tbuckley/cabot-search huggingface dataset:
Chronic myelogenous leukemia shapes host immunity by selective deletion of high-avidity leukemia-specific T cells
Authors: Jeffrey J. Molldrem, Peter P. Lee, Shreya Kant, Eric Wieder, Weidong Jiang, Sijie Lu, Changqing Wang, Mark M. Davis
Journal: Journal of Clinical Investigation (2003)

We have shown that cytotoxic T lymphocytes specific for PR1, an HLA-A2–restricted nonopeptide derived from proteinase 3, kill leukemia cells and may contribute to the elimination of chronic myelogenous leukemia (CML) after treatment with IFN or allogeneic bone marrow transplant. Some patients with persistent disease also have circulating PR1-specific T cells, however, suggesting the likelihood of immune tolerance. Here we show that both high- and low-avidity PR1-specific T cells from the peripheral blood of healthy donors can be identified and selectively expanded in vitro. Although high-avidity PR1-specific T cells killed CML more effectively than low-avidity T cells, only high-avidity T cells underwent apoptosis when stimulated with high PR1 peptide concentration or when exposed to leukemia that overexpressed proteinase 3. No high-avidity PR1-specific T cells could be identified or expanded from newly diagnosed leukemia patients, whereas low-avidity T cells were readily expanded. Circulating high-avidity PR1-specific T cells were identified in IFN-sensitive patients in cytogenetic remission, however. These results provide evidence that CML shapes the host immune response and that leukemia outgrowth may result in part from leukemia-induced selective deletion of high-avidity PR1-specific T cells.
Is there a glycemic threshold for impaired autonomic control?
Authors: L L Watkins, R S Surwit, P Grossman, A Sherwood
Journal: Diabetes Care (2000)

OBJECTIVE: Although hyperglycemia has been recognized as a predictor of cardiovascular autonomic neuropathy in diabetic patients, the glucose threshold at which autonomic control begins to become impaired has not been evaluated. This study examined whether fasting plasma glucose (FPG) or fasting plasma insulin (FPI) is associated with reductions in baroreflex sensitivity (BRS) in healthy volunteers. RESEARCH DESIGN AND METHODS: FPG and FPI were measured after an overnight fast in 162 healthy volunteers (91 men, 71 women) who were 25-44 years of age. BRS was measured with power spectral analysis. RESULTS: Univariate analyses showed that FPG was negatively correlated with BRS (r = -0.25, P &amp;lt; or = 0.001) with significant reductions observed in volunteers with FPG in the upper 2 quintiles (i.e., 93-124 mg/dl). However, after adjustment for other predictors of BRS (e.g., age, blood pressure, and BMI), the relationship between FPG and BRS was no longer significant. In contrast, FPI was negatively correlated with BRS in univariate analyses (r = -0.32, P &amp;lt; 0.0001) as well as after covariate adjustment, with close to a 50% reduction in BRS observed in the volunteers with insulin values in the highest quintile (i.e., 16-36 microU/ml). CONCLUSIONS: These findings suggest that high normal levels of FPG are associated with reduced autonomic control secondary to the effects of aging, obesity, and elevated blood pressure on FPG levels and that elevations in FPI are associated with substantial reductions in autonomic cardiac control independent of other covariates.
Free Somatostatin Receptor Fraction Predicts the Antiproliferative Effect of Octreotide in a Neuroendocrine Tumor Model: Implications for Dose Optimization
Authors: Pedram Heidari, Eric Wehrenberg-Klee, Peiman Habibollahi, Daniel Yokell, Matthew Kulke, Umar Mahmood
Journal: Cancer Research (2013)

Somatostatin receptors (SSTR) are highly expressed in well-differentiated neuroendocrine tumors (NET). Octreotide, an SSTR agonist, has been used to suppress the production of vasoactive hormones and relieve symptoms of hormone hypersecretion with functional NETs. In a clinical trial, an empiric dose of octreotide treatment prolonged time to tumor progression in patients with small bowel neuroendocrine (carcinoid) tumors, irrespective of symptom status. However, there has yet to be a dose optimization study across the patient population, and methods are currently lacking to optimize dosing of octreotide therapy on an individual basis. Multiple factors such as total tumor burden, receptor expression levels, and nontarget organ metabolism/excretion may contribute to a variation in SSTR octreotide occupancy with a given dose among different patients. In this study, we report the development of an imaging method to measure surface SSTR expression and occupancy level using the PET radiotracer (68)Ga-DOTATOC. In an animal model, SSTR occupancy by octreotide was assessed quantitatively with (68)Ga-DOTATOC PET, with the finding that increased occupancy resulted in decreased tumor proliferation rate. The results suggested that quantitative SSTR imaging during octreotide therapy has the potential to determine the fractional receptor occupancy in NETs, thereby allowing octreotide dosing to be optimized readily in individual patients. Clinical trials validating this approach are warranted.
Hypoxia Is Important in the Biology and Aggression of Human Glial Brain Tumors
Authors: Sydney M. Evans, Kevin D. Judy, Isolde Dunphy, W. Timothy Jenkins, Wei-Ting Hwang, Peter T. Nelson, Robert A. Lustig, Kevin Jenkins, Deirdre P. Magarelli, Stephen M. Hahn, Ruth A. Collins, M. Sean Grady, Cameron J. Koch
Journal: Clinical Cancer Research (2004)

