bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade of interleukin 10 potentiates antitumour immune function in human colorectal cancer liver metastases
Authors: Sullivan Kevin M , Jiang Xiuyun , Guha Prajna , Lausted Christopher , Carter Jason A , Hsu Cynthia , Labadie Kevin P , Kohli Karan , Kenerson Heidi L , Daniel Sara K , Yan Xiaowei , Meng Changting , Abbasi Arezou , Chan Marina , Seo Y David , Park James O , Crispe Ian Nicholas , Yeung Raymond S , Kim Teresa S , Gujral Taranjit S , Tian Qiang , Katz Steven C , Pillarisetty Venu G 
Published: June 2022

ObjectiveProgrammed cell death protein 1 (PD-1) checkpoint inhibition and adoptive cellular therapy have had limited success in patients with microsatellite stable colorectal cancer liver metastases (CRLM). We sought to evaluate the effect of interleukin 10 (IL-10) blockade on endogenous T cell and chimeric antigen receptor T (CAR-T) cell antitumour function in CRLM slice cultures.DesignWe created organotypic slice cultures from human CRLM (n=38 patients’ tumours) and tested the antitumour effects of a neutralising antibody against IL-10 (αIL-10) both alone as treatment and in combination with exogenously administered carcinoembryonic antigen (CEA)-specific CAR-T cells. We evaluated slice cultures with single and multiplex immunohistochemistry, in situ hybridisation, single-cell RNA sequencing, reverse-phase protein arrays and time-lapse fluorescent microscopy.ResultsαIL-10 generated a 1.8-fold increase in T cell-mediated carcinoma cell death in human CRLM slice cultures. αIL-10 significantly increased proportions of CD8+T cells without exhaustion transcription changes, and increased human leukocyte antigen - DR isotype (HLA-DR) expression of macrophages. The antitumour effects of αIL-10 were reversed by major histocompatibility complex class I or II (MHC-I or MHC-II) blockade, confirming the essential role of antigen presenting cells. Interrupting IL-10 signalling also rescued murine CAR-T cell proliferation and cytotoxicity from myeloid cell-mediated immunosuppression. In human CRLM slices, αIL-10 increased CEA-specific CAR-T cell activation and CAR-T cell-mediated cytotoxicity, with nearly 70% carcinoma cell apoptosis across multiple human tumours. Pretreatment with an IL-10 receptor blocking antibody also potentiated CAR-T function.ConclusionNeutralising the effects of IL-10 in human CRLM has therapeutic potential as a stand-alone treatment and to augment the function of adoptively transferred CAR-T cells.
Escape from cell-cell and cell-matrix adhesion dependence underscores disease progression in gastric cancer organoid models
Authors: Tong Yin , Cheng Priscilla S W , Or Chung Sze , Yue Sarah S K , Siu Hoi Cheong , Ho Siu Lun , Law Simon Y K , Tsui Wai Yin , Chan Dessy , Ma Stephanie , Lee Siu Po , Chan Annie S Y , Chan April S , Yun Shui Wa , Hui Ho Sang , Yuen Siu Tsan , Leung Suet Yi , Yan Helen H N 
Published: June 2022

ObjectiveCell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells.DesignWe explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix or both to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers:ARHGAPfusions,RHOAandCDH1,in modulating CC (CCi) or CM (CMi) adhesion independence.Results97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to three public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling viaRHOAmutation orARHGAPfusions. Inducible knockout ofARHGAPfusions in CCi/CMi tumour organoids led to resensitisation to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype and inhibited xenograft formation. Normal gastric organoids engineered withCDH1orRHOAmutations became CMi or CCi, respectively.ConclusionsThe CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.
Measuring CP nature of $$h\tau {{\bar{\tau }}}$$ coupling at $$e^-p$$ collider
Authors: Dutta Sukanta , Goyal Ashok , Kumar Mukesh , Swain Abhaya Kumar 
Published: June 2022

AbstractThe proposed future $$e^- p$$

e
-

p

collider provides sufficient energies to produce the Standard Model Higgs Boson (h) through $$W^\pm $$

