bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term evaluation parameters in GNE myopathy: a 5-year observational follow-up natural history study
Authors: Mori-Yoshimura Madoka , Yajima Hiroyuki , Oya Yasushi , Mizuno Katsuhiro , Noguchi Satoru , Nishino Ichizo , Takahashi Yuji 
Published: December 2022

BackgroundA number of clinical trials targeting GNE myopathy patients have been conducted. However, useful clinical parameters for postmarketing surveillance and long-term clinical observation have not yet been established.ObjectiveWe conducted a 5-year observational follow-up natural history study to identify evaluation parameters, which may be useful for the long-term observation of GNE myopathy patients.MethodsThirty-three genetically confirmed GNE myopathy patients were recruited and evaluated at study entry (baseline) and yearly in a 5-year follow-up. Hand-held dynamometer measurements of knee extension strength, grip power and pinch power, summed Manual Muscle Testing (MMT) score of 17 muscles, Gross Motor Function Measure (GMFM), 6 min walk test, percent vital capacity and percent forced vital capacity (%FVC), lean body mass (whole body, arms and legs), creatine kinase, Barthel Index, modified Rankin Scale and 36-item Short Form Survey national standard scores were examined.ResultsOf the 33 patients, 22 (66%) completed evaluations for the entire 5-year follow-up period. These patients had a significant reduction in summed MMT score (p=0.005), GMFM (p=0.005), pinch power (p<0.001) and %FVC (p<0.001) at the fifth year evaluation relative to baseline. Among these parameters, summed MMT score, GMFM, pinch power and %FVC showed significant changes even in non-ambulant patients.ConclusionsMMT, GMFM, pinch power and %FVC are useful parameters for the long-term evaluation of GNE myopathy patients.
Influence of prior intravenous thrombolysis in patients treated with mechanical thrombectomy for M2 occlusions: insight from the Endovascular Treatment in Ischemic Stroke (ETIS) registry
Authors: Le Floch Agathe , Clarençon Frédéric , Rouchaud Aymeric , Kyheng Maeva , Labreuche Julien , Sibon Igor , Boulouis Gregoire , Gory Benjamin , Richard Sébastien , Caroff Jildaz , Blanc Raphaël , Seners Pierre , Eker Omer F , Cho Tae-Hee , Consoli Arturo , Bourcier Romain , guillon benoit , Dargazanli Cyril , Arquizan Caroline , Denier Christian , Eugene Francois , Vannier Stephane , Gentric Jean-Christophe , Gauberti Maxime , Naggara Olivier , Rosso Charlotte , Turc Guillaume , Ozkul-Wermester Ozlem , Cognard Christophe , Albucher Jean François , Timsit Serge , Bourdain Frederic , Le Bras Anthony , Richter Sebastian , Moulin Solène , Pop Raoul , Heck Olivier , Moreno Ricardo , L'Allinec Vincent , Lapergue Bertrand , Marnat Gaultier 
Published: December 2022

BackgroundIntravenous thrombolysis (IVT) for patients treated with mechanical thrombectomy (MT) for proximal occlusions has recently been questioned through randomized trials. However, few patients with M2 occlusions were included. We investigated the influence of prior IVT for patients presenting M2 occlusions treated with MT in comparison with MT alone.MethodsWe conducted a retrospective analysis of the Endovascular Treatment in Ischemic Stroke (ETIS) registry, a multicenter observational study. Data from consecutive patients treated with MT for M2 occlusions between January 2015 and January 2022 at 26 comprehensive stroke centers were analyzed. The primary endpoint was 90-day modified Rankin Scale score of 0–2. Outcomes were compared using propensity score approaches. We also performed sensitivity analysis in relevant subgroups of patients.ResultsAmong 1132 patients with M2 occlusions treated with MT, 570 received prior IVT. The two groups were comparable after propensity analysis. The rate of favorable functional outcome was significantly higher in the IVT+MT group compared with the MT alone group (59.8% vs 44.7%; adjusted OR 1.38, 95% CI 1.10 to 1.75, P=0.008). Hemorrhagic and procedural complications were similar in both groups. In sensitivity analysis excluding patients with anticoagulation treatment, favorable recanalization was more frequent in the IVT+MT group (OR 1.37, 95% CI 1.11 to 1.70, P=0.004).ConclusionsIn cases of M2 occlusions, prior IVT combined with MT resulted in better functional outcome than MT alone, without increasing the rate of hemorrhagic or procedural complications. These results suggest the benefit of IVT in patients undergoing MT for M2 occlusions.
Review of recent developments of the functional renormalization group for systems out of equilibrium
Authors: Camacho G. , Klöckner C. , Kennes D. M. , Karrasch C. 
Published: December 2022

