tbuckley/cabot-search huggingface dataset:
Abstract 2078: A multiscale map of DNA damage response in human cells
Authors: Anton Kratz, Minkyu Kim, Fan Zheng, Christopher A. Koczor, Samson Fong, Jianfeng Li, Robert W. Sobol, Nevan Krogan, Trey Ideker
Journal: Cancer Research (2021)

Abstract The DNA damage response (DDR) ensures error-free genome replication and transcription, but is often disrupted in cancer. We developed DDRAM, a multilayered map of DDR derived from our own high-throughput physical interaction screen as well as genome, transcriptome, and proteome datasets from published sources. DDRAM organizes 328 genes into 41 hierarchical pathways. We identify 55 (17%) novel DDR genes with functions distributed across various pathways, and novel and more specific roles for 153 (47%) of established DDR genes. We perform epistasis mapping to support novel pathway assignments of FOXK1 in nucleotide metabolism and XRCC3 in the Fanconi anemia pathway. Using quantitative imaging of a fluorescent probe, in some cases confirmed by epistasis mapping, we experimentally validate members of the Short Patch Base Excision Repair pathway over a time course, revealing a more complete model of poly(ADP-ribose)-dependent recruitment to sites of DNA damage. Citation Format: Anton Kratz, Minkyu Kim, Fan Zheng, Christopher A. Koczor, Samson Fong, Jianfeng Li, Robert W. Sobol, Nevan Krogan, Trey Ideker. A multiscale map of DNA damage response in human cells [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 2078.
Abstract 1451: AN3025: A novel anti-human TNFR2 antibody that exhibits immune activation and strong anti-tumor activity <i>in vivo</i>
Authors: Yonglin Chen, Manxue Jia, Sherry Xu, Yanhui Zhao, Eric Chan, Meng Zhang, Emma Chen, Yi Zhang
Journal: Cancer Research (2021)

Abstract Background: The unique biology and expression pattern of tumor necrosis factor receptor-2 (TNFR2) make it an attractive therapeutic target for immuno-oncology. TNFR2 highly expresses on a subset of regulatory T cells (Tregs) and MDSCs within tumor microenvironment that can activate these cells through nuclear factor kappa B (NF-kB) pathway. TNFR2+ Treg has been shown to be most suppressive among all Treg populations in tumor. On the other hand, TNFR2 is also abundantly expressed on the surface of many human tumors. TNFR2 blocking antibody is expected to relieve TNFR2-mediated immunosuppression and inhibit TNFR2-expressing tumor cell survival. AN3025 is a novel humanized IgG1 (variant) anti-hTNFR2 antibody under preclinical development. The immunomodulatory and anti-tumor activity of AN3025 were evaluated both in vitro and in vivo. Materials and methods: AN3025 was generated through rabbit immunization followed by phage display, then humanized by CDRs grafting. The binding affinity and specificity were studied by ELISA and FACS. The ability of AN3025 to mitigate TNF/TNFR2 signaling pathway was characterized using TNFR2 overexpressing Jurkat cell line in vitro. The in vivo anti-tumor activity was evaluated in TNFR2 humanized mouse model bearing MC38 tumor. The tumor samples from control and AN3025 treated mice were taken for further FACS and RNA seq analysis. Results: AN3025 binds to the extracellular domain of human TNFR2 with sub-nanomolar affinity and specificity. It cross-reacts with cynomolgus TNFR2 with similar affinity, but not with mouse or rat TNFR2. Mechanistically, AN3025 partially competes with TNFα for binding to TNFR2 receptor and inhibits TNFα induced hTNFR2 overexpressing Jurkat cell death, however it lacks of agonist activity towards TNFR2 even in the presence of hFC crosslinking. In vivo AN3025 significantly inhibits MC38 tumor growth as a monotherapy in hTNFR2 mouse model, while no impact on body weight. Subsequent FACS analysis suggests decreased Tregs% in AN3025 treated tumor. RNA seq suggests immune activation such as increased IFN-gamma and Granzyme expression. In addition, AN3025 enhances anti-tumor efficacy of mPD-1 antibody in a combination study. Conclusions: AN3025 is a novel anti-hTNFR2 antibody and demonstrates immunomodulatory activity and potent anti-tumor efficacy in vivo, supporting its clinical development for the treatment of human cancers. Citation Format: Yonglin Chen, Manxue Jia, Sherry Xu, Yanhui Zhao, Eric Chan, Meng Zhang, Emma Chen, Yi Zhang. AN3025: A novel anti-human TNFR2 antibody that exhibits immune activation and strong anti-tumor activity in vivo [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 1451.
