The prevalence and risk factors of rheumatoid arthritis-associated interstitial lung disease: a systematic review and meta-analysis.

BACKGROUND: Interstitial lung disease (ILD) is the most widespread and fatal pulmonary complication of rheumatoid arthritis (RA). Existing knowledge on the prevalence and risk factors of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is inconclusive. Therefore, we designed this review to address this gap. MATERIALS AND METHODS: To find relevant observational studies discussing the prevalence and/or risk factors of RA-ILD, EMBASE, Web of Science, PubMed, and the Cochrane Library were explored. The pooled odds ratios (ORs) / hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated with a fixed/ random effects model. While subgroup analysis, meta-regression analysis and sensitivity analysis were carried out to determine the sources of heterogeneity, the I2 statistic was utilized to assess between-studies heterogeneity. Funnel plots and Egger's test were employed to assess publication bias. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, our review was conducted. RESULTS: A total of 56 studies with 11,851 RA-ILD patients were included in this meta-analysis. The pooled prevalence of RA-ILD was 18.7% (95% CI 15.8-21.6) with significant heterogeneity (I2 = 96.4%). The prevalence of RA-ILD was found to be more likely as a result of several identified factors, including male sex (ORs = 1.92 95% CI 1.70-2.16), older age (WMDs = 6.89, 95% CI 3.10-10.67), having a smoking history (ORs =1.91, 95% CI 1.48-2.47), pulmonary comorbidities predicted (HRs = 2.08, 95% CI 1.89-2.30), longer RA duration (ORs = 1.03, 95% CI 1.01-1.05), older age of RA onset (WMDs =4.46, 95% CI 0.63-8.29), positive RF (HRs = 1.15, 95%CI 0.75-1.77; ORs = 2.11, 95%CI 1.65-2.68), positive ACPA (ORs = 2.11, 95%CI 1.65-2.68), higher ESR (ORs = 1.008, 95%CI 1.002-1.014), moderate and high DAS28 (≥3.2) (ORs = 1.87, 95%CI 1.36-2.58), rheumatoid nodules (ORs = 1.87, 95% CI 1.18-2.98), LEF use (ORs = 1.42, 95%CI 1.08-1.87) and steroid use (HRs= 1.70, 1.13-2.55). The use of biological agents was a protective factor (HRs = 0.77, 95% CI 0.69-0.87). CONCLUSION(S): The pooled prevalence of RA-ILD in our study was approximately 18.7%. Furthermore, we identified 13 risk factors for RA-ILD, including male sex, older age, having a smoking history, pulmonary comorbidities, older age of RA onset, longer RA duration, positive RF, positive ACPA, higher ESR, moderate and high DAS28 (≥3.2), rheumatoid nodules, LEF use and steroid use. Additionally, biological agents use was a protective factor.

Novel Triazolopyridine-Based BRD4 Inhibitors as Potent HIV-1 Latency Reversing Agents.

Bromodomain-containing protein 4 (BRD4) inhibitors have been proven to be a promising option for anti-HIV-1 latency therapeutics. We herein describe the design, synthesis, and anti-HIV-1 latency bioevaluation of triazolopyridine derivatives as BRD4 inhibitors. Among them, compound 13d displayed favorable HIV-1 reactivation and prominent safety profile without triggering abnormal immune activation. It exerted strong synergism when combined with the PKC activator prostratin and has the same BRD4-targeting latency mechanism as observed with JQ1, by stimulating Tat-dependent HIV-1 elongation. Besides, it neither affected the antiviral efficacies of antiviral drugs nor caused secondary infections to uninfected cells and the latency reversing potency of 13d, in turn, was not affected by different classes of antiviral drugs.

Lycium barbarum polysaccharide alleviates DSS-induced chronic ulcerative colitis by restoring intestinal barrier function and modulating gut microbiota.

