PPARα phosphorylation regulates colorectal tumor immune escape.

A high level of PD-L1 on cancer cells promotes tumor immune escape and inhibits tumor immunotherapy. Although PD-L1 gene expression is upregulated by multiple pathways, its gene transcriptional repression is still unclear. Here we found that loss of PPARα, one of the peroxisome-proliferator-activated receptors (PPARs) family members, promoted colorectal tumor immune escape. Mechanistically, PPARα directly bound to PD-L1 promoter resulting in its gene transcriptional repression, which in turn increased T cell activity, and PPARα agonist enhanced this event. However, ERK induced PPARα-S12 phosphorylation leading to blockade of PPARα-mediated PD-L1 transcriptional repression, and the combination of ERK inhibitor with PPARα agonist significantly inhibited tumor immune escape. These findings suggest that the ERK-PPARα pathway inhibited PD-L1 gene transcriptional repression and promoted colorectal tumor immune escape.

Temporal patterns of endophytic microbial heterogeneity across distinct ecological compartments within the Panax ginseng root system following deforestation for cultivation.

Alterations in the microbial community significantly impact the yield and quality of ginseng. Yet, the dynamics of microbial community shifts within the root endophytes of ginseng across varying cultivation periods remain inadequately understood. This study zeroes in on the microbial community variations within the xylem (M), phloem (R), and fibrous roots (X) of ginseng during the fourth (F4) and fifth (F5) years of cultivation, aiming to bridge this research gap. We assessed soil physicochemical properties, enzyme activities, and nine individual saponins, complemented by high-throughput sequencing techniques (16S rDNA and ITS) to determine their profiles. The results showed that cultivation years mainly affected the microbial diversity of endophytic bacteria in ginseng fibrous roots compartment: the ASVs number and α-diversity Chao1 index of bacteria and fungi in F5X compartment with higher cultivation years were significantly higher than those in F4X compartment with lower cultivation years. It is speculated that the changes of fibrous roots bacterial groups may be related to the regulation of amino acid metabolic pathway. Such as D-glutamine and D-glutamate metabolism D-glutamine, cysteine and methionine metabolism regulation. The dominant bacteria in ginseng root are Proteobacteria (relative abundance 52.07-80.35%), Cyanobacteria (1.97-42.52%) and Bacteroidota (1.11-5.08%). Firmicutes (1.28-3.76%). There were two dominant phyla: Ascomycota (60.10-93.71%) and Basidiomycota (2.25-30.57%). Endophytic fungi were more closely related to soil physicochemical properties and enzyme activities. AN, TK, OP, SWC and EC were the main driving factors of endophytic flora of ginseng root. Tetracladium decreased with the increase of cultivation years, and the decrease was more significant in phloem (F4R: 33.36%, F5R: 16.48%). The relative abundance of Bradyrhizobium, Agrobacterium and Bacillus in each ecological niche increased with the increase of cultivation years. The relative abundance of Bradyrhizobium and Agrobacterium in F5X increased by 8.35 and 9.29 times, respectively, and Bacillus in F5M increased by 5.57 times. We found a variety of potential beneficial bacteria and pathogen antagonists related to ginseng biomass and saponins, such as Bradyrhizobium, Agrobacterium, Bacillus and Exophiala, which have good potential for practical application and development.

Reinvent Aliphatic Arsenicals as Reversible Covalent Warheads toward Targeted Kinase Inhibition and Non-acute Promyelocytic Leukemia Cancer Treatment.

