tbuckley/cabot-search huggingface dataset:
AB0037 Complicated ra course with onset in elderly age
Authors: AM Satybaldyev, TF Akimova, MM Ivanova
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> <h3>Methods</h3> Disease course in 173 RA pts with onset in age older than 50 was analysed. It was demonstrated that in 101 pts (M:F = 12:89, median onset 58.6 y/o, median disease duration up to complication – 6.9 yrs, median age of last examination 67.5, median observation period 7.5) the following complications developed: aseptic bone necrosis, secondary amyloidosis, expressed osteoporosis with osteoporotic bone fractures and compression of vertebral bodies. <h3>Results</h3> Systemic manifestations (rheumatoid nodes, internal organs lesions, symptoms of serositis) were determined in 36% of pts, rheumatoid factor in 92%. Vasculopathies including livedo reticularis, capillarites and trophic ulcers – in 20% of pts. Aseptic bone necrosis was found in 40 pts (median observation period 10.2 yrs). Their localization: femoral head and/or tectum of cotyloid cavity in 20 pts, subchondral bones of knee joint – in 14, less frequently in wrist, humerus and elbow joints. Repeated aseptic necroses developed in 31 pts. 31 pts had secondary amyloidosis, median disease duration up to diagnosis – 7.6 yrs. This group of pts demonstrated highest inflammatory activity according to clinical and laboratory data. Observation period of pts with already developed amyloidosis was from 2 to 10.5 yrs. 14 pts out of them died during the period of observation. Developed osteoporosis and compression of vertebrae were observed in 35 pts (median age of fractures 63.8). Radiodensitometry in all pts demonstrated reduced mineral bone density more than 2.5 CD. Localization of skeletal bones fractures (in 24 pts) was as follows: femoral head in 35% of cases, ribs – in 20%, humerus – in 15%, less frequently radius, pelvic bones, feet. Multiple fractures were observed in 40% of cases. Compressions of vertebral bodies were found in 19 pts, combinations of osteoporotic fractures and vertebral bodies compression – in 9 pts. <h3>Conclusion</h3> Thus, follow-up of elderly pts enabled us to select the group of pts with complicated disease course aggravated the prognosis. Reducing of high inflammatory activity of the disease by active therapy will be positive for the disease course, decrease the risk of complications associated with amyloidosis, with diseases activity, aseptic bone necrosis, osteoporosis. Preventive measures are recommended to decrease osteoporotic complications from the very beginning of the disease.
Abstract 5644: Claudin 18.2 X 4-1BB bispecific antibody induced potent tumor inhibition through tumor-specific 4-1BB activation
Authors: Wenqing Jiang, Lei Fang, Zhengyi Wang, Taylor B. Guo, Eunyoung Park, Eunsil Sung, Jaeho Jung
Journal: Cancer Research (2020)

