A tumor microenvironment-stimuli responsive nano-prodrug for overcoming gemcitabine chemoresistance by co-delivered miRNA-21 modulator.

Gemcitabine (Gem) has been recommended as a first-line clinical chemotherapeutics for pancreatic ductal adenocarcinoma (PDAC) treatment. Gem treatment could generate chemoresistance associated with abnormal expressions of multiple miRNAs. In the PDAC setting, miRNA-21 (miR-21) overexpression is an important contributing factor of inducing Gem chemoresistance. Inhibition of miR-21 can significantly increase Gem chemosensitivity, which requires an efficient delivery platform to conduct combinational Gem and miR-21 siRNA (miR-21i) therapy. Herein, we synthesized a tumor microenvironment (TME) stimuli-responsive poly(beta-amino ester)s (PBAE)-based polymer nano-prodrug (miR-21i@HA-Gem-SS-P12) that could co-deliver miR-21 siRNA and Gem. The disulfide linkages conjugating GEM onto PBAE can be triggered by elevated reduction stimulus in TME to release the cargo Gem. The hyaluronic acid (HA) fabrication further improved the drug accumulation at the tumor site. Benefiting from the multiple functional improvements and synergism between Gem and miR-21i, the miR-21i@HA-Gem-SS-P12 nano-prodrugs displayed superior tumor inhibition in PDACin vitroandin vivo. This study established an effective stimuli-responsive nano-prodrug strategy for cooperative treatment with small molecule agents and nucleotide modulators in PDAC.

In Situ Formed ROS-Responsive Hydrogel with STING Agonist and Gemcitabine to Intensify Immunotherapy against Pancreatic Ductal Adenocarcinoma.

Immunotherapy, the most revolutionary anticancer strategy, faces major obstacles in yielding desirable outcomes in pancreatic ductal adenocarcinoma (PDAC) due to the highly immunosuppressive tumor microenvironment (TME). Meanwhile, when used alone, the traditional first-line chemotherapeutic agent gemcitabine (GEM) in PDAC treatment is also insufficient to achieve lasting efficacy. In this study, a reactive oxygen species degradable hydrogel system, denoted as GEM-STING@Gel, is engineered to codeliver gemcitabine and the stimulator of interferon genes (STING) agonist DMXAA (5,6-dimethylxanthenone-4-acetic acid) into the tumor site. In this work, the strategy addresses the major challenges of current immunotherapies with a facile platform, which can synergistically activate innate immunity and promote the cytotoxic T lymphocytes infiltration at the tumor site, thereby modulating the immunosuppressive TME. Further, the efficient therapeutic potency of the immunotherapy is confirmed in an orthotopic postsurgical model, unleashing the translational potential to prevent tumor recurrence after surgical resection. This study underscores the advantages of this integrative strategy that combines chemotherapy, immunotherapy, and biomaterial-based hydrogel, including improved therapeutic efficacy, operational convenience, and superior biosafety.

A self-assembly nano-prodrug for triple-negative breast cancer combined treatment by ferroptosis therapy and chemotherapy.

Chemotherapeutics have been recommended as the standard protocol for inoperable patients with triple-negative breast cancer (TNBC) at advanced stage, yet limited success has been achieved in prolonging survival rates by this monotherapy. A major reason for this failure is the chemo-resistance from traditional apoptotic pathways resulting in poor therapeutic effect. Ferroptosis has become a powerful modality of no-apoptotic cell death, which can effectively evade chemo-resistance in apoptotic pathways. Herein, we propose an active-targeting small-molecular self-assembly nano-prodrug for co-delivery of chemotherapeutics (CPT), Ferrocene (Fc) and GPX4 inhibitor (RSL3) to overcome the chemo-resistance from traditional apoptotic pathways. In this nano-prodrug, the disulfide linkage not only serves as a GSH-responsive trigger, but also exhibits a stable self-assembly behavior that forms nanoparticle. Interestingly, the RSL3 can be loaded during this self-assembly process that forms a three-components nano-prodrug. In tumor environment, the high GSH level can disassemble the nano-prodrug to trigger the release of the parent drug, which can improve the therapeutic effect by synergistic effects of ferroptosis and apoptosis. In different TNBC mice models, the nano-prodrug is encapsulated into RGD-modified phospholipid micelles (DSPE-PEG2000-RGD) and exhibits high anti-tumor and anti-metastasis efficacy, especially in orthotopic models. The application of ferroptosis to assist the enhancement of chemotherapeutics may serve as a promising strategy for TNBC treatment. STATEMENT OF SIGNIFICANCE: Chemotherapeutics have been recommended as the standard of care for palliative and adjuvant treatment in patients with triple-negative breast cancer (TNBC), yet limited success has been achieved in prolonging the overall survival of patients by this monotherapy. A major reason for this failure is the chemo-resistance from traditional apoptotic pathways resulting in poor therapeutic effect. Thus, the co-delivery of the apoptosis and ferroptosis drug may overcome or evade the resistance in chemotherapy-induced apoptotic pathways and provide a promising strategy to combat TNBC. In this work, we developed a small-molecular self-assembly nano-prodrug for co-delivery of chemotherapeutics (CPT), Ferrocene (Fc) and ferroptosis resistance inhibitor (RSL3), which could overcome the chemo-resistance and improve the therapeutic effect by synergistic effects of ferroptosis and apoptosis.

