tbuckley/cabot-search huggingface dataset:
Abstract 4345: Environmental determinants for lung cancer mortality among Black men in Berrien County, Michigan: A Multi-media analysis
Authors: Padma P. Tadi Uppala, Brian Wong, Laurel Berman, Motria Caudill, Jean Cadet
Journal: Cancer Research (2020)

Abstract Environmental risk factors such as air, water, soil pollution, chemical exposures, climate change, and radiation contribute to more than 100 diseases. Understanding the connection of the environment to health is a critical pathway to address health disparities and poor health outcomes in communities. Purpose: This study investigates environmental determinants for lung cancer mortality among Black men in Berrien County, Michigan. Methods: We examined environmental contaminants in the land, air, and water. Environmental data was obtained from toxic release Inventories (TRI) and brownfields from the US EPA's TRI databases, My Environment, Environmental justice SCREEN websites, ATSDR public health assessment information for contaminated sites in Berrien County and ATSDR Toxicological Profiles and ToxFAQs for common environmental contaminants and associated health concerns. We created GIS maps overlaid with all-cause mortality data. Using the TOXMAP database, we generated Environmental Health Toxmaps for cancer mortality in Berrien County and overlaid with TRI facilities. Results: Age-adjusted mortality among black males for all malignant cancers (208.90) and cancer of the lung and bronchus (110.70) were high compared to national data. An important observation from this analysis indicated that cancer of the lung and bronchus was 110.70 among black males and was 60.20 among white males in Benton Harbor. According to the overlaid GIS maps, zip codes surrounding the Benton harbor area seems to have the highest number of contaminated sites and high mortality rates. Benton Harbor in Berrien County had the second-highest level of summer Action Days (10 days) in the state. We reviewed the Action Days reported on the Michigan Department of Environmental Quality website (2019) and found that Benton Harbor typically was in the "top" tier for Action Days for several years. Although health disparities were observed among Black and White males for lung cancer, smoking rates were not elevated among black males as compared to the general population. In conclusion, we suggest that in addition to smoking, environmental, and socioeconomic factors may contribute to high lung cancer rates among Black men in Benton Harbor in Berrien County. Citation Format: Padma P. Tadi Uppala, Brian Wong, Laurel Berman, Motria Caudill, Jean Cadet. Environmental determinants for lung cancer mortality among Black men in Berrien County, Michigan: A Multi-media analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4345.
Abstract 893: A chimeric PD1-CD28 switch receptor enhances the activity of TRuC-T cells
Authors: Derrick P. McCarthy, Sarah Guyette, Michael Lofgren, Jyothi Sethuraman, Thamara DeSilva, Ahmar Aziz, Troy Patterson, Shruti Datari, Tiffany Chan, Philippe Kieffer-Kwon, Christopher J. Rold, Reshma Singh, Jian Ding, Holly Horton, R. Anthony Barnitz, Andrew Cornforth, Robert Tighe, Robert J. Hofmeister, Dario A. Gutierrez
Journal: Cancer Research (2020)

Abstract Cluster of differentiation 28 (CD28) and programmed death receptor 1 (PD-1) are members of the CD28 superfamily of co-receptors that have critical roles in the regulation of T cell-mediated immunity and inflammation. Ligation of CD28 synergizes with T cell receptor (TCR) signaling to enhance T cell activation through the PI3K-Akt pathway, while PD-1 ligation by its ligands (PD-L1/L2) sequesters critical mediators of signaling from the TCR complex, thereby shunting T cell activation and effector function. Thus, the expression of PD-L1/L2 in solid tumors may pose a significant barrier to anti-tumor immunity and the efficacy of adoptive T cell therapies (ACT). We have recently described a novel class of engineered T cells that integrate a T cell receptor fusion construct (TRuC®) into the natural TCR complex, thereby reprogramming the specificity of the T cell to recognize tumor surface antigen in a human leukocyte antigen (HLA)-independent fashion. TC-210 T cells expressing mesothelin (MSLN) specific TRuCs demonstrate robust anti-tumor immunity in preclinical models of mesothelioma, protecting mice from tumor re-challenge while inducing lower levels of inflammatory cytokine release when compared to a 2nd generation MSLN-targeted CAR T. Here, we show that co-expression of a PD-1:CD28 switch receptor comprising the PD-1 extracellular domain fused to the CD28 intracellular domain, enhances the activity of TC-210 T cells. When compared to TC-210 expressing only the TRuC, co-expression of PD1:CD28 was able to restore PD-L1 mediated inhibition of cytokine production and proliferation in co-culture with tumor cells. In vivo and molecular mechanistic studies are currently underway. Citation Format: Derrick P. McCarthy, Sarah Guyette, Michael Lofgren, Jyothi Sethuraman, Thamara DeSilva, Ahmar Aziz, Troy Patterson, Shruti Datari, Tiffany Chan, Philippe Kieffer-Kwon, Christopher J. Rold, Reshma Singh, Jian Ding, Holly Horton, R. Anthony Barnitz, Andrew Cornforth, Robert Tighe, Robert J. Hofmeister, Dario A. Gutierrez. A chimeric PD1-CD28 switch receptor enhances the activity of TRuC-T cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 893.
