tbuckley/cabot-search huggingface dataset:
Abstract 2676: Measuring extracellular pH within in vivo tumors using acidoCEST MRI.
Authors: Liu Qi Chen, Christine Howison, Justin Jeffery, Ian Robey, Mark Pagel
Journal: Cancer Research (2013)

Abstract INTRODUCTION. Extracelluar pH (pHe) is a hallmark for tumor microenvironment. We have developed a non-invasive MRI method that can accurately measure pHe to assess tumor acidosis, termed “acidoCEST MRI”. This method measures a ratio of the Chemical Exchange Saturation Transfer (CEST) effects of Iopromide, a FDA approved contrast agent for CT. Iopromide has two amides that generate different CEST effects, and a ratio of these CEST effects is correlated with pH over a range of 6.0-7.2 pH units, with a precision of 0.06 pH units, and in a manner that is independent of the agent's concentration and the sample's T1 relaxation time. We have applied acidoCEST MRI to monitor the effects of bicarbonate treatment on tumors. METHOD. A CEST-FISP pulse sequence (2.8 μT, 5 sec, 90 Hz), with 54 saturation frequencies (+10 to -10 ppm) was used to acquire an acidoCEST image in 4.7 min on 7T MRI scanner. Each CEST spectrum was fitted to a sum of three Lorentzian line shapes (Matlab R2012B). A mouse model of MDA-MB-231 mammary carcinoma subcutaneous flank tumor was treated with 200 mM of bicarbonate ad libitum. acidoCEST MRI was performed 1 day before and 1 day after introducing bicarbonate treatment. A bolus of 200 μL of 976 mM iopromide was injected i.v., followed by an infusion of 150 μL/hour of iopromide. Six series of acidoCEST spectroscopic images were acquired for 28 min. RESULTS: We were able to measure an increased in pH in tumor before and after bicarbonate therapy. As shown in the table, only half of the mice studied showed a significant increase in pH after bicarbonate treatment. This is because the limit of quantification of acidoCEST using Iopromide as contrast agent was pH 7.20. Discussion: acidoCEST MRI using Iopromide as contrast agent can measure pH of the tumor with good precision and can be applied to monitor pH-modulating therapy such as bicarbonate treatment. Our method has strong clinical translation potential because it uses low saturation powers, incomplete saturation, and a clinically approved contrast agent. Summary of acidoCEST measurements on mammary carcinoma tumors before and after bicarbonate treatment Mouse before bicarbonate treatment after bicarbonate treatment #1 pH 6.50 ± 0.09 pH 7.15 ± 0.14 (p &amp;lt; 0.01) #2 pH 6.49 ± 0.09 pH 7.20 ± 0.00 (p &amp;lt; 0.01) #3 pH 6.53 ± 0.10 pH 7.14 ± 0.14 (p &amp;lt; 0.01) #4 pH 6.91 ± 0.11 pH 7.10 ± 0.13 (p &amp;lt; 0.02) #5 pH 7.13 ± 0.12 pH 7.16 ± 0.12 #6 pH 7.02 ± 0.13 pH 7.13 ± 0.10 #7 (necrotic tumor) pH 7.20 ± 0.00 pH 7.19 ± 0.06 #8 (necrotic tumor) pH 7.17 ± 0.09 pH 7.17 ± 0.10 Citation Format: Liu Qi Chen, Christine Howison, Justin Jeffery, Ian Robey, Mark Pagel. Measuring extracellular pH within in vivo tumors using acidoCEST MRI. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2676. doi:10.1158/1538-7445.AM2013-2676
The Novel Role of Tyrosine Kinase Inhibitor in the Reversal of Immune Suppression and Modulation of Tumor Microenvironment for Immune-Based Cancer Therapies
Authors: Junko Ozao-Choy, Ge Ma, Johnny Kao, George X. Wang, Marcia Meseck, Max Sung, Myron Schwartz, Celia M. Divino, Ping-Ying Pan, Shu-Hsia Chen
Journal: Cancer Research (2009)

