bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer
Authors: Wang Zhenghang , Zhang Qi , Qi Changsong , Bai Yuezong , Zhao Feilong , Chen Hui , Li Zhongwu , Wang Xicheng , Chen Mifen , Gong Jifang , Peng Zhi , Zhang Xiaotian , Cai Jinping , Chen Shiqing , Zhao Xiaochen , Shen Lin , Li Jian 
Published: June 2022

BackgroundGastrointestinal (GI) cancer is the second most common cancer type with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) phenotype that is expected to respond to immune-checkpoint inhibitors (ICIs). However, approximately half of the patients with dMMR/MSI-H GI cancer derive no benefit from ICIs. We sought to identify the predictors of primary resistance to ICIs in dMMR/MSI-H GI cancer.MethodsThree independent cohorts were included: (1) the discovery cohort (65 patients with dMMR/MSI-H GI cancer) with ICI efficacy data and pre-ICIs tissue samples for genomic profile and tumor immune infiltration; (2) the validation cohort (22 patients with dMMR/MSI-H GI cancer) with ICI efficacy data and pre-ICIs plasma samples for genomic profile; and (3) the TCGA (The Cancer Genome Atlas) cohort not receiving ICIs (152 patients with MSI-H GI cancer) with genomic profile and survival data.ResultsAKT1 and CDH1 mutations were identified as independent predictors of poor progression-free survival (PFS) and primary resistance to ICIs in dMMR/MSI-H GI cancer. We combined these two genes as an immuno-oncology therapy predictor (IOpred), which could recognize 52.4% (11/21) of dMMR/MSI-H patients with primary resistance to ICIs with a positive predictive value (PPV) of 91.7% (11/12). Receiver operating characteristic analysis demonstrated IOpred with a good performance in predicting primary resistance (area under the curve 0.751). Patients with IOpred-Mut (mutant AKT1 or CDH1) GI cancer had significantly shorter PFS (HR=8.36, p<0.001) and overall survival (OS, HR=5.17, p<0.001) than IOpred-WT (wild-type for both AKT1 and CDH1) cases upon ICI treatment. The validation cohort also confirmed the correlation between IOpred-mutation and poorer prognosis (PFS, HR=4.68, p=0.004; OS, HR=15.98, p<0.001) in dMMR/MSI-H patients after ICIs. The PPV of IOpred in identifying primary resistance to ICIs was 80% (4/5) in the validation cohort. Additionally, IOpred-WT patients could be further stratified by tumor mutational burden (TMB), wherein TMB-low patients (TMB ≤26.19 mutations per megabase (Mb)) had a significantly higher primary resistance rate to ICIs (34.8% vs 6.7%, p=0.014) and poorer PFS (HR=3.46, p=0.008) and OS (HR=4.42, p=0.047) than TMB-high patients (TMB >26.19 mutations/Mb).ConclusionsIOpred was identified as a powerful predictor of primary resistance to ICIs in dMMR/MSI-H GI cancer, which might serve as a promising biomarker to help guide immunotherapy decision-making.
Wilms tumor reveals DNA repair gene hyperexpression is linked to lack of tumor immune infiltration
Authors: Higgs Emily F , Bao Riyue , Hatogai Ken , Gajewski Thomas F 
Published: June 2022