Abstract 1242: RAB20 is a stress-induced regulator of mitochondrial homeostasis
Authors: Sunayana Govind Nayak, Samantha Shaw, Colin Stets, Anthony Dent, Anne Marie Strohecker
Journal: Cancer Research (2020)

Abstract Mitochondrial homeostasis is tightly regulated via a combination of biogenesis and elimination via a form of selective autophagy called mitophagy. Given the importance of mitochondria for energy production, cellular redox status, and apoptotic signaling, the mitophagy pathway is of particular interest in cancer. While mitophagy has been reported to both assist and hinder tumorigenesis in different studies, the emerging consensus is that mitophagy supports tumor growth. Intriguingly, only a subset of the canonical autophagy machinery is required for mitophagy. Upstream regulators including ULK1, the phosphatidyl-inositol-3-phosphate (PI3P) effectors and components of the omegaosome DFCP1 and WIPI, and ATG9 are recruited to mitochondria independent of LC3. How these components are recruited to mitochondria and the mechanisms involved in engulfment/creation/scaling of the autophagosome around the mitochondrion are unclear. Here we report a novel role for the small GTPase RAB20 in mitochondrial homeostasis. Rab GTPases are master regulators of vesicle trafficking, templating membrane identity, coordinating vesicle docking, fusion, and cargo selection in concert with SNAREs and membrane tethers. Rab20 is normally expressed at low levels but can be induced by in vitro simulated metabolic stress (1% oxygen, glucose deprivation) or secondary to the stress of an actively growing tumor in vivo. Surprisingly, we discovered that silencing RAB20 in multiple Non-Small Cell Lung Cancer (NSCLC) cell lines impairs ischemia-induced mitophagy without impacting autophagic flux measured by LC3 lipidation. This defect is accompanied by an increase in mitochondrial mass. RAB20 silencing is associated with increased Reactive Oxygen Species both under nutrient replete and ischemic conditions. Further, Rab20 appears to influence mitochondrial network organization, manifest as elevated numbers of fragmented mitochondria in the Rab20 silenced cells compared to non-targeting vector isogenic vector control cells. Finally, mitochondrial respiration is impaired in RAB20 silenced cells. Taken together, this work indicates an important role for RAB20 in maintaining mitochondrial fitness. We are actively assessing the functional consequences of Rab20 ablation on lung tumorigenesis in an established mouse model of lung cancer driven by BrafV600E; Trp53−/−. These studies will be important in determining the role of RAB20 and its involvement in mitophagy on tumor progression in vivo. Citation Format: Sunayana Govind Nayak, Samantha Shaw, Colin Stets, Anthony Dent, Anne Marie Strohecker. RAB20 is a stress-induced regulator of mitochondrial homeostasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1242.
