tbuckley/cabot-search huggingface dataset:
Abstract 1872: Generation of bispecific and trispecific T cell engagers (TCEs) and NK cell engagers (NKE)s without prior IgG reengineering
Authors: Remon van Geel, Floris van Delft
Journal: Cancer Research (2021)

Abstract T cell and NK cell-redirecting antibodies are emerging as promising modalities in targeted immunotherapy. New technologies are overcoming the limitations of 1st generation immune cell-redirecting bispecifics, especially extending half-life, reducing immunogenicity and improving safety. For example, in the field of T cell engagers (TCEs), a plethora of molecular architectures has entered the clinic, the vast majority generated by genetic engineering of an IgG to bind both a tumor-associated antigen (TAA) and CD3 or 4-1BB. Similarly, recombinant DNA technology enables the C-terminal fusion of a cytokine (e.g. IL-2 or IL-15) to an IgG to obtain NK cell engagers (NKEs). We have shown earlier that the native glycan of a monoclonal antibody provides a privileged site for attachment of cytotoxic payloads,1 providing antibody-drug conjugates (ADCs) with significantly enhanced therapeutic index. This technology, known as GlycoConnect™, has been adapted by various drug developers (e.g. ADC Therapeutics, Mersana Therapeutics and others) and is now applied in two (2) clinical programs as well as multiple late-stage preclinical programs. Here we demonstrate how GlycoConnect™ technology can be applied to generate TCEs or NKEs by selective attachment of scFv (anti-CD3, anti-CD28) or cytokines (IL-15), with concomitant Fc-silencing. Moreover, an existing bispecific TCE (TAA/CD3) can be further boosted by attachment of anti-CD28 scFv for further T cell activation. Molecular architectures can be readily tailored to 2:2 or 2:1 ratio (TAA:scFv or cytokine) to mitigate adverse events like cytokine release syndrome, and even 2:1:1 formats. Structural and functional studies will be presented to corroborate the architecture and biological activity of these GlycoConnect™ bispecifics and trispecifics, in terms of binding, immune cell engagement and cell-killing potential. 1van Geel et al. Chemoenzymatic Conjugation of Toxic Payloads to the Globally Conserved N-Glycan of Native mAbs Provides Homogeneous and Highly Efficacious Antibody−Drug Conjugates. Bioconj. Chem. 2015, 26, 2233-2242. Citation Format: Remon van Geel, Floris van Delft. Generation of bispecific and trispecific T cell engagers (TCEs) and NK cell engagers (NKE)s without prior IgG reengineering [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 1872.
Abstract 2135: Functional models of chromosome arm aneuploidies in lung squamous cell carcinoma
Authors: Alison Marie Taylor, Sejal Jain, Juliann Shih, Andrew D. Cherniack, Rameen Beroukhim, Matthew Meyerson
Journal: Cancer Research (2021)

Abstract Aneuploidy, which we define as whole chromosome or chromosome arm copy number imbalance, is a near-universal characteristic of human cancers. Cancer subtypes are often characterized by tumor specific patterns of chromosome arm copy number alterations; for example, squamous cell carcinomas (SCCs) from different tissues of origin (including lung, head and neck, esophagus, and bladder) have a pattern of chromosome 3p loss and chromosome 3q gain. Although these alterations are frequent, they are not well understood due to difficulty in modeling specific aneuploidy alterations in the matching cell type. However, recent advances in genome engineering allow generation of large chromosomal alterations. We used the CRISPR-Cas9 system to delete one copy of chromosome 3p in human immortalized lung epithelial cells most similar to upper airway basal cells. Deletion of chromosome 3p was validated by whole genome sequencing and karyotyping. Consistent with patient data, expression of 3p genes was decreased upon deletion, as well as increased expression of interferon response genes. Phenotypic characterization revealed that cells with chromosome 3p deletion initially proliferated more slowly than their siblings. These chromosome 3p deleted cells had increased G1 arrest but did not undergo increased apoptosis or cell death. Interestingly, after several passages in culture, the proliferation defect was rescued in chromosome 3p deleted cells. Genome sequencing and karyotype analyses found that evidence of chromosome 3 duplication, transitioning the cell to a state of chromosome 3q gain. We isolated sibling cells with chromosome 3p deletion or chromosome 3q gain and demonstrated that duplication of chromosome 3 could indeed rescue proliferation rates. With our cellular model of chromosome arm-level aneuploidy, we uncovered a selection mechanism that allowed aneuploidy tolerance in vitro, and a possible explanation for joint alteration of both arms of chromosome 3. In conclusion, our genome engineering approach to model chromosome arm-level deletions provides a robust model that will address a gap in our understanding of aneuploidy in cancer. Citation Format: Alison Marie Taylor, Sejal Jain, Juliann Shih, Andrew D. Cherniack, Rameen Beroukhim, Matthew Meyerson. Functional models of chromosome arm aneuploidies in lung squamous cell carcinoma [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 2135.
Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey
Authors: Mine Durusu Tanriover, Hamdi Levent Doğanay, Murat Akova, Hatice Rahmet Güner, Alpay Azap, Sıla Akhan, Şükran Köse, Fatma Şebnem Erdinç, Emin Halis Akalın, Ömer Fehmi Tabak, Hüsnü Pullukçu, Özgür Batum, Serap Şimşek Yavuz, Özge Turhan, Mustafa Taner Yıldırmak, İftihar Köksal, Yeşim Taşova, Volkan Korten, Gürdal Yılmaz, Mustafa Kemal Çelen, Sedat Altın, İlhami Çelik, Yaşar Bayındır, İlkay Karaoğlan, Aydın Yılmaz, Aykut Özkul, Hazal Gür, Serhat Unal, Bircan Kayaaslan, İmran Hasanoğlu, Ayça Dalkıran, Ömer Aydos, Güle Çınar, İrem Akdemir-Kalkan, Ahmet Çağkan İnkaya, Mehtap Aydin, Hatice Çakir, Jale Yıldız, Özenir Kocabıyık, Sonay Arslan, Bayram Nallı, Ömer Demir, Sarp Singil, Çiğdem Ataman-Hatipoğlu, Günay Tuncer-Ertem, Sami Kınıklı, Uğur Önal, Bilgül Mete, Gözde Dalgan, Meltem Taşbakan, Tansu Yamazhan, Berna Kömürcüoğlu, Enver Yalnız, Aysun Benli, Çağla Keskin-Sarıtaş, Mustafa Gökhan Ertosun, Özlenen Özkan, Salih Emre, Seçil Arıca, Ferit Kuşçu, Aslıhan Candevir, Buket Ertürk-Şengel, Fadime Ayvaz, Firdevs Aksoy, Çiğdem Mermutluoğlu, Yakup Demir, Gülşah Günlüoğlu, Seda Tural-Önür, Ayşin Kılıç-Toker, Esma Eren, Barış Otlu, Ayşe Özlem Mete, Kübra Koçak, Hale Ateş, İlkay Koca-Kalkan, Kurtuluş Aksu
Journal: The Lancet (2021)
Abstract 2858: <i>DEPDC1B</i> functions as an oncogene in promoting melanoma growth and metastasis
Authors: Feng Hu, Ki On Fong, May Pui Lai Cheung, Xintao Yang, Martin Cheung
Journal: Cancer Research (2021)

Abstract Background: Melanoma is one of the most aggressive skin cancers due to its therapeutic resistance, and high capacity to metastasize as a late manifestation. The limited effectiveness of the current treatment regimen prompts us to identify new druggable targets in governing the systemic spread of melanoma. Despite the oncogenic role of DEPDC1B in different types of cancer, its functional importance in melanoma growth and metastasis are not fully revealed. Methods: The expression of DEPDC1B mRNA levels between skin cutaneous melanoma patients and normal samples were compared using TCGA database. Surgically procured tumor specimens from melanoma patients were obtained to investigate the protein levels of DEPDC1B expression by immunofluorescence. Melanoma cell lines WM266-4 and SK-MEL-28 were used for loss- and gain-of-function studies of DEPDC1B in AlamarBlue, EdU staining, colony formation and trans-well invasion assays. Subcutaneous and intravenous injection of melanoma cells treated with either DEPDC1B knockdown (KD) or DEPDC1B overexpression into immunodeficient mice were conducted to examine the effects on tumor growth and lung metastasis respectively. Results: The expression levels of DEPDC1B mRNA in melanoma biopsies were higher than normal samples and were negatively corelated with both overall survival and disease-free survival. Loss-of-function studies showed that DEPDC1B KD reduced the growth rate, proliferation capacity and colony formation ability of melanoma cells. Consistently, DEPDC1B KD cells gave rise to smaller xenograft tumors and fewer number of lung nodules. In contrast, DEPDC1B overexpression promoted melanoma cell proliferation, colony formation and invasion in vitro, and enhanced xenograft tumor growth and lung metastasis. Conclusion: The results obtained so far indicate that DEPDC1B acts as an oncogene in promoting melanoma cell growth and metastasis, suggesting a potential drug target in melanoma treatment. Citation Format: Feng Hu, Ki On Fong, May Pui Lai Cheung, Xintao Yang, Martin Cheung. DEPDC1B functions as an oncogene in promoting melanoma growth and metastasis [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 2858.
