N6-methyladenosine-modified circPLPP4 sustains cisplatin resistance in ovarian cancer cells via PIK3R1 upregulation.

BACKGROUND: Cisplatin (CDDP) is the first-line chemotherapeutic strategy to treat patients with ovarian cancer (OC). The development of CDDP resistance remains an unsurmountable obstacle in OC treatment and frequently induces tumor recurrence. Circular RNAs (circRNAs) are noncoding RNAs with important functions in cancer progression. Whether circRNAs function in CDDP resistance of OC is unclear. METHODS: Platinum-resistant circRNAs were screened via circRNA deep sequencing and examined using in situ hybridization (ISH) in OC. The role of circPLPP4 in CDDP resistance was assessed by clone formation and Annexin V assays in vitro, and by OC patient-derived xenografts and intraperitoneal tumor models in vivo. The mechanism underlying circPLPP4-mediated activation of miR-136/PIK3R1 signaling was examined by luciferase reporter assay, RNA pull-down, RIP, MeRIP and ISH. RESULTS: circPLPP4 was remarkably upregulated in platinum resistant OC. circPLPP4 overexpression significantly enhanced, whereas circPLPP4 silencing reduced, OC cell chemoresistance. Mechanistically, circPLPP4 acts as a microRNA sponge to sequester miR-136, thus competitively upregulating PIK3R1 expression and conferring CDDP resistance. The increased circPLPP4 level in CDDP-resistant cells was caused by increased RNA stability, mediated by increased N6-methyladenosine (m6A) modification of circPLPP4. In vivo delivery of an antisense oligonucleotide targeting circPLPP4 significantly enhanced CDDP efficacy in a tumor model. CONCLUSIONS: Our study reveals a plausible mechanism by which the m6A -induced circPLPP4/ miR-136/ PIK3R1 axis mediated CDDP resistance in OC, suggesting that circPLPP4 may serve as a promising therapeutic target against CDDP resistant OC. A circPLPP4-targeted drug in combination with CDDP might represent a rational regimen in OC.

Inducing the Abscopal Effect in Liver Cancer Treatment: The Impact of Microwave Ablation Power Levels and PD-1 Antibody Therapy.

Microwave ablation (MWA) is an effective treatment for liver cancer (LC), but its impact on distant tumors remains to be fully elucidated. This study investigated the abscopal effects triggered by MWA treatment of LC, at different power levels and with or without combined immune checkpoint inhibition (ICI). We established a mouse model with bilateral subcutaneous LC and applied MWA of varied power levels to ablate the right-sided tumor, with or without immunotherapy. Left-sided tumor growth was monitored to assess the abscopal effect. Immune cell infiltration and distant tumor neovascularization were quantified via immunohistochemistry, revealing insights into the tumor microenvironment and neovascularization status. Th1- and Th2-type cytokine concentrations in peripheral blood were measured using ELISA to evaluate systemic immunological changes. It was found that MWA alone, especially at lower power, promoted distant tumor growth. On the contrary, combining high-power MWA with anti-programmed death (PD)-1 therapy promoted CD8+ T-cell infiltration, reduced regulatory T-cell infiltration, upregulated a Th1-type cytokine (TNF-α) in peripheral blood, and inhibited distant tumor growth. In summary, combining high-power MWA with ICI significantly enhances systemic antitumor immune responses and activates the abscopal effect, offering a facile and robust strategy for improving treatment outcomes.

A novel nomogram integrated with PDL1 and CEA to predict the prognosis of patients with gastric cancer.

