Clinical Observation on the Therapeutic Effect of Port-Wine Stains with Intravenous Injection of Hematoporphyrin Monomethyl Ether (HMME).

Background: Hematoporphyrin monomethyl ether (HMME) is a promising photosensitizer for photodynamic therapy (PDT) and has found wide application in the treatment of port-wine stains (PWS). Objective: This study aims to observe and analyze the clinical efficacy and safety of HMME-PDT in the treatment of PWS patients. It also aims to evaluate the usefulness of color Doppler flow imaging (CDFI), an ultrasound technique for detecting blood flow in skin lesions, in assessing clinical efficacy. Methods: Thirty-three patients with PWS underwent HMME-PDT at our dermatology outpatient clinic between January 2019 and March 2020. Data on patient demographics, lesion location, lesion type (pink, purple, nodular thickening), treatment frequency, and pre- and post-treatment images were collected and retrospectively analyzed. CDFI was performed on three patients. Results: All patients received intravenous HMME and underwent irradiation with 532 nm green LED light. Of these, 5 patients received 1 session of HMME-PDT, 14 received 2 sessions, 9 received 3 sessions and the remaining 5 patients received more than 3 sessions. Of the 33 patients, 9 were cured (27.27%), 10 showed improvement (30.30%), 11 experienced a reduction in symptoms (33.33%), and 3 showed no significant improvement (9.09%). Most patients reported local pain and oedema, and no systemic adverse effects were observed. Clinical efficacy correlated with lesion type and total number of treatment sessions. CDFI appears to be an excellent technique for assessing clinical efficacy. Conclusion: HMME-PDT is a safe and effective method for the treatment of PWS. CDFI examination appears to be a promising assessment tool. However, further validation with larger sample sizes is warranted.

Identification of a novel LFNG variant in a Chinese fetus with spondylocostal dysostosis and a systematic review.

Spondylocostal dysostosis (SCDO) encompasses a group of skeletal disorders characterized by multiple segmentation defects in the vertebrae and ribs. SCDO has a complex genetic etiology. This study aimed to analyze and identify pathogenic variants in a fetus with SCDO. Copy number variant sequencing and whole exome sequencing were performed on a Chinese fetus with SCDO, followed by bioinformatics analyses, in vitro functional assays and a systematic review on the reported SCDO cases with LFNG pathogenic variants. Ultrasound examinations in utero exhibited that the fetus had vertebral malformation, scoliosis and tethered cord, but rib malformation was not evident. We found a novel homozygous variant (c.1078 C > T, p.R360C) within the last exon of LFNG. The variant was predicted to cause loss of function of LFNG by in silico prediction tools, which was confirmed by an in vitro assay of LFNG enzyme activity. The systematic review listed a total of 20 variants of LFNG in SCDO. The mutational spectrum spans across all exons of LFNG except the last one. This study reported the first Chinese case of LFNG-related SCDO, revealing the prenatal phenotypes and expanding the mutational spectrum of the disorder.

Research progress on prediction of postoperative intraocular lens position.

With the progress in refractive cataract surgery, more intraocular lens (IOL) power formulas have been introduced with the aim of reducing the postoperative refractive error. The postoperative IOL position is critical to IOL power calculations. Therefore, the improvements in postoperative IOL position prediction will enable better selection of IOL power and postoperative refraction. In the past, the postoperative IOL position was mainly predicted by preoperative anterior segment parameters such as preoperative axial length (AL), anterior chamber depth (ACD), and corneal curvature. In recent years, some novel methods including the intraoperative ACD, crystalline lens geometry, and artificial intelligence (AI) of prediction of postoperative IOL position have been reported. This article attempts to give a review about the research progress on prediction of the postoperative IOL position.

Tumor Necrosis Factor-Alpha (+489 G/A) Polymorphism Can Predict the Response to Adalimumab in Chinese Han Patients With Ankylosing Spondylitis.

