Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. In the past decade, there have been improvements in non-drug therapies and drug therapies for HCC treatment. Non-drug therapies include hepatic resection, liver transplantation, transarterial chemoembolization (TACE) and ablation. The former two surgical treatments are beneficial for patients with early and mid-stage HCC. As the first choice for non-surgical treatment, different TACE methods has been developed and widely used in combination therapy. Ablation has become an important alternative therapy for the treatment of small HCC or cases of unresectable surgery. Meanwhile, the drugs including small molecule targeted drugs like sorafenib and lenvatinib, monoclonal antibodies such as nivolumab are mainly used for the systematic treatment of advanced HCC. Besides strategies described above are recommended as first-line therapies due to their significant increase in mean overall survival, there are also potential drugs in clinical trials or under preclinical development. In addition, a number of potential preclinical surgical or adjuvant therapies are being studied, such as oncolytic virus, mesenchymal stem cells, biological clock, gut microbiome composition and peptide vaccine, all of which have shown different degrees of inhibition on HCC. With some potential anti-HCC drugs being reported, many promising therapeutic targets in related taxonomic signaling pathways including cell cycle, epigenetics, tyrosine kinase and so on that affect the progression of HCC have also been found. Together, the rational application of existing therapies and drugs as well as the new strategies will bring a bright future for the global cure of HCC in the coming decades.

Recent progress in treatment of hepatocellular carcinoma.

Abstract Background In the American population, the relationship between the triglyceride-glucose (TyG) index and TYG combined with indicators of obesity and cardiovascular disease (CVD) and its mortality has been less well studied. Methods This cross-sectional study included 11,937 adults from the National Health and Nutrition Examination Survey (NHANES) 2003–2018. Cox proportional hazards model, binary logistic regression analyses, restricted cubic spline (RCS), and receiver operating characteristic (ROC) were used to analyze the relationship between TyG and its combined obesity-related indicators and CVD and its mortality. Mediation analysis explored the mediating role of glycated hemoglobin and insulin in the above relationships. Results In this study, except for no significant association between TyG and CVD mortality, TyG, TyG-WC, TyG-WHtR, and TyG-BMI were significantly and positively associated with CVD and CVD mortality. TyG-WHtR is the strongest predictor of CVD mortality (HR 1.66, 95% CI 1.21–2.29). The TyG index correlated better with the risk of coronary heart disease (OR 2.52, 95% CI 1.66–3.83). TyG-WC correlated best with total CVD (OR 2.37, 95% CI 1.77–3.17), congestive heart failure (OR 2.14, 95% CI 1.31–3.51), and angina pectoris (OR 2.38, 95% CI 1.43–3.97). TyG-WHtR correlated best with myocardial infarction (OR 2.24, 95% CI 1.45–3.44). RCS analyses showed that most of the above relationships were linear (P-overall &lt; 0.0001, P-nonlinear &gt; 0.05). Otherwise, ROC curves showed that TyG-WHtR and TyG-WC had more robust diagnostic efficacy than TyG. In mediation analyses, glycated hemoglobin mediated in all the above relationships and insulin-mediated in partial relationships. Conclusions TyG-WC and TyG-WtHR enhance CVD mortality prediction, diagnostic efficacy of CVD and its mortality, and correlation with some CVD over and above the current hottest TyG. TyG-WC and TyG-WtHR are expected to become more effective metrics for identifying populations at early risk of cardiovascular disease and improve risk stratification. 

The association between triglyceride-glucose index and its combination with obesity indicators and cardiovascular disease: NHANES 2003–2018

In view of the advancement in the understanding about the most diverse types of cancer and consequently a relentless search for a cure and increased survival rates of cancer patients, finding a therapy that is able to combat the mechanism of aggression of this disease is extremely important. Thus, oncolytic viruses (OVs) have demonstrated great benefits in the treatment of cancer because it mediates antitumor effects in several ways. Viruses can be used to infect cancer cells, especially over normal cells, to present tumor-associated antigens, to activate "danger signals" that generate a less immune-tolerant tumor microenvironment, and to serve transduction vehicles for expression of inflammatory and immunomodulatory cytokines. The success of therapies using OVs was initially demonstrated by the use of the genetically modified herpes virus, talimogene laherparepvec, for the treatment of melanoma. At this time, several OVs are being studied as a potential treatment for cancer in clinical trials. However, it is necessary to be aware of the safety and possible adverse effects of this therapy; after all, an effective treatment for cancer should promote regression, attack the tumor, and in the meantime induce minimal systemic repercussions. In this manuscript, we will present a current review of the mechanism of action of OVs, main clinical uses, updates, and future perspectives on this treatment.