FRI0072 Methotrexate in rheumatoid arthritis: a 5 year prospective study
Authors: AM Stankovic, BK Lovic, JM Nedovic, AN Dimic, SK Stojanovic, BN Stamenkovic, VR Skakic
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The aim was to evaluate the efficacy and tolerability of low dose of longterm Methotrexate (MTX) treatment of rheumatoid arthritis (RA). <h3>Methods</h3> This study examines prospectively the response to oral MTX (5 ? 12,5 mg) over a 5 year period of 70 patients (pts) with active RA. 54 pts were female, mean age 53,61 ± 12,8 years range (27 ? 76) and mean diseases duration 9,76 ± 7,58 years (range 0,6 ? 35). Patients who were receiving Prednizone at entry to the trial, were maintained by the same dose, not exceeding 10 mg/day. Clinical evaluation were performed by the same physician ? investigator every 3 months for the first year of the study and every 6 months thereafter. Every 4 weeks complete blood cound and every 12 weeks thereafter complete erytrocyte sedimentation (ERS), blood count, serum creatinine and liver blood tests were obtained. Patients were assessed at 0 stage (beginning) with 70 pts, after 3 months (mts) (with 62), 6 mts (with 52), 12 mts (with 49), 24 mts (with 36), 36 mts (with 26), 48 mts (with 13), and after 60 mts (with 11) patients. <h3>Results</h3> 11 (15,7%) pts completed the 5 year study, 14 (20%) dropped out because of an adverse event or due to inefficacy. After 3, 6, 12, 24, 36 mts of treatment a good clinical response was shown by signiffcant clinical improvement in the joint swelling (p &lt; 0, 001), morning siffness (p &lt; 0, 001), as well as in both physicians and patients assessment of the disease activity (p &lt; 0, 001) compared to pretreatment values. The clinical improvement was also associated with a decrease of ESR after 3, 6, 12 mts (p &lt; 0, 001), after 24 and 36 mts (p &lt; 0, 05). Although a sustained clinical response was noted in the diseases variables during the 5 year study, there was no significant difference noted in the improvement in the joint swelling after 48 and 60 mts, in duration of morning stiffness and in decrease of ESR after 60 mts of treatment. <h3>Conclusion</h3> Methotrexate therapy appears to be effective and safe in the treatment of RA in this 5 year prospective study <h3>Reference</h3> Weinblatt ME, Maier AL, Fraser PA, Coblyn S. Longterm prospective study of methotrexate in rheumatoid arthritis. Conclusion after 132 months of therapy. J Rheum. 1998;25(2):239–42
Abstract 19960: Prognostic Value of Persistent Hypochloremia in Patients With Chronic Heart Failure: A Prospective Comparative Study With Neutrophil to Lymphocyte Ratio
Authors: Masahiro Seo, Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Tsutomu Kawai, Iyo Ikeda, Eiji Fukuhara, Jun Nakamura, Makoto Abe, Kiyomi Kayama, Kazuya Tanabe, Masatsugu Kawahira, Masatake Fukunami
Journal: Circulation (2017)

Backgrounds: Recently, it has been reported that hypochloremia is associated with poor outcome in patients (pts) with chronic heart failure (CHF), and we previously reported that persistent hypochl...
Pharmacologic Approaches to Glycemic Treatment of Type 2 Diabetes: Synopsis of the 2020 American Diabetes Association's Standards of Medical Care in Diabetes Clinical Guideline
Authors: Kacie Doyle-Delgado, James J. Chamberlain, Jay H. Shubrook, Neil Skolnik, Jennifer Trujillo
Journal: Annals of Internal Medicine (2020)

Description: The American Diabetes Association (ADA) updates the Standards of Medical Care in Diabetes annually to provide clinicians, patients, researchers, payers, and other interested parties with evidence-based recommendations for the diagnosis and management of diabetes. Methods: To develop the 2020 Standards, the ADA Professional Practice Committee, comprising physicians, adult and pediatric endocrinologists, diabetes educators, registered dietitians, epidemiologists, pharmacists, and public health experts, continuously searched MEDLINE (English language only) from 15 October 2018 through August–September 2019 for pertinent studies, including high-quality trials that addressed pharmacologic management of type 2 diabetes. The committee selected and reviewed the studies, developed the recommendations, and solicited feedback from the larger clinical community. Recommendations: This synopsis focuses on guidance relating to the pharmacologic treatment of adults with type 2 diabetes. Recommendations address oral and noninsulin injectable therapies, insulin treatment, and combination injectable therapies. Results of recent large trials with cardiovascular and renal outcomes are emphasized.
