tbuckley/cabot-search huggingface dataset:
Abstract 689: Strong anti-tumor activity and stability of IL-2/anti IL-2 conjugate SLC-3010 in preclinical experiments
Authors: Geon-A Kim, Da-Eun Kim, Yoo-Jin Kim, Kyung-Mi Han, Hee-Sung Kim, Soon-Hye Park, Jae-Hyun Park, Eun-Jihn Roh, Gil-Tae Wie, Jun-Young Lee
Journal: Cancer Research (2021)

Abstract To achieve successful anti-cancer response with IL-2, it is necessary to develop a method delivering selective IL-2 signaling on CD8 T and NK cells than Tregs We report preclinical results with SLC-3010 that consist of IL-2 conjugate with anti-IL-2 antibody named TCB2 TCB2 is a humanized mouse antibody that specifically recognize the epitope on IL-2 where interact with CD25 as demonstrated with crystallography To develop SLC-3010, stable cell lines producing wild type human IL-2 or TCB2 were separately manufactured using mammalian cell system The pharmacokinetics analysis of SLC-3010 revealed 8-12h of half-life in mouse Although SLC-3010 dose not employ any artificial linker between IL-2 and TCB2, the half-life of SLC-3010 is comparable with other IL-2 based molecules thereby demonstrating stable binding of TCB2 against IL-2 under physiological condition In mouse model, single dosing of SLC-3010 preferentially stimulates CD8 T cells than Tregs in both secondary lymphoid organ and tumor microenvironment SLC-3010 exhibited strong anti-tumor activity which is demonstrated with circulating B cell lymphoma, metastatic solid tumor, and traditional solid tumor models Furthermore, synergistic anti-tumor response was observed by SLC-3010 with various anti-cancer drugs including chemotherapeutic reagents, targeted therapeutics, and checkpoint inhibitors such as anti PD-1 and anti CTLA-4 Once the transplanted tumor was completely cured by SLC-3010, the mice acquired strong memory response against the rejected tumor indicating strong immunological memory formation against recurrent tumors Non-human primate (NHP) efficacy test revealed that single dosing of SLC-3010 expanded CD8 T and NK cells in dose dependent manner, hence the number of CD8 T cells were increased up to 5 fold in the PBMC population with non-toxic dose of SLC3010 The peak of response in NHP was day 6-7 as analyzed the number of CD8 T cells in PBMC The strong activation of CD8 and NK cells with NHP model indicating that the binding of TCB2 and IL-2 is stable in the system as well The SLC-3010 induced selective stimulation of CD8 T cells was also demonstrated with human T cells using humanized NSG mice thereby providing an insight for developing future clinical trials with SLC-3010. Citation Format: Geon-A Kim, Da-Eun Kim, Yoo-Jin Kim, Kyung-Mi Han, Hee-Sung Kim, Soon-Hye Park, Jae-Hyun Park, Eun-Jihn Roh, Gil-Tae Wie, Jun-Young Lee. Strong anti-tumor activity and stability of IL-2/anti IL-2 conjugate SLC-3010 in preclinical experiments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 689.
Triple negative breast cancer and non-small cell lung cancer: Clinical challenges and nano-formulation approaches
Authors: Saikat Ghosh, Ankit Javia, Saritha Shetty, Denish Bardoliwala, Kuntal Maiti, Shubhadeep Banerjee, Ajay Khopade, Ambikanandan Misra, Krutika Sawant, Subhas Bhowmick
Journal: Journal of Controlled Release (2021)
Development and Validation of a Simulation Model–Based Clinical Decision Tool: Identifying Patients Where 21-Gene Recurrence Score Testing May Change Decisions
Authors: Jinani Jayasekera, Joseph A. Sparano, Suzanne O'Neill, Young Chandler, Claudine Isaacs, Allison W. Kurian, Lawrence Kushi, Clyde B. Schechter, Jeanne Mandelblatt
Journal: Journal of Clinical Oncology (2021)