AbstractWe recapitulate recent developments of the functional renormalization group (FRG) approach to the steady state of systems out of thermal equilibrium. In particular, we discuss second-order truncation schemes which account for the frequency-dependence of the two particle vertex and which incorporate inelastic processes. Our focus is on two different types of one-dimensional fermion chains: (i) infinite, open systems which feature a translation symmetry, and (ii) finite systems coupled to left and right reservoirs. In addition to giving a detailed and unified review of the technical derivation of the FRG schemes, we briefly summarize some of the key physical results. In particular, we compute the non-equilibrium phase diagram and analyze the fate of the Berezinskii–Kosterlitz–Thouless transition in the infinite, open system.Graphic abstract
Abstract B006: PBRM1-deficient PBAF complexes target de novo genomic loci to activate NF-κB pathway in kidney cancer
Authors: Yao Xiaosai , Hong Jing Han , Nargund Amrita , Teh Bin Tean 
Published: December 2022

Abstract
Polybromo-1 (PBRM1) is the second most commonly mutated gene in kidney cancer after VHL, occurring at a frequency of 30-40%. PBRM1 loss represents a tumor-initiating event and the combined loss of VHL and PBRM1 is necessary and sufficient for renal malignancy. Functionally, PBRM1 is the defining subunit of the polybromo BRG1-associated factor (PBAF) subclass of SWItch/Sucrose Non-Fermentable (SWI/SNF) remodeling complex which regulates chromatin accessibility by sliding, depositing or evicting nucleosomes. Determining context-specific chromatin remodeling by PBRM1 is paramount to understanding how PBRM1 deficiency drives kidney tumorigenesis. We compared the association of SWI/SNF subunits in the presence or absence of PBRM1 and found that PBRM1 loss resulted in a PBAF complex that has undergone alterations in its configuration and targeting specificity: First, the histone binding lobe disengages from the central ATPase subunit. Second, the PBRM1-deficient complexes, despite retaining the DNA binding lobe, occupy aberrant sites, redistributing from promoter proxy regions to distal enhancer regions. The aberrant sites mapped to regions enriched for NF-κB motifs. Indeed, PBRM1-deficient tumors show enhanced NF-κB activity across isogenic tumor models, genetically modified mouse models and clinical samples. We believe that the PBRM1-deficient PBAF complexes enhance the recruitment of nuclear factor RELA, a subunit of the NF-κB complex - this recruitment requires the ATPase function of the SWI/SNF complexes since BRG1/BRM ATPase inhibitor dampens the expression of NF-κB target genes and RELA chromatin occupancy. Proteasome inhibitor bortezomib reverses NF-κB activity by reducing RELA binding at regions bound by PBRM1-deficient PBAF and delays PBRM1-deficient tumor growth. In conclusion, the PBRM1 tumor suppressor safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes. Inhibition of NF-κB activity by bortezomib could be a therapeutic strategy for PBRM1-deficient kidney cancer.
Citation Format: Xiaosai Yao, Jing Han Hong, Amrita Nargund, Bin Tean Teh. PBRM1-deficient PBAF complexes target de novo genomic loci to activate NF-κB pathway in kidney cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B006.
Abstract IA008: Chromatin regulation by reversible chromatin-associated RNA methylation
Authors: He Chuan 
Published: December 2022

