Real-world treatment patterns and outcomes for patients with advanced hepatocellular carcinoma initially treated with PD-1 inhibitors.

BACKGROUND: Programmed cell death protein-1 (PD-1) inhibitors have shown promising clinical efficacy in treating advanced hepatocellular carcinoma (HCC). However, little evidence exists regarding their treatment patterns and outcomes in real-world practice in China. This study aimed to investigate real-world treatment patterns and outcomes of PD-1 inhibitors as first-line therapies for patients with advanced HCC in China. METHODS: The study population included adult patients with advanced HCC who were initially treated with PD-1 inhibitors from April 2020 to November 2022 in China. Descriptive statistics were used to report first-line treatment patterns and associations between patient characteristics and the most frequently used treatment patterns. The effectiveness of first-line treatment with PD-1 inhibitors was also evaluated according to survival and tumor response. RESULTS: The analyses enrolled 480 patients. The four most frequently used first-line treatment patterns of camrelizumab, tislelizumab, camrelizumab + TACE, and tislelizumab + TACE showed statistical differences in patient characteristics of gender, HBV infection, liver cirrhosis, BCLC stage, and portal vein tumor thrombus (all P < 0.05). However, there was no significant difference in median progression-free survival among the first-line treatments of tislelizumab, camrelizumab, and tislelizumab + TACE (not reached vs. 4.4 months vs. 3.6 months, P = 0.5178). The three groups had similar objective response rates (25.0 % vs. 28.6 % vs. 28.6 %, P = 0.927), and disease control rates (73.1 % vs. 78.6 % vs. 64.3 %, P = 0.573) with no statistical significance. CONCLUSIONS: Our findings provided insights into potential therapeutic strategies of PD-1 inhibitors in first-line settings for advanced HCC in real-world practice in China. It was recommended to consider patient characteristics associated with therapeutic options when making clinical decisions. Prospective randomized controlled studies with larger sample sizes and longer follow-up times were warranted further to verify the potential clinical benefits of PD-1 inhibitors.

Pharmacoeconomic evaluation of anti-obesity drugs for chronic weight management: a systematic review of literature.

Introduction: Pharmacological therapy is recommended as a second-line alternative to reverse obesity. Currently, five anti-obesity drugs (AODs) have been approved by the U.S. Food and Drug Administration (FDA) for chronic weight management. The aim of this paper is to investigate the pharmacoeconomic evaluation of AODs through a systematic review with a special focus on methodological considerations. Methods: We searched the general and specific databases to identify the primary pharmacoeconomic evaluation of AODs. Results: A total of 18 full-text articles and three conference abstracts were included in this review. Most of the economic assessments were still about Orlistat. And the observations we could make were consistent with the previous systematic review. A few studies were on the combined therapies (i.e. PHEN/TPM ER and NB ER) compared to different comparators, which could hardly lead to a generalized summary of the cost-effectiveness. Most recently, pharmacoeconomic evidence on the newest GLP 1 RA approved for the indication of obesity or obesity with at least one comorbidity emerged gradually. Modelling-based cost-utility analysis is the major type of assessment method. In the modelling studies, a manageable number of the key health states and the state transitions were structured to capture the disease progression. In particular, the principal structure of the decision model adopted in the three studies on the newly approved drug was nearly the same, which enables more in-depth comparisons and generalizations of the findings. Conclusion: This study provided an up-to-date overview of the strengths and areas for improvement in the methodological design of the pharmacoeconomic evaluation of the licensed drugs for chronic weight management. Future modelling evaluations would benefit from a better understanding of the long-term weight loss effects of the current therapeutic options and the weight rebound process after the discontinuation of treatment. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022302648, identifier CRD42022302648.

Soil organic carbon stocks increased across the tide-induced salinity transect in restored mangrove region.

