We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were ...more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC.
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•We build the genomic and transcriptomic landscape of 465 primary TNBCs•Chinese TNBC cases demonstrate more PIK3CA mutations and LAR subtype•Transcriptomic data classify TNBCs into four subtypes•Multi-omics profiling identifies potential targets within specific TNBC subtypes
Jiang et al. characterize primary Chinese triple-negative breast cancer (TNBC) and classify it into four subtypes. They find that these TNBCs have more frequent PIK3CA mutations and chromosome 22q11 copy-number gains than non-Asian TNBCs and that the LAR subtype has more ERBB2 somatic mutations and CDKN2A loss.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Accumulating evidence has shown that miR-34a serves as a posttranscriptional regulatory molecule of lipid metabolism in mammals. However, little studies about miR-34a on lipid metabolism in poultry ...have been reported until now. To gain insight into the biological functions and action mechanisms of miR-34a on hepatic lipid metabolism in poultry, we firstly investigated the expression pattern of miR-34a-5p, a member of miR-34a family, in liver of chicken, and determined its function in hepatocyte lipid metabolism by miR-34a-5p overexpression and inhibition, respectively. We then validated the interaction between miR-34a-5p and its target using dual-luciferase reporter assay, and explored the action mechanism of miR-34a-5p on its target by qPCR and Western blotting. Additionally, we looked into the function of the target gene on hepatocyte lipid metabolism by gain- and loss-of-function experiments. Our results indicated that miR-34a-5p showed a significantly higher expression level in livers in peak-laying hens than that in pre-laying hens. miR-34a-5p could increase the intracellular levels of triglycerides and total cholesterol in hepatocyte. Furthermore, miR-34a-5p functioned by inhibiting the translation of its target gene, long-chain acyl-CoA synthetase 1 (
), which negatively regulates hepatocyte lipid content. In conclusion, miR-34a-5p could increase intracellular lipid content by reducing the protein level, without influencing mRNA stability of the
gene in chickens.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Behavioral and clinical studies have revealed a critical role of substance P (SP) in aggression; however, the neural circuit mechanisms underlying SP and aggression remain elusive. Here, we show that ...tachykinin-expressing neurons in the medial amygdala (MeA
neurons) are activated during aggressive behaviors in male mice. We identified MeA
neurons as a key mediator of aggression and found that MeA
→ventrolateral part of the ventromedial hypothalamic nucleus (VMHvl) projections are critical to the regulation of aggression. Moreover, SP/neurokinin-1 receptor (NK-1R) signaling in the VMHvl modulates aggressive behaviors in male mice. SP/NK-1R signaling regulates aggression by influencing glutamate transmission in neurons in the VMHvl. In summary, these findings place SP as a key node in aggression circuits.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Three analogous lanthanide-containing complexes were isolated, with the molecular formula Ln 4 (μ 3 -OH) 2 (tmhd) 4 L 6 ·2CH 3 CN (where Ln = Eu( 1 ), Gd( 2 ) and Dy( 3 ); HL = ...5-phenyl-8-hydroxylquinoline; and Htmhd = 2,2,6,6-tetramethyl-3,5-heptanedione). Single-crystal X-ray diffraction measurements performed on 1–3 revealed that they were all composed of Ln 4 (μ 3 -OH) 2 centers with butterfly-shaped arrangements. Investigations into the luminescence properties and lifetime of 1 showed characteristic emission peaks of the Eu 3+ ion and an average luminescence lifetime of 9.26 μs. Detailed magnetic studies suggested that antiferromagnetic interactions existed in 2 and 3 , and that there was a remarkable magnetocaloric effect with a −Δ S m value of 17.94 J K −1 kg −1 for 2 , and a slow magnetic relaxation process with an energy barrier Δ E / k B of 35.8 K for 3 .
