tbuckley/cabot-search huggingface dataset:
ATPS-83REPURPOSING MEBENDAZOLE AS A REPLACEMENT FOR VINCRISTINE FOR THE TREATMENT OF BRAIN TUMORS
Authors: Alex Gamble, Michelle De Witt, Daniel Markowitz, Derek Hanson, Caitlin Powell, Mark Atlas, Rosamaria Ruggieri, Marc Symons
Journal: Neuro-Oncology (2015)

The microtubule inhibitor vincristine is currently used to treat a number of brain tumors, including newly diagnosed diffuse low-grade and anaplastic glioma. Vincristine however does not penetrate well into brain tumor tissue and moreover, it displays dose-limiting toxicities, including peripheral neuropathy. Mebendazole, an anti-helminthic with an excellent safety profile, has recently been shown to display strong therapeutic efficacy in animal models of both glioma and medulloblastoma (Bai R-Y et al, 2011 and Bai R-Y et al, 2014). In addition, appropriate formulations of mebendazole yield therapeutically effective concentrations in the brain (Bai R-Y et al, 2015). Mebendazole has been shown to inhibit microtubule formation, but it is not known whether its potency against tumor cells is mediated by this microtubule inhibitory effect. To investigate this, we examined the effects of mebendazole on GL261 glioblastoma cell viability, metaphase arrest and microtubule polymerization and found that the effective concentrations to inhibit these functions are very similar. In addition, using mebendazole as a seed for the NCI COMPARE program revealed that the top-scoring drugs were highly enriched in microtubule-targeting drugs. Taken together, these results indicate that the cell toxicity of mebendazole indeed is caused by inhibiting microtubule formation. We also have compared the therapeutic efficacies of mebendazole and vincristine against GL261 orthotopic tumors at their respective maximum tolerated doses (respectively 100 mg/kg/day and 1 mg/kg/week). We found that mebendazole showed a 61% increase in animal survival time, whereas vincristine failed to show any efficacy. However, we did observe significant neuropathy (as measured by sensory allodynia) induced by mebendazole treatment, similar to that caused by vincristine. In conclusion, our results strongly support the clinical use of mebendazole as a replacement for vincristine for the treatment of brain tumors.
Abstract 3300: Gal-GalNAc overexpressed in colorectal carcinoma mediates attachment and colonization of Fusobacterium nucleatum utilizing the Fap2 lectin
Authors: Jawad H. Abed, Johanna Emgård, Stella Chaushu, Wendy Garrett, Gilad Bachrach
Journal: Cancer Research (2016)

Abstract Recent reports revealed overabundance of oral Fusobacterium nucleatum (Fn) in colorectal carcinoma (CRC) compared to adjacent healthy tissue. This study aims to investigate the molecular mechanisms that mediate CRC colonization by Fn. Using the orthotopic Colon-26 colorectal cancer model, we found that intravascular injected Fn colonizes CRC more than adjacent healthy tissue. Fusobacterial localization in the colon is tumor-dependent, as injected fusobacteria were undetected in the colons of tumor-free mice. CRC colonization is species specific as the gram-negative, anaerobe and periodontitis-related pathogen Prophyromonas gingivalis, which was shown to be abundant in oral tumors failed to colonize CRC. Higher levels of D-galactose-β(1-3)-N-acetyl-D-galactosamine (Gal-GalNAc) are known to be detected in CRC. We recently identified the fusobacterial Fap2 outer-surface protein as a galactose binding lectin, suggesting that it might promote binding of fusobacteria to CRC. A fluorescent-labeled Peanut Agglutinin lectin (PNA) detected more Gal-GalNAc in human and mouse CRC compared to adjacent healthy tissues. Binding of FITC-labeled Fn corresponded with the levels of Gal-GalNAc and colocalized with Gal-GalNAc in the tumor. Flow cytometry revealed that Fap2-deficient Fn mutants are impaired in binding to CRC cell lines compared with their WT parent. Soluble GalNAc inhibited the binding of PNA and WT Fn to CRC cells in a dose-dependent manner, but did not affect the residual CRC binding of fap2 mutated Fn. Furthermore, in the colorectal cancer murine model, tumor colonization by Fap2-deficient Fn mutants was significantly lower than that of the Fap2 sufficient parental strain. Our results demonstrate that the fusobacterial Fap2 lectin binds to Gal-GalNAc on CRC and mediates the tumor-specific attachment of Fn. Understanding the interaction of Fn with CRC, may enable future development of novel diagnostic and therapeutic agents for this disease. Citation Format: Jawad H. Abed, Johanna Emgård, Stella Chaushu, Wendy Garrett, Gilad Bachrach. Gal-GalNAc overexpressed in colorectal carcinoma mediates attachment and colonization of Fusobacterium nucleatum utilizing the Fap2 lectin. [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 3300.
Ongoing Antigen Interactions In Splenic Marginal Zone Lymphoma: Revelations From The Analysis Of Intraclonal Diversification In Immunoglobulin Light Chain Genes
Authors: Maria Karypidou, Evangelia Stalika, Panagiotis Baliakas, Vasilis Bikos, Zadie Davis, George Kanellis, Achilles Anagnostopoulos, Theodora Papadaki, David Oscier, Anastasia Hadzidimitriou, Nikos Darzentas, Chrysoula Belessi, Kostas Stamatopoulos
Journal: Blood (2013)
Can the sequence of chemotherapy regimens influence outcome in patients with metastatic pancreatic adenocarcinoma (MPAC)?
Authors: Shannon Leah Schmidt, Vipal Durkal, Shinoj Pattali Jayavalsan, Paul S. Ritch, James P. Thomas, Beth Erickson, Kathleen K. Christians, Susan Tsai, Douglas B. Evans, Ben George
Journal: Journal of Clinical Oncology (2016)

