[Liver cancer treatment with mitochondrial homeostasis].

Systemic treatment, including molecular targeted therapy, immunotherapy, and chemotherapy, is an important means of achieving long-term survival in patients with intermediate-and advanced-stage liver cancer. However, some patients are insensitive to treatment and even develop drug resistance. Mitochondria are the center of cellular energy metabolism and, at the same time, are the priority targets for systemic therapy. Mitochondrial homeostasis plays an important role in the treatment of liver cancer. The relationship between the two advances is elucidated so as to provide better ideas for the clinical treatment of liver cancer.

[Research progress on the mechanism and response strategies of molecular targeted drug resistance in liver cancer].

Molecular targeted drugs are one of the treatments for hepatocellular carcinoma (HCC), the primary factor influencing their therapeutic efficacy is drug resistance. Diminished drug intake, greater efflux, improved DNA damage repair capacity, aberrant signal pathways, hypoxia, epithelial-mesenchymal cell transition, and the cellular autophagy system are summarized herein as aspects of the drug resistance mechanism. Simultaneously, effective strategies for addressing drug resistance are elaborated, providing ideas for better clinical treatment of HCC.

Designing thermal radiation metamaterials via a hybrid adversarial autoencoder and Bayesian optimization.

Designing thermal radiation metamaterials is challenging especially for problems with high degrees of freedom and complex objectives. In this Letter, we develop a hybrid materials informatics approach which combines the adversarial autoencoder and Bayesian optimization to design narrowband thermal emitters at different target wavelengths. With only several hundreds of training data sets, new structures with optimal properties can be quickly determined in a compressed two-dimensional latent space. This enables the optimal design by calculating far less than 0.001% of the total candidate structures, which greatly decreases the design period and cost. The proposed design framework can be easily extended to other thermal radiation metamaterials design with higher dimensional features.

[Efficacy analysis of selective genicular artery embolization in the treatment of knee pain secondary to osteoarthritis].

Objective: To evaluate the efficacy and safety of selective genicular artery embolization for the treatment of the knee pain secondary to osteoarthritis. Methods: From October 2020 to July 2021, 17 patients (23 knees) aged (68±7) years with moderate to severe knee pain secondary to knee osteoarthritis were prospectively included in the General Hospital of Ningxia Medical University. There were 6 males and 11 females included in this research. Patients were assessed with knee pain, stiffness, and function with the Visual Analogue Scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at baseline, using the Kellgren-Lawrence (K-L) grading to evaluate the severity of KOA, and using the Magnetic Resonance Knee Osteoarthritis Score (MOAKS) to evaluate the MR imaging characteristics of the affected knee. Selective genicular artery embolization (GAE) was performed in all patients. The patients were followed up for 6 months after the procedure. Patients were assessed with the VAS score and WOMAC scale at 1 d, 1 week and 1, 3 and 6 months after the procedure to evaluate the clinical outcomes, including the improvement of knee joint pain, stiffness and function, as well as the occurrence of adverse reactions. Results: Three to seven genicular artery branches were superselected and embolized in 23 knees, and 4 to 7 genicular artery branches were embolized in 7 patients with K-L grade 4. The clinical improvement was 95.6% (22/23) at 1 month, 86.9% (20/23) at 3 months, and 91.3% (21/23) at 6 months. Twenty-three knees completed the 6-month follow-up, and the VAS score, WOMAC pain score, and total WOMAC score at 1, 3, and 6 months after surgery were (2.5±1.3), (3.4±2.4), and (19.7±9.8) points, (3.0±1.8), (4.5±3.4), and (22.3±11.3) points, (2.8±1.5), (4.1±3.0), and (20.5±11.0) points, which were lower than the (6.6±0.9), (11.4±2.6) and (47.0±12.0) points at baseline (all P<0.001). During the follow-up period, 7 patients had adverse reactions: 3 cases had skin ecchymosis in the femoral artery puncture area, 4 cases had knee joint stiffness and pain within 1 day after operation, which were relieved spontaneously in 1 week, 6 patients had joint clicking during extension and flexion activities after operation, of which 3 cases subsided spontaneously within 3 months after operation. None of the patients had major procedure-related adverse events. Conclusion: GAE has a high clinical improvement rate and a low incidence of adverse reactions in the treatment of the pain secondary to knee osteoarthritis, which provides a new treatment option for patients who fail to respond to conservative treatment.

