bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P23: Mitochondrial Delivery of Functional Nucleic Acids for Targeting of Mitochondrial Dysfunction
Authors: Ruan Jinglin , Patzel Volker 
Published: April 2024

Abstract
Mitochondria is the main power supply for cellular activity and a key player for the regulation of cellular metabolism, and they contain their own DNA. Critical proteins for mitochondrial functions are not only encoded by nuclear DNA (nDNA) but also by mitochondrial DNA (mtDNA). Abnormalities in mitochondrial functions could lead to diseases including neurodegeneration, diabetes, and cancer progression.
The ability for a non-coding RNA (β2.7) of human cytomegalovirus (CMV) to localize to the host mitochondria revealed its potential to be used as a tool for mitochondria gene targeting. Using computational methods, our lab identified four thermodynamically conserved structural subdomains (D1 to D4) within the β2.7 RNA. While all four domains exhibited mitochondrial uptake potential, sub-domain D3 exhibited the highest absolute mitochondrial targeting activity and sub-domain D2 the highest activity per nucleotide. Further modifications on different sub-domain alignments found that maximum uptake efficiency was achieved by tandem repeats of 4 copies of D3 domains followed by 4 copies of D2 domains (abbreviated as D3 × 4_D2 × 4). Delivery of a GFP-coding mRNA or antisense RNA targeting mitochondrial genes mt-ATP6 and mt-ATP8 both confirmed its ability to co-deliver functional RNA into mitochondria.
To cleave and destroy mutated mitochondrial genomes for future gene therapeutic applications, we explore mitochondrial delivery of the CRISPR-Cas9 system. The mRNAs coding for the wild-type Cas9 as well as more specific Cas9 variants were fused to the mitochondrial delivery vector (D3 × 4_D2 × 4). Latest RT-qPCR on mitochondrial RNA showed delivery of Cas9 mRNA into mitochondria of HepG2 cells. Currently, we investigate co-delivery of single-guide RNA and quantify Cas9 expression in mitochondria. In an alternative approach we deliver sequences coding for functional mitochondrial protein. Examples are the mRNAs coding for mitochondrial proteins mt-ND1, -ND4 or -ND6 which are frequently mutated is patients with Leber’s hereditary optic neuropathy (LHON).
Citation Format: Jinglin Ruan, Volker Patzel. Mitochondrial Delivery of Functional Nucleic Acids for Targeting of Mitochondrial Dysfunction [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P23.
Abstract P46: Small Extracellular Vesicles from Therapy-induced Senescent TNBC Elicit Paracrine Anti-tumour Effects
Authors: Robert Matius , Jakhar Rekha , Au Bijin Veonice , Eng Gracie Wee Ling , Gao Alvin Kunyao , Chuah You Heng , Sachaphibulkij Karishma , Lim Lina Hsiu Kim , Ong Derrick Sek Tong , Lim Elaine Hsuen , Itahana Yoko , Itahana Koji , Cheong Jit Kong , Connolly John Edward , Crasta Karen Carmelina 
Published: April 2024

Abstract
Triple-negative breast cancers (TNBC), associated with poor prognosis and high tumour recurrence, are often treated with taxanes. However, cells may bypass treatment-induced cell death via mitotic slippage, resulting in multinucleated polyploid cells and therapy-induced senescence (TIS). TIS cancer cells represent a population of residual disease and may modulate therapy resistance and recurrence through secretion of the senescence-associated secretory phenotype (SASP). While SASP have been heavily linked with pro-tumorigenic behaviour mediated through soluble cytokines, small extracellular vesicles (sEVs) derived from TIS cancer cells represent an underappreciated aspect of the senescent tumour secretome, as its mechanistic role in mediating paracrine effects remains poorly understood.
In this study, we uncovered an unexpected role for TIS-derived sEVs within the secretome, which conferred paracrine anti-tumour activity in recipient TNBC cancer cells, in contrast to SASP that support pro-tumorigenic behaviour. SEVs profiling through mass-spectrometry revealed that DKK1, a negative regulator of WNT signalling, is enriched in TIS-derived sEVs. Further investigation into the tumour microenvironment with animal models and neoadjuvant chemo-treated patient samples revealed STING-dependent immune response. Hence, our study suggests that sEVs should be considered as distinct SASP entities within the senescent tumour secretome and provide an additional basis for combinatorial use of senomorphics with taxanes to potentially modulate senescence-associated sEVs while suppressing pro-tumorigenic SASP factors.
Citation Format: Matius Robert, Rekha Jakhar, Bijin Veonice Au, Gracie Wee Ling Eng, Alvin Kunyao Gao, You Heng Chuah, Karishma Sachaphibulkij, Lina Hsiu Kim Lim, Derrick Sek Tong Ong, Elaine Hsuen Lim, Yoko Itahana, Koji Itahana, Jit Kong Cheong, John Edward Connolly, Karen Carmelina Crasta. Small Extracellular Vesicles from Therapy-induced Senescent TNBC Elicit Paracrine Anti-tumour Effects [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P46.
Abstract P66: Off-The-Shelf Epstein Barr Virus Specific T Cells Armored with B7-H3-Targeting Chimeric Antigen Receptors Is an Effective and Safe Tumor- Agnostic Therapy For B7-H3 Positive Solid Malignancies
Authors: Yeo Siok Ping , Kua Lindsay , Tan Jin Wei , Lim Joanna Kristyn , Wong Fiona , Santos May Delos , Poh Chek Meng , XH Angeline Goh , Yu Koh Xin , Zhou Xiao Hua , R Rajarethinam , Chen Qing Feng , Her Zhisheng , Horak Ivan D , Low Lionel , Tan Kar Wai 
Published: April 2024

