tbuckley/cabot-search huggingface dataset:
Abstract 9292: Can Endothelial Progenitor Cell Dysfunction in Patients with Uncontrolled Diabetes be Normalized by Tight Glycemic Control?
Authors: Eli Lev, Joel Zinger, Dorit Leshem-Lev, Rigler Merav, Oshrat Dadush, Alexander Battler, Ran Kornowski
Journal: Circulation (2011)

Background: Recent evidence has shown that endothelial progenitor cells (EPCs) have an important role in repair process following vascular injury, and that in patients (pts) with diabetes EPCs number and function are reduced. Small studies suggest that tight metabolic control may improve the properties of EPCs in pts with uncontrolled diabetes. However, it is unclear whether following such intensive control EPC properties approach the levels of subjects without diabetes. We, therefore, aimed to examine whether after intensive glycemic control EPCs number and function are similar to the EPC profile in non-diabetics. Methods: Twenty five pts with treated diabetes who underwent intensive glycemic control for a period of 3-4 months (initial HgA1C &gt; 8.5%; HgA1c goal &lt; 7%) were compared to 25 matched non-diabetic subjects. The proportion of peripheral mononuclear cells (PMNCs) expressing VEGFR-2, CD133 and CD34 were evaluated by flow cytometry. EPCs colony forming units (CFUs) were grown from PMNCs, characterized and counted following 7 days of culture. Functional properties of the cultured cells were evaluated by the MTT viability assay, and migration - modified Boyden assay. Results: The two groups (n=25 each) were well-matched: mean age 59.5-61.5 years, 20% women and BMI of 29-31. All pts were treated with aspirin and statins. At baseline pts with diabetes had significantly lower levels of circulating EPCs and reduced functional properties compared with the non-diabetic subjects. After the tight control period HgA1C decreased from 9.5% to 8%, and circulating EPCs increased to a level similar to the non-diabetic group (VEGFR-2 + CD34 + : 1.12±0.15% vs. 1.14±0.14%; VEGFR-2 + CD133 + : 0.66±0.11% vs. 0.72±0.11%, respectively). However, the number of EPC CFUs in the diabetes group after the control period remained lower compared to the non-diabetes group (10.96±1.71 vs. 15.4±1.9 colonies per well, respectively, P=0.001). Furthermore, the MTT viability test and migration were also reduced in the diabetic compared with the non-diabetic group. Conclusions: Following a period of tight glycemic control in pts with diabetes numbers of circulating EPCs increase to a level similar to that of subjects without diabetes, but their functional properties remain attenuated.
The use of anti-GITR antibody treatment in a murine model of glioblastoma multiforme
Authors: Jason Miska, Alan L Chang, Aida Rashidi, Mahua Dey, Yu Han, Lingjiao Zhang, Irina V Balyasnikova, Atique U Ahmed, Maciej S Lesniak
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Glioblastoma multiforme (GBM), is the most common adult brain tumor and despite many new therapies, remains largely incurable. Regulatory T cells (Treg) are highly immunosuppressive cells that accumulate within glioma microenvironment, and reduction of their function or
Sorafenib for the treatment of patients with advanced hepatocellular carcinoma and alcoholic cirrhosis.
Authors: P. Giovanis, V. Vincenzi, C. Manuppelli, R. Berletti, M. Marcante, F. Ricagna, F. Pinto, M. Giusto
Journal: Journal of Clinical Oncology (2011)

