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Background: Intrahepatic cholangiocarcinoma (ICC) remains a significant challenge in cancer therapy, especially due to its resistance to established treatments like Gemcitabine, necessitating novel therapeutic approaches., Methods: This study utilized Gemcitabine-resistant cell lines, patient-derived organotypic tumor spheroids (PDOTs), and patient-derived xenografts (PDX) to evaluate the effects of Saikosaponin-a (SSA) on ICC cellular proliferation, migration, apoptosis, and its potential synergistic interaction with Gemcitabine. Techniques such as transcriptome sequencing, Luciferase reporter assays, and molecular docking were employed to unravel the molecular mechanisms., Results: SSA exhibited antitumor effects in both in vitro and PDX models, indicating its considerable potential for ICC treatment. SSA markedly inhibited ICC progression by reducing cellular proliferation, enhancing apoptosis, and decreasing migration and invasion. Crucially, it augmented Gemcitabine's efficacy by targeting the p-AKT/BCL6/ABCA1 signaling pathway. This modulation led to the downregulation of p-AKT and suppression of BCL6 transcriptional activity, ultimately reducing ABCA1 expression and enhancing chemosensitivity to Gemcitabine. Additionally, ABCA1 was validated as a predictive biomarker for drug resistance, with a direct correlation between ABCA1 expression levels and the IC50 values of various small molecule drugs in ICC gene profiles., Conclusion: This study highlights the synergistic potential of SSA combined with Gemcitabine in enhancing therapeutic efficacy against ICC and identifies ABCA1 as a key biomarker for drug responsiveness. Furthermore, the introduction of the novel PDOTs microfluidic model provides enhanced insights into ICC research. This combination strategy may provide a novel approach to overcoming treatment challenges in ICC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance., Objective: This research explored the effectiveness of integrating anlotinib (a broad-spectrum tyrosine kinase inhibitor) with programmed death-1 (PD-1) blockade and offers mechanistic insights into more effective strategies for treating HCC., Methods: Using patient-derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD-1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time-of-flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples., Results: The combination of anlotinib with an anti-PD-1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF-1α signaling axis. CD8 + T-cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8 + T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti-PD-1 therapy in patients with HCC., Conclusions: Our findings highlight anlotinib's potential to augment the efficacy of anti-PD-1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14-mediated CD8 + T-cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology., Highlights: Synergistic effects of anlotinib and anti-PD-1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF-1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T-cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti-PD-1-based therapies in advanced HCC patients., (© 2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Antimicrobial resistance in Mycobacterium tuberculosis is a serious threat to global tuberculosis(TB) control. WHO listed bedaquiline as one of the first-choice drugs for the treatment of MDR/RR-TB in 2018. Bedaquiline is marketed for adult patients with MDR-TB and XDR-TB. However, there are few studies of bedaquiline in adolescents, pregnant women, the elderly, and other special populations with drug-resistant TB. This paper aimed to review the effectiveness and safety of bedaquiline in the treatment of special populations of drug-resistant TB for the clinical use.

Background: Tuberculosis infection is a major complication of silicosis, but there is no study on whether silicosis can affect the sensitivity of QuantiFERON-TB Gold In-Tube (QFT-GIT) assays. This study will analyze the relationship between silicosis and QFT-GIT, determine the main factor of the QFT-GIT sensitivity decrease in silicosis and explore the methods to increase the sensitivity., Methods: Silicosis patients with positive tubercle bacillus cultures were collected. The QFT-GIT, flow cytometry and blocking antibodies were used., Results: The sensitivity of QFT-GIT in silicosis patients (58.46%) was significantly decreased and the expression of PD-1 on T cells and CD56 + NK cells in pulmonary tuberculosis combined with silicosis were higher than normal tuberculosis patients and silicosis only patients. Further analysis found that the ratio of PD-1 + CD4 + T and IFN-γwere negatively correlated and blockaded the PD-1 pathway with antibodies can restore the sensitivity of QFT-GIT in silicosis., Conclusions: This is the first study to analyze the relationship between immune exhaustion and QFT-GIT in silicosis and found that the sensitivity of QFT-GIT was decreased by the expression of PD-1 on lymphocytes. Antibody blocking experiments increased the expression of IFN-γ and provided a new method to improve the sensitivity of QFT in silicosis. The study also found that silicosis can increase PD-1 expression. As PD-1 functions in infectious diseases, it will promote immune exhaustion in silicosis and lead to tuberculosis from latent to active infection. The study provided theoretical evidence for the diagnosis and immunotherapy of silicosis complications, and it has great value in clinical diagnostics and treatment., (© 2022. The Author(s).)

