Alviss

Asparaginase has played a crucial role in the improvement of survival in children with acute lymphoblastic leukaemia (ALL), which is the commonest cancer among children. Survival rates have steadily increased over decades since the introduction of asparaginase to ALL therapy, and overall survival rates reach 90% with the best contemporary protocols. Currently, polyethylene glycolated native Escherichia coli-derived L-asparaginase (PEG-asparaginase) is the preferred first-line asparaginase preparation. Besides its clinical benefits, PEG-asparaginase is well known for severe toxicities. Agreement on the optimal dose, treatment duration, and frequency of administration has never been reached among clinicians. Primary objective To assess the effect of the number of PEG-asparaginase doses on survival and relapse in children and adolescents with ALL. Secondary objectives To assess the association between the number of doses of PEG-asparaginase and asparaginase-associated toxicities (e.g. hypersensitivity, thromboembolism, pancreatitis and osteonecrosis). To undertake a network meta-analysis at dose-level in order to generate rankings of the number of doses of PEG-asparaginase used in the treatment for ALL, according to their benefits (survival and relapse) and harms (toxicity). We searched CENTRAL, PubMed, Embase, Web of Science databases and three trials registers in November 2021, together with reference checking, citation searching and contact with study authors to identify additional studies. We included randomised controlled trials (RCTs) comparing different PEG-asparaginase treatment regimens in children and adolescents (< 18 years of age) with first-line ALL treated with multiagent chemotherapy including PEG-asparaginase. Using a standardised data collection form, two review authors independently screened and selected studies, extracted data, assessed risk of bias for each outcome using a standardised tool (RoB 2.0) and assessed the certainty of evidence for each outcome using the GRADE approach. Primary outcomes included overall survival, event-free survival and leukaemic relapse. Secondary outcomes included asparaginase-associated toxicities (hypersensitivity, thromboembolism, pancreatitis, sinusoidal obstruction syndrome and osteonecrosis as well as overall asparaginase-associated toxicity). We conducted the review and performed the analyses in accordance with the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We included three RCTs in the review, and identified an additional four ongoing studies. We judged outcomes of two RCTs to be at low risk of bias in all the Cochrane risk of bias (RoB 2) domains. We rated the remaining study as having some concerns regarding bias. Due to concerns about imprecision, we rated all outcomes as having low- to moderate-certainty evidence. One study compared intermittent PEG-asparaginase treatment (eight doses of PEG-asparaginase, 1000 IU/m2, intramuscular (IM) administration) versus continuous PEG-asparaginase treatment (15 doses of PEG-asparaginase, 1000 IU/m2, IM) in 625 participants with non-high risk ALL aged 1.0 to 17.9 years. We found that treatment with eight doses probably results in little to no difference in event-free survival compared to treatment with 15 doses (RR 1.01, 95% CI 0.97 to 1.06; moderate-certainty evidence). Compared to treatment with 15 doses, treatment with eight doses may result in either no difference or a slight reduction in hypersensitivity (RR 0.64, 95% CI 0.21 to 1.93; low-certainty evidence), thromboembolism (RR 0.55, 95% CI 0.22 to 1.36; low-certainty evidence) or osteonecrosis (RR 0.68, 95% CI 0.35 to 1.32; low-certainty evidence). Furthermore, we found that treatment with eight doses probably reduces pancreatitis (RR 0.31, 95% CI 0.12 to 0.75; moderate-certainty evidence) and asparaginase-associated toxicity (RR 0.53, 95% CI 0.35 to 0.78; moderate-certainty evidence) compared to treatment with 15 doses. One study compared low-risk standard treatment with additional PEG-asparaginase (six doses, 2500 IU/m2, IM) versus low-risk standard treatment (two doses, 2500 IU/m2, IM) in 1857 participants aged one to nine years old with standard low-risk ALL. We found that, compared to treatment with two doses, treatment with six doses probably results in little to no difference in overall survival (RR 0.99, 95% CI 0.98 to 1.00; moderate-certainty evidence) and event-free survival (RR 1.01, 95% CI 0.99 to 1.04; moderate-certainty evidence), and may result in either no difference or a slight increase in osteonecrosis (RR 1.65, 95% CI 0.91 to 3.00; low-certainty evidence). Furthermore, we found that treatment with six doses probably increases hypersensitivity (RR 12.05, 95% CI 5.27 to 27.58; moderate-certainty evidence), pancreatitis (RR 4.84, 95% CI 2.15 to 10.85; moderate-certainty evidence) and asparaginase-associated toxicity (RR 4.49, 95% CI 3.05 to 6.59; moderate-certainty evidence) compared to treatment with two doses. One trial compared calaspargase (11 doses, 2500 IU/m2, intravenous (IV)) versus PEG-asparaginase (16 doses, 2500 IU/m2, IV) in 239 participants aged one to 21 years with standard- and high-risk ALL and lymphoblastic lymphoma. We found that treatment with 11 doses of calaspargase probably results in little to no difference in event-free survival compared to treatment with 16 doses of PEG-asparaginase (RR 1.06, 95% CI 0.97 to 1.16; moderate-certainty evidence). However, treatment with 11 doses of calaspargase probably reduces leukaemic relapse compared to treatment with 16 doses of PEG-asparaginase (RR 0.32, 95% CI 0.12 to 0.83; moderate-certainty evidence). Furthermore, we found that treatment with 11 doses of calaspargase results in either no difference or a slight reduction in hypersensitivity (RR 1.17, 95% CI 0.64 to 2.13; low-certainty evidence), pancreatitis (RR 0.85, 95% CI 0.47 to 1.52; low-certainty evidence), thromboembolism (RR 0.83, 95% CI 0.48 to 1.42; low-certainty evidence), osteonecrosis (RR 0.63, 95% CI 0.15 to 2.56; low-certainty evidence) and asparaginase-associated toxicity (RR 1.00, 95% CI 0.71 to 1.40; low-certainty evidence) compared to treatment with 16 doses of PEG-asparaginase. We were not able to conduct a network meta-analysis, and could not draw clear conclusions because it was not possible to rank the interventions. Overall, we found that different numbers of doses of PEG-asparaginase probably result in little to no difference in event-free survival across all studies. In two studies, we found that a higher number of PEG-asparaginase doses probably increases pancreatitis and asparaginase-associated toxicities.