352 Background: Hepatocellular carcinoma (HCC) from alcoholic cirrhosis, associated or not with chronic hepatitis C virus (HCV) infection, is a particularly severe liver disease. Scanty and inconsistent data concerning the efficacy of sorafenib in patients (pts) with this disease are available. Methods: Since February 2009 we screened 26 Child-Pugh liver function class A pts bearing the above characteristics. Sixteen of them (61.5%), 15 males and 1 female with median age of 69 years (range 54-79), received 400 mg sorafenib b.i.d. Predominant cause of HCC was alcohol consumption in 13 pts (81.2%), associated with chronic HCV infection in 2 pts (12.5%), and hemosiderosis in 1 pt (6.2%). All pts suffered from multiple comorbidities, and 3 had been previously treated for Burkitt lymphoma, bladder and breast cancer. One pt with prostate cancer was on treatment with androgen blockade. Median number of concomitant medications was 4 (range 2-9). Four pts never received locoregional treatment, and none had received previous antineoplastic therapy. Results: Twelve pts (73%) discontinued sorafenib after a median time of 2 months (range 2-6). The reasons for treatment discontinuation were disease progression (4 pts), liver function deterioration (5 pts), and mild gastrointestinal adverse events (2 pts): 1 pt refused sorafenib treatment after 15 days. 2/4 patients still on treatment with sorafenib at 7, 8, 11, and 18 months showed partial response (RECIST criteria). Seven pts (40%) died because of disease progression at a median time of 5.5 months (range 2-9) and at a median overall survival time of 36 months from diagnosis (range 2-84). Conclusions: Treatment with sorafenib in pts affected by HCC and alcoholic cirrhosis seems effective and well tolerated with high-level compliance. The most common cause of discontinuation was progression of disease and liver function deterioration. No significant financial relationships to disclose.
Abstract 9536: Computed Tomography Derived Cardiovascular Risk Markers, Incident Cardiovascular Events and All- Cause Mortality In Adults Free of Clinical Cardiovascular Disease. The Multi Ethnic Study of Atherosclerosis
Authors: Joseph Yeboah, Jeffery J Carr, James G Terry, Jingzhong Ding, Irfan Zeb, Songtao Liu, Khurram Nasir, Wendy Post, Roger S Blumenthal, Mathew Budoff
Journal: Circulation (2012)

Introduction: Cardiac CT derived CV risk markers such as coronary artery calcium (CAC), thoracic wall calcium (TAC), aortic valve calcium (AVC), mitral valve calcium (MVC), pericardial adipose tissue volume (PAT) and liver attenuation (LA) have all been associated with CV risk and events. However, there is no head to head comparison of these markers in a single sample using the same statistical approach, and it remains unclear whether a combination of these markers can further improve CV risk prediction. We assessed the predictive value of CAC, TAC, AVC, MVC, PAT, LA and a combination of these markers for incident CVD/CHD/mortality in MESA. Methods: After 9 years of follow up, 327 had adjudicated CHD defined as MI, angina if followed by PTCI/CABG, cardiac arrest or CHD death, 457 had CVD events defined as CHD, stroke/TIA or CVD death and 398 died. Cox proportional hazard, area under curve(auc) and net reclassification improvement (NRI) analyses were used adjusting for age, gender, race, SBP, total and HDL cholesterol, triglycerides, BMI, smoking, BP med and statin use. Results: 6591 MESA participants mean age and BMI, 62 years and 28.4 kg/m 2 , 53% females, 38% Caucasians, 28% African Americans, 22% Hispanics and 11% Chinese. Unlike PAT and LA; CAC, TAC, AVC and MVC were all significantly associated with incident CVD/CHD/ mortality in our multivariable Cox model with CAC having the strongest association. CAC had the highest AUC when used alone to predict incident CHD/CVD whilst LA had the least. The addition of CAC to Framingham Risk Score (FRS) resulted in the most improvement in AUC for incident CVD (0.721 vs. 0.766, p&lt;0.0001) and CHD (0.712 vs. 0.766, p&lt;0.0001). The addition of CAC to the FRS resulted in an NRI of 0.191 for incident CVD and 0.229 for incident CHD. The addition of TAC, AVC, MVC, PAT and LA individually to FRS + CAC resulted in little further improvement in AUC/NRI for the prediction of CHD/CVD. Similar results were obtained when the analysis was limited to participants with intermediate FRS. Any other combination of risk markers yielded inferior results. Conclusion: CAC is superior for improving CV risk prediction over and beyond the FRS. The addition of TAC, AVC, MVC, PAT and LA only minimally improves the predictive accuracy afforded by the combination of FRS and CAC.
Tivantinib in combination with Carboplatin and Pemetrexed as first line treatment in patients with advanced non-squamous NSCLC or Malignant Pleural Mesothelioma: results of phase I trial
Authors: P.A. Zucali, M. Simonelli, F. De Vincenzo, G. Fatuzzo, M. Bertossi, M. Perrino, C. Miggiano, L. Giordano, C. Bonifacio, F. Mrakic Sposta, A. Santoro
Journal: Annals of Oncology (2015)
Effective vaccines of sutologous cancer-derived heat shock protein gp70-complexes in patients with cancer malignancies (pancreatic carcinoma, colorectal cancer)
Authors: J. Dong, J. Wei
Journal: Journal of Clinical Oncology (2005)