Association Between Caseload Surge and COVID-19 Survival in 558 U.S. Hospitals, March to August 2020
Authors: Sameer S. Kadri, Junfeng Sun, Alexander Lawandi, Jeffrey R. Strich, Lindsay M. Busch, Michael Keller, Ahmed Babiker, Christina Yek, Seidu Malik, Janell Krack, John P. Dekker, Alicen B. Spaulding, Emily Ricotta, John H. Powers, Chanu Rhee, Michael Klompas, Janhavi Athale, Tegan K. Boehmer, Adi V. Gundlapalli, William Bentley, S. Deblina Datta, Robert L. Danner, Cumhur Y. Demirkale, Sarah Warner
Journal: Annals of Internal Medicine (2021)

Several U.S. hospitals had surges in COVID-19 caseload, but their effect on COVID-19 survival rates remains unclear, especially independent of temporal changes in survival.To determine the association between hospitals' severity-weighted COVID-19 caseload and COVID-19 mortality risk and identify effect modifiers of this relationship.Retrospective cohort study. (ClinicalTrials.gov: NCT04688372).558 U.S. hospitals in the Premier Healthcare Database.Adult COVID-19-coded inpatients admitted from March to August 2020 with discharge dispositions by October 2020.Each hospital-month was stratified by percentile rank on a surge index (a severity-weighted measure of COVID-19 caseload relative to pre-COVID-19 bed capacity). The effect of surge index on risk-adjusted odds ratio (aOR) of in-hospital mortality or discharge to hospice was calculated using hierarchical modeling; interaction by surge attributes was assessed.Of 144 116 inpatients with COVID-19 at 558 U.S. hospitals, 78 144 (54.2%) were admitted to hospitals in the top surge index decile. Overall, 25 344 (17.6%) died; crude COVID-19 mortality decreased over time across all surge index strata. However, compared with nonsurging (<50th surge index percentile) hospital-months, aORs in the 50th to 75th, 75th to 90th, 90th to 95th, 95th to 99th, and greater than 99th percentiles were 1.11 (95% CI, 1.01 to 1.23), 1.24 (CI, 1.12 to 1.38), 1.42 (CI, 1.27 to 1.60), 1.59 (CI, 1.41 to 1.80), and 2.00 (CI, 1.69 to 2.38), respectively. The surge index was associated with mortality across ward, intensive care unit, and intubated patients. The surge-mortality relationship was stronger in June to August than in March to May (slope difference, 0.10 [CI, 0.033 to 0.16]) despite greater corticosteroid use and more judicious intubation during later and higher-surging months. Nearly 1 in 4 COVID-19 deaths (5868 [CI, 3584 to 8171]; 23.2%) was potentially attributable to hospitals strained by surging caseload.Residual confounding.Despite improvements in COVID-19 survival between March and August 2020, surges in hospital COVID-19 caseload remained detrimental to survival and potentially eroded benefits gained from emerging treatments. Bolstering preventive measures and supporting surging hospitals will save many lives.Intramural Research Program of the National Institutes of Health Clinical Center, the National Institute of Allergy and Infectious Diseases, and the National Cancer Institute.
