bluuebunny/crossref_metadata_2025_split huggingface dataset:
The relationship between social media usage and loneliness among younger and older adults: the moderating effect of shyness
Authors: Wang Ya-Ling , Chen Yi-Jia , Liu Chih-Chi 
Published: June 2024

AbstractDoes social media alleviate or exacerbate loneliness? Past research has shown mixed results regarding the relationship between social media usage and loneliness among younger and older adults. Unlike younger individuals, older adults may decrease their loneliness through social media interactions. Additionally, previous research has indicated that the link between social media use and loneliness can vary depending on one’s shy tendency. Therefore, this study aims to explore the relationship between individuals’ social media use and loneliness while considering age and shyness tendency as moderating variables. The study employed a questionnaire survey conducted through convenience sampling, resulting in 234 valid responses from participants in Northern Taiwan. Among them, 113 were college students (aged 18 to 25, average age 19.40), and 121 were older adults (aged 50 to 82, average age 60.81). Using hierarchical regression analysis, results indicated that (1) age moderates the relationship between personal social media use and loneliness. Minimal differences were observed among younger individuals, but among older adults, increased social media usage time was associated with a significant reduction in loneliness. (2) Shyness tendency moderate the relationship between personal social media use and loneliness. Individuals with higher shyness tendency experience an increase in loneliness as their social media usage time lengthens.
Understanding climate risks to world cultural heritage: a systematic analysis and assessment framework for the case of Spain
Authors: Hu Haisheng , Hewitt Richard J. 
Published: June 2024

Abstract
Understanding the spatial distribution of world cultural heritage in its present-day geographical context is the foundation for the identification of and subsequent protection from key threats and vulnerabilities, particularly those arising from anthropogenic climate change. To address this challenge, we classified 45 Spanish world cultural heritage sites (WCHS) listed in the UNESCO register (as of 2023) according to type, entry date, and creation date. To establish a basis for a detailed analysis of the specific impact of climate change on the Spanish WCHS, a spatial cartographic database was developed showing the relationships between the WCHS and key geographical and climatic variables. We then used historical climate data, combined with a review of the impact mechanism of climate conditions on cultural heritage, to quantitatively evaluate the extent to which the WCHS in Spain are affected by local climate conditions from five aspects: freeze thaw cycle, thermal stress (thermoclastism), hydrodynamic scoring, corrosion, and biodegradation. Based on the above climate condition risks, we identified the five Spanish WCHS with the greatest potential climate condition risks, including Santiago de Compostela (Old Town), Pyrénées—Mont Perdu, the Roman Walls of Lugo, the Routes of Santiago de Compostela: Camino Francés and Routes of Northern Spain, and the Tower of Hercules. Additionally, based on different shared socioeconomic pathways (SSPs), we conducted a qualitative assessment of climate risk changes for WCHS in Spain under climate change. We found that the SSP1-2.6 scenario had the lowest climate risk, emphasizing the importance of achieving carbon neutrality for the protection of the WCHS. Our work translates historical climate conditions into specific climate risk levels for cultural heritage, providing data and theoretical support for effectively assessing the climate risks to Spanish WCHS.
Exploring how the metaverse of cultural heritage (MCH) influences users’ intentions to experience offline: a two-stage SEM-ANN analysis
Authors: He Tong-Liang , Qin Feng 
Published: June 2024

Abstract
The metaverse for cultural heritage (MCH) serves as a digital platform that enables users to access and engage with cultural heritage resources online. With the rapid expansion of cultural digitisation, many organizations have adopted the MCH to increase their impact and reach. However, empirical research is essential to substantiate the role and significance of MCH. This study examines users’ intentions to engage with MCH and their offline experiences. Using the SEM-ANN method, 989 respondents participated in an analysis framed by the NVM approach through questionnaires. The results show a dependence of users' offline experience intentions on their intentions to engage with MCH (β = 0.216, T = 7.915, P < 0.001), along with perceived benefits (β = 0.199, T = 6.576, P < 0.001) and perceived risks (β = − 0.051, T = − 2.008, P = 0.045). Results suggest that MCH has the potential to enhance offline experiences; factors such as creativity, entertainment and narrative significantly influence users' positive evaluations of MCH, while privacy data, performance ethic and negative psychology influences may reduce users' positive evaluations. These findings have important implications for cultural heritage managers, developers and designers, suggesting that the use of the metaverse can enrich the cultural heritage experience, attract a broader user base beyond offline methods, and promote the appreciation and dissemination of traditional culture.
AlphaMissense performance as a classifier of germline and somatic variants of unknown significance in high-grade sarcoma.
Authors: Hassan Andrew Bassim Bassim , Wilkinson Rachael , Brown Stuart , Wallbank Richard , Surakhy Mirvat , Alves-Vasconcelos Sofia , Metz Paul , Qian Qinan , Mallon Hannah , Ren Tanya , Karia Isabel , Branford-White Harriet 
Published: June 2024