428 Background: FOLFIRINOX(FFX)/FOLFOX(FX) and Nab-paclitaxel plus Gemcitabine (NabG) represent standard first line (FL) treatment options for MPAC, but there is no prospective data to ascertain the ideal sequence of these regimens when used off protocol for patients with MPAC. We reviewed our single institution experience to evaluate whether the sequence of these regimens influenced clinical outcome. Methods: All MPAC patients treated with FFX/FX or NabG, in either sequence, from 1/1/11 to 12/31/14 at the Froedtert and Medical College of Wisconsin (MCW) Clinical Cancer Center were identified and their charts reviewed. This study was approved by the Froedtert &amp; MCW Institutional Review Board. Results: Among 64 patients reviewed, the median age at diagnosis was 62. 64.1% were male and 95.3% were Caucasian. Median Ca19-9 and CEA at diagnosis were 855 and 10.4 respectively. 37/64 (57.8%) patients received SL therapy. Details of treatment and disease control rate (DCR) are summarized in the Table. Of patients who were refractory to FL FFX/FX, 4/7 (57.1%) demonstrated disease control (DCR) with SL NabG; numbers were too small for reverse analysis. Median overall survival (OS) of patients who received 2 lines of therapy was 12.1 months, while median OS of patients who received one line was 4.1 months. Median OS associated with sequential therapy is summarized in the Table. Conclusions: Both FFX/FX and NabG are active in the SL setting. Outcomes appear to be fairly similar regardless of sequence. The numerically superior median OS associated with FL NabG followed by SL FFX should be interpreted with caution in the context of small number of patients in this subset. A substantial minority of patients do not receive second line chemotherapy due to deteriorating clinical status and/or patient preference suggesting unfavorable tumor biology. [Table: see text]
Abstract 3130: Adiponectin, Leptin, IGF1 and TNFα serum biomarker as noninvasive diagnosis of colon adenoma
Authors: Hassan Ashktorab, Akbar Soleimani, Alexandra Nichols, Komal Sodhi, Lakshmi Kannan, Laiyemo Adeyinka, Mehdi Nouraie, Hassan Brim
Journal: Cancer Research (2016)

