bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coping strategies, resilience and quality of life: reaction to the COVID-19 pandemic among Romanian physicians
Authors: Crișan Cătălina Angela , Pop Răzvan , Stretea Roland , Milhem Zaki , Forray Alina-Ioana 
Published: May 2024

Abstract
Background
The COVID-19 pandemic has presented multiple psychological challenges for healthcare workers, such as anxiety, depression, burnout, and substance use disorders. In this research, we investigate the different ways Romanian physicians dealt with the difficult period of the COVID-19 pandemic. We also analyze how positive and negative stress-reducing strategies, as well as demographic variables, affect their psychological resilience and quality of life. Our goal is to provide a comprehensive overview of how physicians coped with the unprecedented global health challenges.

Methods
We carried out a national cross-sectional study of 265 physicians in Romania between January 2021 and January 2022 using a web-based questionnaire. The study employed a web-based questionnaire to assess coping mechanisms using the COPE inventory, resilience through the Connor-Davidson Resilience Scale 25 (CD-RISC 25), and quality of life via the WHOQOL-BREF scale. The COPE inventory, consisting of 60 items across 15 subscales, categorizes coping strategies into problem-focused, emotion-focused, and dysfunctional types, with each item rated on a 4-point scale. The CD-RISC 25 measures resilience on a 5-point Likert scale, with total scores ranging from 0 to 100. WHOQOL-BREF assesses quality of life through 26 items in 4 domains: physical, mental, social relations, and environmental, scored from 1 to 5 and converted to a 0–100 scale for domain scores. Univariate and multivariate linear regression models were employed to discern the intricate relationships between coping strategies, resilience levels, quality of life dimensions, and pertinent demographic factors.

Results
The average CD-RISC score among participants was 66.2. The mean scores for the values for the QOL subscales were 64.0 for physical well-being, 61.7 for psychological well-being, 61.2 for social relationships, and 64.7 for environment. Individuals tend to use problem-focused and emotion-focused coping more than dysfunctional mechanisms, according to the COPE inventory. Problem-focused and emotion-focused coping are positively correlated with resilience, while dysfunctional coping is negatively correlated. Resilience is significantly influenced by gender and professional status, with males and senior specialists reporting higher levels while younger physicians and residents reporting lower levels.

Conclusions
Our data points to specific protective characteristics and some detrimental factors on physicians' resilience and quality of life during the pandemic.
Small protein blockers of human IL-6 receptor alpha inhibit proliferation and migration of cancer cells
Authors: Groza Yaroslava , Lacina Lukáš , Kuchař Milan , Rašková Kafková Leona , Zachová Kateřina , Janoušková Olga , Osička Radim , Černý Jiří , Petroková Hana , Mierzwicka Joanna Maria , Panova Natalya , Kosztyu Petr , Sloupenská Kristýna , Malý Jan , Škarda Jozef , Raška Milan , Smetana Karel , Malý Petr 
Published: May 2024

Abstract
Background
Interleukin-6 (IL-6) is a multifunctional cytokine that controls the immune response, and its role has been described in the development of autoimmune diseases. Signaling via its cognate IL-6 receptor (IL-6R) complex is critical in tumor progression and, therefore, IL-6R represents an important therapeutic target.

Methods
An albumin-binding domain-derived highly complex combinatorial library was used to select IL-6R alpha (IL-6Rα)-targeted small protein binders using ribosome display. Large-scale screening of bacterial lysates of individual clones was performed using ELISA, and their IL-6Rα blocking potential was verified by competition ELISA. The binding of proteins to cells was monitored by flow cytometry and confocal microscopy on HEK293T-transfected cells, and inhibition of signaling function was examined using HEK-Blue IL-6 reporter cells. Protein binding kinetics to living cells was measured by LigandTracer, cell proliferation and toxicity by iCELLigence and Incucyte, cell migration by the scratch wound healing assay, and prediction of binding poses using molecular modeling by docking.

Results
We demonstrated a collection of protein variants called NEF ligands, selected from an albumin-binding domain scaffold-derived combinatorial library, and showed their binding specificity to human IL-6Rα and antagonistic effect in HEK-Blue IL-6 reporter cells. The three most promising NEF108, NEF163, and NEF172 variants inhibited cell proliferation of malignant melanoma (G361 and A2058) and pancreatic (PaTu and MiaPaCa) cancer cells, and suppressed migration of malignant melanoma (A2058), pancreatic carcinoma (PaTu), and glioblastoma (GAMG) cells in vitro. The NEF binders also recognized maturation-induced IL-6Rα expression and interfered with IL-6-induced differentiation in primary human B cells.