There is a need for industry-independent decision tools that integrate clinicopathologic features, comorbidities, and genomic information for women with node-negative, invasive, hormone receptor-positive, human epidermal growth factor receptor-2-negative (early-stage) breast cancer.We adapted an extant Cancer Intervention and Surveillance Modeling Network simulation model to estimate the 10-year risk of distant recurrence, breast cancer-specific mortality, other-cause mortality, and life-years gained with chemoendocrine versus endocrine therapy. We simulated outcomes for 1,512 unique patient subgroups based on all possible combinations of age, tumor size, grade, and comorbidity level; simulations were performed with and without 21-gene recurrence scores (RSs). Model inputs were derived from clinical trials, large US cohort studies, registry, and claims data. External validation was performed by comparing results to observed rates in two independent sources. We highlight results for one scenario where treatment choice may be uncertain.Chemoendocrine versus endocrine therapy in a 65-69-year-old woman with a small (≤ 2 cm), intermediate-grade tumor, and mild comorbidities provides a 1.3% absolute reduction in 10-year distant recurrence risk, with 0.23 life-years gained. With these tumor features, a woman like this will have a 28% probability of having an RS 16-20, 18% RS 21-25, and 11% RS 26+. If testing is done, and her RS is 16-20, chemoendocrine therapy reduces 10-year distant recurrence risk to 1%, with 0.20 life-years gained, a similar result as without testing. The absolute benefits would increase to 4.8%-5.5% if the RS was 26+. The model closely reproduced observed rates in both independent data sets.Our validated clinical decision tool is flexible, readily adaptable to include new therapies, and can support discussions about genomic testing and early breast cancer treatment.
Abstract 501: Double-humanized 4-1BB/4-1BBL mouse is an advanced model for liver toxicity and efficacy evaluation of 4-1BB therapeutic antibodies
Authors: Lei Zhao, Linlin Wang, Dirui Li, Li Hui, Qingcong Lin
Journal: Cancer Research (2021)

Abstract 4-1BB is an activation-induced costimulatory TNF receptor family member which is expressed on a variety of cell types such as activated T cells, NK cells, DCs, B cells, monocytes and Neutrophils. 4-1BB/4-1BBL interaction leads to a series of activation effects including increased cytotoxic T lymphocytes (CTL) activity, cytokine induction, prevention of activation-induced cells death (AICD). Agonistic monoclonal antibodies targeting 4-1BB have shown robust anti-tumor activity but has also caused substantial liver toxicity which hampered their clinical development. To better assist the efficacy and toxicity evaluation of anti 4-1BB antibodies, Biocytogen developed a 4-1BB/4-1BBL double humanized knock in mice, which is the second generation of humanized 4-1BB mice. In the double humanized mouse, the exons of mouse 4-1BBL and 4-1BB genes that encode the transmembrane domain and extracellular domain were replaced by human counterpart exons. The expression of knocked in exons were confirmed by both RT-PCR and Flow cytometry. In vivo efficacy study showed that 4-1BB antibodies significantly inhibited tumor growth in mice bearing the colon cancer cell line MC38 and this effect was dose-dependent. The tumor growth inhibition (TGI) reached approximately 70% in the mice group dosed 1mg/kg. More importantly, Toxicity study showed that compared to the single humanized 4-1BB mice, double humanized 4-1BB/4-1BBL mice have higher sensitivity on liver toxicity testing, reflected by sera AST and ALT level as well as liver pathological analysis. These results indicate that the double humanized B-h4-1BB/h4-1BBL mouse model, by mimicking a more human like 4-1BB and 4-1BBL interaction, has been proved to be a more advanced option for preclinical toxicity and efficacy evaluation for 4-1BB therapeutic antibodies compared to single humanized 4-1BB mice. Citation Format: Lei Zhao, Linlin Wang, Dirui Li, Li Hui, Qingcong Lin. Double-humanized 4-1BB/4-1BBL mouse is an advanced model for liver toxicity and efficacy evaluation of 4-1BB therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 501.
Optimising emergency urological care in the older patient – impact of a dedicated Perioperative care for Older People undergoing Surgery (POPS) platform
Authors: Y. Mark, E. Carolan, S. Folkard, M. Abuelnaga, A. Simoes, M. Thomas, L. Forsyth, S.S. Kommu, B.A. Eddy, E. Streeter, C. Meilak
Journal: European Urology (2021)
Abstract 16584: Proteomic Differences Between Heart Failure With Preserved Ejection Fraction Patients and Comorbidity Controls
Authors: Stanley A Swat, Joyce Njoroge, Cynthia L Sanchez, Sanjiv J Shah
Journal: Circulation (2018)

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome, and mechanisms for the development of HFpEF remain unclear. Currently used biomarkers such...
Abstract LB045: Identification of plasma-derived, EV-based biomarkers for glioblastoma
Authors: Yevgenia L. Khodor, Sudipto K. Chakrabortty, Christian Fischer, Martina Rauscher, Leonora Balaj, Bob S. Carter, Seth Yu, Johan Skog
Journal: Cancer Research (2021)