Predicting the risk of respiratory distress in newborns with congenital pulmonary malformations
Authors: Christophe Delacourt, Nathalie Bertille, Laurent J. Salomon, Makan Rahshenas, Alexandra Benachi, Arnaud Bonnard, Laure Choupeaux, Virginie Fouquet, Valérie Goua, Frédéric Hameury, Erik Hervieux, Jean-Marie Jouannic, Naziha Khen-Dunlop, Gwenaelle Le Bouar, Jérôme Massardier, Léa Roditis, Jonathan Rosenblatt, Agnès Sartor, Catherine Thong-Vanh, Nathalie Lelong, Babak Khoshnood
Journal: European Respiratory Journal (2021)

Objectives Most children with prenatally diagnosed congenital pulmonary malformations (CPMs) are asymptomatic at birth. We aimed to develop a parsimonious prognostic model for predicting the risk of neonatal respiratory distress (NRD) in preterm and term infants with CPM, based on the prenatal attributes of the malformation. Methods MALFPULM is a prospective population-based nationally representative cohort including 436 pregnant women. The main predictive variable was the CPM volume ratio (CVR) measured at diagnosis (CVR first) and the highest CVR measured (CVR max). Separate models were estimated for preterm and term infants and were validated by bootstrapping. Results In total, 67 of the 383 neonates studied (17%) had NRD. For infants born at term (&gt;37 weeks, n=351), the most parsimonious model included CVR max as the only predictive variable (receiver operating characteristic (ROC) curve area: 0.70±0.04, negative predictive value: 0.91). The probability of NRD increased linearly with increasing CVR max and remained below 10% for CVR max &lt;0.4. In preterm infants (n=32), both CVR max and gestational age were important predictors of the risk of NRD (ROC: 0.85±0.07). Models based on CVR first had a similar predictive ability. Conclusions Predictive models based exclusively on CVR measurements had a high negative predictive value in infants born at term. Our study results could contribute to the individualised general risk assessment to guide decisions about the need for newborns with prenatally diagnosed CPM to be delivered at specialised centres.
Capabilities of Magnetic Resonance Volumetry in Assessing the Response to Neoadjuvant Therapy of Primary Operable and Locally Advanced Breast Cancer
Authors: M. V. Egorov
Journal: Radiology - Practice (2021)

The aim of the work was to analyze the significance of magnetic resonance volumetric measurement in assessing the response to neoadjuvant therapy for primary operable and locally advanced breast cancer (BC). The study included 77 patients aged 30 to 80 years, of which 40 (67,5 %) patients were with primary resectable and 37 (32,5 %) with locally advanced primary non-resectable ВС. When planning neoadjuvant therapy (NAT), the determining factors were the degree of malignancy (G) and proliferative activity (Ki-67) of the tumor, the level of expression of steroid receptors (estrogen — ER / progesterone — PR) and the HER2/neu protein. Completed from 4 to 6 courses of NAT. Their effectiveness was analyzed according to the data of multiparametric magnetic resonance imaging (mpMRI); changes in the tumor volume and its axial dimensions were taken into account. When comparing the sizes of tumors determined by the results of the analysis of the resection material and MRI, it was found that MR-volumetry has a higher sensitivity (Ac = 89,6; 95 % CI: 64,1–90,9) compared to the RECIST 1.1 criteria, taking into account the linear dimensions (Ac = 78,3; 95 % CI: 53,6–93,0).