Abstract 3004: Establishment of KRAS G12C mutant patient-derived xenograft (PDX) models for pre-clinical evaluation of KRAS G12C targeted anticancer therapy
Authors: Wenting Shi, Xuzhen Tang, Jingying Zhang, Xinhong Kuang, Yan Zhang, Jingjing Wang, Qingyang Gu, Qunsheng Ji
Journal: Cancer Research (2021)

Abstract KRAS is one of the most prevalent oncogenes in human cancers. The G12C mutation results in an amino acid substitution at position 12 in KRAS, from a glycine (G) to a cysteine (C), lead to accretion of GTP-bound activated state KRAS and activation of downstream signaling pathways. In non-small cell lung cancer (NSCLC), KRAS p.G12C is the most common mutation, comprising nearly half of all KRAS mutations. Recent breakthrough work led to the development of selective inhibitors targeting the KRAS G12C mutation, which have shown promise in early clinical trials. However, the therapeutic benefit of targeted therapies can be impaired by intrinsic or acquired resistance mechanisms, suggesting an urgent need of combinatorial strategies to overcome the resistance to drugs targeting KRAS G12C.Here we report on the establishment of a panel of KRAS G12C mutant PDX models, encompass non-small cell lung cancer, colorectal cancer and gastric cancer. The activity of AMG510, a selective KRAS G12C inhibitors in clinical trial, was characterized in these PDX models. Data showed that the validated KRAS G12C mutant models display a range of sensitivity to single treatment of AMG510. Given that in clinic only 50% of NSCLC patients with KRAS G12C mutation would benefit from KRAS G12C targeted inhibitors, in order to provide an insights for clinical therapeutic strategy, we investigated the combinatorial strategies in NSCLC PDX models: (1) AMG510 combined with Opdivo in KRAS G12C/CD274 amplification models in hPBMC humanized mice; (2) AMG510 combined with EGFR inhibitor in KRAS G12C/EGFR overexpression models. The possible mechanisms of combination effect were discussed. Altogether, the panel of KRAS G12C mutant PDX models are valuable for the pre-clinical evaluation of KRAS G12C targeted anti-cancer therapies. Citation Format: Wenting Shi, Xuzhen Tang, Jingying Zhang, Xinhong Kuang, Yan Zhang, Jingjing Wang, Qingyang Gu, Qunsheng Ji. Establishment of KRAS G12C mutant patient-derived xenograft (PDX) models for pre-clinical evaluation of KRAS G12C targeted anticancer therapy [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 3004.
Association of Vision Impairment With Cognitive Decline Across Multiple Domains in Older Adults
Authors: Varshini Varadaraj, Beatriz Munoz, Jennifer A. Deal, Yang An, Marilyn S. Albert, Susan M. Resnick, Luigi Ferrucci, Bonnielin K. Swenor
Journal: JAMA Network Open (2021)

Associations between visual and global cognitive impairments have been previously documented, but there is limited research examining these associations between multiple measures of vision across cognitive domains.To examine the association between vision and cognitive across multiple cognitive domains using multiple measures of vision.This longitudinal cohort study used data from the Baltimore Longitudinal Study of Aging for 2003 to 2019. Participants in the current study were aged 60 to 94 years with vision and cognitive measures. Data analysis was performed from May 2020 to May 2021.Cognitive function was measured across multiple domains, including language, memory, attention, executive function, and visuospatial ability. Cognitive domain scores were calculated as the mean of standardized cognitive test scores within each domain. Visual function was assessed using measures of visual acuity, contrast sensitivity, and stereo acuity at baseline.Analyses included 1202 participants (610 women [50.8%]; 853 White participants [71.0%]) with a mean (SD) age of 71.1 (8.6) years who were followed up for a mean (SD) of 6.9 (4.7) years. Worse visual acuity (per 0.1 logarithm of the minimal angle of resolution) at baseline was associated with greater declines in language (β, -0.0035; 95% CI, -0.007 to -0.001) and memory (β, -0.0052; 95% CI, -0.010 to -0.001) domain scores. Worse contrast sensitivity (per 0.1 log units) at baseline was associated with greater declines in language (β, -0.010; 95% CI, -0.014 to -0.006), memory (β, -0.009; 95% CI, -0.015 to -0.003), attention (β, -0.010; 95% CI, -0.017 to -0.003), and visuospatial ability (β, -0.010; 95% CI, -0.017 to -0.002) domain scores. Over the follow-up period, declines on tests of language (β, -0.019; 95% CI, -0.034 to -0.005) and memory (β, -0.032; 95% CI, -0.051 to -0.012) were significantly greater for participants with impaired stereo acuity compared with those without such impairment.These findings suggest that the association between vision and cognition differs between visual acuity, contrast sensitivity, and stereo acuity and that patterns of cognitive decline may differ by type of vision impairment, with impaired contrast sensitivity being associated with declines across more cognitive domains than other measures of visual functioning.