Abstract We investigated whether increasing levels of tissue hypoxia, measured by the binding of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] or by Eppendorf needle electrodes, were associated with tumor aggressiveness in patients with previously untreated glial brain tumors. We hypothesized that more extensive and severe hypoxia would be present in tumor cells from patients bearing more clinically aggressive tumors. Hypoxia was measured with the 2-nitroimidazole imaging agent EF5 in 18 patients with supratentorial glial neoplasms. In 12 patients, needle electrode measurements were made intraoperatively. Time to recurrence was used as an indicator of tumor aggression and was analyzed as a function of EF5 binding, electrode values and recursive partitioning analysis (RPA) classification. On the basis of EF5 binding, WHO grade 2 tumors were characterized by modest cellular hypoxia (pO2s ≈ 10%) and grade 3 tumors by modest-to-moderate hypoxia (pO2s ≈ 10%- 2.5%). Severe hypoxia (≈0.1% oxygen) was present in 5 of 12 grade 4 tumors. A correlation between more rapid tumor recurrence and hypoxia was demonstrated with EF5 binding, but this relationship was not predicted by Eppendorf measurements.
Harmonic Analysis of Aortic Pressure Pulses in the Dog
Authors: ROBERT L. FARROW, RALPH W. STACY
Journal: Circulation Research (1961)

Aortic pulse waves were recorded in dogs at the junctions of the left renal artery and the inferior mescntcric artery with the aorta, under normal conditions, after administration of norepincphriue and acetylcholine, and after manual blocking of the femoral arteries. These pulses (343) were subjected to Fourier analysis, and apparent phase velocities and foot-of-the-wave velocities were calculated. The results strongly indicate the presence of reflected waves, and it is shown that foot-of-the- wave velocities provide erroneous information. The arterial system is such that in the arteries per se, the reflected wave is a discrete and definable quantity; its origin can be shown to be an apparent site of reflection located in the peripheral one-third of the thighs of the dog.
The effect of exercise and diet on gut microbial diversity
Authors: W Marlicz, I Loniewski
Journal: Gut (2014)

The cancer story is changing, by 2020, almost one in two people will get cancer and 47% of those who died that year will have had cancer. We are reminded that choice at the end of life is so important and Macmillan wants everyone to have more choice. This session looks at the Macmillan Specialist care at Home partnership approach to providing palliative care to people in the community. It's based on the successful model developed in Midhurst where people experienced less frequent A and E attendances, decreased hospital stays and a majority of people died in their preferred place. Macmillan have since identified and supported six innovation centres that have adopted this model. Each centre has adopted the model of person-centred care, which emphasises principles such as having a consultant led multidisciplinary team – doctors, nurses, clinical nurse specialist, occupational therapist, physiotherapists and counsellors; flexible teamwork between specialists, generalists and trained volunteers in the community. This has enabled timely referral, home-based clinical interventions and close, flexible collaboration between primary care and other community-based services. Each centre is working in partnership with many different partners such as commissioners of end of life care, community/hospital providers and hospices. The philosophy that makes the Macmillan Specialist Care at Home approach so successful is to ensure that the person and their families feel well supported and they receive personalised, coordinated care and this session will showcase some of the findings of this project.
Hyperhomocysteinaemia predicts the decline in pulmonary function in healthy male smokers
Authors: Keiko Nunomiya, Yoko Shibata, Shuichi Abe, Sumito Inoue, Akira Igarashi, Keiko Yamauchi, Yasuko Aida, Hiroyuki Kishi, Masamichi Sato, Tetsu Watanabe, Tsuneo Konta, Yoshiyuki Ueno, Takeo Kato, Hidetoshi Yamashita, Takamasa Kayama, Isao Kubota
Journal: European Respiratory Journal (2012)