Abstract Background Claudin 18.2 (CLDN18.2) is a gastric-specific membrane protein. In the healthy tissue, CLDN18.2 expression is restricted to the short-lived differentiated cells of gastric mucosa as a component of tight junction with limited accessibility of antibody treatment. However, it was ectopically expressed at significant levels in a variety of primary lesion and metastases of epithelial tumor entities, including gastric, pancreatic, esophageal, and lung adenocarcinoma cells. Taken together, CLDN18.2 was believed to be an ideal tumor antigen for immunotherapy. Here, we generated and described a bispecific antibody TJ-CD4B which could redirect and activate T cells to CLDN18.2 positive tumor cells by engaging 4-1BB antigen, thus positioned as a potential novel therapy for gastric cancer and other CLDN18.2 positive tumors. Methods TJ-CD4B was evaluated for its antigen binding through protein-based binding and cell based binding assay. The cell-based function of TJ-CD4B was further evaluated in a 4-1BB signaling reporter assay and primary human T cell assay. The in vivo efficacy was validated in 4-1BB humanized C57BL/6 mice transferred with colon cancer cell line MC38 overexpressed with human CLDN18.2. Percentage of tumor infiltrating and peripheral CD8+ T cells was evaluated by FACS analysis. Results TJ-CD4B showed stronger binding capability to CLDN18.2 when compared with benchmark monoclonal antibody against CLDN18.2 (IMAB362). Functional evaluation of TJ-CD4B indicated the activation of 4-1BB signaling was solely dependent on CLDN18.2 expression on the cell. Furthermore, TJ-CD4B showed superior 4-1BB activity than benchmark 4-1BB monoclonal antibody (Urelumab) in the presence of cells expressing a wide range of CLDN18.2 level including CLDN18.2-low cells. Using a humanized 4-1BB mouse model, TJ-CD4B showed strong tumor growth inhibition (TGI) of CLDN18.2 expressing tumor cells. Meanwhile, we also observed TJ-CD4B increased tumor infiltrating lymphocytes while it had no impact on peripheral lymphocytes. Drug developability assessment indicated that TJ-CD4B was a reasonably developable molecule to be taken forward. Conclusions Our data showed that CLDN18.2-targeted 4-1BB bispecific antibody, TJ-CD4B, displayed potent anti-tumor activity only in tumor microenvironment, possibly minimizing the risk of peripheral toxicity. These compelling data supported the further development of TJ-CD4B, which aims to enter clinical phase in early 2021. Citation Format: Wenqing Jiang, Lei Fang, Zhengyi Wang, Taylor B. Guo, Eunyoung Park, Eunsil Sung, Jaeho Jung. Claudin 18.2 X 4-1BB bispecific antibody induced potent tumor inhibition through tumor-specific 4-1BB activation [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 5644.
Abstract 6524: A novel HER2/4-1BB bispecific antibody, YH32367 (ABL105) shows potent anti-tumor effect through tumor-directed T cell activation
Authors: Moo Young Song, Eun-Jung Lee, Hyejin Chung, Yangsoon Lee, Young Bong Park, Min Hyeok Jee, KyeongBae Kim, Mikyeong Ju, Jun Kyung Lee, Byung Hyun Choi, Ju Young Park, DaeWon Kim, Junhwan Kim, Sujin Ahn, Kyoung Kyu Ahn, Kyeongsu Park, Uijung Jung, Wonjun Son, Jaehyun Eom, Eunjung Kim, Donghoon Yeom, Jinhyung Ahn, Daehae Song, Byungje Sung, Weon-kyoo You, Jong Gyun Kim, Se-Woong Oh, Jaeho Jung
Journal: Cancer Research (2020)

Abstract 4-1BB (TNFSF9, CD137) is a member of the tumor necrosis factor receptor superfamily that functions as a potent costimulator to immune cells, especially T-cell. Although current 4-1BB-targeted strong agonistic antibody exhibit a considerable anti-tumor effect through T cell activation, it has a limitation of liver toxicity. To overcome the challenges of targeting the 4-1BB, we developed a bispecific antibody that can induce tumor-directed T cell activation. A novel HER2/4-1BB bispecific antibody, YH32367 (ABL105) targets human epidermal growth factor receptor 2 (HER2) and 4-1BB simultaneously and binds to both targets with high affinity. YH32367 (ABL105) exhibited a strong activation of 4-1BB signal in tumor cells expressing HER2 such as NCI-N87, BT474 and HCC1954 cell lines. In co-culture assay using human peripheral blood mononuclear cell (hPBMC) and HER2-expressing tumor cells, YH32367 (ABL105) stimulated IFN-γ secretion from hPBMC and thereby induced tumor cell lysis. The anti-tumor efficacy of YH32367 (ABL105) was evaluated in HCC1954-bearing hPBMC engrafted humanized mice and MC38/hHER2-bearing h4-1BB knock-in mice. YH32367 (ABL105) had more potent efficacy on tumor growth inhibition in both mouse models compared to the equimolar dosing of trastuzumab. Peripheral T cell increase was not observed in these studies. In particular, YH32367 (ABL105) showed a tumor regression in MC38/hHER2-bearing h4-1BB knock-in mice. In conclusion, YH32367 (ABL105) significantly inhibited tumor growth in a HER2 expression dependent manner and showed potent in vivo efficacy through tumor-directed T cell activation without non-specific systemic T-cell activation. Citation Format: Moo Young Song, Eun-Jung Lee, Hyejin Chung, Yangsoon Lee, Young Bong Park, Min Hyeok Jee, KyeongBae Kim, Mikyeong Ju, Jun Kyung Lee, Byung Hyun Choi, Ju Young Park, DaeWon Kim, Junhwan Kim, Sujin Ahn, Kyoung Kyu Ahn, Kyeongsu Park, Uijung Jung, Wonjun Son, Jaehyun Eom, Eunjung Kim, Donghoon Yeom, Jinhyung Ahn, Daehae Song, Byungje Sung, Weon-kyoo You, Jong Gyun Kim, Se-Woong Oh, Jaeho Jung. A novel HER2/4-1BB bispecific antibody, YH32367 (ABL105) shows potent anti-tumor effect through tumor-directed T cell activation [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 6524.
sgBE: a structure-guided design of sgRNA architecture specifies base editing window and enables simultaneous conversion of cytosine and adenosine
Authors: Yanhong Wang, Lifang Zhou, Rui Tao, Nan Liu, Jie Long, Fengming Qin, Wenling Tang, Yang Yang, Qiang Chen, Shaohua Yao
Journal: Genome biology (2020)