Abstract Background and Aim: The potential role of Adiponectin, Leptin, IGF1 and TNFα as biomarker in colon adenoma has not been studied. Therefore, we investigated the blood serum levels of these biomarkers in colorectal adenoma. Method: The case-control study consisted of 198 African American patients with colon adenoma (cases) and 198 healthy individuals (controls) at Howard University Hospital. We used Elisa for biomarkers detection. Statistical analysis was performed by t-test and multivariate logistic regression. Results: The differences in median leptin, Adiponectin, IGF1 and TNFα levels between control and case groups (6.7 vs.16.4), (11.3 vs.46.0), (4.5 vs.12.9) and (71.4 vs. 130.8) were statistically significant (p&amp;lt;0.05), respectively. In a multivariate model, the odds ratio (ORs) for Adiponectin, TNFα and IGF1 were 2.0 (95% CI = 1.6-2.5; P≤0.001), 1.5 (95% CI = 1.5- 2.0; P 0.004) and 1.6 (95% CI = 1.3-2.0; P≤ 0.001), respectively. There were positive correlations between serum Adiponectin and IGF1 concentrations with age (r = 0.17, P≤ 0.001 and r = 0.13, P = 0.009), also between TNFα, IGF1 and Leptin concentration with Body Mass Index (BMI) (r = 0.44, P≤ 0.001 and r = 0.11, P = 0.03; r = 0.48, P≤0.001), respectively. There was a negative correlation between Adiponectin concentration and BMI (r = -0.40, P≤0.001), respectively. Conclusion: These data support the hypothesis that serum Adiponectin, IGF1 and TNFα are risk biomarkers for noninvasive detection of colorectal adenomas. Citation Format: Hassan Ashktorab, Akbar Soleimani, Alexandra Nichols, Komal Sodhi, Lakshmi Kannan, Laiyemo Adeyinka, Mehdi Nouraie, Hassan Brim. Adiponectin, Leptin, IGF1 and TNFα serum biomarker as noninvasive diagnosis of colon adenoma. [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 3130.
A System to Assess the Competency for Interpretation of Esophageal Manometry Identifies Variation in Learning Curves
Authors: Rena Yadlapati, Rajesh N. Keswani, Jody D. Ciolino, David P. Grande, Zoe I. Listernick, Dustin A. Carlson, Donald O. Castell, Kerry B. Dunbar, Andrew J. Gawron, C. Prakash Gyawali, Philip O. Katz, David Katzka, Brian E. Lacy, Stuart J. Spechler, Roger Tatum, Marcelo F. Vela, John E. Pandolfino
Journal: Clinical Gastroenterology and Hepatology (2016)
Abstract 998: LncRNA WDFY3-AS2 contributes to the EMT and metastasis in breast cancer
Authors: Edward Richards, Sridevi Challa, Yajuan Li, Jennifer Permuth-Wey, Marilyn Bui, Domenico Coppola, Thomas Sellers, Jin Cheng
Journal: Cancer Research (2016)

Abstract The role of TGFβ in promoting mammary cell EMT and breast cancer metastasis was well established. However, the involvement of long non-coding RNA (lncRNA) in this process remains elusive. Here we demonstrated that mouse lncRNA BB179049 and its human ortholog WDFY3-AS2 were significantly increased upon TGFβ-induced EMT. WDFY3-AS2 was frequently elevated in invasive, metastatic and triple-negative breast cancer. Depletion of WDFY3-AS2 abrogated TGFβ-induced EMT and breast cancer metastasis. WDFY3-AS2 positively regulates STAT3 and WDFY3 through interaction with hnRNP-R. These data indicate that WDFY3-AS2 could play a pivotal role in TGFβ-induced EMT and metastasis and serves as a critical therapeutic target in aggressive breast cancer. Citation Format: Edward Richards, Sridevi Challa, Yajuan Li, Jennifer Permuth-Wey, Marilyn Bui, Domenico Coppola, Thomas Sellers, Jin Cheng. LncRNA WDFY3-AS2 contributes to the EMT and metastasis in breast cancer. [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 998.
Abstract 1419: Characterization of the evolution of immune response in lung squamous carcinogenesis
Authors: Celine Mascaux, Mihaela Angelova, Jennifer Beane, Kahkeshan Hijazi, Geraldine Antoine, Karen Willard Gallo, Vincent Ninane, Arsène Burny, Jean-Paul Sculier, Avrum Spira, Jérôme Galon
Journal: Cancer Research (2016)