INTRODUCTION: This study aimed to develop a prognostic nomogram for patients with gastric cancer (GC) based on the levels of programmed death 1 ligand 1 (PDL1) and carcinoembryonic antigen (CEA). METHODS: The nomogram was developed using data from a primary cohort of 247 patients who had been clinicopathologically diagnosed with GC, as well as a validation cohort of 63 patients. Furthermore, the nomogram divided the patients into three different risk groups for overall survival (OS)-the low-risk, middle-risk, and high-risk groups. Univariate and multivariate Cox hazard analyses were used to determine all of the factors included in the model. Decision curve analysis and receiver operating characteristic (ROC) curves were used to assess the accuracy of the nomogram. RESULTS: The Kaplan-Meier survival analysis revealed that metastasis stage, clinical stage, and CEA and PDL1 levels were predictors for progress-free survival (PFS) and OS of patients with GC. Metastasis stage, clinical stage, and CEA and PDL1 levels were found to be independent risk factors for the PFS and OS of patients with GC in a multivariate analysis, and the nomogram was based on these factors. The concordance index of the nomogram was 0.763 [95% confidence interval (CI) 0.740-0.787]. The area under the concentration-time curve of the nomogram model was 0.81 (95% CI 0.780-0.900). According to the decision curve analysis and ROC curves, the nomogram model had a higher overall net efficiency in forecasting OS than clinical stage, CEA and PDL1 levels. CONCLUSION: In conclusion, we proposed a novel nomogram that integrated PDL1 and CEA, and the proposed nomogram provided more accurate and useful prognostic predictions for patients with GC.

IgG1 Is the Optimal Subtype for Treating Atherosclerosis by Inducing M2 Macrophage Differentiation, and Is Independent of the FcγRIIA Gene Polymorphism.

In recent years, it has been established that atherosclerosis is an autoimmune disease. However, little is currently known about the role of FcγRIIA in atherosclerosis. Herein, we sought to investigate the relationship between FcγRIIA genotypes and the effectiveness of different IgG subclasses in treating atherosclerosis. We constructed and produced different subtypes of IgG and Fc-engineered antibodies. In vitro, we observed the effect of different subtypes of IgG and Fc-engineered antibodies on the differentiation of CD14+ monocytes from patients or healthy individuals. In vivo, Apoe-/- mice were fed a high-fat diet (HFD) for 20 weeks and administered injections of different CVI-IgG subclasses or Fc-engineered antibodies. Flow cytometry was used to assess the polarization of monocytes and macrophages. Although CVI-IgG4 reduced the release of MCP-1 compared to the other subtypes, IgG4 did not yield an anti-inflammatory effect by induction of human monocyte and macrophage differentiation in vitro. Furthermore, genetic polymorphisms of FcγRIIA were not associated with different CVI-IgG subclasses during the treatment of atherosclerosis. In vivo, CVI-IgG1 decreased Ly6Chigh monocyte differentiation and promoted M2 macrophage polarization. We also found that the secretion of IL-10 was upregulated in the CVI-IgG1-treated group, whereas V11 and GAALIE exerted no significant effect. These findings highlight that IgG1 is the optimal subtype for treating atherosclerosis, and CVI-IgG1 can induce monocyte/macrophage polarization. Overall, these results have important implications for the development of therapeutic antibodies.

Single-cell RNA-Seq reveals CVI-mAb-induced Lyve1+ M2-like macrophages reduce atherosclerotic plaque area in Apoe-/- mice.

BACKGROUND: Atherosclerosis is a lipid imbalance-induced autoimmune disease. Macrophages participate in the development and progression of atherosclerosis. Although numerous studies have utilized single-cell RNA sequencing to identify the role of various macrophage phenotypes in atherosclerosis, the macrophage subpopulations that have therapeutic benefits against atherosclerosis are not fully understood. METHODS: In this study, a single-cell RNA sequencing analysis was performed on the F4/80+ macrophages of apolipoprotein E-deficient (Apoe-/-) mice on a normal diet (ND), a high-fat diet (HFD), and a high-fat diet (HFD) with collagen VI monoclonal antibodies (CVI-mAb) treatment. A population of M2-like macrophages expressing the hyaluronan receptor Lyve1 was almost exclusively detectable in Apoe-/- mice on an HFD with CVI-mAb treatment, compared with other groups. Differential gene expression and gene ontology enrichment analyses revealed specific gene expression patterns that distinguished this macrophage subset and uncovered its functions. RESULTS: Lyve1+ M2 macrophages appear to have specialized functions in lipid metabolism. Lyve1+ M2-like macrophages were sorted via fluorescence- activated cell sorting (FACS) and adoptively transferred to Apoe-/- mice fed an HFD. CONCLUSION: Our result showed that Lyve1+ M2 macrophages could reduce the plaque areas in Apoe-/- mice.