2591 Background: Tumor derived heat shock protein (hsp)-peptide complexes (particularly hsp70 and grp94/gp96) have been demonstrated to serve as effective vaccines, producing anti-tumor immune responses in animals and in man. To investigate whether antitumor immunity was induced by HSP70 from each patient. A pilot study was designed to test the feasibility, immunogenicity and toxicity of such treatment in cancer patients Methods: HSP70-peptide complexes were purified from fifteen patients with colorectal cancer and nine patients with pancreatic carcinoma after operation, and saved in the -80°C. Each patient was injected subcutaneously six times with aotologous HSP during half year. Results: No vaccine-related toxicities or auto-immune reactions were observed. In this procedure, all patients showed expansion of the CD8(+) T lymphocytes and NK cell population .17/24 of patients immunized elicited a specific response of potent CD8(+) T lymphocytes cytotoxic against pancreatic or colorectal carcinoma cell line in vitro. Conclusions: These observations suggest that immunization of the complex of HSPs and peptides leads to immune responses. No significant financial relationships to disclose.
Metronomic cyclophosphamide regimen electively depletes CD4+ CD25+ regulatory T cells in patients with advanced solid tumors
Authors: F. Ghiringhelli Esq., S. Ladoire, L. Zitvogel, B. Chauffert
Journal: Journal of Clinical Oncology (2006)

2561 Background: CD4 + CD25 + regulatory T cells (Treg) are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that low doses of cyclophosphamide (CPM) could significantly decrease both number and suppressive functions of Treg, facilitating vaccine-induced tumor rejection. Repeated low doses of cyclophosphamide, referred to as metronomic treatment aiming at reducing tumor angiogenesis, are used in patients with advanced, chemoresistant tumors. Methods: Six patients with metastatic solid tumors were treated after informed consent with metronomic CPM - 50 mg orally twice a day, with one week on, and one week off, until progression or limiting toxicity. Peripheral blood mononucleated cells (PBMC) were sampled before and after 4 weeks of treatment. Occurrence of blood leucocyte subpopulation and capacity of Treg to inhibit NK and T cells patients functions were measured. Results: metronomic CPM induced a profound and selective reduction of circulating Treg, both in percentage (7.7 ± 0.8 % before versus 3.3 ± 0.8 % after, p &lt; 0.005) and absolute number (25.2 ± 7.5 cells/mm 3 before versus 6.1 ± 3.3 cells/mm 3 after, p &lt; 0.0006). Inhibitory functions of Treg on conventional T cells and NK cells lead to a restoration of peripheral T cell proliferation - i.e. PBMC from cancer patients exhibited 17 ± 3% T cells proliferation capacity after CD3 CD28 stimulation versus 44 ± 5% (p &lt; 0.01) 1 month after the beginning of the treatment, and versus 45 ± 6% in healthy volunteers- and innate NK killing activities - i.e. PBMC from cancer patients exhibited 9 ± 1% NK killing capacity against K562 target versus 26 ± 5% (p &lt; 0.005) after 4 week treatment. Conclusions: Metronomic CPM has not only effect on tumor angiogenesis, but also strongly curtail immunosuppressive Treg, which could favor a better control of tumor progression. No significant financial relationships to disclose.
Mice with immotile cilia spontaneously cough due to mechanical stimuli of postnasal drip
Authors: Toshiyuki Iwata, Isao Ito, Akio Niimi, Koji Ikegami, Satoshi Marumo, Naoya Tanabe, Hitoshi Nakaji, Hisako Matsumoto, Tsuyoshi Oguma, Hideki Inoue, Tomoko Tajiri, Tadao Nagasaki, Yoshihiro Kanemitsu, Junzo Kamei, Mitsutoshi Setou, Michiaki Mishima
Journal: European Respiratory Journal (2012)

Background: The underlying mechanisms of cough in patients with rhinosinusitis are poorly understood. We reported that tubulin tyrosine ligase-like family member 1 gene ( Ttll1 ) knockout (KO) mice showed disorders of ciliary motility resulting in rhinosinusitis together with cough reflex.

Aim: To examine mechanisms of cough in Ttll1 -KO mice.

Methods and results: We pathologically searched for the causes of cough and examined structural changes of the airway in KO mice. Postnasal drip (PND) was observed in the pharynx. There was no evidence of inflammation and remodeling in the lower airway. Capsaicin cough sensitivity was increased in KO mice compared to WT mice. Moguisteine, which inhibits cough via suppression of rapidly adapting receptor (RAR), decreased cough, while capsazepine, an antagonist of the transient receptor potential vanilloid subfamily 1, did not. Tosufloxacin, a fluoroquinolone antibiotic, improved nasal inflammation but accumulation of mucus and cough remained. To prove that mucus stimuli evoke cough, artificial PND were made to evoke cough in WT mice. WT mice distinctly coughed due to artificial PND. Blue dye and contrast material were administered to study nasal clearance and movement of mucus. We confirmed that nasal ciliary clearance was decreased in KO mice. Further, blocking nasal discharge from flowing to the larynx completely inhibited cough of KO mice.

