[Risk prediction model of hepatitis B associated hepatocellular carcinoma].

Hepatocellular carcinoma is one of the most common malignant tumors in the world, which is a serious threat to human health. HBV infection is one of the most common causes of hepatocellular carcinoma.The diagnosis of most hepatocellular carcinoma has progressed to the middle and late stage, and the prognosis is poor. Early detection, diagnosis and treatment are important supports to improve the clinical outcome of hepatocellular carcinoma. In recent years, scholars at home and abroad have established various hepatocellular carcinoma risk prediction models, which are conducive to improving the early diagnosis rate of hepatocellular carcinoma and reducing the mortality rate. This article reviews the risk factors and risk prediction models of chronic hepatitis B associated hepatocellular carcinoma, in order to provide reference for HBV-associated liver cancer risk monitoring and management decision.

Development and validation of a nomogram model for predicting distant metastasis of aged ≥50 patients with thyroid carcinoma: a SEER database analysis.

OBJECTIVE: This work aimed to construct and validate a model for predicting distant metastasis (DM) in thyroid carcinoma (TC) patients aged≥50. PATIENTS AND METHODS: The research data were collected from the Surveillance, Epidemiology, and End Results (SEER) program databases via SEER*Stat software (https://seer.cancer.gov/). Logistics regression was used to screen the independent risk factors for TC patients. The nomogram was constructed and validated based on the logistics regression results for predicting DM occurrence in TC patients. Moreover, the characteristic curves (ROC) were used to assess the predictive performance. The decision analysis curve (DCA) and the calibration curve were used to test this nomogram's accuracy and discrimination. Additionally, we analyzed survival and risk scores in TC patients with metastasis using the Kaplan-Meier (KM) method. RESULTS: A total of 11,166 TC patients were divided into a training set and a validation set. The results showed that topography (T), lymph node metastasis (N), and (grade) G were crucial risk factors for predicting DM. ROC analysis showed that the model had a good discriminative ability both in the training and validation set. The DCA curve showed greater net benefits across a range of DM risks for the nomogram in the training and validation set. Survival analyses showed that the metastasis cases with low-risk scores have shown a poorer prognosis in this study, both in the training and validation set. CONCLUSIONS: The nomogram model had excellent predictive performance and net benefit for predicting DM of TC patients aged ≥50. The model can help doctors develop treatment plans for their patients.

[Histiocyte-rich rhabdomyoblastic tumor: a clinicopathological and molecular genetic analysis].

Objective: To investigate the clinicopathologic and molecular genetic characteristics, diagnosis, differential diagnosis, treatment and prognosis of histiocyte-rich rhabdomyoblastic tumor (HRRMT). Methods: The clinical data of two cases of HRRMT diagnosed in Fujian Provincial Hospital and Fujian University of Traditional Chinese Medicine Affiliated People's Hospital from 2020 to 2021 were collected. Histopathology and immunohistochemical (IHC) staining were used to assess morphological changes; the genetic changes were analyzed with next-generation sequencing. The relevant literature was reviewed. Results: Both cases showed well-defined solid nodules and soft masses. Microscopically, the tumors had a fibrous pseudocapsule with lymphocytic aggregation, and locally invaded the surrounding skeletal muscle tissue, and the tumor cells were fusiform to epithelioid with an intensive foamy histiocytic infiltrate. No necrosis or mitosis was observed. Immunophenotyping showed the tumor cells were positive for desmin, either one or both skeletal muscle markers (myogenin or MyoD1), and negative for h-caldesmon, ALK and SMA. The Ki-67 index was<5%. Using next-generation sequencing, one case was found to harbour KRAS (G12D) and MSH3 (Q470*) mutations. Conclusions: HRRMT is a newly described skeletal muscle tumor with uncertain malignant potential. Its diagnosis and differential diagnosis depend on morphologic and IHC staining. No specific molecular genetics changes have been identified so far.

Genes and pathways identified in thyroid carcinoma based on bioinformatics analysis.