BACKGROUND: Studies investigating the association between single nucleotide polymorphisms (SNPs) of tumor necrosis factor-alpha (TNFα) and the efficacy of adalimumab (ADA) in ankylosing spondylitis (AS) therapy have reported conflicting results. We aimed to investigate the value of SNP typing of TNFα in predicting the efficacy of ADA in AS. MATERIALS AND METHODS: Eighty patients with active AS who received ADA treatment were followed up for 24 weeks. Six known SNPs of TNFα (+489G/A, -238G/A, -308G/A, -857C/T, -863C/A, and -1031C/T) were subjected to the SNaPshot SNP typing method, which has been proven to be a reliable, efficient, and cost-effective method for detecting SNPs. The relationship between each SNP genotype and the therapeutic efficacy of ADA was analyzed. RESULTS: At the end of the 24-week follow-up, 58.8% of the patients with AS achieved Assessment of SpondyloArthritis International Society (ASAS) partial remission (PR), 67.5% of the patients achieved the criteria of an ASAS40 response (40% improvement on indices), and 53.8% of the patients achieved Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement (MI). The univariate analysis showed that patients with AS carrying the TNFα +489 A allele were more likely to achieve ASAS-PR, ASAS40 response criteria, and ASDAS-MI after ADA treatment. In the multivariate regression analysis, the TNFα +489 A allele was an independent factor influencing the efficacy of ADA in treating AS (ASAS-PR odds ratio (OR) = 2.66, 95% confidence interval (CI) = 1.01-7.01; ASAS40 OR = 4.56, 95% CI = 1.39-15.00; ASDAS-MI OR = 3.31, 95% CI = 1.02-10.69). CONCLUSIONS: The patients carrying the TNFα +489 A allele may be more likely to experience better therapeutic efficacy and achieve the treatment target (ASAS-PR, ASAS40 response, or ASDAS-MI) after receiving ADA treatment. Detection of TNFα +489 G/A may predict the therapeutic efficacy of ADA, which can be used in clinical practice to tailor treatment for individual patients with AS. Further studies with larger sample sizes and longer follow-up periods with imaging evaluation are needed to verify our findings.

Survival analysis in patients with follicular dendritic cell sarcoma: a population-based study.

Follicular dendritic cell sarcoma (FDCS) is a rare low-intermediate grade malignant neoplasm. To date, published data on FDCS clinical courses are sparse, and no conditional survival study has been performed. Thus, we retrospectively analyzed 187 patients diagnosed with FDCS from the Surveillance, Epidemiology, and End Results (SEER) database. In this study, the median age at diagnosis was 50 years and 91 (48.7%) patients were male. The most common primary location was the abdomen/pelvis (82, 43.9%). The 1-year, 3-year, and 5-year overall survival (OS) were 88.7%, 69.0%, and 59.8%, respectively. The 5-year conditional overall survival increased from 65.7% at baseline to 83.8% in 5-year survivors. The 3-year FDCS-specific death rate was 26.7% and the rate of death from other reasons was 3.7%. In addition, the annual death hazard was the highest in the first four years after diagnosis and increased again in the 7th and 8th years. Age > 60 years at diagnosis, metastatic disease, and FDCS in thoracic organs were associated with shorter OS and FDCS-specific survival. In addition, FDCS patients, with either local or metastatic disease, could benefit from surgery therapy. In addition, adjuvant radiotherapy or chemotherapy for local disease provided no significant improvement in overall survival or FDCS-specific survival. We hope these findings may guide treatments and surveillance strategies for FDCS patients in clinical practice.

Comparison of clinical characteristics between adult-onset and juvenile-onset non-radiographic axial spondyloarthritis in Chinese patients: results from the COCAS cohort.