11538 Background: Missense variants associated with high frequency, clinical context, splicing, penetrance and biochemical function are scored as pathogenic by ClinVar/ACMG (scores >99%/>90%). Pathogenic scores that range from this cut-point to 10% (benign) are referred to as variants of unknown significance (VUS). Alphafold2 is a deep neural network algorithm for protein structure trained on known molecular structures. It has informed AlphaMissense (AM) where the impact of every possible single missense variant in the human genome is assessed. The AM continuous pathogenicity score (roughly 0-0.35 benign, 0.36-0.55 ambiguous, 0.56-1.0 pathogenic) are claimed to have 90% accuracy based on ClinVar (based on 1,263 pathogenic and 1,263 benign variants). Methods: Here, we identified VUSs from the Oxford Sarcoma Precision Oncology real world cohort. This included the identification of somatic variants from FoundationOne Heme Sarcoma analysis of Formalin-Fixed Paraffin Embedded (FFPE) tumour samples. Germline variants were identified from whole exome sequencing (WES) (97 genes) from patient blood samples followed by analysis using GATK guidelines. All VUS identified were further analysed using AM. Results: AM reclassified the identified >1000 VUSs from 60 high grade sarcoma gene panels predominantly into benign or pathogenic, with only ~1% remaining as ambiguous. Variants reclassified as pathogenic were assessed for likelihood of pathogenicity based on scientific rationale. This involved evaluating current literature on the variant, determining evolutionary consensus of the residue, structural analysis to assess the potential function of the residue and enrichment of the variant within sarcoma patients compared to known frequencies across the population. Conclusions: In conclusion, the AM classifier dichotomises VUS to either benign or pathogenic, but this is not based on either structural or functional predictions directly. We conclude that it should not be currently used in the analysis of clinical samples seeking actionable variants but could instead stratify potential pathogenic variants for functional investigation.
Incidence of osteonecrosis of the jaw (ONJ) in the randomized non-inferiority phase III trial SAKK 96/12 REDUSE comparing denosumab (DN) administered every 4 weeks (q4w) versus every 12 weeks (q12w).
Authors: Von Moos Roger Anton Fredy , Mueller Andreas , Hayoz Stefanie , Mark Michael Thomas , Fischer Stefanie , Popescu Razvan A. , Fehr Mathias Konrad , Egger Claudine , Anchisi Sandro , Schmid Florian , Zaman Khalil , Ackermann Christoph J , Schreiber Alexander , Bützberger Priska , Uhlmann Nussbaum Catrina , Küng Marc , Schaer Corinne , Gillessen Silke , Templeton Arnoud J. 
Published: June 2024

12067 Background: ONJ is a well-known adverse event of bone-modifying agents that can significantly impact quality of life. It is recognized that the risk of ONJ increases with the duration of treatment and can reach rates of up to 10%. Here, we report ONJ rates in a randomized non-inferiority phase 3 study investigating the optimal dose of DN. Methods: Patients with metastatic breast cancer (mBC) or metastatic castration resistant prostate cancer (mCRPC) (planned N=1380) were randomized 1:1 to receive DN q4w (Arm A) versus q12w (Arm B) after a 3-month induction phase with application q4w. Incidence of ONJ is a key secondary outcome of the study (NCT02051218). An oral inspection at baseline as well as before each application of DN was mandatory. In patients with risk factors for ONJ a prophylactic dentist visit was recommended. Data from patients who received at least 1 dose of DN and who were randomized at least one year before data cut-off (December 11, 2023) were included in this interim safety analysis. Since the differentiation between ONJ and tooth infection can be difficult, we also report this outcome. Results: 1271 patients with a median follow-up time of 3 years were analyzed. During the 3-month induction phase 2/1271 patients experienced an ONJ. In Arm A 48/575 (8.3%), in Arm B 32/561 (5.7%) patients experienced an ONJ. Time to first ONJ and/or tooth infection differs remarkably with a clear advantage for the 3-months arm (HR 0.67; 95% CI 0.48-0.93). Details are shown in the table. Conclusions: The observed ONJ rate of 8.3% is in line with the literature for patients who received denosumab q4w for over two years (mBC: 6.0%, mCRPC: 8.2%). Administration of DN q12w reduces the risk of ONJ and/or tooth infections substantially. The numerical difference of events to the standard arm as well as the time to first ONJ and/or tooth infection is clinically relevant with a risk reduction by 33%. Efficacy data for the primary endpoint time to first symptomatic skeletal event is eagerly awaited. Clinical trial information: NCT02051218 . [Table: see text]
Young lung cancer: Psychosocial needs assessment.
Authors: Florez Narjust , Kiel Lauren , Horiguchi Miki , Kaufman Rebekah , Haradon Danielle , Sanchez Michelle , Lederman Ruth , Voligny Emma , Nguyen Tom , McDonald Stephanie , Wilder Fatima , Pozo-Kaderman Cristina , Janne Pasi A. , Johnson Bruce E. , Partridge Ann H. , Enzinger Andrea Catherine 
Published: June 2024