BackgroundA T cell-rich tumor microenvironment has been associated with improved clinical outcome and response to immune checkpoint blockade therapies in several adult cancers. Understanding the mechanisms for lack of immune cell infiltration in tumors is critical for expanding immunotherapy efficacy. To gain new insights into the mechanisms of poor tumor immunogenicity, we turned to pediatric cancers, which are generally unresponsive to checkpoint blockade.MethodsRNA sequencing and clinical data were obtained for Wilms tumor, rhabdoid tumor, osteosarcoma, and neuroblastoma from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database, and adult cancers from The Cancer Genome Atlas (TCGA). Using an 18-gene tumor inflammation signature (TIS) representing activated CD8+T cells, we identified genes inversely correlated with the signature. Based on these results, adult tumors were also analyzed, and immunofluorescence was performed on metastatic melanoma samples to assess the MSH2 relationship to anti-programmed cell death protein-1 (PD-1) efficacy.ResultsAmong the four pediatric cancers, we observed the lowest TIS scores in Wilms tumor. TIS scores were lower in Wilms tumors compared with matched normal kidney tissues, arguing for loss of endogenous T cell infiltration. Pathway analysis of genes upregulated in Wilms tumor and anti-correlated with TIS revealed activated pathways involved DNA repair. The majority of adult tumors in TCGA also showed high DNA repair scores associated with low TIS. Melanoma samples from an independent cohort revealed an inverse correlation between MSH2+tumor cells and CD8+T cells. Additionally, melanomas with high MSH2+tumor cell numbers were largely non-responders to anti-PD-1 therapy.ConclusionsIncreased tumor expression of DNA repair genes is associated with a less robust immune response in Wilms tumor and the majority of TCGA tumor types. Surprisingly, the negative relationship between DNA repair score and TIS remained strong across TCGA when correcting for mutation count, indicating a potential role for DNA repair genes outside of preventing the accumulation of mutations. While loss of DNA repair machinery has been associated with carcinogenesis and mutational antigen generation, our results suggest that hyperexpression of DNA repair genes might be prohibitive for antitumor immunity, arguing for pharmacologic targeting of DNA repair as a potential therapeutic strategy.
Active counselling and well-controlled disease result in a higher percentage of women with rheumatoid arthritis that breast feed: results from the PreCARA study
Authors: Kemper Erik , Ghalandari Nafise , Wintjes Hetty , Van Steensel-Boon Anneke , Kranenburg Laura , Mulders Annemarie , Crijns Hubertina , Smeele Hieronymus , Dolhain Radboud J EM 
Published: June 2022

ObjectivesPrevious research has demonstrated that patients with rheumatoid arthritis (RA) are less likely to breast feed their offspring. Treatment options for RA during lactation have expanded and the importance of counselling is recognised. The aim of the current research was to study breast feeding among women with RA who benefit from these developments.MethodsPatients were derived from the Preconceptional Counselling in Active Rheumatoid Arthritis (PreCARA) cohort. Patients were treated according to a modified treat-to-target approach aimed at remission and received pregnancy counselling, including counselling on breast feeding. Postpartum visits were scheduled at 4–6, 12 and 26 weeks post partum. Prevalence of breast feeding at each postpartum visit was compared with a historical reference cohort (Pregnancy-induced Amelioration of Rheumatoid Arthritis cohort) and the general population.ResultsData on 171 pregnancies were available for the current analysis. 120 (70.2%) patients with RA initiated breast feeding. 103/171 (60.2%), 68/171 (39.8%) and 45/171 (26.3%) patients with RA breast fed their offspring at 4–6, 12 and 26 weeks post partum, respectively. These percentages were higher at all postpartum visits compared with the historical reference cohort (p<0.001). In comparison with the general population, the rates were similar at each time point.ConclusionPatients with RA in the PreCARA cohort were more likely to breast feed their offspring compared with patients with RA in the historical reference cohort. The breastfeeding rates observed were similar to breastfeeding rates among women in the general population. The increase in breast feeding among patients with RA may be due to the extension of lactation-compatible medication and pregnancy counselling.
Emergence of cosmic space and horizon entropy maximization from Tsallis and Cirto entropy
Authors: Chen Ge-Rui 
Published: June 2022

AbstractIn this note by use of the idea of the emergence of cosmic space suggested by Padmanabhan (Emergence and expansion of cosmic space as due to the quest for holographic equipartition; Res Astro Astrophys 12:891, 2012), we derive the modified Friedmann equation of a Friedmann-Robertson-Walker (FRW) Universe from Tsallis and Cirto entropy in $$(n+1)$$

(
n
+
1
)

dimension with any spatial curvature. We investigate further the consistency of the law of emergence with the maximization of horizon entropy in the context of Tsallis and Cirto horizon entropy. Our results reveal the deep connection between the law of emergence and horizon thermodynamics.
Correlations of mixed systems in confining backgrounds
Authors: Ghodrati Mahdis 
Published: June 2022

AbstractWe show that the entanglement of purification and the critical distance between the two mixed systems is a powerful measure in probing the phase structures of QCD and confining backgrounds, as it can distinguish the scale of chiral symmetry breaking versus the scale of confinement/deconfinement phase transitions. For two symmetric strips with equal and finite width and infinite length, and in the background of several confining geometries, we numerically calculate the critical distance between them where the mutual information vanishes and show that this quantity can probe the very rich phase structures of these backgrounds. The geometries that we study here are AdS-soliton, Witten–Sakai–Sugimoto and deformed Sakai–Sugimoto, Witten-QCD, Klebanov–Strassler, Klebanov–Tseytlin, Klebanov–Witten, Maldacena–Nunez, Nunez–Legramandi metric, and Domain-Wall QCD model. For each background we also present the relation for the entanglement of purification. Finally, we show that the Crofton forms of these geometries also behave in a universal form where a “well” is being observed around the IR wall, and therefore for all confining backgrounds, the Crofton form would also be capable of distinguishing the confining versus conformal backgrounds as it is also a tool in the reconstruction of various bulk geometries.
Einstein–Dirac–Maxwell wormholes: ansatz, construction and properties of symmetric solutions
Authors: Blázquez-Salcedo Jose Luis , Knoll Christian , Radu E. 
Published: June 2022