PURPOSE: This study examined the protective effects and mechanism of Lycium barbarum polysaccharides (LBP) in the context of intestinal barrier function and intestinal microbiota in mice with dextran sulfate sodium (DSS)-induced chronic ulcerative colitis (UC). METHODS: C57BL/6J male mice were assigned to a standard normal diet without DSS (control group), a normal diet with DSS (DSS group, 2% DSS given discontinuously for 3 weeks) or a normal diet supplemented with LBP (1% dry feed weight, LBP group, 2% DSS given discontinuously for 3 weeks) for a total of 8 weeks, at which point colonic tissues and caecal contents were collected. RESULTS: LBP exerted a significant effect against colitis by increasing body weight, colon length, DAI and histopathological scores. LBP inhibited proinflammatory cytokines (IL-1ß, IL-6, iNOS and TNF-α) expression, improved anti-inflammatory cytokine (IL-10) expression, promoted the expression of tight junction proteins (Occludin and ZO-1) via nuclear factor erythroid 2-related factor 2 (Nrf2) activation and decreased Claudin-2 expression to maintain the intestinal mucosal barrier. In addition, the abundances of some probiotics (Ruminococcaceae, Lactobacillus, Butyricicoccus, and Akkermansia) were decreased with DSS treatment but increased obviously with LBP treatment. And LBP reduced the abundance of conditional pathogens associated with UC (Mucispirillum and Sutterella). Furthermore, LBP improved the production of short-chain fatty acids (SCFAs), including acetic acid, propionic acid, butyric acid and isobutyric acid. CONCLUSION: LBP can alleviate DSS-induced UC by regulating inflammatory cytokines and tight junction proteins. Moreover, LBP promotes probiotics, suppresses conditional pathogens and increases SCFAs production, showing a strong prebiotic effect.

Integrative Bioinformatics Analysis Identifies DDX60 as a Potential Biomarker for Systemic Lupus Erythematosus.

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with strong heterogeneity, leading to variable clinical symptoms, which makes diagnosis and activity evaluation difficult. Methods: The original dataset of GSE88884 was analyzed to screen differentially expressed genes (DEGs) of SLE and the correlation between DEGs and clinical parameters (SLEDAI, anti-dsDNA, C3, and C4). The result was validated by microarray GSE121239 and SLE patients with RT-qPCR. Next, receiver operator characteristic (ROC) analysis, correlation analysis, and ordinal logistic regression were applied, respectively, to evaluate the capability of diagnosis and prediction of the candidate biomarker. Subsequently, the biological functions of the candidate biomarker were investigated through KEGG and GO enrichment, protein-protein interaction network, and the correlation matrix. Results: A total of 283 DEGs were screened, and seven of them were overlapped with SLE-related genes. DDX60 was identified as the candidate biomarker. Analyses of GSE88884, GSE121239, and SLE patients with RT-qPCR indicated that DDX60 expression level is significantly higher in patients with high disease activity. ROC analysis and the area under the ROC curve (AUC = 0.8818) suggested that DDX60 has good diagnostic performance. DDX60 expression level was positively correlated with SLEDAI scores (r = 0.24). For every 1-unit increase in DDX60 expression value, the odds of a higher stage of activity of SLE disease are multiplied by 1.47. The function of DDX60 mainly focuses on IFN-I-induced antiviral activities, RIG-I signaling, and innate immune. Moreover, DDX60 plays a synergistic role with DDX58, IFIH1, OASL, IFIT1, and other related genes in the SLE pathogenesis. Conclusions. DDX60 is differently expressed in SLE, and it is significantly related to both serological indicators and the disease activity of SLE. We suggested that DDX60 might be a potential biomarker for SLE diagnosis and management.

The WNT/Ca2+ pathway promotes atrial natriuretic peptide secretion by activating protein kinase C/transforming growth factor-ß activated kinase 1/activating transcription factor 2 signaling in isolated beating rat atria.

