bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endovascular treatment for acute ischaemic stroke due to medium vessel occlusion: data from ANGEL-ACT registry
Authors: Sun Dapeng , ­ Raynald , Huo Xiaochuan , Jia Baixue , Tong Xu , Wang Anxin , Ma Gaoting , Ma Ning , Gao Feng , Mo Dapeng , Miao Zhongrong 
Published: September 2022

ObjectivesTo investigate the safety and efficacy of endovascular treatment (EVT) for acute medium vessel occlusion (MeVO) in the anterior circulation and to explore the independent predictors of the 90-day good outcome for such patients.MethodsData from ANGEL-ACT Registry were analysed in our study. The outcomes, such as the modified Rankin Scale (mRS) at 90 days, successful recanalisation rate and symptomatic intracranial haemorrhage (SICH) rate, were compared between MeVO and acute large vessel occlusions (LVO). Then, the independent predictors of the good outcome at 90 days in MeVO patients were determined by the logistic regression analyses.ResultsWe included 1032 subjects in the analysis, of which, 147 were MeVO and 885 were LVO. mRS at 90 days distribution (3 (0–4) vs 3 (0–5), common odds ratio (OR) =1.00, 95% confidence interval (CI) 0.73 to 1.38, p=0.994), SICH rate (4.8% vs 8.9%; OR=0.59, 95% CI 0.26 to 1.34, p=0.205) and successful recanalisation rate (89.8% vs 89.7%; OR=1.00 95% CI 0.51 to 1.93, p=0.992) were similar between the MeVO and LVO groups after adjusting for the confounders. We identified that baseline neutrophil-to-lymphocyte ratio ≤4.1 (OR=2.13, 95% CI 1.14 to 3.99, p=0.019), baseline National Institutes of Health Stroke Scale ≤14 (OR=1.96, 95% CI 1.02 to 3.80, p=0.045) and mechanical thrombectomy passes ≤1 (OR=2.16, 95% CI 1.14 to 4.11, p=0.021) were independent predictors of the 90-day good outcome in MeVO patients undergoing EVT.ConclusionsPatients with MeVO achieved similar 90-day mRS, SICH rate and successful recanalisation rate after EVT compared with patients with LVO. Several independent predictors of 90-day good outcome in MeVO patients undergoing EVT were determined, which should be highly considered in MeVO stroke management.
Thermodynamics of the Reissner–Nordström-de Sitter spacetime with quintessence
Authors: Zhang Yang , Ma Yu-Bo , Du Yun-Zhi , Li Huai-Fan , Zhang Li-Chun 
Published: September 2022

AbstractFor Anti-de Sitte (AdS) black holes, the isochoric heat capacity of system is vanished, while the isobaric heat capacity is not. However, this situation does not hold on for de Sitter (dS) black holes. In this work, by introducing the interaction between the black hole horizon and the cosmological horizon of the Reissner–Nordström-de Sitter (RNdS) spacetime with quintessence, we discuss the phase transition of this system. The results show that the spacetime not only has the similar phase transition behavior to that of Van der Waals (VdW) system, and the non-vanishing isochoric heat capacity fulfills the whole thermodynamics system. Through the discussion of the entropic force between two horizons, we find out the role of entropic force in the evolution of spacetime. In addition, we also study the influence of various parameters on the phase transition and entropic force, which will provide a new method for exploring the interaction among black hole molecules from a micro perspective.
Abstract IA01: Molecular drivers in hepatocellular carcinoma: The story of what we know and what are we missing
Authors: Zucman-Rossi Jessica 
Published: September 2022

Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, both at the molecular and histological level. High-throughput sequencing and gene expression profiling have identified distinct transcriptomic subclasses and recurrently altered cancer driver genes. Several HCC subtypes characterized by histological features have also been identified. HCC phenotype appears to be closely related to particular gene mutation and driven by various oncogenic pathway alterations. Identification of the origin of HCC development and their trajectory of progression is important to understand tumor evolution and to identify the mechanisms of tumor response or resistance to therapies. We will review the early and late molecular alterations driving HCC occurrence and progression of tumors in the context of patient lifespan and exposure to environmental factors. Several questions remain to be answered, in particular on the identification of the cells at the origin of the malignant transformation into HCC and the mechanism of escape to the immunological monitoring.
Citation Format: Jessica Zucman-Rossi. Molecular drivers in hepatocellular carcinoma: The story of what we know and what are we missing [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 IA01.
Abstract IA03: Polyploidy, DNA damage response driver or gatekeeper of chronic liver diseases
Authors: Desdouets Chantal 
Published: September 2022

Abstract
Polyploidy, also known as whole-genome amplification, is a condition in which the organism has more than the two basic sets of chromosomes. Polyploidy frequently arises during tissue development and repair, and in age-associated diseases, such as cancer. Its consequences are diverse and clearly different between systems. The liver is a particularly fascinating organ in that it can adapt its ploidy to the physiological and pathological context. In human liver parenchyma, polyploidy is mainly cellular (binuclear hepatocytes) with no specific zonation across the liver lobule. During liver tumorigenesis, cellular ploidy is drastically reduced; binuclear polyploid hepatocytes are barely present in HCC tumors. Remarkably, nuclear ploidy is specifically amplified in HCC tumors. In fact, nuclear ploidy is amplified in HCCs harboring a low degree of differentiation and TP53 mutations. Highly polyploid tumors are associated with a poor prognosis. Hepatocytes increase their ploidy also during the proliferative stress that underlies various liver disease conditions. Recently, we investigated mechanisms underlying activation of the DNA damage response during Non-alcoholic Steatotic Liver Disease. We demonstrated that proliferating mouse NAFLD hepatocytes harbor replication stress with an alteration of the replication fork’s speed and activation of ATR pathway which is sufficient to cause DNA breaks. Nucleotide pool imbalance occurring during NAFLD is the key driver of replication stress. Remarkably, DNA lesions drive cGAS/STING pathway activation, a major component of cells’ intrinsic immune response. The translational significance of this study was reiterated by showing that lipid overload in proliferating HepaRG was sufficient to induce replication stress and nucleotide pool imbalance. Moreover, livers from NAFLD human patients displayed nucleotide pathways deregulation and cGAS/STING genes alteration. Altogether, our findings shed new light on the mechanisms by which damaged NAFLD hepatocytes might promote disease progression.
Citation Format: Chantal Desdouets. Polyploidy, DNA damage response driver or gatekeeper of chronic liver diseases [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 IA03.
Abstract IA11: Molecular targeted therapies for advanced HCC
Authors: Llovet Josep M. 
Published: September 2022

Abstract
Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. Current major advancements have impacted the management of patients with advanced HCC substantially improving their life expectancy. Several systemic therapies have resulted in positive III investigations (atezolizumab plus bevacizumab, durvalumab plus tremelimumab, sorafenib, lenvatinib, regorafenib, cabozantinib and ramucirumab) and two additional therapies obtained accelerated FDA approval owing to evidence of efficacy (pembrolizumab and nivolumab plus ipilimumab). Specifically, among TKIs, sorafenib and lenvatininb remain as first line option therapies in patients with contraindications or upon progression to immunotherapies. In second-line, regorafenib, cabozantinib and ramucirumab are the accepted choices. Few studies suggest that biomarkers or treatment related-AEs are associated with better outcome, as it is the case with hand-foot skin reaction with sorafenib, or AFP&gt; 400 ng/ml or hypertension for ramucirumab. The fact that most HCC do not have a dominant actionable target has prevented precision oncology. Nonetheless, current studies are exploring abrogating main drivers previously unactionable, such as wnt signaling. The fact that TKI and VEGF-based MAb have also immunomodulatory activities has boosted their combination with immune therapies which nowadays are dominant in the landscape of management of HCC and ongoing phase III trials.
Citation Format: Josep M. Llovet. Molecular targeted therapies for advanced HCC [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 IA11.
Abstract IA20: Combination therapies including checkpoint inhibitors in HCC: the dawn of a new era
Authors: Finn Richard S. 
Published: September 2022

