tbuckley/cabot-search huggingface dataset:
Treg depletion by low-dose temozolomide
Authors: A. F. Carpentier, C. Banissi, F. Ghiringhelli, L. Chen
Journal: Journal of Clinical Oncology (2008)

3064 Background: CD4+CD25+ regulatory T cells (Treg), which constitute about 2–3% of CD4+ human T cells, are the main contributors to the maintenance of immune tolerance. Cancer patients, including glioblastoma patients, bear an increased number of circulating and tumor infiltrating Treg that exert functional inhibition on tumor-specific T cells. Temozolomide (TMZ) is one of the most effective chemotherapy in glioblastoma (GBM). Lymphopenia is a common side effect of TMZ, but to which extent the Treg compartment is affected by this chemotherapy has been poorly investigated. We therefore studied the impact of various TMZ regimens on Treg cell population in a TMZ- resistant rat model of glioma. Methods: RG2 glioma cells were implanted s.c. in Fischer rats and tumor growth was assessed with a caliper. TMZ was administered orally with schedules designed to mimic the TMZ regimens currently used in humans: 30 mg/kg/day for 5 days; or 10 mg/kg/day for 21 days. In addition, 2 metronomic regimen with low-dose TMZ (2 mg/kg/day and 0.5 mg/kg/day for 21 days) were studied. Splenocytes were analyzed by FACScan with antibodies against CD4, CD25 and CD3. Tumor infiltrating lymphocytes were analyzed similarly, after collagenase digestion of surgically resected tumors. Statistics were determined by the Mann-Whitney or the ANOVA tests. Results: In the spleen of tumor-bearing animals, low-dose TMZ metronomic regimens (0.5 mg/kg and 2 mg/kg for 21 days) induced a significant decrease of Treg/CD4+ levels (13 ± 2; p<0.01 and 14 ± 3; p<0.05, respectively, vs 19 ± 5 for controls). On the contrary, high dose temozolomide regimen (10 mg/kg/day for 21 days or 30 mg/kg for 5 days) did not significantly modify the percentage of Treg/CD4+. Within tumors, treatment with the 0.5 mg/kg TMZ regimen induced a slight and nearly significant decrease in the percentage of Treg/CD4+ after a 2 to 3-week treatment (23 ± 9 vs. 35 ± 11; p=0.06).Treatment with 0.5mg/kg metronomic TMZ-treated animals, but not standard TMZ treatment (30 mg/kg for 5 days), significantly reduced tumor progression when compared to untreated animals. Conclusions: Low-dose metronomic TMZ regimen, but not standard TMZ regimen, reduced the number of circulating Treg. These results can have clinical applications for immunotherapeutic approaches in GBM. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering-Plough
Oncogene-Induced Senescence in Pituitary Adenomas—an Immunohistochemical Study
Authors: Emilija Manojlovic-Gacic, Milica Skender-Gazibara, Vera Popovic, Ivan Soldatovic, Novica Boricic, Savo Raicevic, Sandra Pekic, Mirjana Doknic, Dragana Miljic, Irina Alafuzoff, Fredrik Pontén, Olivera Casar-Borota
Journal: Endocrine Pathology (2015)
Impact of preexisting CNS involvement on the outcome of bone marrow transplantation in adult hematologic malignancies.
Authors: K van Besien, D Przepiorka, R Mehra, S Giralt, I Khouri, J Gajewski, B Andersson, R Champlin
Journal: Journal of Clinical Oncology (1996)

