MicroRNA-299-3p inhibits cell proliferation, motility, invasion and angiogenesis via VEGFA in upper tract urothelial carcinoma.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) is a rare tumor with extraordinarily different features between Eastern and Western countries. Vascular endothelial growth factor-A (VEGFA) was originally identified as a secreted signaling protein and regulator of vascular development and cancer progression. In this study, we aimed to elucidate the molecular mechanisms underlying the regulation of VEGFA by microRNA in UTUC. METHODS: VEGFA expression was evaluated by immunohistochemistry in 140 human UTUC tissue samples. Next, we assessed the regulatory relationship between VEGFA and miR-299-3p by real-time PCR, western blotting, ELISA and dual-luciferase reporter assays using two UTUC cell lines. The role of miR-299-3p/VEGFA in cell proliferation, motility, invasion, and tube formation was analyzed in vitro. RESULTS: High VEGFA expression was significantly associated with tumor stage, grade, distant metastasis and cancer-related death and correlated with poor progression-free and cancer-specific survival. VEGFA knockdown repressed proliferation, migration, invasion and angiogenesis in UTUC cell lines. miR-299-3p significantly reduced VEGFA protein expression and miR-299-3p overexpression inhibited VEGFA mRNA and protein expression by directly targeting its 3'-UTR. Functional studies indicated that VEGFA overexpression reversed the miR-299-3p-mediated suppression of tumor cell proliferation, migration, invasion and angiogenesis. In addition, miR-299-3p/VEGFA suppressed cellular functions in UTUC by modulating the expression of P18 and cyclin E2. CONCLUSIONS: Our findings suggest that miR-299-3p possibly suppresses UTUC cell proliferation, motility, invasion and angiogenesis via VEGFA. VEGFA may act as a prognostic predictor, and both VEGFA and miR-299-3p could be potential therapeutic targets for UTUC.

MOAI: a multi-outcome interaction identification approach reveals an interaction between vaspin and carcinoembryonic antigen on colorectal cancer prognosis.

Identifying and characterizing the interaction between risk factors for multiple outcomes (multi-outcome interaction) has been one of the greatest challenges faced by complex multifactorial diseases. However, the existing approaches have several limitations in identifying the multi-outcome interaction. To address this issue, we proposed a multi-outcome interaction identification approach called MOAI. MOAI was motivated by the limitations of estimating the interaction simultaneously occurring in multi-outcomes and by the success of Pareto set filter operator for identifying multi-outcome interaction. MOAI permits the identification for the interaction of multiple outcomes and is applicable in population-based study designs. Our experimental results exhibited that the existing approaches are not effectively used to identify the multi-outcome interaction, whereas MOAI obviously exhibited superior performance in identifying multi-outcome interaction. We applied MOAI to identify the interaction between risk factors for colorectal cancer (CRC) in both metastases and mortality prognostic outcomes. An interaction between vaspin and carcinoembryonic antigen (CEA) was found, and the interaction indicated that patients with CRC characterized by higher vaspin (≥30%) and CEA (≥5) levels could simultaneously increase both metastases and mortality risk. The immunostaining evidence revealed that determined multi-outcome interaction could effectively identify the difference between non-metastases/survived and metastases/deceased patients, which offers multi-prognostic outcome risk estimation for CRC. To our knowledge, this is the first report of a multi-outcome interaction associated with a complex multifactorial disease. MOAI is freely available at https://sites.google.com/view/moaitool/home.

MicroRNA-145-5p suppresses cell proliferation, migration, and invasion in upper tract urothelial carcinoma by targeting 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase.

Upper tract urothelial carcinoma (UTUC), including renal, pelvic, and ureteral carcinoma, has a high incidence rate in Taiwan, which is different from that in Western countries. Therefore, it is imperative to elucidate the mechanisms underlying UTUC growth and metastasis. To explore the function of miR-145-5p in UTUC, we transfected the BFTC909 cell line with miR-145-5p mimics and analyzed the differences in protein levels by performing two-dimensional polyacrylamide gel electrophoresis. Real-time polymerase chain reaction and Western blot analysis were used to analyze 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inositol monophosphate cyclohydrolase (ATIC) messenger RNA and protein levels. A dual-luciferase assay was performed to identify the target of miR-145-5p in ATIC. The effects of miR-145-5p and ATIC expression by cell transfection on cell proliferation, migration, and invasion were also assessed. miR-145-5p downregulated ATIC protein expression. High ATIC expression is associated with tumor stage, metastasis, recurrence, and a poor prognosis in patients with UTUC. Cell function assays revealed that ATIC knockdown inhibited the proliferation, migration, and invasive abilities of UTUC cells. In contrast, miR-145-5p affected the proliferation, migration, and invasive abilities of UTUC cells by directly targeting the 3'-untranslated regions of ATIC. Furthermore, we used RNA sequencing and Ingenuity Pathway Analysis to identify possible downstream genes regulated by ATIC and found that miR-145-5p regulated the protein levels of fibronectin 1, Slug, cyclin A2, cyclin B1, P57, and interferon-induced transmembrane 1 via ATIC. ATIC may be a valuable predictor of prognosis and a potential therapeutic target for UTUC.