Abstract We present a base editing system, in which base editors are attached to different sites of sgRNA scaffold (sgBE). Each independent sgBE has its own specific editing pattern for a given target site. Among tested sgBEs, sgBE-SL4, in which deaminase is attached to the last stem-loop of sgRNA, yields the highest editing efficiency in the window several nucleotides next to the one edited by BE3. sgBE enables the simultaneous editing of adenine and cytosine. Finally, in order to facilitate in vivo base editing, we extend our sgBE system to an AAV-compatible Cas9, SaCas9 ( Staphylococcus aureus ), and observe robust base editing.
Abstract 5165: Novel approach to colorectal cancer drug target discovery in human FFPE tissue using the Adaptive Dynamic Artificial Polyligand Targeting System
Authors: Stephanie Williams, Chao Sima, Tassilo Hornung, Matthew Rosenow, Teresa Tinder, Varun Maher, Michelle Kassner, Gerri Ortiz, Perrin Mok, Nicholas Helle, Stephen Logie, Heather ONeill, Mark Miglarese, David Spetzler
Journal: Cancer Research (2020)

Abstract Identification of novel biomarkers and drug targets for colorectal cancer remains a critically unmet medical need. Target identification has historically been driven by preclinical models which poorly recapitulate the complex biology of human cancers. We describe a unique approach to drug target identification and comprehensive profiling directly in clinical specimens. Using the Adaptive Dynamic Artificial Polyligand Targeting (ADAPT) system, we aimed to identify such disease specific drug targets using a highly complex library of single-stranded oligodeoxynucleotides (ODNs). To generate the library, the ODNs were enriched using FFPE tissue specimens from pathologically determined colorectal cancer (CRC) and counter-selected against normal adjacent tissue (NAT) regions. Once the specificity of the library was verified via differential binding on independent CRC cases, it was used to affinity purify cognate biding partners from 393 CRC FFPE lysates with appropriate representation of cases with either KRAS, NRAS or BRAF mutations. Greater than 700 proteins were identified by mass spectrometry exclusively in the CRC FFPE tissue lysates and not in the NAT FFPE tissue lysates for all 393 CRC cases. Classification of these proteins into the druggable protein classes revealed G-protein coupled receptors, transporters, voltage-gated ion channels, proteases, and protein kinases. In addition, subsequent verification studies confirmed novel candidate cell surface protein targets appropriate for targeting by antibody-drug conjugates (ADC) or other biologic modalities. mRNA expression corresponding to the 700 potential targets was analyzed in over 1600 CRC FFPE tumor samples and &amp;gt;9000 other cancer types as well as in a broad panel of normal tissues by Whole Transcriptome Sequencing (WTS) and immunohistochemistry (IHC). We conclude that the unbiased ADAPT platform provides a robust and novel approach to drug target discovery with highly selective expression profiles directly from FFPE clinical specimens. Citation Format: Stephanie Williams, Chao Sima, Tassilo Hornung, Matthew Rosenow, Teresa Tinder, Varun Maher, Michelle Kassner, Gerri Ortiz, Perrin Mok, Nicholas Helle, Stephen Logie, Heather ONeill, Mark Miglarese, David Spetzler. Novel approach to colorectal cancer drug target discovery in human FFPE tissue using the Adaptive Dynamic Artificial Polyligand Targeting System [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 5165.
Abstract 3778: MBNL1 regulated alternative splicing of <i>MAP2K7</i> promotes de-differentiation of cancer cells by activating JNK
Authors: Debleena Ray
Journal: Cancer Research (2020)