The objective of this study was to investigate the key genes and pathways associated with thyroid carcinoma. Based on the microarray data of GSE27155, we identified the differentially expressed genes (DEGs) between four types of thyroid carcinoma samples (papillary carcinoma (PTC), oncocytic carcinoma (OTC), follicular carcinoma (FTC) and anaplastic carcinoma (ATC)) and normal controls. With the obtained DEGs, we performed gene functional interaction (FI) network analysis. Then we conducted Venn diagram analysis to identify the intersection and specific DEGs of the four types of thyroid carcinomas. The intersections DEGs were performed by functional enrichment and transcription factor (TF) prediction analyses. These specific DEGs were performed by pathway enrichment analysis. There were respectively 323, 318, 118 and 1005 DEGs identified in PTC, OTC, FTC and ATC. Twelve sub-network modules were extracted based on gene FI network analysis and eight thyroid carcinoma-associated DEGs were involved in the network, such as TIMP1. Based on the Venn diagram analysis, 27 common DEGs were identified, such as HMGB3 which was regulated by TF of NKX3-1. There were 149 PTC-specific DEGs (like CLDN1), 160 OTC-specific DEGs, 94 FTC-specific DEGs (like PPARG), and 789 ATC-specific DEGs (like CDK1). They were enriched in some pathways, such as Cell cycle, Citrate cycle, and Oxidative phosphorylation. TIMP1, HMGB3, CLDN1, CDK1 and PPARG as well as pathways of Cell cycle, Citrate cycle, and Oxidative phosphorylation may play important roles in the progression of thyroid carcinoma.

Role of inflammatory parameters in the susceptibility of cerebral thrombosis.

We aimed to investigate the association of inflammation-related genes such as IL-10, IL-6 and IL-1B with risk of ischemic stroke. We included 426 cases with ischemic stroke and 426 health controls from Xinxiang, China. Genomic DNA was extracted from the buffy coat layer of collected blood with the TIANamp blood DNA kit. Diabetes, hypertension, obesity, and smoking habits were associated with risk of ischemic stroke. We found that individuals carrying the CC genotype of IL-1B rs1864169 had a higher risk of ischemic stroke when compared with the TT genotype (OR = 1.80, 95%CI = 1.16-2.80). The IL-6 rs1800796 TT genotype was associated with increased risk of ischemic stroke. We found that IL-1B rs1864169 and IL-6 rs1800796 polymorphisms may interact with diabetes, hypertension and obesity. Our study suggests that IL-6 rs1800796 and IL-1B rs1864169 polymorphisms are associated with ischemic stroke risk in the Chinese population.

Reversal of multidrug resistance in human breast cancer cells by Curcuma wenyujin and Chrysanthemum indicum.

The emergence of multidrug resistance (MDR) is a big challenge to cancer chemotherapy. Plant-derived agents have great potential to prevent onset or delay progression of the carcinogenic process, and enhance the efficacy of mainstream antitumor agents. In this study, fractionated extracts of Curcuma wenyujin and Chrysanthemum indicum were tested for their potential to modulate the MDR phenotype and function of P-gp in MCF-7/ADR and A549/Taxol cells in vitro. Fractions C. wenyujin C10, E10 from Curcuma wenyujin, and C. indicum E10 from Chrysanthemum indicum, exhibited significant effects in sensitization of these resistant cancer cells at non-toxic concentration to doxorubicin and docetaxel by MTT method. They also increased the intracellular doxorubicin accumulation and retention in MCF-7/ADR cells. In mechanism study, an increase of Rh123 accumulation and a decrease of Rh123 efflux were observed in MCF-7/ADR cells treated with these fractions, indicating a blockage of the activity of P-gp. Furthermore, C. wenyujin C10 had the ability to down-regulate the expression of P-gp. All these fractions could enhance the apoptosis induced by doxorubicin in MCF-7/ADR cells, and restore the effect of docetaxel on the induction of G2/M arrest in A549/Taxol cells. C. wenyujin C10 and E10 also owned the ability to induce S phase arrest. These results showed the therapeutic value of the three fractions as potential MDR-reversing agents and warranted further investigations.

Potential antidepressant properties of Radix Polygalae (Yuan Zhi).