W
±

and Z-Boson fusion in charged and neutral current modes, respectively and to measure its properties. We take this opportunity to investigate the prospect of measuring the CP properties of h through $$h \rightarrow \tau ^{+} \tau ^{-}$$

h
→

τ
+

τ
-

, where $$\tau ^{-}\,\left( \tau ^{+}\right) $$

τ
-

τ
+

decays to a charged pion $$\pi ^-\,\left( \pi ^+\right) $$

π
-

π
+

and a neutral pion $$\pi ^0$$

π
0

in association with neutrino (anti-neutrino). An interesting CP sensitive angular observable $$\alpha _{\mathrm{CP}}$$

α
CP

between the two $$\tau $$
τ
-leptons decay plane in the $$\pi ^+\pi ^-$$

π
+

π
-

centre of mass frame is proposed and investigated in this work. For fixed electron energy of 150 GeV along with 7 (50) TeV of proton energy, the CP phase can be measured approximately to $$25^\circ $$

25
∘

($$14^\circ $$

14
∘

) at integrated luminosity of 1 ab$$^{-1}$$

-
1

for −80% polarised electron at 95% confidence level.
Abstract 1019: Address breast cancer equity through virtual community oncology navigation and engagement (vCONET)
Authors: Salinas Manisha 
Published: June 2022

Abstract
The objective of this study is to develop and test a culturally sensitive, inclusive, and accessible virtual navigation model for Black women to promote and improve breast cancer screening behaviors. Breast cancer is among the leading causes of cancer morbidity and mortality globally, and there is a wide range of racial and ethnic disparities across the cancer continuum. Black women continue to have disproportionately high mortality rates compared to Whites, and are more impacted by triple-negative breast cancer and inflammatory breast cancer earlier in their lives and at more advanced stages. Patient navigation, particularly when culturally tailored to the intended population, is highly effective in reducing the complexity of access to care for cancer prevention and treatment. The growing momentum and usage of telehealth and virtual care has significant potential to reach Black women, to promote higher mammography screening and early detection of breast cancer. Virtual patient navigation can provide a safe, engaging, and accessible space to accelerate the application of practical approaches to address health disparities and increase preventive behaviors in underrepresented community. However, limited information exists on specific factors which impact the design, implementation, and receptivity of virtual navigation in Black communities. This study aims to: 2) Develop and test a culturally-adapted prototype of a virtual patient navigation intervention tool for increasing access to breast cancer screening education and promotion for Black women. 1) Use qualitative focus group methodology to explore the beliefs, attitudes, perceptions, and receptivity of community members of program usability and breast cancer awareness, prevention and screening behaviors among Black women. The study will examine social determinants of health that impact potential challenges to access utilization of mammography screening services. Qualitative focus group discussions will be conducted to guide the details of the virtual patient navigation, such as communication channels, specific messaging approaches, and sociocultural factors to integrate, as well as addressing current challenges and needs faced by the community. The results of this study can provide valuable insight to specific needs regarding outreach and access to screening mammography services to underrepresented communities of color to ultimately reduce breast cancer rates. Data collection is ongoing and preliminary results will be presented.
Citation Format: Manisha Salinas. Address breast cancer equity through virtual community oncology navigation and engagement (vCONET) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1019.
Abstract 1043: Advances in cystine-dense peptide (CDP) screening and therapeutic applications
Authors: Crook Zachary R. , Girard Emily J. , Sevilla Gregory P. , Brusniak Mi-Youn , Rupert Peter B. , Friend Della J. , Gewe Mesfin M. , Clarke Midori , Lin Ida , Ruff Raymond , Phi Doan , Bandaranayake Ashok , Correnti Colin E. , Mhyre Andrew J. , Nairn Natalie W. , Strong Roland K. , Olson James M. 
Published: June 2022

