tbuckley/cabot-search huggingface dataset:
Abstract LB-007: Synergistic inhibition of human gastric and colorectal cancers by Bromelain and N-acetylcysteine: An in vivo study
Authors: Afshin Amini, Samar Masoumi-Moghaddam, Anahid Ehteda, Winston Liauw, Javed Akhter, Krishna Pilai, David L. Morris
Journal: Cancer Research (2015)

Abstract Mucin is well understood to be an adverse prognostic factor in some cancers. We previously reported that a combination of Bromelain (BR) and N-acetylcysteine (NAC) were synergistic in dissolving pseudomyxoma peritonei mucin, had direct in vitro cytotoxic effects on some gastrointestinal cancer cells and sensitized them to some chemotherapy agents. In the present study, we aimed to evaluate the growth-inhibitory effect of BR and NAC as single agent or combination therapy in nude mice models of gastrointestinal cancer. Nude mice received 2 million and 1 million cells of MKN45 (gastric) and LS174T (colorectal) by intraperitoneal injection. At day 14 and 7 post inoculation for MKN45 and LS174T cells, respectively, animals were intraperitoneally administrated BR (3, 6 mg/kg), NAC (300, 500 mg/kg) or their combination every other day over 12 days for MKN45 and 17 days for LS174T models. At the end of the study, the animals were euthanized, the number of peritoneal nodules and their weight were collected, and the peritoneal tumors were subjected to immunohistochemistry for evaluation of MUC2. No toxicity was observed during the experiment. At necropsy, highly significant reductions in the number of tumor nodules and tumor burden were observed, in particular in the combination group, where almost complete inhibition in LS174T group was found. There was more than 95% and 70% decreases in tumor burden and tumor nodules, respectively, in LS174T group after combination treatment. For MKN45 model, the reductions in tumor burden and tumor nodules in combination groups were more than 60% and 70%, respectively. Performing immunohistochemistry on tumor samples, MUC2 staining of the LS174T xenografts showed a greater than 60% reduction of cytoplasmic staining. To the best of our knowledge, this is the first report of the in vivo use of this combination with synergistic inhibition of human gastric and colorectal cancers. The combination of BR and NAC in mucin secreting gastrointestinal tumors is interesting and could be of potential value in peritoneal cancer. Citation Format: Afshin Amini, Samar Masoumi-Moghaddam, Anahid Ehteda, Winston Liauw, Javed Akhter, Krishna Pilai, David L. Morris. Synergistic inhibition of human gastric and colorectal cancers by Bromelain and N-acetylcysteine: An in vivo study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-007. doi:10.1158/1538-7445.AM2015-LB-007
Impact of aspirin as secondary prevention in an unselected cohort of 25,644 patients with colorectal cancer: A population-based study.
Authors: Simer Bains, Milada Mahic, Milada Cvancarova, Sheraz Yaqub, Liv Marit Dørum, Bjørn Atle Bjørnbeth, Bjørn Møller, Kristoffer Watten Brudvik, Kjetil Tasken
Journal: Journal of Clinical Oncology (2015)

3504 Background: Regular use of aspirin (acetylsalicylic acid) has been associated with reduced incidence and mortality of colorectal cancer (CRC). However, the use of aspirin as primary prevention in the general population is still being debated due to the risk of serious hemorrhagic side effects. In contrast, the use of aspirin as secondary prevention in patients with CRC may be more justified from a risk-benefit prospective, and also as we have observed that aspirin reverses tumor immune evasion mechanisms in established colorectal cancer. This study was conducted to examine the association between aspirin use after diagnosis of CRC with CRC-specific survival (CSS) and overall survival (OS) in the largest cohort ever examined. Methods: An observational population-based retrospective cohort study was undertaken by linking patients diagnosed with CRC from 2004 through 2011 (Cancer Registry of Norway) with the use of aspirin in the same patients (The Norwegian Prescription Database). The registries used cover more than 99% of the Norwegian population, and include all cases in an unselected manner. Exposure was defined as having received prescription for more than 6 months of aspirin after diagnosis of CRC. Multivariate Cox proportional hazard and competing risk analyses were used to model survival. The main outcome measures of the study were CSS and OS. Results: In total, 25,644 patients were diagnosed with CRC in the study period and 6,109 of them were defined as exposed to aspirin after the diagnosis of CRC. The median follow-up was 2.2 years. Among aspirin exposed cases (n = 6,109), a total of 2,088 (34.2%) deaths were recorded of which 1,172 (19.2%) were CRC-specific. Among non-exposed aspirin cases (n = 19,535), a total of 7,595 (38.9%) deaths were recorded of which 6,356 (33.5%) were CRC-specific. In multivariate analysis, aspirin exposure after the diagnosis of CRC was independently associated with improved CSS (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.50-0.57; p < 0.001) and OS (HR, 0.71; 95% CI, 0.68-0.75; p < 0.001). Conclusions: Exposure to aspirin after the diagnosis of CRC is independently associated with improved CSS and OS.
Anti-CD28 Antibody and Belatacept Exert Differential Effects on Mechanisms of Renal Allograft Rejection
Authors: Simon Ville, Nicolas Poirier, Julien Branchereau, Vianney Charpy, Sabrina Pengam, Véronique Nerriere-Daguin, Stéphanie Le Bas-Bernardet, Flora Coulon, Caroline Mary, Alexis Chenouard, Jeremy Hervouet, David Minault, Steven Nedellec, Karine Renaudin, Bernard Vanhove, Gilles Blancho
Journal: Journal of the American Society of Nephrology (2016)