Radix Polygalae ("Yuan Zhi", the roots of Polygala tenuifolia Willd., YZ) is an important herb used in traditional Chinese medicine to mediate depression. The present study was designed to verify the antidepressant effects of the standardized YZ ethanol extract (YZE) and its four fractions YZ-30, YZ-50, YZ-70 and YZ-90 on the tail suspension (TST) and forced swimming test (FST). Furthermore, the standardization of the fractions obtained from the separation procedures was carried out by high-performance liquid chromatography (HPLC)-fingerprint. The YZ-50 fraction (Oligosaccharide esters--enriched, oral (200 mg/kg) showed a significant anti-immobility like effects. The data of YZ-50 on the corticosterone-induced injure of SH-SY5Y human neuroblastoma cell indicated that YZ-50 may have biological effects on neuroprotection. Proliferation of cell lines was assessed by dimethylthiazoldiphenyltetrazoliumbromide (MTT) and 5-bromo-2'-deoxyuridine (BrdU) incorporation assays. It was found that YZ-50 and its two bioactive compounds, 3,6'-di-o-sinapoyl-sucrose (DISS) and tenuifoliside A(TEA) showed protection activities in SY5Y cells from the lesion. By using bioassay-screening methods, our results indicate that the presence of oligosaccharide esters such as DISS and TEA in this herb may be responsible for the cytoprotective activity effects.

Phenolic glycosides from leaves of Hopiciopsis lobata.

A new phenolic glycoside, 6'-[(E)-2''-hydroxymethyl, 2''-butenoyl] arbutin (1), and two known phenolic glycosides, 6'-[(E)-4''-hydroxycinnamoyl] arbutin (2) and 6'-[(E)-3'',4''-dihydroxycinnamoyl] arbutin (3), were isolated from the leaves of Heliciopsis lobata (Merr.) Sleum. Their structures were elucidated by various spectroscopic methods including 2D NMR spectroscopy.

Induction of unspliced c-fos messenger RNA in rodent brain by kainic acid and lipopolysaccharide.

The c-fos transcriptional factor forms an activator protein-1 (AP-1) complex with proteins from the Jun family, which plays an important role in the central nervous system. The responses of AP-1 transcriptional factors induced by kainic acid (KA) treatment have been well studied, although the transcriptional regulation of these KA-induced factors has not been clearly characterized. To investigate the role of different stimuli in controlling of the splicing of c-fos mRNA, we performed reverse transcriptional polymerase chain reaction. The results showed that spliced and unspliced c-fos is present in rat brain following KA treatment and in lipopolysaccharide (LPS)-treated primary mouse cortical brain cell cultures. Furthermore, tyrosine kinase and protein phosphatase inhibitors alter the preponderance of c-fos transcripts following LPS treatment.

Frequency and molecular analysis of hprt mutations induced by estradiol in Chinese hamster V79 cells.

The natural hormone estradiol (E2) induces tumors in rodents and various types of DNA damage in vitro and in vivo, but has not been mutagenic in bacterial or mammalian assays. Recent reports of chromosomal and genetic lesions induced by E2 has led us to re-examine the mutation frequency and molecular alterations of the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene in Chinese hamster V79 cells. E2 at both physiological and pharmacological concentrations (10-11, 10-10, and 10-7, 10-6 M) significantly increased the mutation frequency of the hprt gene by 2. 57-, 3.45-, 2.63-, and 8.78-fold, respectively, compared to the controls, while 10-13, 10-12, 10-9, or 10-8 M E2 induced little change (< or =0.93-fold). PCR and a molecular analysis of the hprt coding sequence identified genetic lesions in the cDNA and/or genomic DNA in 15 of the 21 picked E2-induced mutants (71%). Simple base substitutions, such as Tright curved arrow G or Tright curved arrow A transversions, were the most common mutations (8/21 or 38%) and frequently occurred at 122 bp or 407 bp of the hprt coding sequence. Deletion mutations were detected in 6 of the 21 clones (29%). An Aright curved arrow G and a Cright curved arrow T transition and a four-base insertion (TATT) were identified each in one mutant clone. A RT-PCR analysis demonstrated an abundant expression of the estrogen receptor-alpha (ERalpha). However, ICI 182,780, an antagonist of ERalpha, acted in an additive manner with E2 and increased the hprt mutation frequency. In conclusion, E2 induces a low frequency of mutations (deletions and point mutations) in V79 cells, which is consistent with the weak carcinogenic activity of this hormone. The mutagenic effects of E2 in V79 cells are not mediated by the ERalpha.