Conclusion
We report on the generation of small protein blockers of human IL-6Rα using directed evolution. NEF proteins represent a promising class of non-toxic anti-tumor agents with migrastatic potential.
Deubiquitinating enzymes: potential regulators of the tumor microenvironment and implications for immune evasion
Authors: Hsu Sheng-Kai , Chou Chon-Kit , Lin I-Ling , Chang Wen-Tsan , Kuo I-Ying , Chiu Chien-Chih 
Published: May 2024

AbstractUbiquitination and deubiquitination are important forms of posttranslational modification that govern protein homeostasis. Deubiquitinating enzymes (DUBs), a protein superfamily consisting of more than 100 members, deconjugate ubiquitin chains from client proteins to regulate cellular homeostasis. However, the dysregulation of DUBs is reportedly associated with several diseases, including cancer. The tumor microenvironment (TME) is a highly complex entity comprising diverse noncancerous cells (e.g., immune cells and stromal cells) and the extracellular matrix (ECM). Since TME heterogeneity is closely related to tumorigenesis and immune evasion, targeting TME components has recently been considered an attractive therapeutic strategy for restoring antitumor immunity. Emerging studies have revealed the involvement of DUBs in immune modulation within the TME, including the regulation of immune checkpoints and immunocyte infiltration and function, which renders DUBs promising for potent cancer immunotherapy. Nevertheless, the roles of DUBs in the crosstalk between tumors and their surrounding components have not been comprehensively reviewed. In this review, we discuss the involvement of DUBs in the dynamic interplay between tumors, immune cells, and stromal cells and illustrate how dysregulated DUBs facilitate immune evasion and promote tumor progression. We also summarize potential small molecules that target DUBs to alleviate immunosuppression and suppress tumorigenesis. Finally, we discuss the prospects and challenges regarding the targeting of DUBs in cancer immunotherapeutics and several urgent problems that warrant further investigation.
Emerging strategies for treating autoimmune disease with genetically modified dendritic cells
Authors: Ma Yunhan , Shi Ruobing , Li Fujun , Chang Haocai 
Published: May 2024

AbstractGene editing of living cells has become a crucial tool in medical research, enabling scientists to address fundamental biological questions and develop novel strategies for disease treatment. This technology has particularly revolutionized adoptive transfer cell therapy products, leading to significant advancements in tumor treatment and offering promising outcomes in managing transplant rejection, autoimmune disorders, and inflammatory diseases. While recent clinical trials have demonstrated the safety of tolerogenic dendritic cell (TolDC) immunotherapy, concerns remain regarding its effectiveness. This review aims to discuss the application of gene editing techniques to enhance the tolerance function of dendritic cells (DCs), with a particular focus on preclinical strategies that are currently being investigated to optimize the tolerogenic phenotype and function of DCs. We explore potential approaches for in vitro generation of TolDCs and provide an overview of emerging strategies for modifying DCs. Additionally, we highlight the primary challenges hindering the clinical adoption of TolDC therapeutics and propose future research directions in this field.
Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition
Authors: Beauchamp Erwan , Gamma Jay M. , Cromwell Christopher R. , Moussa Eman W. , Pain Rony , Kostiuk Morris A. , Acevedo-Morantes Claudia , Iyer Aishwarya , Yap Megan , Vincent Krista M. , Postovit Lynne M. , Julien Olivier , Hubbard Basil P. , Mackey John R. , Berthiaume Luc G. 
Published: May 2024

Abstract
Background
In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs.

Methods and results
Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes.

Conclusions
Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.
Impact of maternal immune activation and sex on placental and fetal brain cytokine and gene expression profiles in a preclinical model of neurodevelopmental disorders
Authors: Osman Hadley C. , Moreno Rachel , Rose Destanie , Rowland Megan E. , Ciernia Annie Vogel , Ashwood Paul 
Published: May 2024