Transarterial Chemoembolization Followed by Hepatic Arterial Infusion Chemotherapy Combined a Tyrosine Kinase Inhibitor for Treatment of Large Hepatocellular Carcinoma.

OBJECTIVE: Evaluate the efficacy and safety of transarterial chemoembolization (TACE) sequential with hepatic arterial infusion chemotherapy (HAIC) and a tyrosine kinase inhibitor (TKI) for unresectable large hepatocellular carcinoma (HCC). METHODS: Patients with HCC size > 70 mm were included. They received 1-3 cycles of TACE and sequential HAIC every 3-6 weeks for 2-6 cycles, with each cycle given over a period of 48 hours (oxaliplatin plus fluorouracil/leucovorin). Patients also received sorafenib or lenvatinib beginning at the first TACE cycle and continuing until disease progression. Objective response rate (ORR) at 3 months was the primary endpoint. Progression-free survival (PFS) and safety were the secondary endpoints. RESULTS: From January 2020 to December 2020, 41 patients were included, who were divided into the drug-eluting bead TACE (DEB-TACE) group (n=13) and conventional TACE (cTACE) group (n=28). The overall ORR was 56.1% (23/41) using mRECIST criteria and 34.1% (14/41) using RECIST1.1 criteria. The median PFS of the cohort was 8 months. The ORR of the DEB-TACE group was 76.9% (10/13) vs. 46.4% (13/28) for the cTACE group (p = 0.06). The median PFS of the DEBTACE group was 12 months, and 6 months in the cTACE group (p = 0.09). Conversion hepatectomy was performed in 2 patients in the DEB-TACE group (15.4%), and in 3 patients in the cTACE group (10.7%). ALT/AST elevated, hypertension, nausea, and vomiting were the common treatment related adverse events. There was no treatment related death. CONCLUSION: TACE sequential with HAIC combined a TKI is a well-tolerated and promising tripletherapy for large, unresectable HCC.

XperCT facilitates sharp recanalization for the treatment of chronic thoracic venous occlusive disease in hemodialysis patients.

OBJECTIVE: Our objective was to evaluate the feasibility of XperCT combined fluoroscopy to guide sharp recanalization for the treatment of chronic thoracic venous occlusive disease in hemodialysis patients. METHODS: The records of hemodialysis patients with chronic thoracic venous occlusive disease who received endovascular sharp recanalization after conventional techniques failed were retrospectively reviewed. The sharp devices used for recanalization included the stiff end of a guidewire, Chiba biopsy needle, RUPS-100 set, and transseptal needle. The needle was advanced toward a target placed at the opposite end of the occlusion and was guided by fluoroscopy and/or XperCT. While the guidewire crossed the occlusion, endovascular procedures such as percutaneous angioplasty were performed for the treatment of the occlusion. RESULTS: The analysis included 32 sharp thoracic vein recanalization procedures in 29 patients. Two attempts in one patient failed, and in one patient the first attempt failed but the second attempt was successful. In one patient, two separate successful procedures were performed, and the other 26 procedures in 26 patients were successful. The overall technical success rate of sharp recanalization was 90%. The mean number of puncture attempts in the combined group was less than that of the fluoroscopy-guided alone group (2 vs 5, p < 0.05). The success rate of sharp recanalization in the combined group was higher (100% vs 86%), and the recanalization time (28.5 min vs 36 min, p > 0.05) was no different. There was no statistical difference in procedure-related complications between the groups. CONCLUSION: XperCT can facilitate sharp recanalization for the treatment of chronic thoracic venous occlusive disease in hemodialysis patients.