WNT signaling plays an important role in cardiac development, but abnormal activity is often associated with cardiac hypertrophy, myocardial infarction, remodeling, and heart failure. The effect of WNT signaling on regulation of atrial natriuretic peptide (ANP) secretion is unclear. Therefore, the purpose of this study was to investigate the effect of Wnt agonist 1 (Wnta1) on ANP secretion and mechanical dynamics in beating rat atria. Wnta1 treatment significantly increased atrial ANP secretion and pulse pressure; these effects were blocked by U73122, an antagonist of phospholipase C. U73122 also abolished the effects of Wnta1-mediated upregulation of protein kinase C (PKC) ß and γ expression, and the PKC antagonist Go 6983 eliminated Wnta1-induced secretion of ANP. In addition, Wnta1 upregulated levels of phospho-transforming growth factor-ß activated kinase 1 (p-TAK1), TAK1 banding 1 (TAB1) and phospho-activating transcription factor 2 (p-ATF2); these effects were blocked by both U73122 and Go 6983. Wnta1-induced ATF2 was abrogated by inhibition of TAK1. Furthermore, Wnta1 upregulated the expression of T cell factor (TCF) 3, TCF4, and lymphoid enhancer factor 1 (LEF1), and these effects were blocked by U73122 and Go 6983. Tak1 inhibition abolished the Wnta1-induced expression of TCF3, TCF4, and LEF1 and Wnta1-mediated ANP secretion and changes in mechanical dynamics. These results suggest that Wnta1 increased the secretion of ANP and mechanical dynamics in beating rat atria by activation of PKC-TAK1-ATF2-TCF3/LEF1 and TCF4/LEF1 signaling mainly via the WNT/Ca2+ pathway. It is also suggested that WNT-ANP signaling is implicated in cardiac physiology and pathophysiology.

NOX4 stimulates ANF secretion via activation of the Sirt1/Nrf2/ATF3/4 axis in hypoxic beating rat atria.

Silent information regulator factor 2­related enzyme 1 (Sirt1) is involved in the regulation of cell senescence, gene transcription, energy balance and oxidative stress. However, the effect of Sirt1 on atrial natriuretic factor (ANF) secretion, especially under hypoxic conditions is unclear. The present study aimed to investigate the effect of Sirt1, regulated by NADPH oxidase 4 (NOX4), on ANF secretion in isolated beating rat atria during hypoxia. ANF secretion was analyzed using radioimmunoassays and protein expression levels were determined by western blotting and immunofluorescence staining. Intra­atrial pressure was recorded using a physiograph. Hypoxia significantly upregulated Sirt1 and nuclear factor erythroid­2­related factor 2 (Nrf2) protein expression levels, together with significantly increased ANF secretion. Hypoxia­induced protein expression of Sirt1 was significantly blocked by a NOX4 inhibitor, GLX351322, and Nrf2 protein expression levels were significantly abolished using the Sirt1 inhibitor, EX527. Hypoxia also significantly elevated the protein expression levels of phosphorylated­Akt and sequestosome 1 and significantly downregulated Kelch­like ECH­associated protein 1 protein expression levels. These effects were significantly blocked by EX527, preventing hypoxia­induced Nrf2 expression. An Nrf2 inhibitor, ML385, significantly abolished the hypoxia­induced upregulation of activating transcription factor (ATF)3, ATF4, T cell factor (TCF)3 and TCF4/lymphoid enhancer factor 1 (LEF1) protein expression levels, and significantly attenuated hypoxia­induced ANF secretion. These results indicated that Sirt1 and Nrf2, regulated by NOX4, can potentially stimulate TCF3 and TCF4/LEF1 signaling via ATF3 and ATF4 activation, thereby potentially participating in the regulation of ANF secretion in beating rat atria during hypoxia. In conclusion, intervening with the Sirt1/Nrf2/ATF signaling pathway may be an effective strategy for resisting oxidative stress damage in the heart during hypoxia.

Green and efficient in-situ biosynthesis of antioxidant and antibacterial bacterial cellulose using wine pomace.

Biologically active bacterial cellulose (BC) was efficiently synthesized in situ using wine pomace and its hydrolysate. The structural and biomechanical properties together with the biological functions of the BC were investigated. Functional BC from wine pomace and its enzymatic hydrolysate were of high purity and had higher crystallinity indexes (90.61% and 89.88%, respectively) than that from HS medium (82.26%). FTIR results proved the in-situ bindings of polyphenols to the functionalized BC. Compared to BC from HS medium, wine pomace-based BC had more densely packed ultrafine fibrils, higher diameter range distributions of fiber ribbon, but lower thermal decomposition temperatures, as revealed by the SEM micrographs and DSC data. Meanwhile, wine pomace-based BC exhibited higher loads in tensile strength and higher hardness (4.95 ± 0.31 N and 5.13 ± 0.63 N, respectively) than BC in HS medium (3.43 ± 0.14 N). Furthermore, BC synthesized from wine pomace hydrolysate exhibited a slower release rate of phenolic compounds, and possessed more antioxidant activities and better bacteriostatic effects than BC from wine pomace. These results demonstrate that BC synthesized in situ from wine pomace (especially from enzymatic hydrolysate) is a promising biomolecule with a potential application in wound dressing, tissue engineering, and other biomedical fields.

