bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-coding RNAs as modulators of radioresponse in triple-negative breast cancer: a systematic review
Authors: Tofolo Maria Vitoria , Berti Fernanda Costa Brandão , Nunes-Souza Emanuelle , Ruthes Mayara Oliveira , Berti Lucas Freitas , Fonseca Aline Simoneti , Rosolen Daiane , Cavalli Luciane Regina 
Published: October 2024

AbstractTriple-negative breast cancer (TNBC), characterized by high invasiveness, is associated with poor prognosis and elevated mortality rates. Despite the development of effective therapeutic targets for TNBC, systemic chemotherapy and radiotherapy (RdT) remain prevalent treatment modalities. One notable challenge of RdT is the acquisition of radioresistance, which poses a significant obstacle in achieving optimal treatment response. Compelling evidence implicates non-coding RNAs (ncRNAs), gene expression regulators, in the development of radioresistance. This systematic review focuses on describing the role, association, and/or involvement of ncRNAs in modulating radioresponse in TNBC. In adhrence to the PRISMA guidelines, an extensive and comprehensive search was conducted across four databases using carefully selected entry terms. Following the evaluation of the studies based on predefined inclusion and exclusion criteria, a refined selection of 37 original research articles published up to October 2023 was obtained. In total, 33 different ncRNAs, including lncRNAs, miRNAs, and circRNAs, were identified to be associated with radiation response impacting diverse molecular mechanisms, primarily the regulation of cell death and DNA damage repair. The findings highlighted in this review demonstrate the critical roles and the intricate network of ncRNAs that significantly modulates TNBC's responsiveness to radiation. The understanding of these underlying mechanisms offers potential for the early identification of non-responders and patients prone to radioresistance during RdT, ultimately improving TNBC survival outcomes.
Graphical Abstract
Navigating the complexity of a collaborative, system-wide public health programme: learning from a longitudinal qualitative evaluation of the ActEarly City Collaboratory
Authors: Nixon Laura , Sheard Laura , Sheringham Jessica , Creaser Amy , Iqbal Halima , Gansallo Patience , Mansukoski Liina , Bryant Maria , Lockyer Bridget 
Published: October 2024

Abstract
Background
Addressing the upstream social determinants of health (e.g. built environment, education) can reduce the burden of non-communicable diseases. To do so effectively often requires system-wide collaboration. However, collaborating across multiple sectors, organizations and disciplines within a complex system can be challenging. ActEarly was a public health research consortium that aimed to improve child health by building an interdisciplinary, cross-city partnership to develop and/or evaluate upstream interventions, increase research capacity and improve collaboration between researchers, local authorities and communities. This paper explores ActEarly’s experiences of navigating complexity to identify mechanisms that supported its implementation and proposes recommendations for future intersectoral and interdisciplinary population health research collaborations.

Methods
We conducted a longitudinal qualitative study of ActEarly, integrating findings from inductive documentary analysis of internal documents (mainly meetings minutes and reports) (n = 114) and interviews (n = 70) with 45 consortium members at three different timepoints (2018, 2021, 2023). Participants worked across different organizations, cities, roles and levels of seniority in the consortium.

Findings
Clarity, Unity, Flexibility and Feasibility were seen as the key mechanisms required to support ActEarly’s implementation. Clear aims, governance structures and communication were necessary to manage the uncertainty of the complex system. A unified approach, characterized by strong relationships, having a shared vision and communal access to resources supported effective collaboration. Flexibility was required to adjust to different ways of working, respond to wider system events and manage the consortium. Establishing feasible aims that responded to the limitations of the system, the available resources and research infrastructure was required for teams to deliver the work.