Metal nanoclusters (NCs), an important class of nanoparticles (NPs), are extremely small in size and possess quasi-molecular properties. Due to accurate stoichiometry of constituent atoms and ligands, NCs have strong structure-property relationship. The synthesis of NCs is seemingly similar to that of NPs as both are formed by colloidal phase transitions. However, they are considerably different because of metal-ligand complexes in NC synthesis. Reactive ligands can convert metal salts to complexes, actual precursors to metal NCs. During the complex formation, various metal species occur, having different reactivity and fraction depending on synthetic conditions. It can alter their degree of participation in NC synthesis and the homogeneity of final products. Herein, we investigate the effects of complex formation on the entire NC synthesis. By controlling the fraction of various Au species showing different reactivity, we find that the extent of complex formation alters reduction kinetics and the uniformity of Au NCs. We demonstrate that this concept can be universally applied to synthesize Ag, Pt, Pd, and Rh NCs.

Women with polycystic ovary syndrome are prone to develop gestational diabetes mellitus, a disease which may have significant impact on the postpartum health of both mother and infant. We performed a retrospective cohort study to develop and test a model that could predict gestational diabetes mellitus in the first trimester in women with polycystic ovary syndrome. Our study included 434 pregnant women who were referred to the obstetrics department between December 2017 and March 2020 with a diagnosis of polycystic ovary syndrome. Of these women, 104 were diagnosed with gestational diabetes mellitus in the second trimester. Univariate analysis revealed that in the first trimester, Hemoglobin A1c (HbA1C), age, total cholesterol(TC), low-density lipoprotein cholesterol (LDL-C), SBP (systolic blood pressure), family history, body mass index (BMI), and testosterone were predictive factors of gestational diabetes mellitus (P < 0.05). Logistic regression revealed that TC, age, HbA1C, BMI and family history were independent risk factors for gestational diabetes mellitus. The area under the ROC curve of the gestational diabetes mellitus risk prediction model was 0.937 in this retrospective analysis, demonstrating a great discriminatory ability. The sensitivity and specificity of the prediction model were 0.833 and 0.923, respectively. The Hosmer-Lemeshow test also showed that the model was well calibrated.

