Co-delivery of salinomycin and curcumin for cancer stem cell treatment by inhibition of cell proliferation, cell cycle arrest, and epithelial-mesenchymal transition

Malignant cancer is a devastating disease often associated with a poor clinical prognosis. For decades, modern drug discoveries have attempted to identify potential modulators that can impede tumor growth. Cancer stem cells however are more resistant to therapeutic intervention, which often leads to treatment failure and subsequent disease recurrence. Here in this study, we have developed a specific multi-target drug delivery nanoparticle system against breast cancer stem cells (BCSCs). Therapeutic agents curcumin and salinomycin have complementary functions of limiting therapeutic resistance and eliciting cellular death, respectively. By conjugation of CD44 cell-surface glycoprotein with poly(lactic-co-glycolic acid) (PLGA) nanoparticles that are loaded with curcumin and salinomycin, we investigated the cellular uptake of BCSCs, drug release, and therapeutic efficacy against BCSCs. We determined CD44-targeting co-delivery nanoparticles are highly efficacious against BCSCs by inducing G1 cell cycle arrest and limiting epithelial–mesenchymal transition. This curcumin and salinomycin co-delivery system can be an efficient treatment approach to target malignant cancer without the repercussion of disease recurrence

Dissimilar laser welding of a NiTi shape memory alloy to Ti2AlNb

Funding Information: Acknowledgments: This work was supported by National Natural Science Foundation of China (No. 51775091), Science and Technology Project of Sichuan Province (No. 2020ZDZX0015). J.P. Oliveira acknowledges Fundação para a Ciência e a Tecnologia (FCT—MCTES) for its financial support via the project UID/00667/2020 (UNIDEMI). Funding Information: Funding: This work was supported by National Natural Science Foundation of China (No. 51775091), Science and Technology Project of Sichuan Province (No. 2020ZDZX0015). J.P. Oliveira acknowledges Fundação para a Ciência e a Tecnologia (FCT—MCTES) for its financial support via the project UID/00667/2020 (UNIDEMI). Funding Information: This work was supported by National Natural Science Foundation of China (No. 51775091), Science and Technology Project of Sichuan Province (No. 2020ZDZX0015). J.P. Oliveira acknowledges Funda??o para a Ci?ncia e a Tecnologia (FCT?MCTES) for its financial support via the project UID/00667/2020 (UNIDEMI).NiTi-based shape memory alloys and the Ti2AlNb alloy have gained increasing importance in the aerospace field. The joining of these two materials can further increment the importance and usage of these relevant engineering materials and expand their potential applications. However, when joining NiTi-based shape memory alloys to Ti-based alloys, the formation of brittle Ti-rich intermetallic compounds often occurs, significantly limiting their functionality and use. Dissimilar joints between a NiTi shape memory alloy and Ti2AlNb alloy were obtained using a 0.1 mm thick Niobium (Nb) interlayer via laser welding. By process optimization, sound joints were obtained. The microstructure evolution was assessed by means of electron microscopy, whereas the mechanical strength of the joints was evaluated using lap shear tensile testing. The best performing joints were seen to fracture at maximum loads above 1230 N, thus allowing us to consider this dissimilar pair for structural applications.publishersversionpublishe

Process, microstructure and mechanical properties

Funding Information: This work was supported by National Natural Science Foundation of China (Grant No. 51875168/52002112 ), Natural Science Foundation of Hebei Province (Grant No. E2019208089 ) and “Three-Three-Three Talent Project” Foundation of Hebei Province ( C20221022 ). Sichuan Province Science Funding for Distinguished Young Scholars ( 3NSFJQ0064 ). JPO acknowledges funding by national funds from FCT – Fundação para a Ciência e a Tecnologia, I.P., in the scope of the projects LA/P/0037/2020. Science and Technology Research Project of Colleges and Universities in Hebei Province (Grant No. BJK2022020 ). Publisher Copyright: © 2023 The AuthorsAiming to decouple the inherent relationship between mass transfer and heat transfer in traditional arc-based directed energy deposition, a novel heterogeneous multi-wire indirect arc directed energy deposition (DED) has been developed for in-situ synthesis of Al-Zn-Mg-Cu alloy components. Multi-wires (Al-Cu and Al-Mg) with a bypassing Zn wire have been used to replace the traditional homogeneous twin-wires. The process, microstructure and mechanical properties of the deposited Al-Zn-Mg-Cu alloy components obtained by multi-wire indirect arc DED were investigated. The results indicate that the wire feeding speed, current and angle between the two wires have a significant influence on the multi-wire indirect arc DED process. When the current was 200 A, the different wire feeding speeds could be used for both wires and the angle between them was 90°. The resulting indirect arc presented a ‘heart’ shape and allowed to obtain an Al-5.7Zn-3.4Mg-1.6Cu (wt%) alloy with a high deposition rate of 5.1 kg/h. The Al-5.7Zn-3.4Mg-1.6Cu alloy is mainly composed of α-Al, S (Al2CuMg), η (Mg (Al, Zn, Cu)2) and η′ phases. The composition and phases are in accordance with the 7xxx series aluminum alloys. The microstructure is dominated by columnar and equiaxed grains, and it has obvious periodic distribution along the building direction, which is related to the process thermal cycle. Fine second phases η′ are observed to precipitate during the manufacturing process. Furthermore, the average hardness, ultimate tensile strength and elongation of the fabricated material are 98.6 HV, 243.9 MPa and 5.9%, respectively. These mechanical properties are higher than those of as-cast 7050 aluminum alloy, thus showing the potential of this new process variant to fabricate high strength Al alloys in the as-deposited state. The fracture morphology exhibit features mainly associated to a ductile-like fracture, accompanied by some transgranular and partial cleavage fracture characteristics. This novel multi-wire indirect arc DED provides a new choice for arc-based directed energy deposition of Al-Zn-Mg-Cu alloys and shows great potential for the in-situ synthesis of other high-performance alloys.publishersversionpublishe