We explored the potential activity of compound 16 (Cpd16), a novel small molecule Nrf2 activator, in hydrogen peroxide (H 2 O 2 )-stimulated osteoblasts. In the primary murine/human osteoblasts and MC3T3-E1 murine osteoblastic cells, Cpd16 treatment at micro-molar concentrations caused disassociation of Keap1-Nrf2 and Nrf2 cascade activation. Cpd16 induced stabilization of Nrf2 protein and its nuclear translocation, thereby increasing the antioxidant response elements (ARE) reporter activity and Nrf2 response genes transcription in murine and human osteoblasts. Significantly, Cpd16 mitigated oxidative injury in H 2 O 2 -stimulited osteoblasts. H 2 O 2 -provoked apoptosis as well as programmed necrosis in osteoblasts were significantly alleviated by the novel Nrf2 activator. Cpd16-induced Nrf2 activation and osteoblasts protection were stronger than other known Nrf2 activators. Dexamethasone- and nicotine-caused oxidative stress and death in osteoblasts were attenuated by Cpd16 as well. Cpd16-induced osteoblast cytoprotection was abolished by Nrf2 short hairpin RNA or knockout, but was mimicked by Keap1 knockout. Keap1 Cys151S mutation abolished Cpd16-induced Nrf2 cascade activation and osteoblasts protection against H 2 O 2 . Importantly, weekly Cpd16 administration largely ameliorated trabecular bone loss in ovariectomy mice. Together, Cpd16 alleviates H 2 O 2 -induced oxidative stress and death in osteoblasts by activating Nrf2 cascade., (© 2022. The Author(s).)

In this study, B and T lymphocyte attenuator (BTLA) and herpesvirus entry mediator (HVEM) expression on the surface of circulating CD4 + T and CD8 + T cells of patients with chronic hepatitis B (CHB) was investigated to explore their relationship with hepatitis B virus (HBV) clinical parameters. Both BTLA and HVEM were significantly upregulated on CD4 + T and CD8 + T cells of CHB patients compared with healthy controls ( p  < 0.01). Intriguingly, in CHB patients, the percentage of BTLA expression was positively correlated with that of HVEM (CD4 + T cells: r  = 0.5461, p  < 0.001 and CD8 + T cells: r  = 0.4206, p  < 0.01). Moreover, the percentage of BTLA expression was positively correlated with the levels of aspartate aminotransferase (AST) (CD4 + T cells: r  = 0.3136, p  < 0.05 and CD8 + T cells: r  = 0.3159, p  < 0.05) and alanine aminotransaminase (ALT) (CD4 + T cells: r  = 0.3177, p  < 0.05 and CD8 + T cells: r  = 0.3311, p  < 0.05). At the same time, the percentage of HVEM expression was also positively correlated with AST levels (CD4 + T cells: r  = 0.3721, p  < 0.05 and CD8 + T cells: r  = 0.3325, p  < 0.05) and ALT (CD4 + T cells: r  = 0.3689, p  < 0.05 and CD8 + T cells: r  = 0.3476, p  < 0.05). However, the percentage of BTLA and HVEM expression did not show significant relevance to HBV viral load. Further study demonstrated that BTLA inhibitory signaling could significantly inhibit T cell proliferation, activation, and cytokine production under optimal T cell receptor signaling ( p  < 0.05). Thereby, our findings indicate that the increased BTLA and HVEM expression on the surface of CD4 + and CD8 + T cells might represent a certain clinical significance and be involved in CHB progression during T cell exhaustion.

