Effect of a modified regimen on drug-sensitive retreated pulmonary tuberculosis: A multicenter study in China.

Background and objective: Retreatment pulmonary tuberculosis (PTB) still accounts for a large proportion of tuberculosis, and the treatment outcome is unfavorable. The recurrence of retreatment PTB based on long-term follow-up has not been well demonstrated. This study aimed to evaluate effect of a modified regimen on drug-sensitive retreated pulmonary tuberculosis. Methods: This multicenter cohort study was conducted in 29 hospitals from 23 regions of China from July 1, 2009, to December 31, 2020. Patients were divided into two treatment regimen groups including experimental group [modified regimen (4H-Rt2-E-Z-S(Lfx)/4H-Rt2-E)]and control group [standard regimen (2H-R-E-Z-S/6H-R-E or 3H-R-E-Z/6H-R-E)]. The patients enrolled were followed up of 56 months after successful treatment. We compared the treatment success rate, treatment failure rate, adverse reaction rate, and recurrence rate between two regimens. Multivariate Cox regression model was used to identify the potential risk factors for recurrence after successful treatment with proportional hazards assumptions tested for all variables. Results: A total of 381 patients with retreatment PTB were enrolled, including 244 (64.0%) in the experimental group and 137 (36.0%) in the control group. Overall, the treatment success rate was significant higher in the experimental group than control group (84.0 vs. 74.5%, P = 0.024); no difference was observed in adverse reactions between the two groups (25.8 vs. 21.2%, P > 0.05). A total of 307 patients completed the 56 months of follow-up, including 205 with the modified regimen and 102 with the standard regimen. Among these, 10 cases (3.3%) relapsed, including 3 in the experimental group and 7 in the control group (1.5% vs 6.9%, P = 0.035). Reduced risks of recurrence were observed in patients treated with the modified regimen compared with the standard regimen, and the adjusted hazard ratio was 0.19 (0.04-0.77). Conclusion: The modified retreatment regimen had more favorable treatment effects, including higher treatment success rate and lower recurrence rate in patients with retreated drug-sensitive PTB.

Treatment Outcome of a Shorter Regimen Containing Clofazimine for Multidrug-resistant Tuberculosis: A Randomized Control Trial in China.

BACKGROUND: The emergence of multidrug-resistant tuberculosis (MDR-TB) poses a serious obstacle to global TB control programs. METHODS: We carried out a prospective, randomized, multicenter study in China that was focused on the potential of a shorter regimen containing clofazimine (CFZ) for the treatment of MDR-TB. There were 135 MDR-TB cases that met eligibility requirements and were randomly stratified into either the control group or experimental group. Patients in the control group received an 18-month treatment regimen, whereas patients in the experimental group received a 12-month treatment regimen containing CFZ. RESULTS: At the completion of the treatment period, the difference in sputum-culture conversion rates between the experimental group and the control group was not significant. Notably, by the end of 3 months of treatment, 68.7% patients receiving the experimental regimen had sputum-culture conversion, as compared with 55.9% of those receiving the control regimen; this was a significant difference, suggesting an early sputum conversion (P = .04). There were 67 adverse events reported in 56 patients in this study, including 32 in the control group and 35 in the experimental group. No significant difference in the overall incidences of adverse events was observed between the 2 groups. CONCLUSIONS: The MDR-TB patients treated with the shorter regimen containing CFZ had a comparable successful outcome rate when compared to those with the standard regimen. The patients assigned to the experimental group achieved more rapid sputum-culture conversion, reflecting superior antimicrobial activity against MDR-TB. CLINICAL TRIALS REGISTRATION: Chinese Clinical Trial Registry ChiCTR 1800020391.

Human papillomavirus type 16 E6 oncoprotein promotes proliferation and invasion of non-small cell lung cancer cells through Toll-like receptor 3 signaling pathway.