Valorizing Rice Straw and Its Anaerobically Digested Residues for Biochar to Remove Pb(II) from Aqueous Solution

To seek a new path to valorize rice straw (RS) and its anaerobically digested residues (DRS), biochar production at different temperatures for removing Pb(II) from aqueous solution and its basic physicochemical characteristics for elucidating potentially adsorption mechanisms were investigated. Overall, pH, electrical conductivity (EC), ash, specific surface area (SA), micronutrient content, and aromaticity of RS biochars (RSBCs) and DRS biochars (DRSBCs) increased with the promoted pyrolysis temperature, and opposite trends were found on the yield, volatile matter, H, N, and O. Lower pH and K content but higher yield, carbon stability, and N and P content were achieved by DRSBCs. Consequently, DRSBCs exhibited lower Pb(II) removal, which was 0.15–0.35 of RSBCs. Maximum adsorption capacities of 276.3 and 90.5 mg·g−1 were achieved by RSBC and DRSBC, respectively, at 500°C. However, distinct mechanisms dominated Pb(II) removal, in which carbonates and carboxylates were responsible for RSBCs, and phosphate silicate precipitation and complexation with carboxylate groups controlled DRSBCs

Geniposide Alleviates Glucocorticoid-Induced Inhibition of Osteogenic Differentiation in MC3T3-E1 Cells by ERK Pathway

Glucocorticoid (GC) therapy is the leading cause of secondary osteoporosis and the therapeutic and preventative drugs for GC-induced osteoporosis are limited. In this study, we investigated the protective effects of geniposide on dexamethasone (DEX)-induced osteogenic inhibition in MC3T3-E1 cells. The results showed that there was no obvious toxicity on MC3T3-E1 cells when geniposide was used at the doses ranging from 1 to 75 μM. In DEX-treated MC3T3-E1 cells, geniposide promoted the alkaline phosphatase (ALP) activity and the mineralization. In addition, geniposide also significantly increased the mRNA and protein expression of osteopontin (OPN), Runt-related transcription factor 2 (Runx2), and Osterix (Osx) in DEX-treated MC3T3-E1 cells. Furthermore, geniposide activated ERK pathway in DEX-treated MC3T3-E1 cells. The ERK activation inhibitor U0126 and glucagon-like peptide-1 (GLP-1) receptor antagonist exendin 9-39 abolished the geniposide-induced activation of ERK and inhibited the protective effect of geniposide. Taken together, our study revealed that geniposide alleviated GC-induced osteogenic suppression in MC3T3-E1 cells. The effect of geniposide was at least partially associated with activating ERK signaling pathway via GLP-1 receptor. Geniposide might be a potential therapeutic agent for GC-induced osteoporosis

Evaluation of a new fluorescence quantitative PCR test for diagnosing Helicobacter pylori infection in children

