma norepinephrine levels (r = -0.653; P less than 0.001). IC dobutamine caused a dose-related decrease in plasma norepinephrine (maximal effect, -160 +/- 31 ng/liter; P less than 0.001). Thus, (a) the maximal inotropic response to dobutamine is markedly depressed in patients with severe CHF, and is significantly greater after pretreatment with the phosphodiesterase inhibitor milrinone; (b) the impairment in inotropic response to dobutamine is inversely related to circulating norepinephrine levels; and (c) myocardial stimulation by dobutamine results in withdrawal of sympathetic tone.
Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders
Authors: Hane Lee, Joshua L. Deignan, Naghmeh Dorrani, Samuel P. Strom, Sibel Kantarci, Fabiola Quintero-Rivera, Kingshuk Das, Traci Toy, Bret Harry, Michael Yourshaw, Michelle Fox, Brent L. Fogel, Julian A. Martinez-Agosto, Derek A. Wong, Vivian Y. Chang, Perry B. Shieh, Christina G. S. Palmer, Katrina M. Dipple, Wayne W. Grody, Eric Vilain, Stanley F. Nelson
Journal: JAMA (2014)

Clinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders.To report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types.Clinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available.Clinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES.Of the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants.In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.
Possible involvement of the T4 molecule in T cell recognition of class II HLA antigens. Evidence from studies of CTL-target cell binding.
Authors: W E Biddison, P E Rao, M A Talle, G Goldstein, S Shaw
Journal: The Journal of Experimental Medicine (1984)

The present study examines the potential role of the T4 molecule in functional cell-cell interactions between target cells and human cytotoxic T lymphocyte (CTL) clones that are specific for HLA class II alloantigens encoded by the SB locus. There were marked differences (greater than 30-fold) between the seven SB-specific clones studied with respect to their susceptibility to inhibition by anti-T4 as well as anti-T3 antibodies. We wished to test the hypothesis that such variation among the clones would be due to differences in clonal "affinity" for antigen. To quantitate differences among the CTL clones in the tightness with which they bind target cells, the clones were analyzed using a previously published assay of susceptibility of CTL-target cell conjugates to dissociation in the presence of unlabeled targets. The results revealed that the clones that were most susceptible to inhibition by anti-T4 and anti-T3 were the weakest target cell binders, and vice versa. Anti-T4 antibody could partially induce dissociation of functional CTL-target cell conjugates in the absence of any added cold targets. For the "highest affinity" clone such anti-T4 antibody-induced dissociation could be observed at 4 degrees C but not 23 degrees C. These results indicate that the T4 molecule is functionally involved in target cell binding by CTL, and raise the possibility that although it is easiest to demonstrate the function of the T4 molecule in "low affinity" clones, that function may also be operative in the "high affinity" clones.
Extracellular superoxide dismutase in human tissues and human cell lines.
Authors: S L Marklund
Journal: Journal of Clinical Investigation (1984)

Extracellular-superoxide dismutase is a tetrameric copper-containing glycoprotein that previously has been demonstrated to be the major superoxide dismutase of human extracellular fluids. The occurrence of this enzyme in various human tissues that were removed from two accidental death victims and in 19 different human cultured cell lines was determined. All investigated tissues were found to contain extracellular-superoxide dismutase. There was a larger variation between tissues in the concentration of this enzyme than in CuZn superoxide dismutase and Mn superoxide dismutase. No relation could be demonstrated between the content of extracellular-superoxide dismutase and the content of the other superoxide dismutase isoenzymes in the various tissues. In uterus there was more extracellular-superoxide dismutase than Mn superoxide dismutase, but in all other tissues the content of extracellular-superoxide dismutase was lower than the content of the other isoenzymes. The concentration of extracellular-superoxide dismutase was higher in all investigated human tissues than in human plasma. 19 human cultured cell lines were found to be devoid of or to contain very little extracellular-superoxide dismutase. Most tissues contained more extracellular-superoxide dismutase than did the investigated cell lines.
Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents
Authors: K. Morino
Journal: Journal of Clinical Investigation (2005)