A biomimetic nanodrug for enhanced chemotherapy of pancreatic tumors.

Pancreatic ductal adenocarcinoma (PDAC) remains to be one of the highest malignant tumors due to its poor chemotherapeutic efficacy and multidrug resistance. A major reason for the failure in chemotherapy is poor drug accumulation into PDAC tumor tissues due to the overexpressed extracellular matrix (ECM) stroma, which forms a major obstacle limiting the deep tissue penetration of chemotherapeutics. Herein, we report a tumor microenvironment (TME)-responsive nanodrug, based on PDAC cell membrane-coated gold nanocages (AuNCs), to co-deliver the chemotherapeutics (GEM) and nitrogen oxide (NO) donor (L-Arg) to enhance drug accumulation and reduce chemoresistance. The high glutathione (GSH) level can trigger the cleavage of the disulfide bond on nanodrug to release GEM. Moreover, the elevated ROS level could activate L-Arg to generate NO, which synergistically facilitate GEM to penetrate into deep tissues by means of vasodilation and normalization of blood vessels in the PDAC tumor tissue. In addition, AuNCs not only serve as a photothermal agent for chemotherapy, but also generate photoacoustic signals to monitor drug accumulation and distribution. As expected, the strategy demonstrates to be remarkable in treating different xenograft mice models, especially in orthotopic and patient-derived xenograft (PDX) models. The current study defines a useful therapeutic tool for treating PDAC tumors.

An Ionic Liquid Ablation Agent for Local Ablation and Immune Activation in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma rapidly acquires resistance to chemotherapy, remaining a fatal disease. Immunotherapy is one of the breakthroughs in cancer treatment, which includes immune checkpoint inhibitors, chimeric antigen receptor T-cell immunotherapy, and neoantigen vaccines. However, immunotherapy has not achieved satisfactory results in the treatment of pancreatic cancer. Immunogenic death comprises proinflammatory cell death, which provides a way to enhance tumor immunogenicity and promote an immune response in solid tumors. Herein, an ionic liquid ablation agent (LAA), synthesized from choline and geranic acid, which triggers necrosis-induced immunotherapy by remodeling an immunosuppressive "cold" tumor to an immune activated "hot" tumor is described. The results indicate that LAA-treated tumor cells can enhance immunogenicity, inducing dendritic cell maturation, macrophage M1 polarization, and cytotoxic T lymphocyte infiltration. The results of the present study provide a novel strategy for solid tumor immunotherapy.

Situs inversus totalis with local metastasis of gallbladder carcinoma and variation of the common hepatic artery.

BACKGROUND: Situs inversus totalis (SIT) is a rare congenital anomaly characterized by a complete transposition of all the viscera. SIT cases were usually reported because of the presence of tumors, leading to false association between them. Therefore, any research that advances our understanding on SIT is highly required. This study firstly describes a very rare case of SIT with "jumping" metastasis to pancreas of gallbladder carcinoma. CASE PRESENTATION: A 69-year-old female patient presented at our hospital with complaints of one month of epigastric pain was studied. She had not sought for treatment prior the visit. Imaging examinations of this patient revealed SIT and a variation of the common hepatic artery with concomitant tumors of gallbladder and pancreas. However, there was no evidence of distant metastases beyond the abdominal cavity. She underwent a combination of radical cholecystectomy, total pancreatectomy, splenectomy and hepatic artery-splenic artery reconstruction. Histological analyses revealed metastasis of the gallbladder carcinoma in to the pancreas. Although the patient opted against chemotherapy, she survived without tumor for 16 months following the surgery. A review of the current literature on association with SIT and tumor occurrence was presented. CONCLUSIONS: It is a great surgical challenge for the resection of multicenter hepatobiliary and pancreatic tumors in such rare SIT anatomical abnormalities with vascular variants. A reliable surgical plan based on detailed preoperative imaging and intraoperative anatomical exploration is crucial to achieving radical resection.