12104 Background: Young patients (≤50 years) with lung cancer (LC) face unique needs, including mental health and financial challenges, which are understudied to date. We report preliminary results of an ongoing cohort, prospective study exploring psychosocial needs in patients with LC, focusing on the experiences of young patients. Methods: Eligible patients (pts) were age ≥18 years old, with LC stages I-IV, receiving care at Dana-Farber Cancer Institute, and enrolled within 1 year of diagnosis. The FACT-G and COST questionnaires assessed psychosocial and financial distress, with higher scores indicating a more favorable well-being. Descriptive statistics summarized demographics, clinical characteristics, and prevalence of psychosocial needs. Results: 139 pts were enrolled from April 2023 - January 2024; 61 young pts were included in this analysis. 69% identified as female, 70% as White, 8% as Black, and 22% as another race (Table). Since LC diagnosis, 22 pts (36%) reported being diagnosed with at least one mental health condition. Of a possible total score of 108, the mean FACT-G score was 71 (SD: 20). Mean scores for physical, social, emotional, and functional subscales were 19, 22, 14, and 16 (out of 28, 28, 24, and 28), indicating significant burden in the emotional and functional domains. A majority reported feeling sad or anxious (53%, 59%), and 57% were worried about premature death. Most pts (62%) reported (somewhat-very much) having a lack of energy and nearly half reported having substantial pain and being bothered from treatment side effects (42%, 47%, respectively). Many pts were able to work and enjoy their usual recreational activities (66%, 72%, respectively). Nearly all reported receiving adequate emotional support from their family (95%) and friends (93%) and feeling comfortable discussing their LC with them (93%). When asked if they were satisfied with their sex life, 64% (35/55) stated that they were. Of a maximum score of 44, the mean COST score was 24 (SD: 12), consistent with high financial toxicity in this population. Notably, 40% of pts reported having no or only a little money to pay for treatments and 42% stated that out-of-pocket medical costs were considerably more than expected. 45% felt financially stressed and 41% were concerned about loss of employment; 47% stated that their LC caused a substantial financial hardship and 57% noted significant worry about future financial issues. Conclusions: Young pts with LC report ample financial toxicity and issues impacting physical, emotional, and functional well-being. Fewer social issues were reported. This study will help elucidate the needs of young pts with LC with the ultimate goal of mitigating the disease’s psychosocial impact. [Table: see text]
Targeting GARP–TGF-β1 with livmoniplimab plus anti–PD-1 budigalimab to remodel the immunosuppressive tumor microenvironment.
Authors: Dandamudi Durga B. , Refici Marion , Dillon Myles , Duggan Ryan , Kolahi Kevin , Sutherland Claire , Tribouley Catherine , Uziel Tamar , Chen Jack S.H. 
Published: June 2024