Abstract
Over 150 types of post-transcriptional RNA modifications have been identified in all kingdoms of life. We have previously discovered two RNA demethylases, FTO and ALKBH5, which catalyze oxidative demethylation of the most prevalent modifications of mammalian messenger RNA (mRNA) and other nuclear RNA, N6-methyladenosine (m6A). We have also characterized reader proteins that preferentially recognize methylated transcripts to facilitate either decay or translation of these target RNAs. Most recently we have discovered m6A methylation of chromatin-associated regulatory RNAs (carRNAs), which modulates chromatin state and transcription in mouse embryonic stem cells (mESCs). These findings suggest that reversible RNA modification could impact chromatin regulation analogous to the reversible DNA and histone chemical modifications. I will present recent mechanistic investigation of chromatin and transcription regulation through m6A methylation and demethylation, and impacts on mammalian development and cancer progression.
Citation Format: Chuan He. Chromatin regulation by reversible chromatin-associated RNA methylation. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA008.
Abstract IA019: Ectopic levels of low-complexity domain interactions repress endogenous oncogenic transcription
Authors: Chong Shasha 
Published: December 2022

Abstract
Mammalian transcription factors (TFs) ubiquitously contain intrinsically disordered low-complexity domains (LCDs) that perform transactivation functions. Recent studies have shown that dynamic, multivalent, and selective interactions between TF LCDs play an essential role in transactivation, but how such interactions mediate gene transcription remains unclear. It has been proposed that liquid-liquid phase separation (LLPS) of TFs driven by extensive LCD-LCD interactions is the mechanism underlying transactivation. Here, we investigate how tuning the level and localization of LCD-LCD interactions in vivo affects transcription of endogenous human genes. By quantitative single-cell imaging, we reveal that efficient gene activation by the oncogenic TF EWS/FLI1 requires narrow optimum of LCD-LCD interactions at its target genes associated with GGAA microsatellites. Increasing LCD-LCD interactions toward putative LLPS represses transcription of these genes in Ewing sarcoma cells. Likewise, ectopically creating LCD-LCD interactions to sequester EWS/FLI1 into a well-documented LLPS compartment, the nucleolus, represses EWS/FLI1 -driven transcription and inhibits malignant transformation of Ewing sarcoma. In addition, using live-cell single-molecule imaging, we show that a TF diffuses significantly more slowly in the nucleolus than in the nucleoplasm, demonstrating an important impact of LLPS on TF dynamic behaviors and single-molecule diffusion measurement as an effective approach to diagnose LLPS in vivo. Our findings show how altering the balance of LCD-LCD interactions can influence transcriptional regulation and suggest a potential therapeutic strategy for targeting disease-causing TFs.
Citation Format: Shasha Chong. Ectopic levels of low-complexity domain interactions repress endogenous oncogenic transcription. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA019.
Abstract A004: Molecular adenoma features to predict metachronous colorectal cancer risk: A nested-case control study
Authors: Jodal Henriette C. , Akwiwu Eddymurphy U. , Leon Leticia G. , Lemmens Margriet , Delis-van Diemen Pien , Klotz Dagmar , de Wit Meike , Fijneman Remond , van Leerdam Monique , Dekker Evelien , Spaander Manon C. W. , Meijer Gerrit A. , Bretthauer Michael , Løberg Magnus , Coupé Veerle M. H. , Kalager Mette , Carvalho Beatriz 
Published: December 2022