Oncolytic virus therapy in cancer: A current review

Cancer progression results from activation of various signaling networks. Among these, PI3K/Akt signaling contributes to proliferation, invasion, and inhibition of apoptosis. Hepatocellular carcinoma (HCC) is a primary liver cancer with high incidence rate, especially in regions with high prevalence of viral hepatitis infection. Autoimmune disorders, diabetes mellitus, obesity, alcohol consumption, and inflammation can also lead to initiation and development of HCC. The treatment of HCC depends on the identification of oncogenic factors that lead tumor cells to develop resistance to therapy. The present review article focuses on the role of PI3K/Akt signaling in HCC progression. Activation of PI3K/Akt signaling promotes glucose uptake, favors glycolysis and increases tumor cell proliferation. It inhibits both apoptosis and autophagy while promoting HCC cell survival. PI3K/Akt stimulates epithelial-to-mesenchymal transition (EMT) and increases matrix-metalloproteinase (MMP) expression during HCC metastasis. In addition to increasing colony formation capacity and facilitating the spread of tumor cells, PI3K/Akt signaling stimulates angiogenesis. Therefore, silencing PI3K/Akt signaling prevents aggressive HCC cell behavior. Activation of PI3K/Akt signaling can confer drug resistance, particularly to sorafenib, and decreases the radio-sensitivity of HCC cells. Anti-cancer agents, like phytochemicals and small molecules can suppress PI3K/Akt signaling by limiting HCC progression. Being upregulated in tumor tissues and clinical samples, PI3K/Akt can also be used as a biomarker to predict patients' response to therapy. 

Biological function and therapeutic perspective of targeting PI3K/Akt signaling in hepatocellular carcinoma: promises and challenges.

Importance
Metabolic surgery leads to weight loss and improved health, but these outcomes are highly variable. Poor weight loss is associated with lower circulating levels of glucagon-like peptide-1 (GLP-1).


Objective
To assess the efficacy and safety of the GLP-1 receptor agonist, liraglutide, 3.0 mg, on percentage body weight reduction in patients with poor weight loss and suboptimal GLP-1 response after metabolic surgery.


Design, Setting, and Participants
The Evaluation of Liraglutide 3.0 mg in Patients With Poor Weight Loss and a Suboptimal Glucagon-Like Peptide-1 Response (BARI-OPTIMISE) randomized placebo-controlled trial recruited adult patients at least 1 year after metabolic surgery who had experienced 20% or less body weight loss from the day of surgery and a suboptimal nutrient-stimulated GLP-1 response from 2 hospitals in London, United Kingdom, between October 2018 and November 2019. Key exclusion criteria were type 1 diabetes; severe concomitant psychiatric, gastrointestinal, cardiac, kidney or metabolic disease; and use of insulin, GLP-1 receptor analogues, and medication that can affect weight. The study period was 24 weeks followed by a 4-week follow-up period. Last participant follow-up was completed in June 2020. All participants and clinical study personnel were blinded to treatment allocation. Of 154 assessed for eligibility, 70 met trial criteria and were included in the study, and 57 completed follow-up.


Interventions
Liraglutide, 3.0 mg, once daily or placebo as an adjunct to lifestyle intervention with a 500-kcal daily energy deficit for 24 weeks, on a 1:1 allocation by computer-generated randomization sequence, stratified by surgery type (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy [SG]) and type 2 diabetes status.


Main Outcome and Measures
The primary outcome was change in percentage body weight from baseline to the end of the 24-week study period based on an intention-to-treat analysis. Participant safety was assessed through monitoring of biochemical parameters, including kidney and liver function, physical examination, and assessment for adverse events.


Results
A total of 70 participants (mean [SD] age, 47.6 [10.7] years; 52 [74%] female) with a poor weight loss response following RYGB or SG were randomized to receive 3.0-mg liraglutide (n = 35) or placebo (n = 35). All participants received at least 1 dose of the trial drug. Eight participants discontinued treatment (4 per group), and 2 in the 3.0-mg liraglutide group and 1 in the placebo group were lost to follow-up. Due to COVID-19 restrictions, 3 participants in the 3.0-mg liraglutide group and 7 in the placebo group were unable to attend their final in-person assessment. Estimated change in mean (SD) percentage body weight from baseline to week 24 was -8.82 (4.94) with liraglutide, 3.0 mg (n = 31), vs -0.54 (3.32) with placebo (n = 26). The mean difference in percentage body weight change for liraglutide, 3.0 mg, vs placebo was -8.03 (95% CI, -10.39 to -5.66; P < .001). Adverse events, predominantly gastrointestinal, were more frequent with liraglutide, 3.0 mg (28 events [80%]), than placebo (20 events [57%]). There were no serious adverse events and no treatment-related deaths.


