tbuckley/cabot-search huggingface dataset:
Multivalent immunotherapies are superior in providing anti-tumor protection to immunotherapy approaches using single antigens
Authors: Betty Li, Andrew Simmons, Karin Jooss
Journal: Cancer Research (2008)

2853   A significant challenge to date in cancer immunotherapy is the selection of the appropriate immunizing antigens since rejection antigens are unknown for the majority of cancers. Single antigen approaches attempt to activate an immune response to one particular antigen whereas whole tumor cell immunotherapies have the potential to elicit immune responses to a broad panel of antigens.  To evaluate whether an immune response specific to a broad panel of tumor-related antigens provides better therapeutic benefit to tumor-bearing animals than immunotherapies activating strong immune responses to one tumor-specific antigen only, studies were performed in the murine B16 melanoma model. As multivalent whole cell immunotherapy, a GM-CSF-secreting B16 tumor cell immunotherapy (B16.GMKd) was evaluated; whereas an unrelated cell line, Lewis Lung Carcinoma (LLC), was modified to secrete GM-CSF and over-express either of the two antigens Trp2 (LLC.GMKd.Trp2) or gp100 (LLC.GMKd.gp100), each to serve as immunotherapies that activate immune responses to only one B16-specific antigen. The animals were immunized on day 0 with 3x10 6  immunotherapy cells and challenged 7 days later with a lethal dose of live B16 cells (prevention model). While unmodified LLC.GMKd cells were not therapeutic in the B16 tumor model and only modest anti-tumor protection was provided by LLC.GMKd.gp100 or LLC.GMKd.Trp2, with 20-40% of animals surviving long-term (70 d), anti-tumor protection was significantly improved with the B16.GMKd multivalent immunotherapy, leading to 100% tumor protection and long-term survival. Despite the differences in survival, T-cell responses specific for Trp2 or gp100 were actually greater in animals that received the LLC-based immunotherapies than the B16 multivalent immunotherapy. However, only modest numbers of effector CD8 T-cells infiltrated tumors in mice immunized with the LLC.GMKd.gp100 or LLC.GMKd.Trp2 immunotherapies, with significantly higher numbers of activated CD8 T-cells (CD107a expressing CD8+ T-cells) detected in animals that had received the B16-specific multi-antigen immunotherapy (B16GMKd). Furthermore, re-challenge of animals with a lethal dose of live B16 cells 70 days post immunotherapy demonstrated a more potent memory response in animals that had initially received the multivalent B16 immunotherapy compared to animals treated with either LLC.GMKd.gp100 or LLC.GMKd.Trp2, with 50-70% of animals surviving in the former group compared to 0-20% of animals surviving in the two single antigen groups. These findings suggest that multivalent immunotherapies provide superior anti-tumor protections including improved immunological memory, compared to a single antigen-based approach. A detailed immune analyses and their correlation with therapeutic benefit will be provided.
P20 Delineating The Contribution Of Formylated Peptides And Formyl Peptide Receptor 1 To The Pathogenesis Of Acute Lung Injury
Authors: D. Dorward, C. Lucas, M. Doherty, G. Chapman, E. Scholefield, A. Conway-Morris, T. Kipari, C. Robb, J. Felton, P. Whitfield, C. Haslett, K. Dhaliwal, A. Rossi
Journal: Thorax (2014)

