Triple positive solutions for semipositone fractional differential equations m-point boundary value problems with singularities and p–q-order derivatives

In this paper, by means of Leggett–Williams and Guo–Krasnosel'skii fixed point theorems, together with height functions of the nonlinearity on different bounded sets, triple positive solutions are obtained for some fractional differential equations with p–q-order derivatives involved in multi-point boundary value conditions. The nonlinearity may not only take negative infinity but also may permit singularities on both the time and the space variables

Can the Chinese study on the normal range of FeNO in children evaluate standardized asthma treatment efficacy in 6- to 12-year-old children?

ObjectiveBy examining fractional exhaled nitric oxide (FeNO) levels and performing pulmonary function testing, this study explored whether the multicenter study on the normal range of FeNO in children in China can be used to evaluate standardized treatment efficacy in 6- to 12-year-old children with asthma.MethodsA total of 115 children aged 6–12 years old who were first diagnosed with asthma and received standardized asthma treatment from April 2018 to July 2022 were selected. According to the FeNO level at the first visit, the subjects were divided into different high- and low-FeNO groups according to the American Thoracic Society (ATS) guidelines and the Chinese multicenter study recommendations. The consistency of the two grouping methods and the differences between the high- and low-FeNO groups were compared after standardized treatment. The grouping method that was the most suitable for children in the cross group was discussed.Results(i) There was fair consistency between the Chinese multicenter study recommendations and the ATS guidelines regarding the classification of high- and low-FeNO groups (Kappa = 0.338). (ii) Repeated-measures ANOVA showed that the level of improvement in FVC%, FEV1%, FEF25%, FEF50%, and FeNO in the American high- and low-FeNO groups differed with the duration of therapy (P < 0.05), however, there was no significant difference between the Chinese groups. (iii) FEV1% and FeNO improved more after treatment in the fixed high-FeNO group than in the cross group (P < 0.05).ConclusionThe Chinese multicenter study on the normal range of FeNO in children in China has a limited role in evaluating standardized asthma treatment efficacy in 6- to 12-year-old children. The ATS guidelines are currently recommended for clinical assessment of asthma treatment efficacy

MicroRNA-20b promotes cell growth of breast cancer cells partly via targeting phosphatase and tensin homologue (PTEN)

BACKGROUND: MicroRNAs (miRNAs) are endogenous, small non-coding RNAs that play important roles in multiple biological processes. MiR-20b has been reported to participate in breast cancer tumorigenic progression, however, the functional roles are still unclear and under debating. The aim of this study is to explicit the molecular mechanism of miR-20b underlying breast cancer tumorigenesis. RESULTS: In the present study, we showed that miR-20b was overexpressed in human breast cancer tissues and cell lines compared with paired adjacent normal tissues and normal cell lines, respectively. We identified PTEN, a well-known tumor suppressor, as the functional downstream target of miR-20b. Luciferase assays confirmed that miR-20b could directly bind to the 3′ untranslated region(UTR) of PTEN and suppress translation. Alteration of miR-20b expression changed PTEN protein level but not mRNA expression in ZR-75-30 and MCF-7 breast cancer cells, suggesting miR-20b regulates PTEN gene expression at the posttranscriptional level. Furthermore, upregulation of miR-20b significantly promoted the proliferation, colony formation and DNA synthesis of ZR-75-30 and MCF-7 breast cancer cells. Conversely, knockdown of miR-20b expression inhibited the growth of breast cancer cells in vitro and in vivo. CONCLUSION: Dysregulation of miR-20b plays critical roles in the breast cancer tumorigenesis, at least in part via targeting the tumor suppressor PTEN. This microRNA may serve as a potential diagnostic marker and therapeutic target for breast cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2045-3701-4-62) contains supplementary material, which is available to authorized users

Efficacy of guideline-directed medical treatment in heart failure with mildly reduced ejection fraction.

Heart failure with mildly reduced ejection fraction (HFmrEF) has received increasing attention following the publication of the latest ESC guidelines in 2021. However, it remains unclear whether patients with HFmrEF could benefit from guideline-directed medical treatment (GDMT), referring the combination of ACEI/ARB/ARNI, β-blockers, and MRAs, which are recommended for those with reduced ejection fraction. This study explored the efficacy of GDMT in HFmrEF patients. This was a retrospective cohort study of HFmrEF patients admitted to The First Affiliated Hospital of Dalian Medical University between 1 September 2015 and 30 November 2019. Propensity score matching (1:2) between patients receiving triple-drug therapy (TT) and non-triple therapy (NTT) based on age and sex was performed. The primary outcome was all cause death, cardiac death, rehospitalization from any cause, and rehospitalization due to worsening heart failure. Of the 906 patients enrolled in the matched cohort (TT group, n = 302; NTT group, N = 604), 653 (72.08%) were male, and mean age was 61.1 ± 11.92. Survival analysis suggested that TT group experienced a significantly lower incidence of prespecified primary endpoints than NTT group. Multivariable Cox regression showed that TT group had a lower risk of all-cause mortality (HR 0.656, 95% CI 0.447-0.961, P = 0.030), cardiac death (HR 0.599, 95% CI 0.380-0.946, P = 0.028), any-cause rehospitalization (HR 0.687, 95% CI 0.541-0.872, P = 0.002), and heart failure rehospitalization (HR 0.732, 95% CI 0.565-0.948, P = 0.018). In patients with HFmrEF, combined use of neurohormonal antagonists produces remarkable effects in reducing the occurrence of the primary outcome of rehospitalization and death. Thus, the treatment of HFmrEF should be categorized as HFrEF due to the similar benefit of neurohormonal blocking therapy in HFrEF and HFmrEF. [Abstract copyright: © 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Knockdown of Notch1 inhibits nasopharyngeal carcinoma cell growth and metastasis via downregulation of CCL2, CXCL16, and uPA