Abstract
Cystine-dense peptides (CDPs) are a class of drug-like miniproteins that marry many of the advantages of biologics (high affinity and specificity) and small molecule therapeutics (high tissue permeability and low immunogenicity). The beneficial properties of CDPs, and miniproteins in general, have driven interest in therapeutic applications. However, CDP diversity is vast from every clade of life, and properly interrogating “CDP space” requires specialized screening and modeling tools.
With this in mind, we have created an optimized mammalian surface display platform to screen for CDPs of clinical interest using libraries of structurally-diverse native scaffolds optimized for stability. These native CDPs can be structurally modeled, which we did in determining the structures of over 4200 native CDPs. This modeling permits further selection in silico as well as targeted mutagenesis for favorable target-binding capabilities. Hits from these screens are routinely matured to sub-nM affinity. These CDPs can play numerous roles in a drug design pipeline, from an independent drug candidate to a delivery agent for tissue-targeting to a module in a polyspecific biologic. Recent novel CDP candidates have shown promise in immune-oncology space as part of a bispecific T-cell engager targeting PD-L1, where a single 2-week treatment was capable of eliminating subcutaneous PC3 prostate cancer xenograft tumors in 27/30 mice.
Besides bispecifics, future directions for the platform include exploring targeted protein degradation. Additionally, we are expanding upon our previous work on CDPs to explore CNS or tumor delivery of therapeutic cargo. The versatility of CDPs and novel screening tools to rapidly identify and mature candidates of interest can facilitate rapid advancement of CDP therapeutics to address difficult targets in oncology.
Citation Format: Zachary R. Crook, Emily J. Girard, Gregory P. Sevilla, Mi-Youn Brusniak, Peter B. Rupert, Della J. Friend, Mesfin M. Gewe, Midori Clarke, Ida Lin, Raymond Ruff, Doan Phi, Ashok Bandaranayake, Colin E. Correnti, Andrew J. Mhyre, Natalie W. Nairn, Roland K. Strong, James M. Olson. Advances in cystine-dense peptide (CDP) screening and therapeutic applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1043.
Abstract 1049: Modulating the polymorphic UGT1A1 gene to enhance camptothecin anti-colorectal effect
Authors: Al Saeedy Dalia , Abuhijjleh Reham K. , Gouda Ahmed , El-Khamisy Sherif F. , Al-Abd Ahmed M. 
Published: June 2022

Abstract
Several semisynthetic analogs of camptothecin (CPT) are used clinically for the treatment of various types of cancers, including colorectal (CRC) cancer, despite their severe, potentially life-threatening toxicities. Studies defined key mutations in the UDP-glycosyltransferase 1 polypeptide A1 (UGT1A1) gene in CRC which play a role in the toxicity and resistance of a broad class of anti-cancer drugs that target DNA topoisomerases. UGT-1A1 is responsible for the glucuronidation and detoxification of the active/toxic metabolite of the topoisomerase I poison, CPT and its analogues, SN-38. Herein, we investigated the potential chemomodulatory effects of a UGT1A1-gene inducer, phenytoin, to the anticancer properties of CPT. The cytotoxic effects of CPT, phenytoin and their combination were evaluated against various colorectal cancer cell lines (SW620, HT29 and HCT116) using sulforhodamine-B assay under normoxic and hypoxic conditions. In HT29, CPT alone and after combination treatment had IC50’s of 0.1235 µM and 0.0269 µM, respectively, under normoxic conditions; and 0.1352 µM and 0.0476 µM, respectively, under hypoxic conditions. In SW620, CPT alone and after combination treatment had IC50’s of 1.9861 µM and 0.0087 µM, respectively, under normoxic conditions; and 1.9549 µM and 0.0024 µM, respectively, under hypoxic conditions. In HCT116, CPT alone and after combination treatment had IC50’s of 0.163 µM and 0.0157 µM, respectively, under normoxic conditions; and 0.1013 µM and 0.0766 µM, respectively, under hypoxic conditions. Flow cytometric analysis after annexin-V/FITC staining showed that the combination treatment significantly induced total apoptosis in all cell lines under investigation. In both HT29 and SW620, the combination treatment significantly suppressed the autophagy compared to CPT treatment alone using acridine orange staining coupled with flowcytometry. Cell cycle analysis using DNA content flowcytometry after PI staining showed significant S-phase arrest in the combination treatment when compared to the control across all cell lines under investigation. This indicates that sub-molecular mechanisms of phenytoin induced chemomodulatory effect to CPT anticancer properties is oxygen tension dependent. Further investigation for the intratumoral metabolism of CPT under hypoxic as well as normoxic conditions and particularly those attributed to UGT-1A1 is currently undergoing.
Citation Format: Dalia Al Saeedy, Reham K. Abuhijjleh, Ahmed Gouda, Sherif F. El-Khamisy, Ahmed M. Al-Abd. Modulating the polymorphic UGT1A1 gene to enhance camptothecin anti-colorectal effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1049.
Abstract 1069: OBT076, a clinical-stage ADC, displays synergy with oxaliplatin and cisplatin in preclinical gastric cancer models
Authors: Bisht Arnima , Cox Murray , Peddaboina Chander Sekhar , Crocamo Michael , Fandi Abderrahim , Rohlff Christian 
Published: June 2022