In patients with type 2 diabetes mellitus (T2DM) arterial stiffness is associated with increased cardiovascular and total mortality. Little is known about determinants of arterial stiffness in clinical routine. Identification of potential determinants of arterial stiffness will help to address treatment targets for patients in the early state of T2DM. This is a cross-sectional analysis of arterial stiffness in 266 patients in the early stage of T2DM who did not have cardiovascular or renal complications. Parameters of arterial stiffness such as central systolic blood pressure (cSBP), central pulse pressure (cPP) and pulse wave velocity (PWV) were measured with the SphygmoCor System (AtCor Medical). We investigated the influence of parameters of glucose metabolism, lipid status, body constitution, blood pressure (BP) and inflammation on the stiffness parameters using multivariate regression analysis. The study cohort consisted of male and female patients aged 61 ± 8 years with mean diabetes duration of 6.4 ± 5.1 years, mean HbA1c 7.1 ± 0.9%, mean cSBP 121 ± 12 mmHg, mean cPP 44 ± 10 mmHg and mean PWV 8.9 ± 1.8 m/s. Multiple regression analysis identified waist circumference (WC) (beta = 0.411, p = 0.026), LDL-cholesterol (beta = 0.106, p = 0.006), systolic office BP (beta = 0.936, p < 0.001) and diabetes duration (beta = 0.233, p = 0.043) as potential determinants of cSBP. cPP was determined by sex (beta = 0.330, p = 0.008), age (beta = 0.383, p < 0.001), systolic office BP (beta = 0.370, p < 0.001) and diabetes duration (beta = 0.231, p = 0.028) whereas for PWV the following determinants could be identified: age (beta = 0.405, p < 0.001), systolic office BP (beta = 0.421, p < 0.001) and diabetes duration (beta = 0.073, p = 0.038). In addition to the known parameters age, sex and systolic office BP serum LDL-cholesterol, WC and diabetes duration have been identified as determinants of arterial stiffness in patients with T2DM. Treatment of patients in the early stage of T2DM should focus on these clinical parameters to prevent progression of arterial stiffness and as a consequence reduce cardiovascular mortality. Trial registration: The patients included in the analysis participated in one of the following clinical trials NCT02752113 (registered 26.4.2016), NCT02383238 (09.03.2015), NCT02471963 (15.06.2015), NCT01319357 (21.03.2011) ( http://www.clinicaltrials.gov ).

To evaluate the effect of repetitive transcranial magnetic stimulation (rTMS) combined with task-oriented training (TOT) on upper limb function in stroke patients with hemiplegia. A systematic review and meta-analysis was performed using PRISMA guidelines. Computer searches of PubMed, Cochrane Library, Embase, Web of science, China Knowledge Network, Wanfang, and Wipu databases were conducted from the time of database creation to October 27, 2022. Clinical trials meeting the inclusion criteria were screened, with rTMS combined with TOT in the test group and other therapies in the control group. Literature screening and data extraction were performed independently by 2 investigators, and meta-analysis was performed using Stata software after quality evaluation of the literature. Meta-analysis results showed that repeated transcranial magnetic stimulation combined with TOT was more effective in box and block test (I2 = 0%, P = .820, 95% confidence interval [CI] [-0.20, 0.88]), Fugl-Meyer Assessment (I2 = 0%, P = .569, 95% CI [0.88, 1.26]), and modified Barthel Index (I2 = 39.9%, P = .189, 95% CI [0.45, 1.03]) were not significantly different from controls, and the efficacy was significantly better in motor evoked potentials (I2 = 86.5%, P < .001, 95% CI [-1.38, -0.83]). Data analysis clarified the efficacy of rTMS) combined with TOT on upper extremity motor function disorders after stroke, but there was no significant difference between the efficacy in box and block test, Fugl-Meyer Assessment, and modified Barthel Index and the efficacy in motor evoked potentials between rTMS and the control group, suggesting that the neuro plasticizing effect of rTMS may translate into functional improvement by promoting neuro electrical signaling.

Although many critically ill patients require inter-facility transport for definitive or specialized therapy, the medical equipment required to enhance transport safety remains unclear. This review was performed to summarize the evidence regarding devices used to improve the safety and survival in patients requiring such transport. We searched MEDLINE, the Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi for randomized controlled trials and observational studies comparing outcomes according to the presence or absence of devices (or new vs conventional devices) during transfer of critically ill patients. Four studies focusing on continuous blood pressure monitoring, extracorporeal membrane oxygenation, pelvic circumferential compression devices, and cuffed tracheal tubes, respectively, met the inclusion criteria. A meta-analysis was not performed because the 4 studies focused on different devices. Near-continuous blood pressure monitoring increased interventions such as intravenous fluid administration during transport, shortened the intensive care unit and hospital lengths of stay, and reduced the incidence of multiple-organ failure compared with use of oscillometric devices. Despite the small sample size and varying severity of illness among the groups, transport of patients with severe respiratory failure under extracorporeal membrane oxygenation resulted in fewer hypoxemic events during transport than transport on conventional ventilators. During transport of patients with pelvic fractures, pelvic belts may help to reduce mortality and the transfusion volume. Cuffed (vs uncuffed) tracheal tubes may reduce post-transport tube replacement events in pediatric patients. Studies on devices needed for inter-facility transport of critically ill patients are scarce, but some devices may be beneficial.

