Notch1 promotes resistance to cisplatin by up-regulating Ecto-5'-nucleotidase (CD73) in triple-negative breast cancer cells

Triple-negative breast cancer (TNBC) is an aggressive molecular subtype that due to lack of druggable targets is treated with chemotherapy as standard of care. However, TNBC is prone to chemoresistance and associates with poor survival. The aim of this study was to explore the molecular mechanisms of chemoresistance in TNBC. Firstly, we found that the mRNA expression of Notch1 and CD73 in cisplatin-treated patient material associated with poor clinical outcome. Further, both were upregulated at the protein level in cisplatin-resistant TNBC cell lines. Overexpression of Notch1 intracellular domain (termed N1ICD) increased expression of CD73, whereas knockdown of Notch1 decreased CD73 expression. Using chromatin immunoprecipitation and Dual-Luciferase assay it was identified that N1ICD directly bound the CD73 promoter and activated transcription. Taken together, these findings suggest CD73 as a direct downstream target of Notch1, providing an additional layer to the mechanisms underlying Notch1-mediated cisplatin resistance in TNBC.</p

Prevalence of iron-deficiency anemia in pregnant women with various thalassemia genotypes: Thoughts on iron supplementation in pregnant women with thalassemia genes

BackgroundThere are limited studies on iron-deficiency anemia (IDA) in carriers of various thalassemia genotypes. However, for pregnant women (PW) with high iron demand, ignoring the phenomenon of carrying the thalassemia genes combined with IDA may lead to adverse pregnancy outcomes.MethodsThe hematological phenotype indexes of 15,051 PW who received a prenatal diagnosis of thalassemia in our hospital were analyzed, and the plasma ferritin (PF) of 714 anemic pregnant women (APW) was determined.ResultsThe results showed that 87.43% of APW without thalassemia suffered from IDA. Among APW with various thalassemia genotypes, we found that 40.00∼77.78% of subjects with α-thalassemia silent genotypes [αCS (or QS)α/αα (40.00%), –α3.7(or4.2)/αα (57.65%), and αWSα/αα (77.78%)] and 18.18∼84.21% of subjects with α-thalassemia minor genotypes [αCS (or QS)α/–α3.7(or4.2) (18.18%), –α3.7(or4.2)/–α3.7(or4.2) (40.00%), αα/–SEA (44.55%), and αWSα/–α3.7(or4.2) (84.21%)] developed IDA, while in subjects with α-thalassemia intermedia genotypes, only αWSα/–SEA was associated with IDA, with an incidence of 16.67%. However, the incidence of IDA in APW with common β-thalassemia minor genotypes (βCD17(A&gt;T)/β, βCD41/42 (–TTCT)/β, βCD71/72(+A)/β, βIVS–II–654(C&gt;T)/β, and β–28(A&gt;G)/β) was less than 10.85%. In addition, the APW with β-thalassemia minor had a higher PF level than the APW without thalassemia.ConclusionOur study is the first to reveal differences in the prevalence of IDA among PW with various thalassemia genotypes, indicating that the possibility of IDA should be fully considered when managing PW with α-thalassemia silent or minor genotypes in high-risk areas, and that iron supplementation should be monitored dynamically for PW with β-thalassemia minor genotypes

Reversing tumor stemness via orally targeted nanoparticles achieves efficient colon cancer treatment

The acquisition of stemness in colorectal cancer (CRC) attributed to the recurrence and metastasis in CRC treatment. Therefore, targeting the stemness of CRC forms a basis for the development of novel therapeutic approaches. However, the pain and systemic side effect from long-term of venipuncture injection remain great challenges to neoplastic treatment. Here, we introduce an oral drug delivery system for sustained release of BMI-1 inhibitor (PTC209) that reverse the stemness of CRC to over-come these obstacles. In this system, nanoparticles modified with hyaluronic acid (HA) showed high-affinity to CD44 / CD168 overexpressed-CRC cells, and efficiently targeted to tumor site in a metastatic orthotropic colon cancer mouse model by oral administration. Significantly, the observed tumor growth inhibition is accompanied by decreased expression of stemness markers in the tumor tissues. Furthermore, HA-NPs-PTC209 also significantly prevented metastasis to the gastrointestinal system, while failing to exhibit acute side effects. In summary, we have developed an orally active, easily synthesized nanomedicine that shows promise for the treatment of colon cancer