Abstract
CD205 is a transmembrane glycoprotein, robustly expressed in malignancies from varied histotypes, making it an ideal target for Antibody Drug Conjugate (ADC) therapy. OBT076 is a novel and selective clinical stage ADC with potent activity against CD205-positive liquid and solid tumors. We explored the cellular cytotoxicity profile of combination chemotherapy with OBT076 and two standard-of-care platinum-based compounds, Oxaliplatin (Ox) and Cisplatin (Cis), in preclinical gastric, pancreatic and colorectal cancer models.
A panel of gastric cancer and other solid tumor cell lines were selected, based on mRNA data, for CD205 expression. This was confirmed using flow cytometry. The cell lines were assessed for susceptibility to monotherapy with OBT076, Ox and Cis. Cells lines displaying positive cytotoxic responses were assessed for susceptibility to combination chemotherapy by first treating cells with a single dose of OBT076 for 72 hours, leading to 20% growth inhibition (IC20), and subsequently with either Ox or Cis for 48 hours (OBT-Ox and OBT-CIS, respectively). The ATP-dependent fluorescence-based cellular viability system cell titer-glo was used as the cytotoxic readout.
In our preclinical gastric cancer model, pre-treatment with OBT076 followed by either Ox or Cis displayed synergistic combination effects, reducing the half-maximal inhibitory concentration (IC50) of Ox and Cis by 40- and 10-fold respectively. The resultant cellular cytotoxicity of OBT-Ox and OBT-Cis combination therapy was higher compared to monotherapy with either agent. Moreover, while monotherapy with Ox was less potent than with Cis, OBT-Ox achieved similar potency to OBT076-Cis. For colorectal and pancreatic cancer models, the effects were less pronounced: OBT076-combination therapy increased Platinum sensitivity by 2 to 5 times. No synergistic effects were observed when the treatment order was reversed. These results and those from ongoing in vivo studies in gastric cancer models will be discussed.
In summary OBT076, a clinical stage ADC displays synergistic anti-tumor effects in preclinical gastric cancer models, when used in combination with Ox or Cis. OBT076 is currently being evaluated in the gastric clinical population where Platinum-based therapies remain the mainstay of treatment.
Citation Format: Arnima Bisht, Murray Cox, Chander Sekhar Peddaboina, Michael Crocamo, Abderrahim Fandi, Christian Rohlff. OBT076, a clinical-stage ADC, displays synergy with oxaliplatin and cisplatin in preclinical gastric cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1069.
Abstract 119: Pan-cancer analysis of HIF pathways defines a robust molecular signature that reflects tissue and cellular hypoxia in bulk and single-cell RNA-seq analyses
Authors: Lombardi Olivia , Li Ran , Halim Silvia , Ratcliffe Peter J. , Mole David R. 
Published: June 2022

