tbuckley/cabot-search huggingface dataset:
LASTING BIOLOGICAL EFFECTS OF EARLY ENVIRONMENTAL INFLUENCES
Authors: Chi-Jen Lee, Rene Dubos
Journal: The Journal of Experimental Medicine (1969)

Physicochemical and immunological techniques have been used in an attempt to characterize a filterable agent, separated from the intestines of mice raised under ordinary conditions of husbandry, which produces a lasting depression of weight in specific pathogen-free (SPF) mice when administered to them orally shortly after birth. Although this agent has not yet been identified, it will be tentatively designated here as enterovirus. The mouse enterovirus can be readily sedimented by ultracentrifugation and by precipitation at pH 4.3; it does not pass through cellophane membranes. Its infective power is completely destroyed by ultraviolet radiation, but is resistant to heating at 56 degrees C, exposure to ether, treatment with trypsin, ribonuclease, and deoxyribonuclease. Dialysis and treatment with ether and nucleases greatly increase the infective activity of the intestinal filtrates containing the enterovirus, a finding which suggests that these procedures eliminate or destroy some inhibitory substance(s). The mouse enterovirus causes hemagglutination of mouse red blood cells. When injected into rabbits, it elicits in them an immune response that renders their serum capable of neutralizing its weight-depressing activity. As measured by inhibition of hemagglutination or complement fixation, the sera of infected mice do not exhibit any significant activity against usual mouse viruses. Centrifugation of the mouse enterovirus in 50%-20% sucrose gradient gave almost complete recovery of the infectivity and of hemagglutinating activity in the same fraction. In contrast, the protein content of the material was distributed through the various fractions. Consequently, this procedure resulted in a marked increase of specific activity.
Biomarkers In Early Clinical Trials: the Committed and the Skeptics
Authors: Udai Banerji, Johann de Bono, Ian Judson, Stanley Kaye, Paul Workman
Journal: Clinical Cancer Research (2008)

To the Editors: The article by Goulart et al. (1) and the provocative accompanying editorial by Ratain and Glassman (2) raise important issues. We would like to respectfully take issue with some of the conclusions.First, the quantitative effect of publication bias in phase I trials with negative pharmacodynamic studies is difficult to determine. Moreover, the lack of analytic validation of the assays used is often limiting. Validated biomarkers are key to affecting decision-making but cannot replace toxicity and pharmacokinetic studies. Nonetheless, target blockade in tumors using validated assays provides robust foundations for future drug development (3).Ratain and Glassman also raise concerns about biomarker costs. An additional $6,675 per phase I patient seems to be a good value compared with the quoted billion dollars per drug overall. Indeed, the potential cost of suboptimal dosing schedules being taken forward merits such an investment and may reduce expensive late attrition (4), which may reflect the underutilization of pharmacodynamic biomarkers in early clinical trials. In our experience, biomarkers have an important role in phase I trials and we would highlight two examples of work done at our institution: (a) the successful use of biomarkers for patient selection in a study with the poly-ADP ribose polymerase inhibitor KU-0059436 leading to responses in individuals with BRCA mutations (5), and (b) the application of biomarkers of target inhibition helping to lead dose escalation of the heat shock protein inhibitor 90 (HSP90) 17-allylamino-17-demethoxygeldanamycin (6).Finally, Ratain and Glassman argue that performing tumor biopsies poses an increased risk that may be unethical. There is little evidence that such biopsies pose an increased risk (7). We endorse the use of tumor biopsies at dose levels that satisfy predetermined pharmacokinetic variables and where target inhibition in surrogate tissue is demonstrable. Indeed, conversely failing to obtain such key tumor biopsy information from patients while putting them through a phase I trial could be deemed unethical.Overall, the fact that only 503 of 2,458 (20%) analyzed American Society of Clinical Oncology abstracts used at least one biomarker represents an improvement over previous audits. Reduced enthusiasm to use biomarkers at this point could lead to an increase in the taking forward of a number of ineffective drugs or effective drugs using suboptimal schedules, increasing failure rates and costs. In an era in which health economics will dictate the availability of new and expensive agents, robust biomarkers for dose, schedule, and patient selection must remain an important priority.P. Workman has licensed intellectual property to Vernal1s and Novartis. S. Kaye is a member of the AstraZeneca Advisory Board.
Left ventricular function in experimental aorto-caval fistula with circulatory congestion and fluid retention
Authors: Roger R. Taylor, James W. Covell, John Ross
Journal: Journal of Clinical Investigation (1968)

