tbuckley/cabot-search huggingface dataset:
Abstract 4831: Using reporter-based bioassays and engineered TNFalpha and VEGF+ target cells to measure Fc-mediated ADCC and CDC activity of anti-TNFá and anti-VEGF therapeutic antibodies
Authors: Denise Garvin, Jamison Grailer, Rich Moravec, Jim Hartnett, Chris Heid, Frank Fan, Mei Cong, Jey Cheng
Journal: Cancer Research (2019)

Abstract Fc receptor-mediated effects contribute to the therapeutic response in terms of efficacy and safety of anti-TNF antibodies. Measurement of Fc-mediated antibody-mediated cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) during antibody drug discovery and development is not only important for antibodies that harness ADCC and/or CDC as their primary mechanism of action (e.g. rituximab, trastuzumab), but also for antibodies designed to target and block soluble ligands such as TNFα and VEGF. We previously reported the development of a cell-based reporter bioassay platform which has been used to measure ADCC and ADCP mediated through FcgRI, FcgRIIa and FcgRIIIa. These reporter bioassays exhibit the specificity, accuracy, precision, and robustness necessary for qualification according to ICH guidelines and have been used extensively to characterize and measure the potency of antibody-based biologics drugs that target cell surface immune receptors. In the current study, we sought to evaluate Fc-mediated ADCC and CDC activities of therapeutic antibodies designed to target and block soluble ligands including TNFa and VEGF. To measure ADCC activity of anti-TNFa and anti-VEGF blocking antibodies, we developed engineered target cells that express either membrane-bound TNFα or VEGF. When used as target cells with reporter-based effector cells expressing a relevant FcgR, ADCC activity of adalimumab (anti-TNFa) and bevacizumab (anti-VEGF) was detected in a specific and dose-dependent manner. Similarly, when used in a luminescence-based CDC assay, the engineered target cells elicited an appropriate FcgR-mediated response. The assay signals demonstrated IgG isotype specificity as IgG4 variants showed minimal activity in both ADCC and CDC assays. Our results demonstrate that the combined use of cell-based reporter bioassays with target cells engineered to express membrane-bound soluble ligands can provide a simple, specific, and quantitative platform to measure Fc-mediated effector functions of therapeutic antibodies targeting soluble ligands. Citation Format: Denise Garvin, Jamison Grailer, Rich Moravec, Jim Hartnett, Chris Heid, Frank Fan, Mei Cong, Jey Cheng. Using reporter-based bioassays and engineered TNFalpha and VEGF+ target cells to measure Fc-mediated ADCC and CDC activity of anti-TNFá and anti-VEGF therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4831.
Mechanisms of Innate and Acquired Resistance to Anti-EGFR Therapy: A Review of Current Knowledge with a Focus on Rechallenge Therapies
Authors: Christine M. Parseghian, Stefania Napolitano, Jonathan M. Loree, Scott Kopetz
Journal: Clinical Cancer Research (2019)

Abstract Innate and acquired resistance to anti-EGFR therapy (EGFRi) is a major limitation in the treatment of metastatic colorectal cancer (mCRC). Although RAS genes are the most commonly mutated innate and acquired oncogenes in cancer, there are a number of other mechanisms that limit the effectiveness of EGFRi. Patients with innate resistance have been found to contain BRAFV600E mutations, and possibly MET, MEK, PIK3CA, PTEN, and HER2 alterations. Meanwhile, BRAFV600E mutations may also be involved in acquired resistance to EGFRi, in addition to EGFR ectodomain mutations, MET alterations, and possibly HER2 amplification. In addition, paracrine effects and cell-fate mechanisms of resistance are being increasingly described as contributing to acquired resistance. Utilization of circulating tumor DNA has been paramount in monitoring the dynamic nature of acquired resistance and has helped to guide treatment decisions, particularly in the EGFRi rechallenge setting. Herein, we provide an in-depth review of EGFRi-resistance mechanisms and describe the current therapeutic landscape in the hopes of identifying effective rechallenge strategies.
Dual Inhibition of Mdmx and Mdm2 Using an Alpha-Helical P53 Stapled Peptide (ALRN-6924) As a Novel Therapeutic Strategy in Acute Myeloid Leukemia
Authors: Luis A. Carvajal, Daniela Ben-Neriah, Adrien Senecal, Lumie Bernard, Swathi-Rao Narayanagari, Charles Kenworthy, Victor Thiruthuvanathan, Vincent Guerlavais, D. Allen Annis, Boris Bartholdy, Britta Will, Jesus Anampa, Ioannis Mantzaris, Manuel A. Aivado, Robert H Singer, Robert Coleman, Amit Verma, Ulrich G. Steidl
Journal: Blood (2017)
The Reality of Accessing Transportation for Health Care in New York City
Authors: Surafel Tsega, Hyung J. Cho
Journal: JAMA Network Open (2019)