Abstract
Introduction: In colorectal cancer (CRC) surveillance, adenoma characteristics such as size, number of adenomas, dysplasia, and villous components, are used as indicators for risk of developing metachronous cancer and guide the surveillance interval. The current risk groups (e.g., advanced adenomas) cannot optimally distinguish high risk from low risk, which may result in suboptimal surveillance strategies. Specific DNA copy number aberrations are associated with risk of colorectal adenoma-to-carcinoma progression, but these aberrations are present in only a subset of advanced adenomas. Therefore, we hypothesize that specific DNA copy number aberrations may better predict the risk of CRC than advanced adenoma. Aim: To evaluate whether a molecularly-defined high-risk adenoma is a better risk factor for CRC than the presently used advanced adenoma. Materials and methods: DNA copy number profiles were determined, by means of low-coverage whole genome sequencing, on a series of 529 adenomas, selected from a Norwegian adenoma cohort. We retrieved detailed information on adenoma characteristics and whether adenoma patients were subsequently diagnosed with CRC or not. By univariate and multivariate regression analysis we estimated the odds ratio for association between the development of CRC and baseline presence of advanced adenoma versus presence of a molecularly-defined high-risk adenoma, respectively. Results: Molecular high-risk features were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. The odds ratio for developing metachronous CRC was 3.58 (p=2.84E-8) and 1.90 (p=0.012), when an advanced adenoma or molecular high-risk adenoma was detected at the baseline colonoscopy, respectively. In the multivariate regression analysis only advanced adenoma was as a significant risk factor for CRC. Conclusion: Molecularly-defined high-risk adenomas are associated with an increased risk of CRC. However, the advanced adenoma is a stronger predictor for risk of CRC.
Citation Format: Henriette C. Jodal, Eddymurphy U. Akwiwu, Leticia G. Leon, Margriet Lemmens, Pien Delis-van Diemen, Dagmar Klotz, Meike de Wit, Remond Fijneman, Monique van Leerdam, Evelien Dekker, Manon C. W. Spaander, Gerrit A. Meijer, Michael Bretthauer, Magnus Løberg, Veerle M. H. Coupé, Mette Kalager, Beatriz Carvalho. Molecular adenoma features to predict metachronous colorectal cancer risk: A nested-case control study [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A004.
Abstract PR007: Intestinal intraepithelial T cells limit colorectal cancer progression
Authors: Ghilas Sonia , Raghu Dinesh , Tran Kelly , Liao Yang , Pal Bhupinder , Sterle Shoukat , Dijkstra Christine , Yakou Marina , Parathan Pavitha , Mariadason John , Ernst Matthias , Behren Andreas , Drummond Grant , Shi Wei , Mielke Lisa A. 
Published: December 2022

Abstract
Homeostasis in the gut is achieved by impeccable functioning of tissue resident immune cells that reside and closely interact with the epithelium. The tissue resident immune cells of the intestinal epithelium are predominantly lymphocytes, known as intraepithelial lymphocytes (IELs) and mainly consist of TCRαβ T cells and TCRgd T cells. These IELs are well known to sense microbes, nutrients, and cellular stress but their role in intestinal cancer progression has been controversial. On one hand, gd Τ cells are the primary source of IL-17, an important proinflammatory cytokine that aid in colorectal cancer (CRC) progression. On the other hand, mice lacking gd Τ cells have been showed to have an increased risk of developing carcinogen-induced CRC. Here we used two different mouse model of colon cancer to investigate the role of gd T IELs in colon tumor growth. We showed that in both orthotopic implantation of cancer cells in the colon, and inflammation-driven colon cancer models, gd T cells are essentials to limit tumor growth. Indeed, mice lacking gd T cells had increased tumor incidence with high-grade adenomas compared to control mice. We also performed gene expression analysis of the adenomas in control mice and in mice lacking gd T cells. They revealed distinct transcription profiles with CRC-associated gene expression profile, including inflammatory genes and epithelial to mesenchymal transition genes, particularly enriched in adenomas from gd T cell deficient mice. Moreover, using human tissue microarrays, we investigated whether the presence of gd T cells in tumors of patients with advanced CRC could be used to predict disease outcomes. We revealed that patient disease-free survival was improved if gd T cells could be detected within tumors. Therefore, we showed that gd T cells are primordial in limiting colorectal cancer progression in both mice and humans.
Citation Format: Sonia Ghilas, Dinesh Raghu, Kelly Tran, Yang Liao, Bhupinder Pal, Shoukat Sterle, Christine Dijkstra, Marina Yakou, Pavitha Parathan, John Mariadason, Matthias Ernst, Andreas Behren, Grant Drummond, Wei Shi, Lisa A. Mielke. Intestinal intraepithelial T cells limit colorectal cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr PR007.
Abstract A05: ARF6 inhibition enhances T cell-mediated cytotoxicity in triple negative breast cancer
Authors: Moulana Ishara , Lu Xiongbin 
Published: December 2022