2594 Background: Transforming growth factor (TGF)-β signaling has been shown to induce an immunosuppressive tumor microenvironment (TME) and promote tumor progression. Targeting key immune cells involved in this mechanism, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 macrophages, by altering their function/depleting them is an important strategy in cancer therapeutics. Glycoprotein A repetitions predominant (GARP) is a membrane-bound receptor that complexes with latent TGF-β1 and plays a vital role in the immunosuppressive function of Tregs (1). In addition to Tregs, GARP–TGF-β1 is also expressed on other cells such as macrophages and tumor cells (2). Data from mouse models demonstrated that combined targeting of GARP–TGF-β1 and PD-1 improved antitumor effects compared with anti–PD-1 alone (3). Livmoniplimab (livmo), a first-in-class mAb, targets and stabilizes the GARP–TGF-β1 complex, sequestering TGF-β in its inactive form. Livmo is in clinical trials in combination with the anti–PD-1 mAb budigalimab (budi) (NCT03821935, NCT05822752). Methods: Recently, fresh human tumor-derived tissue culture platforms, which retain autologous TME and immune cell content, have emerged as powerful tools to address the gap between clinical data and preclinical models. To better understand the MOA of livmo + budi, we procured fresh tumors from patients (pts) undergoing surgical resection, minced and cultured them for 48h in the presence of livmo ± budi. The functional activity of livmo and budi was determined by assessing tumor cell viability, T-cell effector function, and modulation of immune-suppressive cells. Results: In tumor explant models from 10 pt samples from various indications (NSCLC: n=2; stomach cancer: n=3; HNSCC: n=2; pancreatic cancer: n=1; bladder cancer: n=1; RCC: n=1), treatment with livmo alone led to reduction of tumor cell viability, increase in T-cell effector function, and decrease in immune-suppressive myeloid cells. This effect was further enhanced in combination with budi. Specifically, within the immune cell components, livmo + budi treatment led to no change in the number of Tregs but a 40% reduction in MDSCs and macrophages, both of which depend on TGF-β1 for sustenance and survival. Furthermore, this decrease corresponded with a 50% increase in secretion of granzyme B/IFNγ antitumor T-cell effector functions. Conclusions: These data demonstrate that livmo induces decrease in tumor cell viability, increased antitumor immune cell activation, and remodeling of the immune-suppressive TME, which is further enhanced in combination with budi. These results support the hypothesis that pts would benefit from therapeutic intervention with livmo + budi. 1. Stockis et al. Mol Biosyst 2017;13:1925-35. 2. Zimmer et al. Front Immunol 2022;13:928450. 3. de Streel et al. Nat Commun 2020;11:4545.
Ponatinib (PON) in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) and the T315I mutation (mut): 4-year results from OPTIC.
Authors: Deininger Michael , Apperley Jane , Arthur Christopher Kevin , Chuah Charles , Hochhaus Andreas , de Lavallade Hugues , Lipton Jeffrey Howard , Lomaia Elza , McCloskey James K. , Maness Lori J. , Mauro Michael J. , Moiraghi Beatriz , Pavlovsky Carolina , Rosti Gianantonio , Rousselot Philippe , Undurraga Sutton Maria , Ren Xiaowei , Vorog Alexander , Kantarjian Hagop M. , Cortes Jorge E. 
Published: June 2024