Conclusions
Implementing multi-faceted programmes in a complex system can be challenging. We recommend that future whole-systems consortia seeking to improve population health build Clarity, Unity, Flexibility and Feasibility into their programmes, noting the complex interrelationships between these factors. Iterative reflections from all parties should support delivery amidst the uncertainty that comes with running a population health research collaboration, and strong leadership and governance should play a key role in ensuring that these are built into foundations the programme.
Establishment and characterization of 18 Sarcoma Cell Lines: Unraveling the Molecular Mechanisms of Doxorubicin Resistance in Sarcoma Cell Lines
Authors: Cho Young-Eun , Kim Soon-Chan , Kim Ha Jeong , Han Ilkyu , Ku Ja-Lok 
Published: October 2024

AbstractSarcomas, malignant tumors from mesenchymal tissues, exhibit poor prognosis despite advancements in treatment modalities such as surgery, radiotherapy, and chemotherapy, with doxorubicin being a cornerstone treatment. Resistance to doxorubicin remains a significant hurdle in therapy optimization. This study aims to dissect the molecular bases of doxorubicin resistance in sarcoma cell lines, which could guide the development of tailored therapeutic strategies. Eighteen sarcoma cell lines from 14 patients were established under ethical approvals and classified into seven subtypes. Molecular, genomic, and transcriptomic analyses included whole-exome sequencing, RNA sequencing, drug sensitivity assays, and pathway enrichment studies to elucidate the resistance mechanisms. Variability in doxorubicin sensitivity was linked to specific genetic alterations, including mutations in TP53 and variations in the copy number of genomic loci like 11q24.2. Transcriptomic profiling divided cell lines into clusters by karyotype complexity, influencing drug responses. Additionally, pathway analyses highlighted the role of signaling pathways like WNT/BETA-CATENIN and HEDGEHOG in doxorubicin-resistant lines. Comprehensive molecular profiling of sarcoma cell lines has revealed complex interplays of genetic and transcriptomic factors dictating doxorubicin resistance, underscoring the need for personalized medicine approaches in sarcoma treatment. Further investigations into these resistance mechanisms could facilitate the development of more effective, customized therapy regimens.
Serum TNFα and IL-17A levels may predict increased depressive symptoms: findings from the Shika Study cohort project in Japan
Authors: Tsuboi Hirohito , Sakakibara Hiroyuki , Minamida-Urata Yuuki , Tsujiguchi Hiromasa , Hara Akinori , Suzuki Keita , Miyagi Sakae , Nakamura Masaharu , Takazawa Chie , Kannon Takayuki , Zhao Jiaye , Shimizu Yukari , Shibata Aki , Ogawa Aya , Suzuki Fumihiko , Kambayashi Yasuhiro , Konoshita Tadashi , Tajima Atsushi , Nakamura Hiroyuki 
Published: October 2024

Abstract
Background
Low-grade systemic inflammation may be a key player in the immune activation that has been reported for mental health deterioration. We hypothesised that elevated serum levels of inflammatory cytokines increase neuroinflammation and exacerbate depressive symptoms.

Methods
The participants were part of a cohort study for whom data was available for both 2015 and 2019. In 2015, blood samples were collected from 232 participants. Their depressive symptoms were assessed both 2015 and 2019 using the Centre for Epidemiologic Studies Depression Scale (CES-D) (n = 33). The multiplex immunoassay system (Luminex® 200) was used to measure the serum concentrations of IL-6, IL-10, IL-12, IL-17A and TNFα. Data were analysed using linear models with the level of significance considered to be p < 0.05.

Results
After controlling for age, BMI, smoking and alcohol consumption, in 2015 the serum concentrations of IL-17A and TNFα in 2015 were significantly positively associated with the CES-D scores of women (standardised β (B) = .027, p < 0.01 and B = 0.26, p < 0.01, respectively). The serum concentrations of IL-17A and TNFα of men were significantly positively associated with the CES-D scores of 2019 (B = 0.62, p = 0.02 and B = 0.59, p = 0.02, respectively).

