bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trametinib sensitizes KRAS-mutant lung adenocarcinoma tumors to PD-1/PD-L1 axis blockade via Id1 downregulation
Authors: Puyalto Ander , Rodríguez-Remírez María , López Inés , Macaya Irati , Guruceaga Elizabeth , Olmedo María , Vilalta-Lacarra Anna , Welch Connor , Sandiego Sergio , Vicent Silvestre , Valencia Karmele , Calvo Alfonso , Pio Ruben , Raez Luis E. , Rolfo Christian , Ajona Daniel , Gil-Bazo Ignacio 
Published: April 2024

Abstract
Background
The identification of novel therapeutic strategies to overcome resistance to the MEK inhibitor trametinib in mutant KRAS lung adenocarcinoma (LUAD) is a challenge. This study analyzes the effects of trametinib on Id1 protein, a key factor involved in the KRAS oncogenic pathway, and investigates the role of Id1 in the acquired resistance to trametinib as well as the synergistic anticancer effect of trametinib combined with immunotherapy in KRAS-mutant LUAD.

Methods
We evaluated the effects of trametinib on KRAS-mutant LUAD by Western blot, RNA-seq and different syngeneic mouse models. Genetic modulation of Id1 expression was performed in KRAS-mutant LUAD cells by lentiviral or retroviral transductions of specific vectors. Cell viability was assessed by cell proliferation and colony formation assays. PD-L1 expression and apoptosis were measured by flow cytometry. The anti-tumor efficacy of the combined treatment with trametinib and PD-1 blockade was investigated in KRAS-mutant LUAD mouse models, and the effects on the tumor immune infiltrate were analyzed by flow cytometry and immunohistochemistry.

Results
We found that trametinib activates the proteasome-ubiquitin system to downregulate Id1 in KRAS-mutant LUAD tumors. Moreover, we found that Id1 plays a major role in the acquired resistance to trametinib treatment in KRAS-mutant LUAD cells. Using two preclinical syngeneic KRAS-mutant LUAD mouse models, we found that trametinib synergizes with PD-1/PD-L1 blockade to hamper lung cancer progression and increase survival. This anti-tumor activity depended on trametinib-mediated Id1 reduction and was associated with a less immunosuppressive tumor microenvironment and increased PD-L1 expression on tumor cells.

Conclusions
Our data demonstrate that Id1 expression is involved in the resistance to trametinib and in the synergistic effect of trametinib with anti-PD-1 therapy in KRAS-mutant LUAD tumors. These findings suggest a potential therapeutic approach for immunotherapy-refractory KRAS-mutant lung cancers.

Graphical Abstract
Dose-response associations of triglyceride to high-density lipoprotein cholesterol ratio and triglyceride–glucose index with arterial stiffness risk
Authors: Zhang Wenkai , Huo Weifeng , Hu Huifang , Li Tianze , Yuan Lijun , Zhang Jinli , Feng Yifei , Wu Yuying , Fu Xueru , Ke Yamin , Wang Mengmeng , Wang Longkang , Chen Yaobing , Gao Yajuan , Li Xi , Sun Liang , Pang Jinyuan , Zheng Zeqiang , Hu Fulan , Zhang Ming , Liu Yu , Hu Dongsheng , Zhao Yang 
Published: April 2024

Abstract
Background
The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and triglyceride-glucose (TyG) index are novel indexes for insulin resistance (IR). We aimed to evaluate associations of TG/HDL-C and TyG with arterial stiffness risk.

Methods
We enrolled 1979 participants from the Rural Chinese Cohort Study, examining arterial stiffness by brachial-ankle pulse wave velocity (baPWV). Logistic and linear regression models were employed to calculate effect estimates. For meta-analysis, we searched relevant articles from PubMed, Embase and Web of Science up to August 26, 2023. The fixed-effects or random-effects models were used to calculate the pooled estimates. We evaluated dose-response associations using restricted cubic splines.

