tbuckley/cabot-search huggingface dataset:
Abstract 2806: Oxidative stress limits metastasis of human melanoma cells
Authors: Elena Piskounova, Michail Agathocleous, Malea Murphy, Zeping Hu, Ralph DeBerardinis, Sean Morrison
Journal: Cancer Research (2016)

Abstract Solid cancer cells commonly enter the blood and disseminate systemically, but are highly inefficient at forming distant metastases for poorly understood reasons. We studied the complex and poorly understood process of metastasis by using a clinically relevant model of melanoma metastasis: patient-derived xenografts (PDX) that differ in their capacity to metastasize in NOD-SCID-Il2rg−/− (NSG) mice, mirroring their metastasis histories in the patients from which they were derived. We systematically dissected distinct steps of the metastatic cascade in vivo to show that melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficiently metastasizing melanomas. Using Liquid Chromatography-Mass Spectrometry (LC-MS) and flow cytometry, we discovered that melanoma cells in the blood and visceral organs experienced high levels of oxidative stress not observed in subcutaneous tumours. This work demonstrates that successfully metastasizing melanomas undergo reversible functional and metabolic changes during metastasis that increases their capacity to withstand oxidative stress through an increased dependence on NADPH-generating enzymes in the folate pathway. Chronic antioxidant treatment promotes circulating melanoma cell survival and distant metastases in NSG mice. Folate pathway inhibition, using low-dose methotrexate or depletion of several NADPH-regenerating enzymes, inhibits distant metastases without significantly affecting the growth of subcutaneous tumours in the same mice. We are currently investigating the role of other NADPH-regenerating pathways such as the pentose phosphate pathway in metastasis of human melanoma cells. Finally, we hypothesize that other stress types may also play a role in limiting metastasis in vivo and we are looking for additional metabolic adaptations that may increase stress-resistance of metastasizing melanoma cells and represent novel therapeutic targets in metastatic disease. Citation Format: Elena Piskounova, Michail Agathocleous, Malea Murphy, Zeping Hu, Ralph DeBerardinis, Sean Morrison. Oxidative stress limits metastasis of human melanoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2806.
Abstract LB-021: LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of triple-negative/basal-B breast cancer cells
Authors: Nucharee Yokdang, Jason Hatakeyama, Jessica Wald, Catalina Simion, Joseph Tellez, Dennis Chang, Manojit Swamynathan, Mingyi Chen, William Murphy, Kermit Carraway, Colleen Sweeney
Journal: Cancer Research (2016)

Abstract LRIG1, a member of the LRIG family of transmembrane leucine rich repeat-containing proteins, is a negative regulator of receptor tyrosine kinase signaling and a tumor suppressor. LRIG1 expression is broadly decreased in human cancer and in breast cancer, low expression of LRIG1 has been linked to decreased relapse-free survival. Recently, low expression of LRIG1 was revealed to be an independent risk factor for breast cancer metastasis and death. These findings suggest that LRIG1 may oppose breast cancer cell motility and invasion, cellular processes which are fundamental to metastasis. However, very little is known of LRIG1 function in this regard. In this study, we demonstrate that LRIG1is down-regulated during epithelial to mesenchymal transition (EMT) of human mammary epithelial cells, suggesting that LRIG1 expression may represent a barrier to EMT. Indeed, depletion of endogenous LRIG1 in human mammary epithelial cells expands the stem cell population, augments mammosphere formation and accelerates EMT. Conversely, expression of LRIG1 in highly invasive triple-negative/Basal B breast cancer cells provokes a mesenchymal to epithelial transition accompanied by a dramatic suppression of tumorsphere formation and a striking loss of invasive growth in three-dimensional culture. LRIG1 expression perturbs multiple signaling pathways and represses markers and effectors of the mesenchymal state. Furthermore, LRIG1 expression in MDA-MB-231 breast cancer cells significantly slows their growth as tumors, providing the first in vivo evidence that LRIG1 functions as a growth suppressor in breast cancer. Citation Format: Nucharee Yokdang, Jason Hatakeyama, Jessica Wald, Catalina Simion, Joseph Tellez, Dennis Chang, Manojit Swamynathan, Mingyi Chen, William Murphy, Kermit Carraway, Colleen Sweeney. LRIG1 opposes epithelial-to-mesenchymal transition and inhibits invasion of triple-negative/basal-B breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-021.
Randomized phase II study of pemetrexed plus carboplatin followed by pemetrexed versus paclitaxel plus carboplatin followed by pemetrexed in advanced nonsquamous, non-small cell lung cancer (LOGIK 0904).
Authors: Koichi Takayama, Koji Inoue, Masafumi Takeshita, Naoki Tashiro, Taishi Harada, Takashi Seto, Tomotoshi Imanaga, Noriko Fujimoto, Noriaki Nakagaki, Masayuki Kawasaki, Junji Kishimoto, Yukito Ichinose
Journal: Journal of Clinical Oncology (2013)