Sulfidic copper tailings (SCTs) with excessive sulfur content are prone to oxidation, leading to the generation of sulfates and causing compatibility issues with cement. To address this problem, this paper proposes upcycling SCTs into alkali-activated slag (AAS) materials to fully utilize the produced sulfates for slag activation. The influence of the sulfur content of the SCTs compound (quartz, SCTs, and fine pyrite) on the properties of AAS was investigated from various aspects including setting time, compressive strength, hydration products, microstructure, and pore structure. The experimental results showed that adding SCTs compound enabled the generation of S-rich expansive products, such as ettringite, sodium sulfate, and gypsum. Moreover, nano-sized spherical particles were formed and well-distributed in pores or micro-cracks in the microstructure of AAS mortars. Consequently, AAS mortars with SCTs compound developed higher compressive strength at all ages than the blank ones, with an increase of 40.2-144.8% at 3 days, 29.4-115.7% at 7 days, and 29.3-136.3% at 28 days. Furthermore, AAS mortars with SCTs compounds enjoyed significant economic and environmental benefits, as demonstrated by cost-benefit and eco-efficiency analyses. The optimal sulfur content of the SCTs compound was found to be 15%.

Herein, four endophytic fungal strains living in healthy roots of garlic were used to produce selenium nanoparticles (Se-NPs) via green synthesis. Penicillium verhagenii was found to be the most efficient Se-NPs producer with a ruby red color that showed maximum surface plasmon resonance at 270 nm. The as-formed Se-NPs were crystalline, spherical, and well-arranged without aggregation, and ranged from 25 to 75 nm in size with a zeta potential value of -32 mV, indicating high stability. Concentration-dependent biomedical activities of the P. verhagenii-based Se-NPs were observed, including promising antimicrobial activity against different pathogens (Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, Candida albicans, C. glabrata, C. tropicalis, and C. parapsilosis) with minimum inhibitory concentration (MIC) of 12.5-100 µg mL-1. The biosynthesized Se-NPs showed high antioxidant activity with DPPH-scavenging percentages of 86.8 ± 0.6% at a concentration of 1000 µg mL-1 and decreased to 19.3 ± 4.5% at 1.95 µg mL-1. Interestingly, the Se-NPs also showed anticancer activity against PC3 and MCF7 cell lines with IC50 of 225.7 ± 3.6 and 283.8 ± 7.5 µg mL-1, respectively while it is remaining biocompatible with normal WI38 and Vero cell lines. Additionally, the green synthesized Se-NPs were effective against instar larvae of a medical insect, Aedes albopictus with maximum mortality of 85.1 ± 3.1, 67.2 ± 1.2, 62.10 ± 1.4, and 51.0 ± 1.0% at a concentration of 50 µg mL-1 for I, II, III, and IV-instar larva, respectively. These data highlight the efficacy of endophytic fungal strains for cost-effective and eco-friendly Se-NPs synthesis with different applications.

Anterior fontanel (AF) sizes in newborns are influenced by ethnicity, gender, genetics, nutrition, and other pathological conditions. However, AF sizes in recent Korean newborns have not been reported yet. Thus, this study aimed to understand variation in AF size and clinical implications of large AF sizes in newborns. This cohort study was conducted on nursery newborns born at a University Hospital between September 2019 and August 2020. AF size was measured at 24 to 48 hours after birth. Newborns with a large AF (> 3.6cm) were examined for other pathological reasons using radiological and laboratory tests. Demographic data were analyzed in relation to AF size. A total of 573 newborns were investigated. Their mean gestational age was 38.5 ± 1.2 weeks at birth and their mean birth weight was 3140 ± 450 g. Their mean AF size was 1.85 ± 0.83 cm (90 and 97-percentile of AF size were 2.96 and 3.65 cm, respectively). Among demographic factors, small for gestational age (SGA) weight, SGA head circumference, and multiple births were correlated with larger AF size. Among 18 infants with a large AF, 2 had intracranial abnormalities and 11 had vitamin D deficiency. This is the first recent study on AF sizes of Korean newborn infants. Their mean AF size was the smallest so far. For the largest AF size, a cutoff of 3.65 cm met the 97-percentile of the cohort. Both SGA weight and head circumference were risk factors for large AF size. For the largest AF size, intracranial lesions and vitamin D deficiency as well as SGA presented clinical implications.

