bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unconventional activation of PRKDC by TNF-α: deciphering its crucial role in Th1-mediated inflammation beyond DNA repair as part of the DNA-PK complex
Authors: Ghonim Mohamed A. , Ju Jihang , Pyakurel Kusma , Ibba Salome V. , Abouzeid Mai M. , Rady Hamada F. , Matsuyama Shigemi , Del Valle Luis , Boulares A. Hamid 
Published: April 2024

AbstractBackgroundThe DNA-dependent protein kinase (DNA-PK) complex comprises a catalytic (PRKDC) and two requisite DNA-binding (Ku70/Ku80) subunits. The role of the complex in repairing double-stranded DNA breaks (DSBs) is established, but its role in inflammation, as a complex or individual subunits, remains elusive. While only ~ 1% of PRKDC is necessary for DNA repair, we reported that partial inhibition blocks asthma in mice without causing SCID.MethodsWe investigated the central role of PRKDC in inflammation and its potential association with DNA repair. We also elucidated the relationship between inflammatory cytokines (e.g., TNF-α) and PRKDC by analyzing its connections to inflammatory kinases. Human cell lines, primary human endothelial cells, and mouse fibroblasts were used to conduct the in vitro studies. For animal studies, LPS- and oxazolone-induced mouse models of acute lung injury (ALI) and delayed-type hypersensitivity (DHT) were used. Wild-type, PRKDC+/−, or Ku70+/−mice used in this study.ResultsA ~ 50% reduction in PRKDC markedly blocked TNF-α-induced expression of inflammatory factors (e.g., ICAM-1/VCAM-1). PRKDC regulates Th1-mediated inflammation, such as DHT and ALI, and its role is highly sensitive to inhibition achieved by gene heterozygosity or pharmacologically. In endothelial or epithelial cells, TNF-α promoted rapid PRKDC phosphorylation in a fashion resembling that induced by, but independent of, DSBs. Ku70 heterozygosity exerted little to no effect on ALI in mice, and whatever effect it had was associated with a specific increase in MCP-1 in the lungs and systemically. While Ku70 knockout blocked VP-16-induced PRKDC phosphorylation, it did not prevent TNF-α − induced phosphorylation of the kinase, suggesting Ku70 dispensability. Immunoprecipitation studies revealed that PRKDC transiently interacts with p38MAPK. Inhibition of p38MAPK blocked TNF-α-induced PRKDC phosphorylation. Direct phosphorylation of PRKDC by p38MAPK was demonstrated using a cell-free system.ConclusionsThis study presents compelling evidence that PRKDC functions independently of the DNA-PK complex, emphasizing its central role in Th1-mediated inflammation. The distinct functionality of PRKDC as an individual enzyme, its remarkable sensitivity to inhibition, and its phosphorylation by p38MAPK offer promising therapeutic opportunities to mitigate inflammation while sparing DNA repair processes. These findings expand our understanding of PRKDC biology and open new avenues for targeted anti-inflammatory interventions.
Prioritization of maternal and newborn health policies and their implementation in the eastern conflict affected areas of the Democratic Republic of Congo: a political economy analysis
Authors: Bigirinama Rosine Nshobole , Mothupi Mamothena Carol , Mwene-Batu Pacifique Lyabayungu , Kozuki Naoko , Chiribagula Christian Zalinga , Chimanuka Christine Murhim’alika , Ngaboyeka Gaylord Amani , Bisimwa Ghislain Balaluka 
Published: April 2024

Abstract
Background
Maternal and neonatal mortality remains a major concern in the Democratic Republic of Congo (DRC), and the country’s protracted crisis context exacerbates the problem. This political economy analysis examines the maternal and newborn health (MNH) prioritization in the DRC, focussing specifically on the conflict-affected regions of North and South Kivu. The aim is to understand the factors that facilitate or hinder the prioritization of MNH policy development and implementation by the Congolese government and other key actors at national level and in the provinces of North and South Kivu.

Methods
Using a health policy triangle framework, data collection consisted of in-depth interviews with key actors at different levels of the health system, combined with a desk review. Qualitative data were analysed using inductive and then deductive approaches, exploring the content, process, actor dynamics, contextual factors and gender-related factors influencing MNH policy development and implementation.