Abstract
Triple negative breast cancer (TNBC) has the poorest clinical outcome owing to the lack of effective treatments out of all the breast cancer subtypes. Immune checkpoint blockade (ICB) therapies have shown promise in these patients but only a small proportion of patients respond to ICB therapy partly due to immune evasion. A primary mechanism by which tumor cells evade immune surveillance is downregulation of antigen presentation by decreasing the levels of antigen-MHC-I (major histocompatibility complex-I) complexes on the cancer cell surface. However, there are no known targets that would boost antigen presentation in the tumor cells and increase T cell functionality simultaneously to increase the efficacy of ICB therapy. The small GTPase ARF6 has been implicated in the internalization of MHC-I molecules into the cell. Additionally, ARF6 also plays a role in CD8+ T cell activation by reorganization of the actin cytoskeleton and inhibits the formation of the immunological sypnase. We hypothesize that by inhibiting ARF6 in both tumor cells and CD8+ T cells, T cell-mediated cytotoxicity would be increased. In cancer cells, ARF6 inhibition will inhibit endocytosis of MHC-I complexes and enhance antigen presentation, while in CD8+ T cells, Arf6 inhibition will promote the formation of the immunological synapse. We tested the dose-dependent effect of an ARF6 inhibitor NAV-2729 on the GTPase activity of ARF6 in tumor cells as it specifically inhibits ARF6 by blocking its GTP-binding domain. We observed a dose-dependent decrease in ARF6-GTP levels with NAV-2729 treatment. To this end, we inhibited ARF6 via the small molecule inhibitor NAV-2729 or knockdown by shRNA in murine and human TNBC cells and found that antigen presentation is enhanced when MHC-I mean fluorescence intensity (MFI) was measured by flow cytometry. We also inhibited ARF6 in CD8+ T cells by NAV-2729 pretreatment, activated them in vitro and measured their functionality by flow cytometry. Interestingly, inhibitor treatment led to higher IFNg, TNFa and IL2 production. In a T cell cytotoxicity assay, we observed increased T cell cytotoxicity in the coculture of T cells and tumor cells when either the tumor cells or CD8+ T cells were treated with inhibitor. Collectively, we show here that ARF6 inhibition in tumor cells and CD8+ T cells will enhance tumor cell killing due to enhanced antigen presentation and T cell functionality respectively. These results give us more insight into the use of Arf6 inhibitors in combination with ICB therapy, thus enhancing treatment efficacy.
Citation Format: Ishara Moulana, Xiongbin Lu. ARF6 inhibition enhances T cell-mediated cytotoxicity in triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A05.
Abstract A19: The joint effect of HLA class I and II alleles shapes antitumor immunity in melanoma patients
Authors: Papp Benjamin Tamás , Fülöp Anna Tácia , Koncz Balázs , Balogh Gergő Mihály , Spekhardt Dóra , Manczinger Máté 
Published: December 2022

Abstract
Neopeptide presentation to T cells by both HLA class I and II molecules is necessary for antitumor immune response. Both classes are extremely diverse and different variants have distinct peptide-binding specificities. HLA diversity and certain HLA variants have been suggested to influence antitumor immunity, however, the findings are controversial. As both HLA class I and II molecules have an essential role in the recognition of tumor cells, we examined their joint effect in melanoma patients. We found numerous HLA class I and II allele combinations associated with better or worse survival in metastatic melanoma patients receiving immune checkpoint blockade (ICB) immunotherapy. Moreover, these combinations predicted the survival of ICB-naive patients, too. Importantly, allele combinations had a much stronger and more robust effect than any HLA class I or II variants alone. In the case of beneficial combinations, both HLA class I and II alleles were likely to bind melanoma-associated mutations. Paradoxically, they bound these mutations even stronger in detrimental combinations. Beneficial and detrimental combinations had a diametrical effect on antitumor immune response in primary and metastatic samples. The former was associated with dendritic cell infiltrate in the microenvironment of primary tumors and an active cytotoxic immune response in metastatic samples. On the contrary, detrimental combinations were associated with cytotoxic immune response in primary tumors, while metastases showed signs of immune evasion and ineffective antitumor immunity. Our results provide evidence of the joint effect of HLA class I and II variants on antitumor immunity. The findings also highlight the importance of the timing of immune response during tumor evolution. While beneficial combinations resulted in an effective immune response in metastases only, detrimental ones caused excessive inflammation already in primary tumors leading to immune evasion in metastatic samples.
Citation Format: Benjamin Tamás Papp, Anna Tácia Fülöp, Balázs Koncz, Gergő Mihály Balogh, Dóra Spekhardt, Máté Manczinger. The joint effect of HLA class I and II alleles shapes antitumor immunity in melanoma patients [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A19.