Abstract Background: Glioblastoma (GBM) is the most malignant and aggressive primary brain cancer in adults, with an incidence of 3.2 per 100,000 people. Currently, diagnosis is only performed via histopathological investigation of a tissue sample from a GBM lesion, complemented with molecular diagnostics for identification of select biomarkers. MRI is the standard of care for follow-up and monitoring of treatment response. Therefore, development of a “liquid biopsy” to obtain disease-relevant information from body fluids is highly desirable.Methods: We present the results from a clinical study in which extracellular vesicle (EV)-derived mRNAs were profiled from the plasma of GBM patients and control individuals for a total of 32 individual RNAseq libraries. Initial biomarker discovery was performed on plasma from 16 patients (8 GBM patients at the time of initial diagnosis and 8 age and sex matched controls). Hybrid capture and RNA-seq were performed via our proprietary pipeline on EV-associated mRNA isolated from 1-2mL plasma. Sequencing data was analyzed for differential gene expression. Validation was done with plasma samples from a new cohort of 8 patients and 8 control individuals.Results: We observed 98 mRNAs as differentially detected between GBM and control samples, with 83 mRNAs enriched in GBM samples and 15 mRNAs decreased (p &amp;lt; 0.05). Correlation based on differentially detected mRNAs separated GBM and control samples into two unique populations. We were able to use the differentially expressed gene signature from the first cohort to separate GBM patients and control individuals in the second cohort. We are currently following up these results with a larger patient population. These data, while preliminary, provide a potential basis for the further development of a GBM gene panel test.Conclusions: We have identified a novel gene signature for GBM in plasma-derived EVs, which differs from previously identified biomarkers isolated from tissue. Further work will refine this signature to enable detection, characterization, and patient monitoring for GBM with less invasive and intensive methods. Citation Format: Yevgenia L. Khodor, Sudipto K. Chakrabortty, Christian Fischer, Martina Rauscher, Leonora Balaj, Bob S. Carter, Seth Yu, Johan Skog. Identification of plasma-derived, EV-based biomarkers for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB045.
A retrospective study evaluating the outcomes of high‐dose methylprednisolone pulse therapy for 483 patients with moderate‐to‐severe alopecia areata
Authors: M. Wada‐Irimada, M. Mizuashi, T. Takahashi, G. Tojo, K. Onami, K. Shido, E. Otake, S. Yusa, K. Tanita, E. Yamazaki, S. Aiba, K. Yamasaki
Journal: British Journal of Dermatology (2021)
Abstract 2306: The ubiquitin-binding non-receptor tyrosine kinase TNK1 is regulated by a MARK-mediated interaction with 14-3-3
Authors: Christina Marie Egbert, Tsz Yin Chan, Logan Larsen, Eranga Roshan Balasooriya, Kristina Kohler, Jeremy Tsang, Madison Frey, Julia Maxson, David Huang, Kenneth A. Christensen, James Moody, Jeffrey W. Tyner, Joshua L. Andersen
Journal: Cancer Research (2021)

Abstract Tyrosine non-receptor kinase 1 (TNK1) is a poorly characterized member of the ACK family of non-receptor tyrosine kinases. We identified TNK1 as a mediator of cell survival in subsets of primary hematological malignancies. Previous studies have indicated a role for TNK1 in driving oncogenic potential; however, the function, regulation, and substrates of TNK1 still remain unknown. We identified an interaction between TNK1 and 14-3-3 that is promoted by a MARK-mediated phosphorylation at S502 on TNK1. 14-3-3 binding sequesters TNK1 to the cytosol. Upon the release of 14-3-3 binding, TNK1 moves to perinuclear puncta and is in a highly active state. This highly active form of TNK1 is able to drive growth factor independent proliferation of lymphoid cells in culture and in mice more potently than TNK1 WT. A unique feature of TNK1 is its C-terminal ubiquitin association domain (UBA) domain. In vitro ubiquitin pulldowns indicate a high affinity between the TNK1 UBA and polyubiquitin of varying linkages, with dissociation constants in the low nanomolar range. Mutation of residues within ubiquitin-binding interfaces of the UBA and ubiquitin leads to a reduction of ubiquitin association and a marked shift of TNK1 from perinuclear puncta to a diffuse cytosolic localization. Importantly, we show that loss of ubiquitin binding reduces TNK1 activity and oncogenic signaling. Taken together, our data uncovers a 14-3-3 and UBA-mediated mechanism of TNK1 regulation. Citation Format: Christina Marie Egbert, Tsz Yin Chan, Logan Larsen, Eranga Roshan Balasooriya, Kristina Kohler, Jeremy Tsang, Madison Frey, Julia Maxson, David Huang, Kenneth A. Christensen, James Moody, Jeffrey W. Tyner, Joshua L. Andersen. The ubiquitin-binding non-receptor tyrosine kinase TNK1 is regulated by a MARK-mediated interaction with 14-3-3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2306.
Abstract LB060: Circulating tumor cells in desmoid tumors
Authors: Alexcia Camila Braun, Fernando Campos, Emne Ali Abdallah, Anna Paula Ruano, Milena Tariki, Fabio Pinto, Celso Abdon de Mello, Vilma Regina Martins, Ludmilla Thome Chinen
Journal: Cancer Research (2021)