PURPOSE To determine the impact of prior or current CNS disease on the outcome of high-dose chemotherapy for patients with hematologic malignancies. PATIENTS AND METHODS In a 54-month period, 373 patients with hematologic malignancies underwent allogeneic or autologous bone marrow transplantation (BMT) or blood stem-cell transplantation using high-dose thiotepa, busulfan, and cyclophosphamide (TBC) as the preparative regimen. Four patients with active CNS disease at BMT and 20 patients with a history of prior CNS disease were identified. The outcomes of those with a history of CNS disease were compared with those of a matched control group. RESULTS Of four patients with active CNS disease at the time of BMT, two had CNS recurrences and one recurred in the bone marrow. One patient died of treatment-related toxicity. Four of 20 patients with prior CNS involvement currently remain free of disease. At 2 years, the disease-free survival (DFS) rate was 23% +/- 19%, and the DFS rate for the control group 39% +/- 24% (P = .053). An increased rate of treatment-related toxicity and especially grades II to IV CNS toxicity accounted for the poorer outcome of patients who had a history of CNS disease. Recurrence rates were not significantly different between the two groups. Prior radiation to the CNS correlated with CNS complications posttransplant (p = .01). CONCLUSION Consolidation with TBC and BMT can induce prolonged DFS in a proportion of patients with a history of CNS disease. Such patients are at increased risk for CNS complications that lead to an inferior overall outcome when compared with a control group.
Abstract 16741: A Novel Cross-Talk Between Epicardial Adipose Tissue and the Human Heart Regulates Myocardial Redox State in Ischaemic Heart Disease
Authors: Alexios S Antonopoulos, Marios Margaritis, Janet Digby, Mario Petrou, Patricia Ciccone, Constantinos Psarros, Rana Sayeed, Barbara Casadei, Keith M Channon, Charalambos Antoniades
Journal: Circulation (2013)

Background: Myocardial redox state plays a critical role in heart biology. Adipose tissue (AT)-secreted adiponectin (AdN) is a molecule with beneficial effects on the cardiovascular system. We’ve s...
Decline in Weight and Incident Mild Cognitive Impairment
Authors: Rabe E. Alhurani, Maria Vassilaki, Jeremiah A. Aakre, Michelle M. Mielke, Walter K. Kremers, Mary M. Machulda, Yonas E. Geda, David S. Knopman, Ronald C. Petersen, Rosebud O. Roberts
Journal: JAMA Neurology (2016)

Unintentional weight loss has been associated with risk of dementia. Because mild cognitive impairment (MCI) is a prodromal stage for dementia, we sought to evaluate whether changes in weight and body mass index (BMI) may predict incident MCI.To investigate the association of change in weight and BMI with risk of MCI.A population-based, prospective study of participants 70 years of age or older from the Mayo Clinic Study of Aging, which was initiated on October 1, 2004. Maximum weight and height in midlife (40-65 years of age) were retrospectively ascertained from the medical records of participants using a medical records-linkage system. The statistical analyses were performed between January and November 2015.Participants were evaluated for cognitive outcomes of normal cognition, MCI, or dementia at baseline and prospectively assessed for incident events at each 15-month evaluation. The association of rate of change in weight and BMI with risk of MCI was investigated using proportional hazards models.Over a mean follow-up of 4.4 years, 524 of 1895 cognitively normal participants developed incident MCI (50.3% were men; mean age, 78.5 years). The mean (SD) rate of weight change per decade from midlife to study entry was greater for participants who developed incident MCI vs those who remained cognitively normal (-2.0 [5.1] vs -1.2 [4.9] kg; P = .006). A greater decline in weight per decade was associated with an increased risk of incident MCI (hazard ratio [HR], 1.04 [95% CI, 1.02-1.06]; P < .001) after adjusting for sex, education, and apolipoprotein E (APOE) ε4 allele. A weight loss of 5 kg per decade corresponds to a 24% increase in risk of MCI (HR, 1.24). A higher decrease in BMI per decade was also associated with incident MCI (HR, 1.08 [95% CI, 1.03-1.13]; P = .003).These findings suggest that increasing weight loss per decade from midlife to late life is a marker for MCI and may help identify persons at increased risk for MCI.
Abstract 13457: High Sensitivity Troponin: Does the 50% Delta Change Alter Clinical Outcomes in Chest Pain Presentations to the Emergency Room?
Authors: Jithin Sajeev, Florence Gunawan, Piyumi Wijesundera, Siddharth Menon, Diana Lewis, Louise Roberts, David Tong, Arul Baradi, Damon Jackson, Pavithra Naidu, Gishel New
Journal: Circulation (2013)