Results
The study highlighted the challenges of prioritizing policies in the face of competing health and security emergencies, limited resources and governance issues. The universal health coverage policy seems to offer hope for improving access to MNH services. Results also revealed the importance of international partnerships and global financial mechanisms in the development of MNH strategies. They reveal huge gender disparities in the MNH sector at all levels, and the need to consider cultural factors that can positively or negatively impact the success of MNH policies in crisis zones.

Conclusions
MNH is a high priority in DRC, yet implementation faces hurdles due to financial constraints, political influences, conflicts and gender disparities. Addressing these challenges requires tailored community-based strategies, political engagement, support for health personnel and empowerment of women in crisis areas for better MNH outcomes.
Rapid cost-effectiveness analysis: hemodialysis versus peritoneal dialysis for patients with acute kidney injury in Rwanda
Authors: Nemzoff Cassandra , Ahmed Nurilign , Olufiranye Tolulope , Igiraneza Grace , Kalisa Ina , Chadha Sukrit , Hakiba Solange , Rulisa Alexis , Riro Matiko , Chalkidou Kalipso , Ruiz Francis 
Published: April 2024

Abstract
Background
To ensure the long-term sustainability of its Community-Based Health Insurance scheme, the Government of Rwanda is working on using Health Technology Assessment (HTA) to prioritize its resources for health. The objectives of the study were to rapidly assess (1) the cost-effectiveness and (2) the budget impact of providing PD versus HD for patients with acute kidney injury (AKI) in the tertiary care setting in Rwanda.

Methods
A rapid cost-effectiveness analysis for patients with AKI was conducted to support prioritization. An ‘adaptive’ HTA approach was undertaken by adjusting the international Decision Support Initiative reference case for time and data constraints. Available local and international data were used to analyze the cost-effectiveness and budget impact of peritoneal dialysis (PD) compared with hemodialysis (HD) in the tertiary hospital setting.

Results
The analysis found that HD was slightly more effective and slightly more expensive in the payer perspective for most patients with AKI (aged 15–49). HD appeared to be cost-effective when only comparing these two dialysis strategies with an incremental cost-effectiveness ratio of 378,174 Rwandan francs (RWF) or 367 United States dollars (US$), at a threshold of 0.5 × gross domestic product per capita (RWF 444,074 or US$431). Sensitivity analysis found that reducing the cost of HD kits would make HD even more cost-effective. Uncertainty regarding PD costs remains.
Budget impact analysis demonstrated that reducing the cost of the biggest cost driver, HD kits, could produce significantly more savings in five years than switching to PD. Thus, price negotiations could significantly improve the efficiency of HD provision.

Conclusion
Dialysis is costly and covered by insurance in many countries for the financial protection of patients. This analysis enabled policymakers to make evidence-based decisions to improve the efficiency of dialysis provision.
The c-Abl-RACK1-FAK signaling axis promotes renal fibrosis in mice through regulating fibroblast-myofibroblast transition
Authors: Bao Qianyi , Wang Anyu , Hong Wenxuan , Wang Yushu , Li Baojie , He Lin , Yuan Xiaodong , Ma Gang 
Published: April 2024

Abstract
Background
Renal fibrosis is a prevalent manifestation of chronic kidney disease (CKD), and effective treatments for this disease are currently lacking. Myofibroblasts, which originate from interstitial fibroblasts, aggregate in the renal interstitium, leading to significant accumulation of extracellular matrix and impairment of renal function. The nonreceptor tyrosine kinase c-Abl (encoded by the Abl1 gene) has been implicated in the development of renal fibrosis. However, the precise role of c-Abl in this process and its involvement in fibroblast-myofibroblast transition (FMT) remain poorly understood.

Methods
To investigate the effect of c-Abl in FMT during renal fibrosis, we investigated the expression of c-Abl in fibrotic renal tissues of patients with CKD and mouse models. We studied the phenotypic changes in fibroblast or myofibroblast-specific c-Abl conditional knockout mice. We explored the potential targets of c-Abl in NRK-49F fibroblasts.

Results
In this study, fibrotic mouse and cell models demonstrated that c-Abl deficiency in fibroblasts mitigated fibrosis by suppressing fibroblast activation, fibroblast-myofibroblast transition, and extracellular matrix deposition. Mechanistically, c-Abl maintains the stability of the RACK1 protein, which serves as a scaffold for proteins such as c-Abl and focal adhesion kinase at focal adhesions, driving fibroblast activation and differentiation during renal fibrosis. Moreover, specifically targeting c-Abl deletion in renal myofibroblasts could prove beneficial in established kidney fibrosis by reducing RACK1 expression and diminishing the extent of fibrosis.