The mechanical properties of left ventricular contraction were described in terms of tension, velocity, length, and time in closed-chest, sedated dogs in which a large aorto-caval fistula had resulted in circulatory congestion, and the results were compared with those in normal dogs. Instantaneous contractile element velocity was calculated from left ventricular pressure and its first derivative during isovolumic left ventricular contractions produced by sudden balloon occlusion of the ascending aorta during diastole. A range of ventricular end-diastolic volumes was induced and heart rate was controlled at 150 beats/min. Wall tension (stress) was derived from ventricular pressure and volume, the latter being obtained from the pressure-volume relation of the passive ventricle. Extrapolated velocity at zero tension, V(max), averaged 3.0 circ/sec in the normal dogs and 2.9 circ/sec in the seven dogs with an aorto-caval fistula and fluid retention; in only one of these seven animals was V(max) below the lower limit of normal of 2.7 circ/sec. Isovolumic tension (P(o)) in dogs with aorto-caval fistulas tended to be slightly greater than normal at low ventricular filling pressures, and there was no difference in P(o) between the two groups of animals at high ventricular filling pressures. Time to peak pressure averaged 151 +/- 6 (SE) msec (normal 139 +/- 3). Left ventricular weight averaged 6.32 +/- 0.23 g/kg of initial body weight (normal 5.25 +/- 0.56 g/kg) (P < 0.001), which reflected moderate ventricular hypertrophy, and ventricular internal volume at a given filling pressure was increased proportionally. Therefore, the ventricular contractile state usually was normal in the dog with a large aorto-caval fistula, and it is proposed that mechanisms for fluid retention that results in circulatory congestion were activated because of the large hemodynamic burden despite normal myocardial contractile properties.
BRAF V600E Disrupts AZD6244-Induced Abrogation of Negative Feedback Pathways between Extracellular Signal-Regulated Kinase and Raf Proteins
Authors: Bret B. Friday, Chunrong Yu, Grace K. Dy, Paul D. Smith, Liang Wang, Stephen N. Thibodeau, Alex A. Adjei
Journal: Cancer Research (2008)

Abstract AZD6244 (ARRY 142886) is a potent and selective mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor currently in early clinical trials. We examined the activity of AZD6244 in a panel of non–small cell lung cancer and a panel of cell lines representing many cancer types using in vitro growth assays. AZD6244 induced G0-G1 cell cycle arrest in sensitive cell lines that primarily included cells containing the BRAF V600E mutation. In these cells, G0-G1 arrest is accompanied by the up-regulation of the cell cycle inhibitors p21WAF1 and p27Kip1 and down-regulation of cyclin D1. In the majority of cell lines tested, including those with K-ras or non-V600E BRAF mutations, AZD6244 induced the accumulation of phospho-MEK, an effect not observed in the most sensitive BRAF V600E-containing cells. Accumulation of phospho-MEK in non–V600E-containing cell lines is due to abrogation of negative feedback pathways. BRAF V600E disrupts negative feedback signaling, which results in enhanced baseline phospho-MEK expression. Exogenous expression of BRAF V600E disrupts feedback inhibition but does not sensitize cells to AZD6244. Specific suppression of endogenous BRAF V600E does not confer resistance to AZD6244 but enhances sensitivity to AZD6244. Thus, our findings show that BRAF V600E marks cells with an in vitro requirement for MAPK signaling to support proliferation. These cells are exquisitely sensitive to AZD6244 (IC50, &amp;lt;100 nmol/L), have high baseline levels of phospho-MEK, and lack feedback inhibition between ERK and Raf. These data suggest an approach to identifying cells that may be sensitive to AZD6244 and other MEK inhibitors. [Cancer Res 2008;68(15):6145–53]
Up‐regulation of histone methyltransferase SETDB1 by multiple mechanisms in hepatocellular carcinoma promotes cancer metastasis
Authors: Chun‐Ming Wong, Lai Wei, Cheuk‐Ting Law, Daniel Wai‐Hung Ho, Felice Ho‐Ching Tsang, Sandy Leung‐Kuen Au, Karen Man‐Fong Sze, Joyce Man‐Fong Lee, Carmen Chak‐Lui Wong, Irene Oi‐Lin Ng
Journal: Hepatology (2015)

