Association between geriatric nutritional risk index and depression prevalence in the elderly population in NHANES.

BACKGROUND: The prevalence of depression is increasing in the elderly population, and growing evidence suggests that malnutrition impacts mental health. Despites, research on the factors that predict depression is limited. METHODS: We included 2946 elderly individuals from National Health and Nutrition Examination Survey (NHANES) spanning the years 2011 through 2014. Depressive symptoms were assessed using the PHQ-9 scale. Multinomial logistic regression was performed to evaluate the independent association between Geriatric Nutritional Risk Index (GNRI) and depression prevalence and scores. Subgroup analysis was conducted to explore potential factors influencing the negative correlation between GNRI and depression. Restricted cubic spline graph was employed to examine the presence of a non-linear relationship between GNRI and depression. RESULTS: The depression group had a significantly lower GNRI than the non-depression group, and multivariate logistic regression showed that GNRI was a significant predictor of depression (P < 0.001). Subgroup analysis revealed that certain demographic characteristics were associated with a lower incidence of depression in individuals affected by GNRIs. These characteristics included being female (P < 0.0001), non-Hispanic black (P = 0.0003), having a moderate BMI (P = 0.0005), having a college or associates (AA) degree (P = 0.0003), being married (P = 0.0001), having a PIR between 1.50 and 3.49 (P = 0.0002), being a former smoker (P = 0.0002), and having no history of cardiovascular disease (P < 0.0001), hypertension (P < 0.0001), and diabetes (P = 0.0027). Additionally, a non-linear negative correlation (non-linear P < 0.01) was found between GNRI and depression prevalence, with a threshold identified at GNRI = 104.17814. CONCLUSION: The GNRI demonstrates efficacy as a reliable indicator for forecasting depression in the elderly population. It exhibits a negative nonlinear correlation with the prevalence of depression among geriatric individuals.

Whether weekend warriors (WWs) achieve equivalent benefits in lipid accumulation products (LAP) reduction as other leisure-time physical activity patterns? -Results from a population-based analysis of NHANES 2007-2018.

BACKGROUND: Obesity is characterized by excessive fat accumulation in the body. Physical activity (PA) is an effective intervention to combat obesity, but the effectiveness of different PA patterns on controlling obesity is unclear. Lipid accumulation product (LAP), derived from waist circumference and triglycerides, is a novel indicator for obesity evaluation. However, the association between PA patterns (i.e., weekend warriors and regularly active) and LAP remains unexplored. This study aims to elucidate the relationship between PA patterns and LAP in US adult population. METHODS: Adult individuals with complete data on LAP, PA patterns, and other covariates from the National Health and Nutrition Examination Survey (NHANES) database (2007-2018) were included in this study. Multivariate linear regression models were utilized to explore the association between PA patterns and LAP. Subgroup analyses, interaction tests, restricted cubic spline (RCS) regression analyses, and threshold and saturation effect analyses were also performed to investigate the stability and nonlinearity of PA-LAP association, respectively. RESULTS: A total of 11,212 participants were included in this study. After adjusting for all potential covariates, being regularly active (RA) (ß=-8.85, P < 0.05) obtained significantly higher LAP reduction as opposed to being weekend warriors (WWs) (ß=-4.70, P = 0.3841). Furthermore, subgroup analyses and interaction tests indicated that the PA-LAP association was more pronounced in individuals with higher education levels (P interaction = 0.0084) and diabetes (P interaction = 0.0062). Additionally, a significant, non-linear, and negative correlation between weekly total PA and LAP in non-inactive individuals was identified by RCS analysis (P for overall < 0.001, P for nonlinearity = 0.009). A threshold of 440 min in weekly total PA was found to arouse favorable LAP reduction. CONCLUSIONS: Being regularly active obtained better LAP reduction as opposed to being WWs. For non-inactive adults, engaging in more than 440 min of PA per week helps to reduce LAP effectively.

Rapid visual detection of Giardia duodenalis in faecal samples using an RPA-CRISPR/Cas12a system.