Conclusions
Our findings suggest that c-Abl plays a pathogenic role in interstitial fibrosis through the regulation of RACK1 protein stabilization and myofibroblast differentiation, suggesting a promising strategy for the treatment of CKD.
​Comprehensive mendelian randomization analysis of plasma proteomics to identify new therapeutic targets for the treatment of coronary heart disease and myocardial infarction
Authors: Sun Ziyi , Yun Zhangjun , Lin Jianguo , Sun Xiaoning , Wang Qingqing , Duan Jinlong , Li Cheng , Zhang Xiaoxiao , Xu Siyu , Wang Zeqi , Xiong Xingjiang , Yao Kuiwu 
Published: April 2024

Abstract
Background
Ischemic heart disease is one of the leading causes of mortality worldwide, and thus calls for development of more effective therapeutic strategies. This study aimed to identify potential therapeutic targets for coronary heart disease (CHD) and myocardial infarction (MI) by investigating the causal relationship between plasma proteins and these conditions.

Methods
A two-sample Mendelian randomization (MR) study was performed to evaluate more than 1600 plasma proteins for their causal associations with CHD and MI. The MR findings were further confirmed through Bayesian colocalization, Summary-data-based Mendelian Randomization (SMR), and Transcriptome-Wide Association Studies (TWAS) analyses. Further analyses, including enrichment analysis, single-cell analysis, MR analysis of cardiovascular risk factors, phenome-wide Mendelian Randomization (Phe-MR), and protein-protein interaction (PPI) network construction were conducted to verify the roles of selected causal proteins.

Results
Thirteen proteins were causally associated with CHD, seven of which were also causal for MI. Among them, FES and PCSK9 were causal proteins for both diseases as determined by several analytical methods. PCSK9 was a risk factor of CHD (OR = 1.25, 95% CI: 1.13–1.38, P = 7.47E-06) and MI (OR = 1.36, 95% CI: 1.21–1.54, P = 2.30E-07), whereas FES was protective against CHD (OR = 0.68, 95% CI: 0.59–0.79, P = 6.40E-07) and MI (OR = 0.65, 95% CI: 0.54–0.77, P = 5.38E-07). Further validation through enrichment and single-cell analysis confirmed the causal effects of these proteins. Moreover, MR analysis of cardiovascular risk factors, Phe-MR, and PPI network provided insights into the potential drug development based on the proteins.

Conclusions
This study investigated the causal pathways associated with CHD and MI, highlighting the protective and risk roles of FES and PCSK9, respectively. FES. Specifically, the results showed that these proteins are promising therapeutic targets for future drug development.
Exosomes in the pathogenesis and treatment of cancer-related cachexia
Authors: Ru Qin , Chen Lin , Xu Guodong , Wu Yuxiang 
Published: April 2024

AbstractCancer-related cachexia is a metabolic syndrome characterized by weight loss, adipose tissue decomposition, and progressive skeletal muscle atrophy. It is a major complication of many advanced cancers and seriously affects the quality of life and survival of cancer patients. However, the specific molecules that mediate cancer-related cachexia remain elusive, and the fundamental cellular and molecular mechanisms associated with muscle atrophy and lipidolysis in cancer patients still need to be investigated. Exosomes, a newly discovered class of small extracellular vesicles that facilitate intercellular communication, have a significant role in the onset and development of various cancers. Studies have shown that exosomes play a role in the onset and progression of cancer-related cachexia by transporting active molecules such as nucleic acids and proteins. This review aimed to provide an overview of exosome developments in cancer-induced skeletal muscle atrophy and adipose tissue degradation. More importantly, exosomes were shown to have potential as diagnostic markers or therapeutic strategies for cachexia and were prospected, providing novel strategies for the diagnosis and treatment of cancer-related cachexia.
Preoperative handgrip strength can predict early postoperative shoulder function in patients undergoing arthroscopic rotator cuff repair
Authors: Liu Yu-Cheng , Huang Shu-Wei , Adams Christopher R. , Lin Chung-Ying , Chen Yu-Pin , Kuo Yi-Jie , Chuang Tai-Yuan 
Published: April 2024

Abstract
Background
Rotator cuff tears (RCTs) are a common musculoskeletal disorder, and arthroscopic rotator cuff repair (ARCR) is widely performed for tendon repair. Handgrip strength correlates with rotator cuff function; however, whether preoperative grip strength can predict functional outcomes in patients undergoing ARCR remains unknown. This study aimed to investigate the correlation between preoperative grip strength and postoperative shoulder function following ARCR.