Abstract Molecular profiling of from pre-invasive bronchial lesions, and particularly the evolution of immune response, may identify promising new biomarkers for early detection and targets for chemoprevention/treatment of lung cancer. mRNA expression was analyzed (Agilent microarrays) from fresh frozen human bronchial biopsies (N = 122, 77 patients) at successive morphological stages of lung squamous carcinogenesis. Modules of co-expressed genes were identified among the stage associated genes, selected using a linear mixed-effects model adjusting for smoking status, gender, and history of cancer as fixed effects and patient as a random effect. Cell type specific signatures were applied to the genes co-expressed in these modules in order to identify the immune response signal through the stages of lung carcinogenesis. Genes expression alterations were grouped into 4 successive molecular steps. Based on their behavior across the 4 steps, 8 modules of genes with different patterns were observed: gene modules primarily up-regulated among the early or late steps, up-regulated in a linearly across the 4 steps, as well as down- then up-regulated (biphasic). Genes signing the presence of activating CD8 and CD4 T cells, as well as some memory B cells were progressively and linearly up-regulated from metaplasia through all stages of carcinogenesis. At the later stages, the transition to high-grade dysplasia, the most significant gene expression changes included immune/inflammatory response genes. At this stage a very strong adaptive immune response is noted involving T cells - mainly Th1 and T regulators - and dendritic cells. In addition, immunosuppressive signals, corresponding to negative co-inhibitory molecules, also significantly appears at the high-grade dysplasia stage. The adaptive CD4/CD8 related immune response starts from the earlier stages (metaplasia) of lung carcinogenesis. The significant modification of inflammatory/immune response genes in association with high-grade lesions suggests, at this critical stage of carcinogenesis, a major role of the surrounding microenvironment with an adaptive immune response, driven by Th1 and Treg cells, and but also, before tumor invasion across the basal membrane, a tumor versus host immunosuppressive response. Citation Format: Celine Mascaux, Mihaela Angelova, Jennifer Beane, Kahkeshan Hijazi, Geraldine Antoine, Karen Willard Gallo, Vincent Ninane, Arsène Burny, Jean-Paul Sculier, Avrum Spira, Jérôme Galon. Characterization of the evolution of immune response in lung squamous carcinogenesis. [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 1419.
Case 17-1973
Authors: Richard C. Cabot, Benjamin Castleman, Robert E. Scully, Betty U. McNeely, Allan L. Friedlich, Willard M. Daggett
Journal: New England Journal of Medicine (1973)

Presentation of CaseA 33-year-old man was admitted to the hospital because of a murmur.The patient was known to have a heart murmur since birth. He recalled frequent epistaxes and headaches during childhood and admitted episodes of dizziness on two occasions while playing squash three months before entry. Otherwise he had been in excellent health and had ignored recommendations to restrict his activities.There was no history of chest pain, palpitation, syncope, dyspnea, peripheral edema, cyanosis or undue fatigue.The temperature was 36.9°C, the pulse 70, and the respirations 14. The blood pressure was 145/105 in the right arm, . . .
Urgent Need to Measure Effects of Direct Oral Anticoagulants
Authors: Jeffrey I. Weitz, John W. Eikelboom
Journal: Circulation (2016)

anticoagulantT he direct oral anticoagulants (DOACs), which include dabigatran, rivaroxaban, apixaban, and edoxaban, were designed to be given in fixed doses without routine coagulation monitoring.When administered in this manner in trials that included >71 000 patients with atrial fibrillation 1 and >27 000 patients with venous thromboembolism, 2 the DOACs were at least as effective as vitamin K antagonists but were associated with less serious bleeding, particularly less intracranial bleeding.Eliminating coagulation monitoring simplifies anticoagulation therapy.This feature, together with their proven efficacy and safety, explains why guidelines give preference to the DOACs over vitamin K antagonists for stroke prevention in atrial fibrillation and for the treatment of venous thromboembolism.Although routine coagulation monitoring is unnecessary, there is an urgent need for readily and rapidly available tests to measure the DOACs.This need will increase with the introduction of costly reversal agents such as idarucizumab for dabigatran 3 and andexanet alfa for rivaroxaban, apixaban, and edoxaban. 4Idarucizumab is already licensed, and andexanet is undergoing regulatory review and could be approved later this year.What tests are currently available, and why do we need new ones?Although currently available global tests of coagulation such as the activated partial thromboplastin time (aPTT) and prothrombin time (PT) can be useful to assess the anticoagulant effects of dabigatran and some of the oral factor Xa inhibitors, respectively, the sensitivity of these tests is variable and reagent dependent. 5Regardless of reagent, the PT is less responsive to apixaban and edoxaban than to rivaroxaban.Unfortunately, because sensitivity to the DO-ACs is rarely considered when reagents are chosen, the utility of the tests may change when laboratories order new lots of reagents.This not only complicates interpretation of test results over time in a single laboratory, but also renders between-laboratory comparisons difficult.These issues highlight the need for standardized tests.The DOACs have half-lives of ≈12 hours.Consequently, circulating drug levels and their subsequent effects on the aPTT and PT depend on when the blood sample was collected relative to the timing of the last drug dose.Even when measured soon after drug intake, a prolonged aPTT in patients taking dabigatran or an elevated PT in those on rivaroxaban, apixaban, or edoxaban gives no information about how much drug is in the circulation, and a normal test result does not exclude the presence of drug.Therefore, more accurate tests are needed.Such tests are currently available in research facilities and include the diluted thrombin time and ecarin clot time or ecarin chromogenic assay for dabigatran, as well as chromogenic anti-factor Xa assays for rivaroxaban, apixaban, and edoxaban. 5Unfortunately, these tests are not widely available, and even if available, the turnaround time is often too slow to be useful.This needs to change.
Abstract 841: Effect of equol on hormone-dependent rat mammary carcinoma induced by ethyl methanesulphonate (EMS)
Authors: MISAKI ONO, Takako Higuchi, Mikako Takeshima, Shuji Nakano
Journal: Cancer Research (2016)