Abstract 1170: Socioeconomic disparities in patients with esophageal cancer at time of diagnosis: A national cancer data base analysis
Authors: Meena Sadaps, Neal Mehta, Wei Wei, Katherine Tullio, Amit Bhatt, Alok Khorana
Journal: Cancer Research (2020)

Abstract Introduction: There have been noted to be significant gender and socioeconomic disparities in the incidence, prognosis, and clinical outcomes of patients with esophageal cancer. The purpose of this study was to characterize disparities amongst patients with esophageal cancer at time of diagnosis, as stratified by their stage, as there is a paucity of published data in this realm. Methods: We identified patients in the National Cancer Data Base diagnosed with esophageal cancer, from 2004 to 2016 and grouped them by stage: early stage (stage I-III) and advanced stage (stage IV). These groupings were then compared based on various patient demographics and socioeconomic factors, including age, gender, insurance status, education, and income. p-values were determined by chi-square test. Results: 102,540 patients (79.5% male; 84.0% Caucasian) were included in our analysis. There was a statistically significant increase in the diagnosis of de novo metastatic disease seen with younger age (⇐59 years), male gender, lack of insurance coverage, residential communities with lower education, and lower income (&amp;lt;$38,000 annual income) as shown in Table 1. Summary Table of Stage at Diagnosis by Patient CharacteristicsTotal NTotal %Stage 0-IIINStage 0-III%Stage IVNStage IV %p-valueAge⇐59298301001840361.691142738.31&amp;lt;0.000160-74475031003244668.31505731.7&amp;gt;=75252071001789971.01730828.99GenderFemale210701001510671.69596428.31&amp;lt;0.0001Male814701005364265.842782834.16InsuranceUnknown2902100194967.1695332.84Government612231004204368.671918031.33&amp;lt;0.0001Not Insured3450100184053.33161046.67Private349651002291665.541204934.46Community Median IncomeUnknown52610035567.4917132.51&amp;lt;38K185611001221065.78635134.22&amp;lt;0.000138-63K526941003531767.021737732.98&amp;gt;=63K307591002086667.84989332.16Percent No High School Degree Quartiles 2012-2016Unknown142710091664.1951135.81&amp;gt;=17.6%197021001290265.49680034.51&amp;lt;0.000110.9-17.5%274621001845067.18901232.826.3-10.8%300291002013867.06989132.94&amp;lt;6.3%239201001634267.053379232.95 Conclusion: Data from the National Cancer Data Base supports the association of younger age and lower socioeconomic status with higher stage at diagnosis in patients with esophageal cancer, highlighting the need for increased awareness and education in these at-risk subgroups. Citation Format: Meena Sadaps, Neal Mehta, Wei Wei, Katherine Tullio, Amit Bhatt, Alok Khorana. Socioeconomic disparities in patients with esophageal cancer at time of diagnosis: A national cancer data base analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1170.
OP0070 Non-malignant lymphoproliferation in sjoegren’s syndrome: proposed classification based on integrated clinico-phatologic and molecular studies and follow-up
Authors: S De Vita, C Scott, M Fabris, R Damato, A Perin, S Sacco, GF Ferraccioli
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Non-neoplastic B-cell lymphoproliferation (NNBLP) is a common feature in Sjoegre’s syndrome (SS) and predisposes to non-Hodgkin’s lymphoma (NHL). It is characterised by extranodal or nodal organ involvement or by the presence of an M-component in biologic fluids, in particular mixed monoclonal cryglobulinemia (MMC). <h3>Objectives</h3> To better address the issue of SS-NNLP of Mucosa-Associated Lymphoid Tissue (MALT), usually involving the major salivary glands, we investigated 13 consecutive patients with primary SS and persistent parotid swelling (12F, 1M; mean age 59.5 years). <h3>Methods</h3> Clinical and pathologic results were integrated with molecular analyses of B-cell clonal expansion in synchronous and metachronous biopsies (mean follow-up: 5.3 years). <h3>Results</h3> At baseline 6/13 patients presented a parotid MESA with lymphoproliferative lesion (Group 1) and 7/13 a MESA with fully benign lymphoid infiltrate (Group 2), according to strict pathologic criteria.