Abstract
In contrast to its limited expression in normal tissues, the B7 homolog 3 protein (B7-H3) is over-expressed in many human tumors, making it an attractive target for chimeric antigen receptor (CAR) T cell therapy.
To address the technical challenges limiting broader patient access to autologous CAR T cell therapy, we armoured Epstein-Barr Virus Specific T Cells (EBVSTs) with CARs as an off-the-shelf therapy against solid tumors. We identified and utilised a nanobody as the domain specifically targeting B7-H3 in our CAR construct to reduce the stability issues associated with scFv-based domains. Our B7H3.CAR armored EBVSTs demonstrated potent in-vitro and in-vivo activity against multiple B7-H3 positive tumor and patient-derived xenografts models. Analysis of human healthy tissues and tumors microarrays indicated that B7-H3 expression, while elevated in patient tumors, was differentially low in healthy tissues. Consistent with this, mouse T cells expressing a murine equivalent of our B7H3.CAR displayed good on-target off-tumor safety in immunocompetent mice bearing syngeneic tumors. Further in-vitro evaluation revealed that while human T, B and NK cells were unaffected by B7H3.CAR EBVSTs targeting, monocytes were readily targeted due to the upregulation of B7-H3. Consequent to this targeting and depletion of B7-H3 positive human myeloid cells which are key mediators of CRS, a low incidence of cytokine release syndrome was observed in humanized mice after B7H3.CAR EBVST treatment. Lastly, we showed that B7H3.CAR EBVSTs can target myeloid-derived suppressor cells (MDSCs) that express B7-H3 and in doing so, alleviate MDSC-driven immune suppression.
Our findings demonstrate that our nanobody-based B7H3.CAR EBVSTs present not only an effective and safe off-the-shelf approach for targeting any B7-H3-positive solid tumor while also addressing challenges that hindered the clinical development of CAR T cells in such indications.
Citation Format: Siok Ping Yeo, Lindsay Kua, Jin Wei Tan, Joanna Kristyn Lim, Fiona Wong, May Delos Santos, Chek Meng Poh, Angeline Goh XH, Xin Yu Koh, Xiao Hua Zhou, Rajarethinam R, Qing Feng Chen, Zhisheng Her, Ivan D Horak, Lionel Low, Kar Wai Tan. Off-The-Shelf Epstein Barr Virus Specific T Cells Armored with B7-H3-Targeting Chimeric Antigen Receptors Is an Effective and Safe Tumor- Agnostic Therapy For B7-H3 Positive Solid Malignancies [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P66.
Abstract P69: Immune Landscape of BRCA1/2 -mutated Breast and Ovarian Cancers in an Asian Cohort
Authors: Chong Siao Ting , Wee Felicia , Ye Jiang Feng , Joseph Craig , Lim Xinru , Neo Zhen Wei , Lee Justina Nadia , Ishak Nur Diana Binte , Toh Ming Ren , Chew Ee Ling , Yeo Claresta , Chan Sock Hoai , Lim Jeffrey , Yeong Joe , Ngeow Joanne 
Published: April 2024

