bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6273: CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting MTAP-deleted human tumors
Authors: Wang Long , Liu Yilin , Shi Hui , Liu Yuanyuan , Ouyang Qiugeng , Guo Jiannan , Wang Yiqin , Wang Youzhen , Xu Guoliang , Mi Yuan , Wu Haiping 
Published: April 2023

Abstract
MTAP deletion is common in about 15% of all human cancers and coincides with the deletion of tumor suppressor locus containing CDKN2A/B. Methylthioadenosine (MTA), the substrate of MTAP, accumulates as a result of MTAP deletion. Increased levels of MTA result in partial inhibition of the PRMT5 enzyme by competing with S-adenosylmethionine (SAM, the methyl donor for PRMT5 substrate) due to structural similarity. Cancer cell lines with MTAP-deletion exhibit profound sensitivity to PRMT5 inhibition, suggesting MTAPnull-selective PRMT5 inhibitors have the potential to treat patients with MTAP deficiency (Kryukov et al., 2016). We identified CTS3157 as an orally bioavailable small molecule MTA-cooperative PRMT5 inhibitor that binds to PRMT5-MTA complex and inhibits PRMT5 enzymatic activity. Cell-based assays revealed that CTS3157 demonstrated potent PRMT5 inhibition as evidenced by suppression of symmetric dimethylarginine (SDMA) and cell growth inhibitory activity for MTAP-deleted cell lines over isogenic MTAPWT cell lines. Moreover, CTS3157 series compounds exhibited strong cell growth inhibition in a diverse panel of MTAPnull human tumor cell lines across several lineages. In vivo, CTS3157 demonstrated potent antitumor response after once-daily oral administration in MTAP-deleted xenograft models. The anti-tumor activity is correlated with PRMT5 modulation as measured by reduced SDMA levels. At molecular level, PRMT5 inhibition by CTS3157 resulted in massive RNA splicing defects and differentially expressed genes involving key cellular activities in MTAPnull cells. In summary, MTAPnull-selective PRMT5 inhibitor CTS3157 showed strong and durable antitumor responses in vitro and in vivo in MTAP-deleted tumors across diverse lineages. CTS3157 is an effective and promising therapeutics against MTAP-deleted tumors.
Citation Format: Long Wang, Yilin Liu, Hui Shi, Yuanyuan Liu, Qiugeng Ouyang, Jiannan Guo, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting MTAP-deleted human tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6273.
Abstract 6279: CTS2190, a next-generation epigenetic inhibitor for targeting type I PRMT deregulated human tumors
Authors: Shi Hui , Fu Xingnian , Ouyang Qiugeng , Huang Jiaxin , Wang Yiqin , Wang Youzhen , Xu Guoliang , Mi Yuan , Wu Haiping 
Published: April 2023

Abstract
Methylation of arginine residues by protein arginine methyltransferases (PRMTs) is involved in the regulation of fundamental cellular processes. Type I PRMTs are frequently overexpressed in a variety of human cancers and associated with poor prognosis. Knockout (KO) of Prmt1 in mice results in decreased asymmetric dimethylarginine (ADMA) on cellular proteins, together with increased monomethylarginine (MMA) and symmetric dimethylarginine (SDMA) (Dhar et al., 2013). A structure-based drug discovery effort led to the identification of CTS2190 that showed single-digit nanomolar enzymatic inhibitory activity on type I PRMTs. Here, we report the development and preclinical characterization of CTS2190, a potent, orally bioavailable small molecule type I PRMT inhibitor. CTS2190 demonstrated strong cellular proliferation inhibitory activity in a large, diverse panel of human hematological and solid tumor cell lines across several lineages. In vivo, oral CTS2190 administration once daily resulted in tumor regression in a variety of xenograft (both CDX and PDX) models across different lineages with good tolerance. The anti-tumor activity was dose-dependent and correlated with the inhibition of type I PRMT activity as measured by decrease in ADMA and increase in MMA. In summary, CTS2190 is a promising type I PRMT inhibitor and clinical trial is underway to explore the proof-of-concept anti-tumor benefit for patients.
Citation Format: Hui Shi, Xingnian Fu, Qiugeng Ouyang, Jiaxin Huang, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS2190, a next-generation epigenetic inhibitor for targeting type I PRMT deregulated human tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6279.
Abstract 6282: EP102: Pharmacological inhibition of METTL3 arrests tumor progression and prolongs survival in CDX and PDX models of AML
Authors: Fraser Graeme , Sorlet Catherine , Parmentier Nicolas , Brunel Elodie , Hartiel Anne-France , Oukoloff Killian , Dutheuil Guillaume 
Published: April 2023