The impact of COVID-19 epidemic on emergency department visits of older patients in Taiwan.

BACKGROUND: The number of emergency department (ED) visits has significantly declined since the COVID-19 pandemic. In Taiwan, an aged society, it is unknown whether older adults are accessing emergency care during the COVID-19 epidemic. Therefore, this study aimed to investigate the impact of COVID-19 on the ED visits and triage, admission, and intensive care unit (ICU) hospitalization of the geriatric population in a COVID-19-dedicated medical center throughout various periods of the epidemic. METHODS: A retrospective chart review of ED medical records from April 9 to August 31, 2021 were conducted, and demographic information was obtained from the hospital's computer database. The period was divided into pre-, early-, peak-, late-, and post-epidemic stages. For statistical analysis, one-way analysis of variance followed by multiple comparison tests (Bonferroni correction) were used. RESULTS: A statistically significant decrease in the total number of patients attending the ED was noted during the peak-, late-, and post-epidemic stages. In the post-epidemic stage, the number of older patients visiting ED was nearly to that of the pre-epidemic stage, indicating that older adults tend to seek care at the ED earlier than the general population. Throughout the entire epidemic period, there was no statistically significant reduction in the number of the triage 1& 2 patients seeking medical attention at the emergency department. In the entire duration of the epidemic, there was no observed reduction in the admission of elderly patients to our hospital or ICU through the ED. However, a statistically significant decrease was observed in the admission of the general population during the peak epidemic stage. CONCLUSIONS: During the peak of COVID-19 outbreak, the number of ED visits was significantly affected. However, it is noteworthy that as the epidemic was gradually controlled, the older patients resumed their ED visits earlier that the general population as indicated by the surge in their number. Additionally, in the patient group of triage 1& 2, which represents a true emergency, the number did not show a drastic change.

Synergistic Effects of Silicate-Platelet Supporting Ag and ZnO, Offering High Antibacterial Activity and Low Cytotoxicity.

Silver nanoparticles (AgNPs) are remarkably able to eliminate microorganisms, but induce cytotoxicity in mammalian cells, and zinc oxide nanoparticles (ZnONPs) are considered to have a wide bactericidal effect with weak cytotoxicity. In this study, both zinc oxide nanoparticles and silver nanoparticles were co-synthesized on a nano-silicate platelet (NSP) to prepare a hybrid of AgNP/ZnONP/NSP. Ultraviolet-visible spectroscopy (UV-Vis), X-ray diffraction (XRD), and transmission electron microscopy (TEM) were used to characterize the formation of nanoparticles on the NSP. Synthesized ZnONP/NSP (ZnONP on NSP) was confirmed by the absorption peaks on UV-Vis and XRD. AgNP synthesized on ZnONP/NSP was also characterized by UV-Vis, and ZnONP/NSP showed no interference with synthesis. The images of TEM demonstrated that NSP provides physical support for the growth of nanoparticles and could prevent the inherent aggregation of ZnONP. In antibacterial tests, AgNP/ZnONP/NSP exhibited more efficacy against Staphylococcus aureus (S. aureus) than ZnONP/NSP (ZnONP was synthesized on NSP) and AgNP/NSP (AgNP was synthesized on NSP). In cell culture tests, 1/10/99 (weight ratio) of AgNP/ZnONP/NSP exhibited low cytotoxicity for mammalian cells (>100 ppm). Therefore, AgNP/ZnONP/NSP, containing both AgNP and ZnONP, with both strong antibacterial qualities and low cytotoxicity, showed potentially advantageous medical utilizations due to its antibacterial properties.