AbstractWe present a discussion of the traversable wormholes in Einstein–Dirac–Maxwell theory recently reported in e-Print: 2010.07317. This includes a detailed description of the ansatz and junction condition, together with an investigation of the domain of existence of the solutions. In this study, we assume symmetry under interchange of the two asymptotically flat regions of a wormhole. Possible issues and limitations of the approach are also discussed.
PI3King the Environment for Growth: PI3K Activation Drives Transcriptome Changes That Support Oncogenic Growth
Authors: Claridge Sally E. , Hopkins Benjamin D. 
Published: June 2022

AbstractPI3K signaling plays an integral role in cells, coordinating the necessary alterations in cellular metabolism and programs to support survival and proliferation. In the first genome-wide analysis of alternative splicing in PIK3CA-mutant breast cancer, Ladewig and colleagues show that activating mutations in PIK3CA alter the use of known exons and splice junctions, leading to changes in gene expression and transcription factor activity that promote an oncogenic phenotype. Their work reveals a novel mechanism underlying the functional impact of PI3K signal activation in the context of breast cancer, where PIK3CA mutations are common and PI3K inhibitors are part of the standard of care. Their studies uncover a feedforward mechanism by which PI3K signaling enables a shift in the spectrum of translated splice variants as another method through which the PI3K pathway has evolved to regulate its own activity, thereby modifying the cellular response to upstream activation based on the signaling that has come before. These findings have profound implications for understanding the evolution of the PI3K pathway and the rewiring of cells in response to prolonged or repeated signal activation.See related article by Ladewig et al., p. 2269
Abstract 104: Targeting NAD(P)H:quinone oxidoreductase 1 (NQO1) in pancreatic ductal adenocarcinoma: An in silco, in vitro and in vivo approach
Authors: Ganji Purnachandra N. , Lesinski Gregory B. , El-Rayes Bassel F. 
Published: June 2022

Abstract
NAD(P)H: quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme. NQO1 is important for catalyzation, detoxification, and reduction of organic compounds including quinone. Elevated NQO1 expression is associated with increased pancreatic ductal adenocarcinoma (PDAC) growth, and metastasis as well as poor prognosis. BBI 608 is a small molecule that exhibits potential therapeutic properties for PDAC due to its powerful anti-inflammatory and antioxidant properties and ability to regulate multiple signaling pathways. The current study explores the binding capacity and ligand efficacy of BBI608 against NQO1 in PDAC. To observe the molecular properties of BBI608 and to analyze the exact mechanism of NQO1 on PDAC, computational approaches were applied, including molecular docking. This investigation provides a detailed understanding of the interaction between NQO1 and BBI608 and its implication in PDAC therapy. To support this computational analysis, we performed in vitro and in vivo studies. The combination of BBI608 with gemcitabine plus irradiation creates higher cytotoxicity (decreased proliferation, clonogenicity and increased Annexin V positive cells; p&lt;0.001) in PDAC cell lines and the mice bearing subcutaneous PANC-02 and MIA PaCa-2 model. Collectively, this investigation offers mechanistic insight into the cytotoxicity initiated by BBI608 and suggests further investigation of its utility for PDAC therapy is warranted.
Citation Format: Purnachandra N. Ganji, Gregory B. Lesinski, Bassel F. El-Rayes. Targeting NAD(P)H:quinone oxidoreductase 1 (NQO1) in pancreatic ductal adenocarcinoma: An in silco, in vitro and in vivo approach [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 104.
Abstract 1041: HBI-2376, HUYABIO clinical stage SHP2 inhibitor, possess robust in vitro potency and in vivo efficacy in several preclinical tumor models carrying KrasG12C or EGFR mutations
Authors: Shojaei Farbod , Shojaei Farbod , Ricono Jill M. , Fang Che , Kabbinavar Fairooz , Goodenow Bob , Gillings Mireille 
Published: June 2022