In tumor-bearing hosts, myeloid-derived suppressor cells (MDSC) and T regulatory cells (Treg) play important roles in immune suppression, the reversal of which is vitally important for the success of immune therapy. We have shown that ckit ligand is required for MDSC accumulation and Treg development. We hypothesized that sunitinib malate, a receptor tyrosine kinase inhibitor, could reverse MDSC-mediated immune suppression and modulate the tumor microenvironment, thereby improving the efficacy of immune-based therapies. Treatment with sunitinib decreased the number of MDSC and Treg in advanced tumor-bearing animals. Furthermore, it not only reduced the suppressive function of MDSCs but also prevented tumor-specific T-cell anergy and Treg development. Interestingly, sunitinib treatment resulted in reduced expression of interleukin (IL)-10, transforming growth factor-beta, and Foxp3 but enhanced expression of Th1 cytokine IFN-gamma and increased CTL responses in isolated tumor-infiltrating leukocytes. A significantly higher percentage and infiltration of CD8 and CD4 cells was detected in tumors of sunitinib-treated mice when compared with control-treated mice. More importantly, the expression of negative costimulatory molecules CTLA4 and PD-1 in both CD4 and CD8 T cells, and PDL-1 expression on MDSC and plasmacytoid dendritic cells, was also significantly decreased by sunitinib treatment. Finally, sunitinib in combination with our immune therapy protocol (IL-12 and 4-1BB activation) significantly improves the long-term survival rate of large tumor-bearing mice. These data suggest that sunitinib can be used to reverse immune suppression and as a potentially useful adjunct for enhancing the efficacy of immune-based cancer therapy for advanced malignancies.
A human in vivo model for the determination of lead bioavailability using stable isotope dilution.
Authors: J H Graziano, C B Blum, N J Lolacono, V Slavkovich, W I Manton, S Pond, M R Moore
Journal: Environmental Health Perspectives (1996)

Beverages stored in lead-crystal glass accumulate extraordinary concentrations of lead. We obtained a lead-crystal decanter manufactured with lead from Australia, where the ratio of 206Pb/207Pb is distinctly different from that in the United States. We sought to determine the bioavailability of crystal-derived lead, using the technique of stable isotope dilution in blood. We conducted a single-dose, nonrandomized cross-over study in which participants were admitted to the Clinical Research Center twice, 1 week apart. During the first admission, subjects ingested sherry obtained from the original bottle. During the second admission, they ingested sherry that had been stored in the crystal decanter and that had achieved a lead concentration of 14.2 mu mol/l. After ingesting decanter-stored sherry, mean blood lead rose significantly (p = 0.0003) from 0.10 to 0.18 mu mol/l, while mean 206Pb/207Pb fell from 1.202 to 1.137 (p = 0.0001). On average, 70% of the ingested dose of lead was absorbed. We conclude that lead derived from crystal glass is highly bioavailable; repeated ingestions could cause elevated blood lead concentration. The technique of stable isotope dilution lends itself to the study of the bioavailability of lead in other matrices, including soil.
Protein kinase Cα: disease regulator and therapeutic target
Authors: Olga Konopatskaya, Alastair W. Poole
Journal: Trends in Pharmacological Sciences (2009)

Protein kinase Cα (PKCα) is a member of the AGC (which includes PKD, PKG and PKC) family of serine/threonine protein kinases that is widely expressed in mammalian tissues. It is closely related in structure, function and regulation to other members of the protein kinase C family, but has specific functions within the tissues in which it is expressed. There is substantial recent evidence, from gene knockout studies in particular, that PKCα activity regulates cardiac contractility, atherogenesis, cancer and arterial thrombosis. Selective targeting of PKCα therefore has potential therapeutic value in a wide variety of disease states, although will be technically complicated by the ubiquitous expression and multiple functions of the molecule. Protein kinase Cα (PKCα) is a member of the AGC (which includes PKD, PKG and PKC) family of serine/threonine protein kinases that is widely expressed in mammalian tissues. It is closely related in structure, function and regulation to other members of the protein kinase C family, but has specific functions within the tissues in which it is expressed. There is substantial recent evidence, from gene knockout studies in particular, that PKCα activity regulates cardiac contractility, atherogenesis, cancer and arterial thrombosis. Selective targeting of PKCα therefore has potential therapeutic value in a wide variety of disease states, although will be technically complicated by the ubiquitous expression and multiple functions of the molecule.
Abstract LB-55: Comparing effects of individual Ras isoforms on cell signaling and growth.
Authors: Cameron L. Pitt, Frank McCormick
Journal: Cancer Research (2013)

