tbuckley/cabot-search huggingface dataset:
Abstract 496: Humanized SIRPA and double humanized SIRPA/CD47 B-NDG mouse models are promising tools for anti-SIRPα antibody <i>in vivo</i> efficacy studies
Authors: Yuting Hu, Lei Zhao, Yujie Liu, Li Hui, Zhaoxue (Luke) Yu
Journal: Cancer Research (2021)

Abstract The CD47/Signal regulatory protein α (SIRPα) axis regulates myeloid cell activation and functions as a crucial myeloid specific immune checkpoint. CD47 is highly expressed on many different types of cancer and upon binding with SIRPα which is abundantly expressed on myeloid cells, transduces inhibitory signals that protect cancer cells from phagocytosis by macrophages and other myeloid cells. Therefore, antibodies that block CD47 and SIRPα binding become encouraging tools for cancer immunotherapy. Biocytogen developed humanized SIRPα B-NDG mice and double humanized SIRPα/CD47 B-NDG mice to provide solid platforms for in vivo efficacy assessment of SIRPα antibodies with or without other immune checkpoint regulators. These mice have a B-NDG mouse background (completely lacking mature T, B and NK cells and were deficient in cytokine signaling) and express human SIRPα protein only or with human CD47 IgV domain and no mouse counterpart expressed. Raji-Luc cells were injected into these mouse models for tumor xenografting and anti-tumor efficacy of anti SIRPα antibody in combination with other antibodies was evaluated. The results showed that the combination of antibodies could effectively control tumor growth in the two mouse models. In addition, B-NDG hSIRPα/hCD47 mice can be used for toxicity assessment for SIRPα or CD47 antibodies. In summary, both B-NDG hSIRPA and B-NDG hSIRPA/hCD47 mice are promising models for preclinical in vivo evaluation of SIRPα antibodies and combined therapy. Citation Format: Yuting Hu, Lei Zhao, Yujie Liu, Li Hui, Zhaoxue (Luke) Yu. Humanized SIRPA and double humanized SIRPA/CD47 B-NDG mouse models are promising tools for anti-SIRPα antibody in vivo efficacy studies [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 496.
Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response
Authors: Christina A. Nelson, Dana Meaney-Delman, Shannon Fleck-Derderian, Katharine M. Cooley, Patricia A. Yu, Paul S. Mead
Journal: MMWR Recommendations and Reports (2021)

This report provides CDC recommendations to U.S. health care providers regarding treatment, pre-exposure prophylaxis, and postexposure prophylaxis of plague. Yersinia pestis, the bacterium that causes plague, leads to naturally occurring disease in the United States and other regions worldwide and is recognized as a potential bioterrorism weapon. A bioweapon attack with Y. pestis could potentially infect thousands, requiring rapid and informed decision making by clinicians and public health agencies. The U.S. government stockpiles a variety of medical countermeasures to mitigate the effects of a bioterrorism attack (e.g., antimicrobials, antitoxins, and vaccines) for which the 21st Century Cures Act mandates the development of evidence-based guidelines on appropriate use. Guidelines for treatment and postexposure prophylaxis of plague were published in 2000 by a nongovernmental work group; since then, new human clinical data, animal study data, and U.S. Food and Drug Administration approvals of additional countermeasures have become available. To develop a comprehensive set of updated guidelines, CDC conducted a series of systematic literature reviews on human treatment of plague and other relevant topics to collect a broad evidence base for the recommendations in this report. Evidence from CDC reviews and additional sources were presented to subject matter experts during a series of forums. CDC considered individual expert input while developing these guidelines, which provide recommended best practices for treatment and prophylaxis of human plague for both naturally occurring disease and following a bioterrorism attack. The guidelines do not include information on diagnostic testing, triage decisions, or logistics involved in dispensing medical countermeasures. Clinicians and public health officials can use these guidelines to prepare their organizations, hospitals, and communities to respond to a plague mass-casualty event and as a guide for treating patients affected by plague.
Multimodal single-cell analysis of cutaneous T-cell lymphoma reveals distinct subclonal tissue-dependent signatures
Authors: Alberto Herrera, Anthony Cheng, Eleni P. Mimitou, Angelina Seffens, Dean George, Michal Bar-Natan, Adriana Heguy, Kelly V. Ruggles, Jose U. Scher, Kenneth Hymes, Jo-Ann Latkowski, Niels Ødum, Marshall E. Kadin, Zhengqing Ouyang, Larisa J. Geskin, Peter Smibert, Terkild B. Buus, Sergei B. Koralov
Journal: Blood (2021)
Carrier-free nanodrugs with efficient drug delivery and release for cancer therapy: From intrinsic physicochemical properties to external modification
Authors: Heng Mei, Shengsheng Cai, Dennis Huang, Huile Gao, Jun Cao, Bin He
Journal: Bioactive Materials (2021)