Abstract Introduction: Desmoid tumor (DT) is a rare neoplasm with high local recurrence rates. CTNNB1 mutations are found in most sporadic cases and are located in exon 3, usually in codons 41 or 45 (p.T41A, p.S45F and p.S45P). Circulating tumor cells (CTCs) isolated from the peripheral blood of patients with sarcomas and other neoplasms can be early biomarkers of tumor invasion and dissemination. Moreover, CTCs can also re-colonize their tumors of origin through a process of “tumor self-seeding.” Objectives: To identify CTCs in the peripheral blood of patients with DT; to evaluate their expressions of β- catenin and vimentin proteins. Materials and methods: We conducted a prospective study of patients with initially diagnosed and relapsed DT with measurable disease. Blood samples from each patient were processed and filtered by ISET® (Rarecells, France) for the isolation and quantification of CTCs. The expressions of β -catenin and vimentin in CTCs were analyzed by immunocytochemistry (ICC). Results: A total of 18 patients were included, and all had detectable CTCs. We found a concordance of β-catenin expression in CTCs and in primary tumors in 42.85% of cases by using ICC and immunohistochemistry respectively. Conclusions: Our study identified a high prevalence of CTCs in DT patients. Concordance of β-catenin expression between primary tumor and CTCs bring new perspectives to assess the dynamics of CTCs in the blood microenvironment, opening new avenues for studying the biology and behavior of DT. In addition, these results open the possibility of using CTCs to predict DT dynamics at the time of progression and during treatment. Further studies with larger sample sizes are needed to validate our findings. Citation Format: Alexcia Camila Braun, Fernando Campos, Emne Ali Abdallah, Anna Paula Ruano, Milena Tariki, Fabio Pinto, Celso Abdon de Mello, Vilma Regina Martins, Ludmilla Thome Chinen. Circulating tumor cells in desmoid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB060.
Abstract 2561: Tumorigenic and metabolomic impacts of adipose-derived monocyte chemotactic protein-1 in a model of obesity-enhanced, male breast cancer
Authors: Lin Yan, Sneha Sundaram, Bret M. Rust, Matthew J. Picklo, Michael R. Bukowski
Journal: Cancer Research (2021)

Abstract Breast cancer is a rare but aggressive disease in men. Approximately, 90% of all breast cancer in men are invasive carcinomas, 25% of which have distant metastasis at the time of clinical presentation. Obesity is a risk factor for breast cancer. Monocyte chemotactic protein-1 (MCP-1) is an adipose-derived cytokine whose concentrations are elevated by obesity. This study tested the hypothesis that adipose-derived MCP-1 contributes to male breast cancer. In a 2x2 design, male MMTV-PyMT mice with or without adipose specific Mcp-1 knockdown [designated as Mcp-1-/- or wild-type (WT)] were fed the standard AIN93G diet or an obesogenic, high-fat diet (HFD) for 25 weeks. The AIN93G diet and HFD contained 16% and 45% of energy from soybean oil, respectively. Mcp-1-/- mice had lower adipose Mcp-1 expression than WT mice. Adipose Mcp-1 deficiency reduced plasma concentrations of MCP-1 in mice fed the HFD. Mice fed the HFD had a greater tumor progression rate than mice fed the AIN93G diet (4679% vs 2430%), regardless of genotype. Mcp-1-/- mice, compared to WT mice, had a longer tumor latency (25.2 weeks vs 18.0 weeks) and lower tumor incidence (19% vs 56%), tumor progression rate (2317% vs 4792%), and tumor weights (0.23 g vs 0.64 g). Metabolomic analysis of plasma identified 87 metabolites, 56 of which differed among the four groups, including 24 that differed between the diets and 22 that differed between the genotypes. Sparse partial least squares-discriminant analysis identified 10 major metabolites that were altered the most among the four groups. These included amino acids (alanine, isoleucine, leucine, phenylalanine, threonine, and valine) and carbohydrate metabolites (fumaric acid, glucuronic acid, hexuronic acid, and malic acid). The integrated pathway analysis of the 87 identified metabolites showed that protein biosynthesis and carbohydrate metabolism pathways are the most disturbed in MMTV-PyMT mice. In conclusion, adipose-derived MCP-1 contributes to mammary tumorigenesis and alters metabolism in male MMTV-PyMT mice. Citation Format: Lin Yan, Sneha Sundaram, Bret M. Rust, Matthew J. Picklo, Michael R. Bukowski. Tumorigenic and metabolomic impacts of adipose-derived monocyte chemotactic protein-1 in a model of obesity-enhanced, male breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2561.
Abstract 926: BYON3521, a novel effective and safe c-Met targeting antibody-drug conjugate
Authors: Patrick Groothuis, Danielle Jacobs, Inge Hermens, Desiree Damming, Ellen Mattaar, Myrthe Rouwette, Monique van der Vleuten, Aloys Sesink, Fred Dijcks, Ruud Coumans, Marion Blomenrohr, Ruud Ubink, Miranda van der Lee, Wim H.A. Dokter
Journal: Cancer Research (2021)