Effects of Therapeutic Platelet-Rich Plasma on Overactive Bladder via Modulating Hyaluronan Synthesis in Ovariectomized Rat.

Postmenopausal women who have ovary hormone deficiency (OHD) may experience urological dysfunctions, such as overactive bladder (OAB) symptoms. This study used a female Sprague Dawley rat model that underwent bilateral ovariectomy (OVX) to simulate post-menopause in humans. The rats were treated with platelet-rich plasma (PRP) or platelet-poor plasma (PPP) after 12 months of OVX to investigate the therapeutic effects of PRP on OHD-induced OAB. The OVX-treated rats exhibited a decrease in the expression of urothelial barrier-associated proteins, altered hyaluronic acid (hyaluronan; HA) production, and exacerbated bladder pathological damage and interstitial fibrosis through NFƘB/COX-2 signaling pathways, which may contribute to OAB. In contrast, PRP instillation for four weeks regulated the inflammatory fibrotic biosynthesis, promoted cell proliferation and matrix synthesis of stroma, enhanced mucosal regeneration, and improved urothelial mucosa to alleviate OHD-induced bladder hyperactivity. PRP could release growth factors to promote angiogenic potential for bladder repair through laminin/integrin-α6 and VEGF/VEGF receptor signaling pathways in the pathogenesis of OHD-induced OAB. Furthermore, PRP enhanced the expression of HA receptors and hyaluronan synthases (HAS), reduced hyaluronidases (HYALs), modulated the fibroblast-myofibroblast transition, and increased angiogenesis and matrix synthesis via the PI3K/AKT/m-TOR pathway, resulting in bladder remodeling and regeneration.

Green extraction and purification of chondroitin sulfate from jumbo squid cartilage by a novel procedure combined with enzyme, ultrasound and hollow fiber dialysis.

Chondroitin sulfate (ChS) from marine sources is gaining attention. The purpose of this study was to extract ChS from jumbo squid cartilage (Dosidicus gigas) using ultrasound-assisted enzymatic extraction (UAEE). An ultrasound with protease assistance, including either alcalase, papain or Protin NY100 was used to extract ChS. The results showed that alcalase had the best extraction efficiency. The response surface methodology was employed to evaluate the relationship between extraction conditions and extraction yield of ChS. The ridge max analysis revealed a maximum extraction yield of 11.9 mg ml- 1 with an extraction temperature of 59.40 °C, an extraction time of 24.01 min, a pH of 8.25, and an alcalase concentration of 3.60%. Compared to ethanol precipitation, purification using a hollow fiber dialyzer (HFD) had a higher extraction yield of 62.72% and purity of 85.96%. The structure characteristics of ChS were identified using FTIR, 1 H-NMR, and 13 C-NMR to confirm that the purified ChS structure was present in the form of chondroitin-4-sulfate and chondroitin-6-sulfate. The results of this study provide a green and efficient process for extraction and purification of ChS and are essential for the use of ChS for the development and production of nutrient food products or pharmaceuticals. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-023-05701-7.

Multistability maintains redox homeostasis in human cells.

Cells metabolize nutrients through a complex metabolic and signaling network that governs redox homeostasis. At the core of this, redox regulatory network is a mutually inhibitory relationship between reduced glutathione and reactive oxygen species (ROS)-two opposing metabolites that are linked to upstream nutrient metabolic pathways (glucose, cysteine, and glutamine) and downstream feedback loops of signaling pathways (calcium and NADPH oxidase). We developed a nutrient-redox model of human cells to understand system-level properties of this network. Combining in silico modeling and ROS measurements in individual cells, we show that ROS dynamics follow a switch-like, all-or-none response upon glucose deprivation at a threshold that is approximately two orders of magnitude lower than its physiological concentration. We also confirm that this ROS switch can be irreversible and exhibits hysteresis, a hallmark of bistability. Our findings evidence that bistability modulates redox homeostasis in human cells and provide a general framework for quantitative investigations of redox regulation in humans.

Breeding for disease resistance in soybean: a global perspective.