Results
For cross-sectional studies, the adjusted ORs (95%CIs) for arterial stiffness were 1.12 (1.01–1.23) and 1.78 (1.38–2.30) for per 1 unit increment in TG/HDL-C and TyG. In the meta-analysis, the pooled ORs (95% CIs) were 1.26 (1.14–1.39) and 1.57 (1.36–1.82) for per 1 unit increment of TG/HDL-C and TyG. Additionally, both TG/HDL-C and TyG were positively related to PWV, with β of 0.09 (95% CI 0.04–0.14) and 0.57 (95% CI 0.35–0.78) m/s. We also found linear associations of TG/HDL-C and TyG with arterial stiffness risk.

Conclusions
High TG/HDL-C and TyG were related to increased arterial stiffness risk, indicating TG/HDL-C and TyG may be convincing predictors of arterial stiffness.
L-shaped association between lean body mass to visceral fat mass ratio with hyperuricemia: a cross-sectional study
Authors: Li Longti , Shao Ya , Zhong Huiqin , Wang Yu , Zhang Rong , Gong Boxiong , Yin Xiaoxv 
Published: April 2024

Abstract
Background
Insufficient attention has been given to examining the correlation between body composition and hyperuricemia, leading to inconsistent findings. The primary objective of this research is to explore the association between lean body mass index (LMI), visceral fat mass index (VFMI), and hyperuricemia. A specific emphasis will be placed on assessing the link between the ratio of lean body mass to visceral fat mass (LMI/VFMI) and hyperuricemia.

Methods
The present study employed a cross-sectional design and involved a total of 9,646 individuals who participated in the National Health and Nutrition Examination Survey (NHANES). To explore the associations among the variables, logistic and linear regressions were employed. Additionally, subgroup analyses and sensitivity analyses were conducted based on various characteristics.

Results
The results showed that LMI was positively associated with hyperuricemia (for Per-SD: OR = 1.88, 95%CI: 1.75, 2.01; for quartiles [Q4:Q1]: OR = 5.37, 95%CI: 4.31, 6.69). Meanwhile, VFMI showed a positive association with hyperuricemia (for Per-SD: OR = 2.02, 95%CI: 1.88, 2.16; for quartiles [Q4:Q1]: OR =8.37, 95%CI: 6.70, 10.47). When considering the effects of In LMI/VFMI, an L-shaped negative association with hyperuricemia was observed (for Per-SD: OR = 0.45, 95%CI: 0.42, 0.49; for quartiles [Q4:Q1]: OR = 0.16, 95%CI: 0.13, 0.20). Subgroup and sensitivity analyses demonstrated the robustness of this association across different subgroups. Additionally, the segmented regression analysis indicated a saturation effect of 5.64 for the In LMI/VFMI with hyperuricemia (OR = 0.20, 95%CI: 0.17, 0.24). For every 2.72-fold increase of In LMI/VFMI, the risk of hyperuricemia was reduced by 80%.

Conclusion
The LMI/VFMI ratio is non-linearly associated with serum uric acid. Whether this association is causal needs to be confirmed in further longitudinal studies or Mendelian randomization.
The redox-active defensive Selenoprotein T as a novel stress sensor protein playing a key role in the pathophysiology of heart failure
Authors: De Bartolo Anna , Pasqua Teresa , Romeo Naomi , Rago Vittoria , Perrotta Ida , Giordano Francesca , Granieri Maria Concetta , Marrone Alessandro , Mazza Rosa , Cerra Maria Carmela , Lefranc Benjamin , Leprince Jérôme , Anouar Youssef , Angelone Tommaso , Rocca Carmine 
Published: April 2024