Ferritin Nanocaged Doxorubicin Potentiates Chemo-Immunotherapy against Hepatocellular Carcinoma via Immunogenic Cell Death.

Although immunotherapy of hepatocellular carcinoma using immune checkpoint inhibitors has achieved certain success, only a subset of patients benefits from this therapeutic strategy. The combination of immunostimulatory chemotherapeutics represents a promising strategy to enhance the effectiveness of immunotherapy. However, it is hampered by the poor delivery of conventional chemotherapeutics. Here, it is shown that H-ferritin nanocages loaded with doxorubicin (DOX@HFn) show potent chemo-immunotherapy in hepatocellular carcinoma tumor models. DOX@HFn is constructed with uniform size, high stability, favorable drug loading, and intracellular acidity-driven drug release. The receptor-mediated targeting of DOX@HFn to liver cancer cells promote cellular uptake and tumor penetration in vitro and in vivo. DOX@HFn triggers immunogenic cell death to tumor cells and promotes the subsequent activation and maturation of dendritic cells. In vivo studies in H22 subcutaneous hepatoma demonstrate that DOX@HFn significantly inhibits the tumor growth with >30% tumors completely eliminated, while alleviating the systemic toxicity of free DOX. DOX@HFn also exhibits robust antitumor immune response and tumoricidal effect in a more aggressive Hepa1-6 orthotopic liver tumor model, which is confirmed by the in situ magnetic resonance imaging and transcriptome sequencing. This study provides a facile and robust strategy to improve therapeutic efficacy of liver cancer.

The c-MYC-WDR43 signalling axis promotes chemoresistance and tumour growth in colorectal cancer by inhibiting p53 activity.

Oxaliplatin chemoresistance is a major challenge in the clinical treatment of colorectal cancer (CRC), which is one of the most common malignancies worldwide. In this study, we identified the tryptophan-aspartate repeat domain 43 (WDR43) as a potentially critical oncogenic factor in CRC pathogenesis through bioinformatics analysis. It was found that WDR43 is highly expressed in CRC tissues, and WDR43 overexpression is associated with poor prognosis of CRC patients. WDR43 knockdown significantly inhibits cell growth by arresting cell cycle and enhancing the effect of oxaliplatin chemotherapy both in vitro and in vivo. Mechanistically, upon oxaliplatin stimulation, c-MYC promotes the transcriptional regulation and expression of WDR43. WDR43 enhances the ubiquitination of p53 by MDM2 through binding to RPL11, thereby reducing the stability of the p53 protein, which induces proliferation and chemoresistance of CRC cells. Thus, the overexpression of WDR43 promotes CRC progression, and could be a potential therapeutic target of chemoresistance in CRC.

Mediastinal Hepatoid Adenocarcinoma Treated With Arterial Interventional Therapy: A Case Report and Review of Literature.

Hepatoid adenocarcinoma (HAC) is an extremely rare extrahepatic carcinoma, which is pathologically featured by hepatocellular carcinoma (HCC) and marked by producing alpha-fetoprotein (AFP). HAC of mediastinum is extremely rare. For inoperable patients, the curative treatment options have not been established, and the outcome of HAC is usually poor. Here, we present a case of mediastinal HAC with normal serum AFP level who achieved well-controlled and good response after local-regional interventional approach combined with systemic PD-1 inhibitor. A 53-year-old male who complained of chest pain was admitted to our hospital in February 2021. A chest CT scan revealed several tumors in his mediastinum. The laboratory data showed normal serum AFP level. HAC was diagnosed through pathological assessment of biopsy. Surgery was not available due to the infiltration of sternum. Local regional FOLFOX chemotherapy was given by transarterial infusion, followed by transcatheter arterial chemoembolization, and thereafter combined with systemic anti-PD-1 treatment. The patient achieved favorable disease control and apparent symptom relief. So transarterial interventional therapy combined immunotherapy may be a possible and promising treatment for mediastinal HAC.

