bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutral effects of SGLT2 inhibitors in acute coronary syndromes, peripheral arterial occlusive disease, or ischemic stroke: a meta-analysis of randomized controlled trials
Authors: Tsai Pei-Chien , Chuang Wei-Jung , Ko Albert Min-Shan , Chen Jui-Shuan , Chiu Cheng-Hsun , Chen Chun-Han , Yeh Yung-Hsin 
Published: March 2023

Abstract
Background
Patients with type 2 diabetes are at increased risk for cardiovascular diseases. Sodium-glucose transport 2 inhibitors (SGLT2i) have been shown to enhance cardiovascular health since their debut as a second-line therapy for diabetes. Acute coronary syndrome (ACS), peripheral arterial occlusive disease (PAOD), and ischemic stroke (IS) are types of atherosclerotic cardiovascular disease (ASCVD), although the benefits of treating these disorders have not been shown consistently.

Methods
We searched four databases (PubMed, Embase, the Cochrane library, and clinicaltrial.gov) for randomized clinical trials (RCTs) until November of 2022. Comparisons were made between SGLT2i-treated and control individuals with type 2 diabetes. Primary outcomes were ACS, PAOD, and IS; secondary outcomes included cardiovascular mortality and all-cause mortality. Risk ratio (RR) and 95% confidence intervals (CI) were determined using a fixed effects model. Cochrane's risk-of-bias (RoB2) instrument was used to assess the validity of each study that met the inclusion criteria.

Results
We enrolled 79,504 patients with type 2 diabetes from 43 RCTs. There was no difference in the risk of ACS (RR = 0.97, 95% CI 0.89–1.05), PAOD (RR = 0.98, 95% CI 0.78–1.24), or IS (RR = 0.95, 95% CI 0.79–1.14) among patients who took an SGLT2i compared to those who took a placebo or oral hypoglycemic drugs. Subgroup analysis revealed that none of the SGLT2i treatments (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) significantly altered outcomes when analyzed separately. Consistent with prior findings, SGLT2i reduced the risk of cardiovascular mortality (RR = 0.85, 95% CI 0.77–0.93) and all-cause mortality (RR = 0.88, 95% CI 0.82–0.94).

Conclusion
Our results appear to contradict the mainstream concepts regarding the cardiovascular effects of SGLT2i since we found no significant therapeutic benefits in SGLT2i to reduce the incidence of ACS, PAOD, or IS when compared to placebo or oral hypoglycemic drugs.
Enhancement of herbicolin A production by integrated fermentation optimization and strain engineering in Pantoea agglomerans ZJU23
Authors: Wang Hongkai , Zhou Yaqi , Xu Sunde , Zhang Boyan , Cernava Tomislav , Ma Zhonghua , Chen Yun 
Published: March 2023

Abstract
Background
The lipopeptide herbicolin A (HA) secreted by the biocontrol agent Pantoea agglomerans ZJU23 is a promising antifungal drug to combat fungal pathogens by targeting lipid rafts, both in agricultural and clinical settings. Improvement of HA production would be of great significance in promoting its commercialization. This study aims to enhance the HA production in ZJU23 by combining fermentation optimization and strain engineering.

Results
Based on the results in the single-factor experiments, corn steep liquor, temperature and initial pH were identified as the significant affecting factors by the Plackett–Burman design. The fermentation medium and conditions were further optimized using the Box-Behnken response surface method, and the HA production of the wild type strain ZJU23 was improved from ~ 87 mg/mL in King’s B medium to ~ 211 mg/mL in HA induction (HAI) medium. A transposon library was constructed in ZJU23 to screen for mutants with higher HA production, and two transcriptional repressors for HA biosynthesis, LrhA and PurR, were identified. Disruption of the LrhA gene led to increased mRNA expression of HA biosynthetic genes, and subsequently improved about twofold HA production. Finally, the HA production reached ~ 471 mg/mL in the ΔLrhA mutant under optimized fermentation conditions, which is about 5.4 times higher than before (~ 87 mg/mL). The bacterial suspension of the ΔLrhA mutant fermented in HAI medium significantly enhanced its biocontrol efficacy against gray mold disease and Fusarium crown rot of wheat, showing equivalent control efficacies as the chemical fungicides used in this study. Furthermore, HA was effective against fungicide resistant Botrytis cinerea. Increased HA production substantially improved the control efficacy against gray mold disease caused by a pyrimethanil resistant strain.