BACKGROUND: Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease predominantly affecting the axial skeleton. We aimed to describe the clinical characteristics of patients with non-radiographic axSpA (nr-axSpA) in China and compare the differences between adult- and juvenile-onset cases. METHODS: A cross-sectional study was conducted using data from 776 patients with nr-axSpA in the Clinical Characteristic and Outcome in Chinese Axial Spondyloarthritis (COCAS) study cohort. Patients were divided into two groups including the adult-onset group (n = 662) and the juvenile-onset group (n = 114) according to age at disease onset. Baseline demographics and clinical characteristics were compared between patients with adult-onset and juvenile-onset nr-axSpA. RESULTS: Overall, the male-to-female ratio was 1.26:1, the prevalence of HLA-B27 positivity was 72.2%, and the median age at disease onset of nr-axSpA was 22 years. Nearly 75% of nr-axSpA patients had peripheral arthritis in the disease course, and the prevalence of extra-articular manifestations was 10.4%. The juvenile-onset group contained a higher proportion of men (66.7% vs. 53.9%, P = 0.011) and a longer baseline disease duration (4.0 [4.0] vs. 1.6 [3.5], P < 0.001) than the adult-onset group. A family history of spondyloarthritis was more frequent in the juvenile-onset group than in the adult-onset group (23.7% vs. 15.4%, P = 0.028), but no significant difference in the prevalence of HLA-B27 positivity was observed between the two groups (P = 0.537). Regarding initial symptoms, peripheral arthritis occurred more often in patients with juvenile-onset nr-axSpA, whereas patients with adult-onset nr-axSpA presented more frequently with axial involvement. The prevalence of inflammatory back pain (IBP) was higher in the adult-onset group than in the juvenile-onset group (85.0% vs. 75.4%, P = 0.010), whereas the juvenile-onset group showed a higher prevalence of peripheral arthritis and enthesitis than the adult-onset group (67.5% vs. 48.5%, P < 0.001; 35.1% vs. 23.3%, P = 0.007, respectively). CONCLUSIONS: Compared with adult-onset nr-axSpA, juvenile-onset nr-axSpA was more common in men and those with a family history of spondyloarthritis. Juvenile-onset nr-axSpA presents with a "peripheral predominant" mode at disease onset and a higher frequency of peripheral arthritis and enthesitis during the disease course.

A nomogram for predicting the risk of venous thromboembolism in patients with solid cancers.

Cancer patients with venous thromboembolism (VTE) are prone to poor prognoses. Thus, we aimed to develop a nomogram to predict the risk of VTE in these patients. We retrospectively analyzed 791 patients diagnosed with solid tumors between January 2017 and May 2021 at Tongji Hospital. Univariate logistic analysis and multivariate logistic regression were adopted in this study. Our results indicated that age ≥ 60 years, tumor stages III-IV, platelet distribution width (PDW) ≤ 12.6%, albumin concentration ≤ 38.8 g/L, lactate dehydrogenase (LDH) concentration ≥ 198 U/L, D-dimer concentration ≥ 1.72 µg/mL, blood hemoglobin concentration ≤ 100 g/dL or the use of erythropoiesis-stimulating agents and cancer types were independent risk factors. The nomogram prediction model was developed based on the regression coefficients of these variables. We assessed the performance of the nomogram by calibration plot and the area under the receiver operating characteristic curve and compared it with the Khorana score. The concordance index (C- index) of the nomogram was 0.852 [95% confidence interval (CI) 0.823 to 0.880], while the Khorana score was 0.681 (95% CI 0.639 to 0.723). Given its performance, this nomogram could be used to select cancer patients at high risk for VTE and guide thromboprophylaxis treatment in clinical practice, provided it is validated in an external cohort.

Adipocyte-Targeting Type I AIE Photosensitizer for Obesity Treatment via Photodynamic Lipid Peroxidation.

Obesity is a surging public health risk and is often associated with fatal diseases, including diabetes, stroke, and myocardial infarction. Common methods for obesity treatment include diet control, weight-loss medicine, and bariatric surgery, but these methods are often ineffective or unsafe. Herein, we introduce a minimally invasive and effective approach to reduce excessive fat accumulation by utilizing red/near-infrared emissive and lipid droplet targeting aggregation-induced emissive luminogens (AIEgens), namely, TTMN and MeTTMN, for specific targeting and photoinduced peroxidation of large lipid droplets in adipocytes. The reported AIEgens can trace and monitor the formation process of adipocytes from pre-adipocytes with a high signal-to-noise ratio. In addition, the presented AIEgens act as Type I photosensitizer that generates highly reactive hydroxyl radicals and superoxides under white light to eliminate mature adipocytes through the chain reactions of lipid peroxidation, even under low oxygen supply. We also demonstrate the use of AIEgens for in vivo photodynamic therapy (PDT) for subcutaneous fat reduction treatment. This work demonstrates the use of AIEgen as a dual imaging and Type I photosensitizer for photodynamic therapeutics to induce adipocyte apoptosis, involving a simple fabrication and treatment process. The suggested in vivo photodynamic obesity treatment processes have negligible toxicity toward nontargeted normal tissues, providing an alternative approach for effective and relatively safer obesity treatment in the future.

Preliminary clinical report of alternate episodes of Posner-Schlossman syndrome and viral keratitis.

