bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA05: Immune mechanisms driving carcinogenesis in NASH
Authors: Heikenwälder Mathias 
Published: September 2022

Abstract
In association with the pandemic spreading of obesity and metabolic syndrome, the prevalence of NAFLD-related HCC is increasing almost exponentially. In recent years, many of the underlining multifactorial causes of NAFLD have been identified, and the cellular mechanisms sustaining disease development have been dissected up to the single-cell level. Still, there is still an urgent need to provide clinicians with more therapeutic targets, with particular attention on NAFLD-induced HCC, where immune checkpoint inhibitors do not work as efficiently. Whereas much effort has been invested in elucidating the role of innate immune response in the hepatic NAFLD microenvironment, only in the past decade have novel critical roles been unraveled for T cells in driving chronic inflammation toward HCC. The metabolic and immune microenvironment interact to recreate a tumor-promoting and immune-suppressive terrain, responsible for resistance to anticancer therapy. Here, I will illustrate the cellular crosstalk with other immune cells, regulatory networks or stimulatory effects of these interactions, and role of the metabolic microenvironment in influencing immune cell functionality in the context of NAFLD and HCC.
Citation Format: Mathias Heikenwälder. Immune mechanisms driving carcinogenesis in NASH [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA05.
Abstract IA09: Role of liquid biopsy in early detection and assessment of response in hepatocellular carcinoma
Authors: Villanueva-Rodriguez Augusto 
Published: September 2022

Abstract
Early hepatocellular carcinoma detection is suboptimal with less than 25% of eligible patients enrolled in surveillance. In addition, recommended tools (biannual abdominal ultrasound with or without AFP) have poor sensitivity (63% for early-stage tumors). This has prompted the development of liquid biopsy approaches to improve performance and increase implementation. Methylation analysis of circulating tumor DNA and RNA sequencing in extracellular vesicles have shown promising performance in case control studies. This technology has also been applied to identify predictor biomarkers of response to systemic therapies. With 9 agents approved and without a clear strategy on how to select patients for therapies, the need to develop minimally-invasive biomarkers in this space cannot be overemphasized.
Citation Format: Augusto Villanueva-Rodriguez. Role of liquid biopsy in early detection and assessment of response in hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA09.
Abstract IA14: Lessons learned from phase III trials in HCC: OS, PFS and ORR
Authors: Zhu Andrew X. 
Published: September 2022

Abstract
Through well conducted phase III trials, recent development of molecularly targeted agents, immune checkpoint inhibitors, and combination strategies in advanced hepatocellular carcinoma (HCC) has significantly improved the treatment outcome in this disease. The median overall survival (OS) for patients receiving the new standard treatment, atezolizumab plus bevacizumab, has approached to 20 months in IMbrave150 trial. While OS remains the gold standard and main endpoint for phase III trials in advanced HCC, there is an increasing need to define surrogate endpoints including progression free survival (PFS) and overall response rate (ORR) that can reliably predict the survival benefits. The author will discuss the rationale and current status of using PFS and ORR as surrogate endpoints in HCC, and the strengths and limitations of PFS and ORR as surrogate endpoints to predict survival.
Citation Format: Andrew X. Zhu. Lessons learned from phase III trials in HCC: OS, PFS and ORR [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA14.
Abstract IA16: Trial enrichment and proof of concept studies
Authors: Villanueva-Rodriguez Augusto 
Published: September 2022

Abstract
Identification of oncogene addiction loops has provided new therapeutic targets in oncology. Selective targeting of the ABL-BCR fusion in patients with chronic lymphocytic leukemia using imatinib was a major clinical breakthrough. Similar approaches in other solid tumors led to the approval of additional biomarker-driver molecular therapies (e.g., vemurafenib in BRAF mutated melanoma). Success of this approach was contingent on the identification of biomarkers that could help identify patients most likely to respond to these therapies. This spurred efforts to implement clinical trials able to detect efficacy in specific patient populations, specifically those enriched in the biomarker under evaluation. This has also been applied in hepatocellular carcinoma with mixed results. Approval of ramucirumab in patient with elevated AFP is the first example of successful trial enrichment, while tivantinib is paradigmatic of a negative biomarker enrichment trial. Lack of recurrent druggable mutations makes biomarker-driven clinical trials in HCC more difficult, which underscores the need for predictive biomarkers of immune therapies.
Citation Format: Augusto Villanueva-Rodriguez. Trial enrichment and proof of concept studies [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA16.
Abstract IA17: Assessing response and time-to-event end-points: RECIST and mRECIST
Authors: Lencioni Riccardo 
Published: September 2022