Conclusions
In this cross-sectional study, we found a significant positive correlation between the depressive symptoms and serum TNFα and IL-17A levels of women. In addition, our longitudinal findings suggest the possibility that TNFα and IL-17A could elevate the depressive symptoms of men.
IRF2 loss is associated with reduced MHC I pathway transcripts in subsets of most human cancers and causes resistance to checkpoint immunotherapy in human and mouse melanomas
Authors: Sari G. , Dhatchinamoorthy K. , Orellano-Ariza L. , Ferreira L. M. , Brehm M. A. , Rock K. 
Published: October 2024

Abstract
Background
In order for cancers to progress, they must evade elimination by CD8 T cells or other immune mechanisms. CD8 T cells recognize and kill tumor cells that display immunogenic tumor peptides bound to MHC I molecules. One of the ways that cancers can escape such killing is by reducing expression of MHC I molecules, and loss of MHC I is frequently observed in tumors. There are multiple different mechanisms that can underly the loss of MHC I complexes on tumor and it is currently unclear whether there are particular mechanisms that occur frequently and, if so, in what types of cancers. Also of importance to know is whether the loss of MHC I is reversible and how such loss and/or its restoration would impact responses to immunotherapy. Here, we investigate these issues for loss of IRF1 and IRF2, which are transcription factors that drive expression of MHC I pathway genes and some killing mechanisms.

Methods
Bioinformatics analyses of IRF2 and IRF2-dependent gene transcripts were performed for all human cancers in the TCGA RNAseq database. IRF2 protein-DNA-binding was analyzed in ChIPseq databases. CRISRPcas9 was used to knock out IRF1 and IRF2 genes in human and mouse melanoma cells and the resulting phenotypes were analyzed in vitro and in vivo.

Results
Transcriptomic analysis revealed that IRF2 expression was reduced in a substantial subset of cases in almost all types of human cancers. When this occurred there was a corresponding reduction in the expression of IRF2-regulated genes that were needed for CD8 T cell recognition. To test cause and effect for these IRF2 correlations and the consequences of IRF2 loss, we gene-edited IRF2 in a patient-derived melanoma and a mouse melanoma. The IRF2 gene-edited melanomas had reduced expression of transcripts for genes in the MHC I pathway and decreased levels of MHC I complexes on the cell surface. Levels of Caspase 7, an IRF2 target gene involved in CD8 T cell killing of tumors, were also reduced. This loss of IRF2 caused both human and mouse melanomas to become resistant to immunotherapy with a checkpoint inhibitor. Importantly, these effects were reversible. Stimulation of the IRF2-deficient melanomas with interferon induced the expression of a functionally homologous transcription factor, IRF1, which then restored the MHC I pathway and responsiveness to CPI.

Conclusions
Our study shows that a subset of cases within most types of cancers downregulates IRF2 and that this can allow cancers to escape immune control. This can cause resistance to checkpoint blockade immunotherapy and is reversible with currently available biologics.
In vitro drug testing using patient-derived ovarian cancer organoids
Authors: Chen Lin-Yu , Chou Yu-Ting , Liew Phui-Ly , Chu Ling-Hui , Wen Kuo-Chang , Lin Shiou-Fu , Weng Yu-Chun , Wang Hui-Chen , Su Po-Hsuan , Lai Hung-Cheng 
Published: October 2024

Abstract
Background
Ovarian cancer is the most lethal gynecological cancer. As the primary treatment, chemotherapy has a response rate of only 60–70% in advanced stages, and even lower as a second-line treatment. Despite guideline recommendations, which drugs will be most effective remains unclear. Thus, a strategy to prioritize chemotherapy options is urgently needed. Cancer organoids have recently emerged as a method for in vitro drug testing. However, limited clinical correlations have been assessed with test results from cancer organoids, particularly in gynecological cancers. We therefore aimed to generate patient-derived organoids (PDOs) of ovarian cancer, to assess their drug sensitivities and correlations with patient clinical outcomes.

Methods
PDOs were generated from fresh tumors obtained during surgical resection, which was then cultured under matrix gel and appropriate growth factors. Morphological and molecular characterization of PDOs were assessed by phase contrast microscopy and paraffin-embedded histopathology. Expressions of PAX8, TP53, WT1, CK7, and CK20 were tested by immunohistochemical staining and compared with parental tumor tissues and the human protein atlas database. PDOs were subjected to in vitro drug testing to determine drug sensitivity using Titer-Glo® 3D Cell Viability Assay. PDO viability was measured, and area under the curve calculated, to compare responses to various compounds. Correlations were calculated between selected patients’ clinical outcomes and in vitro drug testing results.