Engineered a dual-targeting biomimetic nanomedicine for pancreatic cancer chemoimmunotherapy.

The therapeutic effect of chemotherapeutics such as gemcitabine against pancreatic cancer is considerably attenuated by immune-suppressive tumor microenvironment. Improvement of chemotherapeutic efficacy by targeting tumor-associated macrophage and reprograming tumor microenvironment to enhance their efficacy may become a promising strategy. To this end, we developed a biomimetic dual-targeting nanomedicine (PG@KMCM) where gemcitabine-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles are coated with a layer of bioengineered cancer cell membrane that stably expresses peptides targeting M2-like macrophages (M2pep) while reserving tumor-associated antigens (TAAs). The PG@KMCM nanomedicine enables the simultaneous targeted delivery of gemcitabine to pancreatic tumor sites and TAMs to potentiate its therapeutic effects. Furthermore, the combination of an immune checkpoint inhibitor (PD-L1 antibody) with PG@KMCM synergistically enhanced the anti-tumoral effect by reprogramming the immune-suppressive tumor microenvironment, including the elimination of PD-L1-positive macrophages and the downregulation of PD-L1 expression. Our study proved dual-targeting PG@KMCM nanomedicine in combination with PD-L1 immune checkpoint inhibitor therapy is able to effectively reprogram the tumor microenvironment and kill pancreatic cancer cells to enhance overall therapeutic potential.

Direct Synthesis of Photosensitizable Bacterial Cellulose as Engineered Living Material for Skin Wound Repair.

Living materials based on bacterial cellulose (BC) represent a natural and promising candidate for wound dressing. Both physical adsorption and chemical methods have been applied to BC for realizing antibacterial function. However, effective and long-lasting incorporation of bactericidal moieties to BC remains challenging. Herein, a Komagataeibacter sucrofermentans-based direct synthetic method to fabricate photosensitizer-grafted BC through in situ bacterial metabolism in the presence of TPEPy-modified glucose is explored. The results verify that the direct biosynthesis method is efficient and convenient to endow BC with outstanding fluorescence and light-triggered photodynamic bactericidal activity for skin wound repair. This work presents a new approach to fabricate eco-friendly and active wound dressing with light-controlled bactericidal activity by microbial metabolism. The successful modification of the glucose carbon source of microorganisms also offers insights for biosyntheses of other living materials through microbial metabolism.

Gallbladder Adenosquamous Cancer with Situs Inversus Totalis: A Case Report and Literature Review.

BACKGROUND: Situs inversus totalis (SIT) is a rare genetic congenital disease, characterized with complete right-to-left inversion of all the internal organs. We herein describe a meaningful case which was diagnosed as gallbladder adenosquamous carcinoma, a rare histology type of gallbladder cancer, with SIT. CASE PRESENTATION: A 59-year-old Chinese woman was admitted for persistent epigastric distention and intermittent abdominal pain. The abdominal CT scan revealed a huge mass at the gallbladder bottom, involving the adjacent transverse colon and liver. En-bloc radical resection of the gallbladder cancer, including partial colectomy and hepatectomy with regional node dissection, followed by colocolostomy and Roux-en-Y choledochojejunostomy, was successfully performed. Pathology analysis indicated an adenosquamous carcinoma with positive adenocarcinoma markers (CK7, CK19) and squamous carcinoma markers (CK5/6, P63). CONCLUSION: The SIT anomaly might increase the risk of malignancies by sharing genome mutations, suggesting the importance of surveillance in the SIT settings.

Heterochronous Metastases of Lung Adenocarcinoma to Pancreas and Liver: A Case Report from Pathological Perspectives.

Immunohistochemistry (IHC) is a vital tool to distinguish tumor metastases from primary lesions in addition to morphologic analysis. In this study, a 64-year-old female with a past surgical history of lung adenocarcinoma 11 years ago was presented with recurrence of liver nodular lesions after multiple surgical procedures, including the Whipple procedure for pancreatic head adenocarcinoma and cytoreductive surgery for liver metastasis. Liver biopsy and review of the previous specimens, based on IHC analyses, suggested heterochronous metastases of lung adenocarcinoma to the digestive systems in a long-time span, instead of primary pancreatic adenocarcinoma. This case demonstrates the potential for misdiagnoses from morphologic analysis alone and suggests the necessity of IHC analyses to avoid misjudgment on tumor phenotypes, when a previous oncologic history is presented.