Reduction by naloxone of lipopolysaccharide-induced neurotoxicity in mouse cortical neuron-glia co-cultures.

An inflammatory response in the CNS mediated by activation of microglia is a key event in the early stages of the development of neurodegenerative diseases. Using mouse cortical mixed glia cultures, we have previously demonstrated that the bacterial endotoxin lipopolysaccharide induces the activation of microglia and the production of proinflammatory factors. Naloxone, an opioid receptor antagonist, inhibits the lipopolysaccharide-induced activation of microglia and the production of proinflammatory factors. Using neuron-glia co-cultures, we extended our study to determine if naloxone has a neuroprotective effect against lipopolysaccharide-induced neuronal damage and analysed the underlying mechanism of action for its potential neuroprotective effect. Pretreatment of cultures with naloxone (1 microM) followed by treatment with lipopolysaccharide significantly inhibited the lipopolysaccharide-induced production of nitric oxide and the release of tumor necrosis factor-alpha, and significantly reduced the lipopolysaccharide-induced damage to neurons. More importantly, both naloxone and its opioid-receptor ineffective enantiomer (+)-naloxone were equally effective in inhibiting the lipopolysaccharide-induced generation of proinflammatory factors and the activation of microglia, as well as in the protection of neurons. These results indicate that the neuroprotective effect of naloxone is mediated by its inhibition of microglial activity and may be unrelated to its binding to the classical opioid receptors.

Lack of mutations in DNA polymerase beta of estradiol-induced hamster kidney tumors: sequence of hamster DNA polymerase beta cDNA.

We examined the effects of estradiol (E2), the natural estrogenic hormone, on the structure and expression of DNA polymerase beta (DNA pol beta), a DNA repair gene, from E2-induced primary kidney tumors of twelve Syrian hamsters, their metastases, and from kidney tissues surrounding the tumors. We sequenced the coding region of the hamster DNA pol beta and found it to differ from that of the human by 11%. No mutations were detected in the entire coding region including the catalytic domain of the DNA pol beta from E2-induced primary kidney tumors, their metastases, or from kidney tissues surrounding the tumors. The expression of the DNA pol beta mRNA was also not significantly altered in E2-induced kidney tumors or in kidney tissues surrounding the tumors compared to that of control kidney tissues. These results suggest that mutations in the DNA pol beta gene may not be involved in the induction or malignant progression of hamster kidney tumors induced by E2. The nucleotide sequence of the hamster DNA pol beta described here will be useful for the study of the structure and expression of this gene.

Reduction of lipopolysaccharide-induced neurotoxicity in mixed cortical neuron/glia cultures by femtomolar concentrations of pituitary adenylate cyclase-activating polypeptide.

Stimulation of murine primary mixed cortical neuron/glia cultures with lipopolysaccharide, an endotoxin, was used as a model for inflammatory disorders of the central nervous system. Lipopolysaccharide (20 microg/ml) increased the secretion of lactate dehydrogenase, a marker for cell injury, and nitric oxide into the culture medium. The lipopolysaccharide-induced release of lactate dehydrogenase into the culture medium was reduced by pituitary adenylate cyclase-activating polypeptide (PACAP) at 10(-14)-10(-12) M. The 27- and 38-amino-acid forms of PACAP were equipotent and their dose-response curves were U-shaped. PACAP6-38, a specific type I PACAP receptor antagonist, blocked the reduction by PACAP38 of the lipopolysaccharide-induced release of lactate dehydrogenase. The lipopolysaccharide-induced secretion of nitric oxide into the culture medium was reduced by PACAP at 10(-14)-10(-12) M and 10(-8)-10(-6) M. The 27- and 38-amino-acid forms of PACAP were equipotent. PACAP6-38 blocked the reduction of the lipopolysaccharide-induced secretion of nitric oxide by PACAP38 at 10(-12) M, but not at 10(-8) M. Vasoactive intestinal polypeptide reduced the lipopolysaccharide-induced release of lactate dehydrogenase into the culture medium at 10(-14)-10(-12) M, but these concentrations of vasoactive intestinal polypeptide had no effect on the lipopolysaccharide-induced secretion of nitric oxide. PACAP6-38 did not effect the reduction of the lipopolysaccharide-induced release of lactate dehydrogenase into the culture medium by 10(-12) M vasoactive intestinal polypeptide. These results indicate that stimulation of type I PACAP receptors by femtomolar concentrations of PACAP can prevent neuron death in a model for inflammatory disorders of the CNS. These results suggest that PACAP is also an extraordinarily potent inhibitor of some microglial functions.