Posner-Schlossman syndrome (PSS) and viral keratitis have a shared pathogen and are common diseases in China, but there are few case reports on whether these two diseases occur concurrently or alternately. After long-term clinical observations, six patients with alternating episodes of PSS and viral keratitis were confirmed at our hospital in the past 10 years. Of the six patients, three were female and three were male. Four patients had monocular PSS with ipsilateral monocular viral keratitis, one had monocular PSS with bilateral viral keratitis, and one had bilateral PSS with bilateral viral keratitis. Of the six cases, three had epithelial viral keratitis and three had endothelial viral keratitis. In four cases, the interval between the onset of the two diseases ranged from 8 days to 3 years, and two cases showed overlapping manifestations of the two diseases in 3 to 6 days, both with incomplete absorption of keratic precipitates. The six cases had intermittent episodes of both diseases and significant loss of corneal sensation during the onset of viral keratitis, and were effectively treated with antiviral therapy. PSS and viral keratitis may alternate episodically, and clinical attention should be paid to these conditions. The mechanism of the alternate episodes might be associated with viral infection and the use of glucocorticoids.

Rational design of small-molecules to recognize G-quadruplexes of c-MYC promoter and telomere and the evaluation of their in vivo antitumor activity against breast cancer.

DNA G4-structures from human c-MYC promoter and telomere are considered as important drug targets; however, the developing of small-molecule-based fluorescent binding ligands that are highly selective in targeting these G4-structures over other types of nucleic acids is challenging. We herein report a new approach of designing small molecules based on a non-selective thiazole orange scaffold to provide two-directional and multi-site interactions with flanking residues and loops of the G4-motif for better selectivity. The ligands are designed to establish multi-site interactions in the G4-binding pocket. This structural feature may render the molecules higher selectivity toward c-MYC G4s than other structures. The ligand-G4 interaction studied with 1H NMR may suggest a stacking interaction with the terminal G-tetrad. Moreover, the intracellular co-localization study with BG4 and cellular competition experiments with BRACO-19 may suggest that the binding targets of the ligands in cells are most probably G4-structures. Furthermore, the ligands that either preferentially bind to c-MYC promoter or telomeric G4s are able to downregulate markedly the c-MYC and hTERT gene expression in MCF-7 cells, and induce senescence and DNA damage to cancer cells. The in vivo antitumor activity of the ligands in MCF-7 tumor-bearing mice is also demonstrated.

Construction of Influenza Early Warning Model Based on Combinatorial Judgment Classifier: A Case Study of Seasonal Influenza in Hong Kong.

OBJECTIVE: The annual influenza epidemic is a heavy burden on the health care system, and has increasingly become a major public health problem in some areas, such as Hong Kong (China). Therefore, based on a variety of machine learning methods, and considering the seasonal influenza in Hong Kong, the study aims to establish a Combinatorial Judgment Classifier (CJC) model to classify the epidemic trend and improve the accuracy of influenza epidemic early warning. METHODS: The characteristic variables were selected using the single-factor statistical method to establish the influencing factor system of an influenza outbreak. On this basis, the CJC model was proposed to provide an early warning for an influenza outbreak. The characteristic variables in the final model included atmospheric pressure, absolute maximum temperature, mean temperature, absolute minimum temperature, mean dew point temperature, the number of positive detections of seasonal influenza viruses, the positive percentage among all respiratory specimens, and the admission rates in public hospitals with a principal diagnosis of influenza. RESULTS: The accuracy of the CJC model for the influenza outbreak trend reached 96.47%, the sensitivity and specificity change rates of this model were lower than those of other models. Hence, the CJC model has a more stable prediction performance. In the present study, the epidemic situation and meteorological data of Hong Kong in recent years were used as the research objects for the construction of the model index system, and a lag correlation was found between the influencing factors and influenza outbreak. However, some potential risk factors, such as geographical nature and human factors, were not incorporated, which ideally affected the prediction performance to some extent. CONCLUSION: In general, the CJC model exhibits a statistically better performance, when compared to some classical early warning algorithms, such as Support Vector Machine, Discriminant Analysis, and Ensemble Classfiers, which improves the performance of the early warning of seasonal influenza.

Risk factors for progression of juvenile-onset non-radiographic axial spondyloarthritis to juvenile-onset ankylosing spondylitis: a nested case-control study.