Abstract
After a decade of stalled progress in the medical management of advanced HCC we have seen rapid progress in improving survival for patients with advanced HCC. We have gone from incremental improvements with sequencing multi-kinase inhibitors to significant gains with immunotherapy-based combinations. Arguably, the success of combinations is driven by the increased response rates seen with this approach as compared to the challenges seen with single agent checkpoint inhibitors. Until biomarkers of response are identified, the continued development of new combinations will still be driven an all-comers approach, with the empiric addition of new agents to already established doublets. These new combinations will likely benefit from lessons learned in other diseases where immune checkpoint inhibitors have been used for much longer periods of time (melanoma, lung cancer). The challenge though, is when we look at progress in these other diseases, the next combination to move things forward is yet to be determined, whether in the front-line setting, or after progression on IO. Ongoing translational studies are offering insights into the mechanisms by which we are seeing increased activity with combinations, but the clinical utility of these data have not yet been determined. In the lecture we will review the data as it stands today and offer thoughts on the next generation of studies with systemic therapy in HCC.
Citation Format: Richard S. Finn. Combination therapies including checkpoint inhibitors in HCC: the dawn of a new era [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 IA20.
Abstract IA23: Molecular landscapes of hepatocellular carcinoma and cholangiocarcinoma
Authors: Wang Xin Wei 
Published: September 2022

Abstract
Liver cancer is among the top five deadliest cancers in the world, especially in Southeast Asia and Sub-Saharan Africa, and its incidence rates continue to increase in recent decades. Despite considerable efforts towards the development of new prevention, diagnosis and treatment strategies, the improvement of cancer survival is modest. Defined as the unique genotypic and phenotypic differences of cancer cells within a single tumor (intra-tumor) or amongst different patients (inter-tumor), tumor heterogeneity has consistently been linked to worse clinical outcomes in liver cancer. Primary liver cancer mainly consists of two clinical types, i.e., hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), each of which could be further divided into several clinical and molecular subtypes. Chronic liver diseases due to viral hepatitis, alcohol consumption, chemical carcinogens, or nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, are major global health burdens that increase the risk of HCC while parasitic infections may be linked to CCA. It is unclear how complex etiological factors determine tumor subtypes and whether common features may be shared among HCC and CCA. Given the presence of so many clinical and molecular variables, it is imperative to develop well-defined cohorts that include diverse etiologies, race/ethnicities, sex and age, which provides an unbiased platform by minimizing confounding factors to study liver cancer types. Accordingly, we have established several national and international collaborative projects, including the NCI-CLARITY study, the NCI-UMD cohort study, the NCI-Mongolian cohort study, and the TIGER-LC (Thailand) consortium. We have applied molecular-based technologies such as genomics, transcriptomics, metabolomics and microbiomics, including single-cell omics to comprehensively analyze biopsies from diverse populations, in order to better characterize heterogeneity among and within patients, to further define tumor molecular subtypes with unique tumor biology and to understand tumor evolution in response to treatment. These studies have led to the discovery of new cell types and drivers in HCC and CCA, potential new mechanisms of therapy resistance and tumor progression, and new insights into the evolutionary patterns of liver cancer. Our past and future ability to translate our research findings towards patient management through the identification of molecular-based knowledge for understanding of liver cancer pathophysiology with the application of early detection and treatment of liver cancer may have a considerable impact on clinical practice and public health.
Citation Format: Xin Wei Wang. Molecular landscapes of hepatocellular carcinoma and cholangiocarcinoma [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 IA23.
Abstract IA27: Trial Design in the era of precision oncology and combination therapies
Authors: Bridgewater John 
Published: September 2022