Abstract c-Met, the cell-surface receptor for HGF/SF which is widely overexpressed in various solid cancer types, is an attractive target for the development of antibody-based therapeutics. However, the apparently delicate balance between anti-tumor activity and target mediated-toxicities proved to be quite a challenge. As a result, there are currently no c-Met targeting antibodies or antibody-drug conjugates (ADCs) on the market. We developed BYON3521, a novel site-specifically conjugated, duocarmycin-based ADC, comprising a humanized, cysteine-engineered IgG1 monoclonal antibody with low pM binding affinity towards both human and cynomolgus c-Met. In vitro studies showed that BYON3521 internalizes efficiently upon c-Met binding, and induces both target- as well as bystander-mediated cell killing. BYON3521 showed good potency and full efficacy in MET-amplified and high c-Met-expressing cancer cell lines; in moderate and in low c-Met-expressing cancer cell lines partial efficacy was observed. PK/PD studies and a mouse clinical trial in patient-derived xenograft models showed significant anti-tumor activity of BYON3521 upon single dose administration in multiple tumor types. BYON3521 showed responses in non-MET-amplified tumors with low, moderate and high c-Met expression, with partial and complete tumor remission seen in several models with moderate c-Met expression. In the repeat-dose GLP safety assessment in cynomolgus monkeys BYON3521 was well tolerated. In all, BYON3521 was deemed a safe ADC with potential for clinical benefit in patients. Preparations are ongoing to start clinical Phase I in 2021. Citation Format: Patrick Groothuis, Danielle Jacobs, Inge Hermens, Desiree Damming, Ellen Mattaar, Myrthe Rouwette, Monique van der Vleuten, Aloys Sesink, Fred Dijcks, Ruud Coumans, Marion Blomenrohr, Ruud Ubink, Miranda van der Lee, Wim H.A. Dokter. BYON3521, a novel effective and safe c-Met targeting antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 926.
Chondroinductive/chondroconductive peptides and their-functionalized biomaterials for cartilage tissue engineering
Authors: Mingjing Zhu, Wenchao Zhong, Wei Cao, Qingbin Zhang, Gang Wu
Journal: Bioactive Materials (2021)

The repair of articular cartilage defects is still challenging in the fields of orthopedics and maxillofacial surgery due to the avascular structure of articular cartilage and the limited regenerative capacity of mature chondrocytes. To provide viable treatment options, tremendous efforts have been made to develop various chondrogenically-functionalized biomaterials for cartilage tissue engineering. Peptides that are derived from and mimic the functions of chondroconductive cartilage extracellular matrix and chondroinductive growth factors, represent a unique group of bioactive agents for chondrogenic functionalization. Since they can be chemically synthesized, peptides bear better reproducibility, more stable efficacy, higher modifiability and yielding efficiency in comparison with naturally derived biomaterials and recombinant growth factors. In this review, we summarize the current knowledge in the designs of the chondroinductive/chondroconductive peptides, the underlying molecular mechanisms and their-functionalized biomaterials for cartilage tissue engineering. We also systematically compare their in-vitro and in-vivo efficacies in inducing chondrogenesis. Our vision is to stimulate the development of novel peptides and their-functionalized biomaterials for cartilage tissue engineering.
Awareness and prevalence of needle stick injuries among cleaners and health-care providers in Gaza Strip hospitals: a cross-sectional study
Authors: Abdallah Alwali, Ahmed Shaheen, Mohammed Ahmed, Zakaria Mansour, Loay Kanou, Belal AlQanoa, Ahmed Abu-Lamzi, Moath Enshassi, Ahmed kahlout, Noureddin Shaheen, Mahmoud Hamouda, Bettina Böttcher
Journal: The Lancet (2021)