The success of arsenic in acute promyelocytic leukemia (APL) treatment is hardly transferred to non-APL cancers, mainly due to the low selectivity and weak binding affinity of traditional arsenicals to oncoproteins critical for cancer survival. We present herein the reinvention of aliphatic trivalent arsenicals (As) as reversible covalent warheads of As-based targeting inhibitors toward Bruton's tyrosine kinase (BTK). The effects of As warheads' valency, thiol protection, methylation, spacer length, and size on inhibitors' activity were studied. We found that, in contrast to the bulky and rigid aromatic As warhead, the flexible aliphatic As warheads were well compatible with the well-optimized guiding group to achieve nanomolar inhibition against BTK. The optimized As inhibitors effectively blocked the BTK-mediated oncogenic signaling pathway, leading to elevated antiproliferative activities toward lymphoma cells and xenograft tumor. Our study provides a promising strategy enabling rational design of new aliphatic arsenic-based reversible covalent inhibitors toward non-APL cancer treatment.

GSK0660 enhances antitumor immunotherapy by reducing PD-L1 expression.

Blockade of PD-1/PD-L1 immune checkpoint is wildly used for multiple types of cancer treatment, while the low response rate for patients is still completely unknown. As nuclear hormone receptor, PPARδ (peroxisome-proliferator-activated receptor) regulates cell proliferation, inflammation, and tumor progression, while the effect of PPARδ on tumor immune escape is still unclear. Here we found that PPARδ antagonist GSK0660 significantly reduced colon cancer cell PD-L1 protein and gene expression. Luciferase analysis showed that GSK0660 decreased PD-L1 gene transcription activity. Moreover, reduced PD-L1 expression in colon cancer cells led to increased T cell activity. Further analysis showed that GSK0660 decreased PD-L1 expression in a PPARδ dependent manner. Implanted tumor model analysis showed that GSK0660 inhibited tumor immune escape and the combined PD-1 antibody with GSK0660 effectively enhanced colorectal cancer immunotherapy. These findings suggest that GSK0660 treatment could be an effective strategy for cancer immunotherapy.

Efficacy of radiofrequency ablation combined with sorafenib for treating liver cancer complicated with portal hypertension and prognostic factors.

BACKGROUND: Patients with liver cancer complicated by portal hypertension present complex challenges in treatment. AIM: To evaluate the efficacy of radiofrequency ablation in combination with sorafenib for improving liver function and its impact on the prognosis of patients with this condition. METHODS: Data from 100 patients with liver cancer complicated with portal hypertension from May 2014 to March 2019 were analyzed and divided into a study group (n = 50) and a control group (n = 50) according to the treatment regimen. The research group received radiofrequency ablation (RFA) in combination with sorafenib, and the control group only received RFA. The short-term efficacy of both the research and control groups was observed. Liver function and portal hypertension were compared before and after treatment. Alpha-fetoprotein (AFP), glypican-3 (GPC-3), and AFP-L3 levels were compared between the two groups prior to and after treatment. The occurrence of adverse reactions in both groups was observed. The 3-year survival rate was compared between the two groups. Basic data were compared between the survival and non-surviving groups. To identify the independent risk factors for poor prognosis in patients with liver cancer complicated by portal hypertension, multivariate logistic regression analysis was employed. RESULTS: When comparing the two groups, the research group's total effective rate (82.00%) was significantly greater than that of the control group (56.00%; P < 0.05). Following treatment, alanine aminotransferase and aspartate aminotransferase levels increased, and portal vein pressure decreased in both groups. The degree of improvement for every index was substantially greater in the research group than in the control group (P < 0.05). Following treatment, the AFP, GPC-3, and AFP-L3 levels in both groups decreased, with the research group having significantly lower levels than the control group (P < 0.05). The incidence of diarrhea, rash, nausea and vomiting, and fatigue in the research group was significantly greater than that in the control group (P < 0.05). The 1-, 2-, and 3-year survival rates of the research group (94.00%, 84.00%, and 72.00%, respectively) were significantly greater than those of the control group (80.00%, 64.00%, and 40.00%, respectively; P < 0.05). Significant differences were observed between the survival group and the non-surviving group in terms of Child-Pugh grade, history of hepatitis, number of tumors, tumor size, use of sorafenib, stage of liver cancer, histological differentiation, history of splenectomy and other basic data (P < 0.05). Logistic regression analysis demonstrated that high Child-Pugh grade, tumor size (6-10 cm), history of hepatitis, no use of sorafenib, liver cancer stage IIIC, and previous splenectomy were independent risk factors for poor prognosis in patients with liver cancer complicated with portal hypertension (P < 0.05). CONCLUSION: Patients suffering from liver cancer complicated by portal hypertension benefit from the combination of RFA and sorafenib therapy because it effectively restores liver function and increases survival rates. The prognosis of patients suffering from liver cancer complicated by portal hypertension is strongly associated with factors such as high Child-Pugh grade, tumor size (6-10 cm), history of hepatitis, lack of sorafenib use, liver cancer at stage IIIC, and prior splenectomy.