Research suggests that an increase in insurance coverage is associated with increased use of health care services.This should make intuitive sense.Individuals who were previously unable to afford health care services would seek them out once affordability was no longer an issue.This was demonstrated in several situations, including the expansion of Medicaid in Oregon and the introduction of an individual mandate and expansion of heavily subsidized insurance in Massachusetts, both of which predated the Patient Protection and Affordable Care Act (ACA). 1-
Vaginal spermicides that contain Nonoxynol-9 are mutagenic in a bacterial back-mutation assay
Authors: Peter C. Lambert, Claudine L. Peters, Santiago A. Centurion
Journal: Cancer Research (2004)

4862  Cancer of the genital tract, particularly cervical cancer, is an important cause of cancer morbidity and mortality in women in the U.S.A. and elsewhere. Any persistent mutagenic or carcinogenic influence in the vagina is therefore of great potential significance in the causation of cancer. One such potential persistent influence is the presence of a mutagenic spermicidal gel. In the present study, the mutagenicity of three commonly used over-the-counter spermicidal gels containing Nonoxynol-9 as the active ingredient was examined in a bacterial assay, which was a modification of the Ames test. The results were compared with those in which a series of non-antibacterial and antibacterial products were examined. These products included a number of personal products that come into contact with mucous membranes as well as some caustic non-personal home products and a known mutagen, sodium azide. Whether these substances needed to be activated by liver enzymes in order to be mutagenic was also examined. The results showed that all three of the intravaginal spermicidal gels tested were as mutagenic or more mutagenic than the other products tested in each category. One caused frame shift type mutations and the other two point mutations. Although two of these products only became mutagenic following activation by liver extract, suggesting that in a clinical situation they might only be significant mutagens if systemically absorbed or ingested, the third was mutagenic without liver activation. It therefore might be expected to be directly mutagenic in the female, and indirectly in the male, genital tract. These results thus suggest that spermicidal gels, either acting alone or in concert with other potentially mutagenic and carcinogenic agents, may be a significant cause of cancer in women.
Abstract 4189: Limited-versus-extensive staging system for small cell prostate cancer
Authors: Salman Syed, Faisal Ali, Spyridon Basourakos, Zimu Gong
Journal: Cancer Research (2019)

Abstract Introduction: Small cell prostate cancer (SCPC) is one of the most common extrapulmonary small cell cancers as well as one of the most common histology type among non-adenocarcinoma prostate cancers. While small cell lung cancer follows a limited-versus-extensive staging system which is different from the stage I to IV system used for non-small cell lung cancer, the prostate adenocarcinoma staging system is used in SCPC despite its distinct clinical feature and aggressive disease course. Limited by the rarity of SCPC, the optimal staging strategy for SCPC remains unknown. The present study aimed to investigate the prognostic value of limited-vs-extensive staging system in SCPC patients. Method: The Surveillance, Epidemiology, and End Results database was used to analyze the incidence and outcome of small cell prostate cancer. Patients diagnosed between the year 2004 through 2015 were included. Limited stage is defined as those without metastasis regardless of degree of local invasion. Extensive stage is defined as any metastasis to locoregional lymph node, to distant lymph node, or to distant organs. Result: A total of 364 SCPC patients are included in the study cohort, accounting for 0.05% of all prostate cancer cases (n=665,054). Age adjusted incidence of SCPC was 0.959 per 1,000,000 per year over the whole study period. The median age at diagnosis of SCPC is 71 years. The median overall survival is 9 months. In the 322 patients with known metastasis status, 243 (75.5%) patients are in extensive stage, whereas 79 patients are in limited stage. Patients in extensive stage are more likely to have PSA level greater than 20 than those in limited stage (26.3% vs 6%), but a similar proportion of patients in both groups have PSA level less than 4 (44.3% vs 40.0%). Compared to patients with extensive stage, those with limited stage disease had a significantly better overall survival (17 months vs 9 months, p&amp;lt;0.001) as well as disease specific survival (28 months vs 11 months, p&amp;lt;0.001). Limited stage patients with different T stage had a similar overall survival (p=0.43). Similarly, all extensive stage patients had similar outcome despite different types of metastasis (p=0.40). Multivariable analysis of treatment showed that only chemotherapy is associated with improved survival in extensive stage disease with HR of 0.46. Conclusion: SCPC patients can be staged to limited stage and extensive stage based on the absence versus presence of metastasis. T stage in limited stage patient and type of metastasis in extensive stage patient is not associated with different outcome. Citation Format: Salman Syed, Faisal Ali, Spyridon Basourakos, Zimu Gong. Limited-versus-extensive staging system for small cell prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4189.
Abstract 1539: Mechanisms of action of bispecific T cell engager-mediated immune response in a lymphoma tumor model
Authors: Tiffany A. Coupet, Claire Godbersen-Palmer, Charles L. Sentman
Journal: Cancer Research (2019)