Giardiasis is a common intestinal infection caused by Giardia duodenalis, which is a major economic and health burden for humans and livestock. Currently, a convenient and effective detection method is urgently needed. CRISPR/Cas12a-based diagnostic methods have been widely used for nucleic acid-based detection of pathogens due to their high efficiency and sensitivity. In this study, a technique combining CRISPR/Cas12a and RPA was established that allows the detection of G. duodenalis in faecal samples by the naked eye with high sensitivity (10-1 copies/µL) and specificity (no cross-reactivity with nine common pathogens). In clinical evaluations, the RPA-CRISPR/Cas12a-based detection assay detected Giardia positivity in 2% (1/50) of human faecal samples and 47% (33/70) of cattle faecal samples, respectively, which was consistent with the results of nested PCR. Our study demonstrated that the RPA-CRISPR/Cas12a technique for G. duodenalis is stable, efficient, sensitive, specific and has low equipment requirements. This technique offers new opportunities for on-site detection in remote and poor areas.

Glycometabolism regulates hepatitis C virus release.

HCV cell-culture system uses hepatoma-derived cell lines for efficient virus propagation. Tumor cells cultured in glucose undergo active aerobic glycolysis, but switch to oxidative phosphorylation for energy production when cultured in galactose. Here, we investigated whether modulation of glycolysis in hepatocytes affects HCV infection. We showed HCV release, but not entry, genome replication or virion assembly, is significantly blocked when cells are cultured in galactose, leading to accumulation of intracellular infectious virions within multivesicular body (MVB). Blockade of the MVB-lysosome fusion or treatment with pro-inflammatory cytokines promotes HCV release in galactose. Furthermore, we found this glycometabolic regulation of HCV release is mediated by MAPK-p38 phosphorylation. Finally, we showed HCV cell-to-cell transmission is not affected by glycometabolism, suggesting that HCV cell-to-supernatant release and cell-to-cell transmission are two mechanistically distinct pathways. In summary, we demonstrated glycometabolism regulates the efficiency and route of HCV release. We proposed HCV may exploit the metabolic state in hepatocytes to favor its spread through the cell-to-cell transmission in vivo to evade immune response.

Long-term application of silver nanoparticles in dental restoration materials: potential toxic injury to the CNS.

Silver nanoparticles (AgNPs) have durable and remarkable antimicrobial effects on pathogenic microorganisms, such as bacteria and fungi, in dental plaques. As such, they are widely added to dental restoration materials, including composite resins, denture bases, adhesives, and implants, to solve the problems of denture stomatitis, peri-implant inflammation, and oral infection caused by the long-term use of these dental restoration materials. However, AgNPs can be absorbed into the blood circulatory system through the nasal/oral mucosa, lungs, gastrointestinal tract, skin, and other pathways and then distributed into the lungs, kidneys, liver, spleen, and testes, thereby causing toxic injury to these tissues and organs. It can even be transported across the blood-brain barrier (BBB) and continuously accumulate in brain tissues, causing injury and dysfunction of neurons and glial cells; consequently, neurotoxicity occurs. Other nanomaterials with antibacterial or remineralization properties are added to dental restoration materials with AgNPs. However, studies have yet to reveal the neurotoxicity caused by dental restoration materials containing AgNPs. In this review, we summarize the application of AgNPs in dental restoration materials, the mechanism of AgNPs in cytotoxicity and toxic injury to the BBB, and the related research on the accumulation of AgNPs to cause changes of neurotoxicity. We also discuss the mechanisms of neurotoxicity caused by AgNPs and the mode and rate of AgNPs released from dental restorative materials added with AgNPs to evaluate the probability of neurotoxic injury to the central nervous system (CNS), and then provide a theoretical basis for developing new composite dental restoration materials. Mechanism of neurotoxicity caused by AgNPs: AgNPs in the blood circulation enter the brain tissue after being transported across the BBB through transendothelial cell pathway and paracellular transport pathway, and continuously accumulate in brain tissue, causing damage and dysfunction of neurons and glial cells which ultimately leads to neurotoxicity. The uptake of AgNPs by neurons, astrocytes and microglia causes damage to these cells. AgNPs with non-neurotoxic level often increases the secretion of a variety of cytokines, up-regulates the expression of metallothionein in glial cells, even up-regulates autophagy and inflammation response to protect neurons from the toxic damage of AgNPs. However, the protective effect of glial cells induced by AgNPs exposure to neurotoxic levels is insufficient, which leads to neuronal damage and dysfunction and even neuronal programmed cell death, eventually cause neurotoxicity.

Ubiquitin-Like protein 5 interacts with the silencing suppressor p3 of rice stripe virus and mediates its degradation through the 26S proteasome pathway.