Belatacept is a biologic that targets CD80/86 and prevents its interaction with CD28 and its alternative ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4). Clinical experience in kidney transplantation has revealed a high incidence of rejection with belatacept, especially with intensive regimens, suggesting that blocking CTLA-4 is deleterious. We performed a head to head assessment of FR104 ( n =5), a selective pegylated Fab′ antibody fragment antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept ( n =5) in kidney allotransplantation in baboons. The biologics were supplemented with an initial 1-month treatment with low-dose tacrolimus. In cases of acute rejection, animals also received steroids. In the belatacept group, four of five recipients developed severe, steroid–resistant acute cellular rejection, whereas FR104-treated animals did not. Assessment of regulatory T cell–specific demethylated region methylation status in 1-month biopsy samples revealed a nonsignificant trend for higher regulatory T cell frequencies in FR104-treated animals. Transcriptional analysis did not reveal significant differences in Th17 cytokines but did reveal higher levels of IL-21, the main cytokine secreted by CD4 T follicular helper (Tfh) cells, in belatacept-treated animals. In vitro , FR104 controlled the proliferative response of human preexisting Tfh cells more efficiently than belatacept. In mice, selective CD28 blockade also controlled Tfh memory cell responses to KLH stimulation more efficiently than CD80/86 blockade. Our data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation.
Low WT1 Expression At Diagnosis Is a Strong Predictor On Poor Outcome In Patients With t(8;21) Acute Myeloid Leukemia
Authors: Ya-Zhen Qin, Hong-Hu Zhu, Qian Jiang, Dai-Hong Liu, Hao Jiang, Lan-Ping Xu, Huan Chen, Yu Wang, Xiao-hui Zhang, Jun-Yue Chai MM, Li-Ru Wang, Yan-Rong Liu, Xiao-Jun Huang
Journal: Blood (2013)
Injection therapies for plantar fasciopathy (‘plantar fasciitis’): a systematic review and network meta-analysis of 22 randomised controlled trials
Authors: Konstantinos Tsikopoulos, Haris S Vasiliadis, Dimitris Mavridis
Journal: British Journal of Sports Medicine (2016)

Objective To compare the efficacy of different injection therapies for plantar fasciopathy (historically known as ‘plantar fasciitis’). Design Systematic review and network meta-analysis. Data sources Electronic databases (MEDLINE, CENTRAL, Web of Science and Scopus) were searched up to 11 July 2015 for completed studies. Eligibility criteria for selecting studies We considered randomised trials comparing various injection therapies in adults with plantar fasciopathy. The primary outcome was pain relief. Secondary outcomes included functional disability, composite and health-related outcomes. All outcomes were assessed (1) in the short term (up to 2 months), (2) the intermediate term (2–6 months) and (3) the medium term (more than 6 months to 2 years). Quality assessment was performed using the Cochrane risk of bias tool. Results We included 22 trials comprising 1216 patients. Dehydrated amniotic membrane injections were significantly superior to corticosteroids in the short term in achieving the primary and composite outcomes (mean difference (MD) in visual analogue scale (VAS) was −7.32, 95% CIs −11.2 to −3.38; and MD in the foot health status questionnaire was 31.2, 95% CIs 13.9 to 48.6, respectively). For pain relief, botulinum toxin-A provided a significant short-term advantage over placebo, which was still present at 6 months (MD in VAS was −2.9, 95% CIs −4.44 to −1.39; and MD −4.34, 95% CIs −7.18 to −1.54, respectively). Summary Although the dehydrated amniotic membrane provided significant clinical relief at 0–2 months, there were no data about this treatment at 2 months and beyond. Botulinum toxin-A injections significantly reduced pain intensity at 0–6 months. Systematic review registration number CRD42015017353.
A phase I, first-in-human study of ARGX-110, a monoclonal antibody targeting CD70, a receptor involved in immune escape and tumor growth in patients with solid and hematologic malignancies.
Authors: Ahmad Awada, Christian D. Rolfo, Sylvie Rottey, Laure Ysebrant de Lendonck, Wilfried A. Schroyens, Fritz Offner, Karen Silence, Torsten Dreier, Mahan Moshir, Hans de Haard, Marc Peeters, Dominique Bron, Alain Thibault, Philippe G. Aftimos
Journal: Journal of Clinical Oncology (2014)