Ficonalkib (SY-3505) in Advanced ALK-Positive NSCLC: A Multicenter, Open-Label, Single-Arm, Phase 1/2 Study.

INTRODUCTION: Treatment options for second-generation (2nd-gen) ALK tyrosine kinase inhibitor (TKI)-resistant patients are limited. We evaluated the safety, pharmacokinetics, and efficacy of ficonalkib (SY-3505), a third-generation (3rd-gen) ALK TKI, in patients with advanced ALK-positive non-small cell lung cancer. METHODS: This first-in-human, phase 1/2 study (Chinese Clinical Trial Registry identifier: ChiCTR1900025619; ClinicalTrials.gov identifier: NCT05257512) had two parts. Phase 1 included a dose-escalation phase (25-800 mg quaque die [QD]) and a dose-expansion phase (500 mg QD or 600 mg QD). Phase 2 enrolled patients treated at recommended phase 2 dose. Primary end points were safety in phase 1 and objective response rate (ORR) in phase 2. RESULTS: Between April 21, 2020, and August 31, 2023, a total of 127 patients with advanced ALK-positive non-small cell lung cancer were enrolled, with 62 in phase 1. Ficonalkib was well absorbed and tolerated, with one dose-limited toxicity event occurring at 800 mg QD. Treatment-related adverse events occurred in 85.5% of patients, with 19.4% experienced greater than or equal to grade 3 events. The ORR was 38.3% (23 of 60, 95% confidence interval [CI]: 26.1%-51.8%) in phase 1, and 600 mg QD was established as recommended phase 2 dose. In phase 2, a total of 65 patients received ficonalkib at 600 mg QD. In total, 88 patients received ficonalkib at 600 mg QD in phase 1/2, and all had received prior 2nd-gen ALK TKI treatment. Furthermore, 90.9% of the patients experienced treatment-related adverse events and 14.8% experienced greater than or equal to grade 3 events. The ORR in efficacy-assessable patients who received ficonalkib at 600 mg QD was 47.5% (38 of 80, 95% CI: 36.2%-59.0%), with an intracranial ORR of 37.5% (12 of 32, 95% CI: 21.1%-56.3%) in these patients with measurable brain lesions at baseline. CONCLUSIONS: Ficonalkib (SY-3505) was well tolerated, with favorable safety profiles and promising efficacy in patients resistant to prior 2nd-gen ALK TKI.

Integrating Reliable Pt-S Bond-Mediated 3D DNA Nanomachine with Magnetic Separation in a Homogeneous Electrochemical Strategy for Exosomal MicroRNA Detection with Low Background and High Sensitivity.