Ubiquitin like protein 5 (UBL5) interacts with other proteins to regulate their function but differs from ubiquitin and other UBLs because it does not form covalent conjugates. Ubiquitin and most UBLs mediate the degradation of target proteins through the 26S proteasome but it is not known if UBL5 can also do that. Here we found that the UBL5s of rice and Nicotiana benthamiana interacted with rice stripe virus (RSV) p3 protein. Silencing of NbUBL5s in N. benthamiana facilitated RSV infection, while UBL5 overexpression conferred resistance to RSV in both N. benthamiana and rice. Further analysis showed that NbUBL5.1 impaired the function of p3 as a suppressor of silencing by degrading it through the 26S proteasome. NbUBL5.1 and OsUBL5 interacted with RPN10 and RPN13, the receptors of ubiquitin in the 26S proteasome. Furthermore, silencing of NbRPN10 or NbRPN13 compromised the degradation of p3 mediated by NbUBL5.1. Together, the results suggest that UBL5 mediates the degradation of RSV p3 protein through the 26S proteasome, a previously unreported plant defense strategy against RSV infection.

Activation of TLR2 heterodimers-mediated NF-κB, MAPK, AKT signaling pathways is responsible for Vibrio alginolyticus triggered inflammatory response in vitro.

Vibrio alginolyticus is an important zoonotic marine pathogenic bacterium. Previous studies on the mechanism of innate immune against V. alginolyticus infection have been limited to aquatic animals, however, how V. alginolyticus activates mammalian immune cells has not been fully clarified. Here, ELISA combined RT-qPCR assays were used to detect the secretion and transcription level of pro-inflammatory cytokines and TLRs during V. alginolyticus infection of mice peritoneal macrophages (PMϕs). Western blotting was used to explore the phosphorylation levels of p38, JNK, ERK, AKT and NF-κB protein. Immunofluorescence assay was used to determine the location of NF-κB protein. Inhibition assay was used to study the role of up-regulated TLR in activated signaling pathways and the role of these pathways in the release of pro-inflammatory cytokines. Our data showed that V. alginolyticus can up-regulate the expression levels of IL-1ß, IL-6, IL-12 and TNF-α in PMϕs. In addition, V. alginolyticus stimulation activated the phosphorylation of p38, JNK and ERK were TLR2 heterodimers-dependent, whereas inhibitors of SB203580 (p38), SCH772984 (ERK) and SP600125 (JNK) significantly reduced IL-1ß, IL-6, IL-12 and TNF-α production. We further revealed that V. alginolyticus activated the signaling pathways of AKT via TLR2 heterodimers. The inhibitor of MK-2206 2HCl (AKT) negatively regulated the IL-1ß, IL-6 and TNF-α release levels. Moreover, V. alginolyticus infection of PMϕs resulted in TLR2 heterodimers-mediated activation of NF-κB and induced translocation of phosphorylated NF-κB protein from the cytoplasm into the nucleus via IκBα degradation. V. alginolyticus induced IL-1ß, IL-6, IL-12 and TNF-α release were blocked by the specific NF-κB inhibitor, BAY 11-7082. Taken together, our results suggested that activation of the TLR2 heterodimers-mediated downstream signaling pathways NF-κB, MAPK and AKT is responsible for inflammatory response during Vibrio alginolyticus infection in vitro.

Identification of HM13 as a prognostic indicator and a predictive biomarker for immunotherapy in hepatocellular carcinoma.

BACKGROUND: Histocompatibility minor 13 (HM13) is a signal sequence stubbed intramembrane cleavage catalytic protein that is essential for cell signaling, intracellular communication, and cancer. However, the expression of HM13 and its prognostic value, association with tumor-infiltrating immune cells (TIICs) in the microenvironment, and potential to predict immunotherapeutic response in HCC are unknown. METHODS: The HM13 expression, clinicopathology analysis, and its influence on survival were analyzed in multiple public databases and further verified in collected HCC and normal tissues by qRT-PCR and immunohistochemistry staining assay (IHC). Furthermore, the lentivirus vector encoding HM13-shRNA to manipulate HM13 expression was selected to investigate whether HM13 could influence the malignant growth and metastasis potential of HCC cells. Finally, significant impacts of HM13 on the HCC tumor microenvironment (TME) and reaction to immune checkpoint inhibitors were analyzed. RESULTS: Upregulated HM13 was substantially correlated with poor prognosis in patients with HCC, and could facilitate the proliferation and migratory potential of HCC cells. Additionally, patients with high HM13 expression might be more sensitive to immunotherapy. CONCLUSIONS: HM13 might be a prognostic biomarker and potential molecular therapeutic target for HCC.