Children who receive cranial radiation therapy (RT) as a component of treatment for malignancy are often at risk of long-term central endocrine toxicity secondary to radiation to the hypothalamic-pituitary axis (HPA). A comprehensive analysis was performed of central endocrine late effects in survivors of childhood cancer treated with RT as part of the Pediatric Normal Tissue Effects in the Clinic (PENTEC) consortium. A systematic review of the risk of RT-related central endocrine effects was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A total of 4629 publications were identified, of which 16 met criteria for inclusion in dose modeling analysis, with a total of 570 patients in 19 cohorts. Eighteen cohorts reported outcomes for growth hormone deficiency (GHD), 7 reported outcomes for central hypothyroidism (HT), and 6 reported outcomes for adrenocorticotropic hormone (ACTH) deficiency. Normal tissue complication probability modeling for GHD (18 cohorts, 545 patients) yielded D50 = 24.9 Gy (95% CI, 20.9-28.0) and γ50 = 0.5 (95% CI, 0.27-0.78). The normal tissue complication probability model fit for whole brain irradiation in children with a median age of >5 years indicated a 20% risk of GHD for patients who receive a mean dose of 21 Gy in 2-Gy fractions to the HPA. For HT, among 7 cohorts (250 patients), D50 = 39 Gy (95% CI, 34.1-53.2) and γ50 = 0.81 (95% CI, 0.46-1.35), with a 20% risk of HT in children who receive a mean dose of 22 Gy in 2-Gy fractions to the HPA. For ACTH deficiency (6 cohorts, 230 patients), D50 = 61 Gy (95% CI, 44.7-119.4) and γ50 = 0.76 (95% CI, 0.5-1.19); there is a 20% risk of ACTH deficiency in children who receive a mean dose of 34 Gy in 2-Gy fractions to the HPA. RT dose to the HPA increases the risk of central endocrine toxicity, including GHD, HT, and ACTH deficiency. In some clinical situations, these toxicities may be difficult to avoid, and counseling of patients and families with respect to anticipated outcomes is important.

Myocardial infarction (MI) is one of the most dangerous cardiovascular events. Cardiac fibrosis is a common pathological feature of remodeling after injury that is related to adverse clinical results with no effective treatment. Previous studies have confirmed that TRIM44, an E3 ligase, can promote the proliferation and migration of various tumor cells. However, the role of TRIM44 in cardiac fibrosis remains unknown. Models of TGF-β1 stimulation and MI-induced fibrosis were established to investigate the role and potential underlying mechanism of TRIM44 in cardiac fibrosis. The results showed that cardiac fibrosis was significantly inhibited after TRIM44 knockdown in a mouse model of MI, while it was enhanced when TRIM44 was overexpressed. Furthermore, in vitro studies showed that fibrosis markers were significantly reduced in cardiac fibroblasts (CFs) with TRIM44 knockdown, whereas TRIM44 overexpression promoted the expression of fibrosis markers. Mechanistically, TRIM44 maintains TAK1 stability by inhibiting the degradation of k48-linked polyubiquitination-mediated ubiquitination, thereby increasing phosphorylated TAK1 expression in the fibrotic environment and activating MAPKs to promote fibrosis. Pharmacological inhibition of TAK1 phosphorylation reversed the fibrogenic effects of TRIM44 overexpression. Combined, these results suggest that TRIM44 is a potential therapeutic target for cardiac fibrosis.

Tirzepatide reduces HbA1c and body weight, and creatinine-based estimated glomerular filtration rate (eGFR) decline. Unlike creatine-derived eGFR (eGFR-creatinine), cystatin C-derived eGFR (eGFR-cystatin C) is unaffected by muscle mass changes. We assessed effects of tirzepatide on eGFR-creatinine and eGFR-cystatin C. Our primary outcome was eGFR change from baseline at 52 weeks with pooled tirzepatide (5, 10, and 15 mg) and titrated insulin glargine in adults with type 2 diabetes and high cardiovascular risk (SURPASS-4). Least squares mean (SE) eGFR-creatinine (mL/min/1.73 m2) changes from baseline with tirzepatide and insulin glargine were -2.5 (0.38) and -3.9 (0.38) (between-group difference, 1.4 [95% CI 0.3-2.4]) and -3.5 (0.37) and -5.3 (0.37) (between-group difference, 1.8 [95% CI 0.8-2.8]) for eGFR-cystatin C. Baseline, 1-year, and 1-year change from baseline values significantly correlated between eGFR-cystatin C and -creatinine. Measures of eGFR changes did not correlate with body weight changes. Tirzepatide slows the eGFR decline rate, supporting a kidney-protective effect.