Abstract Therapeutic targeting of cancer stem cells (CSCs) is key to relapse-free, lasting response to cancer treatment. Several strategies against CSCs are currently in various stages of clinical development. However, there is need for additional targets. Here, we demonstrate that MBNL1, an RNA binding protein, is a suppressor of cancer-stemness. RNAi mediated down-regulation of MBNL1 promotes tumor-initiation, self-renewal, migration and invasion by up-regulating CSC-specific splice-isoforms. Particularly, the up-regulation of MAP2K7Δexon2 splice-isoform activates JNK signaling and establishes a feedback loop that promotes cancer-stemness. Pharmacological inhibition of JNK reverses CSC phenotypes in MBNL1low/MAP2K7Δexon2high CSC-like cells and these cells also show enhanced susceptibility to JNK inhibition. Remarkably, MBNL1 is down-regulated and MAP2K7Δexon2 splice-isoform is up-regulated in several cancer types. Down-regulation of MBNL1 is correlated with poor survival in gastric, lung and breast adenocarcinoma. In triple negative breast cancer, which is a highly aggressive disease characterised by enrichment of CSC-like cells, low MBNL1 correlates with poor relapse-free and distant metastasis-free survival. Our work shows, low MBNL1 and consequently high MAP2K7Δexon2 expression, is a biomarker for cancer stemness, high JNK activity and enhanced susceptibility to JNK inhibition. Hence, we have identified a novel alternative splicing driven mechanism of cancer cell de-differentiation and have identified biomarkers that can prognosticate patients for JNKi as a strategy to target CSCs. Citation Format: Debleena Ray. MBNL1 regulated alternative splicing of MAP2K7 promotes de-differentiation of cancer cells by activating JNK [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 3778.
Abstract 112: Telomere proteins coordinate intracellular signaling to control telomere maintenance mechanism selection and metastatic recurrence
Authors: Nathaniel J. Robinson, Derek J. Taylor, William P. Schiemann
Journal: Cancer Research (2020)

Abstract The relationship between telomere homeostasis and the development of cancer remains incompletely understood. In breast cancer (BC), these knowledge gaps are magnified by the fact that distinct telomere maintenance mechanisms (TMMs) are utilized across different disease subtypes and stages of progression. Accordingly, we have found that TMM identity in BC possesses an inherent plasticity that portends important prognostic and therapeutic insight, events regulated in part by SLX4-interacting protein (SLX4IP). To better understand how SLX4IP regulates TMM identity in BC, we employed proteomics of isolated chromatin segments (PICh) to capture the telomere proteomes of BC cells harboring differential SLX4IP expression. These analyzes revealed that SLX4IP blocks recruitment of the shelterin protein telomere repeat-binding factor 2-interacting protein (TERF2IP, also known as RAP1) to telomeres. Moreover, telomeres lacking RAP1 were able to be extended via the homologous recombination-based Alternative Lengthening of Telomeres (ALT) pathway. Mechanistically, SLX4IP disrupted the interaction between RAP1 and telomere repeat-binding factor 2 (TRF2), which facilitated the nuclear export of RAP1 and its binding to and activation of the NF-κB regulatory kinase, IKKβ. Activated IKKβ phosphorylated both NF-κB and β-catenin, thereby coordinating a transcriptional network of genes that are essential in promoting ALT. Conversely, loss of SLX4IP yielded telomeric retention of RAP1 with concomitant diminution of IKKβ activity, resulting in β-catenin-dependent stimulation of telomerase. Notably, telomerase was sufficient to drive the metastatic outgrowth of cells that were previously reliant upon ALT independent of its ability to extend telomere DNA. These findings shed new light on the functions of SLX4IP and the myriad roles of telomere proteins in influencing TMM plasticity and disease progression. Citation Format: Nathaniel J. Robinson, Derek J. Taylor, William P. Schiemann. Telomere proteins coordinate intracellular signaling to control telomere maintenance mechanism selection and metastatic recurrence [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 112.
Cytokine Levels in Critically Ill Patients With COVID-19 and Other Conditions
Authors: Matthijs Kox, Nicole J. B. Waalders, Emma J. Kooistra, Jelle Gerretsen, Peter Pickkers
Journal: JAMA (2020)

This study compares levels of tumor necrosis factor α, IL-6, and IL-8 in critically ill patients with coronavirus disease 2019 (COVID-19) vs those with other critical illness to better characterize the contribution of cytokine storm to COVID-19 pathophysiology.
Abstract 4911: Characterizing the role of podocalyxin's cytoplasmic tail domain in collective tumor invasion
Authors: Erin M. Bell, Marcia L. Graves, Pamela Dean, Kelly M. McNagny, Calvin D. Roskelley
Journal: Cancer Research (2020)