The Tuberculosis Drug Accelerator at year 10: what have we learned?
Authors: Bree B. Aldridge, David Barros-Aguirre, Clifton E. Barry, Robert H. Bates, Steven J. Berthel, Helena I. Boshoff, Kelly Chibale, Xin-Jie Chu, Christopher B. Cooper, Véronique Dartois, Ken Duncan, Nader Fotouhi, Fabian Gusovsky, Philip A. Hipskind, Dale J. Kempf, Joël Lelièvre, Anne J. Lenaerts, Case W. McNamara, Valerie Mizrahi, Carl Nathan, David B. Olsen, Tanya Parish, H. Michael Petrassi, Alexander Pym, Kyu Y. Rhee, Gregory T. Robertson, Jeremy Michael Rock, Eric J. Rubin, Betsy Russell, David G. Russell, James C. Sacchettini, Dirk Schnappinger, Michael Schrimpf, Anna M. Upton, Peter Warner, Paul Graham Wyatt, Ying Yuan
Journal: Nature Medicine (2021)
Creating a cumulative equivalent thermal isoeffect dosimetry model in several ex vivo tissue models mimicking focal laser ablation treatment of the prostate
Authors: L.A.M.J.G. Van Riel, R.A.A. Van Kollenburg, T.M. De Reijke, C.D. Savci - Heijink, R. Zweije, J. Crezee, P.R. Bloemen, H.P. Beerlage, T.G. Van Leeuwen, J.R. Oddens, D.M. De Bruin
Journal: European Urology (2021)
Abstract 3175: FAT1 and the immunosuppressive milieu in glioblastoma tumors
Authors: Khushboo Irshad, Chitrangda Srivastava, Nargis Malik, Yakhlesh Gupta, Vaishali Suri, Swati Mahajan, Deepak Gupta, Ashish Suri, Parthaprasad Chattopadhyay, Subrata Sinha, Kunzang Chosdol
Journal: Cancer Research (2021)

Abstract INTRODUCTION: Glioblastoma tumors harbor an immunosuppressive microenvironment which is sustained by key players such as TGF-β1/2 and IL-10 cytokines; and mediators of the PD-1/PD-L1/2 pathway. Previously, our lab has shown the role of a new gene, FAT1, in promoting gliomagenesis by supporting the production of pro-inflammatory cytokines (IL-1β, IL-6, etc.) in glioma cells. Here, we show a potent role of FAT1 gene in regulation of anti-inflammatory genes in human glioma tumors, cell lines and primary cultures. Our findings indicate an additional way in which FAT1 might contribute to gliomagenesis. METHODS: q-PCR was used to analyse transcript levels of FAT1 and genes of the TGF-β1/2, IL-10 and PD-L1/2 pathways in fresh-frozen glioblastoma samples relative to normal brain RNA. Gene expression correlation was analysed using Spearman's test and semi-supervised clustering. TCGA expression data was extracted to analyse the correlation of FAT1 with anti-inflammatory genes. Primary tumor cultures and cell lines were transfected with FAT1-specific siRNA to check the effect on expression of anti-inflammatory cytokines, as well as effect on migratory properties of monocytes towards FAT1-knockdown tumor cells (supernatants). RESULTS: Significant positive correlation was found between upregulation of FAT1 and that of anti-inflammatory genes in fresh-frozen glioblastoma samples as well as TCGA datasets. Upon siRNA-mediated knockdown of FAT1 in in-vitro glioma cell cultures, we observed decreased anti-inflammatory genes' expression. We also found increased transmigration of monocytes towards the supernatants from siFAT1-transfected cells. CONCLUSION: FAT1 favors the immunosuppressive milieu in glioblastoma by supporting expression of anti-inflammatory genes. This is an emerging role of the new oncogene FAT1 and crucial to our understanding of the contributions of FAT1 to hallmarks of cancer. FUNDING: SERB Start-Up Grant (DST, India); DHR Young Scientist Scheme (ICMR, India) Citation Format: Khushboo Irshad, Chitrangda Srivastava, Nargis Malik, Yakhlesh Gupta, Vaishali Suri, Swati Mahajan, Deepak Gupta, Ashish Suri, Parthaprasad Chattopadhyay, Subrata Sinha, Kunzang Chosdol. FAT1 and the immunosuppressive milieu in glioblastoma 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 3175.