Synergistic neurotoxic effects of combined treatments with cytokines in murine primary mixed neuron/glia cultures.

Activation of brain glial cells with the bacterial endotoxin lipopolysaccharide (LPS), the HIV-1 coat protein gp120, or beta-amyloid-derived peptides, stimulates the expression of several cytokines, including tumor necrosis factor-alpha (TNFalpha), interleukin-1 (IL-1) and IL-6. and nitric oxide (NO) which have been proposed as causes of neurodegeneration in the brain. In the present study, the neurotoxic effects of several cytokines, alone or in various combinations, and the correlations of the release of lactate dehydrogenase, the loss of neurons, and the secretion of NO in brain neuronal cell injury were investigated in murine primary mixed neuronal/glial cell cultures. A specific combination of cytokines, i.e., IL-1 (1 ng/ml)+ TNFalpha (10 ng/ml)/interferon-gamma (IFNgamma) (200 u/ml), induced a dramatic neuronal cell injury in the neuron/glia cultures, and its cytotoxic profile was very similar to that seen with the LPS/IFNgamma-induced neuron injury. This indicates that among the many toxic immune mediators secreted in response to LPS, IL-1 and TNFalpha can mimic LPS as the triggering signals and primary mediators for glia-mediated neuron injury in the presence of IFNgamma. This study provides new insights about the cytotoxic mechanism(s) for cytokine-mediated neuron injury.

Protein tyrosine kinase inhibitors decrease lipopolysaccharide-induced proinflammatory cytokine production in mixed glia, microglia-enriched or astrocyte-enriched cultures.

Proinflammatory cytokines, tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6), produced by glial cells have been implicated in the neuropathogenesis of various diseases. However, the signal transduction pathway(s) for the production of these cytokines in glial cells are not well understood. This study examined the effects of two potent protein tyrosine kinase inhibitors, genistein and tyrphostin A25, on lipopolysaccharide (LPS)-induced production of TNF alpha, IL-1 alpha, and IL-6 in mouse primary mixed glia, microglia- or astrocyte-enriched cultures. LPS dose-dependently increased the production of TNF alpha, IL-1 alpha, and IL-6 from the mixed glia cultures. Genistein or tyrphostin A25 significantly inhibited the LPS-induced production of these cytokines. The LPS-induced TNF alpha, IL-1 alpha, and IL-6 production in microglia- or astrocyte-enriched cultures were also inhibited by tyrphostin A25. These results demonstrate that protein tyrosine kinases are involved in the signaling events of the LPS-induced production of TNF alpha, IL-1 alpha, or IL-6 in microglia or astrocytes, which may provide insights into therapeutic interventions in the pathway for cytokine production in the brain.

Inhibition of lipopolysaccharide-induced nitric oxide and cytokine production by ultralow concentrations of dynorphins in mixed glia cultures.

Dynorphins (dyn) are a major class of endogenous opioid peptides that modulate the functions of immune cells. However, the effects of dyn on the immune functions of glial cells in the central nervous system (CNS) have not been well characterized. Because nitric oxide (NO) and the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) produced by glial cells are involved in various physiopathological conditions in the CNS, this study examined the effects of dyn on the production of NO and TNF-alpha from mouse glial cells treated with lipopolysaccharide (LPS). LPS induced a concentration-dependent increase in the production of NO or TNF-alpha from the mouse primary mixed glia cultures. Ultralow concentrations (10(-16)-10(-12) M) of dynorphin (dyn) A-(1-8) significantly inhibited the LPS-induced production of NO or TNF-alpha. The inhibitory effects of dyn A-(1-8) were not blocked by nor-binaltorphimine, a selective kappa opioid receptor antagonist. U50-488H, a selective kappa opioid receptor agonist, did not affect the LPS-induced production of NO or TNF-alpha. Ultralow concentrations (10(-16)-10(-12) M) of des-[Tyr1]-dyn A-(2-17), a nonopioid analog that does not bind to kappa opioid receptors, exhibited the same inhibitory effects as dyn A-(1-17) and dyn A-(1-8). These results suggest that dyn modulate the immune functions of microglia and/or astrocytes in the brain and these modulatory effects of dyn are not mediated by classical kappa opioid receptors.