[Research Progress on the Role of Mitochondrial DNA in the Pathogenesis of Chronic Liver Disease].

Mitochondrial DNA is the mitochondria's own genetic material located within the mitochondrial matrix and is involved in cellular metabolism and energy supply. Mitochondrial DNA damage exacerbates oxidative stress by increasing the release of reactive oxygen species, while mitochondrial DNA release also triggers apoptosis and activates immune inflammatory responses through damage-related molecular patterns. Mitochondrial autophagy regulates mitochondrial DNA damage and release through a negative feedback mechanism to maintain intracellular homeostasis. Recent studies have shown that the occurrence and development of chronic liver disease are closely related to mitochondrial DNA-mediated immune inflammatory responses and oxidative stress.

[Early diagnosis and predictive model for hepatitis B virus-related hepatocellular carcinoma].

Most hepatocellular carcinoma are diagnosed at an advanced stage and thereby have a high mortality rate. Thus, the key to improving patient prognosis is early diagnosis of hepatocellular carcinoma. In recent years, Asian scholars have summarized a series of hepatocellular carcinoma risk score model for population with chronic hepatitis B, which can help to identify high-risk groups early and improve the early diagnosis rate. This paper briefly analyzes the risk factors and validated risk model for early prediction of hepatitis B virus-related hepatocellular carcinoma, and further reviews the effect of antiviral therapy on the risk of hepatocellular carcinoma.

Androgen Receptor Stimulates Hexokinase 2 and Induces Glycolysis by PKA/CREB Signaling in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) escapes growth inhibition by upregulating hexokinase 2 (HK2); however, the mechanism by which tumor cells upregulate HK2 remains unclear. AIM: We aimed to investigate the role of androgen receptor (AR) signalling in promoting HK2 expression in HCC. METHODS: The expressions of AR and HK2 in HCC tissues were analyzed by immunohistochemistry. Cell proliferation was determined using the CCK-8 assay, and the molecular mechanism of AR in the regulation of HK2 was evaluated by immunoblotting and luciferase assays. RESULTS: AR expression is positively correlated with HK2 staining by an immunohistochemical analysis. The manipulation of AR expression changed HK2 expression and glycolysis. AR signaling promoted the growth of HCC by enhancing HK2-mediated glycolysis. Moreover, AR stimulated HK2 levels and glycolysis by potentiating protein kinase A/cyclic adenosine monophosphate response element-binding (CREB) protein signaling. CREB silencing decreased HK2 expression and inhibited AR-mediated HCC glycolysis. AR affected the sensitivity of HCC cells to glycolysis inhibitors by regulating downstream phosphorylated (p)-CREB. CONCLUSIONS: These results indicate that AR at least partially induced glycolysis via p-CREB regulation of HK2 in HCC cells. Thus, this pathway should be considered for the design of novel therapeutic methods to target AR-overexpressing HCC.

[Value of (18)F-FDG PET-CT imaging to predict epidermal growth factor receptor mutations in patients with lung squamous cell carcinoma].