Abstract
In 2010, modified RECIST (mRECIST) criteria were proposed as a way of adapting the RECIST criteria to the particularities of hepatocellular carcinoma (HCC). mRECIST was intended to overcome some limitations of RECIST in measuring tumour shrinkage with local and systemic therapies, and also to refine the assessment of progression that could be misinterpreted with conventional RECIST 1.1, due to clinical events related to the natural progression of chronic liver disease. mRECIST has served its purpose since being adopted or included in clinical practice guidelines (European, American and Asian) for the management of HCC; it has also been instrumental for assessing response and time-to-event endpoints in several phase II and III investigations. Nowadays, mRECIST has become the standard tool for measurement of radiological endpoints at early/intermediate stages of HCC. At advanced stages, guidelines recommend both methods. mRECIST has been proven to capture higher objective response rates in tumours treated with molecular therapies and those responses have shown to be independently associated with better survival. With the advent of novel treatment approaches including immunotherapy combination therapies, there is a need to further refine and clarify some concepts around the performance of mRECIST.
Citation Format: Riccardo Lencioni. Assessing response and time-to-event end-points: RECIST and mRECIST [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA17.
Abstract IA18: Immune checkpoint inhibitors and nonalcoholic steatohepatitis (NASH)
Authors: Yarchoan Mark 
Published: September 2022

Abstract
Hepatocellular carcinoma (HCC) usually arises in the setting of liver cirrhosis from viral or non-viral causes. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is a rising cause of HCC in the United States and many other parts of the world. Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD1) or its ligand have improved outcomes for patients with advanced HCC. In general, clinical biomarkers are not currently used to identify patients most likely to benefit from systemic immunotherapy in HCC, and whether etiology has any effect on immunotherapy responses in HCC has been unclear. In this session, we will review recent preclinical data suggesting that NASH may impair immune responses in HCC. We will also review data from The Cancer Genome Atlas (TCGA) comparing the tumor immune microenvironment of viral-associated and non-viral HCC, and review the preponderance of clinical evidence indicating that HBV, HCV, and non-viral HCC all derive clinical benefit from immune checkpoint inhibitor therapy.
Citation Format: Mark Yarchoan. Immune checkpoint inhibitors and nonalcoholic steatohepatitis (NASH) [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA18.
Abstract IA25: Clinical trials and molecular therapies in iCCA
Authors: Valle Juan W. 
Published: September 2022

Abstract
Cisplatin and gemcitabine (CisGem) has been the stadard of care for patients presenting with advanced iCCA for over a decade. Intensified (triplet) chemotherapy remains investigational except in Japan, where the CisGem and S1 is an option. Robust data has shown that 5FU-based, second-line, combination chemotherapy has modest activity in a molecularly-unselected population. An improved understanding of the biology underpinning iCCA has led to the identification of molecular alterations linked to targeted therapies. The most prominent alterations are mutations in IDH1 and FGFR2 fusions; both of these are addressed later in the session. This presentation will highlight other selected subgroups, including patients whose tumours are harbouring BRAF-V600E mutations, HER2 amplification/over-expression, and NTRK fusions as examples, although additional groups continue to emerge. Cholangiocarcinoma is recognised to have an underlying immune predisposition, in selected cases. Harnessing the immune response has previously provided limited signals of efficacy. However, the TOPAZ-1 study, a randomised phase III study has recently shown an incremental survival benefit in patients with biliary tract cancer with the addition of durvalumab to CisGem chemotherapy, including intrahepatic cholangiocarcinoma. No predictive factors are known to enrich for patients most likely to benefit from immunotherapy to date. Additional analysis of patient subgroups in TOPAZ-1 as well as the results of the KEYNOTE-966 phase III study (CisGem +/- pembrolizumab) are eagerly awaited.
Citation Format: Juan W. Valle. Clinical trials and molecular therapies in iCCA [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA25.
Abstract PO014: Genome-wide mapping of oncogenic pathways and genetic modifiers of chemotherapy using a high-risk hepatoblastoma genetic model
Authors: Yang Jun 
Published: September 2022