Background: Recently, the SARS-CoV-2 variant of concern, Omicron (B.1.1.529), was identified as responsible for a novel wave of COVID-19 worldwide. Here, we compared initial clinical features of hospitalized COVID-19 patients during recent wave (Omicron Variant) with those in ancestral variant wave (2020)., Methods: This is a cohort study of electronic health record (EHR) data from a signal center in the China. The clinical data of 116 cases of Omicron hospitalized in 2022 and 87 cases hospitalized in 2020 were collected. The comparisons were performed with the Mann-Whitney U test, Fisher exact test or the chi-square test, and multivariable logistic regression analysis., Results: Clinically, compared with 2020-cohort, Omicron-cohort was more inclined to cluster in younger population and had more nonsymptomatic (25.0%) and nonsevere cases, as well as suffered from comparable extrapulmonary complication. Radiologically, although the major computed tomography (CT) findings of both cohorts were ground-glass opacities (GGOs), crazy-paving pattern was relatively less seen in the Omicron-cohort. Based on multiple logistic regression analysis, Omicron-cohort was associated with a lower risk of complaining with fever, the presence of lung opacity, and increased Sequential Organ Failure Assessment (SOFA) score., Conclusion: This study provided the data of different patterns of clinic characteristics and reduced severity from infections that occurred in Omicron variant as compared with the outbreak of the epidemic in 2020 wave (ancestral variant).

Long non-coding RNA (LncRNA) THOR (Lnc-THOR) is expressed in testis and multiple human malignancies. Lnc-THOR association with IGF2BP1 (IGF2 mRNA-binding protein 1) is essential for stabilization and transcription of IGF2BP1 targeted mRNAs. We tested its expression and potential functions in non-small cell lung cancer (NSCLC). In primary NSCLC cells and established cell lines, Lnc-THOR shRNA or CRISPR/Cas9-mediated knockout (KO) downregulated IGF2BP1 target mRNAs ( IGF2 , Gli1 , Myc and SOX9 ), inhibiting cell viability, growth, proliferation, migration and invasion. Significant apoptosis activation was detected in Lnc-THOR-silenced/-KO NSCLC cells. Conversely, ectopic overexpression of Lnc-THOR upregulated IGF2BP1 mRNA targets and enhanced NSCLC cell proliferation, migration and invasion. RNA-immunoprecipitation and RNA pull-down assay results confirmed the direct binding between Lnc-THOR and IGF2BP1 protein in NSCLC cells. Lnc-THOR silencing and overexpression were ineffective in IGF2BP1-KO NSCLC cells. Forced IGF2BP1 overexpression failed to rescue Lnc-THOR-KO NSCLC cells. In vivo , intratumoral injection of Lnc-THOR shRNA adeno-associated virus potently inhibited A549 xenograft tumor growth in nude mice. At last we show that Lnc-THOR is overexpressed in multiple NSCLC tissues and established/primary NSCLC cells. Collectively, these results highlighted the ability of Lnc-THOR in promoting NSCLC cell growth by associating with IGF2BP1, suggesting that Lnc-THOR represents a promising therapeutic target of NSCLC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jiao, Tang, Chu, Li, Xu and Ren.)

An ultra-large structure-based virtual screening has discovered iKeap1 as a direct Keap1 inhibitor that can efficiently activate Nrf2 signaling. We here tested its potential effect against hydrogen peroxide (H 2 O 2 )-induced oxidative injury in osteoblasts. In primary murine and human osteoblasts, iKeap1 robustly activated Nrf2 signaling at micromole concentrations. iKeap1 disrupted Keap1-Nrf2 association, causing Nrf2 protein stabilization, cytosol accumulation and nuclear translocation in murine and human osteoblasts. The anti-oxidant response elements (ARE) activity and transcription of Nrf2-ARE-dependent genes (including HO1, NQO1 and GCLC) were increased as well. Significantly, iKeap1 pretreatment largely ameliorated H 2 O 2 -induced reactive oxygen species production, lipid peroxidation and DNA damage as well as cell apoptosis and programmed necrosis in osteoblasts. Moreover, dexamethasone- and nicotine-induced oxidative injury and apoptosis were alleviated by iKeap1. Importantly, Nrf2 shRNA or CRISPR/Cas9-induced Nrf2 knockout completely abolished iKeap1-induced osteoblast cytoprotection against H 2 O 2 . Conversely, CRISPR/Cas9-induced Keap1 knockout induced Nrf2 cascade activation and mimicked iKeap1-induced cytoprotective actions in murine osteoblasts. iKeap1 was ineffective against H 2 O 2 in the Keap1-knockout murine osteoblasts. Collectively, iKeap1 activated Nrf2 signaling cascade to inhibit H 2 O 2 -induced oxidative injury and death of osteoblasts.