Objective: To investigate the value of (18)F-fluorodeoxy glucose ((18)F-FDG) positron emission tomography/computed tomography (PET-CT) in predicting the epidermal growth factor receptor (EGFR) mutations in patients with lung squamous cell carcinoma. Methods: We retrospectively analyzed the clinical data and (18)F-FDG PET-CT imaging data of 206 patients with lung squamous cell carcinoma confirmed by pathology and underwent EGFR mutation test in the First Affiliated Hospital of Nanjing Medical University from June 2013 to October 2018. Receiver operating characteristic (ROC) curve analysis was performed to quantify the predictive value of maximum standard uptake value (SUV(max)), metabolic tumor volume (MTV), total lesion glycolysis (TLG). The Chi-squared test was used to assess the difference in PET parameters. A multivariate Logistic regression analysis was performed to yield the parameters with statistic difference. Results: All of 206 patients with lung squamous cell carcinoma showed a high (18)F-FDG uptake. The median of SUV(max), MTV and TLG were 19.14, 37.69 cm(3) and 291.73, respectively. Among the 206 patients, EGFR mutations were identified in 14 cases, including 7 with exon 21 (L858R) mutation, 6 with exon 19 mutation and 1 with exon 20 mutation. ROC curve showed that the AUC of SUV(max), MTV and TLG were 0.624 (95% CI=0.454-0.794, P=0.122), 0.892 (95% CI=0.811-0.973, P<0.001) and 0.860 (95% CI=0.768-0.952, P<0.001), respectively. The median SUV(max) (19.14) was used as the cutoff points due to the small value of AUC. The cutoff point of MTV was 20.09 cm(3), the cutoff point of TLG was 211.07. Univariate analysis showed that the sex, smoking history, M stage, MTV and TLG were associated with EGFR mutations (all P<0.05). Logistic multivariate analysis showed that the sex, smoking history and TLG were the independent predictors of EGFR mutation (all P<0.05). Conclusion: TLG detected by (18)F-FDG PET/CT is an independent factor for predicting EGFR mutation in patients with lung squamous cell carcinoma, and has certain reference value for predicting EGFR mutation.

[Pancreatoduodenectomy and non-alcoholic fatty liver disease].

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome with similar hepatic histological changes to alcoholic liver disease, but without a history of excessive alcohol intake. Obesity, hyperlipidemia, diabetes, hypertension and other metabolic disorders are closely related to its occurrence and development, and its core mechanism is insulin resistance. In addition, there are also non-metabolic-related factors for the occurrence of non-alcoholic fatty liver disease, such as pancreatoduodenectomy. Pancreatoduodenectomy is the standard procedure for the treatment of tumor around the head of pancreas and ampulla. Postoperative pancreatic malfunction induced by pancreatic exocrine function after pancreatoduodenectomy is associated with the occurrence and development of secondary non-alcoholic fatty liver disease.

[Autophagy in the liver failure].

Liver failure is a severe liver disease syndrome, with massive or sub-massive liver tissues necrosis, and it develops rapidly, with poor clinical prognosis and high mortality. In recent years, autophagy role in the liver failure has received increasing attention. The study of the role of regulatory mechanism of autophagy is of great significance for the in-depth study of the prevention and treatment of liver failure. Based on the research progress of liver failure at home and abroad, this paper explores and summarizes the relationship between autophagy with necrosis and apoptosis, as well as the mechanism and expression level of autophagy in each stage of liver failure, with hope to provide reference for the in-depth research and clinical treatment of liver failure.

[Liver failure and glucocorticoid resistance].

The main pathogenesis of liver failure is immune damage and uncontrolled inflammatory response. Glucocorticoids have strong immunosuppressive and anti-inflammatory effects, and are considered to be useful for the treatment of liver failure. However, the results of many clinical studies have shown that the application of glucocorticoids in patients with liver failure cannot effectively improve the prognosis, but instead increases the chance of infection and endangers life. Provided that, it seems reasonable to assume that glucocorticoid resistance exists in patients with liver failure. This article analyzes the mechanism by which P-glycoprotein reverses glucocorticoid transport, intracellular glucocorticoid signaling pathway dysfunction and related gene mutations when the inflammatory response is uncontrolled. In addition, we also evaluated the sensitivity of glucocorticoids in patients with liver failure, so as to provide theoretical basis for efficacy and medication timing.

Analysis of the bacteria community in wild Cordyceps cicadae and its influence on the production of HEA and nucleosides in Cordyceps cicadae.