Human papillomavirus (HPV) oncoproteins play vital roles in non-small cell lung cancer (NSCLC) pathogenesis, and Toll-like receptors (TLRs) contribute to tumor progression. However, interaction between HPV oncoproteins and TLR signaling in NSCLC progression remains unclear. Thus, the aim of the study was to explore effects of HPV16 E6 oncoprotein-induced TLRs pathway on growth and invasion of NSCLC cells and to examine potential mechanisms being involved. Recombinant plasmid (pcDNA-HPV16 E6) expressing HPV16 E6 protein was constructed. The expression prolife of TLRs was measured in NSCLC cell line A549 with or without pcDNA-HPV16 E6 transfection by real-time reverse polymerase chain reaction and Western blot. Cellular proliferation, invasion, cytokine productions, and downstream signaling pathways were also examined in TLR3-silencing/pcDNA-HPV16 E6 transfect A549 cells. Overexpression of HPV16 E6 increased proliferation, invasion, proliferation cytokine secretion, and TLR3 expression of A549 cells, while TLR3 silence inhibited HPV16 E6-induced tumor bioactivities of A549 cells. Down-regulation of TLR3 suppressed HPV16 E6-induced phosphorylation of Src, but did not affect TRIF expression. Moreover, inhibition of Src pathway also suppressed proliferation and invasion of A549 cells. In conclusion, HPV16 E6 oncoprotein promoted the bioactivities of NSCLC cells. TLR3-Src signaling pathway might be involved in this procession by up-regulation of cytokine production. The interaction between HPV16 E6 protein and TLR3 might contribute to the poor prognosis of NSCLC.

Determinants of multidrug-resistant tuberculosis in Henan province in China: a case control study.

BACKGROUND: Multi-drug resistance (MDR) has been a cause of concern for tuberculosis (TB) control in both developed and developing countries. This study described the characteristics and risk factors associated with MDR-TB among 287 cases and 291 controls in Henan province, China. METHODS: A hospital-based case-control study was conducted between June 2012 and December 2013. The study subjects were selected using multistage probability sampling. Multivariate conditional logistic regression models were used to determine the risk factors associated with MDR-TB. RESULTS: The following risk factors for MDR-TB were identified: previous TB treatment (AOR = 4.51, 95% CI: 3.55-5.56), male sex (AOR = 1.09, 95% CI: 0.24-1.88), high school or lower education degree (AOR = 1.87, 95% CI: 1.27-2.69), unemployment (AOR = 1.30, 95% CI: 0.78-2.52), long distance of residence from the health facility (AOR = 6.66,95% CI: 5.92-7.72), smoking (AOR = 2.07, 95% CI: 1.66-3.19), poor knowledge regarding MDR-TB (AOR = 2.06, 95% CI: 1.66-2.92), traveling by foot to reach the health facility (AOR = 1.85, 95% CI: 1.12-3.09), estimated amount of time to reach the health facility was greater than 3 h (AOR = 1.42, 95% CI: 0.51-2.35), social stigma (AOR = 1.17, 95% CI: 0.27-2.03), having an opportunistic infection (AOR = 1.45, 95% CI: 0.58-2.4), more than 3 TB foci in the lungs (AOR = 1.98, 95% CI: 1.49-3.25), total time of first treatment was more than 8 months (AOR = 1.39, 95% CI: 0.65-2.54), adverse effects of anti-TB medication (AOR = 2.39, 95% CI: 1.40-3.26), and more than 3 prior episodes of anti-TB treatment (AOR = 1.83, 95% CI: 1.26-2.80). CONCLUSION: The identified risk factors should be given priority in TB control programs. Additionally, there is a compelling need for better management and control of MDR-TB, particularly through increasing laboratory capacity, regular screening, enhancing drug sensitivity testing, novel MDR-TB drug regimens, and adherence to medication.

MicroRNA-223 Is Upregulated in Active Tuberculosis Patients and Inhibits Apoptosis of Macrophages by Targeting FOXO3.

