bluuebunny/crossref_metadata_2025_split huggingface dataset:
Challenges and experience of the Ethiopian rural health extension program: implications for reform and revitalization
Authors: Zerfu Taddese Alemu , Tareke Amare Abera , Biadgilign Sibhatu 
Published: November 2023

Abstract
Background
Despite remarkable gains over the past decade, mounting evidence suggests that Ethiopia’s rural health extension program (HEP) is facing serious implementation challenges. We investigated the current and potential future program design and implementation challenges of Ethiopia’s rural HEP based on the lived experiences of health extension workers (HEW) implementing the program at the grassroots level.

Methods
We employed a longitudinal qualitative exploration linked to a larger cluster-randomized trial (RCT) which was implemented in 282 villages randomly selected from 18 Kebeles of the Gedeo zone, southern Ethiopia. Data were collected using in-depth interviews with key informants, focus group discussion, and passive observation of program implementation. The data were analyzed manually using a thematic framework analysis approach. Themes and sub-themes were generated by condensing, summarizing, and synthesizing data collected in the field in the form of extended notes and field observation checklists.

Findings
Despite considerable gains in availing basic health services to the rural population, HEP seems to suffer serious design and implementation flaws that demand thoughtful and immediate adjustment. The design constraints span from the number and type of intervention packages to the means of dissemination (vehicle) as well as the target population emphasized. As such, some low-cost high-impact interventions that were strongly desired by the community were overlooked, while others were inappropriately packed. The means of distribution - female health extension workers trained with basic prevention skills, were lacking essential skills. They also had high burnout rates and with little engagement with men, were repeatedly mentioned flaws of the program demanding revitalization. Furthermore, the sheer structure of HEP precluded adult and adolescent men, non-reproductive women, and the elderly.

Conclusion
Despite significant gains over the last couple of months, Ethiopia’s rural HEP appears to have reached a tipping point that requires a comprehensive revamp of the program package, means of distribution, and target beneficiaries rather than the “usual” tweaks to reap maximum benefits.
Willingness, perceived facilitators and barriers to use remote care among healthcare professionals – a cross-sectional study
Authors: Thomassen Emil Eirik Kvernberg , Berg Inger Jorid , Kristianslund Eirik Klami , Tveter Anne Therese , Østerås Nina 
Published: November 2023

Abstract
Background
Remote care has the potential of improving access to timely care for people with inflammatory joint diseases (IJD), but there is limited knowledge on how this approach is regarded by healthcare professionals (HCP). This study aimed to examine willingness, perceived facilitators, and barriers to use remote care among HCP.

Methods
Employees at 20 rheumatology departments in Norway received a digital survey containing 16 statements regarding willingness, perceived facilitators and barriers to use remote care. Statements were scored using numeric rating scales (NRS, 0–10, 10 = strongly agree), and analysed in linear regression models. Open-ended responses with participant-defined facilitators and barriers were analysed using qualitative manifest analysis.

Results
A total of 130 participants from 17 departments completed the survey. The majority of participants were 45 years or older (n = 84, 54%), 54 (42%) were medical doctors, 48 (37%) nurses, and 27 (21%) were allied healthcare professionals, clinical leaders, or secretaries. A high willingness to use remote care was observed (median NRS: 9, IQR 8–10). The facilitator statement with the highest score was that patients save time and costs by using remote care, whereas the barrier statement with the highest score was the lack of physical examination. Willingness to use remote care was positively associated with the belief that patients wish to use it (β: 0.18, 95% CI: 0.00, 0.34), that patients in remission need less hospital visits (β: 0.30, 95% CI: 0.16, 0.43), and if remote care is widely adopted by co-workers (β: 0.27, 95% CI: 0.15, 0.39). Willingness was negatively associated with mistrust in the technical aspects of remote care (β: -0.26, 95% CI:-0.40, -0.11), and lack of physical examination (β: -0.24, 95% CI: -0.43, -0.06). The open-ended responses showed that technological equipment, eligible patients, user-friendly software, adequate training and work flow could be facilitators, but also that lack of these factors were considered barriers to use remote care.