OBJECTIVE: To evaluate the clinical characteristics of juvenile-onset non-radiographic axial spondyloarthritis (nr-axSpA) and to investigate risk factors associated with progression to juvenile-onset ankylosing spondylitis (JoAS). METHODS: A nested case-control study was conducted using the retrospectively collected data of 106 patients with juvenile-onset nr-axSpA (age at disease onset, <16 years) in the Clinical characteristic and Outcome in Chinese Axial Spondyloarthritis study cohort. Baseline demographic and clinical characteristics and prognosis were reviewed. Logistic regression analyses were performed to investigate risk factors associated with progression to JoAS. RESULTS: Overall, 58.5% of patients with juvenile-onset nr-axSpA presented with peripheral symptoms at disease onset. In 82.1% of these patients, axial with peripheral involvement occurred during the disease course. The rate of disease onset at >12 years and disease duration of ≤10 years were significantly higher in those with progression to JoAS than in those without progression to JoAS (83.0% vs 52.8%, p=0.001; 92.5% vs 56.6%, p<0.001, respectively). Multivariable logistic regression analysis revealed that inflammatory back pain (IBP) (OR 13.359 (95% CI 2.549 to 70.013)), buttock pain (OR 10.171 (95% CI 2.197 to 47.085)), enthesitis (OR 7.113 (95% CI 1.670 to 30.305)), elevated baseline C reactive protein (CRP) levels (OR 7.295 (95% CI 1.984 to 26.820)) and sacroiliac joint-MRI (SIJ-MRI) positivity (OR 53.821 (95% CI 9.705 to 298.475)) were significantly associated with progression to JoAS. CONCLUSION: Peripheral involvement was prevalent in juvenile-onset nr-axSpA. IBP, buttock pain, enthesitis, elevated baseline CRP levels and SIJ-MRI positivity in patients with the disease are associated with higher risk of progression to JoAS.

Radical treatment of severe open fractures of extremities by orthoplastic surgery: a 10-year retrospective study.

OBJECTIVE: This study aimed to retrospectively analyze clinical data of a series of patients with severe open fractures of extremities (Gustilo IIIb or IIIc), who achieved a satisfactory outcome through radical orthoplastic surgery, so as to provide a reference for determining the treatment of severe open fractures of extremities. METHODS: The clinical data of 41 consecutive patients with severe open fracture (Gustilo IIIb or IIIc) of the limb, who underwent successful surgical debridement, fixation, and soft tissue reconstruction in one stage between January 2008 and January 2019, were retrospectively reviewed. Postoperative indicators, including infection rate and union time, were acquired by a regular follow-up and analyzed. RESULTS: The mean (±SD) age of the patients was 38 ± 16 years. A total of 90 open fractures and severe soft tissue damages were analyzed. The soft tissue cover was achieved within 72 h. The overall rate of infection was 14.6% (6/41). Sex and the Mangled Extremity Severity Score were associated with infection. The median union time of 40 patients (one amputation) was 32 weeks. CONCLUSION: The overall rate of infection exhibited a lower tendency in this study compared with previous studies on high-grade open fractures following a two-stage orthopedic approach. The consequence of infection rate and union time was similar to that in previous studies. These results indicated that the single-stage radical orthoplastic treatment was an effective and reliable option for reconstructing severe open fractures.

Tea consumption and colorectal cancer risk: a meta-analysis of prospective cohort studies.

PURPOSE: Data from in vitro and animal studies support the preventive effect of tea (Camellia sinensis) against colorectal cancer. Further, many epidemiologic studies evaluated the association between tea consumption and colorectal cancer risk, but the results were inconsistent. We conducted a meta-analysis of prospective cohort studies to systematically assess the association between tea consumption and colorectal cancer risk. METHODS: A comprehensive literature review was conducted to identify the related articles by searching PubMed and Embase up to June, 2019. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a fixed effect model. RESULTS: Twenty cohort articles were included in the present meta-analysis involving 2,068,137 participants and 21,437 cases. The combined RR of colorectal cancer for the highest vs. lowest tea consumption was determined to 0.97 (95% CI 0.94-1.01) with marginal heterogeneity (I2 = 24.0%, P = 0.093) among all studies. This indicated that tea consumption had no significant association with colorectal cancer risk. Stratified analysis showed that no significant differences were found in all subgroups. We further conducted the gender-specific meta-analysis for deriving a more precise estimation. No significant association was observed between tea consumption and colorectal cancer risk in male (combined RR = 0.97; 95% CI 0.90-1.04). However, tea consumption had a marginal significant inverse impact on colorectal cancer risk in female (combined RR = 0.93; 95% CI 0.86-1.00). Further, we found a stronger inverse association between tea consumption and risk of colorectal cancer among the female studies with no adjustment of coffee intake (RR: 0.90; 95% CI 0.82-1.00, P < 0.05) compared to the female studies that adjusted for coffee intake (RR = 0.97; 95% CI 0.87-1.09, P > 0.05). CONCLUSIONS: Our finding indicates that tea consumption has no significant impact on the colorectal cancer risk in both genders combined, but gender-specific meta-analysis shows that tea consumption has a marginal significant inverse impact on colorectal cancer risk in female.