Abstract
Lack of relevant animal models and cell lines of hepatoblastoma hampers our understanding pathogenesis of and identifying therapeutic targets for this neoplasm. We report a liver-specific MYC-driven hepatoblastoma murine model that faithfully recapitulates the pathological features of mixed fetal and embryonal hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of human disease. Single-cell RNA-sequencing (scRNA-seq) and spatiotranscriptomics identified distinct subpopulations of hepatoblastoma cells. After deriving cell lines from the mouse model, we mapped the cancer dependency genes using CRISPR-Cas9 screening and identified druggable targets shared with human hepatoblastoma (i.e., CDK7, CDK9, PRMT1, PRMT5). Our screen also revealed oncogenes and tumor suppressor genes in hepatoblastoma that engage multiple, druggable cancer signaling pathways. Chemotherapy is the mainstay for human hepatoblastoma treatment. A genetic mapping of doxorubicin response by CRISPR-Cas9 screening identified modifiers whose loss-of-function synergizes and antagonizes with the effect of chemotherapy. The combination of PRKDC inhibition and chemotherapy greatly enhances therapeutic efficacy. Our studies have provided and characterized useful resources including disease models and identified potential therapeutic targets of high-risk hepatoblastoma.
Citation Format: Jun Yang. Genome-wide mapping of oncogenic pathways and genetic modifiers of chemotherapy using a high-risk hepatoblastoma genetic model [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO014.
Abstract PO029: Targeting non-canonical Hippo pathway in NRF2-mutant liver cancer
Authors: Sanghvi Viraj , Rust Aleksander , Leibold Josef , Lowe Scott , Viale Agnes , Chodera John , Hendrickson Ronald C. , de Stanchina Elisa , Wendel Hans-Guido 
Published: September 2022

Abstract
NRF2 is an “undruggable” oncogenic transcription factor recurrently mutated in solid tumors such as liver and lung cancers. Our recent study demonstrates that NRF2 acts by coordinating the redox and metabolic stress responses as well as drug resistance programs in liver and other cancers. Developing an NRF2 inhibitor is a major goal of cancer drug discovery. Here, we identify the non-canonical Hippo pathway protein serine/threonine kinase 38 (STK38/NDR1) as a new NRF2 kinase that is a requirement for its stability and function. STK38 directly phosphorylates NRF2 at two sites (S33 and T559), and both sites contribute to full NRF2 activation. Loss of STK38 disables the redox response in NRF2 driven cancers and leads to tumor regression in vivo. Conversely, STK38 can also activate NRF2 and promote de novo liver cancer development in mice. This oncogenic effect is reflected in low frequency (3%) genomic amplifications in human liver cancers. Importantly, inhibition of the upstream STK38-activating mammalian Hippo kinases STK3/4 (MST2/1) by XMU-MP-1 inactivates STK38-NRF2 regulatory axis in vitroand in vivo. More importantly, XMU-MP-1 produces single agent activity against NRF2-driven liver and lung cancers in vivo in primary and patient derived xenograft (PDX)-based mouse models. In addition, we performed an in-silicoscreen and identified TAE-684 as an STK38 inhibitor that was subsequently confirmed to block STK38 activity in an in vitro kinase assay. TAE-684 treatment resulted in significant growth impairment of NRF2-mutant PDXs in vivo but no activity was observed in NRF2 wildtype counterparts. Together, these results uncover a surprising role of Hippo-related kinase STK38 in NRF2 activation and point to a paradoxical vulnerability in NRF2-driven cancers.
Citation Format: Viraj Sanghvi, Aleksander Rust, Josef Leibold, Scott Lowe, Agnes Viale, John Chodera, Ronald C. Hendrickson, Elisa de Stanchina, Hans-Guido Wendel. Targeting non-canonical Hippo pathway in NRF2-mutant liver cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO029.
Microbes Contribute to Chemopreventive Efficacy, Intestinal Tumorigenesis, and the Metabolome
Authors: Ferrara Carmen R. , Bai Ji Dong K. , McNally Erin M. , Putzel Gregory G. , Zhou Xi Kathy , Wang Hanhan , Lang Alan , Nagle Deborah , Denoya Paula , Krumsiek Jan , Dannenberg Andrew J. , Montrose David C. 
Published: September 2022