Abstract 1056: Potent <i>in vivo</i> anti-tumor activity of D-1553 as a single agent and in combination with targeted therapeutics in a broad spectrum of patient-derived xenograft tumor models with KRas G12C mutation
Authors: Zhe Shi, Jifang Weng, Xiaochong Fan, Qingqing Zhu, Emily Robb, Alyssa Moriarty, Michael Wick, Yueheng Jiang, Ling Zhang, Xing Dai, Yaolin Wang
Journal: Cancer Research (2021)

Abstract Ras protein plays a critical role in cell growth and proliferation by transmitting signal from cell surface receptor tyrosine kinase to downstream cellular proteins such as RAF and MEK. KRas is one of the most frequently mutated oncogenes, with mutations at residues G12, G13, and Q61, found in lung, colon, pancreatic and other solid malignancies. We have developed an orally bioavailable, covalent inhibitor of KRas G12C, D-1553, with potent in vitro biochemical, cellular activity and in vivo efficacy. Here we report the efficacy of D-1553 in a large panel of patient-derived xenograft (PDX) tumor models with KRas G12C mutation. In the lung cancer PDX models, D-1553 exhibited tumor growth inhibition (TGI) from 43.6% to 124.3%, with 4 out of 8 models showing tumor regression. In the colorectal cancer PDX models, the range of TGI was from 60.9% to 105.7%, with 3 out of 9 models showing regression. Combination treatment of D-1553 with chemotherapy and targeted agents demonstrated enhanced anti-tumor activity resulting in more tumor regression compared to single agent treatment. These observations from PDX models support the combination treatment as a key to increased overall response rate to KRas G12C inhibitor in clinical trial. D-1553 is currently in a Phase 1/2 clinical trial for patients with advanced solid tumors harboring KRas G12C mutation (NCT04585035). Citation Format: Zhe Shi, Jifang Weng, Xiaochong Fan, Qingqing Zhu, Emily Robb, Alyssa Moriarty, Michael Wick, Yueheng Jiang, Ling Zhang, Xing Dai, Yaolin Wang. Potent in vivo anti-tumor activity of D-1553 as a single agent and in combination with targeted therapeutics in a broad spectrum of patient-derived xenograft tumor models with KRas G12C mutation [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 1056.
Abstract 1865: Simultaneous de-repression of innate and adaptive immune responses through dual targeting of ILT4 and PD(L)-1 with bispecific antibodies
Authors: Laura Vitale, Mike Murphy, Jeff Weidlick, Anna Wasiuk, Thomas O'Neill, Jenifer Widger, Laura Mills-Chen, Andrea Crocker, Colleen Patterson, James Boyer, Linda Crew, Edward J. Natoli, Jay S. Lillquist, Joel Goldstein, Lawrence J. Thomas, Henry C. Marsh, Diego Alvarado, Tibor Keler
Journal: Cancer Research (2021)

Abstract Activation of innate immunity using targeted therapies has become an attractive approach to stimulate antitumor responses. Dual inhibition of receptors that suppress myeloid and T cell compartments through the generation of bispecific antibodies (bsAbs) is a promising strategy to overcome resistance to checkpoint inhibition. Activation of the ITIM-bearing ILT4/LILRB2 receptor by its cognate ligands (HLA-G and HLA Class I) in myeloid cells induces a strong immunosuppressive response that may be leveraged by tumors to evade immune surveillance. Monoclonal antibodies (mAbs) that inhibit ILT4 activity have demonstrated promising preclinical and early clinical data in combination with PD-1 inhibitors, including in the checkpoint refractory setting. These findings provide a rationale to co-target ILT4 with PD(L)-1 using a single molecule. We describe the discovery and characterization of ILT4 inhibitory mAbs for engineering bsAbs that revert myeloid cell suppression by antagonizing ILT4 and activate T cell responses through PD(L)-1 inhibition. Humanized anti-ILT4 mAbs were generated that specifically bind human and macaque ILT4. These mAbs exhibit sub-nanomolar HLA-G binding to ILT4 expressing cells. Macrophages treated with ILT4 mAbs release inflammatory cytokines/chemokines and upregulate activation markers resulting in polarization to an M1 inflammatory phenotype. These activities are further potentiated in the presence of toll-like receptor activation with lipopolysaccharide (LPS). We engineered tetravalent bsAbs using an Fc-silenced IgG1 linked to scFv format from our anti-ILT4 and anti-PD-L1 mAbs in both orientations. The bsAbs have good biophysical characteristics and retain functional properties similar to the parental mAbs. Further in vitro and in vivo characterization efforts are ongoing to select the bsAb candidate to enter development activities and IND-enabling studies. Citation Format: Laura Vitale, Mike Murphy, Jeff Weidlick, Anna Wasiuk, Thomas O'Neill, Jenifer Widger, Laura Mills-Chen, Andrea Crocker, Colleen Patterson, James Boyer, Linda Crew, Edward J. Natoli, Jay S. Lillquist, Joel Goldstein, Lawrence J. Thomas, Henry C. Marsh, Diego Alvarado, Tibor Keler. Simultaneous de-repression of innate and adaptive immune responses through dual targeting of ILT4 and PD(L)-1 with bispecific 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 1865.