Guidelines on the treatment with integrated traditional Chinese medicine and western medicine for severe coronavirus disease 2019.

Severe Coronavirus Disease 2019 (COVID-19) is characterized by numerous complications, complex disease, and high mortality, making its treatment a top priority in the treatment of COVID-19. Integrated traditional Chinese medicine (TCM) and western medicine played an important role in the prevention, treatment, and rehabilitation of COVID-19 during the epidemic. However, currently there are no evidence-based guidelines for the integrated treatment of severe COVID-19 with TCM and western medicine. Therefore, it is important to develop an evidence-based guideline on the treatment of severe COVID-19 with integrated TCM and western medicine, in order to provide clinical guidance and decision basis for healthcare professionals, public health personnel, and scientific researchers involved in the diagnosis, treatment, and care of COVID-19 patients. We developed and completed the guideline by referring to the standardization process of the "WHO handbook for guideline development", the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, and the Reporting Items for Practice Guidelines in Healthcare (RIGHT).

Bio-conversion of kitchen waste into bacterial cellulose using a new multiple carbon utilizing Komagataeibacter rhaeticus: Fermentation profiles and genome-wide analysis.

A cellulose-producing bacterium Komagataeibacter rhaeticus K15 was isolated from kombucha tea, and its metabolic pathways and cellulose synthesis operon were analyzed by genome sequencing. Different from the reported K. rhaeticus, the K15 produced little gluconic acid (2.26 g/L) when glucose was the sole carbon source and has the capacity for high cellulose production (4.76 g/L) with other carbon sources. Furthermore, six nitrogen-fixing genes were found to be responsible for the survival of K15 on a nitrogen-free medium. Based on its fermentation characteristics, K15 was cultured in a kitchen waste medium as a strategy for green and sustainable bacterial cellulose production. The SEM, XRD, and FTIR results indicated that synthesized cellulose has a mean diameter of 40-50 nm nanofiber, good crystallinity, and the same chemical structure. The K15 strain provides a highly viable alternative strategy to reduce the costs of bacterial cellulose production using agro-industrial residues as nutrient sources.

Transcription factor FOXC1 positively regulates SFRP1 expression in androgenetic alopecia.

Androgenetic alopecia (AGA) is the most common type of hair loss dysfunction. Secreted frizzled related protein 1 (SFRP1) is found to be associated with hair loss, but its role in AGA and the regulation mechanism of its transcription level is unclear. The aim of our study is to explore the expression of SFRP1 in AGA samples and its transcriptional mechanism. Male frontal and occipital scalp hair follicles from AGA patients were collected, and human dermal papilla cells (DPCs) were isolated and cultured. SFRP1 gene was cloned and constructed into recombinant plasmids to perform dual-luciferase reporter assay. Transcription factor binding sites were predicted through the Jaspar website and further confirmed by the chromatin immunoprecipitation (ChIP) assay. Expression of genes in DPCs was determined by immunofluorescence (IF) staining, quantitative real-time PCR (qRT-PCR) and western blotting. Our findings showed that SFRP1 was highly expressed in DPCs of AGA patients. The core promoter region of SFRP1 was from -100 to +50 bp and was found to be positively regulated by forkhead box C1 (FOXC1), a transcription factor related to hair growth, both at mRNA and protein level in DPCs. Our study suggests that FOXC1 plays an important role in regulating SFRP1 transcription, which may provide new insights into the development of therapeutic strategies for the treatment of AGA.

Comparison of Clinical Characteristics and Outcomes of Pediatric and Adult Patients with Coronavirus Disease 2019 in Shenzhen, China.