AIMS: The purpose of this study was to investigate the bacterial community of wild Cordyceps cicadae and explore its effect on the production of N6-(2-hydroxyethyl)-adenosine (HEA) and three nucleosides in C. cicadae. METHODS AND RESULTS: Illumina high-throughput sequencing technology was used to analyse the bacterial community in wild C. cicadae. After C. cicadae was isolated and bacteria were isolated from wild C. cicadae, we identified four bacterial strains that independently altered HEA and nucleoside production in a coculture with C. cicadae and four bacteria separately. After cocultivation, the HEA yield from C. cicadae increased markedly. The bacteria in wild C. cicadae did not produce HEA, and the levels of three nucleosides decreased significantly. Both 16S rRNA and community analyses showed close evolutionary relationships and high abundance ratios for the four selected bacterial strains. CONCLUSIONS: Some bacteria exist in wild C. cicadae and have a high abundance ratio. Moreover, the isolated bacteria inhibited the growth of C. cicadae and prevented the production of HEA in axenic cultures. SIGNIFICANCE AND IMPACT OF THE STUDY: We discuss the bacterial community in wild C. cicadae and provide a new way to increase HEA production in C. cicadae by coculture with bacterial strains isolated from wild C. cicadae.

[Relationship between various histological status of margins of LEEP and residual HSIL or worse at hysterectomy following conization].

Objective: To investigate the relationship between various loop electrosurgical excision procedure (LEEP) margin status and residual high grade squamous intraepithelial lesion (HSIL) or worse at hysterectomy following conization. Methods: The relevant clinicopathological data were collected in the Obstetrics and Gynecology Hospital, Fudan University from Jan. 2014 to Dec. 2015, including 947 cases who underwent hysterectomy within 6 months of LEEP. The residual HSIL or worse at hysterectomy were analyzed among the groups. (1) Clear margins, involved margins, and without 1 mm negative margins. (2) Only one positive margin, two positive margins and three positive margins. (3) A positive margin of internal ostium of cervix, of external ostium of cervix and of the basement. Results: (1) The histological evaluation of the uterine specimens showed residual HSIL or worse in 234 cases (24.7%, 234/947). The proportion of residual lesions was 7.3% (21/286) in population with clear margins, 33.2% (211/635) with involved margins, 7.7% (2/26) without 1 mm negative margins, respectively. The positive margins group had significant difference at the aspect of residual rate in contrast to the negative margins group and the without 1 mm negative margins group (P<0.01). Further studies conclusively showed that the proportion of residual lesions was very similar between the negative margins group and the without 1 mm negative margins group (P>0.05). (2) The involved margins were interpretable in 621 cases. This was detected in 25.3% (111/438) patients with only one positive margin, 47.4% (74/156) with two positive margins and 77.8% (21/27) among three positive margins, respectively (P<0.01). (3) Furthermore, there were 418 cases only one positive margin was definite, and the proportion of residual lesions was 31.0% (62/200) in population with a positive margin of internal ostium of cervix, 18.2% (31/170) of external ostium of cervix and 33.3% (16/48) of the basement. The residual rates were higher in the endocervical and basal margin groups than that in the ectocervical margin group, and the differences were significant (P<0.05). Conclusions: The risk of residual HSIL or worse is significantly greater with involved margins at hysterectomy following LEEP. Both the positive endocervical and basal margin are excellent predictors of residual diseases, while the without 1 mm negative margin may be not. Clinicians should avoid treating it as positive margin and prevent overtreatment.

[Estrogen and its receptors in hepatitis B virus-related hepatocellular carcinoma].

Hepatitis B virus (HBV) infection is the most common cause of hepatocellular carcinoma in China. Epidemiological surveys show that male have a much higher incidence of hepatocellular carcinoma than female. Studies have shown that estrogen and its receptors are associated to gender disparity in hepatocellular carcinoma, but the underlying molecular mechanisms has not yet been fully elucidated. This article reviews the possible mechanisms of estrogen and its receptors in the occurrence and progression of hepatitis B virus-related hepatocellular carcinoma.

Polarization management based on dipolar interferences and lattice couplings.