6501 Background: PON, an approved BCR::ABL1 TKI, potently inhibits native BCR::ABL1 and all reported single-resistance muts, including T315I. In the primary analysis of the phase 2 OPTIC study (NCT02467270) at 12 mo, pts with CP-CML and the T315I mut had robust responses to PON. We present 4-year results from the OPTIC trial in pts with the T315I mut. Methods: Pts with CP-CML resistant to ≥2 TKIs or with the BCR::ABL1 T315I mut were randomized 1:1:1 to PON starting doses of 45, 30, or 15 mg QD, with dose reduction to 15 mg upon achievement of ≤1% BCR::ABL1IS in the 45-mg and 30-mg cohorts. This subgroup analysis evaluated 48-mo ≤1% BCR::ABL1IS, PFS and OS rates and safety outcomes in pts with the T315I mut. Results: Overall, 283 pts received PON (45 mg/30 mg/15 mg: n=94/95/94); 23.8% had the T315I mut (n=25/21/21). At the data cutoff for the 4-year analysis (May 8, 2023), median follow-up in the 45-, 30-, and 15-mg cohorts was 60.6, 63.5, and 60.7 mo, respectively. The proportion of pts with the T315I mut achieving ≤1% BCR::ABL1IS by 48 mo was highest in the 45-mg cohort (64%; Table). Median time to response (mo) and estimated median duration of response (mo) were 6.0 and 16.7 in the 45-mg cohort, 3.1 and 12.0 in the 30-mg cohort, and 6.0 and not reached (NR) in the 15-mg cohort. In the 45- and 30-mg cohorts, 15 and 5 pts had dose reduction to 15 mg after achieving ≤1% BCR::ABL1IS, of which 7 and 2 maintained response; of pts not maintaining response, 6 and 1 regained response after dose re-escalation. Median PFS was NR, 28.4 mo, and 45.6 mo in the 45-, 30-, and 15-mg cohorts, respectively, and median OS was NR in all groups. The 45-mg cohort had the highest 4-year survival rates (OS: T315I 86%; overall 88%; Table). Grade ≥3 TEAE rates in the 45-, 30-, and 15-mg cohorts were 60%, 38%, and 38%, with TEAEs leading to discontinuation in 8%, 14%, and 5%, respectively. Arterial occlusive events (AOEs) occurred in 8%, 14%, and 5% of pts in the 45-, 30-, and 15-mg cohorts; exposure-adjusted AOE rates were 2.4%, 7.3%, and 2.8%, respectively. Conclusions: PON demonstrated robust long-term efficacy and manageable safety in this 4-year update in pts with the T315I mut. A PON starting dose of 45 mg with reduction to 15 mg upon achievement of ≤1% BCR::ABL1IS provided the optimal benefit:risk ratio. Clinical trial information: NCT02467270 . [Table: see text]
Efficacy of GCN2 inhibition by a novel small molecule AP030 in acute leukemia.
Authors: Clemo Nadine , Roman-Trufero Monica , Auner Holger , Butt Richard , Zebisch Armin , Chaida Panagiota , Herzog Sereina , Fuchter Matthew 
Published: June 2024

6532 Background: GCN2 is an evolutionarily conserved kinase and a pivotal regulator of the Integrated Stress Response (ISR) that is activated in response to amino acid scarcity. Active GCN2 phosphorylates translation initiation factor eIF2α resulting in the attenuation of global protein synthesis. ISR signaling primarily promotes cell survival but may trigger cell death, dependent on the cellular context. In hematological tumors GCN2 promotes tumor cell survival under conditions of nutrient scarcity. Several GCN2 inhibitors are in clinical development for treatment of both solid and hematological tumors. Here, we describe the preclinical results of a novel, selective ATP-competitive inhibitor of GCN2. Methods: GCN2 inhibition by AP030 was determined using a biochemical Lanthascreen assay and a cell based HTRF assay measuring eIF2a phosphorylation following stimulation with Borrelidin. Kinase selectivity was determined using KinomeScan, and bespoke biochemical and cell-based assays. Interaction of AP030 with GCN2 was determined using X-ray crystallography. AP030 activity in disease-relevant tumor cell lines was determined using cell viability, caspase activation, protein expression and qPCR gene expression endpoints. Inhibition of hematological tumor growth and induction of cell death was investigated in patient samples, and ALL and AML in vivo animal models. Results: Potent inhibition of GCN2 in the Lanthascreen assay was demonstrated with AP030 (Ki of 4.4nM). Following stimulation with Borrelidin, AP030 inhibited eIF2a phosphorylation with an IC50 of 50.8nM and inhibited downstream targets CHAC1 and DDIT3 measured by qPCR. X-ray crystallography confirmed that AP030 binds to the ATP-binding site of GCN2. The KinomeScan confirmed that AP030 was highly selective against the human kinome. AP030 led to partial or complete reduction of AML cell line viability as a single agent and acted synergistically with asparaginase in ALL cell lines. Caspase 3/7 induction was observed in the AML and ALL cell lines evaluated and AP030 increased the proportion of cells undergoing apoptosis in AML patient primary samples. In the CCRF-CEM ALL systemic in vivo tumor model AP030 inhibited tumor growth in combination with asparaginase (TGI 79.33%). Treatment with 0.5-5mg/kg (q.d.) of AP030 resulted in dose-dependent tumor growth inhibition and regression of the MOLM-16 AML in vivo model (TGI 97.37% 5mg/kg). RNA sequencing of residual tumor cells revealed disruption of amino acid and protein metabolism, consistent with GCN2 inhibition. Conclusions: Targeting hematological tumor reliance on the GCN2 arm of the ISR during nutrient scarcity is a novel approach to preventing tumor cell survival. AP030 a novel, potent, selective, ATP-competitive kinase inhibitor has been shown to lead to impressive efficacy in acute leukemia. Based on these preclinical results, a phase 1/2 study has been initiated in AML.