Abstract Background Numerous diagnostic tests are available to detect Helicobactor pylori (H. pylori). There has been no single test available to detect H. pylori infection reliably. We evaluated the accuracy of a new fluorescence quantitative PCR (fqPCR) for H. pylori detection in children. Methods Gastric biopsy specimens from 138 children with gastritis were sent for routine histology exam, rapid urease test (RUT) and fqPCR. 13C-urea breath test (13C-UBT) was carried out prior to endoscopic procedure. Gastric fluids and dental plaques were also collected for fqPCR analysis. Results 38 children (27.5%) were considered positive for H. pylori infection by gold standard (concordant positive results on 2 or more tests). The remaining 100 children (72.5%) were considered negative for H. pylori. Gastric mucosa fqPCR not only detected all 38 H. pylori positive patients but also detected 8 (8%) of the 100 gold standard-negative children or 11 (10.7%) of the 103 routine histology-negative samples. Therefore, gastric mucosa fqPCR identified 46 children (33.3%) with H. pylori infection, significantly higher than gold standard or routine histology (P<0.01). Both gastric fluid and dental plaque fqPCR only detected 32 (23.2%) and 30 (21.7%) children with H. pylori infection respectively and was significantly less sensitive than mucosa fqPCR (P<0.05) but was as sensitive as non-invasive UBT. Conclusions Gastric mucosa fqPCR was more sensitive than routine histology, RUT, 13C-UBT alone or in combination to detect H. pylori infection in children with chronic gastritis. Either gastric fluid or dental plaque PCR is as reliable as 13C-UBT for H. pylori detection.Peer Reviewe

Assessing Reproducibility of Inherited Variants Detected With Short-Read Whole Genome Sequencing

Background: Reproducible detection of inherited variants with whole genome sequencing (WGS) is vital for the implementation of precision medicine and is a complicated process in which each step affects variant call quality. Systematically assessing reproducibility of inherited variants with WGS and impact of each step in the process is needed for understanding and improving quality of inherited variants from WGS. Results: To dissect the impact of factors involved in detection of inherited variants with WGS, we sequence triplicates of eight DNA samples representing two populations on three short-read sequencing platforms using three library kits in six labs and call variants with 56 combinations of aligners and callers. We find that bioinformatics pipelines (callers and aligners) have a larger impact on variant reproducibility than WGS platform or library preparation. Single-nucleotide variants (SNVs), particularly outside difficult-to-map regions, are more reproducible than small insertions and deletions (indels), which are least reproducible when \u3e 5 bp. Increasing sequencing coverage improves indel reproducibility but has limited impact on SNVs above 30×. Conclusions: Our findings highlight sources of variability in variant detection and the need for improvement of bioinformatics pipelines in the era of precision medicine with WGS

Genomic monitoring of SARS-CoV-2 uncovers an Nsp1 deletion variant that modulates type I interferon response

The SARS-CoV-2 virus, the causative agent of COVID-19, is undergoing constant mutation. Here, we utilized an integrative approach combining epidemiology, virus genome sequencing, clinical phenotyping, and experimental validation to locate mutations of clinical importance. We identified 35 recurrent variants, some of which are associated with clinical phenotypes related to severity. One variant, containing a deletion in the Nsp1-coding region (D500-532), was found in more than 20% of our sequenced samples and associates with higher RT-PCR cycle thresholds and lower serum IFN-beta levels of infected patients. Deletion variants in this locus were found in 37 countries worldwide, and viruses isolated from clinical samples or engineered by reverse genetics with related deletions in Nsp1 also induce lower IFN-beta responses in infected Calu-3 cells. Taken together, our virologic surveillance characterizes recurrent genetic diversity and identified mutations in Nsp1 of biological and clinical importance, which collectively may aid molecular diagnostics and drug design.Peer reviewe

Clinical research evidence of cupping therapy in China: a systematic literature review

<p>Abstract</p> <p>Background</p> <p>Though cupping therapy has been used in China for thousands of years, there has been no systematic summary of clinical research on it.</p> <p>This review is to evaluate the therapeutic effect of cupping therapy using evidence-based approach based on all available clinical studies.</p> <p>Methods</p> <p>We included all clinical studies on cupping therapy for all kinds of diseases. We searched six electronic databases, all searches ended in December 2008. We extracted data on the type of cupping and type of diseases treated.</p> <p>Results</p> <p>550 clinical studies were identified published between 1959 and 2008, including 73 randomized controlled trials (RCTs), 22 clinical controlled trials, 373 case series, and 82 case reports. Number of RCTs obviously increased during past decades, but the quality of the RCTs was generally poor according to the risk of bias of the Cochrane standard for important outcome within each trials. The diseases in which cupping was commonly employed included pain conditions, herpes zoster, cough or asthma, etc. Wet cupping was used in majority studies, followed by retained cupping, moving cupping, medicinal cupping, etc. 38 studies used combination of two types of cupping therapies. No serious adverse effects were reported in the studies.</p> <p>Conclusions</p> <p>According to the above results, quality and quantity of RCTs on cupping therapy appears to be improved during the past 50 years in China, and majority of studies show potential benefit on pain conditions, herpes zoster and other diseases. However, further rigorous designed trials in relevant conditions are warranted to support their use in practice.</p

Multi-ancestry genome-wide association study accounting for gene-psychosocial factor interactions identifies novel loci for blood pressure traits

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP, taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from five ancestry groups. In the combined meta-analyses of stages 1 and 2, we identified 59 loci (p value &lt; 5e−8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel&nbsp;loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A and PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5 and CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations