[Clinical features and prognostic analysis of transarterial chemoembolization combined with targeted immunotherapy in the treatment of patients with hepatitis B virus-related intermediate-and advanced-stage hepatocellular carcinoma with secondary cholestasis].

Objective: To study the clinical features and prognostic impact of transarterial chemoembolization (TACE), immune checkpoint inhibitors (ICIs), and tyrosine kinase inhibitors (TKIs) combination therapy regimens in the treatment of patients with hepatitis B virus-related intermediate-and advanced-stage hepatocellular carcinoma with secondary cholestasis. Methods: Patients with HBV-related intermediate-and advanced-stage hepatocellular carcinoma (HBV) who visited the Affiliated Hospital of Xuzhou Medical University between January 1, 2020, and December 31, 2022, were enrolled. TACE+TKIs +ICIs combination therapy was used to treat all patients. The occurrence and factors influencing cholestasis, as well as the impact on prognosis after combined therapy, were analyzed. The measurement data were compared using a t-test and a non-parametric rank sum test. The count data was compared using the χ(2) test. The survival rates were compared using a log-rank test between different groups. Results: A total of 106 cases with HBV-related intermediate-and advanced-stage hepatocellular carcinoma were enrolled. The probabilities of secondary cholestasis within 3 and 6 months, 1, 2, and 3 years after TACE+ICIs+TKIs combination therapy were 9.4%, 12.3%, 14.2%, 24.5%, and 24.5%, respectively. Patients with secondary cholestasis had persistent symptoms and rapid progression. During the treatment course, the median survival time was significantly longer in patients with hepatocellular carcinoma without secondary cholestasis than that of patients with cholestasis (26.9 months vs. 13.7 months, respectively, P < 0.05). Secondary cholestasis, baseline aspartate aminotransferase, and prothrombin activity levels were independent risk factors that affected the survival and prognosis of patients treated with combination therapy. There was no statistically significant difference in the occurrence of other adverse reactions between the two groups with secondary and non-secondary cholestasis during the treatment course (47.5% vs. 43.3%, χ(2)=0.058, P = 0.810). Conclusion: TACE+ICIs+TKIs therapy combination is relatively common in the treatment of patients with HBV-related intermediate-and advanced-stage hepatocellular carcinoma with secondary cholestasis. Moreover, accelerated disease progression is an independent risk factor affecting the survival and prognosis of patients.

EB-virus latent membrane protein 1 potentiates the stemness of nasopharyngeal carcinoma via preferential activation of PI3K/AKT pathway by a positive feedback loop.

Our previous study reported that Epstein-Barr virus(EBV)-encoded latent membrane protein 1 (LMP1) could induce development of CD44(+/High) stem-like cells in nasopharyngeal carcinoma (NPC). However, the molecular mechanisms that underlie modulation of cancer stem cells (CSCs) in NPC remain unclear. Here, we show that LMP1 induced CSC-like properties through promotion of the expression of epithelial-mesenchymal transition-like cellular markers and through alterations in differentiation markers. Furthermore, LMP1 activated and triggered phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, which subsequently stimulated expression of CSC markers, development of side population and tumor sphere formation. This suggests that PI3K/AKT pathway has an important role in the induction and maintenance of CSC properties in NPC. Similarly, PI3K/AKT pathway was also activated by phosphorylase in LMP1-induced CD44(+/High) cells. In addition, LMP1 greatly increased expression of miR-21 and downregulated expression of the miR-21 target, PTEN. Overexpression of miR-21 by transfection of miR-21 mimics into LMP1-transformed cells led to phosphorylase-mediated activation of the PI3K/AKT pathway and induction of CSCs. On the contrary, phosphorylation of the PI3K/AKT pathway and the expression of CSC were reversed by an miR-21 inhibitor. The specific inhibitor (Ly294002) of PI3K/AKT pathway significantly decreased expression of miR-21 and CSC markers and upregulated the expression of PTEN, which indicates that miR-21 and PTEN are the downstream effectors of PI3K/AKT and that expression of these two effectors are related to the development of NPC CSCs. Taken together, our novel findings indicate that LMP1, PI3K/AKT, miR-21 and PTEN constitute a positive feedback loop and have a key role in LMP1-induced CSCs in NPC.

Cadmium toxicity is alleviated by AtLCD and AtDCD in Escherichia coli.

AIMS: Arabidopsis thaliana l- and d-cysteine desulfhydrases (AtLCD and AtDCD) are two important H(2) S-generating enzymes. This study determined the effects of H(2) S derived from AtLCD and AtDCD on cadmium (Cd) toxicity in Escherichia coli. METHODS AND RESULTS: AtLCD and AtDCD were cloned into pET28a vectors and transformed into wild-type E. coli strain BL21(DE3), named BL21(LCD) and BL21(DCD). In the induced BL21(LCD) and BL21(DCD) compared with wild type, significantly higher H(2) S generation rates were observed. Additionally, higher survival rates, reduced contents of malondialdehyde (MDA) and hydrogen peroxide (H(2) O(2)), decreased activities of superoxide dismutase and catalase under 220 µmol l(-1) Cd stress were noted. We obtained similar results in the wild type treated with NaHS, a H(2) S donor. The above changes were substantially counteracted by the mixture of ammonia and pyruvic acid potassium (NH(3) + C(3) H(3) KO(3)), a synthetic inhibitor of H(2) S. CONCLUSIONS: AtLCD and AtDCD catalyse the H(2) S production, generating an ameliorating effect against Cd-induced oxidative stress and resulting in E. coli resistance to Cd toxicity. SIGNIFICANCE AND IMPACT OF THE STUDY: H(2) S as a gasotransmitter is certified to have an ameliorating effect against Cd toxicity, thus providing information for further research regarding the role of H(2) S in regulating resistance to the heavy metal stress in organisms.

NO mediated increase of Fos protein and NMDA1A R mRNA expression in rat spinal cord during morphine withdrawal.

AIM: To investigate the effects of nitric oxide (NO) on activation of the rat spinal cord neurons during naloxone-precipitated morphine withdrawal. METHODS: Fos immunocytochemistry, NADPH-d histochemistry, Fos/NADPH-d double-labeling, intrathecal injection, antisense oligonucleotides (AS-ONs) techniques, and RT-PCR were used. RESULTS: Acute administration of naloxone and chronic administration of morphine did not change the expression of Fos protein and NADPH-d positive neurons, and there was no expression of Fos/NADPH-d double-labeled neurons in the spinal cord of rats. Morphine withdrawal increased the expression of Fos protein, NADPH-d positive, and Fos/NADPH-d double-labeled neurons, and they were observed in all the laminae of the rat spinal cord. Intrathecal injection of nNOS antisense oligonucleotides (nNOS-AS) inhibited the increase of Fos protein and NMDA(1A)R mRNA expression in the rat spinal cord during morphine withdrawal and decreased the scores of morphine withdrawal symptoms. The effect of nNOS-AS was greater than that of eNOS-AS. There was no effect in nNOS sense oligonucleotides (nNOS-S) group. CONCLUSION: NO mediated the increase of Fos protein and NMDA1A R mRNA expression in the rat spinal cord during morphine withdrawal.

Cardiac responses activated by nicotine in canine ganglial plexus between aorta and pulmonary artery.

In order to study the location and function of nicotine-sensitive neurons of cardiac ganglial plexuses, microdissections of collections of fat pads were carried out, and nicotine (100 micrograms) was injected into the ganglial plexus between aorta and pulmonary artery (A-PGP) in 30 anesthetized open-chest dogs. There were numerous ganglia or neurons in A-PGP. Either positive or negative inotropic and chronotropic responses were elicited following injections of nicotine into A-PGP. Control injections of 0.1 ml saline into A-PGP and injections of nicotine (100 or 200 micrograms) into right marginal ganglial plexus did not elicit any cardiac responses. After acute decentralization, nicotine (100 micrograms) was again injected into the same locus of A-PGP. Some positive and negative responses could still be induced, but their frequencies were reduced. These suggest that nicotine can directly activate the efferent parasympathetic and sympathetic neurons and indirectly activate them by stimulating the afferent neurons existing on the surface of dog heart.

[Comparison between the effects of (-)- and (+)-gossypol on protein kinase C and protein kinase A].

Protein kinase C(PKC) and protein kinase A(PKA) purified from rat liver were incubated with (-)- and (+)-gossypol. The activity of PKC was significantly inhibited in a concentration-dependent manner by both (-)-gossypol and (+)-gossypol. (-)-gossypol was found to inhibit type I PKA, whereas the inhibitory action of (+)-gossypol for type I PKA was less potent. Both (-)-gossypol and (+)-gossypol showed inhibition for type II PKA only at high concentration. These results suggest that administration of gossypol might impair cellular signal transduction.