Conclusion and Relevance
These findings support the use of adjuvant liraglutide, 3.0 mg, for weight management in patients with poor weight loss and suboptimal GLP-1 response after metabolic surgery.


Trial Registration
ClinicalTrials.gov Identifier: NCT03341429.

Safety and Efficacy of Liraglutide, 3.0 mg, Once Daily vs Placebo in Patients With Poor Weight Loss Following Metabolic Surgery: The BARI-OPTIMISE Randomized Clinical Trial.

Importance Homeostatic model assessment for insulin resistance (HOMA-IR) and triglyceride glucose (TyG) index–related parameters [TyG index, triglyceride glucose–waist circumference (TyG-WC), triglyceride glucose–waist-to-height ratio (TyG-WHtR), and triglyceride glucose–body mass index (TyG-BMI)] are gradually considered as convenient and alternative indicators for insulin resistance in various metabolic diseases, but the specific diagnostic capacity and the comparison of the parameters in non-alcoholic fatty liver disease (NAFLD), metabolic-associated fatty liver disease (MAFLD), and liver fibrosis remain uncertain. Objective To comprehensively assess and compare the diagnostic accuracy of the above parameters in NAFLD, MAFLD, and liver fibrosis and identify the appropriate indicators. Methods A total of 1,727 adults were enrolled from the 2017–2018 National Health and Nutrition Examination Surveys. Logistic regressions were used to identify the parameters significantly associated with NAFLD, MAFLD, and liver fibrosis; receiver operating characteristic (ROC) curves were used to evaluate and compare their diagnostic capacity. Subgroup analyses were conducted to validate the concordance, and the optimal cutoff values were determined according to the Youden’s indexes. Results Significant differences were observed between quartile-stratified HOMA-IR and TyG index–related parameters across the NAFLD, MAFLD, and liver fibrosis (P < 0.05). All variables were significantly predictive of different disease states (P < 0.05). The top three AUC values are TyG-WC, TyG-WHtR, and TyG-BMI with AUCs of 0.815, 0.809, and 0.804 in NAFLD. The optimal cutoff values were 822.34, 4.94, and 237.77, respectively. Similar values and the same trend of the above three indexes could be observed in MAFLD and liver fibrosis. Subgroup analyses showed consistent results with the primary research, despite some heterogeneity. Conclusions TyG-WC, TyG-WHtR, and TyG-BMI can be used for early screening of NAFLD and MAFLD. These three parameters and HOMA-IR were more suitable for assessing metabolic risks and monitoring disease progression in patients with NAFLD.

/pdf/potential-screening-indicators-for-early-diagnosis-of-nafld-2zham9uc.pdf

Potential screening indicators for early diagnosis of NAFLD/MAFLD and liver fibrosis: Triglyceride glucose index–related parameters

Background Hepatocellular carcinoma (HCC) accounts for more than 85%-90% of primary liver cancer globally, and approximately 45% of deaths from HCC occur in greater China. This disease poses a significant economic burden for patients, payers and society and significantly affects patients' quality of life (QoL). However, such impact of HCC in greater China has not been well characterized. This review was conducted to analyze the current evidence about the economic and humanistic impact of HCC in greater China for informing national disease management and identifying clinical gaps yet to be resolved. Methods A systematic search literature using seven databases (Web of Science, PubMed, Medline, Cochrane Central, China National Knowledge Infrastructure, Wanfang, and Weipu) was performed to identify interventional and observational studies that reported the impact of HCC on cost or QoL and published before April 6, 2021. The focus population included adult patients with HCC in greater China. This review excluded any studies that focused on any specific treatment. Study quality was assessed using the Effective Public Health Practice Project tool. Results Of 39,930 studies retrieved, 27 were deemed eligible for inclusion. The methodologies, perspectives and data sources used in studies were heterogeneous. In greater China, while few studies reported the health expenditures of HCC patients and investigations about economic burden at national level was lacking, the significant economic impact of HCC on patients and their families had been reported. Health-related costs increased as the disease deteriorated. Additionally, HCC also has a negative impact on the QoL of patients, mostly in terms of physical, cognitive, social functioning and severe symptoms. Conclusions HCC has brought significant economic and QoL burden to patients in greater China. Both physical and psychological factors predicted QoL in patients with HCC in greater China. Future studies should explore the disease-related economic effects on Chinese patients and their families, the effects of physical and psychological factors on QoL and the relationships of physical and psychological factors in the region. Systematic Review Registration: www.crd.york.ac.uk/prospero/display_record.php?RecordID=278421, PROSPERO: CRD42021278421