Abstract
METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-6-methyladenosine (m6A), the most abundant modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML)1. EPICS has discovered and optimized a small molecule inhibitor of METTL3 (“M3i”). M3i was shown to inhibit the enzymatic activity of METTL3 (IC50 = 2 nM, SPA assay) and inhibit the presence of intracellular m6A in a cell-based assay (IC50 = 8 nM, Calu6). The anti-proliferative effects of METTL3 was demonstrated in a spheroid model (NCIH-560, IC50 = 100 nM) as well as cell viability assays in various AML (Kasumi-1, IC50 = 30 nM; LEXF 41283, IC50 = 46 nM; MV-4-11, IC50 = 248 nM) and solid tumor (Calu6, IC50= 6 nM; Caov3, IC50 = 27 nM) cell lines. In vivo efficacy was evaluated in a disseminated xenograft model using established systemic MV-4-11-Luc-mCh-Puro2 in female NSG mice where M3i (30 mg/kg, i.p., QDx31 days) significantly (p&lt;0.01, relative to vehicle control) inhibited cancer progression as measured by in-life imaging in addition to flow cytometry of hCD45+ cells in bone marrow, blood and spleen; M3i had minimal effects on hematopoiesis in this model with no significant changes in RBCs, WBCs and neutrophils, but an increase in platelets (measured by IDEXX). In an orthotopic, patient-derived xenograft model of AML (LEXF 41283, intratibial implantation, female NSG mice), M3i (30 mg/kg, i.p., QDx91 days) significantly prolonged survival (p&lt;0.01, relative to vehicle control) with a commensurate absence of hCD45+ cells following compound treatment. These results confirm that the pharmacological inhibition of METTL3 is a viable strategy for the treatment of AML and support the additional exploration of the role of METTL3 inhibitors in alternate blood cancers as well as solid tumors.
Citation Format: Graeme Fraser, Catherine Sorlet, Nicolas Parmentier, Elodie Brunel, Anne-France Hartiel, Killian Oukoloff, Guillaume Dutheuil. EP102: Pharmacological inhibition of METTL3 arrests tumor progression and prolongs survival in CDX and PDX models of AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6282.
Abstract 651: Revealing the role of lung cancer microbiota in the tumor progression
Authors: Riquelme Erick M. , Valdes Ivania , Aravena Carlos , Valencia Ilse , Mino Barbara , Carvajal Daniel , Martin Alberto 
Published: April 2023

Abstract
Lung cancer (LC) remains as the leading cause of death by cancer worldwide. In Chile, LC is the second cause of cancer-related deaths. Recently, studies in melanoma and non-small cell lung cancer (NSCLC) patients have highlighted the role of the gut microbiota as an important host factor in mediating the responses/resistance to immunotherapy, suggesting that bacteria present in the gut may modulate the immune response in these tumors. However, the role of extra-intestinal microbiota; bacteria living outside of the gut, in cancer pathogenesis and the response to anti-cancer therapies remains largely undetermined. Here we characterize the composition of intratumoral microbiota of NSCLC and seek to establish a functional relationship between it and the composition of the immune microenvironment and the clinicopathological characteristics of NSCLC patients. From the first 157 FFPE NSCLC samples, we extracted DNA from all collected samples, obtaining adequate material in quality and quantity to later be submitted for analysis to 16S sequencing. Using 16S rRNA gene sequencing, we assessed the general landscape of the NSCLC tumor microbiome, revealing the presence of large number of bacterial communities in the NSCLC tumor samples on the different histological subtypes analyzed. We have detected differences in alpha diversity in the histological subtypes studied. Even more interesting, we have detected significant differences in lung adenocarcinoma depending on the degree of histological differentiation, observing a decrease in proteobacteria and an enrichment of Bacteroidales, as cell differentiation is lost. Additionally, we identified taxonomic differences between differentiated and undifferentiated tumors. Differentiated tumors show enrichment in Akkermansia muciniphila and while undifferentiated tumors show enrichment in Actinobacter Corynebacterium. Suggesting that these taxa could contribute to maintaining a differentiated state or inducing cell dedifferentiation, respectively. Our results reveal the presence of a large number of bacterial communities in lung cancer samples in the different histological subtypes analyzed. Suggesting that these communities could play a key role in tumor differentiation and progression.
Citation Format: Erick M. Riquelme, Ivania Valdes, Carlos Aravena, Ilse Valencia, Barbara Mino, Daniel Carvajal, Alberto Martin. Revealing the role of lung cancer microbiota in the tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 651.
Multiple Germline Events Contribute to Cancer Development in Patients with Li-Fraumeni Syndrome
Authors: Subasri Vallijah , Light Nicholas , Kanwar Nisha , Brzezinski Jack , Luo Ping , Hansford Jordan R. , Cairney Elizabeth , Portwine Carol , Elser Christine , Finlay Jonathan L. , Nichols Kim E. , Alon Noa , Brunga Ledia , Anson Jo , Kohlmann Wendy , de Andrade Kelvin C. , Khincha Payal P. , Savage Sharon A. , Schiffman Joshua D. , Weksberg Rosanna , Pugh Trevor J. , Villani Anita , Shlien Adam , Goldenberg Anna , Malkin David 
Published: April 2023