High AKAP8L expression predicts poor prognosis in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a severe disease with high mortality, and is associated with poor prognosis and frequent lymphatic metastasis. Therefore, prognostic indicators for ESCC are urgently needed. A-kinase anchor-protein 8-like (AKAP8L) is a member of the A kinase anchor-protein (AKAPs) family and is overexpressed in many cancers. However, the role of AKAP8L in ESCC remains unclear. The aim of this study is to investigate the expression patterns and prognostic value of AKAP8L in ESCC. METHODS: The mRNA expression of AKAP8L was analyzed from the dataset of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Immunohistochemistry was applied to detect the AKAP8L expression in tissue microarray. Pearson's chi-square test was carried out for the correlation analysis of clinicopathological features and AKAP8L expression. The prognostic significance of clinicopathological features and AKAP8L expression was determined by univariate and multivariate Cox hazard models. Kaplan-Meier survival curve was used for survival analysis. RESULTS: We found that the mRNA level of AKAP8L was higher in tumor tissues than in adjacent tissues in TCGA and GEO dataset. High AKAP8L expression was associated with poor overall survival (OS) in ESCC patients (p = 0.0039). Besides, AKAP8L expression was highly expressed in patients with lymph node metastasis detected by ESCC tissue microarray (p = 0.0014). The comparison of the different clinicopathological features of ESCC between high and low AKAP8L expression groups revealed that high AKAP8L expression was related to lymph node stage (p = 0.041). Kaplan-Meier survival analysis revealed that high AKAP8L expression indicates an unfavorable progression-free survival (PFS) and OS in ESCC patients (p < 0.0001). Univariate and multivariate analyses confirmed that AKAP8L was an independent prognostic factor for PFS and OS in ESCC (p = 0.003 and p < 0.0001). CONCLUSIONS: In conclusion, this study demonstrated that high expression of AKAP8L is associated with poor prognosis of ESCC and can be considered an independent risk factor for ESCC.

Sharp recanalization for treatment of central venous occlusive disease in hemodialysis patients.

BACKGROUND: The purpose of the present study was to evaluate the technical feasibility and safety of sharp recanalization for central venous occlusive disease (CVOD) in patients requiring hemodialysis. METHODS: Patients with CVOD requiring hemodialysis who had undergone endovascular recanalization using sharp devices, including the stiff end of a guidewire, Chiba needle, or RUS-100 to cross occluded segments after conventional techniques had failed were included. The needle was guided toward a target placed at the opposite end of the occlusion. Although the guidewire was passed though the occlusion, subsequent procedures such as percutaneous transluminal angioplasty could be performed. RESULTS: A total of 27 sharp recanalization procedures in 25 patients were performed. Two attempts failed, 1 patient had undergone two separate successful procedures, and 23 procedures in 23 patients were successful. The overall technique success was 92.6%. The stiff end of a guidewire was the first choice for all the procedures, and recanalization was achieved in 18 patients (66.7%). A Chiba biopsy needle was used in six procedures (22.2%), with 100% technical success. A RUPS-100 set was used in two procedures (7.4%), with one aborted because of concern for complications. The occlusion was subsequently crossed using a Chiba needle. Four minor adverse events (two of mediastinal hematoma and two of chest pain) had occurred, and two major adverse events (pericardial tamponade and acute pleural effusion in one patient [4%], treated with the guidewire stiff-end technique, who recovered after drainage) had occurred. CONCLUSIONS: Sharp recanalization is safe and feasible with high technical success for CVOD in patients requiring hemodialysis who cannot be recanalized using conventional techniques.

PSMA-targeted arsenic nanosheets: a platform for prostate cancer therapy via ferroptosis and ATM deficiency-triggered chemosensitization.