To further explore the nature of the mitochondrial dysfunction and insulin resistance that occur in the muscle of young, lean, normoglycemic, insulin-resistant offspring of parents with type 2 diabetes (IR offspring), we measured mitochondrial content by electron microscopy and insulin signaling in muscle biopsy samples obtained from these individuals before and during a hyperinsulinemic-euglycemic clamp. The rate of insulin-stimulated muscle glucose uptake was approximately 60% lower in the IR offspring than the control subjects and was associated with an approximately 60% increase in the intramyocellular lipid content as assessed by H magnetic resonance spectroscopy. Muscle mitochondrial density was 38% lower in the IR offspring. These changes were associated with a 50% increase in IRS-1 Ser312 and IRS-1 Ser636 phosphorylation and an approximately 60% reduction in insulin-stimulated Akt activation in the IR offspring. These data provide new insights into the earliest defects that may be responsible for the development of type 2 diabetes and support the hypothesis that reductions in mitochondrial content result in decreased mitochondrial function, which predisposes IR offspring to intramyocellular lipid accumulation, which in turn activates a serine kinase cascade that leads to defects in insulin signaling and action in muscle.
Noninvasive Characterization of the Effect of Varying PLGA Molecular Weight Blends on <i>In Situ</i> Forming Implant Behavior Using Ultrasound Imaging
Authors: Luis Solorio, Alexander M. Olear, Jesse I. Hamilton, Ravi B. Patel, Ashlei C. Beiswenger, Jon E. Wallace, Haoyan Zhou, Agata A. Exner
Journal: Theranostics (2012)

In situ forming implants (ISFIs) have shown promise in drug delivery applications due to their simple manufacturing and minimally invasive administration. Precise, reproducible control of drug release from ISFIs is essential to their successful clinical application. This study investigated the effect of varying the molar ratio of different molecular weight (Mw) poly(D,L-lactic-co-glycolic acid) (PLGA) polymers within a single implant on the release of a small Mw mock drug (sodium fluorescein) both in vitro and in vivo. Implants were formulated by dissolving three different PLGA Mw (15, 29, and 53 kDa), as well as three 1:1 molar ratio combinations of each PLGA Mw in 1-methyl-2-pyrrolidinone (NMP) with the mock drug fluorescein. Since implant morphology and microstructure during ISFI formation and degradation is a crucial determinant of implant performance, and the rate of phase inversion has been shown to have an effect on the implant microstructure, diagnostic ultrasound was used to noninvasively quantify the extent of phase inversion and swelling behavior in both environments. Implant erosion, degradation, as well as the in vitro and in vivo release profiles were also measured using standard techniques. A non-linear mathematical model was used to correlate the drug release behavior with polymer phase inversion, with all formulations yielding an R(2) value greater than 0.95. Ultrasound was also used to create a 3D image reconstruction of an implant over a 12 day span. In this study, swelling and phase inversion were shown to be inversely related to the polymer Mw with 53 kDa polymer implants increasing at an average rate of 9.4%/day compared with 18.6%/day in the case of the 15 kDa PLGA. Additionally the onset of erosion, complete phase inversion, and degradation facilitated release required 9 d for 53 kDa implants, while these same processes began 3 d after injection into PBS with the 15 kDa implants. It was also observed that PLGA blends generally had intermediate properties when compared to pure polymer formulations. However, release profiles from the blend formulations were governed by a more complex set of processes and were not simply averages of release profiles from the pure polymers preparations. This study demonstrated that implant properties such as phase inversion, swelling and drug release could be tailored to by altering the molar ratio of the polymers used in the depot formulation.
The Uniform Anatomical Gift Act
Authors: CRAWFORD C. MARTIN
Journal: American Journal of Psychiatry (1970)

Recent advances in the use of human organs and tissue in medical research and therapy have dramatized the need for legal guidelines to achieve a balance between the expectations of society and individual rights in this area. The author describes the principal provisions of the Uniform Anatomical Gift Act, which was drafted to meet this need and has now been distributed to the states for consideration.
HIV and alopecia universalis
Authors: Karla Werninghaus, Michael S. Kaminer
Journal: Journal of the American Academy of Dermatology (1993)

Journal of the American Academy of Dermatology Volume 29, Number 4 as is usual in DDD, an increased number ofmelanocytes was not found in our patient, unlike the patient of Kameyama et aI.Kameyama and co-workers suggest that azelaic acid more easily penetrates active melanocytes; perhaps in our patient the melanocyteswere in a less active state.It is also possiblethat the pathogenetic mechanisms in DDD and RAPK differ, especiallywith regard to tyrosinase activity and the regulation of melanocyte activity.A trial on a larger populationcoulddeterminethe responsiveness to azelaic acid of patients with reticulate pigmentation and givemore information about the pathogenesis of this interesting group of disorders.
The lupus band test in oral mucosa, conjunctiva and skin
Authors: S.M. BURGE, P.A. FRITH, P.R. MILLARD, F. WOJNAROWSKA
Journal: British Journal of Dermatology (1989)