Precise and sensitive analysis of exosomal microRNA (miRNA) is of great importance for noninvasive early disease diagnosis, but it remains a great challenge to detect exosomal miRNA in human blood samples because of their small size, high sequence homology, and low abundance. Herein, we integrated reliable Pt-S bond-mediated three-dimensional (3D) DNA nanomachine and magnetic separation in a homogeneous electrochemical strategy for the detection of exosomal miRNA with low background and high sensitivity. The 3D DNA nanomachine was easily prepared via a facile and rapid freezing method, and it was capable of resisting the influence of biothiols, thus endowing it with high stability. Notably, the as-developed magnetic 3D DNA nanomachine not only enabled the detection system to have a low background but also coupled with liposome nanocarriers to synergistically amplify the current signal. Consequently, by ingeniously combining the low background and multiple signal-amplification strategies in homogeneous electrochemical biosensing, highly sensitive detection of exosomal miRNA was successfully achieved. More significantly, with good anti-interference ability, the as-proposed method could effectively discriminate plasma samples from cancer patients and healthy subjects, thus showing a high potential for application in the nondestructive early clinical diagnosis of disease.

Network pharmacology-based exploration identified the antiviral efficacy of Quercetin isolated from mulberry leaves against enterovirus 71 via the NF-κB signaling pathway.

Introduction: Mulberry leaf (ML) is known for its antibacterial and anti-inflammatory properties, historically documented in "Shen Nong's Materia Medica". This study aimed to investigate the effects of ML on enterovirus 71 (EV71) using network pharmacology, molecular docking, and in vitro experiments. Methods: We successfully pinpointed shared targets between mulberry leaves (ML) and the EV71 virus by leveraging online databases. Our investigation delved into the interaction among these identified targets, leading to the identification of pivotal components within ML that possess potent anti-EV71 properties. The ability of these components to bind to the targets was verified by molecular docking. Moreover, bioinformatics predictions were used to identify the signaling pathways involved. Finally, the mechanism behind its anti-EV71 action was confirmed through in vitro experiments. Results: Our investigation uncovered 25 active components in ML that targeted 231 specific genes. Of these genes, 29 correlated with the targets of EV71. Quercetin, a major ingredient in ML, was associated with 25 of these genes. According to the molecular docking results, Quercetin has a high binding affinity to the targets of ML and EV71. According to the KEGG pathway analysis, the antiviral effect of Quercetin against EV71 was found to be closely related to the NF-κB signaling pathway. The results of immunofluorescence and Western blotting showed that Quercetin significantly reduced the expression levels of VP1, TNF-α, and IL-1ß in EV71-infected human rhabdomyosarcoma cells. The phosphorylation level of NF-κB p65 was reduced, and the activation of NF-κB signaling pathway was suppressed by Quercetin. Furthermore, our results showed that Quercetin downregulated the expression of JNK, ERK, and p38 and their phosphorylation levels due to EV71 infection. Conclusion: With these findings in mind, we can conclude that inhibiting the NF-κB signaling pathway is a critical mechanism through which Quercetin exerts its anti-EV71 effectiveness.

Autophagy and Inflammation: Regulatory Roles in Viral Infections.

Autophagy is a highly conserved intracellular degradation pathway in eukaryotic organisms, playing an adaptive role in various pathophysiological processes throughout evolution. Inflammation is the immune system's response to external stimuli and tissue damage. However, persistent inflammatory reactions can lead to a range of inflammatory diseases and cancers. The interaction between autophagy and inflammation is particularly evident during viral infections. As a crucial regulator of inflammation, autophagy can either promote or inhibit the occurrence of inflammatory responses. In turn, inflammation can establish negative feedback loops by modulating autophagy to suppress excessive inflammatory reactions. This interaction is pivotal in the pathogenesis of viral diseases. Therefore, elucidating the regulatory roles of autophagy and inflammation in viral infections will significantly enhance our understanding of the mechanisms underlying related diseases. Furthermore, it will provide new insights and theoretical foundations for disease prevention, treatment, and drug development.

Sex steroid hormones and allergic diseases in children: a pilot birth cohort study in the Japan Environment and Children's Study cohort.