Conclusions
This study reveals that the transcriptional repressor LrhA negatively regulates HA biosynthesis and the defined HAI medium is suitable for HA production. These findings provide an extended basis for large-scale production of HA and promote biofungicide development based on ZJU23 and HA in the future.

Graphical Abstract
Cu-doped TiO2 nanoparticles improve local antitumor immune activation and optimize dendritic cell vaccine strategies
Authors: Hesemans Evelien , Saffarzadeh Neshat , Maksoudian Christy , Izci Mukaddes , Chu Tianjiao , Rios Luci Carla , Wang Yuqing , Naatz Hendrik , Thieme Sebastian , Richter Cornelia , Manshian Bella B. , Pokhrel Suman , Mädler Lutz , Soenen Stefaan J. 
Published: March 2023

AbstractNanoparticle-mediated cancer immunotherapy holds great promise, but more efforts are needed to obtain nanoformulations that result in a full scale activation of innate and adaptive immune components that specifically target the tumors. We generated a series of copper-doped TiO2 nanoparticles in order to tune the kinetics and full extent of Cu2+ ion release from the remnant TiO2 nanocrystals. Fine-tuning nanoparticle properties resulted in a formulation of 33% Cu-doped TiO2 which enabled short-lived hyperactivation of dendritic cells and hereby promoted immunotherapy. The nanoparticles result in highly efficient activation of dendritic cells ex vivo, which upon transplantation in tumor bearing mice, exceeded the therapeutic outcomes obtained with classically stimulated dendritic cells. Efficacious but simple nanomaterials that can promote dendritic cancer cell vaccination strategies open up new avenues for improved immunotherapy and human health.
Graphical Abstract
Eukaryotic Initiation Factor 5A2 localizes to actively translating ribosomes to promote cancer cell protrusions and invasive capacity
Authors: Martínez-Férriz Arantxa , Gandía Carolina , Pardo-Sánchez José Miguel , Fathinajafabadi Alihamze , Ferrando Alejandro , Farràs Rosa 
Published: March 2023

AbstractBackgroundEukaryotic Initiation Factor 5A (eIF-5A), an essential translation factor, is post-translationally activated by the polyamine spermidine. Two human genes encode eIF-5A, being eIF5-A1 constitutively expressed whereas eIF5-A2 is frequently found overexpressed in human tumours. The contribution of both isoforms with regard to cellular proliferation and invasion in non-small cell lung cancer remains to be characterized.MethodsWe have evaluated the use of eIF-5A2 gene as prognosis marker in lung adenocarcinoma (LUAD) patients and validated in immunocompromised mice. We have used cell migration and cell proliferation assays in LUAD lines after silencing each eIF-5A isoform to monitor their contribution to both phenotypes. Cytoskeleton alterations were analysed in the same cells by rhodamine-phalloidin staining and fluorescence microscopy. Polysome profiles were used to monitor the effect of eIF-5A2 overexpression on translation. Western blotting was used to study the levels of eIF-5A2 client proteins involved in migration upon TGFB1 stimulation. Finally, we have co-localized eIF-5A2 with puromycin to visualize the subcellular pattern of actively translating ribosomes.ResultsWe describe the differential functions of both eIF-5A isoforms, to show that eIF5-A2 properties on cell proliferation and migration are coincident with its features as a poor prognosis marker. Silencing of eIF-5A2 leads to more dramatic consequences of cellular proliferation and migration compared to eIF-5A1. Overexpression of eIF-5A2 leads to enhanced global translation. We also show that TGFβ signalling enhances the expression and activity of eIF-5A2 which promotes the translation of polyproline rich proteins involved in cytoskeleton and motility features as it is the case of Fibronectin, SNAI1, Ezrin and FHOD1. With the use of puromycin labelling we have co-localized active ribosomes with eIF-5A2 not only in cytosol but also in areas of cellular protrusion. We have shown the bulk invasive capacity of cells overexpressing eIF-5A2 in mice.ConclusionsWe propose the existence of a coordinated temporal and positional interaction between TFGB and eIF-5A2 pathways to promote cell migration in NSCLC. We suggest that the co-localization of actively translating ribosomes with hypusinated eIF-5A2 facilitates the translation of key proteins not only in the cytosol but also in areas of cellular protrusion.
IL-1β and TNF-α play an important role in modulating the risk of periodontitis and Alzheimer’s disease
Authors: Wang Rachel Pei-Hsuan , Huang Jianpan , Chan Kannie Wai Yan , Leung Wai Keung , Goto Tetsuya , Ho Yuen-Shan , Chang Raymond Chuen-Chung 
Published: March 2023

Abstract
Background
Systemic activation of the immune system can exert detrimental effects on the central nervous system. Periodontitis, a chronic disease of the oral cavity, is a common source of systemic inflammation. Neuroinflammation might be a result of this to accelerate progressive deterioration of neuronal functions during aging or exacerbate pre-existing neurodegenerative diseases, such as Alzheimer’s disease. With advancing age, the progressive increase in the body’s pro-inflammatory status favors the state of vulnerability to both periodontitis and Alzheimer’s disease. In the present study, we sought to delineate the roles of cytokines in the pathogenesis of both diseases.