Abstract Soy isoflavones such as daidzein and its bioactive metabolite equol converted from daidzein by human intestinal bacterial flora, have been proposed to reduce the risk of breast cancer incidence in Asian women probably due to higher number of the inhabitants capable of producing equol in these countries. Although several in vitro studies shows the anti-cancer activity of equol against human breast cancer cells, there have been few reports that have directly showed the preventive role of equol in the experimental animal model of mammary carcinoma. We investigated here the effects of equol on the development of breast cancer using the EMS chemically induced rat model of hormone-dependent mammary carcinoma. Female WKA rats (n = 30) were equally divided into 2 groups, subsequently given EMS orally for 12 weeks and fed the CE2 diets with or without 50 mg equol/g diet throughout the experiments. All EMS-treated rats fed either diet developed ER- and/or PgR- positive hormone-dependent mammary carcinoma by 24 weeks. Compared with the equol-free diet, the diet supplemented with equol could not significantly delay the development of mammary carcinoma, showing any preventive activity on the development of EMS-induced hormone-dependent mammary carcinoma. The body weight, total EMS uptakes, and urine estradiol concentrations were not significantly different between these 2 groups. These data indicate that high dose administration of equol alone does not exert clear preventive effects on hormone-dependent EMS-induced mammary carcinogenesis, and may require other soy isoflavone components such as genistein that has previously been shown to exhibit a great synergy when combined with equol. The in vivo combination studies using genistein and equol are underway. Citation Format: MISAKI ONO, Takako Higuchi, Mikako Takeshima, Shuji Nakano. Effect of equol on hormone-dependent rat mammary carcinoma induced by ethyl methanesulphonate (EMS). [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 841.
Nestin Mediates Hedgehog Pathway Tumorigenesis
Authors: Peng Li, Eric H. Lee, Fang Du, Renata E. Gordon, Larra W. Yuelling, Yongqiang Liu, Jessica M.Y. Ng, Hao Zhang, Jinhua Wu, Andrey Korshunov, Stefan M. Pfister, Tom Curran, Zeng-jie Yang
Journal: Cancer Research (2016)

Abstract The intermediate filament protein Nestin serves as a biomarker for stem cells and has been used to identify subsets of cancer stem–like cells. However, the mechanistic contributions of Nestin to cancer pathogenesis are not understood. Here, we report that Nestin binds the hedgehog pathway transcription factor Gli3 to mediate the development of medulloblastomas of the hedgehog subtype. In a mouse model system, Nestin levels increased progressively during medulloblastoma formation, resulting in enhanced tumor growth. Conversely, loss of Nestin dramatically inhibited proliferation and promoted differentiation. Mechanistic investigations revealed that the tumor-promoting effects of Nestin were mediated by binding to Gli3, a zinc finger transcription factor that negatively regulates hedgehog signaling. Nestin binding to Gli3 blocked Gli3 phosphorylation and its subsequent proteolytic processing, thereby abrogating its ability to negatively regulate the hedgehog pathway. Our findings show how Nestin drives hedgehog pathway–driven cancers and uncover in Gli3 a therapeutic target to treat these malignancies. Cancer Res; 76(18); 5573–83. ©2016 AACR.