Abstract Though proteins in the Ras family signal primarily through identical effectors, each isoform displays unique preferential coupling to cancer types. Membrane localization following modification at the C-terminus is required for Ras activation and downstream signaling. This step provides an avenue for signaling diversity, as the C-terminus is the only site of significant sequence variability between Ras proteins. Differential post-transcriptional modifications at the C-terminus produce different patterns of membrane binding and trafficking between isoforms. Broken up into varied membrane domains, each isoform has unique combinatorial access to activators and repressors of signaling as well as downstream molecules in pathways critical to cancer initiation and tumor maintenance. Introducing individual Ras isoforms around endogenous levels to cells originally devoid of expression of all of the major Ras isoforms has allowed us to separate their effects on cell signaling and interrogate key differences. Expression of any of the four major Ras isoforms is sufficient to restore growth of "Rasless" cells. Our findings display that Ras isoforms are differentially activated by growth factor stimulation and act primarily through different pathways. Expression of N-Ras or K-Ras 4A alone promotes more rapid growth than H-Ras or K-Ras 4B expression alone, likely due to increased pro-apoptotic signaling from H-Ras and K-Ras 4B. H-Ras is uniquely activated by IGF-1 and insulin to signal through PI3K to pAKT. While the kinetics of MAPK activation in response to growth factors vary depending on the Ras isoform expressed, the amplitude of the response through pERK is greatest in N-Ras and K-Ras expressing cells. We are currently performing comparative expression analysis of the downstream components of these two major Ras effector pathways to begin to mechanistically explain the differences observed in signaling. We are also using mutants of the Ras isoforms at the sites that differentiate their processing to determine whether differences in localization due to protein modifications cause a shift in the PI3K/MAPK signaling balance and account for isoform-dependent differences in cells relying on Ras signaling for growth. Citation Format: Cameron L. Pitt, Frank McCormick. Comparing effects of individual Ras isoforms on cell signaling and growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-55. doi:10.1158/1538-7445.AM2013-LB-55
Surfactant Composition in Infants and Young Children with Cystic Fibrosis
Authors: JEREMY HULL, MICHAEL SOUTH, PETER PHELAN, KEITH GRIMWOOD
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

We tested the hypothesis that the composition of bronchial surfactant is normal in infants with cystic fibrosis (CF) in the absence of active lung disease but that it is altered by lower respiratory tract infection and inflammation. We examined the total phospholipid (PL), disaturated phospholipid (DSP), surfactant protein-A (SP-A), surfactant protein B (SP-B), and surface activity in bronchoalveolar lavage fluid from 27 subjects with CF whose mean age was 22.7 (SD 14.5) mo. Six infants with stridor served as non-CF controls. Twelve of the subjects with CF (CF-I group) had evidence of active pulmonary infection or inflammation which was absent in the remaining 15 subjects (CF-NI group). We found no differences in the surfactant composition or activity between controls and the CF-NI group. In contrast, the DSP/PL ratio was lower in the CF-I subjects than in both the CF-NI subjects (p = 0.05) and controls (p < 0.01) suggesting a disturbance of surfactant function. SP-A concentrations were higher in the CF-I group compared to the other two groups (p < 0.05). These results suggest that the bronchial surfactant of infants with CF is altered following lower airway infection and inflammation and is not a primary abnormality associated with this disorder.
TCT-45 Long Term Safety and Effectiveness of XIENCE V® Everolimus Eluting Coronary Stent System in Real-World Population: Three-Year Clinical Outcomes from the XIENCE V® USA Study
Authors: James Hermiller, Mitchell Krucoff, weiying zhao, Luis Gruberg, William Lombardi, David Rutledge, Jin Wang, Vivian Mao
Journal: Journal of the American College of Cardiology (2012)
Abstract C25: The 16p13.3 genomic gain in prostate cancer: A role for PDK1 in disease progression
Authors: Khalil Choucair, Fadi Brimo, Isabela W Cunha, Armen Aprikian, Martin Gleave, Jacques Lapointe, Karl-Philippe Guérard, Joshua Ejdelman, Simone Chevalier, Maisa Yoshimoto, Eleonora Scarlata, Ladan Fazli, Kanishka Sircar, Jeremy A. Squire
Journal: Cancer Research (2012)