Methods
To examine the impacts of periodontitis on the onset and progression of Alzheimer’s disease, 6-month-old female 3 × Tg-AD mice and their age-matched non-transgenic mice were employed. Periodontitis was induced using two different experimental models: heat-killed bacterial-induced periodontitis and ligature-induced periodontitis. To delineate the roles of pro-inflammatory cytokines in the pathogenesis of periodontitis and Alzheimer’s disease, interleukin 1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) were also injected into the buccal mandibular vestibule of mice.

Results
Here, we show that IL-1β and TNF-α were two of the most important and earliest cytokines upregulated upon periodontal infection. The systemic upregulation of these two cytokines promoted a pro-inflammatory environment in the brain contributing to the development of Alzheimer’s disease-like pathology and cognitive dysfunctions. Periodontitis-induced systemic inflammation also enhanced brain inflammatory responses and subsequently exacerbated Alzheimer’s disease pathology and cognitive impairment in 3 × Tg-AD mice. The role of inflammation in connecting periodontitis to Alzheimer’s disease was further affirmed in the conventional magnetization transfer experiment in which increased glial responses resulting from periodontitis led to decreased magnetization transfer ratios in the brain of 3 × Tg-AD mice.

Conclusions
Systemic inflammation resulting from periodontitis contributed to the development of Alzheimer’s disease tau pathology and subsequently led to cognitive decline in non-transgenic mice. It also potentiated Alzheimer’s disease pathological features and exacerbated impairment of cognitive function in 3 × Tg-AD mice. Taken together, this study provides convincing evidence that systemic inflammation serves as a connecting link between periodontitis and Alzheimer’s disease.
TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization: a specialized Tau perspective
Authors: Kapoor Mahima , Chinnathambi Subashchandrabose 
Published: March 2023

AbstractMicrotubule-associated protein, Tau has been implicated in Alzheimer's disease for its detachment from microtubules and formation of insoluble intracellular aggregates within the neurons. Recent findings have suggested the expulsion of Tau seeds in the extracellular domain and their prion-like propagation between neurons. Transforming Growth Factor-β1 (TGF-β1) is a ubiquitously occurring cytokine reported to carry out immunomodulation and neuroprotection in the brain. TGF-β-mediated regulation occurs at the level of neuronal survival and differentiation, glial activation (astrocyte and microglia), amyloid production–distribution–clearance and neurofibrillary tangle formation, all of which contributes to Alzheimer's pathophysiology. Its role in the reorganization of cytoskeletal architecture and remodelling of extracellular matrix to facilitate cellular migration has been well-documented. Microglia are the resident immune sentinels of the brain responsible for surveying the local microenvironment, migrating towards the beacon of pertinent damage and phagocytosing the cellular debris or patho-protein deposits at the site of insult. Channelizing microglia to target extracellular Tau could be a good strategy to combat the prion-like transmission and seeding problem in Alzheimer's disease. The current review focuses on reaffirming the role of TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization and considers utilizing the approach of TGF-β-triggered microglia-mediated targeting of extracellular patho-protein, Tau, as a possible potential strategy to combat Alzheimer's disease.
Blood glucose trajectories and incidence of diabetes mellitus in Ugandan people living with HIV initiated on dolutegravir
Authors: Mulindwa Frank , Castelnuovo Barbara , Brusselaers Nele , Bollinger Robert , Rhein Joshua , Edrisa Mutebi , Buzibye Allan , Amutuhaire Willington , Yendewa George , Nabaggala Sarah , Odongpiny Eva Laker Agnes , Kiguba Ronald , Nakawooza Aisha , Dujanga Simon , Nabwana Martin , Schwarz Jean-Marc 
Published: March 2023

Abstract
Background
Following reports of anti-retroviral therapy (ART) experienced Ugandan people living with HIV (PLHIV) presenting with diabetic ketoacidosis weeks to months following a switch to dolutegravir (DTG), the Uganda Ministry of Health recommended withholding DTG in both ART naïve and experienced PLHIV with diabetes mellitus (T2DM), as well as 3-monthly blood glucose monitoring for patients with T2DM risk factors. We sought to determine if the risk of T2DM is indeed heightened in nondiabetic ART naïve Ugandan PLHIV over the first 48 weeks on DTG.