Conclusion
This study showed that HCP have a high willingness to use remote care, and provides important new knowledge on perceived facilitators and barriers among HCP relevant for implementation of remote care for eligible patients with IJD.
Therapeutic effect and transcriptome-methylome characteristics of METTL3 inhibition in liver hepatocellular carcinoma
Authors: Liu Qingbin , Qi Jingjing , Li Weiyang , Tian Xinchen , Zhang Jiaqi , Liu Fen , Lu Xiulian , Zang Hengchang , Liu Chenqiao , Ma Changlin , Yu Yong , Jiang Shulong 
Published: November 2023

AbstractMethyltransferase-like 3 (METTL3) is the key subunit of methyltransferase complex responsible for catalyzing N6-methyladenosine (m6A) modification on mRNA, which is the most prevalent post-transcriptional modification in eukaryotes. In this study, we utilized online databases to analyze the association between METTL3 expression and various aspects of tumorigenesis, including gene methylation, immunity, and prognosis. Our investigation revealed that METTL3 serves as a prognostic marker and therapeutic target for liver hepatocellular carcinoma (LIHC). Through experimental studies, we observed frequent upregulation of METTL3 in LIHC tumor tissue and cells. Subsequent inhibition of METTL3 using a novel small molecule inhibitor, STM2457, significantly impeded tumor growth in LIHC cell lines, spheroids, and xenograft tumor model. Further, transcriptome and m6A sequencing of xenograft bodies unveiled that inhibition of METTL3-m6A altered genes enriched in SMAD and MAPK signaling pathways that are critical for tumorigenesis. These findings suggest that targeting METTL3 represents a promising therapeutic strategy for LIHC.
Exploiting innate immunity for cancer immunotherapy
Authors: Yi Ming , Li Tianye , Niu Mengke , Mei Qi , Zhao Bin , Chu Qian , Dai Zhijun , Wu Kongming 
Published: November 2023

AbstractImmunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.
Role of surgery in T4N0-3M0 esophageal cancer
Authors: Qi Chen , Hu Liwen , Zhang Chi , Wang Kang , Qiu Bingmei , Yi Jun , Shen Yi 
Published: November 2023

Abstract
Background
This study aimed to investigate an unsettled issue that whether T4 esophageal cancer could benefit from surgery.

Methods
Patients with T4N0-3M0 esophageal cancer from 2004 to 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were included in this study. Kaplan–Meier method, Cox proportional hazard regression, and propensity score matching (PSM) were used to compare overall survival (OS) between the surgery and no-surgery group.

Results
A total of 1822 patients were analyzed. The multivariable Cox regression showed the HR (95% CI) for surgery vs. no surgery was 0.492 (0.427–0.567) (P < 0.001) in T4N0-3M0 cohort, 0.471 (0.354–0.627) (P < 0.001) in T4aN0-3M0 cohort, and 0.480 (0.335–0.689) (P < 0.001) in T4bN0-3M0 cohort. The HR (95% CI) for neoadjuvant therapy plus surgery vs. no surgery and surgery without neoadjuvant therapy vs. no surgery were 0.548 (0.461–0.650) (P < 0.001) and 0.464 (0.375–0.574) (P < 0.001), respectively. No significant OS difference was observed between neoadjuvant therapy plus surgery and surgery without neoadjuvant therapy: 0.966 (0.686–1.360) (P = 0.843). Subgroup analyses and PSM-adjusted analyses showed consistent results.

Conclusion
Surgery might bring OS improvement for T4N0-3M0 esophageal cancer patients, no matter in T4a disease or in T4b disease. Surgery with and without neoadjuvant therapy might both achieve better OS than no surgery.
Hypoxia-inducible factor 1α modulates interstitial pneumonia-mediated lung cancer progression
Authors: Shimoji Kiyofumi , Nakashima Taku , Masuda Takeshi , Namba Masashi , Sakamoto Shinjiro , Yamaguchi Kakuhiro , Horimasu Yasushi , Mimae Takahiro , Miyamoto Shintaro , Iwamoto Hiroshi , Fujitaka Kazunori , Hamada Hironobu , Okada Morihito , Hattori Noboru 
Published: November 2023

Abstract
Background
The prognosis of patients with lung cancer accompanied by interstitial pneumonia is poorer than that of patients with lung cancer but without interstitial pneumonia. Moreover, the available therapeutic interventions for lung cancer patients with interstitial pneumonia are limited. Therefore, a new treatment strategy for these patients is required. The aim of the present study was to investigate the pathophysiological relationship between interstitial pneumonia and lung cancer and explore potential therapeutic agents.