Blue carbon in mangrove ecosystems contributes significantly to the global carbon cycle. However, large uncertainties maintain in the soil organic carbon (SOC) storage throughout the tide-induced salinity and alkalinity transect in the mangrove restoration region in Southern China. Total 125 soil samples were obtained to detect the SOC content and physicochemical properties. The mean SOC content of each layer ranged from 6.82 to 7.86 g kg-1, while the SOC density ranged from 2.99 to 11.41 kg m-2, increasing with soil depths. From different land covers in the study region, the SOC content varied from 4.63 to 9.71 g kg-1, increasing across the salinity and alkalinity transect, while the SOC density fluctuated from 3.01 kg m-2 in mudflats to 10.05 kg m-2 in mangrove forests. SOC concentration was favorably linked with total nitrogen (r = 0.95), and total phosphorus (r = 0.74), and negatively correlated with Cl- (r = - 0.95), electrical conductivity (r = - 0.24), and total dissolved solids (r = - 0.08). There were significant logarithmic relationships between SOC content and the concentrations of clay (r = 0.76), fine silt (r = 0.81), medium silt (r = - 0.82), and coarse silt (r = - 0.78). The spatial patterns of SOC concentration were notably affected by soil texture, physicochemical properties, and land-cover type, providing essential reference for future investigations of blue carbon budget in restored mangrove forests.

Comparative analysis of disease modelling for health economic evaluations of systemic therapies in advanced hepatocellular carcinoma.

BACKGROUND: The objective of this study was to systematically analyse methodological and structural assumptions utilised in model-based health economic evaluations of systemic advanced hepatocellular carcinoma (HCC) therapies, discuss the existing challenges, and develop methodological recommendations for future models in advanced HCC. METHODS: We performed literature searches using five databases (Embase, PubMed, Web of Science, Econlit, and CNKI) up to December 4, 2022. Technology appraisals from Canada, England, Australia, and the United States were also considered. Model-based full economic evaluations of systemic advanced HCC therapies in English or Chinese met the eligibility criteria. The reporting quality was assessed by using the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist. RESULTS: Of 12,863 records retrieved, 55 were eligible for inclusion. Markov model (n = 29, 53%) and partitioned survival model (n = 27, 49%) were the most commonly used modelling techniques. Most studies were based on health-state-driven structure (n = 51, 93%), followed by treatment-line-driven structure (n = 2, 4%) and combination structure (n = 1, 2%). Only three studies (5%) adopted external real-world data to extrapolate the overall survival or calibrate the extrapolation. Few studies reported the assumptions of transition probabilities. Utility modelling approaches were state-based (n = 51, 93%) and time-to-death (n = 1, 2%). Only 13 studies (24%) reported five types of model validation. Economic evaluation results of specific treatment strategies varied among studies. CONCLUSIONS: Disease modelling for health economic evaluations of systemic therapies in advanced HCC has adopted various modelling approaches and assumptions, leading to marked uncertainties in results. By proposing methodological recommendations, we suggest that future model-based studies for health economic evaluation of HCC therapies should follow good modelling practice guidelines and improve modelling methods to generate reliable health and economic evidence.

Exosome-Modified Liposomes Targeted Delivery of Thalidomide to Regulate Treg Cells for Antitumor Immunotherapy.

Thalidomide (THD), a synthetic derivative of glutamic acid, was initially used as a sedative and antiemetic until the 1960s, when it was found to cause devastating teratogenic effects. However, subsequent studies have clearly demonstrated the anti-inflammatory, anti-angiogenic, and immunomodulatory properties of thalidomide, thus providing a rationale for its current use in the treatment of various autoimmune diseases and cancers. Our group found that thalidomide can suppress the regulatory T cells (Tregs), a minor subset of CD4+ T cells (~10%) with unique immunosuppressive activity that have been shown to accumulate in the tumor microenvironment (TME) and represent a major mechanism of tumor immune evasion. Due to the low solubility of thalidomide in its present form of administration, coupled with its lack of specificity for targeted delivery and controlled drug release, it is an urgent need to find potent delivery methods that can significantly enhance its solubility, optimize the desired site of drug action, and mitigate its toxicity. In this study, the isolated exosomes were incubated with synthetic liposomes to form hybrid exosomes (HEs) that carried THD (HE-THD) with uniform size distribution. The results demonstrated that HE-THD could significantly abrogate the expansion and proliferation of Tregs induced by TNF, and this might result from blocking TNF-TNFR2 interaction. By encapsulating THD in hybrid exosomes, our drug delivery system successfully increased the solubility of THD, laying a foundation for future in vivo experiments that validate the antitumor activity of HE-THD by reducing the Treg frequency within the tumor microenvironment.