Conclusions: Mechanical stimulation to larynx due to PND was transduced to the central nervous system via RAR and evoked cough in Ttll1 -KO mice. Ttll1 -KO mice may serve to reveal the mechanisms of cough in patients with PND and to develop new antitussive drugs.
The SDF-1 receptor CXCR4 enhances metastasis in neuroblastoma
Authors: Olga Pena, Rex Moats, Goar Smbatyan, Michael Rosol, Yves DeClerck
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

521 

The homing of cancer cells to metastatic sites has been shown to involve the expression of the chemokine stromal derived factor-1 (SDF-1/CCL12) secreted by many tissues, in particular hematopoietic cells and the expression of its receptor CXCR4 by metastatic tumor cells. In neuroblastoma, the role of SDF-1/CXCR4 has been the subject of conflicting reports. Whereas some investigators have shown that SDF-1 produced by bone marrow-derived cells promotes the migration of CXCR4 expressing neuroblastoma cells (Geminder et al ., J. Immunology, 167: 4747-4757, 2001), other investigators have demonstrated that CXCR4 in neuroblastoma is not functional and that SDF-1 does not stimulate their chemotaxis in vitro (Airoldi et al ., Clin. Cancer Res. 12: 77-82, 2006). These studies, however, have not tested the effect of CXCR4 on metastasis in animal models. To address this issue, SCID mice were intravenously injected with CXCR4 positive CHLA-255 human neuroblastoma cells engineered to express the firefly luciferase reporter gene and their metastatic potential was monitored by luciferin-induced bioluminescence. Several metastatic lesions in the bone, lung, liver, kidney and adrenal gland were identified and cells from these lesions were grown and subcloned. Cells growing from a bone metastatic lesion (CHLA-255-BM2) were found to express high levels of CXCR4 (44 ± 9.4% positive) whereas cells derived from an adrenal lesion (CHLA-255-KM2) expressed low levels of CXCR4 (3.9 ± 4.4% positive). In vitro , high CXCR4 expressing CHLA-255-BM2 cells migrated in the presence of SDF-1 (300 ng/ml) and this effect was partially blocked in the presence of the CXCR4 inhibitor AMD3100 (10 µg/ml) and completely blocked in the presence of an anti-CXCR4 blocking antibody (100 µg /ml). In contrast, SDF-1 had no stimulatory effect on the migration of low CXCR4 expressing CHLA-255-KM2 cells. When injected in the tail vein of SCID mice, CXCR4 high expressing cells formed rapidly growing metastases in the lungs, bone and also in the adrenal gland after 29 to 37 days, whereas CXCR4 low expressing cells failed to form detectable metastases within the same time frame. The data thus suggest that SDF-1/CXCR4 may be an important factor promoting the homing of neuroblastoma cells to metastatic sites.
BENZO[a]PYRENE DIOL EPOXIDE PERTURBATION OF CELL CYCLE KINETICS OF SYNCHRONIZED MOUSE LIVER EPITHELIAL CELLS
Authors: A.L. Pearlman, B.N. Navsky, J.C Bartholomew
Journal: Cancer Research (1980)

A cell cycle synchronization system is described for the analysis of the perturbation of cell cycle kinetics and the cycle-phase specificity of chemicals and other agents. We used the system to study the effects of ({+-})r-7, t-8-dihydroxy-t-9, 10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP diol epoxide) upon the cell cycle of mouse liver epithelial cells(NMuLi). BaP diol epoxide(0.6 uM) was added to replated cultures of NMuLi cells that had been synchronized in various stages of the cell cycle by centrifugal elutriation. DNA histograms were obtained by flow cytometry as a function of time after replating. The data were analyzed by a computer modeling routine and reduced to a few graphs illustrating the 'net effects' of the BaP diol epoxide relative to controls. BaP diol epoxide slowed S-phase traversal in all samples relative to their respective control. Traversal through G{sub 2}M was also slowed by at least 50%. BaP diol epoxide had no apparent effect upon G{sub 1} traversal by cycling cells, but delayed the recruitment of quiescent G{sub 0} cells by about 2 hrs. The methods described constitute a powerful new approach for probing the cell cycle effects of a wide variety of agents. The present system appears to be extremely sensitive and capable ofmore » characterizing the action of agents on each phase of the cell cycle. The methods are automatable and would allow for the assay and possible differential characterization of mutagens and carcinogens.« less
The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux
Authors: Varman T. Samuel, Gerald I. Shulman
Journal: Journal of Clinical Investigation (2016)