Short-term vs Long-term Dual Antiplatelet Therapy for Prevention of Delayed Thromboembolic Events after Stent-Assisted Coiling of Intracranial Aneurysm: A Randomized Clinical Trial
Authors: Hyun Park, Gyojun Hwang, Hyoung Soo Byoun, Kyung Sun Song, Sung Yun Cho, Won Huh, Seong Yeol Ahn, Byong Cheol Kim, Sukh Que Park, Seung Pil Ban, Tackeun Kim
Journal: JAMA Neurology (2018)
Adjustable Continence Therapy (ACT®) balloons: A comparison between neurogenic female urinary incontinence and non-neurogenic
Authors: A. Demeestere, M-L. De Guerry, C. Bergot, A. De Hauteclocque, J. Hascoet, X. Gamé, A-S. Bajeot, B. Peyronnet, G. Capon, M-A. Perrouin-Verbe, X. Biardeau
Journal: European Urology (2021)
Influence of the virtual reality devices on pain and anxiety in patients undergoing cystoscopy performed under local anesthesia
Authors: M. Łuczak, W. Krajewski, Ł. Nowak, J. Chorbińska, K. Galik, P. Kiełb, A. Tukiendorf, K. Kościelska-Kasprzak, B. Małkiewicz, R. Zdrojowy
Journal: European Urology (2021)
Randomized controlled trial comparing holmium laser en-bloc resection with monopolar transurethral resection in patients with large bladder tumors
Authors: A. Iscaife, L.A. Ribeiro Filho, M.W. Aparecido Pereira, F. Pescarmona Gallucci, D. Chade, L. Cardili, R.F. Coelho, A. Sadeki Sarkis, M. Srougi, W.C. Nahas
Journal: European Urology (2021)
Abstract 456: Liquid biopsy for patient stratification and monitoring of dacomitinib clinical trial in patients with EGFR amplified recurrent glioblastoma
Authors: Anudeep Yekula, Robert R. Kitchen, Sudipto K. Chakrabortty, Bob S. Carter, Johan Skog, Leonora Balaj
Journal: Cancer Research (2021)

Abstract Introduction Liquid biopsy for the detection and monitoring of brain tumors is of significant clinical interest. This ability to non-invasively profile tumors, opens new avenues for diagnosis, patient stratification to novel therapies, as well as monitoring. Here, we provide evidence of extracellular vesicle EV RNA-based diagnosis, patient stratification, and assessment of response to therapy in the setting of a clinical trial evaluating the efficacy of dacomitinib, EGFR tyrosine kinase inhibitor in patients with recurrent, EGFR amplified GBM in a multi-armed, multi-institutional clinical trial (NCT01112527). Methods We performed RNASeq on long RNA extracted from the serum samples, pre-treatment and 1-month post-treatment. Results Firstly, our novel RNASeq workflow on EV derived long RNA allowed the detection of thousands of protein coding genes, lincRNAs and antisense RNAs enabling the study of a wider repertoire of potential RNA based biomarkers of GBM. Secondly, we observed a differential expression profile is serum EV RNA of GBM patients and healthy controls. Combining our findings with TCGA data and literature screening, we generated a 25 gene signature representative of critical pathways in several hallmarks of cancer including gliogenesis, epithelial to mesenchymal transition, invasion, regulation of stemness, apoptosis and cell cycle regulation, immune regulation and metabolic remodeling. Thirdly, we observed a differential expression profile is serum EV RNA of responders compared to non-responders in pre-treatment serum. Specifically, the EV mRNAs ZNF35 and LAMTOR2 distinguish responders from non-responders (p-adjusted = 2.6E-8 and 2.4E-6, respectively) allowing