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Competing Interests: Declaration of Competing Interest The authors declare that they do not have any competing interests.

Tripartite motif (TRIM) family proteins play important regulatory roles in innate immune responses, the dysregulation of which cause several infectious diseases. However, the role and function of TRIM family proteins during tuberculosis (TB) infection remains unclear. In this study, we employed real-time quantitative PCR to profile the transcript levels of 72 TRIM genes from a cohort of 5 active TB patients, 5 latent tuberculosis infection (LTBI) subjects, and 5 healthy controls (HCs) in an initial discovery phase. The notable TRIM genes were assessed by in vitro cell infection experiments and further validated in another independent cohort (36 active TB, 24 LTBI and 28 HCs). The receiver operating characteristic (ROC) was used to analyze the diagnostic power of these TRIM genes. Our results revealed that 20 TRIM genes were decreased in active TB compared to LTBI and HCs. In addition, TRIM4, 16, 27, 32, 35, 46, 47, 65 and 68 were further shown to be downregulated in Mycobacterium smegmatis-infected macrophages and were found to be closely correlated with infection time and initial bacteria loads. Furthermore, the ROC analyses showed that TRIM4, 27 and 65 all exhibited the highest areas under the curve (AUC) values of 1.00 in discriminating active TB from LTBI and HCs. Moreover, TRIM27 combined with TRIM32 for an improved AUC value of 0.81 in discriminating LTBI from HCs. These results suggest that TRIM gene dysregulation might be involved in the pathogenesis of TB and that these genes could serve as potential biomarkers for indicating TB status., (Copyright © 2017. Published by Elsevier Ltd.)

Chronic excessive fluoride exposure impairs human health and damages not only the skeletal system and the teeth but also the soft tissues such as the brain, liver, kidneys, pancreas and spinal cord. However, there is limited research regarding the exposure levels and sensitive biomarkers. This study was aimed to establish the relationship between fluoride exposure and sensitive biomarkers. Ninety-six rats were randomly divided into six groups, with each group exposed to 0, 2, 4, 8, 16 and 32 mg NaF/(kg.bw), respectively. Correlation analysis of the exposure levels, the tissue distributions and the effects was done, and the possible mathematical relationship between the exposure and sensitive biomarkers is discussed. Our findings revealed that the level of serum fluoride can serve as one of the sensitive indicators to reflect the ex-exposure levels (in the present article, ex-exposure means the fluoride exposure pathway from the outside, which differs from the burden of the organism). Furthermore, an equation determining the external exposure dose of serum fluoride was obtained by fitting the coefficient 0.901. Simultaneously, enzyme levels were closely compared with the burden of the tissue, which showed that the activities of alkaline phosphatase significantly correlated with serum fluoride levels (R 2  = -0.259, p < 0.05), as well as with the fluoride levels of the lung (R 2  = 0.463, ρ < 0.01), the thymus (R 2  = 0.429, ρ < 0.05) and the ovary/testicle (R 2  = 0.685, ρ < 0.01). Results suggested that excessive fluoride exposure might affect reproduction by altering the activities of alkaline phosphatase. In addition, some indicators related to immunity and calcium absorption exhibited sensitivity to tissue burden, among which activating transcriptional factor 4 (ATF4), an important indicator involved in bone metabolism, was found sensitive to the ex-exposure level. These findings highlight the gap between health effects in epidemiology research and the total intake amount of fluoride from the environment. This study presents a novel insight into the method of establishing the relationship between fluoride exposure and sensitive biomarkers.

Background The effectiveness of available biologics for the treatment of hidradenitis suppurativa (HS) is limited. Additional therapeutic options are needed. Objectives To investigate the efficacy and mode of action of guselkumab [an anti-interleukin (IL)-23p19 monoclonal antibody] 200 mg subcutaneously every 4 weeks for 16 weeks in patients with HS. Methods An open-label, multicentre, phase IIa trial in patients with moderate-to-severe HS was carried out (NCT04061395). The pharmacodynamic response in skin and blood was measured after 16 weeks of treatment. Clinical efficacy was assessed using the Hidradenitis Suppurativa Clinical Response (HiSCR), the International Hidradenitis Suppurativa Severity Score System (IHS4), and the abscess and inflammatory nodule (AN) count. The protocol was reviewed and approved by the local institutional review board (METC 2018/694), and the study was conducted in accordance with good clinical practice guidelines and applicable regulatory requirements. Results Thirteen of 20 patients (65%) achieved HiSCR with a statistically significant decrease in median IHS4 score (from 8.5 to 5.0; P = 0.002) and median AN count (from 6.5 to 4.0; P = 0.002). The overall patient-reported outcomes did not show a similar trend. One serious adverse event, likely to be unrelated to guselkumab treatment, was observed. In lesional skin, transcriptomic analysis revealed the upregulation of various genes associated with inflammation, including immunoglobulins, S100, matrix metalloproteinases, keratin, B-cell and complement genes, which decreased in clinical responders after treatment. Immunohistochemistry revealed a marked decrease in inflammatory markers in clinical responders at week 16. Conclusions Sixty-five per cent of patients with moderate-to-severe HS achieved HiSCR after 16 weeks of treatment with guselkumab. We could not demonstrate a consistent correlation between gene and protein expression and clinical responses. The main limitations of this study were the small sample size and absence of a placebo arm. The large placebo-controlled phase IIb NOVA trial for guselkumab in patients with HS reported a lower HiSCR response of 45.0–50.8% in the treatment group and 38.7% in the placebo group. Guselkumab seems only to be of benefit in a subgroup of patients with HS, indicating that the IL-23/T helper 17 axis is not central to the pathophysiology of HS. [ABSTRACT FROM AUTHOR]