25-Hydroxy vitamin D deficiency predicts inferior prognosis in mantle cell lymphoma.

INTRODUCTION: Mantle cell lymphoma (MCL) is a subtype of B-cell non-Hodgkin lymphoma (NHL), and the purpose of this study was to evaluate the prognostic value of 25-hydroxy vitamin D [25-(OH)D] deficiency among patients with MCL. MATERIALS AND METHODS: Seventy MCL patients with serum 25-(OH)D were enrolled in this study. 25-(OH)D deficiency was defined as a 25-(OH)D level lower than 50 nmol/L, according to International standard of 25-(OH)D classification. The univariate and multivariate Cox regression analyses were used to define the prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curves and the areas under the curve (AUC) were calculated to evaluate the accuracy of combined MIPI-c with 25-(OH)D deficiency. RESULTS: The results showed that 40 patients had 25-OH vitamin D deficiency, with a median follow-up of 25.5 months (range 3.4-65.7 months). Univariate Cox regression analysis showed that 25-(OH)D deficiency group demonstrated unfavorable PFS (P = 0.003) and OS (P = 0.006). Multivariate Cox regression analysis revealed that 25-(OH)D deficiency was an independent prognosis factor for PFS [hazard ratio (HR) 3.713; 95% confidence interval (CI) 1.822-7.565; P < 0.001], and OS (HR 8.305; 95% CI 2.060-33.481; P = 0.003). 25-(OH)D deficiency combined with MIPI-c showed an improved prognostic capacity. CONCLUSION: In summary, 25-(OH)D deficiency was a promising prognostic predictor for MCL.

Microbial bioconversion of the chemical components in dark tea.

Dark tea is a unique fermented tea produced by solid-state fermentation of tea leaves (Camellia sinensis). It includes ripe Pu-erh tea, Fu brick tea, Liupao tea, and other teas. Microbial fermentation is considered to be the key factor controlling the quality of dark tea. It involves a series of reactions that modify the chemical constituents of tea leaves. These chemical conversions during microbial fermentation of dark tea are associated with a variety of functional core microorganisms. Further, Multi-omics approaches have been used to reveal the microbial impact on the conversion of the chemical components in dark tea. In the present review, we provide an overview of the most recent advances in the knowledge of the microbial bioconversion of the chemical components in dark tea, including the chemical composition of dark tea, microbial community composition and dynamics during the fermentation process, and the role of microorganisms in biotransformation of chemical constituents.

EBV-miR-BHRF1-1 Targets p53 Gene: Potential Role in Epstein-Barr Virus Associated Chronic Lymphocytic Leukemia.

PURPOSE: The purpose of this study was to investigate the prognostic impact of Epstein-Barr virus (EBV)-microRNA (miRNA, miR)-BHRF1-1 with chronic lymphocytic leukemia (CLL) as well as role of EBV-miR-BHRF1-1 in p53 gene. MATERIALS AND METHODS: Quantitative reverse transcription-polymerase chain reaction and western blotting were used to quantify EBV-miR-BHRF1-1 and p53 expression in cultured CLL. RESULTS: p53 aberration was associated with the higher expression level of EBV-miR-BHRF1-1 (p < 0.001) which was also an independent prognostic marker for overall survival (p=0.028; hazard ratio, 5.335; 95% confidence interval, 1.193 to 23.846) in 97 newly-diagnosed CLL patients after adjusted with International Prognostic Index for patients with CLL. We identified EBV-miR-BHRF1-1 as a viral miRNA regulator of p53. EBV-miR-BHRF1-1 repressed luciferase reporter activity by specific interaction with the seed region within the p53 3'- untranslated region. Discordance of p53 messenger RNA and protein expression was associated with high EBV-miR-BHRF1-1 levels in CLL patients and cell lines. EBV-miR-BHRF1- 1 inhibition upregulated p53 protein expression, induced cell cycle arrest and apoptosis and decreased cell proliferation in cell lines. EBV-miR-BHRF1-1 mimics downregulated p53 protein expression, decreased cell cycle arrest and apoptosis, and induced cell proliferation in cell lines. CONCLUSION: This study supported the role of EBV-miR-BHRF1-1 in p53 regulation in vitro. Our results support the potential of EBV-miR-BHRF1-1 as a therapeutic target in EBV-associated CLL with p53 gene aberration.