Abstract Bispecific T cell Engagers are molecules composed of two single chain variable fragments where one arm binds CD3 on T cells and redirects them to a tumor antigen with the other arm. This causes immune synapse formation between the T cell and tumor cell resulting in T cell activation and destruction of tumor cells. Bispecific T cell engagers have been used successfully in the clinic, however, it is unclear which activities of the host immune system are required for efficacy. This study investigates the mechanisms of action of a Bispecific protein specific for the B7H6 tumor antigen in an immune intact tumor model of lymphoma. In this lymphoma model the median survival for the B7H6xCD3 bispecific treated group was greater than 80 days while the median survival of the control bispecific treated group was 20 days. Monitoring of cellular changes in the bone marrow, blood, spleen and lymph nodes by flow cytometry 24h after bispecific protein treatment revealed that most cellular changes occurred in the inguinal lymph nodes were increases in CD8+ T cell and NK cells while CD4+ T cells decreased. Additionally, intracellular staining of cytokines IFNγ, Mip1α and TNFα in mouse T cells cultured in vitro with target tumor cells and bispecific protein showed that CD8+ T cells had greater polyfunctionality than CD4+ T cells. We have shown that IFNγ is essential for efficacy against lymphoma in vivo. To study the relative contribution of CD4 and CD8 T cells in vivo, lymphoma bearing mice that were depleted of CD4+ T cells or were deficient in CD8+ T cells were monitored for survival after bispecific protein treatment. While both CD4 or CD8 deficient mice had a greater survival when treated with B7H6xCD3 bispecific compared to control bispecific protein, the loss of either cell type resulted in much lower survival compared to WT mice treated with B7H6xCD3. All WT mice receiving B7H6xCD3 bispecific protein survived at least 65 days compared to CD4-depleted mice (median survival 20 days) and CD8-deficient mice (median survival 30 days) receiving the same treatment. In conclusion, both CD4+ and CD8+ T cells play a critical role in bispecific therapy. Understanding the mechanisms of action of bispecific proteins in vivo will help to develop more effective ways to use these powerful immune activating proteins to treat cancer. Citation Format: Tiffany A. Coupet, Claire Godbersen-Palmer, Charles L. Sentman. Mechanisms of action of bispecific T cell engager-mediated immune response in a lymphoma tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1539.
Potential predictors of fear of progression among long-term prostate cancer survivors: Do illness perceptions and family history matter?
Authors: Kathleen Herkommer, Astrid Hahn, Andreas Dinkel, Birgitt Marten-Mittag, Peter Herschbach, Jürgen E. Gschwend
Journal: Journal of Clinical Oncology (2012)