Tumor-triggered personalized microRNA cocktail therapy for hepatocellular carcinoma.

As one of the most malignant primary cancers, hepatocellular carcinoma (HCC) still lacks an efficient therapeutic strategy to date. Here, we developed a polymer-based nanoplatform PEI-ßCD@Ad-CDM-PEG (PCACP) for functional microRNA (miRNA) therapy. PCACP exhibits excellent stability in physiological solutions, but sensitive PEG detachment and size transformation in an acidic tumor environment due to the breakdown of pH-responsive linkages, promoting tumor penetration and cellular uptake of nanoparticles, further facilitating transfection efficiency due to the proton sponge effect of polycations. We present a novel miRNA cocktail therapy by encapsulating miR-199a/b-3p mimics (miR199) and antimiR-10b (antimiR10b) into PCACP for eliminating HCC. Validated by qRT-PCR, immunoblotting and immunohistochemistry, compared with miR199 or antimiR10b delivered alone, miR-cocktail therapy substantially inhibits HCC cell proliferation and tumor growth by targeting mTOR, PAK4, RHOC and epithelial-mesenchymal transition (EMT) pathways both in vitro and in vivo (i.v. injection). Furthermore, we proposed personalized miR-cocktail therapy by adjusting the encapsulated miRNA formula according to the miRNA profiling of a patient's tumor sample. The personalized PCACP/miR-cocktail system exhibits significant tumor suppression and multitarget regulation on patient derived xenografts (PDXs), representing a notable effect improvement over conventional gene therapy. The tumor-acidity-cleavable PCACP/miR-cocktail system, with loaded miRNA controllability and high transfection efficiency, is a promising personalized therapeutic strategy for future HCC treatment.

A Serosa-Originated Gastric Stromal Tumor Misdiagnosed by Ultrasonography and Frozen Section Pathology: A Case Report.

Gastric gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm, typically arising from the muscularis propria layer of the stomach wall. Serosa-derived GIST is rarely seen and has not been reported yet. A 49-year-old Chinese female was presented with marked abdominal distension. Ultrasonography revealed a retroperitoneal tumor adjacent to the stomach wall with an intact structure of five echo layers, indicating a non-stomach tumor origin. Preoperative radiological studies suggested tight tumor-stomach adjacency, which was confirmed by intraoperative dissection. Initial frozen section indicated a pathological diagnosis of spindle cell tumor, which turned out to be a gastric GIST originated from the serosa layer of the stomach wall. The current case demonstrates the rare occurrence of serosa-derived GIST. This case also suggests difficulties in preoperative diagnosis of gastric GISTs, especially when uncommon pathological conditions like rare tumor origins were presented.

Hemorrhagic cholecystitis with rare imaging presentation: a case report and a lesson learned from neglected medication history of NSAIDs.

BACKGROUND: Gallbladder carcinogenesis, frequently occurredin chronic cholecystitis patients, requires radical resection. We herein describe a hemorrhagic cholecystitis case that failed to be differentiated from gallbladder cancer preoperatively owing to the neglected medication history of long term oral nonsteroidal anti-inflammatory drugs (NSIADs) intake. CASE PRESENTATION: A 57-year-old Chinese female was admitted for right upper quadrant pain with the initial diagnosis of cholecystitis. Radiological studies were unable to exclude the differential diagnosis of suspected gallbladder cancer. During the scheduled radical resection of the suspected lesions, the gross dissection showed an interesting presentation of hemorrhagic cholecystitis, without any pathological evidence of malignancies. Additional postoperative investigation revealed a neglected medication history of long-term NSAIDs use. CONCLUSIONS: This case suggests the importance of preoperative review of medication history and patient education on prescription drug abuse.

Primary Hepatic Neuroendocrine Tumor Mimicking Ruptured Hepatocellular Carcinoma with AFP Elevation: A Case Report and Literature Review.