8111 Background: PARAMOUNT study confirmed the improvement of overall survival with continuation maintenance chemotherapy with pemetrexed (PEM) compared with placebo after 4 cycles of cisplatin plus PEM induction chemotherapy recently. JMEN study also showed the usefulness of switch maintenance with PEM after 4 cycles of platinum doublet without PEM. In this study, we conducted the randomized phase II study comparing switch or continuation maintenance chemotherapy with PEM after standard doublet regimen. Methods: Histologically/cytologically confirmed stage IIIb or IV non-squamous NSCLC patients with mesurable disease, ECOG PS 0-1, age over 20 years and adequate organ function were eligible for the study. Randomization was stratified by gender and stage of disease. Patients received 3 cycles of PEM 500 mg/m 2 plus CB AUC6 (Arm 1) or PAC 200 mg/m 2 plus CB AUC6 (Arm 2). All patients with non-PD after induction chemotherapy continued PEM 500 mg/m 2 until PD. Primary endopoint is progression-free survival (PFS). Results: 140 pts were enrolled and assigned to Arm 1 or Arm 2 randomly. The clinical data of 132 pts were used as full analysis set (median age 64.5 yrs (42-83), 85 male, 120 stage IV, 58 PS0, 127 adenocarcinoma, 46 never smoker). 42 pts had prior treatment including 9 sugery, 1 adjuvant chemotherapy, 24 radiotherapy and 8 others. In both arms, 50% of pts entered into the maintenance treatment with PEM after completion of 3 cycles induction chemotherapy. The median PFS was 92 days in Arm 1 and 143 days in Arm 2, respectively. Cox-proportinal Hazard ratio was 0.827, and 95% HR confidential interval was 0.563-1.248. Stratified Log-Rank test showed no significant difference in both arms. Conclusions: There was no significant difference for PFS in PEM plus CB follwed by PEM and PAC plus CB followed by PEM. Clinical trial information: 000005008.
Pathway analysis of primary human non-small cell lung cancer (NSCLC).
Authors: N. Daraselia, Y. Wang, A. Budoff, A. Lituev, O. Potapova, J. Monforte, V. Ossovskaya
Journal: Journal of Clinical Oncology (2011)

10573 Background: We aimed to increase understanding of NSCLC pathogenesis through characterization of molecular and pathway signatures in primary lung adenocarcinoma (ADC) and squamous cell carcinoma (SSC) samples matched with syngeneic uninvolved normal lung tissue. Methods: Microarrary profiling of ADC and SSC matched with pathologically normal lung tissue (n=20 each) was conducted using the Affymetrix Human Gene 1.0 ST array. The differential expression profile of cancer vs syngeneic normal tissue was calculated for each patient and for combined samples using an unpaired t-test. Pathway analyses based on gene expression profiling were performed using Pathway Studio (Ariadne Genomics, Inc). Functional enrichment was performed using Fisher's exact test and Mann–Whitney test. Results: Transcriptional regulators E2F, CTGF and PDGF were implicated in lung cancer pathogenesis. SSC was characterized by involvement of EGF, IL1F8 and CX3CL1 pathways, while changes in RB1, mir-200 and EMP2 targets were specific for ADC. Cell cycle and metastatic processes were significantly affected in ADC and SCC. Cell cycle genes TOP2A, CCNB1, MELK, MAD2L1, SFN, CDC6, ASPM and TOPBP1 were significantly upregulated in SSC, opposed to just TOP2A in ADC. The biochemical signature pinpoints changes in purine and pyrimidine biosynthesis and energy production pathways, which were common in ADC and SSC. DNA repair genes RBBP8, PRKDC, SHFM1, and PCNA were significantly upregulated (2-fold or more; p<0.001) in SCC. All oncogenes in ADC, and most in SCC, were significantly downregulated, including FOS and FOSB. In SSC, the oncogenes ECT2 and DCUN1D1 were upregulated. In SCC, tumor suppressors DLG1 and DLGAP5 were upregulated, and TGFBR2 was downregulated. No significant changes were detected in DNA repair genes in ADC, in apoptotic genes in ADC or SCC, or in tumor suppressor genes in ADC. Pathway signatures of lung ADC and SCC show both similarities and differences to triple-negative breast cancer (TNBC). Significant changes in NAD metabolism appear to be unique to TNBC and ADC. Conclusions: Lung ADC and SCC are characterized by distinct alterations in DNA repair, cell cycle regulation, and metabolism, thus providing a molecular basis for novel therapeutic strategies.
Abstract 4059: Molecular role of cytochrome P450 (CYP)1A2 in the regulation of hepatic and pulmonary CYP1A1 expression in mice exposed to 3-Methycholanthrene
Authors: Bhagavatula Moorthy, Paramahamsa Maturu, Lihua Wang, Weiwu Jiang
Journal: Cancer Research (2016)