Methods
A total of 52 patients with full-thickness repairable RCTs were prospectively enrolled. Baseline parameters, namely patient characteristics and intraoperative findings, were included for analysis. Postoperative shoulder functional outcomes were assessed using the Quick Disabilities of the Arm, Shoulder, and Hand (QDASH) questionnaire and Constant–Murley scores (CMSs). Patients were followed up and evaluated at three and six months after ARCR. The effects of baseline parameters on postoperative outcomes were measured using generalized estimating equations.

Results
At three and six months postoperatively, all clinical outcomes evaluated exhibited significant improvement from baseline following ARCR. Within 6 months postoperatively, higher preoperative grip strength was significantly correlated with higher CMSs (β = 0.470, p = 0.022), whereas increased numbers of total suture anchors were significantly correlated with decreased CMSs (β =  − 4.361, p = 0.03). Higher body mass index was significantly correlated with higher postoperative QDASH scores (β = 1.561, p = 0.03) during follow-up.

Conclusions
Higher baseline grip strength predicts more favorable postoperative shoulder function following ARCR. A preoperative grip strength test in orthopedic clinics may serve as a predictor for postoperative shoulder functional recovery in patients undergoing ARCR.
A systematic literature review on the health-related quality of life and economic burden of Fabry disease
Authors: Jovanovic Ana , Miller-Hodges Eve , Castriota Felicia , Takyar Shweta , Howitt Heena , Ayodele Olulade 
Published: April 2024

AbstractBackgroundFabry disease (FD) is a rare lysosomal storage disease associated with glycolipid accumulation that impacts multiple physiological systems. We conducted a systematic literature review (SLR) to characterize the humanistic (quality of life [QoL]) and economic burden of FD.MethodsSearches were conducted in the Embase, MEDLINE®, and MEDLINE®In-Process databases from inception to January 19, 2022. Conference abstracts of specified congresses were manually searched. Additional searches were performed in the Cochrane and ProQuest databases for the humanistic SLR and the National Health Service Economic Evaluations Database for the economic SLR. Studies of patients with FD of any sex, race, and age, and published in the English language were included. There was no restriction on intervention or comparator. For the humanistic SLR, studies that reported utility data, database/registry-based studies, questionnaires/surveys, and cohort studies were included. For the economic SLR, studies reporting economic evaluations or assessing the cost of illness and resource use were included.ResultsOf the 1363 records identified in the humanistic search, 36 studies were included. The most commonly used QoL assessments were the 36-item Short-Form Health Survey (n = 16), EQ-5D questionnaire descriptive system or visual analog scale (n = 9), and the Brief Pain Inventory (n = 8). Reduced QoL was reported in patients with FD compared with healthy populations across multiple domains, including pain, physical functioning, and depressive symptoms. Multiple variables—including sex, age, disease severity, and treatment status—impacted QoL. Of the 711 records identified in the economic burden search, 18 studies were included. FD was associated with high cost and healthcare resource use. Contributors to the cost burden included enzyme replacement therapy, healthcare, and social care. In the seven studies that reported health utility values, lower utility scores were generally associated with more complications (including cardiac, renal, and cerebrovascular morbidities) and with classical disease in males.ConclusionFD remains associated with a high cost and healthcare resource use burden, and reduced QoL compared with healthy populations. Integrating information from QoL and economic assessments may help to identify interventions that are likely to be of most value to patients with FD.
LOXL1-AS1 contributes to metastasis in sonic-hedgehog medulloblastoma by promoting cancer stem-like phenotypes
Authors: Do Anh Duy , Wu Kuo-Sheng , Chu Shing-Shung , Giang Le Hien , Lin Yu-Ling , Chang Che-Chang , Wong Tai-Tong , Hsieh Chia-Ling , Sung Shian-Ying 
Published: April 2024