The study aimed to characterize a novel vitexin-producing endophytic fungus Fusarium solani G6 from Cajanus cajan, improve its capability for producing vitexin and evaluate its osteoblastic proliferation activity. A total of 153 endophytic fungi, classified into 6 genera, were isolated from C. cajan. Among them, only one strain, endophyte G6 identified as Fusarium solani, was found to produce vitexin. After the optimization of fermentation conditions, the highest vitexin yield (18.72 mg/L) for the strain was observed in PDB liquid medium containing 20.54 g/L of glucose and 8.90 g/L of ammonium sulfate, at an initial medium pH of 5.1 and at 28 °C for 6 days of cultivation. Moreover, the fungal vitexin exhibited notable osteoblastic proliferation stimulating activity. A novel vitexin-producing endophytic fungus F. solani G6 was characterized from C. cajan for the first time. The findings highlighted its potential use for large-scale production of vitexin and might have a promising use as therapeutic agent for osteoporosis.

Background: World Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP)., Methods: AEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort., Results: By December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1-2) and 33.1% as serious (Grade 3-5). The median duration of bedaquiline treatment was 167.0 [interquartile range (IQR): 75-169] days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually., Conclusions: Bedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline.

Background: Sudden exacerbations and respiratory failure are major causes of death in patients with severe coronavirus disease 2019(COVID-19) pneumonia, but indicators for the prediction and treatment of severe patients are still lacking., Methods: A retrospective analysis of 67 collected cases was conducted and included approximately 67 patients with COVID-19 pneumonia who were admitted to the Suzhou Fifth People's Hospital from January 1, 2020 to February 8, 2020. The epidemiological, clinical and imaging characteristics as well as laboratory data of the 67 patients were analyzed., Results: The study found that fibrinogen (FIB) was increased in 45 (65.2%) patients, and when FIB reached a critical value of 4.805 g/L, the sensitivity and specificity、DA, helping to distinguish general and severe cases, were 100 and 14%、92.9%, respectively, which were significantly better than those for lymphocyte count and myoglobin. Chest CT images indicated that the cumulative number of lung lobes with lesions in severe patients was significantly higher than that in general patients (P < 0.05), and the cumulative number of lung lobes with lesions was negatively correlated with lymphocyte count and positively correlated with myoglobin and FIB. Our study also found that there was no obvious effect of hormone therapy in patients with severe COVID-19., Conclusions: Based on the retrospective analysis, FIB was found to be increased in severe patients and was better than lymphocyte count and myoglobin in distinguishing general and severe patients. The study also suggested that hormone treatment has no significant effect on COVID-19.