BACKGROUND: Numerous studies suggest that sex steroids might play a role in sex disparity observed in allergic diseases in adults. However, whether sex hormones influence allergic diseases in children remains unclear. The aim of the present study was to examine the association of sex steroid hormones with allergic disease in Japanese children. METHODS: The present cross-sectional study included 145 6-year-old children participating in a pilot birth cohort study in the Japan Environment and Children's Study. Data on allergic diseases were obtained from questionnaires, and serum levels of sex steroid hormones and allergen-specific IgE were measured. Logistic regression was performed to evaluate the association of sex hormones with allergic diseases. RESULTS: After adjusted sex, amount of body fat at 6 years, parental history of allergic disease, and exposure to tobacco smoke, serum dehydroepiandrosterone sulfate level was significantly associated with reduced odds of any allergic disease (adjusted odds ratio, 0.58; 95% confidence interval, 0.36-0.93; P = 0.024) and serum follicle-stimulating hormone level was significantly associated with increased odds of any allergic disease (adjusted odds ratio, 2.04; 95% confidence interval, 1.01-4.11, P = 0.046). Dehydroepiandrosterone sulfate level showed a significant association with number of allergic diseases. CONCLUSIONS: The current study findings suggest that sex hormones may play an important role in the development of allergic diseases in prepubertal children.

Pulmonary mucosa-associated lymphoid tissue lymphoma with Sjögren's syndrome and literature review: A case report.

INTRODUCTION: A 54-year-old woman was admitted to hospital with chest tightness, shortness of breath, and chest pain on exertion. Her chest computed tomography showed a space-occupying lesion in the right lower lobe of the lung. CASE PRESENTATION: The ultrasound-guided right lung mass biopsy showed mucosa-associated lymphoid tissue (MALT), and the patient was diagnosed with Sjögren's syndrome (SS). The patient's symptoms were partially relieved with chemotherapy. CONCLUSIONS: Autoimmune diseases like SS and systemic lupus erythematosus are recognized risk factors for pulmonary MALT. It is necessary to identify predictors of malignant transformation of SS to pulmonary MALT lymphoma.

Zeolitic Imidazolate Framework-8 (ZIF-8) as a Drug Delivery Vehicle for the Transport and Release of Telomerase Inhibitor BIBR 1532.

Telomerase is constitutively overexpressed in the majority of human cancers and telomerase inhibition provides a promising broad-spectrum anticancer therapeutic strategy. BIBR 1532 is a well-known synthetic telomerase inhibitor that blocks the enzymatic activity of hTERT, the catalytic subunit of telomerase. However, water insolubility of BIBR 1532 leads to low cellular uptake and inadequate delivery and thus, limits its anti-tumor effects. Zeolitic imidazolate framework-8 (ZIF-8) is considered as an attractive drug delivery vehicle for improved transport, release and anti-tumor effects of BIBR 1532. Herein, ZIF-8 and BIBR 1532@ZIF-8 were synthesized, respectively, and the physicochemical characterizations confirmed the successful encapsulation of BIBR 1532 in ZIF-8 coupled with an improved stability of BIBR 1532. ZIF-8 could alter the permeability of lysosomal membrane probably by the imidazole ring-dependent protonation. Moreover, ZIF-8 encapsulation facilitated the cellular uptake and release of BIBR 1532 with more accumulation in the nucleus. BIBR 1532 encapsulation with ZIF-8 triggered a more obvious growth inhibition of cancer cells as compared with free BIBR 1532. A more potent inhibition on hTERT mRNA expression, aggravated G0/G1 arrest accompanied with an increased cellular senescence were detected in BIBR 1532@ZIF-8-treated cancer cells. Our work has provided preliminary information on improving the transport, release and efficacy of water-insoluble small molecule drugs by using ZIF-8 as a delivery vehicle.

The relationships among symptom experience, family support, health literacy, and fear of progression in advanced lung cancer patients.