/pdf/economic-burden-and-quality-of-life-of-hepatocellular-2488asvx.pdf

Economic Burden and Quality of Life of Hepatocellular Carcinoma in Greater China: A Systematic Review

ABSTRACT Background As the pandemic of obesity presents an increasing serious health challenge worldwide, additional medical interventions, especially pharmacotherapy, should be addressed for the affected people. Liraglutide 3.0 mg, is one of the possible options for long-term anti-obesity treatment. Research design and methods We systematically searched the databases of PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. A meta-analysis was then performed using random-effect models. Results Meta-analyses of seven phase 3 and 4 RCTs (N = 6,028), which were conducted in adults with obesity or overweight for at least 1 year, demonstrated a significant weight reduction with liraglutide 3.0 mg (mean difference of percentage weight change −4.81%; 95% CI: −5.56% to −4.06%; P < 0.00001), relative to placebo. However, more participants taking liraglutide experienced at least one adverse event. More discontinuations due to adverse events were observed among them. In the subgroup analysis among participants with or without diabetes mellitus (DM), pooled result showed that liraglutide was associated with a greater decrease in the percentage of weight change in participants without DM. Conclusions This study provided support for the use of liraglutide 3.0 mg for weight management in adults with obesity or who are overweight.

Efficacy and safety of liraglutide for obesity and people who are overweight: a systematic review and meta-analysis of randomized controlled trials

To evaluate the inhibitory role of a novel oncolytic adenovirus (OA), GP73-SphK1sR-Ad5, on the growth of hepatocellular carcinoma (HCC). GP73-SphK1sR-Ad5 was constructed by integrating Golgi protein 73 (GP73) promoter and sphingosine kinase 1 (SphK1)-short hairpin RNA (shRNA) into adenovirus serotype 5 (Ad5), and transfecting into HCC Huh7 cells and normal human liver HL-7702 cells. The expression of SphK1 and adenovirus early region 1 (E1A) was detected by quantitative real-time PCR (qRT-PCR) and western blot, respectively. Cell viability was detected by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, and apoptotic rate was determined by flow cytometry. An Huh7 xenograft model was established in mice injected intratumorally with GP73-SphK1sR-Ad5. Twenty days after injection, the tumor volume and weight, and the survival time of the mice were recorded. The histopathological changes in tumor tissues were observed by hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM). Transfection of GP73-SphK1sR-Ad5 significantly upregulated E1A and downregulated SphK1 in Huh7 cells, but not in HL7702 cells. GP73-SphK1sR-Ad5 transfection significantly decreased the viability and increased the apoptotic rate of Huh7 cells, but had no effect on HL7702 cells. Intratumoral injection of GP73-SphK1sR-Ad5 into the Huh7 xenograft mouse model significantly decreased tumor volume and weight, and prolonged survival time. It also significantly decreased the tumor infiltration area and blood vessel density, and increased the percentages of cells with nucleus deformation and cells with condensed chromatin in tumor tissues. GP73-SphK1sR-Ad5 serves as a novel OA and can inhibit HCC progression with high specificity and efficacy.

/pdf/a-novel-oncolytic-adenovirus-inhibits-hepatocellular-3i1dgngpik.pdf

A novel oncolytic adenovirus inhibits hepatocellular carcinoma growth.

China has introduced a series of polices and practice to manage the market access of Chinese patent medicine (CPM) products into its healthcare security system, which is less analyzed and reported in current literature. Therefore, this paper aimed to investigate the mechanisms managing market access of CPM products into healthcare security system in China, expecting to provide implications for international integration of traditional medicine products into health systems.This paper used a documentary analysis approach as a qualitative research method. Data were collected from four sources and analyzed in a thematic way.Four mechanisms to manage entry, price adjustment, and exit of innovative brand and generic CPM products are identified, including: (1) price negotiation, mechanism of new entry of innovative brand CPM products into the national reimbursement list; (2) price re-negotiation, mechanism of price adjustment of innovative brand CPM products within the national reimbursement list; (3) mass procurement, mechanism of generic CPM products to healthcare security system; and (4) direct removal, mechanism of removal from the national reimbursement list.China has established market access framework of CPM products by focusing on price negotiation for innovative brand CPM products and mass procurement for generic CPM products. Further studies of CPM products based real-world data are needed to provide clinical and pharmacoeconomic evidence to support market access of CPM products into healthcare security systems. 

/pdf/market-access-of-chinese-patent-medicine-products-to-3q5marzi.pdf

Market access of Chinese patent medicine products to healthcare security system in China: implications for international integration of traditional medicine into health systems

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