The quality and outcomes of curative-intent lung cancer surgery vary in populations. Surgeons are key drivers of surgical quality. We examined the association between surgeon-level intermediate outcomes differences, patient survival differences, and potential mitigation by processes of care. Using a baseline population-based surgical resection cohort, we derived surgeon-level cut points for rates of positive margins, nonexamination of lymph nodes, nonexamination of mediastinal lymph nodes, and wedge resections. Applying the baseline cut points to a subsequent cohort from the same population-based data set, we assign surgeons into three performance categories in reference to each metric: 1 (75th percentile). The sum of performance scores created three surgeon quality tiers: 1 (4-6, low), 2 (7-9, intermediate), and 3 (10-12, high). We used chi-squared, Wilcoxon-Mann-Whitney, and Kruskal-Wallis tests to compare patient characteristics between the baseline and subsequent cohorts and across surgeon tiers. We applied Cox proportional hazards models to examine the association between patient survival and surgeon performance tier, sequentially adjusting for clinical stage, patient characteristics, and four specific processes. From 2009 to 2021, 39 surgeons performed 4,082 resections across the baseline and subsequent cohorts. Among 31 subsequent cohort surgeons, five were tier 1, five were tier 2, and 21 were tier 3. Tier 1 and 2 surgeons had significantly worse outcomes than tier 3 surgeons (hazard ratio [HR], 1.37; 95% CI, 1.10 to 1.72 and 1.19; 95% CI, 1.00 to 1.43, respectively). Adjustment for specific processes mitigated the surgeon-tiered survival differences, with adjusted HRs of 1.02 (95% CI, 0.8 to 1.3) and 0.93 (95% CI, 0.7 to 1.25), respectively. Readily accessible intermediate outcomes metrics can be used to stratify surgeon performance for targeted process improvement, potentially reducing patient survival disparities.

Thoracic aortic aneurysm is characterized by dilation of the aortic diameter by greater than 50%, which can lead to dissection or rupture. Common histopathology includes extracellular matrix remodeling which may affect transmural mass transport, defined as the movement of fluids and solutes across the wall. We measured in vitro ascending thoracic aorta mass transport in a mouse model with partial aneurysm phenotype penetration due to a mutation in the extracellular matrix protein fibulin-4 (Fbln4E57K/E57K, referred to as MU-A [aneurysm] or MU-NA [non-aneurysm]). To push the aneurysm phenotype, we also included MU mice with reduced levels of lysyl oxidase (Fbln4E57K/E57K;Lox+/-, referred to as MU-XA [extreme aneurysm]) and compared all groups to wild-type (WT) littermates. The phenotype variation allows investigation of how aneurysm severity correlates with mass transport parameters and extracellular matrix organization. We found that MU-NA ascending thoracic aortae have similar hydraulic conductance (Lp) to WT, but 397% higher solute permeability (ω) for 4 kDa FITC-dextran. In contrast, MU-A and MU-XA ascending thoracic aortae have 44-68% lower Lp and similar ω to WT. The results suggest that ascending thoracic aortic aneurysm progression involves an initial increase in ω, followed by a decrease in Lp after the aneurysm has formed. All MU ascending thoracic aortae are longer and have increased elastic fiber fragmentation in the extracellular matrix. There is a negative correlation between diameter and Lp or ω in MU ascending thoracic aortae. Changes in mass transport due to elastic fiber fragmentation could contribute to aneurysm progression or be leveraged for treatment.

The cytokine interleukin-6 (IL-6) has considerable pro-inflammatory properties and is a driver of many physiological and pathophysiological processes. Cellular responses to IL-6 are mediated by membrane-bound or soluble forms of the IL-6 receptor (IL-6R) complexed with the signal-transducing subunit gp130. While expression of the membrane-bound IL-6R is restricted to selected cell types, soluble IL-6R (sIL-6R) enables gp130 engagement on all cells, a process termed IL-6 trans-signalling and considered to be pro-inflammatory. sIL-6R is predominantly generated through proteolytic processing by the metalloproteinase ADAM17. ADAM17 also liberates ligands of the epidermal growth factor receptor (EGFR), which is a prerequisite for EGFR activation and results in stimulation of proliferative signals. Hyperactivation of EGFR mostly due to activating mutations drives cancer development. Here, we reveal an important link between overshooting EGFR signalling and the IL-6 trans-signalling pathway. In epithelial cells, EGFR activity induces not only IL-6 expression but also the proteolytic release of sIL-6R from the cell membrane by increasing ADAM17 surface activity. We find that this derives from the transcriptional upregulation of iRhom2, a crucial regulator of ADAM17 trafficking and activation, upon EGFR engagement, which results in increased surface localization of ADAM17. Also, phosphorylation of the EGFR-downstream mediator ERK mediates ADAM17 activity via interaction with iRhom2. In sum, our study reveals an unforeseen interplay between EGFR activation and IL-6 trans-signalling, which has been shown to be fundamental in inflammation and cancer.