Abstract High expression of the single-pass transmembrane sialomucin, podocalyxin, has been shown by many groups to correlate with poor disease outcome in a number of solid tumor types, including colorectal, ovarian, pancreatic and breast cancers. We had previously identified that high podocalyxin expression in invasive ductal breast carcinoma was an independent indicator of poor survival (Somasiri et al., 2004, Cancer Res. 64:15). Further analysis of these tumor samples revealed that this decrease in survival occurred without the loss of membranous, junctional E-cadherin, suggesting that these tumors may have invaded collectively without necessitating an overt epithelial to mesenchymal transition (EMT). Experimentally, forced over-expression of podocalyxin in polarity-disrupted human MCF7 breast cancer cells drives the formation of invasive orthotopic xenograft tumors and elongated, cohesive, and E-Cadherin-expressing spheroids in three-dimensional (3D) culture as compared to control (Graves et al., 2016, Breast Canc. Res. 18:11). Further, treatment of these podocalyxin-overexpressing MCF7 cells with the myosin inhibitor, blebbistatin, and the small molecule inhibitor of ezrin-actin binding, NSC668394, resulted in decreased collective invasion and migration, respectively. Together these data suggest that podocalyxin, through interactions with the actin cytoskeleton via its cytoplasmic tail binding partners, can facilitate increased collective epithelial tumor cell motility, at least in some contexts. To test this hypothesis, we generated podocalyxin null MCF7 clones and cell populations using CRISPR-Cas9 genome editing and reconstituted these cells with mutant forms of podocalyxin that are unable to interact with the scaffolding proteins NHERF and/or ezrin and hence with the actin cytoskeleton. Preliminary results from 3D culture and live imaging of these mutant podocalyxin-expressing cells suggests that loss of podocalyxin's cytoplasmic tail results in decreased spheroid invasion that may be a result of deficiencies in actomyosin contractility. Hence, increased expression and mislocalization of podocalyxin may facilitate aberrant interactions with the actin cytoskeleton and contractile machinery, driving enhanced cell motility and, in certain tumor microenvironments, promote collective tumor invasion. Citation Format: Erin M. Bell, Marcia L. Graves, Pamela Dean, Kelly M. McNagny, Calvin D. Roskelley. Characterizing the role of podocalyxin's cytoplasmic tail domain in collective tumor invasion [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 4911.
Abstract CT022: A first-of-its-kind prospective study of a multi-cancer blood test to screen and manage 10,000 women with no history of cancer
Authors: Nickolas Papadopoulos
Journal: Cancer Research (2020)

Abstract One of the most compelling approaches to reduce cancer-specific morbidity and mortality is earlier detection. Minimally-invasive screening tests, such as liquid biopsies, hold much promise in this regard. However, prospective clinical studies of these new methods are required to ensure that the anticipated benefits outweigh the potential risks. We describe an interim analysis of a study that enrolled 10,006 women 65 to 75 years of age who had no prior history of cancer, in a population with a high degree of compliance with standard-of-care screening. Enrollment occurred between September 2017 and May 2019. The study evaluated the prospective implementation of a multi-cancer, multi-analyte screening blood test (DETECT-A blood test) incorporating DNA and protein markers. Participants with positive DETECT-A blood test results were followed by an imaging test (generally PET-CT) to localize the putative cancer. The DETECT-A blood test combined with standard-of-care screening doubled the number of cancers detected by screening. The DETECT-A blood test effectively identified subjects with multiple types of cancer, with a positive predictive value higher than existing non-invasive screening tests for individual cancers. The DETECT-A blood test identified ten different cancer types, including seven types for which there is currently no screening test available. No serious adverse events were observed in any participants enrolled in the study. 65% of the cancers detected by the blood test were classified as local or regional disease. Somatic mutations in TP53, BRAF, KRAS, or PIK3CA were the most common alterations identified in plasma; in all cases where tumor tissue was available, the mutations detected in plasma were confirmed to be present in the primary tumor. These results are the first to demonstrate that a minimally-invasive multi-cancer blood test can be safely incorporated into routine clinical care. Moreover, this is the first study to show that it can be used to guide patient management in real-time, leading to surgery with intent to cure in asymptomatic individuals. Citation Format: Nickolas Papadopoulos. A first-of-its-kind prospective study of a multi-cancer blood test to screen and manage 10,000 women with no history of cancer [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 CT022.