AbstractMaternal inflammation during gestation is associated with a later diagnosis of neurodevelopmental disorders including autism spectrum disorder (ASD). However, the specific impact of maternal immune activation (MIA) on placental and fetal brain development remains insufficiently understood. This study aimed to investigate the effects of MIA by analyzing placental and brain tissues obtained from the offspring of pregnant C57BL/6 dams exposed to polyinosinic: polycytidylic acid (poly I: C) on embryonic day 12.5. Cytokine and mRNA content in the placenta and brain tissues were assessed using multiplex cytokine assays and bulk-RNA sequencing on embryonic day 17.5. In the placenta, male MIA offspring exhibited higher levels of GM-CSF, IL-6, TNFα, and LT-α, but there were no differences in female MIA offspring. Furthermore, differentially expressed genes (DEG) in the placental tissues of MIA offspring were found to be enriched in processes related to synaptic vesicles and neuronal development. Placental mRNA from male and female MIA offspring were both enriched in synaptic and neuronal development terms, whereas females were also enriched for terms related to excitatory and inhibitory signaling. In the fetal brain of MIA offspring, increased levels of IL-28B and IL-25 were observed with male MIA offspring and increased levels of LT-α were observed in the female offspring. Notably, we identified few stable MIA fetal brain DEG, with no male specific difference whereas females had DEG related to immune cytokine signaling. Overall, these findings support the hypothesis that MIA contributes to the sex- specific abnormalities observed in ASD, possibly through altered neuron developed from exposure to inflammatory cytokines. Future research should aim to investigate how interactions between the placenta and fetal brain contribute to altered neuronal development in the context of MIA.
The gut microbiome and HLA-B27-associated anterior uveitis: a case-control study
Authors: Morandi Sophia C. , Herzog Elio L. , Munk Marion , Kreuzer Marco , Largiadèr Carlo R. , Wolf Sebastian , Zinkernagel Martin , Zysset-Burri Denise C. 
Published: May 2024

Abstract
Background
The human gut microbiome (GM) is involved in inflammation and immune response regulation. Dysbiosis, an imbalance in this ecosystem, facilitates pathogenic invasion, disrupts immune equilibrium, and potentially triggers diseases including various human leucocyte antigen (HLA)-B27-associated autoinflammatory and autoimmune diseases such as inflammatory bowel disease (IBD) and spondyloarthropathy (SpA). This study assesses compositional and functional alterations of the GM in patients with HLA-B27-associated non-infectious anterior uveitis (AU) compared to healthy controls.

Methods
The gut metagenomes of 20 patients with HLA-B27-associated non-infectious AU, 21 age- and sex-matched HLA-B27-negative controls, and 6 HLA-B27-positive healthy controls without a history of AU were sequenced using the Illumina NovaSeq 6000 platform for whole metagenome shotgun sequencing. To identify taxonomic and functional features with significantly different relative abundances between groups and to identify associations with clinical metadata, the multivariate association by linear models (MaAsLin) R package was applied.

Results
Significantly higher levels of the Eubacterium ramulus species were found in HLA-B27-negative controls (p = 0.0085, Mann-Whitney U-test). No significant differences in microbial composition were observed at all other taxonomic levels. Functionally, the lipid IVA biosynthesis pathway was upregulated in patients (p < 0.0001, Mann-Whitney U-test). A subgroup analysis comparing patients with an active non-infectious AU to their age- and sex-matched HLA-B27-negative controls, showed an increase of the species Phocaeicola vulgatus in active AU (p = 0.0530, Mann-Whitney U-test). An additional analysis comparing AU patients to age- and sex-matched HLA-B27-positive controls, showed an increase of the species Bacteroides caccae in controls (p = 0.0022, Mann-Whitney U-test).

Conclusion
In our cohort, non-infectious AU development is associated with compositional and functional alterations of the GM. Further research is needed to assess the causality of these associations, offering potentially novel therapeutic strategies.
Increased levels of GM-CSF and CXCL10 and low CD8+ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people
Authors: Poisson Johanne , El-Sissy Carine , Serret-Larmande Arnaud , Smith Nikaïa , Lebraud Morgane , Augy Jean-Loup , Conti Catherine , Gonnin Cécile , Planquette Benjamin , Arlet Jean-Benoît , Hermann Bertrand , Charbit Bruno , Pastre Jean , Devaux Floriane , Ladavière Cyrielle , Lim Lydie , Ober Pauline , Cannovas Johanna , Biard Lucie , Gulczynski Marie-Christelle , Blumenthal Noémie , Péré Hélène , Knosp Camille , Gey Alain , Benhamouda Nadine , Murris Juliette , Veyer David , Tartour Eric , Diehl Jean-Luc , Duffy Darragh , Paillaud Elena , Granier Clémence 
Published: May 2024

Abstract
Background
Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8+ T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity.

Results
One hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1β, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8+T cells, and (ii) decreased early precursors CD8+ T stem cell-like memory cells (TSCM) and CD27+CD28+. The cytokines mentioned above were found at higher concentrations in the COVID-19+ older cohort compared to a younger cohort in which they were not associated with disease severity.