<sup>1</sup> Tissue B-cell clonal expansion was monoclonal in 5/6 cases in Group 1 and oligo-polyclonal in 6/7 cases in Group 2. B-cell NHL evolution was observed in 2/6 cases in Group 1 and in 0/7 in Group 2. Only the 2 cases evolved into NHL presented previous molecular evidence of ongoing expansion of the same clone or clonal dissemination in multiple biopsies. By contrast, the clinical and laboratory features were not relevant either for the diagnosis of NNLP vs NHL or to predict NHL evolution. MMC was detected in 2/13 cases, not evolved into NHL. <h3>Conclusion</h3> Pathologic features are crucial to distinguish between non-neoplastic and neoplastic extranodal LP in SS. Molecular analyses of B-cell clonal expansion appear relevant to identify a subset of patients with higher risk of NHL progression. When considering the whole spectrum of NNLP in SS and a practical diagnostic approch (“real” disease entities,<sup>1–3</sup>), the following classification is proposed: a) Fully benign lymphoproliferation: fully benign lymphoid infiltrates in MALT sites or reactive lymphoadenopathy in the lack of M-component; b) Lymphoproliferative disorder: lymphoproliferative lesions in MALT sites, nodal atypical lymphoproliferative disorder or persistent MMC or M-component in biologic fluids. A consensus on the classification of NNLP in SS will allow cooperative studies to clarify disease pathobiology and the risk of NHL evolution and to optimise follow-up and treatment. <h3>References</h3> De Vita, et al. Arthritis Rheum. 1997;40:318 Skopouli, <i>et al</i>. Semin Arthritis Rheum. 2000;29:296 De Vita, et al. Arthritis Rheum. 2000;43:94
Abstract 2474: Potent small molecule TEAD inhibitors targeting the Hippo pathway exhibit antiproliferation in vitro and anti-tumor effect in vivo
Authors: Ben Amidon, Sakeena Syed, Jill Cavanaugh, Hyejin Frosch, Prabitha Natarajan, Jeffrey Ecsedy, Karen McGovern, Alfredo C. Castro
Journal: Cancer Research (2020)

Abstract The Hippo signaling cascade is an important pathway for cancer biogenesis and tumor maintenance. The Hippo pathway is heavily mutated across many cancer indications through loss of function mutations in genes such as NF2. These pro-tumor mutations lead to the constitutive activation of the downstream transcriptional coactivators YAP and TAZ that drive the expression of many pro-survival and proliferation genes through the essential interaction with a TEAD protein family member. In addition, this unrestrained transcriptional program drives enhanced immune suppression in the tumor microenvironment. To target this oncogenic pathway we identified novel small molecule inhibitors that selectively bind to TEAD and disrupt their interaction with YAP and TAZ thereby downregulating YAP- and TAZ-dependent transcription. These inhibitors prevent TEAD palmitoylation which is essential for the interaction between YAP and TEAD. Furthermore, they inhibit in vitro proliferation of YAP-dependent (i.e. Hippo pathway-deficient cancer cell lines), but not Hippo pathway wild type cancer cell lines. An attraction of targeting this pathway is that many differentiated cells and tissues do not rely on the Hippo pathway, but notable exceptions have been demonstrated with tissue specific mouse knockouts in the bile duct and kidney podocytes. Importantly, our compounds did not affect survival of a differentiated mouse podocyte cell line or compromise mouse kidney histology. Subsequent experiments in vivo demonstrate these inhibitors downregulate YAP-dependent genes in human tumor xenografts after oral dosing. In addition, these inhibitors exhibit single agent tumor growth inhibition of human tumor xenografts in mice at well tolerated oral doses. These data demonstrate the potential for targeting this critical pathway in cancers with small molecules. Additional studies to identify tumor types that are Hippo pathway-driven and dependent on TEAD function are in progress. Citation Format: Ben Amidon, Sakeena Syed, Jill Cavanaugh, Hyejin Frosch, Prabitha Natarajan, Jeffrey Ecsedy, Karen McGovern, Alfredo C. Castro. Potent small molecule TEAD inhibitors targeting the Hippo pathway exhibit antiproliferation in vitro and anti-tumor effect in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2474.