Long-term expression of the 35,000 mol. wt fos-related antigen in rat brain after kainic acid treatment.

Systemic injection of kainic acid, a rigid analogue of glutamate, induces both the short-term and the long-term expression of activator protein-1 transcription factors. The short-term responses of activator protein-1 factors such as c-fos and fos-related antigens have been well studied. However, the long-term expression of activator protein-1 factor(s) induced by kainic acid is poorly understood. The present study was designed to document the long-term expression (up to seven months) of the fos-related antigens and to map their distributions in the rat brain after systemic treatment with kainic acid. A single dose of kainic acid (8 mg/kg) was injected i.p. into Fischer 344 rats and their epileptic seizure behaviour was monitored. The rats with full limbic seizures were chosen for long-term study. By using immunocytochemistry with an antibody that cross-reacts with all known fos-related antigens, western blot analysis and a gel mobility-shift assay, we have now shown that a 35,000 mol. wt fos-related antigen was induced by kainic acid treatment and expressed at high levels for up to five months. This fos-related antigen still maintains the activator protein-1 DNA binding activity in the rat brain seven months after kainic acid treatment. The fos-related antigens and activator protein-1 binding activity were continuously expressed at high levels throughout the experimental period in the dentate granule cells where mossy fibre collateral sprouting occurred after kainic acid treatment. Our results suggested that long-term expression of fos-related antigen may reflect the pathophysiological changes after kainic acid administration.

The effects of the HIV-1 envelope protein gp120 on the production of nitric oxide and proinflammatory cytokines in mixed glial cell cultures.

Although the neurotoxicity induced by the HIV envelope protein, gp120, has been demonstrated to require the presence of glial cells (microglia/astrocytes), the mechanisms for the gp120-induced neurotoxicity are not well understood. Moreover, the neurotoxic potencies of gp120s obtained from various HIV isolates are different. Since nitric oxide (NO) and proinflammatory cytokines (TNF-alpha, IL-1, IL-6) produced by glial cells have been involved in the neuropathogenesis of various diseases, this study examined the effects of gp120 obtained from two strains, HIV-1IIIB and HIV-1SF2, of the HIV-1 virus on the production of NO, TNF-alpha, IL-1 alpha, IL-1 beta, and IL-6 in murine primary mixed glial cell cultures. The glial cells exposed to HIV-1IIIB gp120 released NO, TNF-alpha, and IL-6 in a dose-dependent manner, whereas IL-1 alpha and IL-1 beta were undetectable. The cells exposed to HIV-1SF2 gp120 increased the release of IL-6 only. The gp120-induced effects were significantly enhanced by priming glial cells with IFN-gamma. To investigate the cellular sources and mechanisms of the gp120-induced IL-6 production, in situ hybridization with mRNA for IL-6 was performed in HIV-1IIIB gp120- or HIV-1SF2 gp120-stimulated microgliaenriched or astrocyte-enriched cultures. HIV-1IIIB gp120 or HIV-1SF2 gp120 induced the expression of IL-6 mRNA in both microglia-enriched and astrocyte-enriched cultures, indicating that both microglia and astrocytes produce IL-6, and that the transcriptional regulation is involved in the gp120-induced IL-6 production. Taken together, these results demonstrate that the production of NO, TNF-alpha, IL-1, or IL-6 from glial cells is differentially regulated by HIV-1IIIB gp120 and HIV-1SF2 gp120. These results may provide insights into the roles of NO and proinflammatory cytokines in the neurotoxicity of gp120s and the neuropathology of different strains of HIV-1 viruses.