KEY MESSAGE: This review provides a comprehensive atlas of QTLs, genes, and alleles conferring resistance to 28 important diseases in all major soybean production regions in the world. Breeding disease-resistant soybean [Glycine max (L.) Merr.] varieties is a common goal for soybean breeding programs to ensure the sustainability and growth of soybean production worldwide. However, due to global climate change, soybean breeders are facing strong challenges to defeat diseases. Marker-assisted selection and genomic selection have been demonstrated to be successful methods in quickly integrating vertical resistance or horizontal resistance into improved soybean varieties, where vertical resistance refers to R genes and major effect QTLs, and horizontal resistance is a combination of major and minor effect genes or QTLs. This review summarized more than 800 resistant loci/alleles and their tightly linked markers for 28 soybean diseases worldwide, caused by nematodes, oomycetes, fungi, bacteria, and viruses. The major breakthroughs in the discovery of disease resistance gene atlas of soybean were also emphasized which include: (1) identification and characterization of vertical resistance genes reside rhg1 and Rhg4 for soybean cyst nematode, and exploration of the underlying regulation mechanisms through copy number variation and (2) map-based cloning and characterization of Rps11 conferring resistance to 80% isolates of Phytophthora sojae across the USA. In this review, we also highlight the validated QTLs in overlapping genomic regions from at least two studies and applied a consistent naming nomenclature for these QTLs. Our review provides a comprehensive summary of important resistant genes/QTLs and can be used as a toolbox for soybean improvement. Finally, the summarized genetic knowledge sheds light on future directions of accelerated soybean breeding and translational genomics studies.

Chromosomal-level genome assembly of the semi-dwarf rice Taichung Native 1, an initiator of Green Revolution.

Here we report the 409.5 Mb chromosome-level assembly of the first bred semi-dwarf rice, the Taichung Native 1 (TN1), which served as the template for the development of the Green Revolution (GR) cultivar IR8 "miracle rice". We sequenced the TN1 genome utilizing multiple platforms and produced PacBio long reads, Illumina paired-end reads, Illumina mate-pair reads and 10x Genomics linked reads. We used a hybrid approach to assemble the 226× coverage of sequences by a combination of de novo and reference-guided approaches. The assembled TN1 genome has an N50 scaffold size of 33.1 Mb with the longest measuring 45.5 Mb. We annotated 37,526 genes, in which 24,102 (64.23%) were assigned Blast2GO annotations. The genome has 4672 or 95.4% complete BUSCOs and a repeat content of 51.52%. We developed our own method of creating a GR pangenome using the orthologous relationships of the proteins of TN1, IR8, MH63 and IR64, identifying 16,999 core orthologue groups of Green Revolution. From the pangenome, we identified a set of shared and unique gene ontology terms for the accessory clusters, characterizing TN1, IR8, MH63 and IR64. This TN1 genome assembly and GR pangenome will be a resource for new genomic discoveries about Green Revolution, and for improving the disease and insect resistances and the yield of rice.

Therapeutic Effect of Platelet-Rich Plasma Improves Bladder Overactivity in the Pathogenesis of Ketamine-Induced Ulcerative Cystitis in a Rat Model.

The present study attempted to elucidate whether intravesical instillation of platelet-rich plasma (PRP) could decrease bladder inflammation and ameliorate bladder hyperactivity in ketamine ulcerative cystitis (KIC) rat model. Female Sprague Dawley (S-D) rats were randomly divided into control group, ketamine-treated group, ketamine with PRP treated group, and ketamine with platelet-poor plasma (PPP) treated group. Cystometry and micturition frequency/volume studies were performed to investigate bladder function. The morphological change of bladder was investigated by Mason's trichrome staining. Western blotting analysis were carried out to examine the protein expressions of inflammation, urothelial differentiation, proliferation, urothelial barrier function, angiogenesis and neurogenesis related proteins. The results revealed that treatment with ketamine significantly deteriorated bladder capacity, decreased voiding function and enhanced bladder overactivity. These pathological damage and interstitial fibrosis may via NF-κB/COX-2 signaling pathways and muscarinic receptor overexpression. PRP treatment decreased inflammatory fibrotic biosynthesis, attenuated oxidative stress, promoted urothelial cell regeneration, and enhanced angiogenesis and neurogenesis, thereafter recovered bladder dysfunction and ameliorate the bladder hyperactivity in KIC rat model. These findings suggested that the PRP therapy may offer new treatment options for those clinical KIC patients.

Comprehensive Transcriptomic and Proteomic Analyses Identify a Candidate Gene Set in Cross-Resistance for Endocrine Therapy in Breast Cancer.