Abstract 3-Methylcholanthrene (MC) is one of the most potent polycyclic aromatic hydrocarbons (PAHs) carcinogens known to date. PAHs are present in cigarette smoke, diesel exhausts, and charcoal broiled meats, etc. Cytochrome P450 (CYP) 1A enzymes play key roles in the activation of PAHs to carcinogenic metabolites. In this investigation, we tested the hypothesis that CYP1A2 plays a mechanistic role in the regulation of hepatic and pulmonary CYP1A1 by MC. Wild type (WT) (C57B6) and Cyp1a2_null mice were divided into two groups. Group I was treated with vehicle corn oil (CO) (8 ml/kg) and group II was treated with four doses of MC (100 μmol/kg), i.p. once daily for 4 days. Four animals from each group were sacrificed at 6, 12, 24, and 48 h, 8 and 15 days after MC withdrawal. The mRNA levels, protein content and enzyme activities of CYP1A1 and 1A2 were determined at different time points. In addition, the binding of MC-AHR-AHR nuclear translocator (ARNT) to the AHREs on the CYP1A1 promoter region was determined by chromatin immunoprecipitation (ChIP) assay in liver and lung tissues. In WT mice, ChIP experiments indicated that transcriptional activation of CYP1A1 was most pronounced at 6 h, followed by 12 h, but declined at later time points. In Cyp1a2_null mice, on the other hand, transcriptional activation of CYP1A1 persisted till 48 h. In lungs, AHR complex binding peak was observed at 12 h and declined later, but Cyp1a2 null mice showed more persistent binding till 48 h with a peak at 24 h. On the other hand, the expression of CYP1A1/1A2 at the mRNA, protein, and enzyme levels persisted for up to 48 h both in lung and liver tissues. These results suggest a mechanistic role for CYP1A2 in the molecular regulation of CYP1A1, and that transcriptional activation of CYP1A1 at 6-12 h is sufficient to result in sustained induction of CYP1A mRNA and protein expression for up to 48 h. These studies have important implications for carcinogenesis mediated by PAHs. Citation Format: Bhagavatula Moorthy, Paramahamsa Maturu, Lihua Wang, Weiwu Jiang. Molecular role of cytochrome P450 (CYP)1A2 in the regulation of hepatic and pulmonary CYP1A1 expression in mice exposed to 3-Methycholanthrene. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4059.
Single-step endoscopic ultrasound-guided fluoroless gallbladder drainage using the Axios lumen-apposing metal stent
Authors: Carmelo Barbera, Giuseppe Grande, Nadia Alberghina, Mauro Manno, Rita Conigliaro
Journal: Endoscopy (2016)

Severe acute cholecystitis is a condition that requires urgent surgical intervention to prevent sepsis and death. Elderly patients can be unfit for surgery because of comorbidities so alternative techniques are required for gallbladder drainage [1].
Abstract 358: In vitro assessment of tumor relapse in a 3D tumor microtissue model
Authors: Sumeer Dhar
Journal: Cancer Research (2016)