Polyphenols, also known as phenolic compounds, are chemical substances containing aromatic rings as well as at least two hydroxyl groups. Natural phenolic compounds exist widely in plants, which protect plants from ultraviolet radiation and other insults. Phenolic compounds have superior pharmacological and nutritional properties (antimicrobial, antibacterial, antiviral, anti-sclerosis, antioxidant, and anti-inflammatory activities), which have been paid more and more attention by the scientific community. Phenols can protect key cellular components from reactive free radical damage, which is mainly due to their property to activate antioxidant enzymes and alleviate oxidative stress and inflammation. It can also inhibit or isolate reactive oxygen species and transfer electrons to free radicals, thereby avoiding cell damage. It has a regulatory role in glucose metabolism, which has a promising prospect in the prevention and intervention of diabetes. It also prevents cardiovascular disease by regulating blood pressure and blood lipids. Polyphenols can inhibit cell proliferation by affecting Erk1/2, CDK, and PI3K/Akt signaling pathways. Polyphenols can function as enhancers of intrinsic defense systems, including superoxide dismutase (SOD) and glutathione peroxidase (GPX). Simultaneously, they can modulate multiple proteins and transcription factors, making them promising candidates in the investigation of anti-cancer medications. This review focuses on multiple aspects of phenolic substances, including their natural origins, production process, disinfection activity, oxidative and anti-inflammatory functions, and the effects of different phenolic substances on tumors.

Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatomyositis (DM) complicated by rapidly progressive interstitial lung disease (RP-ILD) has a high incidence and poor prognosis. The objective of this study was to establish a model for the prediction and early diagnosis of anti-MDA5+ DM-associated RP-ILD based on clinical manifestations and imaging features. A total of 103 patients with anti-MDA5+ DM were included. The patients were randomly split into training and testing sets of 72 and 31 patients, respectively. After image analysis, we collected clinical, imaging, and radiomics features from each patient. Feature selection was performed first with the minimum redundancy and maximum relevance (mRMR) algorithm and then with the best subset selection method. The final remaining features comprised the radscore. Then, a clinical model and imaging model were constructed with the selected independent risk factors for the prediction of non-RP-ILD and RP-ILD. We also combined these models in different ways and compared their predictive abilities. A nomogram was also established. The predictive performances of the models were assessed based on receiver operating characteristic curves, calibration curves, discriminability, and clinical utility. : The analyses showed that 2 clinical factors, dyspnea (p = 0.000) and duration of illness in months (p = 0.001), and 3 radiomics features (p = 0.001, 0.044, 0.008, separately) were independent predictors of non-RP-ILD and RP-ILD. However, no imaging features were significantly different between the two groups. The radiomics model built with the 3 radiomics features performed worse than the clinical model and showed areas under the curve (AUCs) of 0.805 and 0.754 in the training and test sets, respectively. The clinical model demonstrated a good predictive ability for RP-ILD in MDA5+ DM patients, with an AUC, sensitivity, specificity, and accuracy of 0.954, 0.931, 0.837, and 0.847 in the training set and 0.890, 0.875, 0.800, and 0.774 in the testing set, respectively. The combination model built with clinical and radiomics features performed slightly better than the clinical model, with an AUC, sensitivity, specificity, and accuracy of 0.994, 0.966, 0.977, and 0.931 in the training set and 0.890, 0.812, 1.000, and 0.839 in the testing set, respectively. The calibration curve and decision curve analyses showed satisfactory consistency and clinical utility of the nomogram. Our results suggest that the combination model built with clinical and radiomics features could reliably predict the occurrence of RP-ILD in MDA5+ DM patients.