OBJECTIVE: Here we aimed to investigate the difference in clinical characteristics and outcomes between pediatric and adult patients with COVID-19. METHODS: A total of 333 consecutive patients with laboratory-confirmed SARS-CoV-2 infection treated in the departments of Internal medicine of Shenzhen Third People's Hospital from January 11 th to February 10 th, 2020 were included. The data were obtained from electronic medical records. The epidemiological data, clinical characteristics, length of hospital stays, and outcomes of pediatric and adult patients were compared. RESULTS: Compared with adult patients, pediatric patients had a shorter time of symptom onset to hospitalization than adults [median time, 1 ( IQR, 1.0-1.0) d vs. 3 ( IQR, 2.0-6.0) d, P < 0.001], milder or fewer symptoms, less severe chest CT findings. The clinical severity classification of children was less severe than adults. Up to 15 th March, the end of the follow-up, 33 (100%) children and 292 (97.3%) adult patients had been discharged from hospital. Only 2 (0.7%) adult patients died, with an overall case mortality of 0.6%. The median length of hospital stay of pediatric patients was shorter than that of adult patients [19 (95% CI: 16.6-21.4) d vs. 21 (95% CI: 19.9-22.1) d, P = 0.024]. CONCLUSION: Pediatric patients with COVID-19 had milder or less clinical symptoms, less evident pulmonary imaging changes, better prognosis, and shorter length of hospital stay.

Preparation of a Major Metabolite of Iguratimod and Simultaneous Assay of Iguratimod and Its Metabolite by HPLC in Rat Plasma.

Iguratimod is a new synthetic disease-modifying antirheumatic drug intended to treat patients with rheumatoid arthritis. A new method using recombinant human CYP450s yeast cells containing c-DNA expressed P450s was applied to identify the metabolic pathways of iguratimod and to prepare its metabolite. The metabolite was isolated, and its structure was identified by quadrupole time-of-flight-mass spectrometry and nuclear magnetic resonance. Furthermore, a selective and sensitive high performance liquid chromatography (HPLC) method was developed for the simultaneous quantification of iguratimod and its major metabolite in rat plasma for the first time. The results indicated that iguratimod was mainly metabolized to a metabolite by CYP2C9 and CYP2C19 in in-vitro study. The structure of the metabolite was identified as M2 (N-[3-(acetamido)-4-oxo-6-phenoxy-4H-chromen-7-yl]methanesulfonamide). HPLC assay was achieved on a C18 column using methanol-water containing 0.1% trifluoroacetic acid (55:45 v/v) at a flow rate of 1 mL/min with UV detection at 257 nm. Standard calibration curves were obtained in the concentration range of 0.5-20 µg/mL for iguratimod and its metabolite M2. The lower limits of detection of iguratimod and M2 in rat plasma were 0.1 and 0.25 µg/mL, respectively. The intra- and inter-day precision (RSD%) were within 5% for the two analytes. The average recoveries of the analytes were greater than 90%. In conclusion, recombinant human CYP450s whole-yeast transformation system could be successfully used to identify and prepare the major metabolite of iguratimod. The HPLC method we developed could be successfully applied to evaluate pharmacokinetics of iguratimod and its metabolite M2 in rats.

Resectable recurrent colorectal liver metastasis: can radiofrequency ablation replace repeated metastasectomy?

BACKGROUND: Percutaneous radiofrequency ablation (RFA) is used as a first-line treatment for colorectal liver metastases that recur after first liver resection in our institution. We aim to evaluate its therapeutic efficacy compared to repeated surgical resection. METHODS: A retrospective review was performed in 104 patients treated with curative intent for resectable recurrent colorectal liver metastases. RESULTS: Sixty-one patients underwent RFA and 43 patients underwent surgery. The overall recurrence rates were 82% in the RFA group and 65.1% in the resection group (P = 0.05). The local recurrence rate on a lesion-basis was markedly higher after RFA than that after resection (16.7% versus 7.3%, P = 0.04). The difference remained significant in patients with a maximum lesion diameter >3 cm (24.5% versus 7.6%, P = 0.01). RFA treatment was independently associated with recurrence on multivariate analyses (P = 0.01). 69.7% of RFA patients and 42.6% of surgery patients with intrahepatic recurrence were amenable to repeated local treatment (P = 0.05), leading to the equivalent actuarial 3-year progression free survival rates (RFA: 29.1% versus Resection: 33.1%, P = 0.48) and 5-year overall survival rates in the two treatment groups (RFA: 33% versus Resection: 28.4%, P = 0.36). CONCLUSIONS: Surgery remains the treatment of choice for resectable recurrence. RFA may offer similar benefit in selected patients.

Comparison of the Extent Classification and the New Complexity Classification of Hepatectomy for Prediction of Surgical Outcomes: a Retrospective Cohort Study.