The considerable development of carrier-free nanodrugs has been achieved due to their high drug-loading capability, simple preparation method, and offering "all-in-one" functional platform features. However, the native defects of carrier-free nanodrugs limit their delivery and release behavior throughout the in vivo journey, which significantly compromise the therapeutic efficacy and hinder their further development in cancer treatment. In this review, we summarized and discussed the recent strategies to enhance drug delivery and release of carrier-free nanodrugs for improved cancer therapy, including optimizing the intrinsic physicochemical properties and external modification. Finally, the corresponding challenges that carrier-free nanodrugs faced are discussed and the future perspectives for its application are presented. We hope this review will provide constructive information for the rational design of more effective carrier-free nanodrugs to advance therapeutic treatment.
Efficacy and Safety of Cabazitaxel Versus Abiraterone or Enzalutamide in Older Patients with Metastatic Castration-resistant Prostate Cancer in the CARD Study
Authors: Cora N. Sternberg, Daniel Castellano, Johann de Bono, Karim Fizazi, Bertrand Tombal, Christian Wülfing, Gero Kramer, Jean-Christophe Eymard, Aristotelis Bamias, Joan Carles, Roberto Iacovelli, Bohuslav Melichar, Ásgerður Sverrisdóttir, Christine Theodore, Susan Feyerabend, Carole Helissey, Elizabeth M. Poole, Ayse Ozatilgan, Christine Geffriaud-Ricouard, Ronald de Wit
Journal: European Urology (2021)
Association of local progression with deterioration of urinary symptoms and occurrence of genitourinary adverse events (AEs) in nonmetastatic Castration-Resistant Prostate Cancer (nmCRPC): Post hoc analysis of PROSPER
Authors: M-O. Grimm, M. Hussain, A. Stenzl, T. Todenhöfer, G.P. Haas, J. Sugg, R. Brauner, M. Groß-Langenhoff, C.N. Sternberg
Journal: European Urology (2021)
Abstract 657: Folate receptor alpha expression is associated with poor prognosis in patients with cervical cancer
Authors: Shigemasa Takamizawa, Shu Yazaki, Yuki Kojima, Hiroshi Yoshida, Rui Kitadai, Tatsunori Shimoi, Tadaaki Nishikawa, Kazuki Sudo, Tomoyasu Kato, Kan Yonemori
Journal: Cancer Research (2021)