Abstract
SHP2 (Src homology region 2-containing protein tyrosine phosphatase 2) is an attractive target in oncology drug development due to its dual roles on the direct growth and proliferation of cancer cells and also acting as an immune checkpoint molecule to suppress tumor immunity. HBI-2376 is an orally bioavailable selective SHP2 inhibitor that is being developed for the treatment of solid tumors harboring KRAS or EGFR mutations, such as non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Additionally, HBI-2376 has the potential to suppress tumor growth via induction of the activity of immune infiltrating cells in the TME (tumor microenvironment). In a head-to-head comparison, in vitro studies showed greater potency of HBI-2376 to inhibit cell proliferation in a variety of cancer cell lines compared to other SHP2 inhibitors such as TNO-155 (Novartis AG) and RMC-4550 (Revolution Medicines). Consistently, HBI-2376 found to be more efficacious in tumor growth inhibition than TNO-155 and RMC-4550 in NCI-H1975L858R_T790M_C797S osimertinib-resistant cell line and other tumor models. In addition to xenograft models, we tested efficacy of HBI-2376 as single agent or in combination with anti-PD1 mAb in MC38 CRC syngeneic model. Consistent with xenograft data, HBI-2376 showed greater efficacy in tumor growth inhibition vs. TNO-155 and RMC-4550 both as single agent and in combination therapy. IHC data showed reduction in infiltration of M2 macrophages (F4/80+Arg1+) in the HBI-2376 treated tumors suggesting a MoA for its greater efficacy in MC38 model. Furthermore, Western blotting showed inhibition of p-ERK and DUSP6 in HBI-2376 treated cells indicative of a biomarker of response to the therapy. These findings, along with a positive safety profile led to HBI-2376 IND clearance by FDA and suggested promising responses in NSCLC or CRC patients in the forthcoming clinical studies.
Citation Format: Farbod Shojaei, Farbod Shojaei, Jill M. Ricono, Che Fang, Fairooz Kabbinavar, Bob Goodenow, Mireille Gillings. HBI-2376, HUYABIO clinical stage SHP2 inhibitor, possess robust in vitro potency and in vivo efficacy in several preclinical tumor models carrying KrasG12C or EGFR mutations [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 1041.
Abstract 1127: Effect of the combined therapy of sotorasib and metformin in non-small cell lung cancer cell lines
Authors: Hernandez-Pedro Norma Yanet , Lucio-Lozada Jose , Barrios-Bernal Pedro , Ramos-Ramírez Maritza , Arrieta Oscar 
Published: June 2022

Abstract
KRAS is the most frequently mutated oncogene in lung adenocarcinoma, in which is related to poor treatments response and worse survival rates than other driver mutations. KRAS activates MAPK and mTOR pathways, and even after sotorasib treatment, a novel KRAS inhibitor, the duration of responses to this monotherapy are excessively short. In this context, metformin is able to inhibit PI3K and mTOR pathways; therefore, combined use of metformin with sotorasib aids to diminish the activity of both signaling pathways. We performed a dose-effect curve to determine IC50 of sotorasib, and IC10 of metformin to treat lung cancer cell lines harboring different mutational profiles: A549 (KRAS G12S), and H522 (TP53) in order to study the effects of the combination compared to the monotherapy of each drug at MTT assay and western blot analysis. In detail, we evaluated drug-induced cytotoxicity, apoptosis, and activity of MAPK and mTOR pathways. Our results show a synergic effect in cytotoxicity by MTT assay, as well as increased inhibition of MAPK pathway inhibition at combinational treatment, compared to monotherapies in A549 cell lines; conversely, we did not find significant effects on cytotoxicity and signaling inhibition in H522 cell line. In conclusion, the combined treatment of metformin and sotorasib show synergistic effects in drug-induced cytotoxicity and inhibition of MAPK pathways in lung cancer cell lines.
Citation Format: Norma Yanet Hernandez-Pedro, Jose Lucio-Lozada, Pedro Barrios-Bernal, Maritza Ramos-Ramírez, Oscar Arrieta. Effect of the combined therapy of sotorasib and metformin in non-small cell lung cancer cell lines [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 1127.
Abstract 1274: Prognostic relevance of ZnF 649 in clear cell carcinoma
Authors: Reams Renee , Heyliger Simone O. , Saulsbury marilyn , Soliman Karam F. 
Published: June 2022