<h3>Background</h3> Acute respiratory distress syndrome (ARDS) remains an often fatal condition without effective pharmacological therapies. Characteristically, a neutrophil-dominant disorder, it is associated with a dysregulated inflammatory response and tissue injury. Neutrophil migration into inflammatory sites is controlled by a variety of factors; in sterile tissue injury mitochondrial formylated peptides are released following necrotic cell death and bind to formyl peptide receptor 1 (FPR1) on neutrophils to induce migration and activation. <h3>Hypothesis</h3> That mitochondrial formylated peptides are elevated in ARDS and drive FPR1-mediated neutrophil recruitment. Inhibition of FPR1 in sterile lung injury would therefore attenuate the inflammatory response through multiple FPR1-mediated effects. <h3>Methods</h3> Mitochondrial DNA and formylated peptides were quantified in plasma of ARDS patients and healthy controls by qPCR, western blot and LC-MS/MS. Healthy volunteer neutrophils were stimulated with mitochondrial formylated peptides and chemotaxis assays and flow cytometry used to assess neutrophil function. Intracellular signalling was assessed by western blotting. Mouse models of infective (E. coli) and sterile (hydrochloric acid) acute lung injury were used. <h3>Results</h3> Free mitochondrial DNA and formylated peptides were elevated in ARDS patients. Mitochondrial formylated peptides induced FPR1-dependent neutrophil chemotaxis through PI3K- and MAPK-mediated control of the β<sub>2</sub>-integrin heterodimer Mac1. In sterile acid-induced injury FPR1 inhibition resulted in reduced neutrophil migration, pulmonary haemorrhage, protein leak and pro-inflammatory cytokine expression. Furthermore, acid-induced reduction in alveolar macrophage number was inhibited while interstitial macrophages displayed an alternatively activated phenotype. FPR1 was also found to be expressed on mouse type 1 alveolar epithelial cells suggesting further possible mechanisms through which FPR1-mediated alveolar leak occurs. Importantly, delivery of FPR1 antagonists 12 h after injury also reduced acute lung inflammation demonstrating potential therapeutic relevance. In non-sterile E. coli-mediated lung injury partial antagonism of FPR1 resulted in reduced alveolar neutrophil numbers and attenuated vascular leak without altering bacterial clearance. <h3>Conclusions</h3> Mitochondrial formylated peptides and FPR1 play an important role in the pathogenesis of sterile acute lung injury. This appears to be predominantly through neutrophil-dependent means but their role in macrophage and epithelial cell function could also be important. FPR1 antagonism may therefore represent a multi-cellular therapeutic target in the treatment of ARDS.
Abstract 162: Intralipid Protects the Heart in Late Pregnancy Against Ischemia/Reperfusion Injury as Effectively as Ischemic Conditioning
Authors: Jingyuan Li, Andrea Iorga, Siamak Rahman, Mansoureh Eghbali
Journal: Circulation (2012)

Introduction Recently, we found that hearts of late pregnant (LP) mice have higher vulnerability to ischemia/reperfusion (I/R) injury compared to hearts of non-pregnant mice. We have also shown tha...
Methylation-dependent transcriptional silencing of Dab2 is a common early event in human tumorigenesis and predicts metastasis
Authors: O. Garrone, M. Gasco, P. Smith, N. Syed, M. Occelli, G. Numico, A. Comino, E. Fea, P. Farrell, T. Crook
Journal: Journal of Clinical Oncology (2005)

9536 Background: Using pharmacological reversal of methylation, we identified Dab2 as a gene whose expression is silenced by methylation in squamous and breast carcinoma cell lines. Methods: We subsequently used methylation-specific PCR (MSP) to analyse methylation of Dab2 in large series of primary and metastatic carcinomas of the head and neck (HNSCC) and breast. Results: These studies identified methylation-dependent transcriptional silencing of Dab2 in 42% of advanced HNSCC and 39% of breast cancers. In breast cancer, the frequency of Dab2 methylation increased with increasing histological grade. Dab2 methylation was detectable in pre-malignant oral dysplastic lesions and in breast ductal carcinoma in situ, implying that silencing of the gene is an early event in tumorigenesis in these tissues. The hypothesis that loss of Dab2 expression is an early event in epithelial tumorigenesis was further verified by analysis of anogenital squamous cell cancers, wherein methylation of the gene was detecteable in histologically confimed pre-invasive, intra-epithelial neoplastic lesions. Furthermore, methylation of Dab2 was closely associated with metastasis in breast and HNSCC and with less favourable clinical outcome in both tumor types. Conclusions: These results identify Dab2 as gene frequently subject to transcriptional silencing in human solid tumors and imply that analysis of Dab2 methylation/expressive may have utility in identification of individual cancers at high risk of clinically aggressive disease. No significant financial relationships to disclose.
Pegfilgrastim in pediatric sarcoma patients undergoing dose-intensive chemotherapy: Phase II study results
Authors: S. L. Spunt, H. Irving, J. Frost, L. Sender, B. Yang, V. M. Santana
Journal: Journal of Clinical Oncology (2009)