Abstract
Background: The majority of hereditary breast and ovarian cancers (HBOC) harbor defects in the homologous recombination (HR) DNA repair pathway, such as BRCA1 and BRCA2 mutations, which may influence the response to immune checkpoint blockade (ICB) therapy. Recent clinical trials combining poly-ADP ribose inhibitors and ICB therapy in advanced breast and ovarian cancer have shown promising results. This Asian cohort study set out to determine if immune phenotype, specifically the PD-1/PD-L1 axis, was associated with germline BRCA status in advanced breast and ovarian cancer patients and to develop novel biomarkers of HR deficiency to stratify patients for clinical management.
Methods: Tissue microarrays of ovarian tumors and breast tumors were analyzed by multiplex immunohistochemistry (mIHC) to detect the expression of immune markers (CD68, CD8, PD-L1, PD-1) and HR markers (DNA polymerase theta, FANCD2, RAD51, γH2AX, phospho-ATR). The results were used to build a prediction model for BRCA using backward stepwise logistic regression analysis. In addition, we investigated immune infiltration in tumors and performed immune phenotyping on peripheral blood mononuclear cells in a subset of patients.
Results: We identified potential BRCA1/2 predictors by mIHC, namely RAD51 and PD-L1 263 for ovarian tumors and FANCD2 and phospho-ATR for breast tumors. The area under the curve was 0.770 (95% confidence interval [CI]: 0.564, 0.977) in ovarian cancer patients and 0.841 (95% CI: 0.682, 0.999) in breast cancer patients. In addition, the proportion of tumor-infiltrating CD68+PD-L1+ macrophages was significantly upregulated in BRCA1-mutated tumors, while the levels of PD-1 in circulating central memory CD8+ T cells were higher in breast cancer patients with germline BRCA2 mutations, compared with non-BRCA.
Conclusion: This study provides evidence of the association of the PD-1/PD-L1 axis with germline BRCA status in HBOC, which may aid clinical management.
Citation Format: Siao Ting Chong, Felicia Wee, Jiang Feng Ye, Craig Joseph, Xinru Lim, Zhen Wei Neo, Justina Nadia Lee, Nur Diana Binte Ishak, Ming Ren Toh, Ee Ling Chew, Claresta Yeo, Sock Hoai Chan, Jeffrey Lim, Joe Yeong, Joanne Ngeow. Immune Landscape of BRCA1/2 -mutated Breast and Ovarian Cancers in an Asian Cohort [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P69.
Longitudinal Analysis of the Relationship Between Social Isolation and Hypertension in Early Middle Adulthood
Authors: Parker Marie , Self‐Brown Shannon Renee , Rahimi Ali , Fang Xiangming 
Published: April 2024

Background
Most studies have used cross‐sectional or limited follow‐up data to evaluate the relationship between social isolation (SI) and hypertension in older populations. The objective of this analysis was to examine the relationship between longitudinal SI and hypertension in a younger population.

Methods and Results
The present analysis used data from waves I to V of the National Longitudinal Study of Adolescent to Adult Health (1994–2018) and logistic regression models to describe the association of timing, duration, and transitional patterns of SI with hypertension in early middle adulthood. Models were adjusted for demographic variables and adolescent socioeconomic and health‐related confounders. SI was higher across life stages among individuals with hypertension (adolescence: 38% versus 35%, young adulthood: 52% versus 44%, and early middle adulthood: 61% versus 52%). Individuals who were socially isolated in young adulthood or early middle adulthood had greater odds of hypertension in early middle adulthood than those who were not (odds ratio [OR], 1.30 [95% CI, 1.07–1.56]; OR, 1.42 [95% CI, 1.15–1.76], respectively). Early middle adulthood hypertension was significantly associated with persistent SI across all life stages and for those who moved into persistent SI after adolescence (OR, 1.40 [95% CI, 1.02–1.93]; OR, 1.61 [95% CI, 1.18–2.19], respectively).