BACKGROUND: Macrophage apoptosis is a host innate defense mechanism against tuberculosis (TB). AIM: In this study, we aimed to investigate the role of microRNA-223 (miR-223) in macrophage apoptosis of TB. METHODS: We analyzed apoptosis in peripheral blood macrophages of active TB patients, infected human macrophages (TDMs and MDMs) with the Mycobacterium tuberculosis (Mtb) strain H37Rv, and observed the expression of miR-223 to investigate the relationship between miR-223 and macrophage apoptosis induced by Mtb. RESULTS: The apoptosis rate of peripheral blood macrophages decreased in active TB patients compared with healthy controls, and miR-223 expression increased significantly in macrophages after H37Rv infection. Transfection of human macrophages (TDMs and MDMs) with miR-223 inhibited macrophage apoptosis. We also demonstrated that miR-223 directly suppressed forkhead box O3 (FOXO3), and FOXO3 played a critical role as a mediator of the biological effects of miR-223 in macrophage apoptosis. The overexpression of FOXO3 remarkably reversed the apoptosis inhibitory effect of miR-223. CONCLUSION: Our data provide new clues for the essential role of miR-223 in the regulation of anti-Mtb-directed immune responses, which relies on the regulation of FOXO3 expression.

The association between serum miR-155 and natural killer cells from tuberculosis patients.

Tuberculosis (TB) is still an infectious disease that greatly threatens human health, and is always refractory to the current therapeutic modalities. Accumulated evidence revealed that microRNAs (miRNAs) are closely with various pathologies, such as TB. The possibilities of miRNAs as diagnostic biomarkers and therapeutic targets have been proved. However, it is still unknown if miRNA is implicated in the TB-associated immunity. This study revealed that miR-155, which has been shown to suppress the activation of natural killer (NK) cells associated with tumors, was downregulated in serum samples of TB patients (n=90), compared with healthy controls (n=31). Cytotoxicity assays indicated that NK cells, which have been demonstrated to promote TB progression, exhibited lower cytotoxicity in high serum miR-155 TB patients (n=37). There is an inverse relationship between serum miR-155 abundance and NK cell cytotoxicity (R=-0.659, P=0.000). Further studies demonstrated that miR-155 level is inversely associated with the concentration of TNFα secreted by NK cells from TB patients (n=37, R=-0.694, P=0.000). Collectively, serum miR-155 level was shown to be negatively associated with the TB-suppressing activity of NK cells, and this miRNA can be used as a potential therapeutic agent for TB treatment.

Super-compact treatment with a high dose of moxifloxacin in patients with drug-resistant tuberculosis and its resistance mechanisms.

The aim of this study was to investigate the curative effect and resistance mechanisms of high-dose moxifloxacin in the short-term treatment of multidrug-resistant tuberculosis. A total of 92 patients with multidrug-resistant tuberculosis were randomly selected and divided into groups A and B (n=46 per group). The two groups received moxifloxacin treatment with the same dose in total. Group A received a short course of treatment with moxifloxacin (0.6 g/day for 6 months), whereas group B received normal moxifloxacin treatment (0.4 g/day for 9 months). Sputum negative conversion, foci absorption, cavity closure and adverse reactions in the two groups were observed, and the drug resistance mechanism of tuberculosis to moxifloxacin treatment was investigated. Following the treatment, the curative rate of group A was 82.61%, and the curative rate of group B was 84.78%; there was no statistically significant difference between the two groups (P>0.05). The rates of sputum negative conversion, foci absorption and cavity closure were not significantly different between the two groups (P>0.05). However, the rates of reduction in peripheral white blood cell counts, liver function damage and adverse reactions, including symptoms affecting the gastrointestinal and nervous systems, were significantly lower in group A than in group B (P<0.05). The expression levels of the antigen-presenting functional molecules CD80 and CD40 on the surfaces of mononuclear cells were higher in group A than in group B (P<0.05), whereas the difference in HLA-DR expression between groups A and B was not significant (P>0.05). In conclusion, short-term treatment with a high dose of moxifloxacin is effective for multidrug-resistant tuberculosis, and its advantages are a reduction in the incidence of drug-associated adverse reactions and a lack of drug resistance.

High serum miR-183 level is associated with the bioactivity of macrophage derived from tuberculosis patients.