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbor a pathogenic germline variant in the TP53 tumor suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS (n = 396) with variant (n = 374) or wildtype TP53 (n = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6, and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633–0.810).

Significance:
Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond TP53. More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene.
Phase I Trial of Autologous RNA-electroporated cMET-directed CAR T Cells Administered Intravenously in Patients with Melanoma and Breast Carcinoma
Authors: Shah Payal D. , Huang Alexander C. , Xu Xiaowei , Orlowski Robert , Amaravadi Ravi K. , Schuchter Lynn M. , Zhang Paul , Tchou Julia , Matlawski Tina , Cervini Amanda , Shea Joanne , Gilmore Joan , Lledo Lester , Dengel Karen , Marshall Amy , Wherry E. John , Linette Gerald P. , Brennan Andrea , Gonzalez Vanessa , Kulikovskaya Irina , Lacey Simon F. , Plesa Gabriela , June Carl H. , Vonderheide Robert H. , Mitchell Tara C. 
Published: April 2023

Purpose:
Treatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET.

Experimental Design:
Metastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated.

Results:
Mean age was 50 years (35–64); median Eastern Cooperative Oncology Group 0 (0–1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue, and malaise. One subject had grade 1 cytokine release syndrome. No grade 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. mRNA signals corresponding to CAR T cells were detected by RT-PCR in all patients’ blood including in 3 subjects on day +1 (no infusion administered on this day). Five subjects underwent postinfusion biopsy with no CAR T-cell signals seen in tumor. Three subjects had paired tumor tissue; IHC showed increases in CD8 and CD3 and decreases in pS6 and Ki67.

Conclusions:
Intravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible.

Significance:
Data evaluating CAR T therapy in patients with solid tumors are limited. This pilot clinical trial demonstrates that intravenous cMET-directed CAR T-cell therapy is safe and feasible in patients with metastatic melanoma and metastatic breast cancer, supporting the continued evaluation of cellular therapy for patients with these malignancies.
Teachers’ Subjective Wellbeing During the Covid-19 Pandemic: Its Relation to Religiosity and Trust in Science
Authors: Balbuena Sherwin E. , Balbuena Princess Z. 
Published: April 2023

This study investigated the association between religiosity and teachers’ subjective wellbeing and between their trust in science and subjective wellbeing during the COVID-19 pandemic. Using a correlational research design, a survey was conducted involving 170 schoolteachers in Southern Bicol, Philippines. Results of the study showed that religiosity and wellbeing had a significant positive linear correlation. Religiosity was found to be a significant predictor of wellbeing. Furthermore, distrust in science and wellbeing had a significant monotonic relationship. Distrust in science was also a significant predictor of subjective wellbeing. This study concludes that when teachers have higher levels of distrust in science, their level of subjective wellbeing deteriorates. On the other hand, when teachers’ level of religiosity becomes high, their subjective wellbeing improves. These two traits of trust may have helped the teachers cope with the emotional stress experienced during the pandemic.
“
It’s Overwhelming With the Grief”
A Qualitative Study of Families’ Experiences When a Young Relative Dies of Sudden Cardiac Death
Authors: Allan Katherine S. , Mason Katherine L. , Garner Jodi , Dainty Katie N. , Huyer Dirk , Cunningham Kris , Dorian Paul , Lewis Krystina B. 
Published: April 2023

Background:
Sudden cardiac death (SCD) in younger individuals is frequently caused by heritable cardiac conditions. The unexpected nature of SCD leaves families with many unanswered questions and an insufficient understanding of the cause of death and their own risk for heritable disease. We explored the experiences of families of young SCD victims upon learning about their relative’s cause of death and how they perceive their own risk for heritable cardiac conditions.

Methods:
We conducted a qualitative descriptive study, by interviewing families of young (ages 12–45) SCD victims, who died between 2014 and 2018 from a heritable cardiac condition and were investigated by the Office of the Chief Coroner of Ontario, Canada. We used thematic analysis to analyze the transcripts.