Endocrine therapy (ET) of selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs) has been used as the gold standard treatment for hormone-receptor-positive (HR+) breast cancer. Despite its clinical benefits, approximately 30% of patients develop ET resistance, which remains a major clinical challenge in patients with HR+ breast cancer. The mechanisms of ET resistance mainly focus on mutations in the ER and related pathways; however, other targets still exist from ligand-independent ER reactivation. Moreover, mutations in the ER that confer resistance to SERMs or AIs seldom appear in SERDs. To date, little research has been conducted to identify a critical target that appears in both SERMs/SERDs and AIs. In this study, we conducted comprehensive transcriptomic and proteomic analyses from two cohorts of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) to identify the critical targets for both SERMs/SERDs and AIs of ET resistance. From a treatment response cohort with treatment response for the initial ET regimen and an endocrine therapy cohort with survival outcomes, we identified candidate gene sets that appeared in both SERMs/SERDs and AIs of ET resistance. The candidate gene sets successfully differentiated progress/resistant groups (PD) from complete response groups (CR) and were significantly correlated with survival outcomes in both cohorts. In summary, this study provides valuable clinical implications for the critical roles played by candidate gene sets in the diagnosis, mechanism, and therapeutic strategy for both SERMs/SERDs and AIs of ET resistance for the future.

MicroRNA-145 suppresses cell migration and invasion in upper tract urothelial carcinoma by targeting ARF6.

ADP-ribosylation factor 6 (ARF6) is a well-studied protein that is involved in multiple biological functions including cell migration and invasion. The mechanism by which ARF6 regulates the migration and invasion of upper tract urothelial carcinoma (UTUC) is still unknown. MiR-145-5p is a tumor suppressor microRNA, which is downregulated in several cancer types. We aimed to elucidate the molecular mechanism underlying the regulation of ARF6 by miR-145-5p in UTUC. ARF6 expression was observed to be higher in UTUC tissues than paired adjacent normal tissues. A reverse correlation between ARF6 and miR-145-5p was found in UTUC tissues. MiR-145-5p inhibited ARF6 expression by directly targeting its 3'-UTR. The functional studies indicated that ARF6 expression reversed the miR-145-5p-reduced tumor cell migration and invasion. Notably, miR-145-5p reduced MMP2, N-cadherin, FAK and MMP7, and elevated E-cadherin protein levels in vitro; however, the above effects were reversed by ARF6. Further, the expression of epithelial-to-mesenchymal transition (EMT) markers and cell invasion was suppressed by knocking down MMP7 in UTUC cells. These findings suggest that miR-145-5p may suppress UTUC cell motility and invasion by targeting ARF6/MMP7 through EMT.

High Transaldolase 1 expression predicts poor survival of patients with upper tract urothelial carcinoma.

Upper tract urothelial carcinoma (UTUC) is a rare tumor with an incidence that varies greatly between Eastern and Western countries. Transaldolase 1 (TALDO1) is a rate-limiting enzyme of the pentose phosphate pathway. In humans, aberrant TALDO1 activity has been implicated in various autoimmune diseases and malignancies; however, the function of TALDO1 in UTUC has not been previously investigated. Here we evaluated the clinical significance of TALDO1 expression in 115 paraffin-embedded tumor samples from patients with UTUC using immunohistochemistry. Our results demonstrated that there was an association between high TALDO1 expression and advanced stage (P = 0.011), tumor size (P = 0.005), tumor location (P = 0.047), distant metastases (P = 0.023), local recurrence (P = 0.002), and cancer death (P = 0.003). Using univariate and multivariate analyses, we found that chemotherapy was an independent factor for bladder recurrence-free survival. Late stage (III/IV) and high TALDO1 expression were independent prognostic factors for progression-free and cancer-specific survival. In summary, increased TALDO1 expression in UTUC was significantly correlated with late stage, tumor size, tumor location, distant metastases, local recurrence, and cancer death. Therefore, high TALDO1 expression could be a predictor of poor survival in patients with UTUC. Further studies are necessary to investigate the role of TALDO1 in UTUC development.

DNA Repair Protein Rad51 Induces Tumor Growth and Metastasis in Esophageal Squamous Cell Carcinoma via a p38/Akt-Dependent Pathway.