As a major health threat, tuberculosis (TB) is resistant against the current therapeutic strategies. Increasing evidence indicates that miRNAs are implicated in various disorders by affecting specific target genes. Recently, the association of miRNAs with TB has also been established by several studies, and their potentials in the prognosis and treatment of TB have also been verified. miR-183 is shown to promote the activation of macrophage through NF-κB pathway. However, it is still unclear if serum miR-183 can be used to assess the activity of TB-associated macrophage. This study was aimed to address this issue. We employed qPCR assay to detect the expression level of miR-183 in blood from TB patients and healthy individuals. miR-183 abundance was found to be increased in serum samples from TB patients, compared with healthy controls. Further analysis revealed that miR-183 level is positively associated with the activity of macrophages from TB patients, evidenced by their increased phagocytosis rates and enzyme activity in high serum miR-183 group. In conclusions, high level of serum miR-183 is associated with the activity of macrophage originating from TB patients.

The protective effect of curcumin against the 19­kDa Mycobacterium tuberculosis protein-induced inflammation and apoptosis in human macrophages.

The Mycobacterium tuberculosis 19-kDa lipoprotein (P19) is both cell wall-associated and secreted and is a candidate virulence factor that could cause the apoptosis of human macrophages infected with M. tuberculosis. P19 induces TLR2 activation, resulting in the upregulation of death receptors and ligands, followed by a death-receptor signaling cascade. The mechanisms by which P19 induces macrophage apoptosis are not fully characterized. Curcumin, a natural polyphenol, exhibits a variety of pharmacological effects such as antioxidant, anti-inflammatory and antitumor properties. In the present study, we investigated the effect of curcumin on P19-induced apoptosis in human macrophage cells and the underlying mechanisms. The results showed that both P19 and curcumin inhibit the growth of macrophages in a dose- and time-dependent manner. A low dose of curcumin (10 or 20 µM) attenuated both the macrophage cell growth inhibition and the increase in the expression of IL-6 and TNF-α induced by P19. Curcumin also decreased the phosphorylation of JNK and p38 that were induced by P19. However, JNK but not p38 inhibitors reversed the effect of P19 on the growth inhibition of macrophages. These data suggest that curcumin may protect macrophages from P19-induced cell apoptosis via a TLR2-mediated JNK-dependent pathway.

Diagnostic accuracy of tumor necrosis factor-alpha, interferon-gamma, interleukin-10 and adenosine deaminase 2 in differential diagnosis between tuberculous pleural effusion and malignant pleural effusion.

BACKGROUND: The current study was performed to investigate the potential biomarkers for the differential diagnosis of tuberculous pleural effusion (TPE) and malignant pleural effusions (MPE). METHODS: Among ninety patients (n = 90) involved in the study, 47 with tuberculous pleural effusion aged from 18 to 70 and 43 with secondary malignant pleural effusion aged from 34 to 78. We tested the pleural levels of TNF-α, IFN-γ and IL-10 as well as the enzyme activity of ADA2, and then we compared the differential diagnostic efficiencies of those biochemical parameters with ADA between the two groups. RESULTS: Our results show that, the concentrations of pleural TNF-α (45.55 ± 15.85 ng/L), IFN-γ (114.97 ± 27.85 ng/L) as well as activities of ADA2 (35.71 ± 10.00 U/L) and ADA (39.39 ± 10.60 U/L) in tuberculous group were significantly higher compared to malignant group. Furthermore, according to the ROC curve analysis the thresholds of TNF-α, IFN-γ, ADA2 and ADA were found to be 30.3 ng/L, 103.65 ng/L, 29.45 U/L, and 39.00 U/L, respectively. TNF-α, IFN-γ and ADA2 yielded better sensitivity, specificity, and accuracy of the diagnosis than ADA. Our investigation further revealed that the combinations of TNF-α and ADA2 further increased the specificity and accuracy for the differential diagnosis. CONCLUSION: In conclusion, we found that TNF-α, IFN-γ, ADA and ADA2 all increased in TPE. Combinations of the TNF-α and ADA2 yielded the best specificity and accuracy for the differential diagnosis of TPE from MPE. Our investigation suggests that the applications of TNF-α together with ADA2 may contribute to more efficient diagnosis strategies in the management of discrimination between tuberculous and malignant pleural effusions.