Methods
A novel hybrid murine model of lung cancer with interstitial pneumonia was established via bleomycin-induced pulmonary fibrosis followed by orthotopic lung cancer cell transplantation into the lungs. Changes in tumor progression, lung fibrosis, RNA expression, cytokine levels, and tumor microenvironment in the lung cancer with interstitial pneumonia model were investigated, and therapeutic agents were examined. Additionally, clinical data and samples from patients with lung cancer accompanied by interstitial pneumonia were analyzed to explore the potential clinical significance of the findings.

Results
In the lung cancer with interstitial pneumonia model, accelerated tumor growth was observed based on an altered tumor microenvironment. RNA sequencing analysis revealed upregulation of the hypoxia-inducible factor 1 signaling pathway. These findings were consistent with those obtained for human samples. Moreover, we explored whether ascorbic acid could be an alternative treatment for lung cancer with interstitial pneumonia to avoid the disadvantages of hypoxia-inducible factor 1 inhibitors. Ascorbic acid successfully downregulated the hypoxia-inducible factor 1 signaling pathway and inhibited tumor progression and lung fibrosis.

Conclusions
The hypoxia-inducible factor 1 pathway is critical in lung cancer with interstitial pneumonia and could be a therapeutic target for mitigating interstitial pneumonia-mediated lung cancer progression.
6mA-StackingCV: an improved stacking ensemble model for predicting DNA N6-methyladenine site
Authors: Huang Guohua , Huang Xiaohong , Luo Wei 
Published: November 2023

AbstractDNA N6-adenine methylation (N6-methyladenine, 6mA) plays a key regulating role in the cellular processes. Precisely recognizing 6mA sites is of importance to further explore its biological functions. Although there are many developed computational methods for 6mA site prediction over the past decades, there is a large root left to improve. We presented a cross validation-based stacking ensemble model for 6mA site prediction, called 6mA-StackingCV. The 6mA-StackingCV is a type of meta-learning algorithm, which uses output of cross validation as input to the final classifier. The 6mA-StackingCV reached the state of the art performances in the Rosaceae independent test. Extensive tests demonstrated the stability and the flexibility of the 6mA-StackingCV. We implemented the 6mA-StackingCV as a user-friendly web application, which allows one to restrictively choose representations or learning algorithms. This application is freely available at http://www.biolscience.cn/6mA-stackingCV/. The source code and experimental data is available at https://github.com/Xiaohong-source/6mA-stackingCV.
Upregulated expression of miR-4443 and miR-4488 in drug resistant melanomas promotes migratory and invasive phenotypes through downregulation of intermediate filament nestin
Authors: Castaldo Vittorio , Minopoli Michele , Di Modugno Francesca , Sacconi Andrea , Liguoro Domenico , Frigerio Rachele , Ortolano Arianna , Di Martile Marta , Gesualdi Luisa , Madonna Gabriele , Capone Mariaelena , Cirombella Roberto , Catizone Angiolina , Del Bufalo Donatella , Vecchione Andrea , Carriero Maria Vincenza , Ascierto Paolo Antonio , Mancini Rita , Fattore Luigi , Ciliberto Gennaro 
Published: November 2023

Abstract
Background
BRAF-mutant melanoma patients benefit from the combinatorial treatments with BRAF and MEK inhibitors. However, acquired drug resistance strongly limits the efficacy of these targeted therapies in time. Recently, many findings have underscored the involvement of microRNAs as main drivers of drug resistance. In this context, we previously identified a subset of oncomiRs strongly up-regulated in drug-resistant melanomas. In this work, we shed light on the molecular role of two as yet poorly characterized oncomiRs, miR-4443 and miR-4488.

Methods
Invasion and migration have been determined by wound healing, transwell migration/invasion assays and Real Time Cell Analysis (RTCA) technology. miR-4488 and miR-4443 have been measured by qRT-PCR. Nestin levels have been tested by western blot, confocal immunofluorescence, immunohistochemical and flow cytometry analyses.