AIMS: Fear of progression of cancer patients can affect their psychological well-being, while research on fear of progression of advanced lung cancer patients is limited. This study aimed to describe fear of progression among advanced lung cancer patients and explore the relationships among symptom experience, family support, health literacy, and fear of progression. DESIGN: This study was a cross-sectional study. METHODS: Convenience sampling was used to select advanced lung cancer patients from September 2021 to January 2022. The Chinese version of the Fear of Progression Questionnaire-Short Form, Lung Cancer Module of the MD Anderson Symptom Inventory, Family Support Questionnaire, and Health Literacy Scale for Patients with Chronic Disease were used to collect data. The structural equation modelling was used to analyse the relationships among symptom experience, family support, health literacy, and fear of progression. RESULTS: Of 220 patients, 31.8% had dysfunctional fear of progression. Better symptom experience, higher family support, and higher health literacy were correlated directly with lower fear of progression. Higher health literacy was associated indirectly with lower fear of progression through the mediation of better symptom experience. CONCLUSION: Fear of progression among advanced lung cancer patients needs attention. Strengthening symptom management, building a strong system of family support, and improving patients' health literacy may be effective strategies to reduce fear of progression. IMPACT: The research aimed to increase our understanding of the relationships among symptom experience, family support, health literacy, and fear of progression. Fear of progression screening should be integrated into the healthcare trajectory of advanced lung cancer patients. The results emphasize that improving symptom management, family support, and health literacy is important to alleviate fear of progression. Further interventions are warranted to relieve fear of progression for advanced lung cancer patients. PATIENT OR PUBLIC CONTRIBUTION: No public or patient involvement.

Metal-mediated Fe3O4@polydopamine-aptamer capture nanoprobe coupling multifunctional MXene@Au@Pt nanozyme for direct and portable photothermal analysis of circulating breast cancer cells.

Breast cancer (BC) is the most common cancer in the world and circulating tumor cells (CTCs) are reliable biomarkers for early breast cancer diagnosis in a non-invasive manner. However, effective isolation and sensitive detection of BC-CTCs by portable devices in human blood samples are extremely challenging. Herein, we proposed a highly sensitive and portable photothermal cytosensor for direct capture and quantification of BC-CTCs. To achieve efficient isolation of BC-CTCs, aptamer functionalized Fe3O4@PDA nanoprobe was facilely prepared through Ca2+-mediated DNA adsorption. To further detect the captured BC-CTCs with high sensitivity, multifunctional two-dimensional Ti3C2@Au@Pt nanozyme was synthesized, which not only possessed superior photothermal effect but also exhibited high peroxidase-like activity for catalyzing 3,3',5,5'-tetramethylbenzidine (TMB) to produce TMB oxide (oxTMB) with a strong photothermal characteristic, combining with Ti3C2@Au@Pt to synergistically amplify the temperature signal. Moreover, numerous Ti3C2@Au@Pt nanocomposites would be selectively attained on the BC-CTCs surface through multi-aptamer recognition and binding strategy, which further enhanced the specificity and facilitated signal amplification. Therefore, direct separation and highly sensitive detection of BC-CTCs was successfully achieved in human blood samples. More significantly, the controlled release of the captured BC-CTCs without affecting cell viability could be straightforwardly realized by a simple strand displacement reaction. Thus, with the distinct features of portability, high sensitivity, and easy operation, the current method holds great promise for early diagnosis of breast cancer.

Toward a better understanding of microalgal photosynthesis in medium polluted with microplastics: a study of the radiative properties of microplastic particles.

Due to the wide presence of microplastics in water, the interaction between microplastic particles and microalgae cells in medium merits the attention of researchers. Microplastic particles can impact the original transmission of light radiation in water bodies since the refractive index of microplastics is different from that of water bodies. Accordingly, the accumulation of microplastics in water bodies will certainly impact microalgal photosynthesis. Therefore, experimental measurements and theoretical studies characterizing the radiative properties of the interaction between light and microplastic particles are highly significant. The extinction and absorption coefficient/cross-section of polyethylene terephthalate and polypropylene were experimentally measured using transmission and integrating methods in the spectral range of 200-1,100 nm. The absorption cross-section of PET shows remarkable absorption peaks in the vicinity of 326 nm, 700 nm, 711 nm, 767 nm, 823 nm, 913 nm, and 1,046 nm. The absorption cross-section of PP has distinctive absorption peaks near 334 nm, 703 nm, and 1,016 nm. The measured scattering albedo of the microplastic particles is above 0.7, indicating that both microplastics are scattering dominant media. Based on the results of this work, an in-depth understanding of the interaction between microalgal photosynthesis and microplastic particles in the medium will be obtained.