AbstractMaladaptive cardiac hypertrophy contributes to the development of heart failure (HF). The oxidoreductase Selenoprotein T (SELENOT) emerged as a key regulator during rat cardiogenesis and acute cardiac protection. However, its action in chronic settings of cardiac dysfunction is not understood. Here, we investigated the role of SELENOT in the pathophysiology of HF: (i) by designing a small peptide (PSELT), recapitulating SELENOT activity via the redox site, and assessed its beneficial action in a preclinical model of HF [aged spontaneously hypertensive heart failure (SHHF) rats] and against isoproterenol (ISO)-induced hypertrophy in rat ventricular H9c2 and adult human AC16 cardiomyocytes; (ii) by evaluating the SELENOT intra-cardiomyocyte production and secretion under hypertrophied stimulation. Results showed that PSELT attenuated systemic inflammation, lipopolysaccharide (LPS)-induced macrophage M1 polarization, myocardial injury, and the severe ultrastructural alterations, while counteracting key mediators of cardiac fibrosis, aging, and DNA damage and restoring desmin downregulation and SELENOT upregulation in the failing hearts. In the hemodynamic assessment, PSELT improved the contractile impairment at baseline and following ischemia/reperfusion injury, and reduced infarct size in normal and failing hearts. At cellular level, PSELT counteracted ISO-mediated hypertrophy and ultrastructural alterations through its redox motif, while mitigating ISO-triggered SELENOT intracellular production and secretion, a phenomenon that presumably reflects the extent of cell damage. Altogether, these results indicate that SELENOT could represent a novel sensor of hypertrophied cardiomyocytes and a potential PSELT-based new therapeutic approach in myocardial hypertrophy and HF.
Graphical Abstract
HERV-W upregulation expression in bipolar disorder and schizophrenia: unraveling potential links to systemic immune/inflammation status
Authors: Rangel Sara Coelho , da Silva Michelly Damasceno , Natrielli Filho Décio Gilberto , Santos Samuel Nascimento , do Amaral Jonatas Bussador , Victor Jefferson Russo , Silva Kevin Cezar Nascimento , Tuleta Izabela Dorota , França Carolina Nunes , Shio Marina Tiemi , Neves Lucas Melo , Bachi André Luis Lacerda , da Silva Nali Luiz Henrique 
Published: April 2024

Abstract
Background
Bipolar disorder (BD) and schizophrenia (SZ) are the two main mental disorders with unknown etiology that significantly impact individuals’ quality of life. The potential pro-inflammatory role in their pathogenesis is postulated and Human Endogenous Retrovirus W (HERV-W) is an emerging candidate to modulate this pathogenic finding. HERVs, ancient retroviruses in the human genome, may play roles in inflammation and disease pathogenesis. Despite HERVs’ involvement in autoimmune diseases, their influence on mental disorders remains underexplored. Therefore, the aim of this study was to assess the level of HERV-W-env expression and the systemic inflammatory profile through the concentration of IL-2, IL-4, IL-6, IL-10, TNF-α and INF-γ cytokines in BD and SZ patients.

Results
All participants showed HERV-W-env expression, but its expression was higher in mental disorder patients (p < 0.01) than in control. When separated, SZ individuals exhibited higher HERV-W expression than the control group (p < 0.01). Higher serum levels of TNF-α and IL-10 were found in BD (p = 0.0001 and p = 0.001, respectively) and SZ (p = 0.01) and p = 0.01, respectively) than in the control group, while SZ showed decreased levels IFN-γ and IL-2 as compared to controls (p = 0.05) and BD patients (p = 0.05), respectively. Higher TNF-α/IL-4 and TNF-α/IL-10 ratios, and lower IFN-γ/IL-10 were observed in BD and SZ patients than controls. Significant negative correlation between HERV-W-env expression and IL-10 (r=-0.47 p < 0.05), as well as positive correlations between HERV-W-env expression and TNF-α/IL-10 or IFN-γ/IL-10 ratios (r = 0.48 p < 0.05 and r = 0.46 p < 0.05, respectively) were found in BD patients.

Conclusion
These findings suggest not only a potential link between HERV-W-env expression both in BD and SZ, but also a possible involvement of systemic inflammatory status in BD patients.
Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection
Authors: Luo Kai , Peters Brandilyn A. , Moon Jee-Young , Xue Xiaonan , Wang Zheng , Usyk Mykhaylo , Hanna David B. , Landay Alan L. , Schneider Michael F. , Gustafson Deborah , Weber Kathleen M. , French Audrey , Sharma Anjali , Anastos Kathryn , Wang Tao , Brown Todd , Clish Clary B. , Kaplan Robert C. , Knight Rob , Burk Robert D. , Qi Qibin 
Published: April 2024

Abstract
Background
Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear.

Methods
We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women’s Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria–diabetes associations are explained by altered metabolites and proteins.

Results
Seven gut bacterial genera were identified to be associated with diabetes (FDR-q <  0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q <  0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera–diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV.