Abstract Background: The folate receptor alpha (FRα) is a glycosyl-phosphatidylinositol-anchored membrane protein that binds and internalizes folate for purine and thymidine DNA biosynthesis, repair, and methylation. FRα have a role in cellular migration and invasion, and overexpression of this receptor is associated with tumor progression. FRα is known to be over-expressed in numerous epithelial malignancies and considered a potential target for anticancer treatment. However, the association between FRα expression and clinicopathologic features and prognosis in cervical cancer remains unclear. Methods: This retrospective study included patients diagnosed with cervical cancer who underwent primary surgery between 2000 and 2020. Immunohistochemical staining of FRα was performed using Anti-Folate Binding Protein/FBP antibody (abcam, ab67422). The evaluation of FRα expression was performed by an experienced pathologist. FRα-positive was defined as &amp;gt; 5% tumor staining. FRα-high was defined as ≥ 50% tumor staining with 2+ or 3+ intensity. A possible influence of FRα expression on survival was studied by multivariate Cox regression adjusting for established risk factors for postoperative recurrence. Results: Overall, 123 patients were enrolled, and 136 tumor samples (13 paired primary and metastatic samples) were assessed. The histopathologic classification was squamous cell carcinoma, 67; adenocarcinoma, 27; adenosquamous carcinoma, 13; other, 16. FRα-positive was found in 100% (136/136), and FRα-high was 20.8% (15/72) of squamous cell carcinoma and 33.3% (10/30) of adenocarcinoma. The FRα expression of the metastatic tumor was significantly higher than the primary tumor (H-score, 180 vs. 105, p=0.006). In 69.2% (9/13) of cases with paired samples of primary and metastatic, FRα expression was elevated in metastatic tumors than primary.In a multivariate analysis, FRα-high was associated with poor recurrence-free survival (hazard ratio [HR] 2.30, 95% confidence interval [CI] 1.17-4.52, p=0.016) and overall survival (HR 5.45, 95% CI 1.91-15.5, p=0.002). Conclusion: FRα was widely expressed regardless of histological subtypes. FRα expression was elevated in metastatic tumors, and its expression was independently associated with postoperative recurrence and decreased survival in patients with cervical cancer. FRα may be a potential target for therapy of cervical cancer. Citation Format: Shigemasa Takamizawa, Shu Yazaki, Yuki Kojima, Hiroshi Yoshida, Rui Kitadai, Tatsunori Shimoi, Tadaaki Nishikawa, Kazuki Sudo, Tomoyasu Kato, Kan Yonemori. Folate receptor alpha expression is associated with poor prognosis in patients with cervical 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 657.
Procalcitonin use for the screening of bacterial infections in pregnant women in the emergency ward: A prospective study
Authors: Florence Runyo, Marie Claude Beaudoin, Boualem Hammadi, Marjolaine Morgand, Marine Driessen, Yann Sellier, Laurent J. Salomon, Marianne Leruez-Ville, Emmanuelle Bille, Olivier Lortholary, Caroline Charlier
Journal: Journal of Infection (2021)
Nothing about us without us: involving patient collaborators for machine learning applications in rheumatology
Authors: Stephanie J W Shoop-Worrall, Katherine Cresswell, Imogen Bolger, Beth Dillon, Kimme L Hyrich, Nophar Geifman
Journal: Annals of the Rheumatic Diseases (2021)

Novel machine learning methods open the door to advances in rheumatology through application to complex, high-dimensional data, otherwise difficult to analyse. Results from such efforts could provide better classification of disease, decision support for therapy selection, and automated interpretation of clinical images. Nevertheless, such data-driven approaches could potentially model noise, or miss true clinical phenomena. One proposed solution to ensure clinically meaningful machine learning models is to involve primary stakeholders in their development and interpretation. Including patient and health care professionals’ input and priorities, in combination with statistical fit measures, allows for any resulting models to be well fit, meaningful, and fit for practice in the wider rheumatological community. Here we describe outputs from workshops that involved healthcare professionals, and young people from the Your Rheum Young Person’s Advisory Group, in the development of complex machine learning models. These were developed to better describe trajectory of early juvenile idiopathic arthritis disease, as part of the CLUSTER consortium. We further provide key instructions for reproducibility of this process.Involving people living with, and managing, a disease investigated using machine learning techniques, is feasible, impactful and empowering for all those involved.
Abstract LB133: Targetting IL-6/gp130 signalling axis attenuates acquired drug resistance in medulloblastoma
Authors: Lakshana Sreenivasan, Pascal Leclair, Chinten James Lim
Journal: Cancer Research (2021)