Effects and safety of Ginkgo biloba on blood metabolism in type 2 diabetes mellitus: a systematic review and meta-analysis.

Background: There has existed controversy regarding the use of Ginkgo biloba (GKB) for blood metabolism among type 2 diabetes mellitus(T2DM) patients, and we tried to analyze the effects and safety of GKB on T2DM patients. Methods: We conducted a literature search between January 2003 and December 2022 of seven online databases (PubMed, Scopus, Embase, Google Scholar, Web of Sciences, Cochrane Library, and China National Knowledge Infrastructure). A systematic literature review and meta-analysis were performed to compare the effects and safety of GKB among T2DM patients. Four groups of parameters were extracted and analyzed: hemorheology parameters, lipid profile, glycemic control markers, and adverse events. Results: In the end, 13 eligible articles with 11 indicators among 1573 patients were included. In the hemorheology parameters section, GKB showed significantly lower plasma viscosity (PV) (SMD=-0.91, 95%CI [-1.45, -0.36], P<0.01) and hematocrit (Hct) (SMD=-0.60, 95%CI [-0.97, -0.24], P<0.01) than the control group. GKB shoed higher velocity of the dorsalis pedis artery (VDPA) (SMD=0.51, 95%CI [0.26, 0.76], P<0.01) and ankle brachial index (ABI) (SMD=0.71, 95%CI [0.32, 1.10], P<0.01) than the control. In both the lipid profile and glycemic control markers sections, we did not find any difference between GKB and control groups, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), hemoglobin A1c (HbA1c), and fasting serum glucose (FSG). In addition, we saw no difference in adverse events (AE). The sensitivity analysis and funnel plot showed that the results in this research were robust and had no publication bias. Conclusion: In conclusion, GKB might safely reduce the risk of peripheral arterial or even systemic cardiovascular disease. However, GKB did not directly improve lipid and blood glucose levels in T2DM patients. Systematic review registration: https://inplasy.com/, identifier INPLASY202350096.

Analysis of risk factors for acute attacks complicated by respiratory failure in children with asthma.

Objective: To describe the proportion and clinical characteristics of hospitalized children with acute asthma attacks complicated by respiratory failure and to analyze the risk factors. Methods: This retrospective study analyzed hospital admissions of children and adolescents with acute asthma attacks between January 2016 and December 2021. Inclusion criteria were used to identify eligible cases, and demographic information and disease characteristics were collected. Patients were categorized into respiratory failure group and the other group based on the result of artery blood gas analysis. Multivariate logistic regression was utilized to investigate the risk factors associated with respiratory failure resulting from acute asthma attacks. The data were analyzed using SPSS 22.0, and significance was considered at P < 0.05. Results: Our research involved 225 participants, with 18.7% diagnosed with respiratory failure. The respiratory failure group was found to be younger and have higher percentage of male, while birth weight, nationality, and type of residence did not differ between the two groups. In the respiratory failure group, a significant difference was observed in emergency hospitalization, ICU treatment, severe to critical attack, dyspnea and allergy history. The two groups did not differ in admission season, first asthma diagnosis, respiratory infection and comorbidity. The respiratory failure group exhibited a higher proportion of atopy-only asthma and a lower proportion of T2-high asthma. The eosinophil count, and eosinophil percentage were lower in the respiratory failure group, while neutrophil count was higher. Having a history of allergies (OR = 2.46, 95% CI: 1.08-5.59) and neutrophil count (OR = 1.10, 95% CI: 1.00-1.21) were the risk factors for respiratory failure in children with asthma. There also existed that the risk of respiratory failure increases with decreasing age of the children (OR = 0.85, 95% CI: 0.73-0.99). Conclusion: Notably, risk factors for respiratory failure in hospitalized asthma children include age, having a history of allergies, and neutrophil count. The identification of the above factors and the implementation of timely intervention can optimize the treatment of asthma in children.