Background:  The National Heart Foundation (NHF) of Australia ACS guidelines recommends the use of high sensitivity troponin assay (hsTrop). Upon introduction of hsTrop assay at Box Hill Hospital (BHH) in February of 2011, 30% Δ was used as the cut off. However, this was changed to 50% Δ 6 months later following an addendum recommendation published in August of 2011.   Aim:  Determine the clinical impact of 30 to 50%Δ change for patients presenting with chest pain.   Method:  We retrospectively collected data for all patients >18 years presenting with chest or abdominal pain and had hsTrop test between January-June 2012. There were 1804 patients who met the above criteria. 751 (42%) patients who had a STEMI, lacked serial hsTrop values, were on dialysis or had trauma-related chest pain were excluded. All remaining patients were followed up.   Results:  Of 1053 patients, 422(40%) with serial hsTrop had at least one abnormal troponin (>14ng/ml). 41 (3.9%) fell within 30-50%Δ. 24 had clinical indications suggestive of ACS and went on to have cardiac investigations and care. Of the remainder, three patients were medically managed for NSTEACS, 14 patients with non-cardiac diagnosis had no further tests. At follow up of these 14 patients, 1 had repeat presentation with unstable angina and was appropriately treated, three died of non cardiac causes, and the remainder had no further cardiac events.   Conclusion:  Our data supports the safety of Australian NHF recommendation for change in Δ to 50%.This change affected only 3.9% of the patients and only one patient re-presented with chest pain for investigation. Our clinical decision to investigate 24 of the 41 patients who had Δ
Oncogenic Fusion Gene <i>CD74-NRG1</i> Confers Cancer Stem Cell–like Properties in Lung Cancer through a IGF2 Autocrine/Paracrine Circuit
Authors: Takahiko Murayama, Takashi Nakaoku, Masato Enari, Tatsunori Nishimura, Kana Tominaga, Asuka Nakata, Arinobu Tojo, Sumio Sugano, Takashi Kohno, Noriko Gotoh
Journal: Cancer Research (2016)

The CD74-Neuregulin1 (NRG1) fusion gene was recently identified as novel driver of invasive mucinous adenocarcinoma, a malignant form of lung cancer. However, the function of the CD74-NRG1 fusion gene in adenocarcinoma pathogenesis and the mechanisms by which it may impart protumorigenic characteristics to cancer stem cells (CSC) is still unclear. In this study, we found that the expression of the CD74-NRG1 fusion gene increased the population of lung cancer cells with CSC-like properties. CD74-NRG1 expression facilitated sphere formation not only of cancer cells, but also of nonmalignant lung epithelial cells. Using a limiting dilution assay in a xenograft model, we further show that the CD74-NRG1 fusion gene enhanced tumor initiation. Mechanistically, we found that CD74-NRG1 expression promoted the phosphorylation of ErbB2/3 and activated the PI3K/Akt/NF-κB signaling pathway. Furthermore, the expression of the secreted insulin-like growth factor 2 (IGF2) and phosphorylation of its receptor, IGF1R, were enhanced in an NF-κB-dependent manner in cells expressing CD74-NRG1. These findings suggest that CD74-NRG1-induced NF-κB activity promotes the IGF2 autocrine/paracrine circuit. Moreover, inhibition of ErbB2, PI3K, NF-κB, or IGF2 suppressed CD74-NRG1-induced tumor sphere formation. Therefore, our study provides a preclinical rationale for developing treatment approaches based on these identified pathways to suppress CSC properties that promote tumor progression and recurrence.
Semi-volatile organic compounds in exhaled breath condensate: a new approach in differential diagnosis of asthma and COPD
Authors: E.K. Anaev, T.N. Anokhina, A.I. Revelsky, A.A. Rodionov, I.A. Revelsky, V.B. Kudryavtsev, A.G. Chuchalin
Journal: European Respiratory Journal (2009)
Effects of Interleukin-12 on the Immune Response to a Multipeptide Vaccine for Resected Metastatic Melanoma
Authors: P. Lee, F. Wang, J. Kuniyoshi, V. Rubio, T. Stuge, S. Groshen, C. Gee, R. Lau, G. Jeffery, K. Margolin, V. Marty, J. Weber
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Forty-eight patients with high-risk re-sected stage III or IV melanoma were immunized with two tumor antigen epitope peptides derived from gp100 209-217 (210M) (IMDQVPSFV) and tyrosin-ase 368-376 (370D) (YMDGTMSQV) emulsified with incomplete Freund’s adjuvant (IFA). Patients received peptides/IFA with or without interleukin (IL)-12 30 ng/kg to evaluate the toxicities and immune responses in either arm with time to relapse and survival as secondary end points. PATIENTS AND METHODS: Immunizations were administered every 2 weeks for 8 weeks, then every 4 weeks for 12 weeks, and then once 8 weeks later. A leukapheresis to obtain peripheral-blood mononuclear cells for immune analyses was done before and after vaccination. Skin testing with peptides and recall reagents was performed before and after vaccinations. RESULTS: Local pain and granuloma formation, fever, and lethargy of grade 1 or 2 were observed. Transient vaccine-related grade 3—but no grade 4—toxicity was observed. Thirty-four of 40 patients developed a positive skin test response to the gp100 peptide but none to tyrosinase. Immune responses were measured by release of gamma-interferon in an enzyme-linked immunosorbent assay (ELISA) by effector cells in the presence of peptide-pulsed antigen-presenting cells or by an antigen-specific tetramer flow cytometry assay. Thirty-three of 38 patients demonstrated an immune response by ELISA after vaccination, as did 37 of 42 patients by tetramer assay. Twenty-four of 48 patients relapsed with a median follow-up of 20 months, and 10 patients in this high-risk group have died. CONCLUSION: These data suggest a significant proportion of patients with resected melanoma mount an antigen-specific immune response against a peptide vaccine and indicate that IL-12 may increase the immune response and supporting further development of IL-12 as a vaccine adjuvant.
Phase Ib Trial to Evaluate Capecitabine (C), Erlotinib (E), and Bevacizumab (B) in Patients (Pts) with Unresectable and/or Metastatic Pancreatic Cancer (Umpc) – Preliminary Results of the Rebeca Trial Including Pharmacokinetics (Pk) and Circulating Tumor Cells (Ctcs)
Authors: C. Dittrich, P. Buchner, A. Sahmanovic, R. Königsberg, M. Lichtneckert, G. Nirnberger, M. Czejka, K. Geissler
Journal: Annals of Oncology (2014)
Influence of UGT1A1 and UGT1A9 polymorphism on relative cancer risk in Korean populations
Authors: Jung Ran Choi, Dae Ryong Kang, Jeong-Oh Kim, In Kyung Kim, Hyun Suk Chae, Jin-Hyoung Kang
Journal: Cancer Research (2008)