Abstract Medulloblastoma (MB) is the most common pediatric brain tumour comprising of four distinct molecular subgroups exhibiting high level of intertumoural heterogeneity. The standard multimodal treatment yields a survival rate of 70% but the aggressive treatment affects the long-term sequelae of MB patients. The tumour microenvironment (TME) is a regulator of cancer progression and affects therapeutic efficacy in primary and metastatic brain malignancies. Mechanistic insights into the tumor-promoting role of the individual components of the brain TME will aid in identifying key survival pathways and design of potential therapeutics to combat drug resistance and pathogenesis of the disease. We hypothesize that tumor associated macrophages (TAMs) in the brain TME facilitate drug resistance via the IL-6/STAT3 signalling axis in MB. To understand the role of paracrine signaling resulting from TAMs, a co-culture system was used to evaluate the expression of pSTAT3 and correlated with drug sensitivity and/or resistance in Med8A cell line. When co-cultured with HMC3, a human microglia cell line, the chemosensitive Med8A-S cells exhibited enhanced pSTAT3 expression and acquired drug resistance. Interestingly, Med8A cells lacking expression of IL-6 receptor (IL6R-/-) also exhibited high pSTAT3 levels and drug resistance; suggesting that HMC3 may release soluble factors in addition to IL-6 sufficient to drive chemoresistance in Med8A variants. To assess this, we conditioned cells with stimulatory cytokines belonging to the IL-6 family. We found that oncostatin M (OSM), interleukin-11 (IL-11) and leukemia inhibitory factor (LIF) induced drug resistance and enhanced pSTAT3 levels in IL6R-/- cells. Receptors of the IL-6 family share a common signal transducing beta subunit, glycoprotein (gp130) that transduces the signal intracellularly and phosphorylates janus activated kinases (JAKs) and subsequently STAT3. Our results suggest that paracrine proinflammatory cytokines found in the TME can promote MB drug resistance by signalling through a common signal transducer gp130, hence targeting any one cytokine receptor of the IL-6 family of cytokines may not sufficiently abrogate acquired drug resistance. Currently, we are evaluating the efficacy of agents that target common downstream elements of the IL-6/STAT3 signalling axis, including gp130, JAKs and STAT3, as a potentially improved therapeutic strategy to circumvent acquired drug resistance in medulloblastoma. Citation Format: Lakshana Sreenivasan, Pascal Leclair, Chinten James Lim. Targetting IL-6/gp130 signalling axis attenuates acquired drug resistance in medulloblastoma [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 LB133.
Efficacy, Safety, and Biomarker Analysis of Combined PD-L1 (Atezolizumab) and VEGF (Bevacizumab) Blockade in Advanced Malignant Peritoneal Mesothelioma
Authors: Kanwal Raghav, Suyu Liu, Michael J. Overman, Anneleis F. Willett, Mark Knafl, Szu-Chin Fu, Anais Malpica, Seema Prasad, Richard E. Royal, Christopher P. Scally, Paul F. Mansfield, Ignacio I. Wistuba, Andrew P. Futreal, Dipen M. Maru, Luisa M. Solis Soto, Edwin R. Parra Cuentas, Honglei Chen, Pamela Villalobos, Anuj Verma, Armeen Mahvash, Patrick Hwu, Patricia Cortazar, Edward McKenna, Cindy Yun, Shannon Dervin, Katja Schulze, Walter C. Darbonne, Ajaykumar C. Morani, Scott Kopetz, Keith F. Fournier, Scott E. Woodman, James C. Yao, Gauri R. Varadhachary, Daniel M. Halperin
Journal: Cancer Discovery (2021)

Malignant peritoneal mesothelioma (MPeM) is a rare but aggressive malignancy with limited treatment options. VEGF inhibition enhances efficacy of immune-checkpoint inhibitors by reworking the immunosuppressive tumor milieu. Efficacy and safety of combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) was assessed in 20 patients with advanced and unresectable MPeM with progression or intolerance to prior platinum-pemetrexed chemotherapy. The primary endpoint of confirmed objective response rate per RECISTv1.1 by independent radiology review was 40% [8/20; 95% confidence interval (CI), 19.1-64.0] with median response duration of 12.8 months. Six (75%) responses lasted for >10 months. Progression-free and overall survival at one year were 61% (95% CI, 35-80) and 85% (95% CI, 60-95), respectively. Responses occurred notwithstanding low tumor mutation burden and PD-L1 expression status. Baseline epithelial-mesenchymal transition gene expression correlated with therapeutic resistance/response (r = 0.80; P = 0.0010). AtezoBev showed promising and durable efficacy in patients with advanced MPeM with an acceptable safety profile, and these results address a grave unmet need for this orphan disease. SIGNIFICANCE: Efficacy of atezolizumab and bevacizumab vis-à-vis response rates and survival in advanced peritoneal mesothelioma previously treated with chemotherapy surpassed outcomes expected with conventional therapies. Biomarker analyses uncovered epithelial-mesenchymal transition phenotype as an important resistance mechanism and showcase the value and feasibility of performing translationally driven clinical trials in rare tumors.See related commentary by Aldea et al., p. 2674.This article is highlighted in the In This Issue feature, p. 2659.
Abstract 2794: Blocking histamine receptor H1 on macrophages with anti-allergy drugs restores T-cell anti-tumor immunity
Authors: Hongzhong Li, Yi Xiao, Jun Yao, Xiangliang Yuan, Xuedong Yin, Yuan Zhang, Yohei Saito, Hideo Yagita, Don Gibbons, Dihua Yu
Journal: Cancer Research (2021)