Abstract
Clinical studies in precision medicine have tested the long-standing conventional model built around the randomized phase 3 study. Multiple uncertainties with respect to incidence, molecular profiling and realistic level of evidence have challenged tried and tested paradigms for trialists, clinicians and reimbursement authorities. I will discuss how we determine the incidence of uncommon subgroups of uncommon cancers, the definition of these subgroups using bespoke clinical and molecular criteria, the availability, efficacy and heterogeneity of molecular testing, the availability of specialists, the quality of the data in order to permit reimbursement and the sustainability of treating patients in the era of precision medicine. With the continuing evolution of precision medicine, old dogs will have to become familiar with many new tricks.
Citation Format: John Bridgewater. Trial Design in the era of precision oncology and combination therapies [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 IA27.
Abstract PO002: Pretreatment immune cell composition and checkpoint ligand expression define the response to immunotherapy in advanced HCC: a study using single-cell sequencing
Authors: Cappuyns Sarah , Philips Gino , Vandecaveye Vincent , Verslype Chris , Van Cutsem Eric , Lambrechts Diether , Derkervel Jeroen 
Published: September 2022

Abstract
The novel combination of atezolizumab/bevacizumab has demonstrated unprecedented response rates in a subgroup of advanced hepatocellular carcinoma (aHCC) patients. In order to understand why only a subset of aHCC patients respond to immunotherapy targeting the PD-1/PD-L1 axis, we subjected pre-treatment tissue biopsies from 31 aHCC patients, with mainly non-viral etiologies, to simultaneous single-cell transcriptome (scRNAseq) and T-cell receptor (scTCRseq) sequencing, providing an integrative view of the tumor-microenvironment of aHCC (n=91 169 cells). The therapeutic targets, PD-1 and PD-L1 are expressed in tumor-infiltrating T-cells versus myeloid cells and tumor cells, respectively. Myeloid cells in tumors responding to immunotherapy (according to mRECIST) express significantly higher levels of PD-L1 (p=0.014) compared to non-responders and this is driven by pro-inflammatory PD-L1 expressing CXCL10+ macrophages, involved in T-cell recruitment. In contrast, non-responding tumors are infiltrated by immature CX3CR1+ macrophages and CCR2+ ‘monocyte-like’ macrophages (p=0.009 and p=0.01, respectively). Interestingly, the composition of tumor-infiltrating T-cells did not differ significantly between patient groups. However, responding tumors were characterized by a more clonal baseline T-cell receptor repertoire (p=0.007). Single-cell T-cell receptor sequencing revealed that this clonality was present in activated, effector T-cells, while non-responders had a higher proportion of non-clonal T-cells (p=0.01) concentrated within naïve and memory-like T-cell phenotypes. In conclusion, this is the first and largest aHCC cohort to correlate single-cell sequencing data with clinical outcomes. Prior to treatment, differences in abundancy and ligand expression in small clusters of immune cells as well as difference in baseline T-cell clonality drive response to checkpoint inhibition in aHCC.
Citation Format: Sarah Cappuyns, Gino Philips, Vincent Vandecaveye, Chris Verslype, Eric Van Cutsem, Diether Lambrechts, Jeroen Derkervel. Pretreatment immune cell composition and checkpoint ligand expression define the response to immunotherapy in advanced HCC: a study using single-cell sequencing [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 PO002.
Abstract PO005: Obesity-associated Visfatin, and Silibinin in an In Vitro and In Vivo Model of Liver Cancer
Authors: Pedone Elisa , Green Kelly N , Thornton Kelly R , Price Ramona S. 
Published: September 2022