Epigenetic deregulation plays an important role in liver carcinogenesis. Using transcriptome sequencing, we examined the expression of 591 epigenetic regulators in hepatitis B‐associated human hepatocellular carcinoma (HCC). We found that aberrant expression of epigenetic regulators was a common event in HCC. We further identified SETDB1 (SET domain, bifurcated 1), an H3K9‐specific histone methyltransferase, as the most significantly up‐regulated epigenetic regulator in human HCCs. Up‐regulation of SETDB1 was significantly associated with HCC disease progression, cancer aggressiveness, and poorer prognosis of HCC patients. Functionally, we showed that knockdown of SETDB1 reduced HCC cell proliferation in vitro and suppressed orthotopic tumorigenicity in vivo . Inactivation of SETDB1 also impeded HCC cell migration and abolished lung metastasis in nude mice. Interestingly, SETDB1 protein was consistently up‐regulated in all metastatic foci found in different organs, suggesting that SETDB1 was essential for HCC metastatic progression. Mechanistically, we showed that the frequent up‐regulation of SETDB1 in human HCC was attributed to the recurrent SETDB1 gene copy gain at chromosome 1q21. In addition, hyperactivation of specificity protein 1 transcription factor in HCC enhanced SETDB1 expression at the transcriptional level. Furthermore, we identified miR‐29 as a negative regulator of SETDB1. Down‐regulation of miR‐29 expression in human HCC contributed to SETDB1 up‐regulation by relieving its post‐transcriptional regulation. Conclusion : SETDB1 is an oncogene that is frequently up‐regulated in human HCCs; the multiplicity of SETDB1 activating mechanisms at the chromosomal, transcriptional, and posttranscriptional levels together facilitates SETDB1 up‐regulation in human HCC. (H epatology 2016;63:474–487)
Results of two worldwide surveys into physician awareness and perceptions of extended-spectrum β-lactamases
Authors: H. Goossens, S. Malhotra-Kumar, H. Eraksoy, S. Unal, B. Grabein, R. Masterton, C. Mendes, J.-A. Garcia-Rodriguez, G. Russo, R.N. Jones
Journal: Clinical Microbiology and Infection (2004)
S128 Reduction of lung metastasis by engineered Mesenchymal stem cells expressing secreted soluble TRAIL
Authors: ZQY Yuan, KK Kolluri
Journal: Thorax (2013)

<h3></h3> Bone marrow–derived mesenchymal stem cells (MSC) are promising tools for cancer therapy because they are able to home to and incorporate within tumour tissue. Tumour necrosis factor–related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic protein that induces selective apoptosis of tumour cells, while sparing normal cells. Therefore it is expected that MSCs engineered to produce TRAIL would home to and kill cancer cells in a lung metastatic cancer model. Two lentiviral vectors were constructed to express the full-length (FL) TRAIL and a truncated soluble form (ILZ-sT), respectively. A secretion peptide and an isoleucine zipper (ILZ) peptide were added to the N-terminal of the soluble form to force its secreted expression and to enhance its trimerization. Human MSCs were transduced with viruses and both constructs produced soluble TRAIL into cell media that can rapidly induced apoptosis of cancer cells. However the ILZ-sT fusion construct expresses significantly higher level of soluble TRAIL, and causes better <i>in vitro</i> lung cancer cell (A549) killing than the FL one. In coculture experiments both construct viruses transduced MSCs caused lung (A549), breast (MDAMB231), squamous (H357), and cervical (Hela) cancer cell apoptosis and death with similar efficiencies. A synergistic effect of cancer cell killing was observed for the combinational treatment of MSC-TRAIL cells with Saha, a histone deactylase inhibitor. When systemically delivered both MSC-FLT and MSC-ILZ-sT cells showed significant reduction of lung metastasis in a pulmonary metastasis murine model. Interestingly, ILZ-sT expressing cells demonstrated higher efficiency of metastasis reduction than FLT cells. These findings suggests that TRAIL expressing MSCs particularly ILZ-sT cells could be potentially developed as a therapy for lung metastasis diseases.
When Is Diabetes Distress Clinically Meaningful?
Authors: Lawrence Fisher, Danielle M. Hessler, William H. Polonsky, Joseph Mullan
Journal: Diabetes Care (2012)