Conclusions
Our results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care.
Prevailing of HPV-16 and 52 genotype in 2022–2023 in Sanandaj, Iran
Authors: Haddadi Mohammad , Atefmehr Leila , Motlaghzadeh Saeed , Hejami Fatemeh , Elyasi Fatemeh Sadat , Zafarian Negar , Taghiabadi Zahra , Aboofazeli Amir , Yarahmady Hadi , Modaresi Parisa , Dadgar Aniseh , Arbabinia Mersede , Naderisemiromi Mina , Najafpour Sonya , Sharifi Asra , Gholami Anvar , Mamandi Arvin , Letafati Arash 
Published: May 2024

Abstract
Introduction
Human papillomavirus (HPV) presents a potential threat to the onset of carcinogenesis in the cervix, anogenital regions, and oropharynx. HPV encompasses over 200 types, with at least 12 having the potential to cause cancer, impacting the majority of sexually active individuals. In this current research, we explore the occurrence and spread of HPV genotypes.

Material and methods
During this cross-sectional study conducted in Sanandaj, Iran from Feb 2022 to Aug 2023, diverse samples including oral, vaginal, and genital were collected from individuals referred to private laboratories in Sanandaj, Iran. After sample collection and DNA extraction (FAVORGEN, Taiwan), they were subjected to PCR and genotyping (MehrViru, Iran). The subsequent statistical analysis unveiled infection rates across different demographics and age groups. STATA (version 17) were used for statistical analysis. We examined infection rates across demographics using t-tests and Odds Ratio.

Results
Overall, 26% (249) out of 950 cases tested positive for HPV, with 69% of these classified as high-risk. Among the examined population, 98% (933) were female, and 2% (17) were male. Females aged 31–40 exhibited the highest percentage of HPV prevalence (115/460) in the study with the majority of positive cases belonging to HR genotypes. The overall most frequent genotypes identified were 6, 16, 52, 53, 51, 58, and 56. HPV-16 exhibited the highest frequency among HR genotypes, accounting for 42 (17%) occurrences, followed by HPV-52 with a frequency of 32 (13%).

Conclusion
Our findings emphasize the significant prevalence of HPV among females, particularly in the 21–30 age group. The identification of high-risk genotypes, underscores the importance of targeted interventions for specific age cohorts. The age-stratified analysis highlights a consistent predominance of high-risk HPV across age groups, indicating the need for age-specific preventive measures. These results contribute valuable information for designing effective screening and vaccination strategies, to alleviate the impact of diseases associated with HPV.
Global smoking-related deaths averted due to MPOWER policies implemented at the highest level between 2007 and 2020
Authors: Lyle Greg , Hendrie Delia 
Published: May 2024

Abstract
Background
In response to the harm caused by tobacco use worldwide, the World Health Organization (WHO) World Health Assembly actioned the WHO Framework Convention on Tobacco Control (FCTC) in 2005. To help countries meet their FCTC obligations, the WHO introduced in 2008 the MPOWER policy package and by 2020 the FCTC had been ratified by 182 parties. The package consists of six evidence-based demand reduction smoking cessation policies to assist countries to achieve best practice. We used published evaluation results and replicated the published model to estimate current policy achievement and demonstrate the impact and equity of the MPOWER policy package in reducing the global number of smokers and smoking-attributable deaths (SADs) between 2007 and 2020.

Methods
We replicated an evaluation model (the Abridged SimSmoke model) used previously for country impact assessments and validated our replicated reduction in SADs for policies between 2014 and 2016 against the published results. The replicated model was then applied to report on the country level SADs averted from achieving the highest level of implementation, that is best practice in MPOWER policies, between 2016 and 2020. The latest results were then combined with past published results to estimate the reduction in SADs since the commencement of the MPOWER policy package. Country level income status was used to investigate the equity in the uptake of MPOWER policies worldwide.

Results
Identical estimates for SADs in 41 out of 56 MPOWER policies implemented in 43 countries suggested good agreement in the model replication. The replicated model overestimated the reduction in SADs by 159,800 (1.5%) out of a total of 10.5 million SADs with three countries contributing to the majority of this replication discrepancy. Updated analysis estimated a reduction of 8.57 million smokers and 3.37 million SADs between 2016 and 2020. Between 2007 and 2020, 136 countries had adopted and maintained at least one MPOWER policy at the highest level which was associated with a reduction in 81.0 million smokers and 28.3 million SADs. Seventy five percent of this reduction was in middle income countries, 20% in high income and less than 5% in low income countries.

Conclusions
Considerable progress has been made by MPOWER policies to reduce the prevalence of smokers globally. However, there is inequality in the implementation and maintenance, reach and influence, and the number of SADs averted. Future research to modify the model could provide a more comprehensive evaluation of past and future progress in tobacco control policies, worldwide.