10024 Background: Children with cancer undergoing dose-intensive chemotherapy often require G-CSF support. Patients (pts) &lt; 2 yrs have the highest risk of prolonged neutropenia due to imprecise dosing and immature drug clearance. Once-per-cycle pegfilgrastim may be beneficial due to neutrophil-mediated clearance that allows adequate serum levels throughout the neutropenic period. Young pts, who receive relatively more myeloablative chemotherapy, should have the highest pegfilgrastim exposure. Methods: Pts ≤21 yrs (age groups 0–5, 6–11, and ≥12 yrs) with sarcoma and scheduled to receive VAdriaC (cycles 1 &amp; 3) and IE (cycles 2 &amp; 4) were randomized 6:1 to receive pegfilgrastim 100 μg/kg or filgrastim (5 μg/kg/d until ANC ≥ 10×10 9 /L) 24 hrs after chemotherapy administration. Post-nadir ANC recovery, incidence of ANC recovery by day 21 of cycles 1 &amp; 3, pharmacokinetics (PK), and safety by age group were evaluated. Results: 43 pts (63% male) received pegfilgrastim (n=37) or filgrastim (n=6). Maximum pegfilgrastim concentration was achieved ∼24-hrs postdose and sustained until ANC nadir. Pegfilgrastim levels fell rapidly as ANC recovered. One child did not achieve ANC recovery by day 21 in cycle 1: an 8-mo-old 7.9-kg boy with non-metastatic undifferentiated sarcoma had 24 days of severe neutropenia in cycle 1. The youngest age group (including this child) had longer duration of severe neutropenia and, consequently, higher pegfilgrastim exposure ( Table ). Treatment-related adverse events were generally mild to moderate (pegfilgrastim 22%, filgrastim 33%); the only treatment-related event reported by &gt;1 pt was bone pain (pegfilgrastim=11%, filgrastim=17%). Conclusions: ANC, PK, and safety profiles in pediatric patients were comparable with those in adults and support pegfilgrastim dosing across pediatric age groups. Consistent with neutrophil-mediated clearance, adequate exposure to pegfilgrastim was maintained in the youngest pts who received the most myelosuppressive chemotherapy. [Table: see text] [Table: see text]
Quality of life after radical prostatectomy or external beam radiotherapy for localized prostate cancer: A controlled prospective study
Authors: S. M. Di Stasi, A. Giannantoni, L. Storti, F. Chiarotti, F. Attisani, E. A. Jannini, G. Zampa, G. Vespasiani
Journal: Journal of Clinical Oncology (2005)