Hyperhomocysteinaemia is associated with chronic obstructive pulmonary disease. However, the relationship between plasma homocysteine levels and spirometric measures has not been investigated in a general population. We aimed to determine whether homocysteine levels are predictive for a rapid decline in lung function among healthy current smokers. Blood sampling and spirometry were performed on subjects participating in a community-based annual health check in Takahata, Japan, from 2004 to 2006 (n=3257). Spirometry was re-evaluated in 147 male current smokers in 2009. On initial assessment, forced vital capacity (FVC) % predicted and forced expiratory volume in 1 s (FEV1) % predicted correlated inversely with homocysteine levels and were predictive for homocysteine levels, independent of various clinical factors. Homocysteine levels were higher in subjects with restrictive, obstructive or mixed ventilatory disorders. In addition, homocysteine levels were higher in subjects with mixed ventilatory disorders, compared with restrictive or obstructive disorders. On follow-up, subjects showing a decline in FEV1 had higher homocysteine levels than those who did not. Logistic regression analysis indicated that homocysteine levels were predictive for a decline in FEV1. FVC % pred and FEV1 % pred were significantly associated with homocysteine levels, and hyperhomocysteinaemia predicted the annual rate of decline in FEV1 among male smokers.
Coexpression of Erythropoietin and Erythropoietin Receptor in Von Hippel-Lindau Disease–Associated Renal Cysts and Renal Cell Carcinoma
Authors: Youn-Soo Lee, Alexander O. Vortmeyer, Irina A. Lubensky, Timothy W.A. Vogel, Barbara Ikejiri, Sophie Ferlicot, Gérard Benoît, Sophie Giraud, Edward H. Oldfield, W. Marston Linehan, Bin T. Teh, Stéphane Richard, Zhengping Zhuang
Journal: Clinical Cancer Research (2005)

Abstract Von Hippel-Lindau (VHL) disease is characterized by multiple tumors in specific target organs. The tumors at different sites share distinct morphologic and genetic characteristics but their cell of origin is unknown. We show that VHL disease–associated renal clear cell carcinomas (RCC) consistently coexpress erythropoietin (Epo) and Epo receptor (EpoR). In addition, coexpression of Epo and EpoR is detected in many renal cysts, providing further evidence that renal cysts are potential precursors for RCC. In conjunction with VHL gene deficiency, coexpression of Epo and EpoR in renal cysts and tumors may reflect a developmental arrest in immature mesenchymal cells. Such arrest may lead to autocrine stimulation, cell proliferation, and renal tumor development, similar to tumorigenesis of VHL disease–associated hemangioblastomas.
The in vitro inhibition of insulin secretion by diphenylhydantoin
Authors: J. Stephen Kizer, Mario Vargas-Cordon, Klaus Brendel, Rubin Bressler
Journal: Journal of Clinical Investigation (1970)

Glucose intolerance has been observed following diphenylhydantoin (DPH) intoxication. Because of this association between DPH and hyperglycemia, the effect of DPH on insulin release in vitro using preparations of isolated islets of Langerhans and pancreatic pieces was examined. In concentrations identical with those considered necessary for adequate anticonvulsant therapy in man, DPH markedly decreases the insulin secretory response of pancreatic pieces to methacholine, 1 mug/ml, tolbutamide, 250 mug/ml, and glucose, 200 mg/100 ml, without any demonstrable alteration in the oxidative conversion of glucose-1-(14)C or glucose-6-(14)C to (14)CO(2) by isolated islets. This DPH-induced inhibition of insulin secretion is not reversed by higher concentrations of glucose (600 mg/100 ml) or by increasing concentrations of extracellular calcium ion (4-6 mmoles/liter). 0.1 mM potassium and 10(-4) M ouabain, however, effectively restore the DPH-induced block of insulin secretion in pancreatic pieces. 60 mM potassium ion, on the other hand, not only restores the insulin secretory response to glucose (200 mg/100 ml) but results in an added stimulation of insulin secretion in the presence of DPH. In the presence of DPH, (22)Na accumulation by isolated islets is decreased by 26-40% as compared with controls. Such evidence is considered to indirectly support the postulate that the electrophysiological properties of DPH on the pancreas are due to a stimulation of the membrane sodium-potassium-magnesium ATPase.
Protein Kinase Cζ Mediates Epidermal Growth Factor–Induced Growth of Head and Neck Tumor Cells by Regulating Mitogen-Activated Protein Kinase
Authors: Ezra Eddy Wyssam Cohen, Mark W. Lingen, Bangmin Zhu, Hongyan Zhu, Michael Wayne Straza, Carolyn Pierce, Leslie E. Martin, Marsha Rich Rosner
Journal: Cancer Research (2006)