To identify the pattern of relationships between the 17-item Diabetes Distress Scale (DDS17) and diabetes variables to establish scale cut points for high distress among patients with type 2 diabetes.Recruited were 506 study 1 and 392 study 2 adults with type 2 diabetes from community medical groups. Multiple regression equations associated the DDS17, a 17-item scale that yields a mean-item score, with HbA(1c), diabetes self-efficacy, diet, and physical activity. Associations also were undertaken for the two-item DDS (DDS2) screener. Analyses included control variables, linear, and quadratic (curvilinear) DDS terms.Significant quadratic effects occurred between the DDS17 and each diabetes variable, with increases in distress associated with poorer outcomes: study 1 HbA(1c) (P < 0.02), self-efficacy (P < 0.001), diet (P < 0.001), physical activity (P < 0.04); study 2 HbA(1c) (P < 0.03), self-efficacy (P < 0.004), diet (P < 0.04), physical activity (P = NS). Substantive curvilinear associations with all four variables in both studies began at unexpectedly low levels of DDS17: the slope increased linearly between scores 1 and 2, was more muted between 2 and 3, and reached a maximum between 3 and 4. This suggested three patient subgroups: little or no distress, <2.0; moderate distress, 2.0-2.9; high distress, ≥3.0. Parallel findings occurred for the DDS2.In two samples of type 2 diabetic patients we found a consistent pattern of curvilinear relationships between the DDS and HbA(1c), diabetes self-efficacy, diet, and physical activity. The shape of these relationships suggests cut points for three patient groups: little or no, moderate, and high distress.
Treatment of Brain Inflammatory Diseases by Delivering Exosome Encapsulated Anti-inflammatory Drugs From the Nasal Region to the Brain
Authors: Xiaoying Zhuang, Xiaoyu Xiang, William Grizzle, Dongmei Sun, Shuangqin Zhang, Robert C Axtell, Songwen Ju, Jiangyao Mu, Lifeng Zhang, Lawrence Steinman, Donald Miller, Huang-Ge Zhang
Journal: Molecular Therapy (2011)

In this study, exosomes used to encapsulate curcumin (Exo-cur) or a signal transducer and activator of transcription 3 (Stat3) inhibitor, i.e., JSI124 (Exo-JSI124) were delivered noninvasively to microglia cells via an intranasal route. The results generated from three inflammation-mediated disease models, i.e., a lipopolysaccharide (LPS)-induced brain inflammation model, experimental autoimmune encephalitis and a GL26 brain tumor model, showed that mice treated intranasally with Exo-cur or Exo-JSI124 are protected from LPS-induced brain inflammation, the progression of myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE), and had significantly delayed brain tumor growth in the GL26 tumor model. Intranasal administration of Exo-cur or Exo-JSI124 led to rapid delivery of exosome encapsulated drug to the brain that was selectively taken up by microglial cells, and subsequently induced apoptosis of microglial cells. Our results demonstrate that this strategy may provide a noninvasive and novel therapeutic approach for treating brain inflammatory-related diseases. In this study, exosomes used to encapsulate curcumin (Exo-cur) or a signal transducer and activator of transcription 3 (Stat3) inhibitor, i.e., JSI124 (Exo-JSI124) were delivered noninvasively to microglia cells via an intranasal route. The results generated from three inflammation-mediated disease models, i.e., a lipopolysaccharide (LPS)-induced brain inflammation model, experimental autoimmune encephalitis and a GL26 brain tumor model, showed that mice treated intranasally with Exo-cur or Exo-JSI124 are protected from LPS-induced brain inflammation, the progression of myelin oligodendrocyte glycoprotein (MOG) peptide induced experimental autoimmune encephalomyelitis (EAE), and had significantly delayed brain tumor growth in the GL26 tumor model. Intranasal administration of Exo-cur or Exo-JSI124 led to rapid delivery of exosome encapsulated drug to the brain that was selectively taken up by microglial cells, and subsequently induced apoptosis of microglial cells. Our results demonstrate that this strategy may provide a noninvasive and novel therapeutic approach for treating brain inflammatory-related diseases.
Overexpression of Extracellular Superoxide Dismutase Attenuates Heparanase Expression and Inhibits Breast Carcinoma Cell Growth and Invasion
Authors: Melissa L.T. Teoh, Matthew P. Fitzgerald, Larry W. Oberley, Frederick E. Domann
Journal: Cancer Research (2009)