Notch pathway is a highly conserved cell signaling system that plays very important roles in controlling multiple cell differentiation processes during embryonic and adult life. Multiple lines of evidence support the oncogenic role of Notch signaling in several human solid cancers; however, the pleiotropic effects and molecular mechanisms of Notch signaling inhibition on nasopharyngeal carcinoma (NPC) remain unclear. In this study, we evaluated Notch1 expression in NPC cell lines (CNE1, CNE2, SUNE1, HONE1, and HK1) by real-time quantitative PCR and Western blot analysis, and we found that CNE1 and CNE2 cells expressed a higher level of Notch1 compared with HONE1, SUNE1, and HK1 cells. Then Notch1 expression was specifically knocked down in CNE1 and CNE2 cells by Notch1 short hairpin RNA (shRNA). In Notch1 knockdown cells, cell proliferation, migration, and invasion were significantly inhibited. The epithelial-mesenchymal transition of tumor cells was reversed in Notch1-shRNA-transfected cells, accompanied by epithelioid-like morphology changes, increased protein levels of E-cadherin, and decreased expression of vimentin. In addition, knockdown of Notch1 markedly inhibited the expression of urokinase plasminogen activator (uPA) and its receptor uPAR, and chemokines C-C motif chemokine ligand 2 and C-X-C motif chemokine ligand 16, indicating that these factors are downstream targets of Notch1. Furthermore, deleting uPA expression had similar effects as Notch1. Finally, knockdown of Notch1 significantly diminished CNE1 cell growth in a murine model concomitant with inhibition of cell proliferation and induction of apoptosis. These results suggest that Notch1 may become a novel therapeutic target for the clinical treatment of NPC.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151248/1/mc23082_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151248/2/mc23082.pd

Preparation and PEGylation of recombinant human interferon lambda3

The purpose of this study was to express recombinant human interferon lambda3 (rhIFN-λ3) in Escherichia coli, and prepare PEGylated recombinant human interferon lambda3 (PEG-rhIFN-λ3). The rhIFN-λ3 gene was inserted into pThioHisA vector after codon optimization and transformed into E. coli top10 strain, and then it was induced with isopropyl-β-D-thio-galactoside (IPTG). The recombinant protein was subjected to mPEG-ButyrALD modification after dialysis, renaturation and chromatographic purification. Subsequently, the modified product was preliminary isolated and purified for determining its activity. Results show that the recombinant protein was expressed in the form of inclusion bodies. After ion exchange, molecular sieve and other column chromatography purification, the purity of the purified rhIFN-λ3 was as high as 90% and the purity of the mono-PEGylated rhIFN-λ3 after cation-exchange chromatography was as high as 86%. The 50% effective concentration (EC50) of rhIFN-λ3 in WISH cells against vesicular stomatitis virus (VSV) was 8.43 ng/mL, while the EC50 of mono-PEGylated rhIFN-λ3 was 49.19 ng/mL, which reserved 17.14% of the in vitro activity and supported further studies of this new type of investigational interferon. Further study is needed to better understand the in vivo immunogenicity, antigenicity, stability and antiviral activity of PEG-rhIFN-λ3.Keywords: Recombinant human interferon lambda3, prokaryotic expression, purification, mPEG-ButyrALD, antiviral activity

An assessment of land energy balance over East Asia from multiple lines of evidence and the roles of the Tibet Plateau, aerosols, and clouds

With high emissions of aerosols and the known world's “Third Pole” of the Tibet Plateau (TP) in East Asia, knowledge on the energy budget over this region has been widely concerned. This study first attempts to estimate the present-day land energy balance over East Asia by combining surface and satellite observations as well as the atmospheric reanalysis and Coupled Model Intercomparison Project Phase 6 (CMIP6) simulations. Compared to the global land budget, a substantially larger fraction of atmospheric shortwave radiation of 5.2 % is reflected, highly associated with the higher aerosol loadings and more clouds over East Asian land. While a slightly smaller fraction of atmospheric shortwave absorption of 0.6 % is unexpectedly estimated, possibly related to the lower water vapor content effects due to the thinner air over the TP to overcompensate for the aerosol and cloud effects over East Asian land. The weaker greenhouse effect and fewer low clouds due to the TP are very likely the causes of the smaller fraction of East Asian land surface downward longwave radiation. Hence, high aerosol loadings, clouds, and the TP over East Asia play vital roles in the shortwave budgets, while the TP is responsible for the longwave budgets during this regional energy budget assessment. The further obtained cloud radiative effects suggest that the presence of clouds results in a larger cooling effect on the climate system over East Asian land than that over the globe. This study provides a perspective to understand fully the roles of potential factors in influencing the different energy budget assessments over regions.</p

Application of emerging technologies in ischemic stroke: from clinical study to basic research

Stroke is a primary cause of noncommunicable disease-related death and disability worldwide. The most common form, ischemic stroke, is increasing in incidence resulting in a significant burden on patients and society. Urgent action is thus needed to address preventable risk factors and improve treatment methods. This review examines emerging technologies used in the management of ischemic stroke, including neuroimaging, regenerative medicine, biology, and nanomedicine, highlighting their benefits, clinical applications, and limitations. Additionally, we suggest strategies for technological development for the prevention, diagnosis, and treatment of ischemic stroke