Abstract CD8+ T lymphocytes in tumors often become dysfunctional, prompting cancer immune escape and immunotherapy resistance. Restoring T-cell anti-tumor immunity remains an unmet challenge. Here, we show that histamine receptor H1 (HRH1) is highly expressed and tightly associated with T-cell dysfunction in human cancers. Histamine, the HRH1 ligand, is also increased in human and mouse tumors. HRH1 is predominantly expressed on tumor-associated macrophages (TAMs) and is activated by cancer cell-secreted histamine. The histamine/HRH1 axis in TAMs confers CD8+ T-cell dysfunction via increasing membrane localization of V-domain Ig suppressor of T cell activation (VISTA), an inhibitory immune checkpoint that promotes immunotherapy resistance. Blocking HRH1, genetically, or by anti-allergy drugs, reversed immunosuppressive TAMs, activated T-cells, and inhibited tumor growth in vivo. HRH1-targeting anti-allergy drugs more efficaciously enhanced immunotherapy response than anti-VISTA antibodies. Markedly, allergy-induced histamine also activates HRH1 on macrophages to induce T-cell dysfunction and immunotherapy resistance, which were reversed by the over-the-counter anti-allergy drug. Taken together, tumor cell-derived and allergy-released histamines activate HRH1 on TAMs to concede immunosuppression, pro-tumor function, and immunotherapy resistance, which can be negated by inexpensive and safer anti-allergy drugs. Citation Format: Hongzhong Li, Yi Xiao, Jun Yao, Xiangliang Yuan, Xuedong Yin, Yuan Zhang, Yohei Saito, Hideo Yagita, Don Gibbons, Dihua Yu. Blocking histamine receptor H1 on macrophages with anti-allergy drugs restores T-cell anti-tumor immunity [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 2794.
Accuracy of rapid point-of-care antibody test in patients with suspected or confirmed COVID-19
Authors: Rama Vancheeswaran, Merlin Luke Willcox, Beth Stuart, Matthew Knight, Hala Kandil, Andrew Barlow, Mayon Haresh Patel, Jade Stockham, Aisling O'Neill, Tristan W Clark, Tom Wilkinson, Paul Little, Nick Francis, Gareth Griffiths, Michael Moore
Journal: Journal of Infection (2021)
Abstract LB065: Prostate cancer molecular immunophenotypes in biopsies with high vs average radiation sensitivity as predicted by post-operative radiation therapy outcomes (PORTOS) scores
Authors: Sandra M. Gaston, Sanoj Punnen, Oleksandr Kryvenko, Alan Pollack, Elai Davicioni, Seagle Liu, Radka Stoyanova
Journal: Cancer Research (2021)

Abstract Background: The combination of radiation therapy and immunotherapy has emerged as an exciting field of research with the potential for significant clinical benefit. Using pre-treatment prostate biopsies from two clinical trials we explored the hypothesis that a validated gene expression signature of postoperative radiation therapy outcome score (PORTOS) is associated with differences in tumor molecular immunophenotype. In this study, we compared prostate tumors with high vs average PORTOS scores for expression of 32 molecular immunophenoscores that reflect cancer antigen profiles and the cellular composition of tumor infiltrating lymphocytes. Methods: Gene expression profiles were obtained from microdissected tumor tissue from 242 treatment naïve-prostate biopsy cores obtained from 92 patients enrolled in the University of Miami MAST (NCT02242773) and BLaStM (NCT02307058) clinical trials. For each biopsy the PORTOS score (PMID: 27743920) and 32 tumor molecular immunophenoscores (PMID: 28052254) were determined from Affymetrix Human Exon 1.0 ST microarray data using published methods. Results: 14% of the biopsy cores were predicted by the PORTOS signature to be more responsive to radiation therapy. Compared to the cores with average PORTOS scores, the “high PORTOS” biopsies showed a 2 fold or greater level of the tumor immunoactivation markers Act CD4, Act CD8, EC, HLA DPA1 and Tem CD8 and a 2 fold or lower level of the tumor immunosuppression markers MDSC, SC, TIM3 and T reg (Mann-Whitney P value of &amp;lt;0.0001 for all nine comparisons of medians). Discussion: Preliminary studies suggest that prostate cancers with PORTOS scores that predict greater sensitivity to radiation therapy also have immunophenotype profiles consistent with a higher level of overall immunogenicity. Citation Format: Sandra M. Gaston, Sanoj Punnen, Oleksandr Kryvenko, Alan Pollack, Elai Davicioni, Seagle Liu, Radka Stoyanova. Prostate cancer molecular immunophenotypes in biopsies with high vs average radiation sensitivity as predicted by post-operative radiation therapy outcomes (PORTOS) scores [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 LB065.