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

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 monotherapy and combination therapy of immune checkpoint inhibitors as first-line treatment for unresectable hepatocellular carcinoma: a systematic review, meta-analysis and network meta-analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the cancers with the highest morbidity and mortality. Sorafenib used to be the main treatment for unresectable HCC patients. However, regimens based on immune checkpoint inhibitors (ICIs) have attracted attention in recent years because of their reported benefits. This study aimed to evaluate the efficacy and safety of monotherapy and combination therapy of ICIs as first-line treatment for unresectable HCC patients by conducting a systematic review, meta-analysis, and network meta-analysis. METHODS: Studies published up to 11st August 2022 were searched from 4 commonly used databases, including PubMed, Web of Science, Embase, and Clinical trials.gov. All eligible clinical trials were included. Data about reported objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs) were extracted. RESULTS: Of the 8579 studies retrieved, 24 met the inclusion criteria. In patients with unresectable HCC taking ICIs-based therapy as first-line treatment, the pooled result of median PFS and median OS was 5.76 months (95% CI 4.82-6.69) and 16.35 months (95% CI 15.19-17.51) The ORR and DCR were 25.1% (95% CI 20.8-29.5%) and 75.2% (95% CI 70.3-80.2%) measured by RECIST v1.1 or 40.2% (95% CI 31.7-48.6%) with 75.2% (95% CI 68.3-82.1%) measured by mRECIST v1.1. Compared to sorafenib, ICIs-based therapy significantly prolonged OS. The combination treatment of sintilimab plus IBI305 had the highest ORR, while atezolizumab plus bevacizumab had the highest DCR. The pooled incidence of any grade TRAEs was 82.3% (95% CI 73.9-90.7%), with highest incidence appeared in dysphonia. CONCLUSIONS: This study demonstrated that first-line ICIs-based therapies could provide survival benefits for patients with unresectable HCC, with manageable TRAEs. The potential of combination treatment to become the new treatment trend in clinical practice is promising.

Long-Term Cost-Effectiveness Analysis of Once-Weekly Semaglutide versus Dulaglutide in Patients with Type 2 Diabetes with Inadequate Glycemic Control in China.

INTRODUCTION: The objective of the current study was to assess the long-term cost-effectiveness of once-weekly semaglutide 0.5 mg and 1.0 mg versus dulaglutide 1.5 mg for the treatment of patients with type 2 diabetes uncontrolled on metformin in the Chinese setting. METHODS: The Swedish Institute of Health Economics Diabetes Cohort Model (IHE-DCM) was used to evaluate the long-term health and economic outcomes of once-weekly semaglutide and dulaglutide. Analysis was conducted from the perspective of the Chinese healthcare systems over a time horizon of 40 years. Data on baseline cohort characteristics and treatment effects were sourced from the SUSTAIN 7 clinical trial. Costs included treatment costs and costs of complications. Projected health and economic outcomes were discounted at a rate of 5% annually. The robustness of the results was evaluated through one-way sensitivity analyses and probabilistic sensitivity analyses. RESULTS: Compared with dulaglutide 1.5 mg, once-weekly semaglutide 0.5 mg and 1.0 mg were associated with improvements in discounted life expectancy of 0.04 and 0.10 years, respectively, and improvements in discounted quality-adjusted life expectancy of 0.08 and 0.19 quality-adjusted life years (QALYs), respectively. Clinical benefits were achieved at reduced costs, with lifetime cost savings of 8355 Chinese Yuan (CNY) with once-weekly semaglutide 0.5 mg and 11,553 CNY with once-weekly semaglutide 1.0 mg. Sensitivity analyses verified the robustness of the research results. CONCLUSIONS: Once-weekly semaglutide was suggested to be dominant (more effective and less costly) versus dulaglutide 1.5 mg in patients with type 2 diabetes uncontrolled on metformin treatment in China.

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

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.

Pharmacoeconomic evaluation of dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus: a systematic literature review.