Insulin resistance arises when the nutrient storage pathways evolved to maximize efficient energy utilization are exposed to chronic energy surplus. Ectopic lipid accumulation in liver and skeletal muscle triggers pathways that impair insulin signaling, leading to reduced muscle glucose uptake and decreased hepatic glycogen synthesis. Muscle insulin resistance, due to ectopic lipid, precedes liver insulin resistance and diverts ingested glucose to the liver, resulting in increased hepatic de novo lipogenesis and hyperlipidemia. Subsequent macrophage infiltration into white adipose tissue (WAT) leads to increased lipolysis, which further increases hepatic triglyceride synthesis and hyperlipidemia due to increased fatty acid esterification. Macrophage-induced WAT lipolysis also stimulates hepatic gluconeogenesis, promoting fasting and postprandial hyperglycemia through increased fatty acid delivery to the liver, which results in increased hepatic acetyl-CoA content, a potent activator of pyruvate carboxylase, and increased glycerol conversion to glucose. These substrate-regulated processes are mostly independent of insulin signaling in the liver but are dependent on insulin signaling in WAT, which becomes defective with inflammation. Therapies that decrease ectopic lipid storage and diminish macrophage-induced WAT lipolysis will reverse the root causes of type 2 diabetes.
Induction of complete remission in metastatic hormone-refractory prostate cancer: A combined anti-inflammatory therapy approach
Authors: A. Reichle, B. Walter, A. Berand, M. Vogelhuber, K. Bross, J. Wilke, W. Wieland, R. Andreesen, S. Rogenhofer
Journal: Journal of Clinical Oncology (2007)

15636 Background: The present multi-centre phase II study was designed to support the hypothesis that networking agents binding to ubiquitous accessible targets in metastatic hormone-refractory prostate cancer (HRPC) may counteract neoplasia-specific aberrant cellular functions, thereby mediating objective response (primary endpoint). Method: Patients with metastatic HRPC, received both an anti- inflammatory and angiostatic therapy consisting of low-dose chemotherapy with capecitabine 1 g twice daily for 14 days every 3 weeks, day 15+, COX-2 blockade with etoricoxib 60 mg daily, day 1+, combined with two transcription modulators, pioglitazone 60 mg daily, day 1+, plus dexamethason 1 mg daily for 14 days, every 3 weeks, day 15+, until disease progression. The study was planned using the Simon optimal design. Results: Thirty-six consecutive patients (N= 22 (61%) chemo-naive, n= 14 (39%) with preceding chemotherapies, mean 2.1 regimen) with metastatic HRPC, confirmed PSA increase, assessable response, and ECOG 0–2 were enrolled between 1/03 to 5/06. Objective response occurred in 10 of 13 cases (N/n: 41%/7%) with PSA (and C-reactive protein) response &gt;50% (N/n: 45%/21%). Median time to PSA response was 2.4 months (range 1.0 to 7.3 months). Two of three patients responding with PSA &lt;4 ng/ml achieved complete remission after 9 and 16 months, 16 patients stable disease (N/n: 41%/64%), and 5 patients experienced progressive disease (N/n: 14%/14%). Median progression-free survival (PFS) was 3.6 months (range 0.5 to 28.5) and median overall survival (OS) 14.4 months (range 0.6 to 37.2). Multivariate analysis recognized pre-treatment with chemotherapy as negative predictor for both OS (hazard ratio 2.26 (CI 95%: 0.970; 5.277), p=0.05) and PFS (HR 2.47 (CI 95%: 1.146; 5.348), p= 0.02), and &lt;50% PSA response as negative predictor for PFS (HR 0.38 (CI 95%: 0.171; 0.857), p= 0.01). Toxicities &gt; WHO grade II were reported: Hand-foot syndrome (n=1), anemia (n=6), edema (n=1), cushing syndrome (n=1), hydronephrosis (n=1). Conclusions: This is the first study reporting continuous complete remissions in HRPC with a biomodulatory therapy approach. Further, the study may clinically support the upper mentioned hypothesis. No significant financial relationships to disclose.