Conclusions
SI in young or early middle adulthood significantly increased the odds of hypertension, as did moving into SI and the accumulation of SI across life stages. Our analysis provides insights regarding timing for effective interventions to reduce hypertension earlier in the life course, which may prevent future adverse cardiovascular‐related events.
The Christian Population of 16th-Century Ottoman Anatolia: An Overview and Preliminary Observations on Its Location and Numbers in the 1520s
Authors: Moustakas Konstantinos , Kontopanagou Aikaterini Konstantina , Kastrinakis Petros 
Published: April 2024

Abstract
By the 15th century, the transformation of Anatolia into a region with a large Muslim majority had been completed. By then the Christian population in most of Anatolia was either small—in absolute numbers as well as in comparison to Muslims—or non-existent. This general picture has long been known to scholarship, yet no effort has been made to date to provide a systematic overall perspective of the Christian presence in Ottoman Anatolia. This article offers a preliminary overview of the location and relative strength or weakness of that presence in the different parts of Anatolia, based on data from Ottoman fiscal registers that reflect the situation in the 1520s.
CCN Activation and Droplet Growth in Pi Chamber Simulations with Lagrangian Particle–Based Microphysics
Authors: Grabowski Wojciech W. , Kim Yongjoon , Yum Seong Soo 
Published: April 2024

Abstract
Numerical simulations of turbulent moist Rayleigh–Bénard convection driving CCN activation and droplet growth in the laboratory Pi chamber are discussed. Supersaturation fluctuations come from isobaric mixing of warm and humid air rising from the lower boundary with colder air featuring lower water vapor concentrations descending from the upper boundary. Lagrangian particle–based microphysics is used to represent the growth of haze CCN and cloud droplets with kinetic, solute, and surface tension effects included. Dry CCN spectra in the range between 2- and 200-nm radii from field observations are considered. Increasing the total CCN concentration from pristine to polluted conditions results in an increase in the droplet concentration and reduction in the mean droplet radius and spectral width. These are in agreement with Pi chamber observations and numerical simulations, as well as with numerous past studies of CCN cloud-base activation in natural clouds. The key result is that a relatively small fraction of the available CCN is activated in the Pi chamber fluctuating supersaturations, from about a half in the pristine case to only a 10th in the polluted case. The activation fraction as a function of the dry CCN radius is similar in all simulations, close to zero at the CCN small end, increasing to a maximum at CCN radius around 50 nm, and decreasing to close to zero at the large CCN end. This is explained as too small supersaturations to activate small CCN as in natural clouds and insufficient time to allow large CCN reaching the critical radius.

Significance Statement
Impact of turbulence on the formation and growth of cloud droplets is an important cloud physics problem. Laboratory experiments in the Michigan Technological University cloud chamber provide key insights into this problem. Numerical simulations of cloud chamber processes discussed in this paper complement laboratory experiments by providing insights difficult or impossible to obtain in the laboratory. The study contrasts the formation and growth of cloud droplets in the laboratory cloud chamber with processes taking place in natural clouds. The differences documented in this paper pose questions concerning the impact of turbulence on the formation and growth of cloud droplets as a result of interactions of clouds with their environment.
The association of the prothrombin A19911G single-nucleotide polymorphism and the risk of venous thromboembolism: A systematic review and meta-analysis
Authors: Xiang Kehong , Xu Huan , Zhang Yamei , Leng Qiuju , Zhang Feng 
Published: April 2024

Background The study employed meta-analysis to provide a comprehensive synthesis of evidence regarding the association between the prothrombin A19911G polymorphism and the risk of venous thromboembolism (VTE). Method The databases were searched to identify studies investigating the association between the prothrombin A19911G polymorphism and the risk of VTE. Meta-analysis was conducted using Stata 14.0 software. Results A total of five literature studies were included, involving 14,001 participants. Meta-analysis demonstrated that prothrombin A19911G polymorphism increased the risk of VTE (G vs A: OR = 1.17, 95% CI = 1.11–1.22, p < .00001; GG + AG vs AA: OR = 1.22, 95% CI = 1.13–1.31, p < .00001; GG vs AG + AA: OR = 1.23, 95% CI = 1.14–1.33, p < .00001; AG vs AA: OR = 1.15, 95% CI = 1.06–1.25, p = .0006; GG vs AA: OR = 1.34, 95% CI = 1.22–1.48, p < .00001). Conclusion The polymorphism of prothrombin A19911G enhances the susceptibility to VTE.
Human epididymal protein 4 and its combined detection show good diagnostic value in lung cancer: A retrospective study
Authors: Wu Lifang , Chen Xiang , Peng Tingting , Tang Enyan , Bai Wenjing , Chen Liya 
Published: April 2024