Ferroptosis, a newly recognized form of non-apoptotic cell death, has recently been introduced for effective cancer therapy. The reported ferroptosis-inducing nanomaterials mainly consisted of metal-based components. Herein, we designed an inorganic metal-free nanoplatform, PSMA-targeted arsenic nanosheets (PMANs), which simultaneously increased glutathione (GSH) consumption, suppressed solute carrier family 7 member 11 (SLC7A11) and glutathione-dependent peroxidase 4 (GPX4) expression, and promoted the generation of reactive oxygen species (ROS) and lipid peroxides (LPO). In addition, owing to the large surface area, PMANs efficiently transported doxorubicin (DOX) to prostate cancer for synergistic therapy. Surprisingly, we found that PMANs could sensitize prostate cancer cells to DOX through downregulating the expression of ataxia telangiectasia mutated (ATM), which further augmented the GPX4 downregulation-mediated ferroptotic tumoricidal effect. Given that arsenic trioxide has been routinely and successfully used in the clinical treatment of leukemia for a long time, we anticipate that PMANs will offer a promising strategy for prostate cancer therapy.

Prognostic value of splenic volume in hepatocellular carcinoma patients receiving transarterial chemoembolization.

BACKGROUND: Liver function is a key determinant for the survival of hepatocellular carcinoma (HCC) patients receiving transarterial chemoembolization (TACE). However, establishing robust prognostic indicators for liver insufficiencies and patient survival remains an unmet demand. This retrospective study evaluated the prognostic value of splenic volume (SV) in HCC patients undergoing TACE. METHODS: A total of 67 HCC patients who underwent at least two consecutive TACE procedures were retrospectively included in this study. Comprehensive clinical information and follow-up data were collected, and the SV was measured based on dynamic contrast enhanced images. Risk factors of SV enlargement were assessed. The prognostic value of SV on survival was analyzed and compared with Child-Pugh (CP) classification and albumin-bilirubin (ALBI) grade. RESULTS: The baseline SV was 299.74±143.63 cm3, and showed a moderate and statistically significant correlation with CP classification (R=0.31, P<0.05). The SV increased remarkably after the first and second TACE procedures (330.16±155.38 cm3, P<0.01, and 355.63±164.26 cm3, P<0.01, respectively). In survival analysis, the optimal cut-off value of SV was determined as 373 cm3 using X-tile software, and the patients were divided into the small SV group and the large SV groups accordingly. Based on the pre-TACE SV, the median overall survival (mOS) for patients in the small SV group and the large SV group was 458 days and 249 days, respectively (P<0.05). After the first and second TACE, the mOS in the small SV group and the large SV group were 454 vs. 266 days (P<0.05) and 526 vs. 266 days (P<0.05), respectively. No prognostic value of CP classification and ALBI grade was identified for these patients. Furthermore, there were no significant differences between the small and large SV groups in age, tumor stage, and ALBI grade, except for CP classification (P<0.05). CONCLUSIONS: SV was correlated with CP classification and was a robust predictor for HCC patients undergoing TACE treatment.

Automatic Production and Preliminary PET Imaging of a New Imaging Agent [18F]AlF-FAPT.

BACKGROUND: Fibroblast activating protein (FAP) has become an important target for cancer diagnostic imaging and targeted radiotherapy. In particular, [18F]FAPI-42 has been successfully applied to positron emission tomography (PET) imaging of various tumors. However, it exhibits high hepatobiliary metabolism and is thus not conducive to abdominal tumor imaging. This study reports a novel 18F-labeled FAP inhibitor, [18F]AlF-FAPT, a better FAPI imaging agent than [18F]FAPI-42. MATERIALS AND METHODS: The precursor of [18F]AlF-FAPT (NOTA-FAPT) was designed and synthesized using the standard FMOC solid phase synthesis method. [18F]AlF-FAPT was subsequently synthesized and radiolabeled with 18F using the AllInOne synthesis module. Dynamic MicroPET and biodistribution studies of [18F]AlF-FAPT were then conducted in xenograft tumor mouse models to determine its suitability. RESULTS: The precursors NOTA-FAPT were obtained with a chemical purity of > 95%. [18F]AlF-FAPT was synthesized automatically using the cassette-based module AllInOne within 40 min. The non-decay corrected radiochemical yield was 25.0 ± 5.3% (n=3). In vivo imaging and biodistribution studies further demonstrated that compared with [18F]-FAPI-42, [18F]AlF-FAPT had a lower hepatobiliary uptake than [18F]FAPI-42, which was advantageous for imaging abdominal tumors. CONCLUSION: [18F]AlF-FAPT can be synthesized automatically using a one-step method of aluminum fluoride. Collectively, [18F]AlF-FAPT is a better FAPI imaging agent than [18F]FAPI-42. This study proves the feasibility of using [18F]AlF-FAPT as a new radioactive tracer for PET imaging.