Results
We established 31 PDOs. Among them, 28 PDOs can be expanded, including 15, 11, and 2 from ovarian, endometrial, and cervical cancers, respectively. The PDOs preserved the histopathological profiles of their originating tumors. In vitro drug testing of 10 ovarian cancer PDOs revealed individual differential responses to recommended drugs, and interpersonal heterogeneity in drug sensitivity, even with the same histology type. Among four patients who were platinum sensitive, resistant, or refractory, PDO drug responses correlated well with their clinical courses.

Conclusion
In vitro drug testing using ovarian cancer organoids is feasible and correlates well with patient clinical responses. These results may facilitate development of precision chemotherapy and personalized screening for repurposed or new drugs.
Multi-omics analysis reveals the key factors involved in the severity of the Alzheimer’s disease
Authors: Meng Lingqi , Jin Han , Yulug Burak , Altay Ozlem , Li Xiangyu , Hanoglu Lutfu , Cankaya Seyda , Coskun Ebru , Idil Ezgi , Nogaylar Rahim , Ozsimsek Ahmet , Shoaie Saeed , Turkez Hasan , Nielsen Jens , Zhang Cheng , Borén Jan , Uhlén Mathias , Mardinoglu Adil 
Published: October 2024

AbstractAlzheimer’s disease (AD) is a debilitating neurodegenerative disorder with a global impact, yet its pathogenesis remains poorly understood. While age, metabolic abnormalities, and accumulation of neurotoxic substances are potential risk factors for AD, their effects are confounded by other factors. To address this challenge, we first utilized multi-omics data from 87 well phenotyped AD patients and generated plasma proteomics and metabolomics data, as well as gut and saliva metagenomics data to investigate the molecular-level alterations accounting the host-microbiome interactions. Second, we analyzed individual omics data and identified the key parameters involved in the severity of the dementia in AD patients. Next, we employed Artificial Intelligence (AI) based models to predict AD severity based on the significantly altered features identified in each omics analysis. Based on our integrative analysis, we found the clinical relevance of plasma proteins, including SKAP1 and NEFL, plasma metabolites including homovanillate and glutamate, and Paraprevotella clara in gut microbiome in predicting the AD severity. Finally, we validated the predictive power of our AI based models by generating additional multi-omics data from the same group of AD patients by following up for 3 months. Hence, we observed that these results may have important implications for the development of potential diagnostic and therapeutic approaches for AD patients.
Deep learning-based multi-frequency denoising for myocardial perfusion SPECT
Authors: Du Yu , Sun Jingzhang , Li Chien-Ying , Yang Bang-Hung , Wu Tung-Hsin , Mok Greta S. P. 
Published: October 2024

Abstract
Background
Deep learning (DL)-based denoising has been proven to improve image quality and quantitation accuracy of low dose (LD) SPECT. However, conventional DL-based methods used SPECT images with mixed frequency components. This work aims to develop an integrated multi-frequency denoising network to further enhance LD myocardial perfusion (MP) SPECT denoising.

Methods
Fifty anonymized patients who underwent routine 99mTc-sestamibi stress SPECT/CT scans were retrospectively recruited. Three LD datasets were obtained by reducing the 10 s acquisition time of full dose (FD) SPECT to be 5, 2 and 1 s per projection based on the list mode data for a total of 60 projections. FD and LD projections were Fourier transformed to magnitude and phase images, which were then separated into two or three frequency bands. Each frequency band was then inversed Fourier transformed back to the image domain. We proposed a 3D integrated attention-guided multi-frequency conditional generative adversarial network (AttMFGAN) and compared with AttGAN, and separate AttGAN for multi-frequency bands denoising (AttGAN-MF).The multi-frequency FD and LD projections of 35, 5 and 10 patients were paired for training, validation and testing. The LD projections to be tested were separated to multi-frequency components and input to corresponding networks to get the denoised components, which were summed to get the final denoised projections. Voxel-based error indices were measured on the cardiac region on the reconstructed images. The perfusion defect size (PDS) was also analyzed.

Results
AttGAN-MF and AttMFGAN have superior performance on all physical and clinical indices as compared to conventional AttGAN. The integrated AttMFGAN is better than AttGAN-MF. Multi-frequency denoising with two frequency bands have generally better results than corresponding three-frequency bands methods.