3023 Background: Distribution of CD70, a TNF superfamily receptor involved in transient, rapid-onset immune response, is normally restricted to subsets of T-, B-, and dendritic cells. It is chronically over-expressed in patients with malignancies in whom it mediates tumor growth and immune escape. ARGX-110, a monoclonal IgG1 SIMPLE Antibody glyco-engineered for enhanced ADCC (POTELLIGENT), is undergoing Phase 1 testing (ClinicalTrials.gov Identifier: NCT01813539). Methods: As of December 2013, 19 patients (median age: 56 years; prior chemo: 82%; prior biologics/TKIs: 29%) with > 10% tumor cells staining positive for CD70 by immunohistochemistry were treated at 0.1, 1, 5, and 10 mg/kg IV q3 weeks; n = 6, 5, 3, and 5) and received a total of 82 cycles (median = 4; range 1-11). Results: The most common drug-related adverse events (AE) observed in 14 patients were: infusion-related reaction (26%), fatigue (21%) and diarrhea (16%). Drug-related Grade 3 AEs (hypoxia, anorexia, fatigue) were observed in 2 patients. No immune-related AE was observed. Pharmacokinetics were dose-linear (T 1/2 = 11 days). Saturated target-mediated clearance (Ctarget) was observed as of 1 mg/kg. ADCC and depletion of circulating CD70+ cells (qPCR) were demonstrated in all patients. Complement-derived cytotoxicity (CDC) was maximal at > 0.1 mg/kg. Circulating Tregswere reduced by ≥ 50% in most patients treated at the highest doses. One CR (in blood) was confirmed in a patient with stage IVA (T2NxM0B2) Sézary syndrome. Five patients maintained SD for > 6 months (RCC, parotid, myoepithelial, platinum-resistant ovarian, mesothelioma). Conclusions: Based on the clinical and immunological parameters an intermediate dose level of 2 mg/kg is being studied. Full results will be presented. Clinical trial information: NCT01813539. Dose 0.1 mg/kg 1 mg/kg 5 mg/kg 10 mg/kg PK (Ctarget) Not saturated Saturated Saturated Saturated ADCC Yes Yes Yes Yes CDC Not saturated Maximal Maximal Maximal CD70 qPCR 70% ↓ 61%↓ 72%↓ NA B-cell count Stable Stable Stable Stable T-cell count Stable Stable Stable Stable
Use of chemotherapy in the last three months of life: A retrospective single centre analysis
Authors: S. Braga, A. Miranda, M. Dias, R. Fonseca, J. L. Passos-Coelho, A. Fernandes, J. D. Costa, A. Moreira
Journal: Journal of Clinical Oncology (2005)

8073 Background: There is concern that terminally ill cancer patients (pts) are overtreated with chemotherapy (CT), even when such treatment is unlikely to palliate symptoms. The study objective was to evaluate the use of CT, in the last three months of life, in a cohort of pts with advanced solid tumours. Methods: All pts who died in our hospital, in 2003 and received CT for advanced cancer, were included. Detailed data concerning chemotherapy and toxicity, in the last three months of life, was collected in pts clinical charts. Pts with hematological and pediatric tumors were not included. Descriptive statistics, chi-square and univariate analysis was performed using Statistical Software Stata 6.2. Results: A total of 319 pts (124 male, 195 female) were included. Median age was 61.0 yrs (range 21; 92 yrs). Breast cancer was the most frequent primary (33%). Median time from diagnosis of metastatic disease to death was 11 months. The proportion of pts who received CT in the last three months of life was 66% (n=211), in the last month 37% and in the last two weeks 21%. Among pts who received CT in the last three months of life, 67% started a new CT regimen in this period and 25% in the last month. Sixteen percent of pts who received CT in the last three months were admitted to hospital and 24% had at least one emergency room visit due to CT toxicity. There was an increased risk of receiving CT in the last three months of life for pts with <50yo (OR=5.53; CI 2.4–12.6), and for pts with breast, ovary or pancreatic cancer (OR=3.14; CI 1.94–5.71). Conclusions: There is a large proportion of pts who received CT in the last three months of life, including initiation of a new regimen within the last 30 days. Thus, further study is needed to evaluate if such aggressive attitude results in better palliation of symptoms at the end of life. No significant financial relationships to disclose.
Case 12-1980
Authors: Richard C. Cabot, Robert E. Scully, James J. Galdabini, Betty U. McNeely, Ruben F. Gittes, Gilbert L. Brodsky
Journal: New England Journal of Medicine (1980)