Design, synthesis, and biological evaluation of novel napabucasin-melatonin hybrids as potent STAT3 inhibitors.

The current work developed diverse novel napabucasin-melatonin hybrids as potent STAT3 inhibitors. Several biological studies have suggested many compounds demonstrating potent inhibition against different tumor cells. Among these, compound 7e depicted enhanced inhibition against HepG2, MDA-MB-231, and A549 cells than napabucasin, with IC50 values of 1.06, 1.38, and 1.3 µM, respectively. Based on fluorescence polarization analysis, compound 7e was bound to the SH2 domain in STAT3, with an IC50 value of 12.95 µM. Molecular docking further confirmed the 7e binding mode inside the SH2 domain of STAT3. Further mechanistic studies indicated that 7e inhibited the activation of STAT3 (Y705), and thus reduced the expression of STAT3 downstream genes (CyclinD1, Bcl-2 and c-Myc) instead of affecting p-STAT1 expression. Meanwhile, the phosphorylation levels of its upstream kinases JAK2 and bypass kinase Erk1/2 remain unaffected. Simultaneously, 7e induced cancer cell apoptosis in a concentration-dependent manner. Significantly, 20 mg/kg (i.p.) compound 7e suppressed the mouse HepG2 xenograft development in vivo without body weight loss, suggesting that it could be an effective antitumor agent.

Propensity score matching analysis of efficacy of drug-eluting beads (DEB)-TACE loaded with different drugs in the treatment of hepatocellular carcinoma.

OBJECTIVE: To evaluate the efficacy of drug-eluting beads transarterial chemoembolization (DEB-TACE) in the treatment of hepatocellular carcinoma (HCC) by propensity score matching (PSM) technique. METHODS: The clinical data of HCC patients treated with DEB-TACE in the First Affiliated Hospital of Zhengzhou University from June 2017 to June 2020 as well as their 36-month-follow-up data were retrospectively analyzed. The subjects were matched in pairs based on baseline data and laboratory indicators using the PSM method and divided into a pirarubicin group (n = 34), raltitrexed group (n = 34), and arsenic trioxide group (n = 34). Clinical efficacy was evaluated according to mRECIST criteria. The levels of alpha fetal protein (AFP), carcinoma embryonic antigen (CEA) and carbohydrate antigen-125 (CA125) in serum were detected by enzyme-linked immunosorbent assay (ELISA). The progression-free survival (PFS) and overall survival (OS) were recorded by outpatient, inpatient, and telephone follow-up. Adverse reactions were counted. RESULTS: After PSM, no significant differences were seen in gender, age, tumor burden, Child-Pugh grade, portal vein tumor thrombus or TACE frequency among the three groups (all P>0.05). The ORR rate of the pirarubicin group and arsenic trioxide group at both 3rd and 6th month post-operation was significantly higher than that of the raltitrexed group (all P<0.05). Before and 1 month after treatment, there were no significant differences in the aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin (TBIL) levels between the three groups (all P>0.05). Before treatment, no significant differences were observed in AFP, CEA, or CA125 levels among the three groups (all P>0.05). After treatment, the levels of AFP in the pirarubicin group and arsenic trioxide group were lower than those in the raltitrexed group (both P<0.05), but there were no significant differences in CEA and CA125 levels (all P>0.05). There were no significant differences in PFS and OS among the three groups (all P>0.05), and the incidence of fever, abdominal pain, and myelosuppression showed no significant differences among the three groups (all P>0.05). CONCLUSION: The efficacies of DEB-TACE loaded with pirarubicin, raltitrexed, or arsenic trioxide in treating HCC were generally comparable, and the survival benefit of patients was similar. The short-term efficacy of the pirarubicin group and arsenic trioxide group was slightly better than that of the raltitrexed group.