Protein kinase C (PKC) zeta has been implicated as a mediator of epidermal growth factor (EGF) receptor (EGFR) signaling in certain cell types. Because EGFR is ubiquitously expressed in squamous cell carcinomas of the head and neck (SCCHN) and plays a key role in tumor progression, we determined whether PKCzeta is required for tumor cell proliferation and viability. Examination of total and phosphorylated PKCzeta expression in normal oral mucosa, dysplasia, and carcinoma as well as SCCHN tumor cell lines revealed a significant increase in activated PKCzeta expression from normal to malignant tissue. PKCzeta activity is required for EGF-induced extracellular signal-regulated kinase (ERK) activation in both normal human adult epidermal keratinocytes and five of seven SCCHN cell lines. SCCHN cells express constitutively activated EGFR family receptors, and inhibition of either EGFR or mitogen-activated protein kinase (MAPK) activity suppressed DNA synthesis. Consistent with this observation, inhibition of PKCzeta using either kinase-dead PKCzeta mutant or peptide inhibitor suppressed autocrine and EGF-induced DNA synthesis. Finally, PKCzeta inhibition enhanced the effects of both MAPK/ERK kinase (U0126) and broad spectrum PKC inhibitor (chelerythrine chloride) and decreased cell proliferation in SCCHN cell lines. The results indicate that (a) PKCzeta is associated with SCCHN progression, (b) PKCzeta mediates EGF-stimulated MAPK activation in keratinocytes and SCCHN cell lines, (c) PKCzeta mediates EGFR and MAPK-dependent proliferation in SCCHN cell lines; and (d) PKCzeta inhibitors function additively with other inhibitors that target similar or complementary signaling pathways.
Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study.
Authors: H B Hubert, M Feinleib, P M McNamara, W P Castelli
Journal: Circulation (1983)

The relationship between the degree of obesity and the incidence of cardiovascular disease (CVD) was reexamined in the 5209 men and women of the original Framingham cohort. Recent observations of disease occurrence over 26 years indicate that obesity, measured by Metropolitan Relative Weight, was a significant independent predictor of CVD, particularly among women. Multiple logistic regression analyses showed that Metropolitan Relative Weight, or percentage of desirable weight, on initial examination predicted 26-year incidence of coronary disease (both angina and coronary disease other than angina), coronary death and congestive heart failure in men independent of age, cholesterol, systolic blood pressure, cigarettes, left ventricular hypertrophy and glucose intolerance. Relative weight in women was also positively and independently associated with coronary disease, stroke, congestive failure, and coronary and CVD death. These data further show that weight gain after the young adult years conveyed an increased risk of CVD in both sexes that could not be attributed either to the initial weight or the levels of the risk factors that may have resulted from weight gain. Intervention in obesity, in addition to the well established risk factors, appears to be an advisable goal in the primary prevention of CVD.
Human hepatoma cells synthesize and secrete lysozyme: Modulation by cytokines
Authors: Norbert Köbsel, Giuliano Ramadori
Journal: Hepatology (1994)

Plasma lysozyme levels are elevated in several different pathological conditions. In our study we show that well differentiated human hepatoma cells Hep3B and HepG2 are active synthesis sites of lysozyme and that this synthesis can be modulated by acute phase mediators. The production and modulation of lysozyme synthesis was studied by means of Northern-blot analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and a specific bioassay after treatment of the cells with interleukin-1β, interleukin-6 and tumor necrosis factor-α. Hep3B and HepG2 cells constitutively synthesize high amounts of lysozyme. Lysozyme synthesis and secretion were found to be augmented by interleukin-1β and tumor necrosis factor-α in both cell lines. Interleukin-6 caused an increase in lysozyme production in Hep3B but a decrease in the HepG2 cells. As expected, the synthesis of albumin was decreased in both cell lines. Furthermore we demonstrated that HepG2 and Hep3B cells produce a biologically active form of the enzyme as measured by a specific bioassay. The results demonstrate that lysozyme is constitutively synthesized by Hep3B and HepG2 hepatoma cell lines and that lysozyme synthesis is modulated by acute-phase mediators. Well differentiated human hepatoma cells may respond differently to different cytokines. (HEPATOLOGY 1994;19:1182–1188.)
Unique Chemotactic Response Profile and Specific Expression of Chemokine Receptors Ccr4 and Ccr8 by Cd4+Cd25+ Regulatory T Cells
Authors: Andrea Iellem, Margherita Mariani, Rosmarie Lang, Helios Recalde, Paola Panina-Bordignon, Francesco Sinigaglia, Daniele D'Ambrosio
Journal: The Journal of Experimental Medicine (2001)