Abstract Increased expression of heparanase stimulates the progression of various human cancers, including breast cancer. Therefore, a deeper understanding of the mechanisms involved in regulating heparanase is critical in developing effective treatments for heparanase-overexpressing cancers. In this study, we investigated the potential use of extracellular superoxide dismutase (EcSOD) to enhance the inhibitory effects of heparin/low molecular weight heparin (LMWH) in breast cancer cells. EcSOD binds to cell surfaces and the extracellular matrix through heparin-binding domain (HBD). Deleting this HBD rendered the protein a more potent inhibitor of breast cancer growth, survival, and invasion. Among the treatment combinations examined, EcSODΔHBD plus LMWH provided the best tumor suppressive effects in inhibiting breast cancer growth and invasion in vitro. We have further shown that overexpression of EcSOD decreased accumulation of vascular endothelial growth factor in the culture medium and increased the level of intact cell surface-associated heparan sulfate, thus implicating inhibition of heparanase expression as a potential mechanism. Overexpression of EcSOD inhibited steady-state heparanase mRNA levels by &amp;gt;50% as determined by quantitative reverse transcription-PCR. Moreover, heparanase promoter activation was suppressed by EcSOD as indicated by a luciferase reporter assay. These findings reveal a previously unrecognized molecular pathway showing that regulation of heparanase transcription can be mediated by oxidative stress. Our study implies that overexpression of EcSOD is a promising strategy to enhance the efficacy of heparin/LMWH by inhibiting heparanase as a novel treatment for breast cancer. [Cancer Res 2009;69(15):6355–63]
Dehydration
Authors: Andrew D. Weinberg
Journal: JAMA (1995)

<h3>Objective.</h3> —To review published literature regarding dehydration in older individuals and formulate a consensus on the evaluation and treatment of this unrecognized cause of hospitalizations, morbidity, and mortality. <h3>Data Sources and Study Selection.</h3> —The literature concerning dehydration in the elderly population from MEDLINE was reviewed from 1976 through 1995. Search terms included<i>dehydration, elderly, evaluation, hospitalization</i>, and<i>treatment</i>. Particular emphasis was placed on articles describing original research leading to the development of new information on the evaluation and treatment of dehydration and review articles relating to the epidemiology, detection, treatment and health outcomes of this syndrome common in the geriatric population, including frail, institutionalized individuals. <h3>Data Extraction.</h3> —Data contributing to a broad scientific understanding of dehydration were initially grouped according to topic areas of the physiology of normal aging, illness-associated clinical reports of dehydration in the elderly population, and diagnostic and therapeutic interventions. The authors developed a consensus based on the weight of evidence presented and the authors' experience in the field. <h3>Conclusions.</h3> —Early diagnosis is sometimes difficult because the classical physical signs of dehydration may be absent or misleading in an older patient. Many different etiologies place the elderly at particular risk. In patients identified as being at risk for possible dehydration, an interdisciplinary care plan with regard to prevention of clinically significant dehydration is critical if maximum benefit is to result. (<i>JAMA</i>. 1995;274:1552-1556)
THE PHYSIOLOGICAL TREATMENT OF PATHOLOGICAL SCOLIOSIS BY ROTATION
Authors: A. M. Forbes
Journal: BMJ (1913)

rose above 100°, lhowever, and in twelve to twenty-four hours it fell to normiial.Two cases were exceptional.In one, thirty hours after injection, the child had epistaxis, withi increased nasal discharge, and the temperature ran up to 1040.It continued above 103°for three days, and then, within twelve hours, fell to normal, and continued so.The otlher case (synovitis of knees) was brought in with a swinging temperature, whiclh ran up at niglht to 101.5°.After salvarsan was given thlis swinging temperature became normal in seven days.Recurrence of Synqptoms.-Inolnly one of our cases, a chlild of 3 montlhs, witli epiplhysitis, lhave we seen any re- currence of symptoms of svpllilis after treatment witl salvarsan.All tlle symptoms disappeared quickly after the injection, and tlle child afterwards lhad mercurial treat- ment (hiyd.c. cret.) for five m-onths.The motlher then ceased coming to tlle lhospital, but two montlhs later shie reappeared with the child, who was in good health but lhad developed a condyloma at the anus.This soon dis- appeared unider furtlher treatment with mlercury.CONCLUSIONS.
Treatment of advanced Hodgkin’s disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin’s Lymphoma Study Group HD6 trial
Authors: M. Sieber, H. Tesch, B. Pfistner, U. Rueffer, U. Paulus, R. Munker, R. Hermann, G. Doelken, P. Koch, J. Oertel, S. Roller, P. Worst, H. Bischof, A. Glunz, R. Greil, K. von Kalle, K.P. Schalk, D. Hasenclever, O. Brosteanu, E. Duehmke, A. Georgii, A. Engert, M. Loeffler, V. Diehl
Journal: Annals of Oncology (2004)