Methods
Between January and October 2021, 243 PLHIV without T2DM were initiated on DTG based ART for 48 weeks. Two-hour oral glucose tolerance tests (2-h OGTT) were performed at baseline, 12, and 36 weeks; fasting blood glucose (FBG) was measured at 24 and 48 weeks. The primary outcome was the incidence of T2DM. Secondary outcomes included: incidence of pre-Diabetes Mellitus (pre-DM), median change in FBG from baseline to week 48 and 2-h blood glucose (2hBG) from baseline to week 36. Linear regression models were used to determine adjusted differences in FBG and 2hBG from baseline to weeks 48 and 36 respectively.

Results
The incidence of T2DM was 4 cases per 1000 PY (1/243) and pre-DM, 240 cases per 1000 person years (PY) (54/243). There was a significant increase in FBG from baseline to week 48 [median change from baseline (FBG): 3.6 mg/dl, interquartile range (IQR): − 3.6, 7.2, p-value (p) = 0.005] and significant reduction in 2hBG (2hBG: − 7.26 mg/dl, IQR: − 21.6, 14.4, p = 0.024) at week 36. A high CD4 count and increased waist circumference were associated with 2hBG increase at week 36.

Conclusion
We demonstrated a low incidence of T2DM in Ugandan ART-naïve patients receiving DTG. We also demonstrated that longitudinal changes in BG were independent of conventional risk factors of T2DM in the first 48 weeks of therapy. Restricting the use of dolutegravir in Ugandan ART naïve patients perceived to be high risk for diabetes mellitus may be unwarranted.
High-demand tasks show that ACL reconstruction is not the only factor in controlling range of tibial rotation: a preliminary investigation
Authors: Zee Mark , Keizer Michele , van Raaij Jos , Hijmans Juha , van den Akker-Scheek Inge , Diercks Ron 
Published: March 2023

Abstract
Background
Excessive range of tibial rotation (rTR) may be a reason why athletes cannot return to sports after ACL reconstruction (ACLR). After ACLR, rTR is smaller in reconstructed knees compared to contralateral knees when measured during low-to-moderate-demand tasks. This may not be representative of the amount of rotational laxity during sports activities. The purpose of this study is to determine whether rTR is increased after ACL injury compared to the contralateral knee and whether it returns to normal after ACLR when assessed during high-demand hoptests, with the contralateral knee as a reference.

Methods
Ten ACL injured subjects were tested within three months after injury and one year after reconstruction. Kinematic motion analysis was conducted, analysing both knees. Subjects performed a level-walking task, a single-leg hop for distance and a side jump. A paired t-test was used to detect a difference between mean kinematic variables before and after ACL reconstruction, and between the ACL-affected knees and contralateral knees before and after reconstruction.

Results
RTR was greater during high-demand tasks compared to low-demand tasks. Pre-operative, rTR was smaller in the ACL-deficient knees compared to the contralateral knees during all tests. After ACLR, a greater rTR was seen in ACL-reconstructed knees compared to pre-operative, but a smaller rTR compared to the contralateral knees, even during high-demand tasks.

Conclusion
The smaller rTR, compared to the contralateral knee, seen after a subacute ACL tear may be attributed to altered landing technique, neuromuscular adaptation and fear of re-injury. The continued reduction in rTR one year after ACLR may be a combination of this neuromuscular adaptation and the biomechanical impact of the reconstruction.
Trial registration: The trial was registered in the Dutch Trial Register (NTR: www.trialregister.nl, registration ID NL7686).
Novel ideas for the comprehensive evaluation of varus knee osteoarthritis: radiological measurements of the morphology of the lateral knee joint
Authors: Ma Wenru , Wang Fengkun , Sun Shengnan , Ding Lei , Wang Lu , Yu Tengbo , Zhang Yi 
Published: March 2023

Abstract
Background
The lateral anatomical and morphological characteristics of knees with varus knee osteoarthritis (OA) have not received sufficient attention. This study used several radiological parameters to describe the morphological characteristics of the lateral knee with OA to determine whether there are relationships between varus knee OA and parameters such as lateral plateau widening (LPW), proximal fibula curvature (PFC), and fibula height (FH).