Liver cancer is a common malignant disease in China, while the primary hepatic neuroendocrine tumor (PHNET) is extremely rare presented with various manifestations. We herein describe an interesting PHNET case, which was clinically diagnosed as hepatocellular carcinoma (HCC) based on strong clinical evidence and the national guideline, but confirmed to be PHNET by pathology. A42-year-old Chinese male was admitted for persistent upper abdominal pain, and CT scan revealed a huge liver tumor in the left lobe. The tumor presented attributes of tumor rupture, portal vein tumor thrombus, elevated serum AFP level, background hepatitis B virus infection history, and radiological features mimicking typical HCC. After left semi-hepatectomy was performed for curative treatment of the primary "HCC", the pathology demonstrated the correct diagnosis be poorly differentiated neuroendocrine carcinoma (NEC). The immunohistochemistry assays showed positive neuroendocrine markers of CgA and Syn and negative HCC markers of Hep Par 1 and GPC3, ruling out concurrent HCC. This case and literature review suggest that in spite of rare incidence, PHNET should be considered as a possible diagnosis when lacking a confirmative pathology result, even when sufficient evidence of typical presentation exist to establish the clinical diagnosis of HCC.

A dendritic, redox-responsive, supramolecular (Dr.S) system for lysis-triggered delivery for drug-resistant renal cancer.

Purpose: Aiming to improve the drug loading capacity of dendritic nanoparticles and enhance delivery efficacy in drug-resistant cancer, we developed and optimized a more advanced dendritic, redox-responsive, supramolecular (Dr.S) system for intravenous RAD001 administration. Materials and methods: The Dr.S system was engineered by linking 3rd generation polyamidoamine dendrimers (G3 PAMAM) with 8-arm polyethylene glycol (PEG) to encapsulate a molecular targeted agent RAD001. The drug-loading capacity was measured by ultraviolet-visible spectrophotometry. In vitro release behavior was determined with a two-compartment model, and the in vivo distribution pattern was tracked by Cy5.5 fluorescence. The therapeutic effect of Dr.S/RAD001 was evaluated in RAD001-resistant cancer cells and tumor-bearing nude mice, respectively. Results: The Dr.S system encapsulating RAD001 with a loading efficiency of 10.6% formed a core-shell structure, by shifting hydrophobic PAMAM/RAD001 components towards inner space and exposing the hydrophilic PEG on the surface. The Dr.S/RAD001 system could respond to a lysis-mimicking reduction stimulus, and functionally release cargoes to facilitate tumor accumulation and cellular internalization. These features contributed to the enhanced anti-tumor activity of RAD001 in renal cancers in vitro and in vivo. The Dr.S/RAD001 system also reversed acquired RAD001-resistance by a 60-fold increase in tumor accumulation of the therapeutics. Conclusion: The functional Dr.S/RAD001 system enables lysis-triggered release of RAD001 to achieve better tumor accumulation, which helps overcome acquired drug resistance in renal cancers.

Endogenous Interleukin 18 Suppresses Liver Regeneration After Hepatectomy in Mice.

The comprehensive role of interleukin (IL) 18 during liver regeneration is barely studied. Our aim is to evaluate the role of IL18 in liver regeneration after partial hepatectomy (PH) in mice. The expression profile of IL18 in the liver and the gut after 70% PH was measured. Liver samples after 70% and 85% PH from IL18 knockout (IL18-/- ) mice and wild type (WT) mice were collected for comparison of liver regeneration. The effect of recombinant IL18 on liver regeneration was tested in IL18-/- mice, and the utility of IL18 binding protein (BP) was also evaluated following 70% PH in WT mice. Expression levels of IL18 in the liver and the gut elevated after 70% PH. The liver weight/body weight ratios (LBWRs) after PH were significantly higher in IL18-/- mice than those in WT mice. Recombinant IL18 injection significantly decreased LBWR at 7 days after 70% PH in IL18-/- mice. The expression of cyclin D1, EdU labeling index, and Ki-67 proliferation index were much higher in IL18-/- mice than those in WT mice after 70% PH. The expression level of glypican 3 (GPC3) in WT mice significantly elevated during liver regeneration. In contrast, the expression level of GPC3 in IL18-/- mice remained roughly unchanged during liver regeneration. IL18BP injection significantly increased the LBWR at 7 days after 70% PH in WT mice. In conclusion, endogenous IL18 inhibited liver regeneration after PH in mice, possibly through up-regulating GPC3. IL18BP may be an effective agent to promote liver regeneration after PH.

Reverting chemoresistance of targeted agents by a ultrasoluble dendritic nanocapsule.