INTRODUCTION: Dipeptidyl peptidase-4 inhibitors (DPP-4i) are widely used oral antidiabetic agents that exert antihyperglycemic effects in type 2 diabetes mellitus (T2DM) without increased risk of weight gain or hypoglycemic events. The objective of this paper was to systematically review the latest evidence that was associated with the pharmacoeconomic evaluation of DPP-4i for the treatment of patients with T2DM. AREAS COVERED: We conducted a systematic literature search of eligible articles published since inception up to March 2021 in Web of Science, MEDLINE (via PubMed), and ECONLIT. Fifty-four eligible articles were included in our review, in which DPP-4i were compared to metformin (4 studies), sulphonylurea (SU) (16 studies), alpha-glucosidase inhibitors (AGI) (3 studies), thiazolidinediones (TZD) (4 studies), other DPP-4i (3 studies), sodium-glucose co-transporter-2 inhibitors (SGLT-2i) (10 studies), glucagon-like peptide 1 receptor agonist (GLP-1RA) (18 studies), insulin (5 studies), and other antidiabetic therapies (5 studies). EXPERT OPINION: This study provided the updated evidence of systematic pharmacoeconomic evaluation associated with DPP-4i for the treatment of patients with T2DM. The evidence from the literature suggested that DPP-4i may be more cost-effective compared to SU and insulin as second-line therapy after metformin but not a cost-effective alternative compared to SGLPT-2i and GLP-1RA.

Epidemiology and disease burden of non-alcoholic steatohepatitis in greater China: a systematic review.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a progression of non-alcoholic fatty liver disease. The increasing burden of NASH has become a major concern of public health in greater China. This study aimed to characterize the epidemiology, disease burden, and treatment of NASH in greater China to better inform national disease management and delivery of health services. METHODS: We conducted a systematic review searching four English databases (Web of Science, PubMed, Medline, and Cochrane Central) and three Chinese databases (CNKI, Wanfang, and VIP). We identified articles published from database inception to October 10, 2020 which reported NASH epidemiology, disease burden, and/or intervention in Chinese adults. RESULTS: Of 44,115 articles retrieved, 33 were eligible for inclusion. Overall prevalence of NASH ranged from 2.4 to 6.1% in greater China, with a more substantial burden among males, the aged, and those in Hong Kong and Taiwan. Most NASH patients suffered from several comorbidities, including obesity, diabetes, and cardiovascular conditions. PNPLA3 rs738409 G allele and haptoglobin 2-2 genotype drove the fibrosis progression in NASH. Increasingly prevalent cases of cirrhosis and hepatocellular carcinoma caused a higher NASH-related mortality. Compared with normal population, NASH patients experienced markedly poorer quality of life and heavier costs. CONCLUSION: This is the first comprehensive overview of NASH among Chinese population that revealed an overwhelming impact of social and healthcare burden associated with the condition. Further high-quality studies are needed to improve the understanding and management of NASH in greater China.

Efficacy and Safety of First-Line Targeted Treatment and Immunotherapy for Patients with Biliary Tract Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Biliary tract cancer is one of the most aggressive and fatal tumours. Gemcitabine with cisplatin chemotherapy has long been the first-line treatment, but the prognosis is poor. In recent years, targeted treatment and immunotherapy have produced encouraging outcomes requiring a thorough review and meta-analysis. METHOD: For this systematic review and meta-analysis, we searched four databases, starting from the inception dates of databases to 11 January 2022. This study comprised randomised clinical trials and cohort studies that used immunotherapy or targeted treatment as the first line of treatment for patients with biliary tract cancer. RESULTS: From the 888 studies extracted, 33 trials were examined and found to meet the criteria. These included 3087 patients, 16 single-arm trials, 13 RCTs, one nRCT, a prospective single-arm pilot study, and a clinical setting in the real world. From 2010 to 2020, 33 studies were conducted using targeted treatment or immunologic therapies as first-line treatments for BTC patients, and 18 of those studies had positive outcomes. CONCLUSION: This study demonstrates that immunotherapy combined with chemotherapy as first-line treatment can provide survival benefits by improving the objective response rate for patients with unresectable biliary tract cancer. The potential for combination therapy to become a new trend in clinical treatment is promising but needs further clinical evaluation.