The prevalence and clinical significance of subepithelial immunoglobulin and complement deposition (the lupus band) were examined in the uninvolved sun-protected skin of the forearm, the uninvolved sun-protected lip mucosa and sun-protected bulbar conjunctival mucosa in systemic lupus erythematosus (SLE) and chronic cutaneous lupus erythematosus (CCLE). In SLE, linear deposition of an immunoreactant at the BMZ was detected in 32% (6/19) of skin biopsies; 21% (4/19) of lip mucosal biopsies and 42% (5/12) of conjunctival biopsies. There was no significant difference in the sensitivity of the test at different sites in SLE and no correlation between a positive test in skin, lip or conjunctiva and clinical mucosal involvement. In CCLE, linear deposition of an immunoreactant at the BMZ was found in 3% (1/32) of skin biopsies; 3% (1/29) of lip mucosal biopsies and 50% (10/20) of conjunctiva and clinical mucosal involvement. In the conjunctiva, IgG was present in all but one of the biopsies and was the only immunoreactant in 90% (9/10) of positive CCLE biopsies and 60% (3/5) of positive SLE biopsies. In lupus erythematosus immunoreactants may be deposited in the basement membrane zone beneath non-keratinizing mucosal surfaces of the lip and the eye as well as the skin. In CCLE, the test may be positive in conjunctiva when skin and lip are negative.
COPROANTIBODY AND BACTERIAL ANTAGONISM AS PROTECTIVE FACTORS IN EXPERIMENTAL ENTERIC CHOLERA
Authors: Rolf Freter
Journal: The Journal of Experimental Medicine (1956)

Passive oral immunization with O-antiserum was found to protect guinea pigs against fatal enteric cholera. The number of vibrios recoverable from the intestines of infected animals was not noticeably reduced by active and oral passive immunization. Passive immunization by the intraperitoneal route was not protective even though high titers of circulating antibody were obtained shortly after injection. Oral administration of H-antiserum also had no protective effect. Introduction of E. coli into the intestinal tract increased the resistance of guinea pigs to fatal enteric cholera.
Measles Elimination in the Americas
Authors: Ciro A. de Quadros, Jean Marc Olivé, Bradley S. Hersh, Marc A. Strassburg, Donald A. Henderson, David Brandling-Bennett, George A. O. Alleyne
Journal: JAMA (1996)

In February 1992, PAHO hosted an Informal Consultation of Measles Elimination in the Americas in Washington, D.C. to review past and current control and elimination efforts, to weigh the scientific and technical feasibility of eliminating measles from the Americas, and to suggest a role for PAHO to further the program. When the measles vaccine 1st appeared in the 1960s, coverage rose, the periods between epidemics increased, and the epidemics involved fewer numbers of people afflicted with measles. The Gambia began vaccinating all 5-year old children in 1967 and it had interrupted measles transmission between 1968-70. It stopped the strategy that achieved this and transmission levels increased. In the US, the Childhood Immunization Initiative begun in 1978 set out to eliminate indigenous transmission of measles by 1982. The US achieved 95% coverage of children entering school and measles incidence fell 99% Yet the US could not eliminate measles. Obstacles included imported measles cases, missed vaccination opportunities, shifting epidemiology of measles to 10-19 year old susceptibles, and high degrees of contagiousness. In 1988, Cuba began its campaign to eliminate indigenous measles transmission. By 1989, it may have achieved transmission interruption. In the last 3 years, authorities have identified only 3 imported cases. The English-speaking Caribbean began a program in 1988. It planned to strengthen routine delivery of measles vaccine to all health facilities and to vaccinate all 1-14 year old children regardless of vaccination status. The mass campaign started in May 1991. By September 1991, authorities had identified only 4 measles cases. Sao Paulo State, Brazil began its mass vaccination campaign (all 1-14 year old children) in 1987. Measles-related deaths fell 98% between 1987-90. The meeting participants believed the Americas could indeed be the 1st region to eliminate measles since it was the 1st to eliminate smallpox and is close to eliminating polio. They hoped PAHO would support present initiatives to eliminate measles in the Americas.
The onset of ultraviolet erythema
Authors: B.L. DIFFEY, A.M. OAKLEY
Journal: British Journal of Dermatology (1987)

The onset of erythema induced by UVB and by UVC radiation was monitored in two subjects using a reflectance instrument. It was shown that vasodilation occurred some time before erythema became visible, even with small exposure doses of UVB or UVC, after which visible erythema was not apparent for several hours. In one subject, vasodilation was detected very shortly after irradiation and may have even begun during irradiation. In the other subject vasodilation was detected later at most exposure doses, but still some time before erythema became visible. We conclude that the so-called 'latent period' between irradiation and appearance of erythema is an artificial concept arising from the insensitivity of the eye.