Conclusion
Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera–diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.
Self-management including exercise, education and activity modification compared to usual care for adolescents with Osgood-Schlatter (the SOGOOD trial): protocol of a randomized controlled superiority trial
Authors: Krommes Kasper , Thorborg Kristian , Clausen Mikkel Bek , Rathleff Michael Skovdal , Olesen Jens Lykkegaard , Kallemose Thomas , Hölmich Per 
Published: April 2024

Abstract
Background
Osgood-Schlatter is the most frequent growth-related injury affecting about 10% of physically active adolescents. It can cause long-term pain and limitations in sports and physical activity, with potential sequela well into adulthood. The management of Osgood-Schlatter is very heterogeneous. Recent systematic reviews have found low level evidence for surgical intervention and injection therapies, and an absence of studies on conservative management. Recently, a novel self-management approach with exercise, education, and activity modification, demonstrated favorable outcomes for adolescents with patellofemoral pain and Osgood-Schlatter in prospective cohort studies.

Aim
The aim of this trial is to assess the effectiveness of the novel self-management approach compared to usual care in improving self-reported knee-related function in sport (measured using the KOOS-child ‘Sport/play’ subscale) after a 5-month period.

Methods
This trial is a pragmatic, assessor-blinded, randomized controlled trial with a two-group parallel arm design, including participants aged 10–16 years diagnosed with Osgood-Schlatter. Participants will receive 3 months of treatment, consisting of either usual care or the self-management approach including exercise, education, and activity modification, followed by 2 months of self-management. Primary endpoint is the KOOS-child ‘Sport/play’ score at 5 months. This protocol details the planned methods and procedures.

Discussion
The novel approach has already shown promise in previous cohort studies. This trial will potentially provide much-needed level 1 evidence for the effectiveness of the self-management approach, representing a crucial step towards addressing the long-term pain and limitations associated with Osgood-Schlatter.

Trial registration
Clinicaltrials.gov: NCT05174182. Prospectively registered December 30th 2021. Date of first recruitment: January 3rd 2022. Target sample size: 130 participants.
Peripartal management of dichorial twin pregnancy in a bicornuate bicollis uterus: a case report and review of the literature
Authors: Schubert Melanie , Tihon Anastasia , Andresen Kristin , Ruchay Zino , Farrokh André , Maass Nicolai , Elischer Philipp , Longardt Ann Carolin , Tesch Karolin , Lebenatus Annett , Krüger Magret , Alkatout Ibrahim 
Published: April 2024

Abstract
Introduction
The management of a pregnancy in a bicornuate uterus is particularly challenging. A bicornuate uterus is a rare occurrence and a twin pregnancy in a bicornuate uterus even more rare. These pregnancies call for intensive diagnostic investigation and interdisciplinary care.

Case presentation
We report on a 27-year-old European woman patient (gravida I, para 0) with a simultaneous pregnancy in each cavity of a bicornuate bicollis uterus after embryo transfer. The condition was confirmed by hysteroscopy and laparoscopy. Several unsuccessful in vitro fertilization (IVF) attempts had been performed earlier before embryo transfer in each cornus. After a physiological course of pregnancy with differential screening at 12 + 6 weeks and 22 + 0 weeks of gestation, the patient presented with therapy-resistant contractions at 27 + 2 weeks. This culminated in the uncomplicated spontaneous delivery of the leading fetus and delayed spontaneous delivery of the second fetus.

Discussion
Only 16 cases of twin pregnancy in a bicornuate unicollis uterus have been reported worldwide and only 6 in a bicornuate bicollis uterus. The principal risks in such pregnancies are preterm labor, intrauterine growth restriction, malpresentation and preeclampsia. These typical risk factors of a twin pregnancy are greatly potentiated in the above mentioned setting.

