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BackgroundTriple-negative breast cancer (TNBC) is refractory and heterogeneous, comprising various entities with divergent phenotype, biology, and clinical presentation. As an aggressive subtype, Chinese TNBC patients with special morphologic patterns (STs) were restricted to its incidence of 10-15% in total TNBC population.MethodsWe recruited 89 patients with TNBC at Guangdong Provincial People’s Hospital (GDPH) from October 2014 to May 2021, comprising 72 cases of invasive ductal carcinoma of no-special type (NSTs) and 17 cases of STs. The clinical data of these patients was collected and statistically analyzed. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) with cancer-related, 520- or 33-gene assay. Immunohistochemical analysis of FFPE tissue sections was performed using anti-programmed cell death-ligand 1(PD-L1) and anti-androgen receptor antibodies.ResultsCases with NSTs presented with higher histologic grade and Ki-67 index rate than ST patients (NSTs to STs: grade I/II/III 1.4%, 16.7%,81.9% vs 0%, 29.4%, 58.8%; p

Natural polyketides play important roles in clinical treatment, agriculture, and animal husbandry. Compared to natural hosts, heterologous chassis (especially Actinomycetes) have many advantages in production of polyketide compounds. As a widely studied model Actinomycete, Saccharopolyspora erythraea is an excellent host to produce valuable heterologous polyketide compounds. However, many host factors affect the expression efficiency of heterologous genes, and it is necessary to modify the host to adapt heterologous production. In this study, the CRISPR-Cas9 system was used to knock out the erythromycin biosynthesis gene cluster of Ab (erythromycin high producing stain). A fragment of 49491 bp in genome (from SACE_0715 to SACE_0733) was deleted, generating the recombinant strain AbΔery in which erythromycin synthesis was blocked and synthetic substrates methylmalonyl-CoA and propionyl-CoA accumulated enormously. Based on AbΔery as heterologous host, three genes, AsCHS, RgTAL, and Sc4CL, driven by strong promoters Pj23119, PermE, and PkasO, respectively, were introduced to produce novel polyketide by L-tyrosine and methylmalonyl-CoA. The product (E)-4-hydroxy-6-(4-hydroxystyryl)-3,5-dimethyl-2H-pyrone was identified in fermentation by LC-MS. High performance liquid chromatography analysis showed that knocking out ery BGC resulted in an increase of methylmalonyl-CoA by 142% and propionyl-CoA by 57.9% in AbΔery compared to WT, and the yield of heterologous product in AbΔery:AsCHS-RgTAL-Sc4CL was higher than WT:AsCHS-RgTAL-Sc4CL. In summary, this study showed that AbΔery could potentially serve as a precious heterologous host to boost the synthesis of other valuable polyketone compounds using methylmalonyl-CoA and propionyl-CoA in the future.

Accumulating evidence has indicated that embryonic inflammation could accelerate age-associated cognitive impairment, which can be attributed to dysregulation of synaptic plasticity-associated proteins, such as RNA-binding proteins (RBPs). Staufen is a double-stranded RBP that plays a critical role in the modulation of synaptic plasticity and memory. However, relatively few studies have investigated how embryonic inflammation affects cognition and neurobiology during aging, or how the adolescent psychosocial environment affects inflammation-induced remote cognitive impairment. Consequently, the aim of this study was to investigate whether these adverse factors can induce changes in Staufen expression, and whether these changes are correlated with cognitive impairment. In our study, CD-1 mice were administered lipopolysaccharides (LPS, 50 μg/kg) or an equal amount of saline (control) intraperitoneally during days 15–17 of gestation. At 2 months of age, male offspring were randomly exposed to stress (S), an enriched environment (E), or not treated (CON) and then assigned to five groups: LPS, LPS+S, LPS+E, CON, and CON+S. Mice were evaluated at 3-month-old (young) and 15-month-old (middle-aged). Cognitive function was assessed using the Morris water maze test, while Staufen expression was examined at both the protein and mRNA level using immunohistochemistry/western blotting and RNAscope technology, respectively. The results showed that the middle-aged mice had worse cognitive performance and higher Staufen expression than young mice. Embryonic inflammation induced cognitive impairment and increased Staufen expression in the middle-aged mice, whereas adolescent stress/an enriched environment would accelerated/mitigated these effects. Meanwhile, Staufen expression was closely correlated with cognitive performance. Our findings suggested embryonic inflammation can accelerate age-associated learning and memory impairments, and these effects may be related to the Staufen expression.