Abstract One of the most pressing problems in the treatment of cancer is tumor relapse. Although many tumors regress in response to neoadjuvant chemotherapy, residual tumor cells are detected in most cancer patients post-treatment. These residual tumor cells are thought to remain dormant for years before resuming growth, resulting in tumor recurrence. Considering that recurrent tumors are most often responsible for patient mortality, there exists an urgent need to study signaling pathways that drive tumor dormancy/recurrence. Current in vitro assays based on monolayer cultures do not provide the required time frame to study tumor recurrence. We developed a new method to study tumor relapse in a 3D in vitro tumor microtissue model. HCT116 colorectal tumor microtissues were produced and dosed with 3 reference compounds, Taxol (cell division inhibitor), Staurosporine (protein kinase inhibitor) and Doxorubicin (DNA synthesis inhibitor). Based on an initial range finding to determine IC20 and IC50 values, tumor growth was monitored via size profiling and viability (intra-tissue ATP content) over 10 days. Three different conditions were tested: (i) continuous treated tumor microtissues, (ii) microtissues which were supplemented with the drug for 5 days and (iii) non-treated tumor microtissues. Growth differences couldn't be observed comparing IC20 concentrations, however growth profiles significantly varied comparing IC50 concentrations. Whereas a 5-day treatment of Taxol was leading to a complete growth inhibition after removing the drug, Staurosporine treated tumor microtissues relapsed even with a similar growth kinetic as the untreated control group. Pulsed treatment of Doxorubicin was leading to a slower growth kinetic as compared to the control but not to a complete reminiscence. Based on the individual growth profiles relative to the continuous treated and non-treated groups we calculated a relapse index (ReI, patent pending) to enable classification of compounds and compound combinations according to their risk for tumor relapse. Here we present a novel in vitro tumor relapse assay method based on a 3-dimensional tumor microtissue model, to enable compound classification based on their efficiency to prevent tumor relapse. Citation Format: Sumeer Dhar. In vitro assessment of tumor relapse in a 3D tumor microtissue model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 358.
European Society of Clinical Microbiology and Infectious Diseases: update of the diagnostic guidance document for Clostridium difficile infection
Authors: M.J.T. Crobach, T. Planche, C. Eckert, F. Barbut, E.M. Terveer, O.M. Dekkers, M.H. Wilcox, E.J. Kuijper
Journal: Clinical Microbiology and Infection (2016)

In 2009 the first European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guideline for diagnosing Clostridium difficile infection (CDI) was launched. Since then newer tests for diagnosing CDI have become available, especially nucleic acid amplification tests. The main objectives of this update of the guidance document are to summarize the currently available evidence concerning laboratory diagnosis of CDI and to formulate and revise recommendations to optimize CDI testing. This update is essential to improve the diagnosis of CDI and to improve uniformity in CDI diagnosis for surveillance purposes among Europe. An electronic search for literature concerning the laboratory diagnosis of CDI was performed. Studies evaluating a commercial laboratory test compared to a reference test were also included in a meta-analysis. The commercial tests that were evaluated included enzyme immunoassays (EIAs) detecting glutamate dehydrogenase, EIAs detecting toxins A and B and nucleic acid amplification tests. Recommendations were formulated by an executive committee, and the strength of recommendations and quality of evidence were graded using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. No single commercial test can be used as a stand-alone test for diagnosing CDI as a result of inadequate positive predictive values at low CDI prevalence. Therefore, the use of a two-step algorithm is recommended. Samples without free toxin detected by toxins A and B EIA but with positive glutamate dehydrogenase EIA, nucleic acid amplification test or toxigenic culture results need clinical evaluation to discern CDI from asymptomatic carriage.
Prognostic values of baseline circulating endothelial progenitor level for advanced hepatocellular carcinoma (HCC) patients under antiangiogenic therapy.
Authors: Y. Shao, Z. Lin, T. Chen, C. Hsu, Y. Shen, A. Cheng
Journal: Journal of Clinical Oncology (2010)