NEK4 kinase regulates EMT to promote lung cancer metastasis.

Epithelial-to-mesenchymal transition (EMT) is a dynamic transitional state from the epithelial to mesenchymal phenotypes. Numerous studies have suggested that EMT and its intermediate states play important roles in tumor invasion and metastasis. To identify novel regulatory molecules of EMT, we screened a siRNA library targeting human 720 kinases in A549 lung adenocarcinoma cells harboring E-cadherin promoter-luciferase reporter vectors. NIMA-related kinase-4 (NEK4) was identified and characterized as a positive regulator of EMT in the screening. Suppression of NEK4 resulted in the inhibition of cell migration and invasion, accompanying with an increased expression of cell adhesion-related proteins such as E-cadherin and ZO1. Furthermore, NEK4 knockdown caused the decreased expression of the transcriptional factor Zeb1 and Smads proteins, which are known to play key roles in EMT regulation. Consistently, overexpression of NEK4 resulted in the decreased expression of E-cadherin and increased expression of Smad3. Using a mouse model with tail vein injection of NEK4 knockdown stable cell line, we found a lower rate of tumor formation and metastasis of the NEK4-knockdown cells in vivo. Thus, this study demonstrates NEK4 as a novel kinase involved in regulation of EMT and suggests that NEK4 may be further explored as a potential therapeutic target for lung cancer metastasis.

A Network Pharmacology-Based Analysis of Multi-Target, Multi-Pathway, Multi-Compound Treatment for Ovarian Serous Cystadenocarcinoma.

BACKGROUND AND OBJECTIVES: Pharmacological control against ovarian serous cystadenocarcinoma has received increasing attention. The purpose of this study was to investigate multi-drug treatments as synergetic therapy for ovarian serous cystadenocarcinoma and to explore their mechanisms of action by the network pharmacology method. METHODS: Genes acting on ovarian serous cystadenocarcinoma were first collected from GEPIA and DisGeNET. Gene Ontology annotation, Kyoto Encyclopedia of Genes and Genomes pathway, Reactome pathway, and Disease Ontology analyses were then conducted. A connectivity map analysis was employed to identify compounds as treatment options for ovarian serous cystadenocarcinoma. Targets of these compounds were obtained from the Search Tool for Interacting Chemicals (STITCH). The intersections between the ovarian serous cystadenocarcinoma-related genes and the compound targets were identified. Finally, the Kyoto Encyclopedia of Genes and Genomes and Reactome pathways in which the overlapped genes participated were selected, and a correspondence compound-target pathway network was constructed. RESULTS: A total of 541 ovarian serous cystadenocarcinoma-related genes were identified. The functional enrichment and pathway analyses indicated that these genes were associated with critical tumor-related pathways. Based on the connectivity map analysis, five compounds (resveratrol, MG-132, puromycin, 15-delta prostaglandin J2, and valproic acid) were determined as treatment agents for ovarian serous cystadenocarcinoma. Next, 48 targets of the five compounds were collected. Following mapping of the 48 targets to the 541 ovarian serous cystadenocarcinoma-related genes, we identified six targets (PTGS1, FOS, HMOX1, CASP9, PPARG, and ABCB1) as therapeutic targets for ovarian serous cystadenocarcinoma by the five compounds. By analysis of the compound-target pathway network, we found the synergistic anti-ovarian serous cystadenocarcinoma potential and the underlying mechanisms of action of the five compounds. CONCLUSION: In summary, latent drugs against ovarian serous cystadenocarcinoma were acquired and their target actions and pathways were determined by the network pharmacology strategy, which provides a new prospect for medicamentous therapy for ovarian serous cystadenocarcinoma. However, further in-depth studies are indispensable to increase the validity of this study.