We have achieved efficient polarization manipulations based on dipolar interferences and lattice couplings in one-dimensional cylindrical metalattices. First, we employ the scattering asymmetry factor g to quantify the directional scattering ability and find the maximum |g|max=1/2 for a cylinder with effective excitations of electric and magnetic dipoles simultaneously. Further, the strong negative-g (gp = -0.38) for p-polarization and positive-g (gs = 0.68) for s-polarization are obtained within a narrow visible band using c-Si with experimental data. Inspired by the polarization-dependent phenomena, we design a metalattice-based linear polarizer considering lattice effects with an optimal particle arrangement. The metalattice performs near-perfect reflection for p-polarized waves but with zero reflection for s-polarized waves with large extinction ratios for transmission (17 dB) and reflection (24 dB). The perfect functionalities can be attributed to the near-field lattice couplings with dipolar interferences. And, we reveal that the polarization-dependent scattering coefficients, which are sensitive to the lattice period, can be largely tuned owing to lattice effects, therefore contributing to modifying far-field scattering patterns. More specifically, the proposed linear polarizers also show robust and reliable functionalities when considering lattice imperfections, the effects of system sizes, oblique incident angles, and the tunbility for different working wavelengths. The present study paves a way to stimulate many advanced practical implements based on multipolar interferences and lattice couplings.

[Application of clustered regularly interspaced short palindromic repeats- associated protein 9 gene editing technology for treatment of HBV infection].

A lack of effective drugs and technical means to eradicate hepatitis B virus (HBV) is a bottleneck that limits the ability to fully cure HBV infection. Recently, genome-editing technology based on clustered regularly interspaced short palindromic repeats -associated protein 9 is an emerging technique for editing specific gene loci, which can specifically target HBV covalently closed circular DNA, effectively inhibits HBV DNA replication and regulates HBV functional protein expression, and is expected to become a powerful gene therapy tool for the complete eradication of HBV. Considering this, it has become the focus of attention for scholars at home and abroad that how to use clustered regularly interspaced short palindromic repeats -associated protein 9 to accomplish modification of HBV genomes for complete eradication of HBV. This paper summarizes the latest progress based on the latest research results at home and abroad in the application of clustered regularly interspaced short palindromic repeats -associated protein 9 gene editing technology in anti-HBV infection treatment, and expounds its potential and challenges as a radical cure for HBV infection.

[Efficacy and safety of paritaprevir/ritonavir/ombitasvir combined with dasabuvir in non-cirrhotic Asian adult patients with newly diagnosed and treated chronic HCV genotype 1b infection: a randomized, double-blind, placebo-controlled study - China data].

Objective: To evaluate the safety and efficacy of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) 25/150/100 mg once daily combined with dasabuvir 250mg, twice daily in non-cirrhotic Chinese adult patients with newly diagnosed and treated chronic HCV genotype 1b infection. Methods: A randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial was conducted in mainland China, Korea, and Taiwan.Safety and efficacy of OBV/PTV/r plus DSV administered for 12 weeks were evaluated in a newly diagnosed and treated (interferon alpha /pegylated interferon alpha) and ribavirin non-cirrhotic adults with chronic HCVgenotype 1b infection. Patients randomly received OBV/PTV/r plus DSV for 12 weeks (Group A), or placebo for 12 weeks (Group B) followed by an open-label phase of OBV/PTV/r plus DSV for 12 weeks. Sustained response (SVR12) rate obtained at 12 weeks and (SVR24) 24 weeks after discontinuation of treatment, and the incidence of adverse events and laboratory abnormalities after double-blind and open-label phase treatment were assessed. Results: A total of 410 cases of Chinese patients were included and randomly assigned to group A and B (with 205 cases in each group) in a 1:1 ratio. The rates of SVR12 and SVR24 were 99% (95% CI: 94.8% - 99.8%) in the newly diagnosed patients in group A (205 patients) and the rates of SVR12 and SVR24 were 100% in treated patients (95% CI: 96.3% - 100%). Different baseline characteristics had no effect on SVR12 and SVR24 rates. Most of the adverse events occurred were mild, asymptomatic, and≥ 3 laboratory abnormalities during treatment were rare, including elevation of alanine aminotransferase (2 cases in double-blind stage A group), aspartate aminotransferase (Double-blind stage A (3 cases) and total bilirubin (1 case in open-label phase B group); however, those mild adverse events could be recovered after drug withdrawal or discontinuation. only1 person discontinued drugs due to adverse events (Group B, open-label phase). Conclusion: The 12 weeks treatment course of OBV/PTV/r combined with DSV produced 99% ~ 100% rates of SVR12 and SVR24 in non-cirrhotic Asian adult patients with newly diagnosed and treated chronic HCV genotype 1b infection, and the tolerance and safety were good.