Presentation of CaseA 54-year-old woman was admitted to the hospital because of a mass in the flank.She was well until three months earlier, when she experienced the sudden onset of severe pain in the left flank, with radiation into the left side of the back, the left groin, and the left lower abdominal quadrant; she was sweaty and vomited several times. She entered another hospital, where examination showed tenderness in the left costovertebral angle; abdominal and rectal examinations were negative.The urine was normal. The hematocrit was 37 per cent; the white-cell count was 14,300, with 72 per . . .
FOXM1 and FOXQ1 Are Promising Prognostic Biomarkers and Novel Targets of Tumor-Suppressive miR-342 in Human Colorectal Cancer
Authors: Wenhao Weng, Yoshinaga Okugawa, Shusuke Toden, Yuji Toiyama, Masato Kusunoki, Ajay Goel
Journal: Clinical Cancer Research (2016)

Colorectal cancer ranks as the third most frequent cancer type, and its incidence continues to rise gradually worldwide, highlighting the need to identify previously unrecognized molecular events that propel development of this malignancy. Recent evidence suggests that dysregulated expression of FOX family of transcription factors may be critical in various genetic disorders as well as cancer; however, the functional and clinical significance of this pathway in colorectal cancer remains unclear.Herein, we performed a systematic and comprehensive discovery step by evaluating the expression of FOX family members, and identified that FOXM1 and FOXQ1 are frequently overexpressed in colorectal cancer. We subsequently confirmed these findings in two large testing cohorts (n = 550) and an independent clinical validation cohort (n = 134), in which high expression of FOXM1 and FOXQ1 emerged as an independent prognostic factor in colorectal cancer patients. We corroborated these findings by performing functional assays in which knockdown of FOXM1 and FOXQ1 resulted in inhibited cell proliferation and suppressed migration and invasion in colorectal cancer cells. Furthermore, using bioinformatic approaches, we identified miR-342 as a novel regulator of both FOXM1 and FOXQ1. Overexpression or inhibition of miR-342 modulated the expression of both genes and contributed to phenotypic alterations in colorectal cancer cells, which was subsequently validated in a xenograft animal model.Collectively, we have firstly identified FOXM1 and FOXQ1 as promising prognostic biomarkers in colorectal cancer patients, and provided novel evidence that therapeutic targeting of these genes or miR-342 may be a potential treatment approach in colorectal cancer patients. Clin Cancer Res; 22(19); 4947-57. ©2016 AACR.
Can abscopal effects of local radiotherapy be predicted by modeling T cell trafficking?
Authors: Sandra Demaria, Silvia C. Formenti
Journal: Journal for ImmunoTherapy of Cancer (2016)

The abscopal effect of radiation describes tumor regression in metastases outside of the field upon treatment of one site, and is mediated by radiation-induced anti-tumor T cells. The ability of radiation to generate an in situ tumor vaccine and improve responses to immunotherapy is under intense investigation in the clinic. Preclinical and clinical evidence shows that multiple factors regulate radiation interaction with the immune system within and outside of the irradiated tumor. Poleszczuk and colleagues developed a mathematical model of T cell trafficking between metastases, and in a recent publication propose that the specific metastatic site irradiated determines the ability of T cells to traffic to other metastases and mediate abscopal responses and should dictate clinical decision making [Poleszczuk et al. Cancer Res 76:1009-18, 2016]. Here we critically discuss this model in light of the currently available information about abscopal responses in mice and patients. Caution in relying upon overly simplified models, before validation in real patients, is recommended.
Case 7-1982
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Faysal M. Hasan, Eugene J. Mark
Journal: New England Journal of Medicine (1982)