Intestinal injury is one of the major side effects that are induced by medical radiation exposure, and has limited effective therapies. In this study, we investigated the beneficial effects of ...sanguinarine (SAN) on intestinal injury induced by ionizing radiation (IR) both in vitro and in vivo. Mice were exposed to whole abdominal irradiation (WAI) to mimic clinical scenarios. SAN was injected intraperitoneally to mitigate IR-induced injury. Histological examination was performed to assess the tissue injuries of the spleen and small intestine. A small intestinal epithelial cell line-6 (IEC-6) was analyzed for its viability and apoptosis in vitro under different treatments. Inflammation-related pathways and serum inflammatory cytokines were detected via Western blot analysis and ELISA, respectively. High-throughput sequencing was used to characterize the gut microbiota profile. High-performance liquid chromatography was performed to assess short-chain fatty acid contents in the colon. In vitro, SAN pretreatment protected cell viability and reduced apoptosis in IEC-6 cells. In vivo, SAN pretreatment protected immune organs, alleviated intestinal injury, and promoted intestinal recovery. SAN also reduced the levels of inflammatory cytokines, suppressed high mobility group box 1 (HMGB1)/ Toll-like receptor 4 (TLR4) pathway activation, and modulated gut microbiota composition. Our findings demonstrate that the beneficial properties of SAN alleviated intestinal radiation injury. Thus, SAN represents a therapeutic option for protecting against IR-induced intestinal injury in preclinical settings.
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•SAN protected radiation-induced intestinal injury by downregulation of HMGB1/TLR4 pathway and reduction of proinflammatory cytokines.•SAN regulated composition and function of gut microbiota in irradiated mice.•SAN is a promising therapeutic option for treatment of adverse side effects of radiation exposure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lupus nephritis (LN) is an autoimmune disease with multiple system involvement and is also one of the most serious forms of organ damage in systemic lupus erythematosus (SLE), which is mainly caused ...by the formation and deposition of immune complexes in glomeruli. More than 50% of SLE patients have clinical manifestations of renal damage. At present, the treatment of lupus nephritis is mainly based on glucocorticoids and immunosuppressants. However, due to adverse drug reactions and frequent recurrence or aggravation after drug reduction or withdrawal, the prognosis remains poor; thus, it is still one of the most important causes of end-stage renal failure. Therefore, new treatment strategies are urgently needed. This article aims to review the application of traditional Chinese medicine and natural extracts in the treatment of lupus nephritis to provide the basic mechanisms of treatment and a new treatment strategy with clear effects and high safety performance.
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•Traditional Chinese medicine improve lupus nephritis by inhibiting the formation of immune complexes or complement activation.•Natural extracts or Prescription may promote blood circulation and avoid invasion of heat to provide a new treatment strategy.•The combination of Chinese and Western medicine can reduce hormone dosage, reduce adverse effects and increase efficacy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Premature ovarian insufficiency (POI) is one major cause of female infertility, minichromosome maintenance complex component 8 (MCM8) has been reported to be responsible for POI.
Methods
...Whole‐exome sequencing was performed to identify the genetic variants of women with POI. Sanger sequencing was used to validate the variants in all the family members. Various bioinformatic software was used for the pathogenicity assessment. Reverse transcription polymerase chain reaction (RT‐PCR), real‐time quantitative PCR, and a chromosomal instability study induced by mitomycin C were performed to analyze the functional effects of the variant.
Results
A novel homozygous frameshift mutation (NM_032485.4:c.351_354delAAAG) of MCM8 gene was identified in the patients, segregated with POI in this family. This mutation is predicted to produce truncated MCM8 protein and to be pathogenic. Reverse transcription polymerase chain reaction revealed that the frameshift mutation led to a remarkably reduced level of MCM8 transcript products, and chromosomal instability study showed that the ability of mutant MCM8 to repair DNA breaks was impaired.
Conclusion
We identified a novel homozygous frameshift mutation in the MCM8 gene in two affected sisters with POI, and functional analysis revealed that this mutation is pathogenic. Our findings enrich the MCM8 mutation spectrum and might help clinicians to make a precise diagnosis, thereby allowing better family planning and genetic counseling.
In our study, a novel homozygous frameshift mutation in the MCM8 gene was identified in a consanguineous Han Chinese family by whole‐exome sequencing, which segregates with POI in this family. Furthermore, functional characterization revealed that this frameshift mutation is pathogenic.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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