BACKGROUND: In predicting the risk for posthepatectomy complications, hepatectomy is traditionally classified into minor or major resection based on the number of resected segments. Recently, a new hepatectomy complexity classification was proposed. This study aimed to compare the value of the traditional and that of the new classification in perioperative outcomes prediction. METHODS: Demographics, perioperative laboratory tests, intraoperative and postoperative outcomes, and follow-up data of patients with hepatocellular carcinoma who underwent liver resection were retrospectively analyzed. RESULTS: A total of 302 patients were included in our study. Multivariable analysis of intraoperative variables showed that the complexity classification could independently predict the occurrence of blood loss > 800 mL, operation time > 4 h, intraoperative transfusion, and the use of Pringle's maneuver (all p < 0.05). For postoperative outcomes, the high-complexity group was independently associated with severe complications, and hepatic-related complications (all p < 0.05); the traditional classification was independently associated only with posthepatectomy liver failure (PHLF) (p = 0.004). CONCLUSIONS: Complexity classification could be used to assess the difficulty of surgery and was independently associated with postoperative complications. The traditional classification did not reflect operation complexity and was associated only with PHLF.

Risk factors and prediction of postoperative hypoparathyroidism among patients with papillary thyroid carcinoma.

BACKGROUND: We aimed to study the incidence rate of hypoparathyroidism, its risk factors, and identify its predictive factors among patients with papillary thyroid carcinoma (PTC) who had undergone total or near-total thyroidectomy and central neck dissection (CND). METHODS: Ninety-three PTC patients who had undergone total or near-total thyroidectomy and CND were analyzed for hypoparathyroidism. The association between clinicopathological factors and hypoparathyroidism was tested by χ2 test and multivariate logistic regression. The ROC curve and a 2×2 contingency table were used to evaluate the performance of postoperative parathyroid hormone (PTH) and serum calcium concentration in prediction of hypothyroidism. RESULTS: Hypothyroidism was observed in 46 patients (49.5%), among whom 2 had permanent hypothyroidism. Univariate analysis showed that tumor size (P=0.034), extraglandular invasion (P=0.028), bilateral tumors (P=0.045), and bilateral CND (P=0.028) were significant risk factors of hypothyroidism. Multivariate analysis showed that extraglandular invasion (P=0.003) and bilateral CND (P=0.044) were independent risk factors. The patients with hypothyroidism had an average PTH level of 8.51 ng/L on the first day after surgery, and those without, 21.39 ng/L (P<0.001). When the PTH level on the first day after surgery was used to predict postoperative hypothyroidism, the ROC curve analysis showed that the area under curve (AUC) was 0.875. CONCLUSIONS: Hypothyroidism is a common complication of total or near-total thyroidectomy and CND, for which extraglandular invasion and bilateral CND are independently significant risk factors and the level of PTH is a reliable and early predictor.

A Low Neutrophil to Lymphocyte Ratio Before Preoperative Chemotherapy Predicts Good Outcomes After the Resection of Colorectal Liver Metastases.

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is a marker of inflammation and is associated with poor outcomes. We aimed to evaluate the role of the pretreatment NLR in predicting the outcomes after preoperative chemotherapy in patients with colorectal liver metastases (CRLM). METHODS: A retrospective review was performed for 183 patients with CRLM. The NLR was measured before chemotherapy, and a receiver operating characteristic (ROC) curve was used to estimate the cutoff value. Logistic regressions were applied to analyze potential predictors of the pathological response. The Cox proportional hazard method was used to analyze survival. RESULTS: The pre-chemotherapy NLR was 2.4 ± 1.1, whereas the post-chemotherapy NLR was 2.1 ± 1.6 (p < 0.001). The pretreatment NLR of 2.3 was a significant predictive marker for the pathological response. The pathological response rates were 67.1% in the patients with an NLR ≤ 2.3 and 48.1% in patients with an NLR > 2.3 (p = 0.01). Multivariate analysis revealed that the factors independently associated with pathological responses were a low pretreatment NLR (p = 0.043), radiological response to chemotherapy (p < 0.001), first-line chemotherapy (p = 0.001), and targeted therapy (p = 0.002). The median overall survival (OS) and recurrence-free survival (RFS) were worse in the increased NLR cohort than in the low NLR cohort (OS: 31.1 vs. 43.1 months, p = 0.012; RFS: 6.5 vs. 9.4 months, p = 0.06). According to multivariate analyses, a high pretreatment NLR was a significant predictor for both worse OS (HR = 2.43, 95%CI = 1.49-3.94, p < 0.001) and RFS (HR = 1.53, 95%CI = 1.08-2.18, p = 0.017). CONCLUSIONS: An increased pretreatment NLR was a significant predictor of a poor pathological response and worse prognosis after preoperative chemotherapy. The NLR is a simple biomarker for assessing chemotherapy efficacy.

Human leukocyte antigen gene polymorphisms are associated with systemic inflammation in hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: Systemic inflammation (SI) is associated with tumor progression and overall survival (OS) in patients with hepatocellular carcinoma (HCC). The presence of some single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region can influence the prognosis of patients with hepatitis B virus (HBV)-related HCC, although the mechanism remains unknown. This study aimed to analyze the correlations between HLA gene polymorphisms and SI. PATIENTS AND METHODS: This study included 330 patients with HCC. The clinical parameters were reviewed, and five SNPs, namely rs2647073, rs3997872, rs3077, rs7453920, and rs7768538, were genotyped using the MassARRAY system. RESULTS: The rs3997872, rs7453920, and rs7768538 genotypes were found to be significantly associated with OS (P<0.05). The rs7453920 genotype was significantly associated with the neutrophil/lymphocyte ratio (NLR; P=0.001), which was used as an SI index with a threshold determined by receiver operating characteristic analysis. An elevated NLR was also an independent predictor of OS according to univariate and multivariate analyses (P<0.001). CONCLUSION: Our data show that HLA gene polymorphisms are associated with SI in patients with HBV-related HCC, and the absence of minor allele A (rs7453920) promotes SI and shortens OS.

Discovery of Novel Topoisomerase II Inhibitors by Medicinal Chemistry Approaches.

DNA topoisomerase II (topo II) is an important enzyme involved in DNA replication, recombination, and repair. Despite the popular applications of topo II inhibitors in cancer therapy, there is still an urgent need to upgrade topo II inhibitors to cope with drug resistance and severe adverse effects. Accordingly, novel topo II catalytic or multitarget topo II inhibitors are gaining more attention and make it possible to ease the toxic limitations of topo II poisons. In this review, medicinal chemistry approaches are mainly discussed toward the development of potent topo II inhibitors with low toxicities.

LW106, a novel indoleamine 2,3-dioxygenase 1 inhibitor, suppresses tumour progression by limiting stroma-immune crosstalk and cancer stem cell enrichment in tumour micro-environment.

BACKGROUND AND PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1) is emerging as an important new therapeutic target for treatment of malignant tumours characterized by dysregulated tryptophan metabolism. However, the antitumour efficacy of existing small-molecule inhibitors of IDO1 is still unsatisfactory and the underlying mechanism remains largely undefined. Hence, we discovered a novel potent small-molecule inhibitor of IDO1, LW106, and studied its antitumour effects and the underlying mechanisms in two tumour models. EXPERIMENTAL APPROACH: C57BL6 mice, athymic nude mice or Ido1-/- mice were inoculated with IDO1-expressing and -nonexpressing tumour cells and treated with vehicle, epacadostat or increasing doses of LW106. Xenografted tumours, plasma, spleens and other vital organs were harvested and subjected to kynurenine/tryptophan measurement and flow cytometric, histological and immunohistochemical analyses. KEY RESULTS: LW106 dose-dependently inhibited the outgrowth of xenografted tumours that were inoculated in C57BL6 mice but not nude mice or Ido1-/- mice, showing a stronger antitumour efficacy than epacadostat, an existing IDO1 inhibitor. LW106 substantially elevated intratumoural infiltration of proliferative Teff cells, while reducing recruitment of proliferative Treg cells and non-haematopoietic stromal cells such as endothelial cells and cancer-associated fibroblasts. LW106 treatment resulted in a reduced subpopulation of cancer stem cells (CSCs) in xenografted tumours in which fewer proliferative/invasive tumour cells and more apoptotic tumour cells were observed. CONCLUSIONS AND IMPLICATIONS: LW106 inhibits tumour outgrowth by limiting stroma-immune crosstalk and CSC enrichment in the tumour micro-environment. LW106 has potential as a immunotherapeutic agent for use in combination with immune checkpoint inhibitors and (or) chemotherapeutic drugs for cancer treatment.