A novel stemness-hypoxia-related signature for prognostic stratification and immunotherapy response in hepatocellular carcinoma.

BACKGROUND: The specific differentiation potential, unlimited proliferation, and self-renewal capacity of cancer stem cells (CSCs) are closely related to the occurrence, recurrence, and drug resistance of hepatocellular carcinoma (HCC), as well as hypoxia. Therefore, an in-depth analysis of the relationship between HCC stemness, oxygenation status, and the effectiveness of immunotherapy is necessary to improve the poor prognosis of HCC patients. METHODS: The weighted gene co-expression network analysis (WGCNA) was utilized to find hypoxia-related genes, and the stemness index (mRNAsi) was evaluated using the one-class logistic regression (OCLR) technique. Based on stemness-hypoxia-related genes (SHRGs), population subgroup categorization using NMF cluster analysis was carried out. The relationship between SHRGs and survival outcomes was determined using univariate Cox regression. The LASSO-Cox regression strategy was performed to investigate the quality and establish the classifier associated with prognosis. The main effect of risk scores on the tumor microenvironment (TME) and its response to immune checkpoint drugs was also examined. Finally, qRT-PCR was performed to explore the expression and prognostic value of the signature in clinical samples. RESULTS: After identifying tumor stemness- and hypoxia-related genes through a series of bioinformatics analyses, we constructed a prognostic stratification model based on these SHRGs, which can be effectively applied to the prognostic classification of HCC patients and the prediction of immune checkpoint inhibitors (ICIs) efficacy. Independent validation of the model in the ICGC cohort yielded good results. In addition, we also constructed hypoxic cell models in Herp3B and Huh7 cells to verify the expression of genes in the prognostic model and found that C7, CLEC1B, and CXCL6 were not only related to the tumor stemness but also related to hypoxia. Finally, we found that the constructed signature had a good prognostic value in the clinical sample. CONCLUSIONS: We constructed and validated a stemness-hypoxia-related prognostic signature that can be used to predict the efficacy of ICIs therapy. We also verified that C7, CLEC1B, and CXCL6 are indeed associated with stemness and hypoxia through a hypoxic cell model, which may provide new ideas for individualized immunotherapy.

Protective Activities of Scutellarin against Alcohol-Induced Acute Kidney Injury.

Acute alcohol consumption has adverse effects in the kidney, resulting in kidney damage and disease, which are typically accompanied by oxidation and inflammation. Scutellarin (SCU) is the major effective ingredient of breviscapine and its anti-inflammation and antioxidant efficacy has been previously reported. The present study revealed the protective effective of SCU as therapeutic medicine against alcohol-induced inflammation and oxidative stress, leading to acute kidney injury (AKI). The AKI model was established by giving 50 % ethanol (12 mL/kg) via lavage. Kidney tissues were collected and used for histopathology analysis, biochemical assays and qRT-PCR analysis. The therapeutic effects of SCU were evaluated by observing pathological changes from HE-stained kidney tissues. Additionally, the anti-inflammation activity of SCU was evaluated by measuring the relative mRNA expression levels of Tnf-α, Il-1ß, Il-6 and the activity of iNOS. The antioxidant capacity was assessed by measuring the lipid peroxidation marker 'MDA' and antioxidant enzymes activity of SOD, CAT and GSH-Px. The results showed that serious swelling and damage occurred in the renal tubular epithelium of alcohol intake group, accompanying with glomerular atrophy, necrosis and increase of inflammatory infiltration. SCU treatment significantly reduced the damage of diseased renal tubular epithelium and glomerular, and less inflammatory cell emerged. The inflammation cytokines expression levels were elevated and oxidative stress index decreased after alcohol intake compared to the control group. In conclusion, inflammation and oxidative stress occur in the kidney after acute and excessive alcohol intake, SCU exhibited protective roles via its anti-inflammation and antioxidant activity in AKI.