BACKGROUND: Rad51 is a protein which plays a vital role in DNA double-strand break repair and maintenance of telomeres. However, the underlying mechanism for its action in esophageal squamous cell carcinoma (ESCC) remains unclear. PATIENTS AND METHODS: Eighty-seven patients with ESCC were enrolled in this study. Expression of Rad51 in ESCC was determined by immunohistochemistry and correlated with clinicopathological variables by Chi square test. The role of Rad51 in patient survival was determined by Kaplan-Meier estimates. The effects of Rad51 knockdown and overexpression on esophageal cancer growth, migration, and invasion were examined using TE8, CE81T, and KYSE70 cells. The mechanisms involved were also analyzed. Nude mice models were used for assessment of tumor growth. RESULTS: Rad51 staining was predominantly observed in ESCC patients. ESCC patients with high Rad51 expression had significantly decreased survival (P < 0.001) combined with increased tumor size (P = 0.034) and lymph node metastasis (P = 0.039). Rad51 overexpression promoted, while its knockdown attenuated, esophageal cancer cell viability through cell cycle entry and migration/invasion via epithelial-mesenchymal transition. Moreover, Rad51 overexpression increased colony formation in vitro and tumor growth in vivo. In addition, high Rad51 expression increased cancer progression through the p38/Akt/Snail signaling pathway. CONCLUSIONS: This study indicates a new biological role for Rad51 in ESCC progression. Rad51 may serve as a potential prognostic biomarker and therapeutic target for ESCC patients.

Association Between Emotional Disorders and Speech and Language Impairments: A National Population-Based Study.

Anxiety and depression are common emotional problems in children and adolescents. This study used a long-term tracking large database to investigate whether the proportion of children who were diagnosed with speech and language impairments were later diagnosed with anxiety or depression were significantly greater than that of matched group of the same age and gender without speech and language impairments. More than 4300 eligible children with speech and language impairments and matched controls were identified and assessed for anxiety and depression. The risk of anxiety and depressive disorders in children with speech and language impairments were examined with Cox regression analyses and adjusting for covariables (gender, age, and comorbidities). The results showed that speech and language impairments were positively associated with anxiety disorders (adjusted hazard ratio [AHR] 2.87, 95% confidence interval [CI] 2.20-3.76) and depressive disorders (AHR 2.51, 95% CI 1.52-4.13). The number of boys with speech and language impairments was more than twofold that of girls, but boys did not different from girls in the risk of anxiety disorders (AHR 0.95, 95% CI 0.75-1.20) and depressive disorders (AHR 0.72, 95% CI 0.47-1.11). Infantile autism and intellectual disabilities were positively associated with anxiety (AHR 1.54, 95% CI 1.07-2.21; AHR 1.47, 95% CI 1.09-1.98), and the latter was positively associated with depression (AHR 1.83, 95% CI 1.06-3.17). In addition to speech and language impairments interventions, our findings supported the necessity of identification and interventions in anxiety and depressive disorders among children with speech and language impairments from elementary school until youth.

New use for old drugs: The protective effect of atypical antipsychotics on hepatocellular carcinoma.

It has been encouraged to use large existing data like insurance claims data to investigate the new indications of old drugs. New strategies of research are warranted to identify feasible drugs. We conducted a dual research model with a population-based case-control study using Taiwan's National Health Insurance Research Database and an in vitro study to investigate the association between atypical antipsychotic and Hepatocellular carcinoma (HCC) risk. The study herein consists of two components. The first is a population-based case-control study using existing data from the Taiwan National Health Insurance Research Database. The second component was an in vitro study in which HCC cell lines (Huh7 and Hep G2) were treated with risperidone, quetiapine and clozapine. after treatment of the foregoing antipsychotics, the HCC cell lines were assessed for cell proliferation, invasion and apoptosis. Multivariate conditional logistic regression analysis revealed that antipsychotic use was independently and inversely associated with HCC risk (adjusted odds-ratio [aOR]:0.85, 95% CI: 0.81-0.89). The protective effect was dose-dependent: compared to the low cumulative defined daily dose (cDDD) group (0-29 cDDD), the 30-89 cDDD and ≥90 cDDD groups were associated with significantly reduced risk for HCC (aOR: 0.56, 95% CI: 0.41-0.76; aOR: 0.37, 95% CI: 0.27-0.50, respectively). In vitro study results indicated that risperidone, quetiapine and clozapine significantly inhibited cell proliferation, invasion and induced apoptosis in human HCC cell lines. Our results herein suggested that antipsychotic use might reduce the risk of HCC and may provide evidence for new uses of old drugs.

Essential Role of Visfatin in Lipopolysaccharide and Colon Ascendens Stent Peritonitis-Induced Acute Lung Injury.