Methods
The study retrospectively analyzed 1072 subjects who underwent standard radiography for diagnosing or evaluating symptomatic knee joint disease. The 163 Kellgren and Lawrence (K–L) grades 0 and I knees were categorized into the no-knee-OA group, and the 909 K–L grades II–IV knees were classified into the knee-OA group. Medial proximal tibial angle, joint line convergence angle, hip–knee–ankle angle, LPW, PFC, and FH were measured. T tests and chi-square tests were used to compare each index between the two groups. Binary logistic regression was performed to examine the correlation between indexes and knee OA occurrence. Ordinal logistic analysis, principal component analysis, and multivariable linear regression analysis were performed to examine the correlations between the three lateral parameters and K–L grades and the degree of varus deformity.

Results
LPW and PFC were significantly greater and FH was significantly smaller in the knee-OA group than in the no-knee-OA group. LPW, PFC, and FH were correlated with knee OA occurrence. One principal component, named the comprehensive principal component score of varus deformity, was extracted from the three indexes, and the total variance of the principal component interpretation was 76.60%. Ordinal logistics and multivariable linear regression analysis showed that, after adjusting for age and BMI, LPW and PFC were positively correlated with K–L grading and varus deformity. FH was significantly and negatively correlated with K–L grading and varus deformity (all P < 0.05).

Conclusions
Regular morphological changes take place in the lateral knee with varus OA, including lateral dislocation of the tibial plateau, proximal fibula bending, and upward movement of the fibular head. Changes in LPW, PFC, and FH could enable a more comprehensive assessment of varus knee OA occurrence, severity, and deformity.
Level of evidence Retrospective Study Level III.
Multilayered blow-spun vascular prostheses with luminal surfaces in Nano/Micro range: the influence on endothelial cell and platelet adhesion
Authors: Łopianiak Iwona , Rzempołuch Wiktoria , Civelek Mehtap , Cicha Iwona , Ciach Tomasz , Butruk-Raszeja Beata A. 
Published: March 2023

AbstractBackgroundIn this study, two types of polyurethane-based cylindrical multilayered grafts with internal diameters ≤ 6 mm were produced by the solution blow spinning (SBS) method. The main aim was to create layered-wall prostheses differing in their luminal surface morphology. Changing the SBS process parameters, i.e. working distance, rotational speed, volume, and concentration of the polymer solution allowed to obtain structures with the required morphologies. The first type of prostheses, termed Nano, possessed nanofibrous luminal surface, and the second type, Micro, presented morphologically diverse luminal surface, with both solid and microfibrous areas.ResultsThe results of mechanical tests confirmed that designed prostheses had high flexibility (Young’s modulus value of about 2.5 MPa) and good tensile strength (maximum axial load value of about 60 N), which meet the requirements for vascular prostheses. The influence of the luminal surface morphology on platelet adhesion and the attachment of endothelial cells was investigated. Both surfaces did not cause hemolysis in contact with blood, the percentage of platelet-occupied area for Nano and Micro surfaces was comparable to reference polytetrafluoroethylene (PTFE) surface. However, the change in morphology of surface-adhered platelets between Nano and Micro surfaces was visible, which might suggest differences in their activation level. Endothelial coverage after 1, 3, and 7 days of culture on flat samples (2D model) was higher on Nano prostheses as compared with Micro scaffolds. However, this effect was not seen in 3D culture, where cylindrical prostheses were colonized using magnetic seeding method.ConclusionsWe conclude the produced scaffolds meet the material and mechanical requirements for vascular prostheses. However, changing the morphology without changing the chemical modification of the luminal surface is not sufficient to achieve the appropriate effectiveness of endothelialization in the 3D model.
Conservative management of low-risk papillary thyroid carcinoma: a review of the active surveillance experience
Authors: Smulever Anabella , Pitoia Fabian 
Published: March 2023

AbstractThe detection of low-risk thyroid carcinoma has increased in recent decades, although disease-specific mortality remained without changes. The high prevalence of occult carcinomas in autopsy studies, and hence the underlying indolent course of this entity, prompted the emergence of active surveillance as an alternative approach to these tumors. This strategy aims to recognize the minority group of patients who will develop clinical progression and probably benefit from deferred surgery. Experience around the world has shown that during active surveillance these tumors are mostly unchanged in size, with very-slow growth and even a decrease in diameter. Moreover, the rates of lymph node metastases were low and easily handled by rescue surgery, and distant metastases have not been reported. Given the high prevalence of small thyroid carcinomas and the excellent outcomes for observation, active surveillance provides a safe and feasible alternative in properly selected patients with low-risk thyroid cancer.