A versatile UCST-type composite microsphere for image-guided chemoembolization and photothermal therapy against liver cancer.

The development of novel chemoembolization agents to improve the treatment efficacy of transarterial chemoembolization (TACE) against liver cancer remains an urgent need in clinical practice. Herein, a versatile composite microsphere with upper critical solution temperature (UCST) properties was prepared to encapsulate polydopamine coated superparamagnetic iron oxide nanoparticles (SPION@PDA) and doxorubicin for simultaneous chemoembolization and photothermal therapy. The microspheres were spherical with an average diameter of 100-300 µm and exhibited favorable drug loading capability as well as strong photothermal effect. Strikingly, synergistic enhancement of photothermal therapy and chemotherapy against chemoresistant liver cancer cells was achieved. The in vivo therapeutic efficacy and safety evaluations were performed using rabbit VX2 liver tumor models. It was revealed that a single treatment of the combination of TACE and photothermal procedure resulted in 87.5% complete response and 12.5% partial response for the microsphere group, whereas all tumors in the control group progressed rapidly. Contrast-enhanced computed tomography (CT) evaluation indicated that the tumor diameter decreased by 91.5% after treatment, while that in the control group increased by 86.5%. The pathology-proven tumor necrotic rate was 87.2%, which significantly surpassed that of 65.2% in the control group. Furthermore, serum liver enzyme and biochemical studies indicated a temporary liver injury which can be fully recovered. Our findings demonstrated that this microsphere may be advantageous for enhancing therapeutic efficacy of TACE against liver cancer.

Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance.

Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS, NRAS, and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA, PTEN, TP53, MET, HER3, IRS2, FGFR1, and MAP2K1, the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.

The potential of microRNA-126 in predicting disease risk, mortality of sepsis, and its correlation with inflammation and sepsis severity.

BACKGROUND: MicroRNA-126 (miR-126) has been investigated in autoimmune diseases and organ failures, whereas its implication in sepsis is rarely reported. Our study initially explored the value of miR-126 in diagnosing sepsis and predicting disease severity, degree of inflammation, and mortality. METHODS: Totally, 208 sepsis patients and 210 healthy controls were enrolled; then, their plasma samples were collected for detecting circulating miR-126 by quantitative polymerase chain reaction. For sepsis patients, their cytokine levels in plasma samples were detected by enzyme-linked immunosorbent assay. RESULTS: miR-126 was upregulated in sepsis patients compared with healthy controls, and it was of certain value in distinguishing sepsis patients from healthy controls (AUC: 0.726 (95% CI: 0.678-0.774)). miR-126 expression was positively correlated with acute physiology and chronic health evaluation II score, serum creatinine, and C-reactive protein but not albumin or white blood cell count in sepsis patients. Regarding cytokines, miR-126 was positively correlated with tumor necrosis factor-α, interleukin (IL)-6, and IL-8, but negatively correlated with IL-10 in sepsis patients. As for mortality, miR-126 expression was higher in deaths compared with survivors, and ROC curve displayed that it could predict mortality of sepsis patients to some extent with AUC of 0.619 (95% CI: 0.533-0.705). CONCLUSION: miR-126 potentially serves as an assistant diagnostic and prognostic biomarker for sepsis.