4782   Genetic polymorphisms of uridine diphosphate glucuronosyltransferases ( UGTs ) are involved in individual and ethnic differences in drug metabolism. Nine different functional  UGT1A  enzymes are generated from a single  UGT1A  gene by alternative splicing, with each enzyme having a unique exon 1. To reveal co-occurrence of the  UGT1A  polymorphisms, we retrospectively aim to characterize the  UGT1A1 - UGT1A9  haplotype structures in Koreans and gain insights on their association with increased cancer incidence. We genotyped the  UGT1A1  (-3279T>G, -3156G>A, -53(TA) 6>7 , 211G>A and 686C>A) and  UGT1A9  (-2152C>T, -275T>A and -118T 9>10 ) variants by direct sequencing analysis in 68 cancer patients (lung and colorectal cancer) and 154 healthy subjects. The haplotype structure across the  UGT1A  locus was constructed using 4 haplotype-tagging SNPs (htSNPs). For polymorphisms in  UGT1A1  and  UGT1A9 , we observed no significant differences in the allele frequency between the two groups. The strongest linkage disequilibrium (LD) was observed between the  UGT1A1  -53(TA) 6>7  and 211G>A and lower LD was observed between the  UGT1A1  -53(TA) 6>7  variant and the -118T 9>10  UGT1A9  variant. Eight  UGT1A1 - UGT1A9  haplotypes were found and the three most common haplotypes were haplotype 10-T-6-G, 9-T-6-A and 9-G-6-G (76% of all haplotypes) in two groups. Overall, no significant differences exist in the haplotype frequency between cases and controls (likelihood ratio statistic 8.56, df=15, p=0.89). Logistic regression analysis indicated a significant association between the  UGT1A1 - UGT1A9  diplotypes harboring 4 minor alleles and the incresed cancer incidence (OR 11.64, 95% confidence interval 1.70-79.43). The  UGT1A  genotypes might be clinically useful in predicting incresed incidence of lung and colorectal cancer in Koreans.
...though vaccine's efficacy is unproved
Authors: K Vithayathil, D Rowen, R Patel, F E Willmott
Journal: BMJ (1995)