Presentation of Case First admission. A 35-year-old man was admitted to the hospital because of an abnormal x-ray film of the chest.He was in vigorous health until eight weeks earlier, when he began to experience constant substernal distress similar to heartburn but unrelated to meals, activity, or position. A physician found no abnormality on examination, and an electrocardiogram was normal. X-ray films and tomographic examination of the chest showed superior mediastinal and bilateral hilar lymphadenopathy; a well-defined lobulated serpentine density, 8.5 by 6 cm, was evident in the medial portion of the left lower lobe; no vessels were . . .
Comparison of postoperative immune function in patients with thoracic esophageal cancer after video-assisted thoracoscopic surgery or conventional open esophagectomy
Authors: Jun-Tao Tan, Jian-Hong Zhong, Yang Yang, Nai-Qun Mao, De-Seng Liu, Ding-Ming Huang, Yong-Xiang Zhao, Chuan-Tian Zuo
Journal: International Journal of Surgery (2016)
Cell Cycle–Dependent Mechanisms Underlie Vincristine-Induced Death of Primary Acute Lymphoblastic Leukemia Cells
Authors: Anisha Kothari, Walter N. Hittelman, Timothy C. Chambers
Journal: Cancer Research (2016)

Microtubule-targeting agents (MTA), such as the taxanes and vinca alkaloids, are used to treat a variety of cancers due to their ability to perturb microtubule dynamics. In cell culture, MTAs exert their anticancer effects primarily by causing mitotic arrest and cell death. However, accumulating indirect evidence suggests that MTAs may exert their cytotoxicity in human tumors by interfering with interphase microtubules. In this study, we sought to develop and characterize an experimental system in which to test the hypothesis that MTAs induce cell death during interphase. Primary adult acute lymphoblastic leukemia (ALL) cells treated with vincristine only weakly exhibited colocalization between mitotic and apoptotic markers and major characteristics of mitotic death, such as an increase in cells with 4N DNA content before the appearance of cells with <2N DNA content, suggesting a mixed response. Therefore, we separated ALL cells into distinct phases of the cell cycle by centrifugal elutriation, labeled cells with 5-ethynyl-2'-deoxyuridine (EdU), and then treated each population with vincristine. Cells isolated during G1 underwent cell death without evidence of EdU uptake, indicating that the cytotoxic effects of vincristine took place during G1 Conversely, cells isolated during S or G2-M phases underwent death following mitotic arrest. Thus, vincristine induces distinct death programs in primary ALL cells depending on cell-cycle phase, and cells in G1 are particularly susceptible to perturbation of interphase microtubules. Primary ALL cells may therefore provide a powerful model system in which to study the multimodal mechanisms underlying MTA-induced cell death. Cancer Res; 76(12); 3553-61. ©2016 AACR.
Sequence-defined cMET/HGFR-targeted Polymers as Gene Delivery Vehicles for the Theranostic Sodium Iodide Symporter (NIS) Gene
Authors: Sarah Urnauer, Stephan Morys, Ana Krhac Levacic, Andrea M Müller, Christina Schug, Kathrin A Schmohl, Nathalie Schwenk, Christian Zach, Janette Carlsen, Peter Bartenstein, Ernst Wagner, Christine Spitzweg
Journal: Molecular Therapy (2016)

The sodium iodide symporter (NIS) as well-characterized theranostic gene represents an outstanding tool to target different cancer types allowing noninvasive imaging of functional NIS expression and therapeutic radioiodide application. Based on its overexpression on the surface of most cancer types, the cMET/hepatocyte growth factor receptor serves as ideal target for tumor-selective gene delivery. Sequence-defined polymers as nonviral gene delivery vehicles comprising polyethylene glycol (PEG) and cationic (oligoethanoamino) amide cores coupled with a cMET-binding peptide (cMBP2) were complexed with NIS-DNA and tested for receptor-specificity, transduction efficiency, and therapeutic efficacy in hepatocellular cancer cells HuH7. In vitro iodide uptake studies demonstrated high transduction efficiency and cMET-specificity of NIS-encoding polyplexes (cMBP2-PEG-Stp/NIS) compared to polyplexes without targeting ligand (Ala-PEG-Stp/NIS) and without coding DNA (cMBP2-PEG-Stp/Antisense-NIS). Tumor recruitment and vector biodistribution were investigated in vivo in a subcutaneous xenograft mouse model showing high tumor-selective iodide accumulation in cMBP2-PEG-Stp/NIS-treated mice (6.6 ± 1.6% ID/g (123)I, biological half-life 3 hours) by (123)I-scintigraphy. Therapy studies with three cycles of polyplexes and (131)I application resulted in significant delay in tumor growth and prolonged survival. These data demonstrate the enormous potential of cMET-targeted sequence-defined polymers combined with the unique theranostic function of NIS allowing for optimized transfection efficiency while eliminating toxicity.