IL-6/ERK signaling pathway participates in type I IFN-programmed, unconventional M2-like macrophage polarization.

Type I interferons (IFN-Is) have been harnessed for cancer therapies due to their immunostimulatory functions. However, certain tumor-tolerating activities by IFN-Is also exist, and may potentially thwart their therapeutic effects. In this respect, our previous studies have demonstrated a monocyte-orchestrated, IFN-I-to-IL-4 cytokine axis, which can subsequently drive M2-skewed pro-tumoral polarization of macrophages. Whether other IFN-dependent signals may also contribute to such an unconventional circumstance of M2-like macrophage skewing remain unexplored. Herein, we first unveil IL-6 as another ligand that participates in IFN-dependent induction of a typical M2 marker (ARG1) in transitional monocytes. Indeed, IL-6 significantly promotes IL-4-dependent induction of a major group of prominent M2 markers in mouse bone marrow-derived macrophages (BMDMs) and human peripheral blood-derived macrophages, while it alone does not engage marked increases of these markers. Such a pattern of regulation is confirmed globally by RNAseq analyses in BMDMs, which in turn suggests an association of IL-6-amplified subset of M2 genes with the ERK1/2 signaling pathway. Interestingly, pharmacological experiments establish the role of SHP2-ERK cascade in mediating IL-6's enhancement effect on these M2 targets. Similar approaches also validate the involvement of IL-6/ERK signaling in promoting the IFN-dependent, unconventional M2-skewing phenotype in transitional monocytes. Furthermore, an inhibitor of ERK signaling cooperates with an IFN-I inducer to enable a greater antitumor effect, which correlates with suppression of treatment-elicited ARG1. The present work establishes a role of IL-6/ERK signaling in promoting M2-like macrophage polarization, and suggests this axis as a potential therapeutic target for combination with IFN-I-based cancer treatments.

Effect of Ligustri Lucidi Fructus on myelosuppression in mice induced by cytoxan.

In this study, we aimed to demonstrate the therapeutic effect of Ligustri Lucidi Fructus on chemotherapy-induced myelosuppression and elucidate its mechanism. A pharmacological study was conducted to investigate the mechanism of the inhibiting effects of Ligustri Lucidi Fructus on cyclophosphamide-induced bone marrow suppression in mice. HPLC was used to measure the chemical components. We demonstrated that medium and high doses of Ligustri Lucidi Fructus increased the amount of white blood cells and bone marrow nucleated cells (p < 0.05) in the cyclophosphamian-induced mouse model, and at the same time reduced granulocyte-macrophage-colony stimulating factor and thrombopoietin in the serum of myelosuppression mice (p < 0.01). Medium and high doses of Ligustri Lucidi Fructus can also adjust the thymus index and spleen index(p < 0.05). Ligustri Lucidi Fructus regulates the balance of bcl-2/bax, inhibits the expression of Caspase-3 and meanwhile stimulates the expression of mitogen-activated protein (MEK) and phospho extracellular regulated protein kinases (p-ERK) on the MAPK pathway. Five chemical constituents of Ligustri Lucidi Fructus, which may be related to myelosuppression, were analyzed. The content of specnuezhenide was 0.281%, that of ligustroflavone was 0.004%, that of salidroside was 0.094%, that of hydroxytyrosol was 0.060% and that of tyrosol was 0.069%. The effect of Ligustri Lucidi Fructus on myelosuppression after chemotherapy may be related to its multicomponent and multitarget nature. Ligustri Lucidi Fructus may be a promising potential drug for treatment after chemotherapy.