EDITOR,--A Jain and colleagues elegantly reviewed published work on the efficacy of pneumococcal vaccine in HIV infection.1 Failure of protection in the United Kingdom has been reported and the question of efficacy raised elsewhere.2 3 We recently conducted a postal survey of 176 consultants in genitourinary medicine in the United Kingdom on the routine …
POSTTRAUMATIC NEUROSES
Authors: R P MACKAY
Journal: JAMA (2011)

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Potential role of luminal potassium in tubuloglomerular feedback.
Authors: V Vallon, H Osswald, R C Blantz, S Thomson
Journal: Journal of the American Society of Nephrology (1997)

Transport through the Na+-2Cl(-)-K+ cotransporter in the luminal membrane of macula densa cells is considered critical for tubuloglomerular feedback (TGF). Although various studies could support the importance of luminal Na+ and Cl-, the role of luminal K+ in TGF has not been thoroughly addressed. The study presented here examines this issue in nephrons with superficial glomeruli of anesthetized male Munich-Wistar-Frömter rats. Ambient Na+ concentration in early distal tubular fluid was approximately 22 mM, suggesting collection sites relatively close to the macula densa segment. First, it was found that ambient early distal tubular K+ concentration is approximately 1.3 mM, i.e., close to the K+ affinity of the Na+-2Cl(-)-K+ cotransporter in the thick ascending limb. Second, it was observed that a change in late proximal tubular flow rate, i.e., a maneuver that is known to induce a TGF response, significantly alters early distal tubular K+ concentration. Third, previous experiments failed to show an inhibition in TGF response during retrograde perfusion of the macula densa with K+-free solutions. Because of a potential K+ influx into the lumen between the perfusion site and the macula densa, however, the K+ channel blocker U37883A was added to the K+-free perfusate. TGF response was assessed as the fall in nephron filtration rate in response to retrograde perfusion of the macula densa segment from early distal tubular site. It was observed that luminal U37883A (100 microM) significantly attenuated TGF. Because adding 5 mM KCl to the perfusate restored TGF in the presence of U37883A and because the inhibitory action of U37883A on tubular K+ secretion was confirmed, the effect of U37883A on TGF was most likely caused by inhibition of K+ influx into the perfused segment, which decreased luminal K+ concentration at the macula densa. The present findings support a potential role for luminal K+ in TGF, which is in accordance with a transmission of the TGF signal across the macula densa via Na+-2Cl(-)-K+ cotransporter.
PDLIM1 Stabilizes the E-Cadherin/β-Catenin Complex to Prevent Epithelial–Mesenchymal Transition and Metastatic Potential of Colorectal Cancer Cells
Authors: Hai-Ning Chen, Kefei Yuan, Na Xie, Kui Wang, Zhao Huang, Yan Chen, Qianhui Dou, Min Wu, Edouard C. Nice, Zong-Guang Zhou, Canhua Huang
Journal: Cancer Research (2016)

Metastasis is a major cause of death in patients with colorectal cancer, and increasing evidence supports the contribution of the epithelial-mesenchymal transition (EMT) to cancer progression. The dissociation of the E-cadherin/β-catenin adhesion complex represents a key step in EMT and promotes cancer invasion and metastasis, but the upstream signaling pathways regulating this interaction are poorly understood. Here, we show that PDLIM1, a member of the PDZ and LIM protein family, was downregulated in highly metastatic colorectal cancer cells and liver metastases from colorectal cancer patients. We found that loss of PDLIM1 promoted the expression of EMT markers and increased the invasive and migratory properties of multiple colorectal cancer cell lines. Furthermore, PDLIM1 knockdown increased colon-derived liver metastasis in an orthotopic colorectal cancer model and promoted distant metastatic colonization in an experimental lung metastasis model. Mechanistic investigations revealed that PDLIM1 interacted with and stabilized the E-cadherin/β-catenin complex, thereby inhibiting the transcriptional activity of β-catenin and preventing EMT. Accordingly, PDLIM1 overexpression attenuated EMT of colorectal cancer cells. Moreover, the downregulation of PDLIM1 in colorectal cancer samples correlated with reduced E-cadherin and membrane β-catenin levels, and was associated with shorter overall survival. In conclusion, our study demonstrates that PDLIM1 suppresses EMT and metastatic potential of colorectal cancer cells by stabilizing β-catenin at cell-cell junctions, and its loss in metastatic tissues may represent a potential prognostic marker of aggressive disease.