This study aimed to investigate the feasibility of the establishment of a human cancer xenograft model using samples from computed tomography (CT)-guided percutaneous biopsy. Fresh tumor tissues ...obtained from 10 cancer patients by CT-guided percutaneous biopsy were subcutaneously inoculated into NOD-Prkdcem26Il2rgem26Nju (NCG) mice to establish human patient-derived tumor xenograft (PDTX) models. The formation of first and second generation xenografts was observed, and tumor volume was recorded over time. Tumor tissue consistency between the PDTX model and primary tumors in patients was compared using H&E staining and immunohistochemistry. Pharmacodynamic tests of clinically used chemotherapeutic drugs were conducted on second generation xenografts, and their effects on tumor growth and body weight were observed. CT-guided percutaneous biopsy samples were successfully collected from 10 patients with advanced cancers. The PDTX model was established in mice using tumor samples obtained from 4 cancer patients, including one small cell carcinoma sample, two adenocarcinoma samples, and one squamous cell carcinoma sample. The success rate was 40%. The obtained PDTX model maintained a degree of differentiation, and morphological and structural characteristics were similar to primary tumors. The pharmacodynamic test of chemotherapeutic drugs in the PDTX model revealed a therapeutic effect on tumor growth, as expected. CT-guided percutaneous biopsy samples can be effectively used to establish a PDTX model, and test these chemotherapy regimens.
In addition to high-fat diet (HFD) and inactivity, inflammation and microbiota composition contribute to obesity. Inhibitory immune receptors, such as NLRP12, dampen inflammation and are important ...for resolving inflammation, but their role in obesity is unknown. We show that obesity in humans correlates with reduced expression of adipose tissue NLRP12. Similarly, Nlrp12−/− mice show increased weight gain, adipose deposition, blood glucose, NF-κB/MAPK activation, and M1-macrophage polarization. Additionally, NLRP12 is required to mitigate HFD-induced inflammasome activation. Co-housing with wild-type animals, antibiotic treatment, or germ-free condition was sufficient to restrain inflammation, obesity, and insulin tolerance in Nlrp12−/− mice, implicating the microbiota. HFD-fed Nlrp12−/− mice display dysbiosis marked by increased obesity-associated Erysipelotrichaceae, but reduced Lachnospiraceae family and the associated enzymes required for short-chain fatty acid (SCFA) synthesis. Lachnospiraceae or SCFA administration attenuates obesity, inflammation, and dysbiosis. These findings reveal that Nlrp12 reduces HFD-induced obesity by maintaining beneficial microbiota.
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•NLRP12 expression is reduced in the adipose tissue of humans with increased obesity•Nlrp12−/− mice show increased weight gain and adipose tissue inflammation•Nlrp12-mediated protection from obesity and inflammation is microbiota dependent•Lachnospiraceae and short-chain fatty acids mitigate obesity and insulin resistance
Truax et al. show that myeloid-expressed NLRP12 restrains high-fat-diet-induced obesity and type 2 diabetes by attenuating TNF, IL-6, NF-kB, MAPK, M1-macrophage polarization, and inflammasome activation in adipose tissue. This protective function of NLRP12 is microbiota dependent, and is associated with Lachnospiraceae and their metabolites, which mitigate obesity.
Although a series of studies have evaluated the potential association between N-acetyltransferase 2 (NAT2) polymorphisms and the risk of anti-tuberculosis drug-induced liver injury (ATLI), the ...results have generally been controversial and inadequate, mainly due to limited power. The present meta-analysis sought to resolve this problem.
PubMed, Embase and Web of Science were searched using the following key words: 'N-acetyltransferase 2' or 'NAT2' and 'polymorphism' and 'tuberculosis' or 'TB' and 'hepatotoxicity' or 'liver injury'. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were summarised in forest plots and set out in a table.
A total of 14 studies, comprising 474 cases and 1446 controls, were included in the meta-analysis. A significant association was observed between NAT2 slow acetylators and the risk of ATLI. The OR for NAT2 slow acetylators compared with rapid acetylators was 4.697 (95%CI 3.291-6.705, P < 0.001). Subgroup analyses indicate that both Asian and non-Asian cases with slow acetylators develop ATLI more frequently, which is similar to patients with slow acetylators receiving first-line combination treatment. On comparing NAT2 intermediate acetylators with rapid acetylators, the OR for ATLI was 1.261 (95%CI 0.928-1.712, P = 0.138).