Chemokines dictate regional trafficking of functionally distinct T cell subsets. In rodents and humans, a unique subset of CD4+CD25+ cytotoxic T lymphocyte antigen (CTLA)-4+ regulatory T cells (Treg) has been proposed to control peripheral tolerance. However, the molecular basis of immune suppression and the trafficking properties of Treg cells are still unknown. Here, we determined the chemotactic response profile and chemokine receptor expression of human blood-borne CD4+CD25+ Treg cells. These Treg cells were found to vigorously respond to several inflammatory and lymphoid chemokines. Treg cells specifically express the chemokine receptors CCR4 and CCR8 and represent a major subset of circulating CD4+ T cells responding to the chemokines macrophage-derived chemokine (MDC)/CCL22, thymus and activation-regulated chemokine (TARC)/CCL17, I-309/CCL1, and to the virokine vMIP-I (ligands of CCR4 and CCR8). Blood-borne CD4+ T cells that migrate in response to CCL1 and CCL22 exhibit a reduced alloproliferative response, dependent on the increased frequency of Treg cells in the migrated population. Importantly, mature dendritic cells preferentially attract Treg cells among circulating CD4+ T cells, by secretion of CCR4 ligands CCL17 and CCL22. Overall, these results suggest that CCR4 and/or CCR8 may guide Treg cells to sites of antigen presentation in secondary lymphoid tissues and inflamed areas to attenuate T cell activation.
Enzyme/Prodrug-Based Tumor Vaccination: All Politics (and Immunity) Are Local
Authors: J. C. Morris
Journal: JNCI Journal of the National Cancer Institute (1999)

A major focus of gene therapy for cancer has been the effort to introduce into cancer cells a number of foreign genes that encode enzymes that will selectively convert nontoxic prodrugs into toxic compounds, producing high local concentrations that result in tumor cell killing—so-called “suicide” gene therapy. A number of enzyme/prodrug systems have been described [reviewed in (1)], including herpes simplex virus-thymidine kinase (HSV-tk)/ganciclovir (GCV) and Escherichia coli cytosine deaminase (CD)/5-fluorocytosine. A surprising early observation in many of these systems was that not every cell in a tumor need express the transgene to achieve meaningful cell killing and tumor regression (2,3). This phenomenon, the bystander effect, is defined as the ability of the genetically modified cells, in the presence of the prodrug, to cause cytotoxic effects in cells that lack the suicide gene. The result is that the fraction of cells killed is in excess of the fraction in the tumor that actually expresses the suicide gene (4). The bystander effect is a powerful enhancement of many suicide gene/prodrug systems that compensates for the inability of current vector systems to transduce all but a small fraction cells in a given tumor (5). The degree and mechanism of the bystander effect differ with various cell lines and the enzyme/prodrug system studied. At the cellular level, several explanations have been advanced for the bystander effect; however, current evidence supports direct transfer of activated prodrug from the transgene-expressing cells to untransduced wild-type cells (6–8). In the HSV-tk/GCV system, in which the activated prodrug is highly ionized and is unable to diffuse across cell membranes, the bystander effect appears to be mediated by transfer of phoshorylated GCV through cellular gap junctions (6,8,9). Nonadherent cells and those with few gap junctions do not exhibit a significant HSVtk/GCV bystander effect. 5-Fluorouracil (5-FU), the activated prodrug of the CD/5-fluorocytosine system, is a small nonpolar molecule that passively diffuses across the cell membrane down its concentration gradient, from CD+ cells to untransduced cells (7,10). The clinical importance of the bystander effect is illus-
Novel Pharmacogenetic Germline Candidates of Bevacizumab-Related Survival in the Icon7 Trial of Advanced Stage Ovarian Cancer
Authors: H. Mackay, O. Espin-Garcia, K. Owzar, S. Marsh, T. Perrin, C. Adusei, L. Farrelly, A. Embleton, A.M. Swart, M.K. Parmar, R. Kaplan, M. Kubo, M.J. Ratain, K. Matsuda, W. Xu, A.M. Oza, G. Liu
Journal: Annals of Oncology (2014)