Results
We demonstrate that the two oncomiRs are responsible for the enhanced migratory and invasive phenotypes, that are a hallmark of drug resistant melanoma cells. Moreover, miR-4443 and miR-4488 promote an aberrant cytoskeletal reorganization witnessed by the increased number of stress fibers and cellular protrusions-like cancer cell invadopodia. Mechanistically, we identified the intermediate filament nestin as a molecular target of both oncomiRs. Finally, we have shown that nestin levels are able to predict response to treatments in melanoma patients.

Conclusions
Altogether these findings have profound translational implications in the attempt i) to develop miRNA-targeting therapies to mitigate the metastatic phenotypes of BRAF-mutant melanomas and ii) to identify novel biomarkers able to guide clinical decisions.

Graphical Abstract
Hsa_circ_0009092/miR-665/NLK signaling axis suppresses colorectal cancer progression via recruiting TAMs in the tumor microenvironment
Authors: Song Jialin , Liu Qing , Han Lei , Song Tiantian , Huang Sihao , Zhang Xinyao , He Qiuming , Liang Chenxi , Zhu Shuai , Xiong Bin 
Published: November 2023

Abstract
Background
It has been demonstrated that circularRNA (circRNAs) plays a critical role in various cancers. While the potential molecular mechanism of circRNAs in the progression of colorectal cancer (CRC) remains uncertain.

Methods
Differentially expressed circRNAs were identified by RNA sequencing. RT-qPCR detected the expression of circ_0009092, miR-665, and NLK in CRC tissues and cells. Functions of circ_0009092 on tumor cell proliferation, migration, and invasion were investigated by a series of in vitro assays. The underlying mechanism of circ_0009092 was explored by bioinformatics analysis, RNA immunoprecipitation (RIP) and luciferase assays. A co-culture assay in vitro was performed to detect the affection of circ_0009092 on macrophage recruitment in the tumor microenvironment (TME). A xenograft mouse model was used to explore the effect of circ_0009092 on tumor growth.

Results
Circ_0009092 was downregulated in CRCand predicted a good prognosis. Overexpression of circ_0009092 reduced tumor cell EMT, proliferation, migration, and invasion in vitro and in vivo. Mechanistically, circ_0009092 elevated the NLK expression via sponging miR-665 and suppressed the Wnt/β-catenin signaling pathway. EIF4EA3 induced circ_0009092 expression in CRC cells. In addition, NLK regulates phosphorylation and O-GlcNAcylation of STAT3 by binding to STAT3, thereby inhibiting CCL2 expression, in which it inhibits macrophage recruitment in the tumor microenvironment (TME).

Conclusion
EIF4A3 suppressed circ_0009092 biogenesis, whichinhibits CRC progression by sponging miR-665 to downregulate NLK. Circ_0009092/miR-665/NLK suppressed tumor EMT, proliferation, migration, and invasion by acting on the Wnt/β-catenin signaling pathway. NLK directly interacted with STAT3 and decreased the CCL2 expression, inhibiting the recruitment of tumor-associated macrophages (TAMs) in the TME. Our study provided novel insights into the roles of circ_0009092 as a novel promising prognostic and therapeutic target in CRC.
RSK3 switches cell fate: from stress-induced senescence to malignant progression
Authors: Huna Anda , Flaman Jean-Michel , Lodillinsky Catalina , Zhu Kexin , Makulyte Gabriela , Pakulska Victoria , Coute Yohann , Ruisseaux Clémence , Saintigny Pierre , Hernandez-Vargas Hector , Defossez Pierre-Antoine , Boissan Mathieu , Martin Nadine , Bernard David 
Published: November 2023

Abstract
Background
TGFβ induces several cell phenotypes including senescence, a stable cell cycle arrest accompanied by a secretory program, and epithelial-mesenchymal transition (EMT) in normal epithelial cells. During carcinogenesis cells lose the ability to undergo senescence in response to TGFβ but they maintain an EMT, which can contribute to tumor progression. Our aim was to identify mechanisms promoting TGFβ-induced senescence escape.