This meta-analysis showed that tuberculosis patients with slow acetylators had a higher risk of ATLI than other acetylators. Screening of patients for the NAT2 genetic polymorphisms will be useful for the clinical prediction and prevention of ATLI.
Heterogeneity of cancer stem/progenitor cells that give rise to different forms of cancer has been well demonstrated for leukemia. However, this fundamental concept has yet to be established for ...solid tumors including breast cancer. In this communication, we analyzed solid tumor cancer stem cell markers in human breast cancer cell lines and primary specimens using flow cytometry. The stem/progenitor cell properties of different marker expressing-cell populations were further assessed by in vitro soft agar colony formation assay and the ability to form tumors in NOD/SCID mice. We found that the expression of stem cell markers varied greatly among breast cancer cell lines. In MDA-MB-231 cells, PROCR and ESA, instead of the widely used breast cancer stem cell markers CD44(+)/CD24(-/low) and ALDH, could be used to highly enrich cancer stem/progenitor cell populations which exhibited the ability to self renew and divide asymmetrically. Furthermore, the PROCR(+)/ESA(+) cells expressed epithelial-mesenchymal transition markers. PROCR could also be used to enrich cells with colony forming ability from MB-361 cells. Moreover, consistent with the marker profiling using cell lines, the expression of stem cell markers differed greatly among primary tumors. There was an association between metastasis status and a high prevalence of certain markers including CD44(+)/CD24(-/low), ESA(+), CD133(+), CXCR4(+) and PROCR(+) in primary tumor cells. Taken together, these results suggest that similar to leukemia, several stem/progenitor cell-like subpopulations can exist in breast cancer.
Apolygus lucorum is the predominant pest of Bacillus thuringiensis (Bt) cotton in China. 20‐hydroxyecdysone (20E) plays a key role in the reproduction of this insect. To better understand the ...mechanism underlying 20E‐regulated reproduction, the nuclear hormone receptor E75 isoform‐A of Ap. lucorum (Al‐E75A) was cloned and its expression analysed. A 2241‐bp sequence of Al‐E75A cDNA encoded an open reading frame of a polypeptide with a predicted molecular mass of 69.04 kDa. Al‐E75A mRNA was detected in female adult stages of Ap. lucorum with peak expression in 7‐day‐old animals. Al‐E75A was also expressed in several tissues, particularly in the fat body and ovary. A 3.2 kb Al‐E75A mRNA was detected in all tissues by Northern blot. The fecundity and longevity were significantly decreased in female adults treated with Al‐E75A small interfering RNA. The rates of egg incubation rates were considerably lower in the RNA interference‐treated animals compared to the untreated controls. In order to investigate the molecular mechanism underlying the effects described above, vitellogenin (Al‐Vg) was selected for further investigation. The expression pattern of Al‐Vg was similar to that of Al‐E75A and was up‐regulated by 20E. After knockdown of Al‐E75A, the expression profile of Al‐Vg and the protein levels were down‐regulated. These findings suggest that Al‐E75A plays a crucial role in the regulation of Al‐Vg expression in Ap. lucorum.
The inflammasome initiates innate defence and inflammatory responses by activating caspase-1 and pyroptotic cell death in myeloid cells
. It consists of an innate immune receptor/sensor, ...pro-caspase-1, and a common adaptor molecule, ASC. Consistent with their pro-inflammatory function, caspase-1, ASC and the inflammasome component NLRP3 exacerbate autoimmunity during experimental autoimmune encephalomyelitis by enhancing the secretion of IL-1β and IL-18 in myeloid cells
. Here we show that the DNA-binding inflammasome receptor AIM2
has a T cell-intrinsic and inflammasome-independent role in the function of T regulatory (T
) cells. AIM2 is highly expressed by both human and mouse T
cells, is induced by TGFβ, and its promoter is occupied by transcription factors that are associated with T
cells such as RUNX1, ETS1, BCL11B and CREB. RNA sequencing, biochemical and metabolic analyses demonstrated that AIM2 attenuates AKT phosphorylation, mTOR and MYC signalling, and glycolysis, but promotes oxidative phosphorylation of lipids in T
cells. Mechanistically, AIM2 interacts with the RACK1-PP2A phosphatase complex to restrain AKT phosphorylation. Lineage-tracing analysis demonstrates that AIM2 promotes the stability of T
cells during inflammation. Although AIM2 is generally accepted as an inflammasome effector in myeloid cells, our results demonstrate a T cell-intrinsic role of AIM2 in restraining autoimmunity by reducing AKT-mTOR signalling and altering immune metabolism to enhance the stability of T
cells.
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