Abstract Prostate cancer (PCa) is a leading cause of cancer death and distinguishing life threatening tumors from indolent ones is a major challenge. The identification and characterization of genomic alterations associated with advanced disease may lead to the development of new markers of progression and more efficient therapeutic approaches. Array-CGH data have shown that gain of chromosome 16p13.3 to be associated with lymph node (LN) metastases of PCa, but this region remained uncharacterized. Our goal was to establish the prognostic value of 16p13.3 gain, and identify the cancer relevant genes residing within this region. In this study, we performed Fluorescence In Situ Hybridization (FISH) to detect the copy number gain of chromosome 16p13.3 in 75 PCa samples including 10 lymph node (LN) metastases and their matched primary tumors, 9 transurethral resections of prostate (TURP) tissue samples of castration-resistant prostate cancer (CRPC), and 46 additional primary PCa specimens with clinicopathological parameters. We detected the gain in 5/10 LN metastases and 3/5 matched primary tumors, 3/9 CRPC samples, and 9/46 (20 %) primary tumors. In the latter set of samples, the 16p13.3 alteration was associated with high Gleason score (P=0.002) and elevated pre operative prostate specific antigen (PSA) levels (P=0.047). The levels of 16p13.3 gain were higher in LN metastasis and CRPC specimens compared to primary PCa (P&amp;gt;0.05). Chromosome mapping revealed a focal gain that spans PDPK1 encoding the 3-Phosphoinositide-dependent protein kinase-1 (PDK1). RNA interference-mediated knock down of PDK1 in three different PCa cell lines reduced cell motility without affecting growth and re-expressing PDK1 rescued motility (P&amp;gt;0.05). Our results support that the 16p13.3 gain is relevant to PCa progression and may represent an early marker of metastasis, since retrieved in primary PCa which is sampled by biopsies at time of diagnosis. PDK1 is implicated in PCa cell motility, a critical step for progression to metastasis. These findings provide further rationale for considering PDK1 as a target for cancer therapies and the development of new specific inhibitors of PDK1. Citation Format: Khalil Choucair, Fadi Brimo, Isabela W Cunha, Armen Aprikian, Martin Gleave, Jacques Lapointe, Karl-Philippe Guérard, Joshua Ejdelman, Simone Chevalier, Maisa Yoshimoto, Eleonora Scarlata, Ladan Fazli, Kanishka Sircar, Jeremy A. Squire. The 16p13.3 genomic gain in prostate cancer: A role for PDK1 in disease progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr C25.
STUDIES ON INFLAMMATION
Authors: Valy Menkin
Journal: The Journal of Experimental Medicine (1933)