Released micromachined beams utilizing laterally uniform porosity porous silicon

© 2014, Sun et al.; licensee Springer. Abstract: Suspended micromachined porous silicon beams with laterally uniform porosity are reported, which have been fabricated using standard photolithography processes designed for compatibility with complementary metal-oxide-semiconductor (CMOS) processes. Anodization, annealing, reactive ion etching, repeated photolithography, lift off and electropolishing processes were used to release patterned porous silicon microbeams on a Si substrate. This is the first time that micromachined, suspended PS microbeams have been demonstrated with laterally uniform porosity, well-defined anchors and flat surfaces. PACS: 81.16.-c; 81.16.Nd; 81.16.R

Identification of potential biomarkers and pathways for asthenozoospermia by bioinformatics analysis and experiments

BackgroundAsthenozoospermia, a type of male infertility, is primarily caused by dysfunctional sperm mitochondria. Despite previous bioinformatics analysis identifying potential key lncRNAs, miRNAs, hub genes, and pathways associated with asthenospermia, there is still a need to explore additional molecular mechanisms and potential biomarkers for this condition.MethodsWe integrated data from Gene Expression Omnibus (GEO) (GSE22331, GSE34514, and GSE160749) and performed bioinformatics analysis to identify differentially expressed genes (DEGs) between normozoospermia and asthenozoospermia. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to gain insights into biological processes and signaling pathways. Weighted Gene Co-expression Network Analysis (WGCNA) identified gene modules associated with asthenozoospermia. Expression levels of key genes were assessed using datasets and experimental data. Gene Set Enrichment Analysis (GSEA) and correlation analysis identified pathways associated with the hub gene and explore the relationship between the ZNF764 and COQ9 and mitochondrial autophagy-related genes. Competitive endogenous RNA (ceRNA) networks were constructed, and in vitro experiments using exosome samples were conducted to validate this finding.ResultsCOQ9 was identified as a marker gene in asthenozoospermia, involved in autophagy, ATP-dependent chromatin remodeling, endocytosis, and cell cycle, etc. The ceRNA regulatory network (LINC00893/miR-125a-5p/COQ9) was constructed, and PCR demonstrated that LINC00893 and COQ9 were downregulated in asthenozoospermia, while miR-125a-5p and m6A methylation level of LINC00893 were upregulated in asthenozoospermia compared to normozoospermic individuals.ConclusionThe ceRNA regulatory network (LINC00893/miR-125a-5p/COQ9) likely plays a crucial role in the mechanism of asthenozoospermia. However, further functional experiments are needed to fully understand its significance

A global reference for human genetic variation

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies

RETRACTED ARTICLE: RUNX3-regulated circRNA METTL3 inhibits colorectal cancer proliferation and metastasis via miR-107/PER3 axis

Abstract Colorectal cancer (CRC) is one of the most prevalent and lethal malignancies. Exploring the underlying molecular mechanisms is very helpful for the development of new therapy. Here, we investigated the function of circMETTL3/miR-107/PER3 in CRC. Human CRC tissues from diagnosed CRC patients and six CRC cell lines, one normal human colon cell line were used. qRT-PCR and western blotting were performed to determine expression levels of RUNX3, circMETTL3, miR-107, PER3, and proliferation-, and migration-related proteins. CCK-8, colony formation assay, transwell assay, and scratch wound assay were utilized to assess CRC cell proliferation and invasion. ChIP, EMSA, biotin-pull down, RIP assay, and dual luciferase reporter assay were performed to validate interactions of RUNX3/METTL3 promoter, circMETTL3/miR-107, and miR-107/PER3. FISH was used to characterize circMETTL3. MSP was employed to measure methylation level. Nude mouse xenograft model was used to determine the effects on tumor growth and metastasis in vivo. RUNX3, circMETTL3, and PER3 were diminished while miR-107 was elevated in CRC tissues and cells. Low levels of RUNX3 and circMETTL3 correlated with poor prognosis of CRC. Overexpression of RUNX3, circMETTL3, or PER3 suppressed while miR-107 mimics promoted, CRC cell proliferation and invasion, as well as tumor growth and metastasis in vivo. Mechanistically, RUNX3 bound to METTL3 promoter and activated circMETTL3 transcription. circMETTL3 directly bound with miR-107 which targeted PER3. circMETTL3/miR-107 regulated CRC cell proliferation and invasion via PER3. CircMETTL3, transcriptionally activated by RUNX3, restrains CRC development and metastasis via acting as a miR-107 sponge to regulate PER3 signaling