4555 Background: General and disease specific health-related quality of life (HRQOL) were assessed within the framework of a randomized trial to compare the outcomes of radical retropubic prostatectomy (RP) versus external beam radiotherapy (EBRT) in patients with clinically localized prostate cancer. Methods: 137 patients were randomly treated with RP (n=70) or EBRT (n=67). Before treatment and at 1, 3, 6, 12 and 24 months of follow-up, 96 evaluable patients, 47 in RP and 49 in EBRT group, completed a questionnaire assessing the general HRQOL of life and specific changes in bowel, urinary and sexual functions. Results: In the first month after treatment, RP group reported a significant decrease in general HRQOL than that observed in patients receiving EBRT (p<0.001). At 12 months, the scores were not statistically different from the baseline scores in both treatment groups (p=0.431). After treatment the RP group showed a significantly lower urinary function score than the EBRT group (p<0.001). Urinary function improved with time during the first year after RP but remained fairly constant during year 2. Approximately 10.6% of RP and 2.9% of EBRT patients (OR=3.9, 95% CI=1.4 to 5.9) were incontinent at 2 years. The EBRT group was associated with significantly worse bowel function than RP group throughout follow-up time (p<0.001). Approximately 26.5% of EBRT and 6.1% of RP patients (OR=0.23, 95% CI=0.1 to 0.5) had bowel dysfunction at 2 years. Sexual function was significantly better in EBRT than RP group just after treatment (p<0.001). During follow-up, the EBRT group showed a modest but statistically significant decline in sexual function, whereas the RP group improving over time. However, at 2 years sexual dysfunction was more prevalent in the RP than in the EBRT group (70.2% versus 61.2%; OR=2.5, 95% CI=1.6 to 3.8). The bothersome scores generally correlated with the functionality scores. Conclusions: A decrease in general HRQOL was evident only in the first month after RP. Patients undergoing RP report significantly worse urinary function, but better bowel function than those treated with EBRT. Both groups have a decline in sexual function throughout the post-treatment period. No significant financial relationships to disclose.
Quantification of atorvastatin in human plasma by liquid chromatography tandem mass spectrometry and its application for bioequivalence study of three formulations
Authors: Yahdiana Harahap, Santi Purnasari, None Harmita, Rina Rahmawati, Krisnasari Dian, None Pratami, Witri Sansris, Siti Fatriyah
Journal: Asian Journal of Pharmaceutical Sciences (2015)
High expression levels of the h-prune protein is correlated with advanced breast cancer
Authors: G. Palmieri, A. Andrè, A. Cossu, M. Budroni, G. Arrigoni, M. C. Sini, A. D’Angelo, N. Marino, F. Tanda, M. Zollo
Journal: Journal of Clinical Oncology (2005)

9575 Background: Metastatic spread is the leading cause of death in human cancers. Increased enzymatic activity of the h-prune protein, stimulated by its interaction with the nm-23 metastasis-suppressor protein, is strongly involved in stimulating cellular motility and promoting cancer metastasis. We here better defined the clinical role of h-prune in breast cancer patients. Methods: Using immunohistochemistry, we assessed h-prune and nm23-H1 protein expression in two series of breast cancer patients: (i) in 2,109 cases with pathological reports on primary tumors; and (ii) in 412 cases with detailed clinical information. To assess the role of DNA amplification in gene activation, the h-prune copy number was evaluated by fluorescence in situ hybridization analysis in 1,016 breast cancer cases. Results: In the patients tested (2,463), 1,340 (54%) had an increased level of h-prune expression; a positive immunostaining for nm23-H1 was observed in 615 of 2,061 (30%) cases. Overexpression of h-prune was associated with multiple gene-copy number at chromosome 1q21.3 in a very limited fraction of cases (68 of 1,016; 6.7%), strongly indicating that alternative pathways induce h-prune activation in breast cancer. Multivariate Cox regression analysis showed that neither h-prune overexpression nor decreased nm23-H1 immunostaining are independent prognostic factors. However, a significant association of h-prune overexpression with either advanced lymph node status (p=0.017) or presence of distant metastases (p=0.029) was observed. Conclusions: Although not significantly correlated with overall survival, positive h-prune immunostaining identifies subsets of breast cancer patients with higher tumor aggressiveness. Further investigations using larger collections of advanced breast cancer patients are required for assessing the predictive role of h-prune in breast cancer.Work was supported by Associazione Italiana Ricerca sul Cancro. No significant financial relationships to disclose.
Biweekly liposomal pegylated doxorubicin in elderly women with advanced breast cancer: A prospective multicenter trial focusing on tolerability and cardiotoxicity.
Authors: U. Basso, A. Roma, C. Falci, A. Brunello, P. Fiduccia, L. Vamvakas, A. Bononi, M. Gusella, A. Banzato, S. Monfardini
Journal: Journal of Clinical Oncology (2010)

1138 Background: To assess tolerability and activity of liposomal pegylated doxorubicin (PLD) in women older than 70 years with locally advanced or metastatic breast cancer within a multicenter prospective trial. Methods: All pts underwent Multidimensional Geriatric Assessment (MGA) and frail pts (dependence in Activities of Daily Living; three or more severe comorbidities, geriatric syndromes) were excluded. Normal cardiac function was required at baseline. Bi-weekly schedule of 20 mg/m2 was adopted. More than 12 doses were prescribed only to responsive pts. Results: From Feb 2006 to Sep 2009, 28 pts were enrolled, median age 77 yrs (range 70-93), 10.7% had locally advanced disease, 10.7% only bone metastases, 78.6% visceral involvement; 28.6% of pts had been pre-treated with one or more lines of chemotherapy for advanced disease. After MGA, 35.7% were deemed fit and 64.3% vulnerable. A mean of 7.2 doses were delivered (range 1 to 20), with an actual dose intensity of 8.9 mg/m2/week (range 5.2-10). Worst toxicity experienced by pts is outlined in table. No cardiac events were registered. Only 1 pt received both G-CSF and erythropoietin. Causes of treatment interruption were progression 46.4%, refusal/loss at follow-up 21.4%, toxicities 10.7%, other or ongoing 10.7%. RECIST response was obtained in 34.8% of 23 evaluable pts, 30.4% remained stable; with a median TTP of 4.4 mo (11 censored), and a median OS of 15.4 mo. Receiving full dose intensity vs <9 mg/m2/week did not impact on response (p=0.26) and progression (p=0.6), as well as MGA status (vulnerable vs FIT, p=0.65 for response, p=0.9 for progression). Conclusions: Biweekly PLD monochemotherapy is well tolerated in terms of hematological and cardiac safety both by fit and vulnerable pts, with an apparently fairly good response rate. Close follow-up of pts is recommended in order to monitor skin toxicity and avoid early refusal/loss at follow-up. Accrual is still ongoing. Toxicity according to CTCAE v3 Grade 1-2 Grade 3-4 Neutropenia 23% 0 Thrombocytopenia 5% 0 Anemia 18% 9% Palmar-plantar erythrodysesthesia 41% 9% Nausea/vomiting 32% 0 Mucositis 18% 9% Infection 0 5% No significant financial relationships to disclose.
Dose escalation phase of a phase I/II study of GTI-2501, an antisense to the R1 subunit of ribonucleotide reductase (RNR) and docetaxel in patients with metastatic hormone-refractory prostate cancer
Authors: Y. Ko, S. North, S. R. Berry, D. S. Ernst, L. Klotz, P. Murray, P. Venner
Journal: Journal of Clinical Oncology (2006)

2078 Background: GTI-2501 (GTI) is a 20-mer oligonucleotide that is complementary to the R1 subunit of the RNR mRNA. The R1 protein is overexpressed in multiple tumour cell lines. GTI displays anti-tumour activity against prostate cancer xenografts in mice as a single agent and in combination with mitoxantrone. GTI also adds to the anti-tumour efficacy of taxanes in breast cancer xenografts in mice. A Phase 1 study of a 14 day continuous infusion of GTI in patients with solid tumours showed no dose limiting toxicities at doses up to 210.9 mg/m 2 /day. The objective of this dose escalation phase of a phase I/II study was to define a safe phase II dose of GTI in combination with docetaxel (D) in men with metastatic hormone refractory prostate cancer (HRPC). Methods: Men with metastatic HRPC were enrolled at 3 centres in Canada. GTI was given as a 14d continuous IV infusion every 21d with D IV infusion started 2 hrs prior to the end of the GTI infusion. Planned dose escalation cohorts are summarized in table . Results: 13 men were enrolled to the 3 cohorts. All patients are evaluable for toxicity. There was one possible DLT - an episode of grade 4 neutropenia reported at cycle 2 day 1 in the highest dose cohort - but the duration of neutropenia could not be confirmed. 3 additional patients were accrued to that cohort with no DLTs. The most common gr 3/4 toxicity was attributable to D (10 pts with Gr 3/4 neutropenia). The observed incidence of Gr 3/4 neutropenia was expected since patients had weekly CBCs. Only 1 patient had febrile neutropenia. 11 pts had fatigue (4 Gr 3) related to D and /or GTI. Other GTI attributable adverse events were Gr 1/2 including transient rises in transaminases and PTT. The pharmacokinetic data which is summarized in the table will be presented in full at the meeting. Conclusions: GTI can be given safely at its highest planned dose with standard doses of D. A Phase II evaluation of the GTI + D combination is planned for men with HRPC. [Table: see text] [Table: see text]
A Phase 1 Study Evaluating Abt-414 with Concurrent Radiotherapy (Rt) and Temozolomide (Tmz) in Newly Diagnosed Glioblastoma (Gbm)
Authors: H.K. Gan, L. Fichtel, A. Lassman, R. Merrell, M.J. van den Bent, P. Kumthekar, A. Scott, M. Pedersen, E. Gomez, J. Fischer, W. Ames, H. Xiong, M. Dudley, L. Roberts-Rapp, P.J. Ansell, K. Holen, D.A. Reardon
Journal: Annals of Oncology (2014)
Two galactose-α-1,3-galactose carrying peptidases from pork kidney mediate anaphylactogenic responses in delayed meat allergy
Authors: C. Hilger, J. Fischer, K. Swiontek, F. Hentges, C. Lehners, B. Eberlein, M. Morisset, T. Biedermann, M. Ollert
Journal: Allergy (2016)

Serum IgE antibodies directed at galactose-α-1,3-galactose (α-Gal) are associated with a novel form of delayed anaphylaxis occurring upon consumption of red meat or innards. Pork kidney is known as the most potent trigger of this syndrome, but the culprit allergens have not yet been identified. The aim of this study was the identification and characterization of pork kidney proteins mediating delayed anaphylactic reactions through specific IgE to α-Gal.A cohort of 59 patients with specific IgE to α-Gal was screened by immunoblot for IgE-reactive proteins in pork kidney. Proteins were identified by peptide mass fingerprinting. Isolated proteins were assayed in ELISA and ELISA inhibition, basophil activation and skin prick test.Several IgE-binding proteins of high molecular weight (100- >200 kDa) were detected in pork kidney extracts by immunoblot using patient sera and an anti-α-Gal antibody. Two major IgE-binding proteins were identified as porcine angiotensin-I-converting enzyme (ACE I) and aminopeptidase N (AP-N). Reactivity of patient sera and anti-α-Gal antibody to both proteins was abolished by carbohydrate oxidation. The α-Gal IgE epitopes were resistant to heat denaturation. Pork kidney extract, isolated ACE I, and AP-N were able to activate patient basophils and elicit positive responses in skin prick tests.Two cell-membrane proteins carrying α-Gal epitopes were identified in pork kidney. For the first time, isolated meat proteins were shown to induce basophil activation in patients with delayed anaphylaxis to red meat providing further confirmation for the clinical relevance of these α-Gal-carrying proteins.
Income and mortality in the United States
Authors: K. Judge
Journal: BMJ (1996)

It is not necessary for Toozs-Hobson and Car- dozo to claim that the whole female population is diseased in order to recommend prophylaxis; we recommend supplementation with folic acid for women before conception and in the first trimester without believing that they all have a dietary deficiency.There may well be a very good argu- ment for all postmenopausal women to take hormone replacement therapy, based on evidence of a favourable ratio of benefits to risks.For the women who are being recommended lifelong hormone replacement therapy, convincing arguments of this sort will be more persuasive than labelling a universal life event as a disease.