Abstract 768: Predictive role of circulating tumor cells in women with ovarian cancer
Authors: Swarnima Singh, Uday Kumar
Journal: Cancer Research (2021)

Abstract Background: “Liquid biopsy”, where body fluids is screened for biomarkers is gathering substantial research. We aimed to examine women with suspected ovarian cancer for the presence of circulating tumor cells (CTCs) and study its role in prediction of chemoresistance and survival. Methods: Magnetic powder labeled monoclonal antibodies for epithelial cell adhesion molecule (EpCAM), Mucin 1 cell surface associated ( MUC1) ,mucin 16, cell surface associated MUC16 or CA125 were prepared according to the manufacturer's protocol. Expression of three ovarian cancer related genes were detected in CTCs using multiplex reverse transcriptase-polymerase chain reaction (Multiplex RT-PCR). CTCs and serum CA125 were measured in 100 patients with suspected ovarian cancer. Correlations with clinicopathological parameters and treatment were analyzed. Results: CTCs were detected in 18/70 (25.7%) of women with malignancy compared to 0/30 (0.0%) in those with benign gynecologic diseases (p=0.001). The sensitivity and specificity of the CTC test for predicting a malignant histology in pelvic masses was 27.7% (95% CI :16.3%,37.7%) and 100% (95% CI: 85.8%, 100%), respectively. The number of CTCs correlated with stage of ovarian cancer (p=0.030). The presence of EpCAM+CTC at primary diagnosis in ovarian cancer was found to be an independent predictor of a poor progression free survival (PFS) (HR,3.3; 95% CI, 1.3-8.4; p=0.010), overall survival (OS) (HR, 2.6; 95% CI,1.1-5.6; p=0.019) and resistance to chemotherapy (OR 8.6; 95% CI, 1.8-43.7; p=0.009). Conclusion: Expression of EpCAM in CTC positive patients predicts chemotherapy resistance and prognosis, could aid clinicians in individualizing therapy, saving the patient from unnecessary side effects and systemic toxicity of platinum-based chemotherapy. Also, EpCAM expression can be a strong basis for further investigating anti-EpCAM targeted therapies in ovarian cancer. Citation Format: Swarnima Singh, Uday Kumar. Predictive role of circulating tumor cells in women with ovarian 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 768.
Abstract 886: Prediction of outcome in Li-Fraumeni Syndrome: Development of an integrative function-based prognostic model
Authors: Nicholas Fischer, David Malkin
Journal: Cancer Research (2021)

Abstract Li-Fraumeni Syndrome (LFS) is a highly penetrant familial cancer disorder caused by germline TP53 mutations. Hundreds of different germline TP53 mutations with a wide gradient of functional consequences have been found in association with LFS, which has a remarkably diverse clinical spectrum in terms of tumor type, age of onset, penetrance, and survival rates. Clinical tools for prognostication and risk stratification are needed to guide clinical decision making. We performed an integrated analysis combining five large-scale mutant p53 functional screens to identify three functionally distinct groups of mutations. Combined functional scores measuring multiple parameters (loss-of-function, dominant negative activity, growth inhibition, oligomeric status, and transcriptional activity) were used to classify mutations as high, intermediate, or low pathogenicity. Patients identified with germline TP53 mutations at The Hospital for Sick Children and other institutes (174 patients from 50 families) provided the discovery set. An external validation cohort included 1674 patients from 1522 families with germline TP53 mutations collected from the International Agency for Research on Cancer database. Our mutation classifications stratified carriers into three distinct risk groups with significantly different overall survival outcomes in the discovery (P=0.02) and validation cohorts (P&amp;lt;0.0001). In the discovery dataset, patients in the high-risk group had considerably shorter median life expectancy (28 years; n=21) compared to the intermediate-risk group (61 years; n=51) and low-risk group (median survival not reached; n=10). On average, 92% (24/26) of patients in the high-risk group developed tumors compared to only 63% (32/51) in the low-risk group (P=0.005). This model remained significant when applied to the validation cohort. In conclusion, patients at increased risk of cancer mortality can be identified to guide treatment and cancer surveillance strategies. Citation Format: Nicholas Fischer, David Malkin. Prediction of outcome in Li-Fraumeni Syndrome: Development of an integrative function-based prognostic model [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 886.