Results:
Between 2018 and 2020, we interviewed 19 family members, of which 10 were males and 9 were females, ages ranging from 21 to 65 (average 46.2±13.1). Four main themes were revealed, each representing a distinct time period that families experience along a trajectory: (1) interactions between bereaved family and others, in particular coroners, shaped their search for answers about their relative’s cause of death, with the types, formats, and timing of communication varying by case; (2) searching for answers and processing the cause of death; (3) incidental implications of the SCD event, such as financial strain and lifestyle changes contributed to cumulative stress; (4) receiving answers (or not) and moving forward.

Conclusions:
Families rely on communication with others, yet the type, formats, and timing of information received varies, which can influence families’ experiences of processing the death (and its cause), their perceived risk and their decision to pursue cascade screening. These results may provide key insights for the interprofessional health care team responsible for the delivery and communication of the cause of death to families of SCD victims.
Youth Inclusion Projects and Violence Reduction: Perceptions from the NYS Cohorts Programme in Mathare and Kibera
Authors: Mutahi Patrick , Kimari Wangui 
Published: April 2023

Abstract
This paper seeks to address the connection between economic opportunities and violence prevention, through an in-depth study of the National Youth Service (NYS) Community Cohorts Programme – the biggest youth empowerment programme in Kenya’s recent history. Using field data, it seeks to answer the following question: To what extent did the National Youth Service Community Cohorts Programme in Kenya contribute to violence prevention in the low-income neighborhoods of Mathare and Kibera? Empirically, using the NYS as a case study, the paper will provide new data on the impact of youth programs that simultaneously seek to promote livelihoods and economic opportunities towards dealing with the challenges of violence and exclusion. It will also explore the impact of such projects in reducing violence at the local level. Theoretically, the study will contribute to broader scholarly discussions on youth and violence in Africa, as well as the economic incentives and motivations argument in preventing and reducing violence. Redesigned in 2013, the NYS programme sought to reach thousands of youth in poor urban areas, and by offering them jobs to improve their neighborhoods, the goal was to provide them with a new sense of purpose in their life, and potentially, steer them away from deviant behavior. The NYS initiative is the most ambitious jobs and economic opportunities project for urban and rural youth in Kenya. Given its scale and the resource commitment from the Kenya government, the NYS initiative will continue to be a reference for other youth-focused initiatives and, thus, provides a useful case for the study of the economic opportunities-violence nexus.
Regulating Religious Choices: Foundations and Legitimacy of Anti-conversion Laws in India
Authors: Parashar Sakshi , Gupta Setu 
Published: April 2023

Abstract
In the last few years, there has been a conspicuous upsurge in the enactment of anti-conversion laws by many Indian states. Even though some states have had such laws since the 1960s, the recent ones are more aggressive and stringent, primarily aimed at making the conversion process cumbersome and illegal on additional grounds including marriage of inter-faith couples. The recent laws have been targeted for furthering the political agenda of love-jihad and violating the secular ideals enshrined in the Constitution. This article argues that the object of the recent anti-conversion enactments is largely political and reflects majoritarian disposition. It is further asserted that the inherent ambiguities in the grounds of unlawful conversion and procedural provisions of these laws are arbitrary, discriminatory, and violative of the right to equality, freedom of religion, marriage, and privacy recognised by the Constitution.
Space Diplomacy
Authors: Wörner Jan 
Published: April 2023

Summary
After the Cold War and the race in space, space activities increasing became a geopolitical arena of co-operation. This article is based on my personal experience gathered over fifteen years leading European space institutions: in 2007 I became the Chairman of the Executive Board of the German Aerospace Center. In that position I led the German delegation to the European Space Agency (ESA). From 2015 to 2021 I had the honour and pleasure of being the Director General of ESA. During the whole period from 2007 to today I have had various political interactions that developed my current mindset. Even in times of geopolitical difficulties we need some aspects of international interaction; space can play this role.
Hate Speech and Discrimination as Mundane Violence against Rohingya Refugees during covid-19
Authors: Auethavornpipat Ruji 
Published: April 2023

Abstract
This article advances the critical atrocity lens in challenging the dominant atrocity framework that overly emphasises systematic and large-scale killings in conflict settings. To do so, it argues for the broadened scope of violence to illustrate that hate speech and discrimination produce similar consequences of stripping vulnerable populations of their rights and livelihoods despite the absence of mass killings. This article captures such mundane violence by unpacking the interplay between atrocity crimes, hate speech and discrimination against Rohingya refugees during the covid-19 pandemic. The findings urge scholars and practitioners to consider broader human rights protection during peace time to address root causes of atrocities. In doing so, it can foster inter-communal respect and tolerance, hence preventing grievances from turning into incitement of mass violence.