4063 Background: Antiangiogenic therapy, including sorafenib and metronomic chemotherapy, is effective in the treatment of advanced HCC. Circulating endothelial progenitor cells (CEPs) and circulating endothelial cells (CECs) are potential surrogate markers for angiogenic activity. The study evaluated their significance as prognostic or predictive markers in advanced HCC patients (pts) under anti-angiogenic therapy. Methods: Advanced HCC pts, enrolled in a phase II study (Shen et al: ASCO annual meeting 2009: Abs 4589) and its extended cohort, were treated with sorafenib plus metronomic oral tegafur/uracil until disease progression. Tumor response was performed every two months following RECIST criteria. CEPs and CECs were enumerated before treatment, 2 weeks and 4 weeks after start of therapy by six-color flow-cytometry. CD31+/CD45-/CD146+/CD133- cells were defined as CECs, and CD31+/CD45-/CD146+/CD133+ cells as CEPs. 7-AAD staining was used to differentiate viable and apoptotic cells. Results: 68 pts have been treated with sorafenib plus metronomic tegafur/uracil. The best tumor response were 4 PR (6%) and 35 SD (52%); the median PFS and OS were 3.7 (95% CI, 2.4-5.0) and 7.2 months (95% CI, 2.5-11.8), respectively. 40 pts consented to participate in the biomarker study. Of them, there were 1 (3%) PR and 20 (50%) SD; the median PFS and OS were 3.2 (95% CI, 0.6-5.8) and 5.6 (95% CI, 2.2-8.9) months, respectively. No significant associations between baseline CEP/CEC levels and patient characteristics were found. Baseline CEP/CEC levels did not predict disease control rate (CR+PR+SD). By univariate analysis, however, higher baseline CEP level was a significant predictor for poorer PFS and OS. Higher baseline CEP level remained an independent significant predictor for poor PFS (HR 1.953, p = 0.049) and OS (HR 3.077, p = 0.002) in multivariate analysis. Conclusions: Higher baseline CEP level predicts poorer PFS and OS for advanced HCC pts under anti-angiogenic therapy. This finding mandates further validation in large studies. This study was supported by the grant of NSC 98-3112-B-002-038. No significant financial relationships to disclose.
Regression of Chemotherapy-Resistant Polymerase ϵ (POLE) Ultra-Mutated and MSH6 Hyper-Mutated Endometrial Tumors with Nivolumab
Authors: Alessandro D. Santin, Stefania Bellone, Natalia Buza, Jungmin Choi, Peter E. Schwartz, Joseph Schlessinger, Richard P. Lifton
Journal: Clinical Cancer Research (2016)

The management of endometrial carcinoma no longer amenable to treatment with surgery or radiotherapy has not improved significantly with modern chemotherapy. Alternative therapeutic options are desperately needed.We describe 2 heavily pretreated patients with recurrent disease refractory to surgery, radiotherapy, and chemotherapy who were treated with the anti-PD-1 immune checkpoint inhibitor nivolumab.Patient #1 harbored an ultra-mutated tumor (mutation load/MB = 117.3, total mutations = 4,660) driven by mutation in the exonuclease domain of the DNA polymerase ε gene. Patient #2 harbored a hyper-mutated tumor (mutation load/MB = 33.5, total mutations = 1,037) due to a germinal MSH6 gene mutation. Both patients demonstrated a remarkable clinical response to the anti-PD-1 immune checkpoint inhibitor nivolumab. Patients' clinical responses remain unchanged at the time of the writing of this report, with no grade 3 or higher side effects reported to date.Anti-PD-1 inhibitors represent a novel treatment option for recurrent/metastatic, ultra/hyper-mutated human tumors refractory to salvage treatment. Clin Cancer Res; 22(23); 5682-7. ©2016 AACRSee related commentary by Piulats and Matias-Guiu, p. 5623.
Long-Term Outcomes in Psychopathology Research: Rethinking the Scientific Agendaedited by Evelyn J. Bromet, Ph.D. New York, Oxford University Press, 2015, 360 pp., $89.95 (hardcover).
Authors: Thomas J. Raedler
Journal: American Journal of Psychiatry (2016)

Child analysts who treat young children intensively are always involved in action and talking.Children play and interact.The analyst utilizes the nature of the play to try to understand the important issues for the child.Within the play the child may ask the analyst or therapist to touch the child, and vice versa.Obviously the analyst has to limit such actions.In addition, the use of toys or other material as displacements from the body can promote further reflection of the child's wishes and conflicts.Can insights such as this one be helpful in the treatment of adults, who obviously are not children?To my knowledge, Gabbard and others working in the field have not explored potential contributions to the treatment of adults based on the intensive work with children.Finally, it is unfortunate that the title of the book limits itself to the field of psychoanalysis.How many readers of the Journal, for example, will not look at this book because of its title?Perhaps adding to the title the words "and Psychotherapy" for the next printing would increase readership.We all have to commend and thank Glen O. Gabbard for this rich resource.