Methods
In vitro experiments were performed with primary human mammary epithelial cells (HMEC) immortalized by hTert. For kinase library screen and modulation of gene expression retroviral transduction was used. To characterize gene expression, RNA microarray with GSEA analysis and RT-qPCR were used. For protein level and localization, Western blot and immunofluorescence were performed. For senescence characterization crystal violet assay, Senescence Associated-β-Galactosidase activity, EdU staining were conducted. To determine RSK3 partners FLAG-baited immunoprecipitation and mass spectrometry-based proteomic analyses were performed. Proteosome activity and proteasome enrichment assays were performed. To validate the role of RSK3 in human breast cancer, analysis of METABRIC database was performed. Murine intraductal xenografts using MCF10DCIS.com cells were carried out, with histological and immunofluorescence analysis of mouse tissue sections.

Results
A screen with active kinases in HMECs upon TGFβ treatment identified that the serine threonine kinase RSK3, or RPS6KA2, a kinase mainly known to regulate cancer cell death including in breast cancer, reverted TGFβ-induced senescence. Interestingly, RSK3 expression decreased in response to TGFβ in a SMAD3-dependent manner, and its constitutive expression rescued SMAD3-induced senescence, indicating that a decrease in RSK3 itself contributes to TGFβ-induced senescence. Using transcriptomic analyses and affinity purification coupled to mass spectrometry-based proteomics, we unveiled that RSK3 regulates senescence by inhibiting the NF-κΒ pathway through the decrease in proteasome-mediated IκBα degradation. Strikingly, senescent TGFβ-treated HMECs display features of epithelial to mesenchymal transition (EMT) and during RSK3-induced senescence escaped HMECs conserve EMT features. Importantly, RSK3 expression is correlated with EMT and invasion, and inversely correlated with senescence and NF-κΒ in human claudin-low breast tumors and its expression enhances the formation of breast invasive tumors in the mouse mammary gland.

Conclusions
We conclude that RSK3 switches cell fate from senescence to malignancy in response to TGFβ signaling.
Psychoactive substances and previous hospital admissions, triage and length of stay in rural injuries: a prospective observational study
Authors: Wilson Thomas , Wisborg Torben , Vindenes Vigdis , Jamt Ragnhild Elèn Gjulem , Bogstrand Stig Tore 
Published: November 2023

Abstract
Background
Patients admitted to hospital after an injury are often found to have used psychoactive substances prior to the injury. The aim of this study was to investigate the associations between psychoactive substances (alcohol, psychoactive medicinal drugs and illicit drugs) and previous hospital admissions, triage and length of stay in the arctic Norwegian county of Finnmark.

Methods
Patients ≥ 18 years admitted due to injury to trauma hospitals in Finnmark from January 2015 to August 2016 were approached. Parameters regarding admittance and hospital stay were collected from 684 patients and blood was analysed for psychoactive substances. Using a prospective, observational design, time, triage, length of stay in hospital, use of intensive care unit (ICU), injury severity, Alcohol Use Disorder Identification Test—Consumption (AUDIT-C) and number of previous admittances were investigated by bivariable testing and logistical regression analysis.

Results
Of 943 patients approached, 81% consented and 684 were included in the study. During the weekend, 51.5% tested positive for any substance versus 27.1% Monday–Friday. No associations were identified between testing positive and either triage or injury severity for any substance group although triage level was lower in patients with AUDIT-C ≥ 5. Short length of stay was associated with alcohol use prior to injury [odds ratio (OR) 0.48 for staying > 12 h, confidence interval (CI) 0.25–0.90]. The OR for staying > 24 h in the ICU when positive for an illicit substance was 6.33 (CI 1.79–22.32) while negatively associated with an AUDIT-C ≥ 5 (OR 0.30, CI 0.10–0.92). Patients testing positive for a substance had more often previously been admitted with the strongest association for illicit drugs (OR 6.43 (CI 1.47–28.08), compared to patients in whom no substances were detected.

Conclusions
Triage level and injury severity were not associated with psychoactive substance use. Patients using alcohol are more often discharged early, but illicit substances were associated with longer ICU stays. All psychoactive substance groups were associated with having been previously admitted.