Clinical Outcomes Associated with Monotherapy and Combination Therapy of Immune Checkpoint Inhibitors as First-Line Treatment for Advanced Hepatocellular Carcinoma in Real-World Practice: A Systematic Literature Review and Meta-Analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs)-based therapy has recently been demonstrated to greatly ameliorate survival outcomes in advanced hepatocellular carcinoma (HCC). We aimed to evaluate clinical outcomes of ICIs-based monotherapy and combination therapy as first-line treatment of adults with advanced HCC in real-world practice by conducting a systematic literature review and meta-analysis. METHODS: PubMed, Web of Science, and Embase were searched up to 25 April 2022. Retrospective or prospective real-world studies evaluating progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) of patients with advanced HCC receiving first-line ICIs-based therapy were included. RESULTS: Of 7805 studies retrieved, 38 were deemed eligible for inclusion. For patients receiving first-line ICIs-based therapy in real-world practice, the pooled median PFS and OS were 7.03 (95% CI: 5.55-8.51) and 14.39 (95% CI: 10.91-17.86) months. The ORR and DCR were 0.432 (95% CI: 0.327-0.538) and 0.756 (95% CI: 0.677-0.836), according to mRECIST 1.1, 0.317 (95% CI: 0.218-0.416) and 0.740 (95% CI: 0.644-0.835), judged by RECIST 1.1. The best outcomes of survival and response rate were observed in ICIs-based combination therapy of ICIs, TKIs, plus LRTs. Furthermore, ORR, DCR judged by mRECIST 1.1, and PFS could be potential prognostic factors for OS. CONCLUSIONS: This research revealed diversified first-line ICIs-based therapies for advanced HCC in real-world practice. Future studies are needed to adopt prospective, multicentric and comparative designs to test the ICIs-based combination therapies, especially triple therapies of ICIs, TKIs, plus LRTs.

Dichloroacetate restores colorectal cancer chemosensitivity through the p53/miR-149-3p/PDK2-mediated glucose metabolic pathway.

The development of chemoresistance remains a major challenge that accounts for colorectal cancer (CRC) lethality. Dichloroacetate (DCA) was originally used as a metabolic regulator in the treatment of metabolic diseases; here, DCA was assayed to identify the mechanisms underlying the chemoresistance of CRC. We found that DCA markedly enhanced chemosensitivity of CRC cells to fluorouracil (5-FU), and reduced the colony formation due to high levels of apoptosis. Using the microarray assay, we noted that miR-149-3p was involved in the chemoresistance of CRC, which was modulated by wild-type p53 after DCA treatment. In addition, PDK2 was identified as a direct target of miR-149-3p. Mechanistic analyses showed that overexpression of miR-149-3p enhanced 5-FU-induced apoptosis and reduced glucose metabolism, similar to the effects of PDK2 knockdown. In addition, overexpression of PDK2 partially reversed the inhibitory effect of miR-149-3p on glucose metabolism. Finally, both DCA treatment and miR-149-3p overexpression in 5-FU-resistant CRC cells were found to markedly sensitize the chemotherapeutic effect of 5-FU in vivo, and this effect was also validated in a small retrospective cohort of CRC patients. Taken together, we determined that the p53/miR-149-3p/PDK2 signaling pathway can potentially be targeted with DCA treatment to overcome chemoresistant CRC.

On simulating cold-stunned sea turtle strandings on Cape Cod, Massachusetts.

Kemp's ridley sea turtles were on the verge of extinction in the 1960s. While these sea turtles have slowly recovered, they are still critically endangered. In the last few years, the number of strandings on the beaches of Cape Cod, Massachusetts has increased by nearly an order of magnitude relative to preceding decades. This study uses a combination of ocean observations and a well-respected ocean model to investigate the causes and transport of cold-stunned sea turtles in Cape Cod Bay. After validating the model using satellite-tracked drifters and local temperature moorings, ocean currents were examined in Cape Cod Bay in an attempt to explain stranding locations as observed by volunteers and, for some years, backtracking was conducted to examine the potential source regions. The general finding of this study is that sub 10.5°C water temperatures in combination with persistently strong wind stress (>0.4 Pa), results in increased strandings along particular sections of the coast and are dependent on the wind direction. However, it is still uncertain where in the water column the majority of cold-stunned turtles reside and, if many of them are on the surface, considerable work will need to be done to incorporate the direct effects of wind and waves on the advective processes.

Dichloroacetate Overcomes Oxaliplatin Chemoresistance in Colorectal Cancer through the miR-543/PTEN/Akt/mTOR Pathway.