Abstract
Low levels of tissue oxygen, or intra-tumor hypoxia, is a common feature of many solid cancers in which dysregulated cell proliferation often outstrips the ability to develop new functional blood vessels. Furthermore, hypoxia pathways may also be activated in response to mutation in key tumor suppressor genes or oncogenes. Importantly, in many types of cancer, activation of hypoxia pathways is associated with a clinically aggressive phenotype as well as with resistance to therapy. Indeed, hypoxia drives many of the “hallmarks” of cancer, including cell proliferation, apoptosis, metabolism, immune responses, genomic instability, vascularization, invasion and metastasis. However, the full-range of genes activated by hypoxia varies greatly between cell-types and for many this remains uncharacterized. The key mediator of the cellular transcriptional response to hypoxia is the HIF (hypoxia-inducible factor) family of transcription factors. Here, we generate pan-genomic datasets encompassing HIF ChIP-seq and RNA-seq across cancer cell lines from diverse common tumor types. We then employ integrated analysis of our 72 transcriptome and whole-genome-binding datasets to define a core set of HIF-target genes that are conserved across multiple cell types. We show that these genes can be used to identify HIF activation and tumor hypoxia in bulk RNA-seq analysis of solid tumors, and that this can be applied to large tumor databases (TCGA). We then leverage this analysis to identify tumor-type-specific HIF-associated genes in 32 different cancer types, including those lacking cell-culture models. We further show that these conserved HIF-target genes can be applied to single cell RNA-seq datasets from solid tumors and used to examine intra-tumor heterogeneity in HIF-pathway activation within individual cancer samples. Importantly, using a panel of genes reduces the phenomenon of “drop-out” typically observed in gene-level expression in these datasets. Lastly, applying this gene signature to single cell data allows the hypoxia response to be deconvoluted across diverse cell-types in heterogenous tumor samples. This includes not only the identification of HIF-activity in cancer cells, but also in non-cancer cells within the tumor, thereby allowing the effects of intra-tumor hypoxia on stromal responses (such as tumor angiogenesis) to be studied in vivo in solid tumors.
Citation Format: Olivia Lombardi, Ran Li, Silvia Halim, Peter J. Ratcliffe, David R. Mole. Pan-cancer analysis of HIF pathways defines a robust molecular signature that reflects tissue and cellular hypoxia in bulk and single-cell RNA-seq analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 119.
Abstract 1190: MMHCdb: A knowledgebase for the evolving landscape of mouse models of human cancer
Authors: Begley Dale A. , Krupke Debbie M. , Neuhauser Steven , Sundberg John , Bult Carol J. 
Published: June 2022

Abstract
The laboratory mouse is the premier mammalian model organism for interrogating the genetic and molecular basis of human cancer and for preclinical investigations into targets for the prevention and treatment of cancer. The distributed and heterogenous nature of information about these model systems makes it difficult for researchers to integrate and interpret the information to determine the state of the field and to identify the most relevant models for basic and preclinical research. The Mouse Models of Human Cancer database (http://tumor.informatics.jax.org) is an expertly curated knowledgebase about genetically defined mouse strains and Patient Derived Xenograft (PDX) models of human cancer. Data in MMHCdb are obtained from peer-reviewed scientific publications and direct data submissions from individual investigators and large-scale programs. MMHCdb is built on FAIR data management principles (Findable, Accessible, Interoperable, Reusable). The enforcement of metadata standards and official gene, allele and strain nomenclature ensure accurate and comprehensive search results for cancer models. MMHCdb has long represented data from spontaneous or endogenously induced tumors from genetically defined mice and for PDXs which have been the foundation of basic cancer research and preclinical studies for decades. MMHCdb has expanded to include cancer models such as Diversity Outbred and Collaborative Cross mice which are ideally suited for research into the relationship of genetic variation with cancer susceptibility and for modeling the genetics of variability in treatment responses. The MMHCdb contains over 109,266 curated tumor frequency records for over 8,275 mouse strains. Tumor types in the database have been indexed to over 21,000 literature citations. PDX models and data available in MMHCdb are also accessible from the Patient Derived Cancer Models resource at EMBL-EBI which currently provides information for over 4,000 PDXs (https://cancermodels.org).MMHCdb is supported by NCI R01 CA089713
Citation Format: Dale A. Begley, Debbie M. Krupke, Steven Neuhauser, John Sundberg, Carol J. Bult. MMHCdb: A knowledgebase for the evolving landscape of mouse models of human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1190.