Acute lung injury (ALI) is a life-threatening syndrome characterized by acute and severe hypoxemic respiratory failure. Visfatin, which is known as an obesity-related cytokine with pro-inflammatory activities, plays a role in regulation of inflammatory cytokines. The mechanisms of ALI remain unclear in critically ill patients. Survival in ALI patients appear to be influenced by the stress generated by mechanical ventilation and by ALI-associated factors that initiate the inflammatory response. The objective for this study was to understand the mechanisms of how visfatin regulates inflammatory cytokines and promotes ALI. The expression of visfatin was evaluated in ALI patients and mouse sepsis models. Moreover, the underlying mechanisms were investigated using human bronchial epithelial cell lines, BEAS-2B and NL-20. An increase of serum visfatin was discovered in ALI patients compared to normal controls. Results from hematoxylin and eosin (H&E) and immunohistochemistry staining also showed that visfatin protein was upregulated in mouse sepsis models. Moreover, lipopolysaccharide (LPS) induced visfatin expression, activated the STAT3/NFκB pathway, and increased the expression of pro-inflammatory cytokines, including IL1-ß, IL-6, and TNF-α in human bronchial epithelial cell lines NL-20 and BEAS-2B. Co-treatment of visfatin inhibitor FK866 reversed the activation of the STAT3/NFκB pathway and the increase of pro-inflammatory cytokines induced by LPS. Our study provides new evidence for the involvement of visfatin and down-stream events in acute lung injury. Further studies are required to confirm whether the anti-visfatin approaches can improve ALI patient survival by alleviating the pro-inflammatory process.

Is asthma a protective factor for dengue fever? In vitro experiment and nationwide population-based cohort analysis.

BACKGROUND: Dengue fever (DF) is the most rapidly spreading mosquito-borne viral disease. Practical vaccines or specific therapeutics are still expected. Environmental factors and genetic factors affect the susceptibility of Dengue virus (DV) infection. Asthma is a common allergic disease, with house dust mites (HDMs) being the most important allergens. Asthmatic patients are susceptible to several microorganism infections. METHODS: A nationwide population-based cohort analysis was designed to assess whether to determine whether asthma can be a risk factor for DF. RESULTS: Unexpectedly, our data from a nationwide population-based cohort revealed asthmatic patients are at a decreased risk of DF. Compared to patients without asthma, the hazard ratio (HR) for DF in patients with asthma was 0.166 (95% CI: 0.118-0.233) after adjustment for possible confounding factors. In the age stratification, the adjusted HR for DF in young adult patients with asthma was 0.063. Dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN) of dendritic cells (DCs) is an important entry for DV. Through another in vitro experiment, we found that HDM can diminish surface expression of DC-SIGN in monocyte-derived DCs and further decrease the cellular entry of DV. CONCLUSIONS: Decreased DC-SIGN expression in DCs of allergic asthmatic patient may be one of many factors for them to be protected against DF. This could implicate the potential for DC-SIGN modulation as a candidate target for designing therapeutic strategies for DF.

Cumulative receiver operating characteristics for analyzing interaction between tissue visfatin and clinicopathologic factors in breast cancer progression.

BACKGROUND: Visfatin has been reported to be associated with breast cancer progression, but the interaction between the visfatin and clinicopathologic factors in breast cancer progression status requires further investigation. To address this problem, it is better to simultaneously consider multiple factors in sensitivity and specificity assays. METHODS: In this study, a dataset for 105 breast cancer patients (84 disease-free and 21 progressing) were chosen. Individual and cumulative receiver operating characteristics (ROC) were used to analyze the impact of each factor along with interaction effects. RESULTS: In individual ROC analysis, only 3 of 13 factors showed better performance for area under curve (AUC), i.e., AUC > 7 for hormone therapy (HT), tissue visfatin, and lymph node (LN) metastasis. Under our proposed scoring system, the cumulative ROC analysis provides higher AUC performance (0.746-0.886) than individual ROC analysis in predicting breast cancer progression. Considering the interaction between these factors, a minimum of six factors, including HT, tissue visfatin, LN metastasis, tumor stage, age, and tumor size, were identified as being highly interactive and associated with breast cancer progression, providing potential and optimal discriminators for predicting breast cancer progression. CONCLUSION: Taken together, the cumulative ROC analysis provides better prediction for breast cancer progression than individual ROC analysis.