AbstractBacteria are believed to play an important role in intestinal tumorigenesis and contribute to both gut luminal and circulating metabolites. Celecoxib, a selective cyclooxygenase-2 inhibitor, alters gut bacteria and metabolites in association with suppressing the development of intestinal polyps in mice. The current study sought to evaluate whether celecoxib exerts its chemopreventive effects, in part, through intestinal bacteria and metabolomic alterations. Using ApcMin/+ mice, we demonstrated that treatment with broad-spectrum antibiotics (ABx) reduced abundance of gut bacteria and attenuated the ability of celecoxib to suppress intestinal tumorigenesis. Use of ABx also impaired celecoxib's ability to shift microbial populations and gut luminal and circulating metabolites. Treatment with ABx alone markedly reduced tumor number and size in ApcMin/+ mice, in conjunction with profoundly altering the metabolite profiles of the intestinal lumen and blood. Many of the metabolite changes in the gut and circulation overlapped and included shifts in microbially derived metabolites. To complement these findings in mice, we evaluated the effects of ABx on circulating metabolites in patients with colon cancer. This showed that ABx treatment led to a shift in blood metabolites, including several that were of bacterial origin. Importantly, changes in metabolites in patients given ABx overlapped with alterations found in mice that also received ABx. Taken together, these findings suggest a potential role for bacterial metabolites in mediating both the chemopreventive effects of celecoxib and intestinal tumor growth.Prevention Relevance:This study demonstrates novel mechanisms by which chemopreventive agents exert their effects and gut microbiota impact intestinal tumor development. These findings have the potential to lead to improved cancer prevention strategies by modulating microbes and their metabolites.
New genus and new species in American Apomecynini (Coleoptera, Cerambycidae, Lamiinae)
Authors: Bezark Larry G. , Santos-Silva Antonio 
Published: September 2022

Three new species and one new genus are described in Apomecynini: Adetaptera setigera sp. nov., from Mexico; Osckayia obrieni sp. nov., from Mexico; and Capaciphrynidius extensus, gen. nov., sp. nov., from Honduras.
International Negotiation and Information Technology
Authors: Spector Bertram I. 
Published: September 2022

Abstract
Advances in information technology (IT) have not only become the subject of international negotiation, but also an important channel by which the international negotiation process operates. International agreements have been negotiated to regulate and govern e-commerce, technology transfer, cybersecurity, and electronic communications. As well, IT applications using the internet offer a vehicle for real-time cyber diplomacy, especially when parties cannot gather face-to-face. IT-based analytical tools have also been developed to enable negotiators to better analyze the context and their options for upcoming talks, in addition to testing and simulating the possible implications of alternate strategies and tactics. This thematic issue of International Negotiation updates earlier studies, addressing the impact of IT on negotiation from various angles.
Women in the Ethiopian Pentecostal Movement
Authors: Worku Kebede Daniel 
Published: September 2022

Abstract
In the early 1960s a Pentecostal movement broke out in Ethiopia and formed the Mulu Wongel (the Full Gospel) Church throughout the country. During the free spirited revival at the early stage of the movement and when the church was closed during the socialist regime, women enjoyed key ministerial and leadership positions. However, women ministers were sidelined when peace was restored and an organized body was established. This article is mainly interested in uncovering women’s role in the history of Ethiopian Pentecostal revival and its aftermath based on the information gained from main participants of the movement and important secondary documents. It also underlines the eventual achievement of ministerial equality between men and women despite problems that are still hindering women’s involvement in the higher ministerial posts.
Genomic surveillance of SARS-COV-2 reveals diverse circulating variant lineages in Nairobi and Kiambu Counties, Kenya
Authors: Kuja Josiah O. , Kanoi Bernard N. , Balboa Renzo F. , Shiluli Clement , Maina Michael , Waweru Harrison , Gathii Kimita , Mungai Mary , Masika Moses , Anzala Omu , Mwau Matilu , Clark Taane G. , Waitumbi John , Gitaka Jesse 
Published: September 2022

AbstractGenomic surveillance and identification of COVID-19 outbreaks are important in understanding the genetic diversity, phylogeny, and lineages of SARS-CoV-2. Genomic surveillance provides insights into circulating infections, and the robustness and design of vaccines and other infection control approaches. We sequenced 57 SARS-CoV-2 isolates from a Kenyan clinical population, of which 55 passed quality checks using the Ultrafast Sample placement on the Existing tRee (UShER) workflow. Phylo-genome-temporal analyses across two regions in Kenya (Nairobi and Kiambu County) revealed that B.1.1.7 (Alpha; n = 32, 56.1%) and B.1 (n = 9, 15.8%) were the predominant lineages, exhibiting low Ct values (5–31) suggesting high infectivity, and variant mutations across the two regions. Lineages B.1.617.2, B.1.1, A.23.1, A.2.5.1, B.1.596, A, and B.1.405 were also detected across sampling sites within target populations. The lineages and genetic isolates were traced back to China (A), Costa Rica (A.2.5.1), Europe (B.1, B.1.1, A.23.1), the USA (B.1.405, B.1.596), South Africa (B.1.617.2), and the United Kingdom (B.1.1.7), indicating multiple introduction events. This study represents one of the genomic SARS-CoV-2 epidemiology studies in the Nairobi metropolitan area, and describes the importance of continued surveillance for pandemic control.