Objectives This study aimed to assess the diagnostic value of human epididymal protein 4 (HE4), a potential novel biomarker for lung cancer, and its combined detection with five other conventional biomarkers in lung cancer diagnosis and subtyping. Methods In this retrospective study, 115 lung cancer patients, 50 patients with benign pulmonary disease, and 50 healthy controls were included. Serum HE4, progastrin-releasing peptide (ProGRP), squamous cell carcinoma (SCC) antigen, cytokeratin-19 fragment (CYFRA21-1), neuron-specific enolase (NSE), and carcinoembryonic antigen (CEA) were analyzed using the electrochemiluminescence immunoassay and chemiluminescence immunoassay. The receiver operating characteristic curve was performed to analyze the diagnostic efficacy of individual biomarkers in identifying both lung cancer and its histologic subtypes. Results All six biomarkers showed significantly elevated levels in the lung cancer group compared to both benign pulmonary disease and control groups ( P < 0.05). Among the biomarkers evaluated, HE4 exhibited the highest diagnostic performance for lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma with area under the curve (AUC) values of 0.921, 0.891, and 0.937, respectively. ProGRP was the optimal biomarker for small cell lung cancer with an AUC of 0.973. The combination of all six biomarkers yielded the largest AUCs in the diagnosis of lung cancer subtypes (0.937 for lung adenocarcinoma, 0.998 for lung squamous cell carcinoma, and 0.985 for small cell lung cancer). Furthermore, specific combinations, such as HE4 + CEA, HE4 + SCC, and ProGRP + HE4 + NSE, showed strong diagnostic performance in lung cancer. Conclusions HE4 and its combined detection held substantial clinical significance in the diagnosis of lung cancer and its histologic subtyping, especially for lung adenocarcinoma and lung squamous cell carcinoma.
The Involvement of Caregivers in the End-of-life Care of an Older Adult Living in a Long-term Care Home: A Qualitative Case Study with Nurses and Relatives
Authors: Auclair Isabelle , Bourbonnais Anne 
Published: April 2024

Background A key role of nurses working in long-term care homes (LTCHs) is to promote the involvement of care partners in end-of-life (EOL) care. However, studies on the involvement of care partners in EOL care in LTCHs have focused on care planning and decision-making. While care partners can participate in other ways, it's unclear how they are currently involved in EOL care by staff. Purpose We aimed to explore the involvement of care partners in the EOL care of an older adult living in a LTCH. Methods A qualitative case study was conducted. Data was collected from a sample of four nurses and three care partners, using sociodemographic questionnaires, individual semi-structured interviews, documents pertaining to the LTCH's philosophy for EOL care, and a field diary. Results The results of a thematic analysis showed the broad scope of care partners’ possible involvement, including contributing to care, obtaining information, and being present. As there was some variation in care partners’ desire to be involved, nurses seemed to rely on them to convey their wishes. To promote this involvement, some strategies aimed at health professionals and managers were suggested. Conclusions These results can guide improvement in clinical practices and raise awareness on the EOL care experiences of care partners.
Evaluating treatment efficacy in hospitalized COVID-19 patients, with applications to Adaptive COVID-19 Treatment Trials
Authors: Lin Dan-Yu , Wang Jianqiao , Gu Yu , Zeng Donglin 
Published: April 2024

Background The current endpoints for therapeutic trials of hospitalized COVID-19 patients capture only part of the clinical course of a patient and have limited statistical power and robustness. Methods We specify proportional odds models for repeated measures of clinical status, with a common odds ratio of lower severity over time. We also specify the proportional hazards model for time to each level of improvement or deterioration of clinical status, with a common hazard ratio for overall treatment benefit. We apply these methods to Adaptive COVID-19 Treatment Trials. Results For remdesivir versus placebo, the common odds ratio was 1.48 (95% confidence interval (CI) = 1.23–1.79; p < 0.001), and the common hazard ratio was 1.27 (95% CI = 1.09–1.47; p = 0.002). For baricitinib plus remdesivir versus remdesivir alone, the common odds ratio was 1.32 (95% CI = 1.10–1.57; p = 0.002), and the common hazard ratio was 1.30 (95% CI = 1.13–1.49; p < 0.001). For interferon beta-1a plus remdesivir versus remdesivir alone, the common odds ratio was 0.95 (95% CI = 0.79–1.14; p = 0.56), and the common hazard ratio was 0.98 (95% CI = 0.85–1.12; p = 0.74). Conclusions The proposed methods comprehensively characterize the treatment effects on the entire clinical course of a hospitalized COVID-19 patient.