Conclusions
AttGAN-MF and AttMFGAN are promising to further improve LD MP SPECT denoising.
Robustifying and simplifying high-dimensional regression with applications to yearly stock return and telematics data
Authors: Marchese Malvina , Martínez-Miranda María Dolores , Nielsen Jens Perch , Scholz Michael 
Published: October 2024

AbstractThe availability of many variables with predictive power makes their selection in a regression context difficult. This study considers robust and understandable low-dimensional estimators as building blocks to improve overall predictive power by optimally combining these building blocks. Our new algorithm is based on generalized cross-validation and builds a predictive model step-by-step from a simple mean to more complex predictive combinations. Empirical applications to annual financial returns and actuarial telematics data show its usefulness in the financial and insurance industries.
Entomopathogenic potential of indigenous Simplicillium subtropicum (Hypocreales: Cordycipitaceae) isolates from Tamil Nadu, India, against the cotton aphid, Aphis gossypii Glover (Hemiptera: Aphididae)
Authors: Mariappan Krishnaveni , Samuel Jeyarajan Nelson , Sevugapperumal Nakkeeran , Uthandi Sivakumar , Subbarayalu Mohankumar , Krishnamoorthi Premalatha 
Published: October 2024

Abstract
Background
Aphis gossypii Glover (Hemiptera: Aphididae) is an economically important polyphagous pest species infesting many agricultural and horticultural crops causing severe yield losses. In order to develop biopesticides for the management of aphids in an environmentally safe manner, 6 indigenous entomopathogenic fungi Simplicillium subtropicum were isolated from soils of Tamil Nadu and their pathogenicity was tested against A. gossypii under laboratory conditions after characterization.

Results
Phenotypic and molecular characterization was performed for all the isolates for species identification. Results of the pathogenicity test showed that the isolate S6 (PP446637) performed well among other isolates causing 58.33% mortality on 7 days after treatment (DAT) @ 1 × 108 spores/ml. The LC50 and LT50 values were found to be 2.36 × 107 spores/ml at 7 DAT and 160.20 h @ 1 × 108 spores/ml, respectively. SEM images of A. gossypii treated with the isolate S6 (PP446637) revealed that initial phase of infection, i.e., adhesion, formation of germ tube and appressoria starts within 24 h post-infection (hpi), hyphal development and penetration of cuticle occurred within 48 hpi and extrusion of mycelium and conidiogenesis occurred within 72 hpi.

Conclusion
This study reveals the entomopathogenic potential of indigenous S. subtropicum isolates against A. gossypii and suggests their use for the eco-friendly management of aphids.
Multicolor single-molecule localization microscopy: review and prospect
Authors: Chen Xi , Wang Xiangyu , Huang Fang , Ma Donghan 
Published: October 2024

AbstractSingle-molecule localization microscopy (SMLM) surpasses the diffraction limit by randomly switching fluorophores between fluorescent and dark states, precisely pinpointing the resulted isolated emission patterns, thereby reconstructing the super-resolution images based on the accumulated locations of thousands to millions of single molecules. This technique achieves a ten-fold improvement in resolution, unveiling the intricate details of molecular activities and structures in cells and tissues. Multicolor SMLM extends this capability by imaging distinct protein species labeled with various fluorescent probes, providing insights into structural intricacies and spatial relationships among different targets. This review explores recent advancements in multicolor SMLM, evaluates the strengths and limitations of each variant, and discusses the future prospects.
Mortality associated with clozapine: what is the evidence?
Authors: Fernandez-Egea Emilio , Flanagan Robert J. , Taylor David , Gaughran Fiona , Lawrie Stephen M. , Jenkins Christopher , Smith Shubulade , Howes Oliver D. , MacCabe James H. 
Published: October 2024

SummaryWhile clozapine has risks, relative risk of fatality is overestimated. The UK pharmacovigilance programme is efficient, but comparisons with other drugs can mislead because of reporting variations. Clozapine actually lowers mortality, partly by reducing schizophrenia-related suicides, but preventable deaths still occur. Clozapine should be used earlier and more widely, but there should be better monitoring and better management of toxicity.