Abstract
Background
Medulloblastomas (MBs) are one of the most common malignant brain tumor types in children. MB prognosis, despite improvement in recent years, still depends on clinical and biological risk factors. Metastasis is the leading cause of MB-related deaths, which highlights an unmet need for risk stratification and targeted therapy to improve clinical outcomes. Among the four molecular subgroups, sonic-hedgehog (SHH)-MB harbors clinical and genetic heterogeneity with a subset of high-risk cases. Recently, long non-coding (lnc)RNAs were implied to contribute to cancer malignant progression, but their role in MB remains unclear. This study aimed to identify pro-malignant lncRNAs that have prognostic and therapeutic significance in SHH-MB.

Methods
The Daoy SHH-MB cell line was engineered for ectopic expression of MYCN, a genetic signature of SHH-MB. MYCN-associated lncRNA genes were identified using RNA-sequencing data and were validated in SHH-MB cell lines, MB tissue samples, and patient cohort datasets. SHH-MB cells with genetic manipulation of the candidate lncRNA were evaluated for metastatic phenotypes in vitro, including cell migration, invasion, sphere formation, and expressions of stemness markers. An orthotopic xenograft mouse model was used to evaluate metastasis occurrence and survival. Finally, bioinformatic screening and in vitro assays were performed to explore downstream mechanisms.

Results
Elevated lncRNA LOXL1-AS1 expression was identified in MYCN-expressing Daoy cells and MYCN-amplified SHH-MB tumors, and was significantly associated with lower survival in SHH-MB patients. Functionally, LOXL1-AS1 promoted SHH-MB cell migration and cancer stemness in vitro. In mice, MYCN-expressing Daoy cells exhibited a high metastatic rate and adverse effects on survival, both of which were suppressed under LOLX1-AS1 perturbation. Integrative bioinformatic analyses revealed associations of LOXL1-AS1 with processes of cancer stemness, cell differentiation, and the epithelial-mesenchymal transition. LOXL1-AS1 positively regulated the expression of transforming growth factor (TGF)-β2. Knockdown of TGF-β2 in SHH-MB cells significantly abrogated their LOXL1-AS1-mediated prometastatic functions.

Conclusions
This study proved the functional significance of LOXL1-AS1 in SHH-MB metastasis by its promotion of TGF-β2-mediated cancer stem-like phenotypes, providing both prognostic and therapeutic potentials for targeting SHH-MB metastasis.
The effect of dexmedetomidine on the postoperative recovery of patients with severe traumatic brain injury undergoing craniotomy treatment: a retrospective study
Authors: Deng Zhu , Gu Yong , Luo Le , Deng Lin , Li Yingwei , Huang Wanyong 
Published: April 2024

Abstract
Background
Traumatic brain injury (TBI) has been a worldwide problem for neurosurgeons. Patients with severe TBI may undergo craniotomy. These patients often require sedation after craniotomy. Dexmedetomidine (DEX) has been used in patients receiving anesthesia and in intensive care units. Not much is known about the postoperative effect of DEX in patients with severe TBIs undergoing craniotomy. The purpose of this study was to explore the effects of postoperative DEX administration on severe TBI patients who underwent craniotomy.

Methods
Patients who underwent craniectomy for severe TBI at our hospital between January 2019 and February 2022 were included in this study. The patients were admitted to the intensive care unit (ICU) after surgery to receive sedative medication. The patients were then divided into DEX and control groups. We analyzed the sedation, hemodynamics, and other conditions of the patients (hypoxemia, duration of ventilation during endotracheal intubation, whether tracheotomy was performed, and the duration in the ICU) during their ICU stay. Other conditions, such as delirium after the patients were transferred to the general ward, were also analyzed.

Results
A total of 122 patients were included in this study. Among them, 53 patients received DEX, and the remaining 69 did not. The incidence of delirium in the general ward in the DEX group was significantly lower than that in the control group (P < 0.05). The incidence of bradycardia in the control group was significantly lower than that in the DEX group (P < 0.05). Other data from the DEX group and the control group (hypotension, hypoxemia, etc.) were not significantly different (P > 0.05).

Conclusion
The use of DEX in the ICU can effectively reduce the incidence of delirium in patients who return to the general ward after craniotomy. DEX had no adverse effect on the prognosis of patients other than causing bradycardia.