e15157 Background: Fear of illness progression (FoP) or recurrence is known to be one of the most prominent fears in patients with prostate cancer (PCa) even years after treatment. To improve detection of men at risk, possible predictors need to be discovered. So far, little is known about the influence of patients' illness perceptions (IP) and family history on dysfunctional FoP (dysFoP). Methods: A nationwide mail survey was sent out to a total of 6.305 men who had been treated with radical prostatectomy. Median time since diagnosis was 7.4 years. Patients were divided into 2 subgroups according to their family history: 68.9% (n=4.341) sporadic and 31.1% (n=1.964) familial (at least 1 first-degree relative with PCa). FoP was assessed with the short form of the Fear of Progression Questionnaire (FoP-Q-SF), IP were assessed with the Brief Illness Perception Questionnaire (B-IPQ). We also evaluated sociodemographic and clinical parameters and their influence on FoP. Results: Dysfunctional FoP was identified in 3.4% of all patients. Patients worried most about family, being dependent on others, and whether the children would also be diagnosed with PCa. Younger age, worse subjective economic situation, shorter time since diagnosis and disease progression were significantly associated with dysFoP (p&lt;.01). IP and prevalence of dysFoP did not differ significantly between patients with sporadic and familial PCa, but familial PCa was associated with a higher mean level of FoP. IP explained a high amount of variance in FoP (R²=.435). Stronger perceptions of worry and negative emotions were significant predictors of FoP (p&lt;.001). Furthermore, having at least one son (p=.004), time since diagnosis &lt;5 years (p=.006) and worse subjective economic situation (p=.030) were predictive of dysFoP. Conclusions: In this study only a minority of patients reported dysFoP. The study findings suggest the importance of addressing IP, especially worries, negative emotions, and perceived consequences as key factors of FoP. Prevalence of dysFoP did not differ depending on family history, however patients with familial PCa showed higher mean levels of FoP.
Abstract 3020: An essential role for <i>Argonaute 2</i> in EGFR-KRAS signaling in pancreatic cancer development
Authors: Sunita Shankar, Jean Tien, Ronald F. Siebenaler, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Kristin M. Juckette, Alice Xu, Malay Mody, Andrew Goodrum, Grace Tsaloff, Ingrid J. Apel, Lisha Wang, Javed Siddiqui, Jiaqi Shi, Chandan Kumar-Sinha, Arul Chinnaiyan
Journal: Cancer Research (2018)

Abstract KRAS and EGFR have been shown to function as essential mediators of pancreatic cancer development. In addition, KRAS and EGFR have been separately shown to interact with and perturb the function of Argonaute 2 (AGO2), a key mediator of RNA-mediated gene silencing. Here, we employed a genetically engineered mouse model of pancreatic cancer to define the effects of conditional loss of AGO2 in KRASG12D driven pancreatic cancer. Genetic ablation of AGO2 does not interfere with development of the normal pancreas or KRASG12D driven early precursor pancreatic intraepithelial (PanIN) lesions. However, AGO2 loss prevents progression from early to late PanIN lesions, development of pancreatic ductal adenocarcinoma (PDAC), and metastatic progression. This results in a dramatic increase in survival of KRASG12D mutant mice deficient in AGO2 expression. In both mouse and human pancreatic tissues, increased AGO2 expression at the plasma membrane is associated with PDAC progression. Mechanistically, within early precursor PanIN lesions, loss of AGO2 elevates phospho-EGFR levels and activates wild-type RAS, antagonizing KRASG12D activation and PDAC development. Furthermore, we observe that phosphorylation of AGO2Y393 by EGFR disrupts the interaction of wild-type RAS with AGO2, but does not affect the interaction of mutant KRAS with AGO2. Taken together, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR and wild-type RAS signaling, and an AGO2-dependent phase wherein the KRAS-AGO2 interaction is critical to the progression from PanIN to PDAC. A recent study by Phillip Sharp and Tyler Jacks describes a requirement for the oncogenic KRAS-AGO2 interaction in the development of a transplant mouse model of plasmablastic lymphoma, and together these studies substantiate the role of the interaction in KRAS oncogenesis. Citation Format: Sunita Shankar, Jean Tien, Ronald F. Siebenaler, Vijaya L. Dommeti, Sylvia Zelenka-Wang, Kristin M. Juckette, Alice Xu, Malay Mody, Andrew Goodrum, Grace Tsaloff, Ingrid J. Apel, Lisha Wang, Javed Siddiqui, Jiaqi Shi, Chandan Kumar-Sinha, Arul Chinnaiyan. An essential role for Argonaute 2 in EGFR-KRAS signaling in pancreatic cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3020.
Abstract 1210: Targeting the IDO1-Kynurenine-AhR pathway for cancer immunotherapy
Authors: Sheena Pinto, Christoph Steeneck, Michael Albers, Simon Anderhub, Manfred Birkel, Larisa Buselic-Wölfel, Gisela Eisenhardt, Claus Kremoser, Thomas Hoffmann, Ulrich Deuschle
Journal: Cancer Research (2019)