Objectives: The aim of this study is to investigate the clinical usefulness of metagenomic Next-generation sequencing (mNGS) on bronchoalveolar lavage fluid (BALF) samples to discriminate pulmonary tuberculosis (PTB) from Non-TB community-acquired pneumonia (CAP) in PTB suspects., Methods: We investigate the performance of mNGS on BALF samples from 110 PTB suspects, in comparison with conventional microbiological testing (solid media culture, acid-fast bacilli staining (AFS), Xpert) of BALF or sputum samples and final clinical diagnosis., Results: We finally clinically diagnosed 48 cases of pulmonary tuberculosis patients and 62 cases of non-tuberculosis patients. Comparing to the final clinical diagnosis, mNGS produced a sensitivity of 47.92%, which was similar to that of Xpert (45.83%) and culture (46.81%), but much higher than that of AFS (29.17%) for TB diagnosis in BALF samples. Apart from detecting Mycobacterium tuberculosis, mNGS also identified mixed infections in PTB patients, including 3 fungal cases and 1 bacteria case. Meanwhile, mNGS efficiently identified 14 of 22 (63.63%) cases of non-tuberculous mycobacteria (NTM), 7 cases of fungi, 1 case of viral infection, and other common bacterial pathogens in Non-PTB group. Finally, mNGS identified 67.23% infection cases within 3 days, while the conventional methods identified 49.58% infection cases for over 90 days., Conclusion: Our data show that mNGS of BALF represents a potentially effective tool for the rapid diagnosis of PTB suspects., Competing Interests: Declaration of Competing Interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2020 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Background: There was much evidence suggesting that the serum lactate dehydrogenase (LDH) levels reflect the extent of various pathophysiological processes. However, the current information about dynamic change of LDH in COVID-19 pneumonia has not been well investigated., Methods: Study was performed in 87 cases confirmed by COVID-19 infection. The serum LDH levels were determined at diagnosis and follow-up visits. The evaluation of clinical response to therapy was based on chest CT scan. We selected the value of LDH around the data of chest CT scan (- 1 ~ + 1 day)., Results: At diagnosis, significant differences in LDH levels were found between non-severe and severe group (P < 0.05). It was demonstrated that increase or decrease of LDH was indicative of radiographic progress or improvement (P < 0.05). The time to LDH normalization (5.67 ± 0.55, days) was positively correlated with the time to radiographic absorption (5.57 ± 0.65 days, r = 0.53, P < 0.05). Applying the cut-off value of the increase in LDH has good specificity to predict disease progression., Conclusions: Serum LDH was validated for its potential usefulness as markers for evaluating clinical severity and monitoring treatment response in COVID-19 pneumonia.

Background: The Chinese government has pay attention about tuberculosis infection among medical staff in infectious disease hospitals, but the effects have not yet been reported. This study will explore latent infection and immune function in the medical staff and systematically analyze the associated influencing factors., Methods: Ninety-four medical staffs were enrolled and 20 medical staffs were defined as low risk group and others were high risk group. We used IFN-γ release assay and flow cytometry to analyze the latent TB infection status and immune function. Logistic regression analyses were performed to identify the independent risk factors of latent TB infection., Results: This study explored and compared the infection status of medical workers and found that the rate of positive TB-IGRA results was higher among high risk group than in low risk group. Working environment, occupational history and work type were risk factors for TB infection in hospital. This study also found that high risk group had higher IFN-γ expression and a lower ratio of CD4+ to CD8+ T cells and further analysis found that this immune disorder is associated with wards and occupations., Conclusions: This study through rigorous sample collection and analysis found the risk factors of latent tuberculosis infection in health care workers. This finding may provide a theoretical basis to be used by the countries with a high TB burden to further improve their strategies for the prevention of TB infections in hospitals and may give an indication for improving the personal health of medical staff in infectious disease hospitals., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Evolutionally conserved Wnt, Hedgehog (Hh) and Notch morphogen pathways play essential roles in the development, homeostasis and pathogenesis of multicellular organisms. Nevertheless, mechanisms that intracellularly coordinate these signal inputs remain poorly understood. Here we found that parafibromin, a component of the PAF complex, competitively interacts with β-catenin and Gli1, thereby potentiating transactivation of Wnt- and Hh-target genes in a mutually exclusive manner. Parafibromin also binds to the Notch intracellular domain (NICD), enabling concerted activation of Wnt- and Notch-target genes. The transcriptional platform function of parafibromin is potentiated by tyrosine dephosphorylation, mediated by SHP2 phosphatase, while it is attenuated by tyrosine phosphorylation, mediated by PTK6 kinase. Consequently, acute loss of parafibromin in mice disorganizes the normal epithelial architecture of the intestine, which requires coordinated activation/inactivation of Wnt, Hh and/or Notch signalling. Parafibromin integrates and converts signals conveyed by these morphogen pathways into appropriate transcriptional outputs in a tyrosine phosphorylation/dephosphorylation-regulated manner.