Malignancies treated by insoluble targeted agents show low dose exposure and therapeutic responses, therefore easily develop drug resistance. Nanoparticle-modified drugs might disrupt chemoresistance by increasing dose exposure and altering resistance pathways, as administrated via the intravenous route to maximize efficacy. Herein, we proposed a self-assembled nanocapsulation strategy to construct a nanocomplex with multiarm polymer and novel dendrimer series (MAP-mG3) for encapsulating insoluble inhibitors by nucleotide lock. MAP-mG3 delivering the mammalian target of rapamycin (mTOR) inhibitor OSI-027 (MAP-mG3/OSI-027) showed higher loading capacity, enhanced solubility, controlled release, and increased intracellular tumoral accumulation. MAP-mG3/OSI-027, more efficiently than the free targeted agents, attenuated mTOR phosphorylation and inhibited growth of pancreatic cancer cells. In addition, MAP-mG3/OSI-027 reverted chemoresistance to OSI-027 in drug resistance pancreatic cancer by increasing intracellular dose exposure, as well as regulating ABCB1 expression and compensatory pathways. The optimized nanocapsulation design provides an effective strategy to engineer and reactivate insoluble targeted agents for chemoresistant applications.

A novel approach with holmium laser ablation for endoscopic management of intrahepatic biliary stricture.

BACKGROUND: Hepatolithiasis, featuring high incidence, severe symptoms, and common recurrence, poses a heavy disease burden. Endoscopic management provides an opportunity to cure hepatolithiasis, but fails to properly resolve biliary stricture without additional interventional techniques. An innovative approach towards endoscopic management of biliary stricture is required. METHODS: Holmium laser ablation was applied to biliary strictures via endoscopic access. Patients' demographic, operative, and follow-up data after receiving holmium laser ablation were retrospectively collected for analysis. RESULTS: A total of 15 patients (4 males and 11 females) underwent stricture ablation by holmium laser via cholangioscopy. All the patients successfully received holmium laser ablation, indicating a technical success rate of 100%. No postoperative mortality or no major perioperative complication was observed. During the follow-up period, the recurrence-free rate was 73% at 2 years and 67% at 5 years. CONCLUSIONS: We successfully developed a novel technique of biliary stricture removal by cholangioscopic holmium laser ablation with satisfying clinical outcomes.

Impact of national Human Development Index on liver cancer outcomes: Transition from 2008 to 2018.

BACKGROUND: Liver cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide. Socioeconomic development, indicated by the Human Development Index (HDI), is closely interconnected with public health. But the manner in which social development and medical advances influenced liver cancer patients in the past decade is still unknown. AIM: To investigate the influence of HDI on clinical outcomes for patients with existing liver cancer from 2008 to 2018. METHODS: The HDI values were obtained from the United Nations Development Programme, the age-standardized incidence and mortality rates of liver cancer were obtained from the GLOBOCAN database to calculate the mortality-to-incidence ratio, and the estimated 5-year net survival of patients with liver cancer was provided by the CONCORD-3 program. We then explored the association of mortality-to-incidence ratio and survival with HDI, with a focus on geographic variability across countries as well as temporal heterogeneity over the past decade. RESULTS: From 2008 to 2018, the epidemiology of liver cancer had changed across countries. Liver cancer mortality-to-incidence ratios were negatively correlated and showed good fit with a modified "dose-to-inhibition response" pattern with HDI (r = -0.548, P < 0.0001 for 2018; r = -0.617, P < 0.0001 for 2008). Cancer survival was positively associated with HDI (r = 0.408, P < 0.01) and negatively associated with mortality-to-incidence ratio (r = -0.346, P < 0.05), solidly confirming the interrelation among liver cancer outcome indicators and socioeconomic factors. Notably, in the past decade, the HDI values in most countries have increased alongside a decreasing tendency of liver cancer mortality-to-incidence ratios (P < 0.0001), and survival outcomes have simultaneously improved (P < 0.001), with significant disparities across countries. CONCLUSION: Socioeconomic factors have a significant influence on cancer outcomes. HDI values have increased along with improved cancer outcomes, with significant disparities among countries.

A PEGylated megamer-based microRNA delivery system activatable by stepwise microenvironment stimulation.

We developed a biodegradable, oncosensitive, megamer-based delivery system for miRNA therapy. The miRNA nanotherapeutics, activatable by stepwise stimulation of acidity and reduction mimicking tumor microenvironment, efficiently improve liver-specific miR-122 expression, increasing the possibility of translational application of miR-122 therapy against liver cancer.