Chemoresistance is responsible for most colorectal cancer (CRC) related deaths. In this study, we found that dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, can be used as a sensitizer for oxaliplatin (L-OHP) chemoresistant CRC cells. The aim of this study was to explore the ability of DCA to overcome L-OHP resistance in CRC cells and to identify the underlying molecular mechanisms. We found that DCA sensitizes chemoresistant CRC cells to L-OHP-induced cytotoxic effects by inhibiting clone formation capacity and promoting cell apoptosis. A microRNA (miRNA) array was used for screen, and miR-543 was identified and shown to be downregulated after DCA treatment. The expression of miR-543 was higher in chemoresistant CRC cells than in chemosensitive CRC cells. Overexpression of miR-543 increased chemoresistance in CRC cells. The validated target gene, PTEN, was negatively regulated by miR-543 both in vitro and in vivo, and PTEN was upregulated by DCA through miR-543. In addition, overexpression of miR-543 reversed the inhibition of colony formation after DCA treatment. Furthermore, the Akt/mTOR pathway is activated by miR-543 and is involved in the miR-543 induced chemoresistance. There was a significant inverse relationship between miR-543 expression and PTEN level in CRC patients, and high miR-543 expression was associated with worse prognosis. In conclusion, DCA restored chemosensitivity through miR-543/PTEN/Akt/mTOR pathway, and miR-543 may be a potential marker or therapeutic target for chemoresistance in CRC.

Tetrandrine inhibits differentiation of proinflammatory subsets of T helper cells but spares de novo differentiation of iTreg cells.

Tetrandrine (TET) is an anti-inflammatory compound isolated from Chinese herb Stephania tetrandra S. Moore. It was reported recently that the differentiation of Th17 cells was inhibited, while the generation of induced Treg cells (iTregs) was promoted, by TET treatment. We therefore carefully examined the effect of TET on the differentiation of four major subsets of T helper cells. The results showed that in vitro treatment with TET potently inhibited the differentiation of Th1, Th2 and Th17 cells. Administration of LPS resulted in a mixed Th1, Th2 and Th17 responses in normal mice, and such effect of LPS was inhibited by in vivo TET treatment as well. In contrast, TET did not promote or inhibit the in vitro generation of iTregs from naïve CD4+CD25-Foxp3/gfp- T cells. Furthermore, spontaneous and rapamycin-induced conversion of naïve CD4+CD25-Foxp3/gfp- T cells into Foxp3-expressing iTregs in congenic mice was not affected by TET treatment. Thus, TET had the capacity to inhibit the differentiation of proinflammatory Th1, Th2 and Th17 cells, while sparing the generation of Tregs. As a Treg-friendly and broad spectrum anti-inflammatory agent, the molecular mechanism and the therapeutic potential of TET in various human inflammatory diseases should be further studied.

Modulation of Regulatory T Cell Activity by TNF Receptor Type II-Targeting Pharmacological Agents.

There is now compelling evidence that tumor necrosis factor (TNF)-TNF receptor type II (TNFR2) interaction plays a decisive role in the activation, expansion, and phenotypical stability of suppressive CD4+Foxp3+ regulatory T cells (Tregs). In an effort to translate this basic research finding into a therapeutic benefit, a number of agonistic or antagonistic TNFR2-targeting biological agents with the capacity to activate or inhibit Treg activity have been developed and studied. Recent studies also show that thalidomide analogs, cyclophosphamide, and other small molecules are able to act on TNFR2, resulting in the elimination of TNFR2-expressing Tregs. In contrast, pharmacological agents, such as vitamin D3 and adalimumab, were reported to induce the expansion of Tregs by promoting the interaction of transmembrane TNF (tmTNF) with TNFR2. These studies clearly show that TNFR2-targeting pharmacological agents represent an effective approach to modulating the function of Tregs and thus may be useful in the treatment of major human diseases such as autoimmune disorders, graft-versus-host disease (GVHD), and cancer. In this review, we will summarize and discuss the latest progress in the study of TNFR2-targeting pharmacological agents and their therapeutic potential based on upregulation or downregulation of Treg activity.