Atherosclerosis is a chronic inflammatory disease with its molecular basis incompletely understood. Here, we determined whether the Golgi phosphoprotein 73 (GP73), a novel protein highly related to inflammation and disrupted lipid metabolism, was involved in the development of atherosclerosis. Public microarray databases of human vascular samples were analyzed for expression patterns. Apolipoprotein-E-gene-deficient (ApoE-/-) mice (8-week-old) were randomly assigned to either a chow diet group or a high-fat diet group. The levels of serum GP73, lipid profiles and key inflammatory cytokines were determined by ELISA. The aortic root plaque was isolated and used for by Oil Red O staining. PMA-differentiated THP-1 macrophages were transfected with GP73 small interfering RNA (siRNA) or infected with adenovirus expressing GP73, and then stimulated with ox-LDL. The expressions of pro-inflammatory cytokines and signal pathway key targets were determined by ELISA kit and Western blot respectively. In addition, ichloro-dihydro-fluorescein diacetate (DCFH-DA) was used to measure the intracellular ROS levels. The expressions of GP73 and NLRP3 were substantially upregulated in human atherosclerotic lesions. There were significant linear correlations between GP73 and inflammatory cytokines expression. High-fat diet-induced atherosclerosis and increased levels of plasma inflammatory mediators (IL-1β, IL-18, and TNF-α) were observed in ApoE-/- mice. Besides, the expression of GP73 in the aorta and serum was significantly upregulated and positively correlated with the NLRP3 expression. In the THP-1 derived macrophages, ox-LDL treatment upregulated the expression of GP73 and NLRP3 proteins and activated the inflammatory responses in a concentration-dependent and time-dependent manner. Silencing of GP73 attenuated the inflammatory response and rescued the decreased migration induced by ox-LDL, inhibiting the NLRP3 inflammasome signaling and the ROS and p-NF-κB activation. We demonstrated that GP73 promoted the ox-LDL-induced inflammation in macrophages by affecting the NF-κB/NLRP3 inflammasome signaling, and may play a role in atherosclerosis.

Gut microbiota is associated with hyperuricemia progression and can be regulated by Lactobacillus plantarum. However, the role of Lactobacillus plantarum in hyperuricemia is still unknown. Thus, we constructed the mouse model of hyperuricemia using potassium oxonate and hypoxanthine treatment to explore the effects of Lactobacillus plantarum LLY-606 supplementation on the development of hyperuricemia. The results showed that Lactobacillus plantarum LLY-606 significantly reduced the level of serum uric acid through inhibiting uric acid secretion and regulating uric acid transport. We also found that Lactobacillus plantarum LLY-606 supplementation inhibited the inflammatory response and the activation of the TLR4/MyD88/NF-κB signaling pathway in mice. Microbiome sequencing and analysis suggested the successful colonization of probiotics, which could regulate intestinal flora dysbiosis induced by hyperuricemia. The abundance of Lactobacillus plantarum was significantly negatively correlated with hyperuricemia-related indicators. Notably, the functional abundance prediction of microbiota indicated that lipopolysaccharide biosynthesis protein pathways and lipopolysaccharide biosynthesis pathways were inhibited after the probiotic intervention. In conclusion, Lactobacillus plantarum LLY-606 can serve as a potential functional probiotic to affect the development of hyperuricemia through modulating gut microbiota, downregulating renal inflammation, and regulating uric acid metabolism.

Heavy metal pollution has been a worldwide prevalent problem, and particularly a threat to ecosystem integrity and animals' health. Previous studies on the mechanisms of heavy metal toxicity have focused on protein-coding genes, whereas most genomic transcripts are long non-coding RNAs (lncRNAs). Although lncRNAs are known to play important regulatory roles in biological processes, their role in heavy metal stress regulation is still not fully understood. We here developed an insect embryo cell model for studying metal toxicity and the underlying regulatory mechanisms. We performed genome-wide screening and functional characterization of lncRNAs induced by two essential and two non-essential heavy metals in Drosophila embryo-derived S2 cells. We identified 4894 lncRNAs, of which 1410 were novel. Forty-one lncRNAs, together with 328 mRNAs, were induced by all the four heavy metals. LncRNA-mRNA co-expression network and pathway enrichment analysis showed that detoxification metabolism, circadian rhythm, and apoptosis regulation pathways were activated in response to heavy metal stress. LncRNA CR44138 was remarkably upregulated in cells exposed to the four heavy metals and was associated with the apoptosis pathway. Expression interference confirmed that CR44138 aggravated cytotoxicity-induced apoptosis in cells under heavy metals stress. This study highlights the important role of lncRNAs in regulating the cellular response to heavy metals. This study also lays the foundation for discovering the novel regulatory mechanisms and developing diagnostic biomarkers of the toxic effects of heavy metal pollutants on organisms.