A novel tumor doubling time-related immune gene signature for prognosis prediction in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) has become a global health issue of wide concern due to its high prevalence and poor therapeutic efficacy. Both tumor doubling time (TDT) and immune status are closely related to the prognosis of HCC patients. However, the association between TDT-related genes (TDTRGs) and immune-related genes (IRGs) and the value of their combination in predicting the prognosis of HCC patients remains unclear. The current study aimed to discover reliable biomarkers for anticipating the future prognosis of HCC patients based on the relationship between TDTRGs and IRGs. METHODS: Tumor doubling time-related genes (TDTRGs) were acquired from GSE54236 by using Pearson correlation test and immune-related genes (IRGs) were available from ImmPort. Prognostic TDTRGs and IRGs in TCGA-LIHC dataset were determined to create a prognostic model by the LASSO-Cox regression and stepwise Cox regression analysis. International Cancer Genome Consortium (ICGC) and another cohort of individual clinical samples acted as external validations. Additionally, significant impacts of the signature on HCC immune microenvironment and reaction to immune checkpoint inhibitors were observed. RESULTS: Among the 68 overlapping genes identified as TDTRG and IRG, a total of 29 genes had significant prognostic relevance and were further selected by performing a LASSO-Cox regression model based on the minimum value of λ. Subsequently, a prognostic three-gene signature including HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), C-type lectin domain family 1 member B (CLEC1B), and Collectin sub-family member 12 (COLEC12) was finally identified by stepwise Cox proportional modeling. The signature exhibited superior accuracy in forecasting the survival outcomes of HCC patients in TCGA, ICGC and the independent clinical cohorts. Patients in high-risk subgroup had significantly increased levels of immune checkpoint molecules including PD-L1, CD276, CTLA4, CXCR4, IL1A, PD-L2, TGFB1, OX40 and CD137, and are therefore more sensitive to immune checkpoint inhibitors (ICIs) treatment. Finally, we first found that overexpression of CLEC1B inhibited the proliferation and migration ability of HuH7 cells. CONCLUSIONS: In summary, the prognostic signature based on TDTRGs and IRGs could effectively help clinicians classify HCC patients for prognosis prediction and individualized immunotherapies.

Establishment and validation of prognostic nomograms to predict overall survival and cancer-specific survival for patients with osteosarcoma.

This study aimed to develop and validate nomograms predicting the survival of osteosarcoma patients from the SEER database and our hospital. Data of 1,066 osteosarcoma patients from the SEER database were randomly divided into a development cohort (n=800) and validation cohort one (n=266). Another cohort of 126 patients from our hospital was utilized as validation cohort two. Univariate and multivariate Cox analyses were performed to identify the independent prognostic factors for overall survival (OS) and cancer-specific survival (CSS). Nomograms predicting the 3- and 5-year OS and CSS probability were constructed and validated. The predictive performances of the established nomograms were evaluated by the concordance index (C-index) and the calibration plot. Variables of age, surgical stage, surgery, grade, tumor site, and tumor size were identified as independent prognosticators for OS and CSS in Cox analyses. The C-indexes for OS and CSS in the development cohort were 0.818 and 0.829. Comparatively, the C-indexes for OS and CSS were 0.843 and 0.834, 0.736 and 0.782 for validation cohort one and two, respectively. Calibration plots showed excellent consistency between nomogram prediction and actual survival. Nomograms based on the SEER database are of high accuracy and can serve as a reliable tool for individualized consultation and survival prediction in osteosarcoma patients.

Prognostic value of DCTA scoring system in heart failure.

OBJECTIVE: The aim of this study was to evaluate the prognostic value of a novel scoring system, based on D­dimer, total cholesterol, high-sensitivity cardiac troponin T (hs-cTnT), and serum albumin levels, in patients with heart failure. METHODS: A total of 221 patients diagnosed with heart failure between May 2016 to January 2020 were enrolled in this retrospective study. The prognostic significance of the biomarkers D­dimer, total cholesterol, hs-cTnT, and serum albumin was determined with univariate and multivariate Cox proportional hazard models. A novel prognostic score based on these predictors was established. The Kaplan-Meier method and log-rank test were used to compare the adverse outcomes of patients in different risk groups. RESULT: Results from univariate and multivariate analyses showed that high D­dimer, low serum albumin, high hs-cTnT, and low total cholesterol levels were independent prognostic factors for adverse outcomes (D-dimer >0.63 mg/l, HR = 1.84, 95% CI = 1.16-2.94, p = 0.010; serum albumin >34 g/l, HR = 0.67, 95% CI = 0.45-0.99, p = 0.046; hs-cTnT >24.06 pg/ml, HR = 1.65, 95% CI = 1.08-2.53, p = 0.020; total cholesterol >3.68 mmol/l, HR = 0.63, 95% CI = 0.43-0.92, p = 0.017). Moreover, all the patients were stratified into low-risk or high-risk group according to a scoring system based on these four markers. Kaplan-Meier analyses demonstrated that patients in the high-risk group were more prone to having adverse outcomes compared with patients in the low-risk group. CONCLUSION: D­dimer, total cholesterol, hs-cTnT, and serum albumin levels were independent prognostic factors in the setting of heart failure. A novel and comprehensive scoring system based on these biomarkers is an easily available and effective tool for predicting the adverse outcomes of patients with heart failure.