Abstract
Introduction: Obesity, specifically body fatness, is a risk factor for the development of liver cancer. The link between obesity and liver cancer is likely to be mediated in part by a state of chronic inflammation. However, it has yet to be determined if visfatin inhibition, a pro-inflammatory adipocytokine upregulated by obesity, is sufficient to prevent or delay the progression of liver cancer. Obesity-induced inflammatory factors may promote cancer progression by increasing cell proliferation, motility, invasion, and metastasis.The use of dietary compounds may break the pro-inflammatory cycle induced by the obese state, thus attenuating the cancer process. Silibinin, a polyphenol in milk thistle seed, has been shown to have anti-inflammatory properties. Studies have yet to determine whether silibinin can be used to break the obesity-cancer link to delay progression of liver cancer. The objective of this cell culture and mouse study is to determine the efficacy of silibinin in the prevention of obesity-associated liver cancer progression. Methods: SNU-449 and HepG2 liver cancer cells were exposed to the following experimental conditions; control, FBS, visfatin (80 ng/ml), visfatin + silibinin 40 μM, silibinin (40 μM). Cell proliferation, lipogenesis, lactate dehydrogenase secretion, and ROS production were measured. Immunoblot was used to measure phospho-Akt, phospho-Erk, NF-kB, Bcl-xL, and actin. Eight-week-old C57BL/6J male mice were randomized to a high-fat DIO (n=6) or control diet (n=6). At 14 weeks, mice will be injected subcutaneously with syngeneic Hepa1-6 murine liver cancer cells. At 15-weeks, mice will receive peritoneal injections of silibinin 3 times per week for 2 weeks. Tumors will be measured and assessed for visfatin, Akt, Erk, and NF-kB protein expression. Results from the animal study are on-going and will be presented at time of the conference. Results: SNU-449 and HepG2 cells exposed to visfatin significantly increased cell proliferation and lipogenesis when compared to control. Further, the addition of silibinin inhibited the visfatin-induced proliferation and lipogenesis in both cell lines. Visfatin increased the phosphorylation of Akt and Erk, and NF-kB expression in both liver cancer cell lines. The addition of silibinin differently suppressed phosphorylation of Akt and Erk in SNU-449 and HepG2 cells. Conclusion: Silibinin differentially inhibits visfatin-induced cell growth, lipogenesis, and promotes cytotoxicity which may lead to increased cancer cell death.
Citation Format: Elisa Pedone, Kelly N Green, Kelly R Thornton, Ramona S. Price. Obesity-associated Visfatin, and Silibinin in an In Vitro and In Vivo Model of 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 PO005.
Abstract PO017: HBV alters YAP regulation in liver cancer by remodeling PP2A complexes
Authors: Gordan John , Pitea Adriana , Turnham Rigney E , Eckhardt Manon , Jang Gwendolyn M , Lim Huat , Choi Alex L , Bandyopadhyay Sourav , Swaney Danielle , Shokat Kevan , Ideker Trey , Krogan Nevan 
Published: September 2022

Abstract
Viral hepatitis promotes hepatocellular carcinoma (HCC) initiation by inducing inflammation, cellular stress and cell death. However, the cell-intrinsic effects of viral infection in advanced HCC remain unclear. We used affinity purification mass spectrometry to develop a complete map of 145 interactions among Hepatitis B Virus (HBV) and host proteins in the HUH7 HCC tumor cell line, identifying known and novel HBV/host protein-protein interactions. We integrated this map with HCC genomes, identifying 61 proteins with preferential mutation in non-HBV HCC, suggesting that their interaction with HBV plays a role in cancer. Focusing on proteins that directly interact with the HBV oncoprotein X (HBx), we found that HBx rewires the effect of the PP2A phosphatase on HCC signaling. HBx binding excluded striatin-family regulatory subunits from the PP2A complex, causing Hippo kinase activation. This effect creates a requirement for integrin signaling to mTOR complex 2 to maintain expression of the YAP oncoprotein, critical for HCC growth. Thus, HBV rewires HCC signaling and may promote targetable dependencies.
Citation Format: John Gordan, Adriana Pitea, Rigney E Turnham, Manon Eckhardt, Gwendolyn M Jang, Huat Lim, Alex L Choi, Sourav Bandyopadhyay, Danielle Swaney, Kevan Shokat, Trey Ideker, Nevan Krogan. HBV alters YAP regulation in liver cancer by remodeling PP2A complexes [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 PO017.