Trypan blue injected into an area of cutaneous inflammation induced by Staphylococcus aureus failed to drain readily to the tributary lymphatics when the dye was injected as early as 1 hour after the inoculation of the microorganisms. Trypan blue introduced into an area of cutaneous inflammation induced by Pneumococcus Type I was retained in situ when the dye was injected about 6 or more hours after the inoculation of the bacteria. When an area of cutaneous inflammation was induced by the inoculation of a culture of Streptococcus hemolyticus, trypan blue injected into it drained readily to the tributary lymphatics for the first 30 hours following the onset of the inflammatory reaction. When the inflammation had lasted for 45 hours or longer, the dye was fixed in situ and failed in most instances to reach readily the tributary lymphatics. The rapidity of fixation of the dye in the instances given would appear to depend on mechanical obstruction in the form of both a fibrinous network and thrombosed lymphatics or thrombosed lymphatics alone at the site of inflammation. Inasmuch as staphylococci, pneumococci, and streptococci spread from the site of cutaneous inoculation primarily through lymphatic channels, the difference in the rapidity with which mechanical obstruction is set up in the areas inflamed by them will help to explain the differing invasive abilities of these pyogenic organisms.
Recombinant Human Erythropoietin in Combination with Chemotherapy Increases Breast Cancer Metastasis in Preclinical Mouse Models
Authors: Benjamin D. Hedley, Jenny E. Chu, D. George Ormond, Michel S. Beausoleil, Alexandra Boasie, Alison L. Allan, Anargyros Xenocostas
Journal: Clinical Cancer Research (2011)

Erythropoiesis-stimulating agents (ESA) are used clinically for treating cancer-related anemia. Recent clinical trials have reported increased adverse events and reduced survival in ESA-treated breast cancer patients receiving chemotherapy, potentially related to erythropoietin (EPO)-induced cancer progression. However, minimal preclinical data are available about the impact of EPO on metastatic cell behavior and/or the metastatic process, and this was the goal of our study.Breast cancer cell lines were treated with recombinant human EPO (rHuEPO) and screened for expression of EPO receptors (EPOR). MDA-MB-231 and MDA-MB-435 cell lines were used for functional assays in vitro (two-dimensional/three-dimensional growth and survival) and in vivo (tumorigenicity and metastasis), in the presence or absence of EPO and/or cytotoxic agents.A large variation in EPOR expression across cell lines was observed. In vitro, rHuEPO had a protective effect on radiation-treated MDA-MB-435 cells (P < 0.05); however, rHuEPO treatment alone or combined with chemotherapy or hypoxia did not influence cell survival. In vivo, rHuEPO increased lung metastases in immunocompromised mice injected with MDA-MB-231 or MDA-MB-435 cells and treated with chemotherapy relative to mice treated with chemotherapy alone (P < 0.05).The lack of an in vitro effect of rHuEPO highlights the importance of in vivo studies to delineate the effects of EPO on the metastatic process. These studies may begin to uncover the underlying functional explanation for the observed EPO-related adverse events and decreased survival in ESA-treated metastatic breast cancer patients undergoing chemotherapy.
Health status in rheumatoid arthritis over 7 years
Authors: A Boonen
Journal: Annals of the Rheumatic Diseases (2005)

The challenge is to separate fully the effect of the year of inclusion in the register and the effect of duration of the disease

A pivotal question when evaluating the long term outcome of patients with rheumatoid arthritis (RA) is how the disease itself evolves over time and to what extent new treatments contribute to such changes. Insight into the evolution of the manifestations of RA can help to define agendas for research and healthcare delivery world wide. In this issue of the Annals Heiberg et al describe “7 year changes in health status and priorities for improvement of health in patients with rheumatoid arthritis” and conclude that “although pain remained the area of highest priority for improvement among patients, the health status improved from 1994 to 2001, probably owing to access to better and more aggressive treatments”.1 In this editorial, we will briefly elaborate on the strengths of longitudinal observational studies (LOS), in general, and on the relative importance of research on patient priorities in such studies, in particular. Next, we will discuss the subject of time and change over time in longitudinal studies in the light of the conclusion drawn from the present study.

### Longitudinal observational studies and patient perspective as an outcome

The conclusion of the authors is based on an analysis of data from the Oslo RA Register (ORAR), a continuing LOS that was started in 1994 as a prevalent population based register, and annually updated with new cases since then.2 Longitudinal studies are particularly helpful in answering questions on causation, prognosis, and long term outcomes in the “real world” of healthcare delivery. In comparison with randomised clinical trials (RCTs), LOS are characterised by a higher level of external validity (because patients are not selected for high disease activity or unfavourable prognosis, etc), an emphasis on long term evaluation, and a view on …