NLRP3 inflammasome signal pathway involves in Vibrio harveyi-induced inflammatory response in murine peritoneal macrophages in vitro.

Vibrio harveyi, an important zoonotic pathogen, can infect wounds and cause inflammatory response. Understanding the inflammatory response pathways could facilitate the exploration of molecular mechanisms for treating V. harveyi infection. NLR family pyrin domain-containing 3 (NLRP3) inflammasome is involved in the interaction between hosts and pathogenic microorganisms and could be sensed by various pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). Nonetheless, the function of NLRP3 inflammasome in V. harveyi infection remains unclear. In the present study, we established a V. harveyi infection model using murine peritoneal macrophages (PMs). Various techniques, including western blot analysis, enzyme-linked immunosorbent assay (ELISA), RT-qPCR, immunofluorescence, and inhibition assays, were used to explore the molecular mechanism of V. harveyi-induced inflammation. The results showed that many inflammatory cytokines participated in V. harveyi infection, with interleukin (IL)-1ß being the most abundant. Pan-caspase inhibitor pretreatment significantly decreased the secretion of IL-1ß in murine PMs. Moreover, the identification of V. harveyi involved a large number of NLR molecules, especially the NLRP3 receptor, and further studies revealed that NLPR3 inflammasome was activated by V. harveyi infection, as evidenced by puncta-like NLRP3 surrounding cell nuclear, ASC specks in the nucleus and cytoplasm, and ASC oligomerization. Inhibition of NLRP3 inflammasome impaired the release of mature IL-1ß in V. harveyi-infected murine PMs. Furthermore, blocking the secretion of mature IL-1ß could markedly decrease the release of other proinflammatory cytokines, including IL-6, IL-12, and tumor necrosis factor-α. Overall, these data indicated that NLRP3 inflammasome was activated in response to V. harveyi infection and enhanced inflammatory response by promoting IL-1ß secretion in murine PMs.

Apatinib as targeted therapy for advanced bone and soft tissue sarcoma: a dilemma of reversing multidrug resistance while suffering drug resistance itself.

Bone and soft tissue sarcomas are rare malignant tumors originated from mesenchymal tissues. They harbor more than 50 distinct subtypes and differ in pathological features and clinical courses. Despite the significant improvements in modern multi-modality treatment, the outcomes and overall survival rates remain poor for patients with advanced, refractory, metastatic, or relapsed diseases. The growth and metastasis of bone and soft tissue sarcoma largely depend on angiogenesis, and VEGF/VEGFR pathway is considered as the most prominent player in angiogenesis. Therefore, blockade of VEGF/VEGFR pathways is a promising therapeutic strategy to retard neovascularization. Several VEGFR inhibitors have been developed and revealed their favorable anti-neoplastic effects in various cancers, but such desirable anti-tumor effects are not obtained in advanced sarcomas because of multiple reasons, such as drug tolerance, short duration of response, and severe adverse effects. Fortunately, preclinical and clinical studies have indicated that apatinib is a novel promising VEGFR2 inhibitor showing potent anti-angiogenic and anti-neoplastic activities in advanced sarcomas. Especially, apatinib has showed notable characteristics in multidrug resistance reversal, tumor regression, vascular normalization, immunosuppression alleviation, and enhancement of chemotherapeutic and radiotherapeutic effects. However, apatinib also gets struck in dilemma of reversing multidrug resistance of chemotherapeutic agents while suffering drug resistance itself, and several difficulties should be tackled before full use of apatinib. In this review, we discuss the outstanding characteristics and main predicaments of apatinib as targeted therapy in advanced sarcomas. Bone and soft tissue sarcomas are rare but malignant tumors originated from mesenchymal tissues. They harbor more than 100 distinct subtypes and differ in features of pathologies and clinical courses. Despite the significant improvements in modern multi-modality treatment, the outcomes and overall survival rates remain poor for patients with advanced, refractory, metastatic, or relapsed lesions. The growth and metastasis of bone and soft tissue sarcoma largely depend on angiogenesis and VEGF/VEGFR pathways play a pivotal role in angiogenesis. Therefore, blockade of VEGF/VEGFR pathways is a promising therapeutic strategy. Several VEGFR inhibitors have been developed and verified in clinical trials but with unfavorable outcomes. Fortunately, preclinical studies and clinical trials have indicated that apatinib is a novel promising VEGFR2 inhibitor showing potent anti-angiogenic and anti-neoplastic activities in advanced sarcomas. Actually, apatinib has showed notable characteristics in multidrug resistance reversal, tumor regression, vascular normalization, immunosuppression alleviation, enhancement of chemotherapeutic and radiotherapeutic effects. However, apatinib also gets struck in dilemma of reversing multidrug resistance of chemotherapeutic agents while suffering drug resistance itself, and several difficulties should be tackled before full use of apatinib. In this review, we discuss the outstanding characteristics and main predicaments of apatinib as targeted therapy in advanced sarcomas.