Conclusion
A twin pregnancy in the presence of a uterine malformation is rare and difficult to manage. These rare cases must be collected and reported in order to work out algorithms of monitoring and therapy as well as issue appropriate recommendations for their management.
A cloud-edge collaborative computing framework using potential games for space-air-ground integrated IoT
Authors: Peng Yuhuai , Guang Xiaoliang , Zhang Xinyu , Liu Lei , Wu Cemulige , Huang Lei 
Published: April 2024

AbstractAs a critical component of space-air-ground integrated IoT, the aerial network provides highly reliable, low-latency and ubiquitous information services to ground users by virtue of their high mobility, easy deployment and low cost. However, the current computation and resource management model of air-ground integrated networks are insufficient to meet the latency demanding of emerging intelligent services such as autonomous systems, extended reality and haptic feedback. To tackle these challenges, we propose a computation offloading and optimization method based on potential game. First, we construct an cloud-edge collaborative computing model. Secondly, we construct Offloading Decision Objective Functions (ODOF) with the objective of minimum task processing latency and energy consumption. ODOF is proved to be a Mixed Inferior Nonlinear Programming (MINLP) problem, which is hard to solve. ODOF is converted to be a full potential game, and the Nash equilibrium solution exists. Then, a computational resource allocation algorithm based on Karush–Kuhn–Tucker (KKT) conditions is proposed to solve resource allocation problem. On this basis, a distributed game-based computational offloading algorithm is proposed to minimize the offloading cost. Extensive simulation results demonstrate that the convergence performance of the proposed algorithm is reduced by 50%, the convergence time is reduced by 13.3% and the average task processing delay is reduced by 10%.
Frequent burning and limited stand-replacing fire supports Mexican spotted owl pair occupancy
Authors: Jones Gavin M. , Clément Marion A. , Latimer Christopher E. , Wright Marilyn E. , Sanderlin Jamie S. , Hedwall Shaula J. , Kirby Rebecca 
Published: April 2024

AbstractChanging fire regimes have the potential to threaten wildlife populations and communities. Understanding species’ responses to novel fire regimes is critical to formulating effective management and conservation strategies in an era of rapid change. Here, we examined the empirical effects of recent and historical wildfire activity on Mexican spotted owl (Strix occidentalis lucida) populations in the southwestern United States. Using region-wide, standardized detection/non-detection data of Mexican spotted owl breeding pairs collected from 2015 to 2022, we found (i) higher rates of pair occupancy at sites that experienced more frequent fires in the three decades prior to the initiation of our study, and (ii) lower rates of local persistence at sites that experienced more extensive high-severity fire during the study. Historical fire regimes throughout much of our study area were characterized by high fire frequencies and limited high-severity components, indicating that Mexican spotted owls responded to wildfire in a manner consistent with their evolutionary environment. Management activities such as prescribed burning and mechanical thinning that aim to reduce stand-replacing fire risk and re-introduce the potential for frequent-fire regimes will likely benefit Mexican spotted owl conservation objectives, as well as promote more resilient forest landscapes.
Sports and Exercise Therapy in Holistic Strategy for Treating Chronic Diseases – literature review
Authors: Bieńko Mateusz , Rutkowska Marta , Król Tomasz , Toborek Michalina , Marchaj Magdalena , Korta Karolina , Putra Anna , Niedziela Natalia , Margas Mikołaj 
Published: April 2024

Introduction
The convergence of sports and health is a developing area, focusing on the therapeutic potential of physical activities in numerous chronic disease management strategies as a necessary part of a holistic strategy. Acknowledging sports as a therapeutic tool emphasizes the necessity for a comprehensive understanding of how sports engagement contributes to innovative healthcare interventions.

Purpose
This research aims to investigate the therapeutic potential of prescribing sports and physical exercise in treating primary chronic diseases, exploring its integration into healthcare practices with a focus on efficacy and implications for disease management.

State of Knowledge
Physical activity is recommended for treating diabetes, chronic obstructive pulmonary disease, asthma, and rheumatoid arthritis. It reduces the risk of cardiovascular disease and death, lowers blood pressure, ads prevents and manages atherosclerosis and osteoporosis. Non-physical sports like chess and board games also promise protection against dementia, depression, and Alzheimer's.

Conclusions
Incorporating sports into healthcare policies and prescribing personalized exercise are essential components of holistic chronic disease management and show widespread benefits. Professional guidance and clear recommendations, aligned with disease-specific guidelines, play a crucial role in ensuring safe and effective physical activity for patients. Potential risks in specific populations, particularly injury risks, can be minimized through proper preventive measures, adjusting the character of exercises, and heightened patient awareness. To ensure good compliance, exercise prescriptions should offer clear and precise guidelines.