potential patient stratification. Finally, we also observed a differential expression profile is serum EV RNA of responders compared to non-responders in post-treatment serum. EV mRNA DNMT3A is significantly enriched (p-adjusted = 1.8E-4) in post-treatment serum of responders compared to non-responders to dacomitinib allowing potential monitoring of response to therapy. Conclusion This study is unique because it represents the first longitudinal profiling of the EV RNA in a cohort of genomically selected GBM patients. These findings are a tantalizing step toward liquid biopsy-based biomarkers for the detection of GBM, as well as patient stratification and monitoring. Citation Format: Anudeep Yekula, Robert R. Kitchen, Sudipto K. Chakrabortty, Bob S. Carter, Johan Skog, Leonora Balaj. Liquid biopsy for patient stratification and monitoring of dacomitinib clinical trial in patients with EGFR amplified recurrent 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 456.
Abstract 2592: Boosting immune surveillance by low-dose PI3K inhibitor facilitates early intervention of breast cancer
Authors: Yuan Zhang, Jinyang Wang, Yi Xiao, Xiangliang Yuan, Ping Li, Yimin Duan, Victoria L. Seewaldt, Dihua Yu
Journal: Cancer Research (2021)

Abstract Prevention of estrogen receptor–negative (ER-) breast cancer is an unmet challenge, although tamoxifen and aromatase inhibitors can successfully decrease the incidence of ER-positive (ER+) breast cancer. PI3K pathway activation has been detected in tamoxifen-resistant ER- breast lesions of patients. Here, we further ratified that the PI3K pathway is significantly activated in premalignant ER- breast lesions compared with paired normal tissues of patients, which prompted our assessment of targeting PI3K on inhibition of ER- mammary tumor initiation and progression. Both genetic knockdown of PIK3CA or intervention with low-doses of a PI3K inhibitor (GDC-0941) prevented the dysplasia phenotype of semi-transformed human ER- mammary epithelial cells in 3-dimensional culture in vitro. Importantly, low-dose GDC-0941 treatment significantly delayed mammary tumor initiation in the MMTV-neu mouse model without exhibiting discernable adverse effects. Interestingly, increased CD8+/GZMB+ T-cells were detected in mammary tissue after GDC-0941 treatment, suggesting enhanced immune surveillance. Mechanistically, elevated expression of potent T-cell chemo-attractants, including CCL5 and CXCL10, were detected both in vitro and in vivo after GDC-0941 treatment. Furthermore, inhibition of PI3K significantly increased T-cell recruitment in a CCL5/CXCL10–dependent manner. In human ER- breast cancer, PI3K activation is correlated with significantly reduced CCL5, CXCL10 and CD8A expression, suggesting that the decreased CD8+ T-cell recruitment and escape of immune surveillance may contribute to ER- breast cancer development. In summary, our study indicates that low-dose PI3K inhibitor treatment may intervene early stage ER- breast cancer development by enhancing immune surveillance via CCL5/CXCL10. Citation Format: Yuan Zhang, Jinyang Wang, Yi Xiao, Xiangliang Yuan, Ping Li, Yimin Duan, Victoria L. Seewaldt, Dihua Yu. Boosting immune surveillance by low-dose PI3K inhibitor facilitates early intervention of 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 2592.