Abstract
Clear cell renal carcinoma (ccRCC) is the most common form of neoplastic disease affecting the kidneys that accounts for at least 70% of all kidney cancers. Given its resistance to medications and high mortality at later stages, there is a need to identify biomarkers that can detect ccRCC. KRAB Zinc finger proteins (KRAB-ZFPs) are the largest family of mammalian transcription regulators. They are differentially expressed in various tissues during cellular development and phenotypic differentiation. Though poorly understood, these transcription factors, are also differentially expressed in several cancers though very few have been reported to be implicated in ccRCC. Using bioinformatics techniques, we have demonstrated that ZNF649 and its paralog ZNF613 are suppressed in clear cell renal carcinomas (p&lt;0.001) relative to normal tissues. Moreover, The ZNF649 and ZNF613 transcripts were downregulated across all histological grades and pathological stages (p&lt;0.001). In addition, both ZNF649 and ZNF613 downregulation was associated with metastasis and unsatisfactory patient survival (p&lt;0.001). Univariate and multivariante Cox regression analysis of age, gene expression, gender, pathological stage, histological grade, and pathological N in relationship to overall survival in ccRCC patients revealed that ZNF649 expression was predictive of overall survival. Gene Set Enrichment Analysis of the Gene Ontology Biological Processes database indicate that the top pathways enriched with genes correlated to ZNF649 expression were associated with angiogenesis, cellular motility and mitochondrial regulation (p&lt;0.001 and FDR &lt;0.05). Taken collectively, our observations indicate that ZNF649 is a prognostic marker and is a putative tumor suppressor gene in clear cell renal carcinoma.
Citation Format: Renee Reams, Simone O. Heyliger, marilyn Saulsbury, Karam F. Soliman. Prognostic relevance of ZnF 649 in clear cell carcinoma [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 1274.
Abstract 1297: Chemotherapy-induced senescence activates robust, parallel programs of immune checkpoint expression that can be targeted with immunotherapy
Authors: Shahbandi Ashkan , Chiu Fang-Yen , Ungerleider Nathan A. , Anderson Ashlyn Y. , Machado Heather L. , Pursell Zachary F. , Kvadas Raegan , Rao Sonia G. , Jackson James G. 
Published: June 2022

Abstract
We and others have previously shown that the breast cancers most difficult to eradicate with chemotherapy are TP53 wild-type, and these are among the most lethal breast cancers. For instance, chemotherapy-treated TNBC patients with TP53 wild-type tumors have a median overall survival of 45 months, vs 263 months for TP53 mutant tumors. Treatments fail to eradicate these cancers for two reasons: the tumor cells 1) avoid intrinsic cell death, and 2) escape immune clearance. We have shown that p53 drives a program of senescence that arrests the cell cycle to prevent intrinsic modes of cell death such as mitotic catastrophe, apoptosis and nutrient deprivation. However, it is not currently understood how breast cancer cells that enter senescence to survive chemotherapy escape immune clearance.
Here, we show tumor cells from mice and human patients that survive chemotherapy activate complex programs of immune modulation. Surprisingly, the surviving, senescent tumor cells are highly enriched for many antigen presentation genes and positive regulators of T cell activation, suggesting they have switched from immunologically “cold” to “hot”. Unfortunately, these senescent tumors concurrently upregulate redundant expression of many T cell inhibitory checkpoint genes, including CD80 and PD-L1. scRNA-seq and cell imaging revealed that CD80 and PD-L1 each mark unique populations of cells in the treated tumor, typified by p53 signaling or interferon signaling, respectively.
In p53 wild-type, syngeneic, orthotopic mouse mammary tumor models that recapitulate human breast cancer response to chemotherapy, treatment of tumors with chemotherapy followed by targeting of the PD-L1 and/or CD80 axes improved response, including complete eradication in some instances. Unfortunately, however, even combination strategies failed to elicit a cure in the majority of cases. Our findings reveal the formidable challenge of eliminating residual disease populated by senescent cells that express multiple redundant immune inhibitory pathways and suggest rational strategies are needed based on the specific checkpoint pathways expressed in residual disease.
Citation Format: Ashkan Shahbandi, Fang-Yen Chiu, Nathan A. Ungerleider, Ashlyn Y. Anderson, Heather L. Machado, Zachary F. Pursell, Raegan Kvadas, Sonia G. Rao, James G. Jackson. Chemotherapy-induced senescence activates robust, parallel programs of immune checkpoint expression that can be targeted with immunotherapy [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 1297.