Abstract The aryl hydrocarbon receptor (AhR) is a ligand-controlled transcription factor that is primarily known to be a sensor of xenobiotics and tumor-promoting activities of halogenated hydrocarbons and polycyclic aromatic hydrocarbons. Several endogenous ligands such as metabolites produced by commensal microorganisms on skin and in gut and metabolites of L-Tryptophan - produced under control of the Tryptophan dioxygenases IDO1 and TDO2 such as L-Kynurenine and Kynurenic acid are known to modulate the transcriptional activity of AhR. The activity of AhR is predominant in many different immune and epithelial cells, thereby balancing immune responses towards various signals. Activation of the IDO1-Kyn-AhR pathway and accumulation of nuclear AhR protein is frequently seen in different tumor types and possibly linked to the observed diminished anti-tumor immune response. AhR agonizing ligands produced by cancer cells and/or lymphocytes recruited to the TME reduce the anti-tumor immune response through increasing the numbers and function of regulatory T cells while reducing that of cytotoxic CD8+ T cells. In order to reduce AhR-mediated immune-suppression in cancer patients, Phenex Pharmaceuticals initiated a program to identify small molecule AhR antagonists to block activated downstream signaling of AhR. To this end, we have identified novel AhR antagonists, which showed strong antagonistic activity against agonist-activated human AhR in a cell based CYP1A1 promoter-driven luciferase reporter assay in HepG2 cells. The compound series display good oral bioavailability and low clearance in mice. Our AhR antagonist molecules show single agent anti-tumor activity and increase the efficacy of Gemcitabine and anti-PD-L1 checkpoint inhibition in different syngeneic mouse tumor models. Overall, AhR antagonist treatment increased CD8+ T cell and M1 macrophage numbers, and decreased IL22 levels, which might be of functional relevance in the tumor context. Future research is directed to determine PK-PD markers suitable for clinical development and identification of human malignancies likely of responding to AhR antagonist treatment. Citation Format: Sheena Pinto, Christoph Steeneck, Michael Albers, Simon Anderhub, Manfred Birkel, Larisa Buselic-Wölfel, Gisela Eisenhardt, Claus Kremoser, Thomas Hoffmann, Ulrich Deuschle. Targeting the IDO1-Kynurenine-AhR pathway for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1210.
Abstract 17635: Can Published Reference Values Predict Patient-prosthesis Mismatch?
Authors: Prerna Bansal, Muaz Abudiab, Kalyan Chaliki, Marella Punnaiah, Hari Chaliki
Journal: Circulation (2015)

Background: Patient-prosthesis mismatch (PPM) is still a frequently encountered problem after aortic valve surgery for aortic stenosis(AS). Advanced planning for prevention of PPM would be beneficial. We hypothesized that identification of severe PPM based on chosen surgical valve will predict development of severe PPM after surgery. Methods: Fifty one patients (74±13yrs) with severe aortic valve stenosis who underwent aortic valve surgery had postoperative echocardiogram (TTE) within 6 months. Severe PPM was defined as effective orifice area index (EOAI)&lt;0.65 cm2/m2.We calculated predicted severe PPM using published references values of the prosthetic valve. We used mean value and the values one standard deviation above and below. We compared these values to the actual PPM based on postoperative TTE. Results: All patients had severe AS (MG50±7 mm Hg) and an LV EF of 56±15%. Forty four patients had tissue valves implanted and 7 had mechanical valves implanted. Mean time between postoperative TTE and surgery was 39± 60 days. When the mean reference values for the valve implanted was used, only 1 patient (2%) was predicted to have severe PPM. However, based on postoperative TTE, 6 patients (13%) had severe PPM. There was no correlation between EOAI based on postop TTE and mean published reference values (Figure).When the EOAI below one SD of the published reference value was chosen, the predicted incidence of severe PPM was 38%. When the EOAI above one SD was chosen for the reference value none of the patients were predicted to have PPM. Sensitivity and specificity to identify severe PPM was 17% and 100% for mean published reference value while it was 0% and 100% for +1 SD and 83% and 68% for -1 SD. Conclusions: 1) Use of mean published reference values markedly under estimate the true incidence of post-operative PPM and has unacceptably low sensitivity. 2) Predicted occurrence of PPM was widely variable (0% to 38%) based on the published reference values. Larger studies are needed.