Horizontal Transfer of a Retrotransposon from the Rice Planthopper to the Genome of an Insect DNA Virus.

Horizontal transfer of genetic materials between virus and host has been frequently identified. Three rice planthoppers, Laodelphax striatellus, Nilaparvata lugens, and Sogatella furcifera, are agriculturally important insects because they are destructive rice pests and also the vector of a number of phytopathogenic viruses. In this study, we discovered that a small region (∼300 nucleotides [nt]) of the genome of invertebrate iridescent virus 6 (IIV-6; genus Iridovirus, family Iridoviridae), a giant DNA virus that infects invertebrates but is not known to infect planthoppers, is highly homologous to the sequences present in high copy numbers in these three planthopper genomes. These sequences are related to the short interspersed nuclear elements (SINEs), a class of non-long terminal repeat (LTR) retrotransposons (retroposons), suggesting a horizontal transfer event of a transposable element from the rice planthopper genome to the IIV-6 genome. In addition, a number of planthopper transcripts mapped to these rice planthopper SINE-like sequences (RPSlSs) were identified and appear to be transcriptionally regulated along the different developmental stages of planthoppers. Small RNAs derived from these RPSlSs are predominantly 26 to 28 nt long, which is a typical characteristic of PIWI-interacting RNAs. Phylogenetic analysis suggests that IIV-6 acquires a SINE-like retrotransposon from S. furcifera after the evolutionary divergence of the three rice planthoppers. This study provides further examples of the horizontal transfer of an insect transposon to virus and suggests the association of rice planthoppers with iridoviruses in the past or present.IMPORTANCE This study provides an example of the horizontal transfer event from a rice planthopper genome to an IIV-6 genome. A small region of the IIV-6 genome (∼300 nt) is highly homologous to the sequences presented in high copy numbers of three rice planthopper genomes that are related to the SINEs, a class of retroposons. The expression of these planthopper SINE-like sequences was confirmed, and corresponding Piwi-interacting RNA-like small RNAs were identified and comprehensively characterized. Phylogenetic analysis suggests that the giant invertebrate iridovirus IIV-6 obtains this SINE-related sequence from Sogatella furcifera through a horizontal transfer event in the past. To the best of our knowledge, this is the first report of a horizontal transfer event between a planthopper and a giant DNA virus and also is the first evidence for the eukaryotic origin of genetic material in iridoviruses.

Prognostic value of pre-treatment Naples prognostic score (NPS) in patients with osteosarcoma.

BACKGROUND: This study aimed to evaluate the clinical significance of pre-treatment Naples prognostic score (NPS) in patients with osteosarcoma. METHODS: The clinical data of 133 osteosarcoma patients between January 2011 and February 2018 in our hospital was retrospectively collected and analyzed. NPS was calculated from four parameters, including serum albumin level, serum total cholesterol (TC), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR). Patients were divided into three groups (group 1-3) based on NPS. The relationships between NPS and clinical features, overall survival (OS), and progression-free survival (PFS) were analyzed. Two prediction models based on NPS and clinical parameters were developed: clinical parameters model (model A), and the combined model of NPS and clinical parameters (model B). Their predictive performances were further evaluated and compared. RESULTS: The median follow-up time of this cohort was 46.0 (range, 5-75) months, while the median OS and PFS was 40 (range, 5-75) months and 36 (range, 5-71) months, respectively. NPS was significantly correlated with gender, tumor location, Enneking stage, pathological fracture, local recurrence, and metastasis (all P < 0.05). Variables of NPS, Enneking stage, local recurrence, metastasis, and NLR were confirmed as independent prognostic factors for OS and PFS by univariate and multivariate Cox analysis. Prediction model B obtained larger AUCs for OS and PFS and showed better consistency between nomogram-predicted and actual survival than that of model A at the follow-up time of 1-, 3-, and 5-year. CONCLUSIONS: NPS was a novel, reliable, and multidimensional prognostic scoring system with favorable predictive performance for patients with osteosarcoma.

[Characterization of a novel allele of Aw33 subtype of the ABO blood group].

OBJECTIVE: To explore the molecular basis for an A subtype of the ABO blood group. METHODS: The forward and reverse typing of the ABO blood group were identified by gel card and test tube methods. The ABO gene of the patient was detected by PCR-sequence specific primer (PCR-SSP). Exons 1 to 7 of the ABO gene was amplified by PCR and sequenced. The ABO gene was also subjected to subclone sequencing for haplotype analysis. RESULTS: The patient's red cells showed weak agglutination with anti-A but non-agglutination with anti-B. The patient's serum showed 1+ agglutination with A cells and 4+ agglutination with B cells. Based on above serological characteristics, the patient was defined as Aw subtype of the ABO blood group. Sequencing analysis showed that the patient was heterozygous for c.106G>T, c.188G>A, c.189C>T, c.220C>T, c.297A>G, c.467C>T, c.543G>C, c.646T>A, c.681G>A, c.771C>T, c.829G>A, in addition with a c.261G deletion. Combined with the result of subclone sequencing, the ABO genotype of the patient was determined as ABO*AW.33. new/O.01.02, which harbored c.467C>T and c.543G>C variants compared with ABO*A1.01 and c.543G>C variant compared with ABO*A1.02. The novel allele has been submitted to GenBank with an accession number of MK302122. CONCLUSION: A novel allele of Aw33 subtype has been identified with its GTA transferase gene harboring c.467C>T and c.543G>C variants compared with A1.01.

LncHOXA10 drives liver TICs self-renewal and tumorigenesis via HOXA10 transcription activation.

BACKGROUND: Liver cancer is one of the most deadly cancers in the world. There are various cells in liver tumor bulk, including liver tumor initiating cells (TICs), which account for liver tumorigenesis, drug resistance, relapse and metastasis. The homeobox (HOX) transcription factors play critical roles in many physiological and pathological processes, while, their roles in liver TICs and liver tumorigenesis remain unknown. METHODS: An unbiased screening was performed using online-available datasets. Liver TICs were sorted by FACS using surface markers CD133, CD13 and EPCAM, or enriched by oncosphere formation assay. TIC self-renewal was examined by oncosphere formation and tumor initiation assay. Loss of function and gain of function assays were performed to examine the role of lncRNA. RNA pulldown, RNA immunoprecipitation, ChIP, Western blot and double FISH were used to explore the molecular mechanism of lncRNA. RESULTS: Here, we examined the expression pattern of HOX transcription factors, and found HOXA10 was overexpressed in liver cancer samples. Moreover, a divergent lncRNA of HOXA10 (termed lncHOXA10 hereafter) was also highly expressed in liver cancer and liver TICs. LncHOXA10 drove liver TIC self-renewal and liver tumorigenesis through HOXA10-dependent manner. LncHOXA10 interacted with SNF2L and recruited NURF chromatin remodeling complex to HOXA10 promoter, and thus initiated the transcription of HOXA10. Through HOXA10 transcriptional regulation, lncHOXA10 activated HOXA10 in liver TICs. LncHOXA10-HOXA10 signaling can be targeted to eliminate liver TICs. Altogether, lncHOXA10 drove HOXA10 expression and thus promoted liver TIC self-renewal. CONCLUSION: HOXA10 was the most highly expressed HOX transcription factor in liver cancer and liver TICs. LncHOXA10 drove the transcriptional activation of HOXA10. This work revealed the important role of HOX transcription factor in liver TIC self-renewal and added a new layer for liver TIC regulation.