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High infiltration of M2-polarized macrophages in the primary tumor indicates unfavorable prognosis and poor overall survival in the patients with triple-negative breast cancer (TNBC). Thus, reversing M2-polarized tumor-associated macrophages in the tumors has been considered as a potential therapeutic strategy for TNBC. Sphingomyelin synthase 2 (SMS2) is the key enzyme for sphingomyelin production, which plays an important role in plasma membrane integrity and function. In this study we investigated whether SMS2 inhibitor or SMS2 gene knockout could reduce macrophages M2 polarization and tumor progression in a mouse model of TNBC. We showed that SMS2 mRNA expression was linked to immunosuppressive tumor microenvironment and poor prognosis in TNBC patients. The knockout of SMS2 or application of 15w (a specific SMS2 inhibitor) markedly decreased the generation of M2-type macrophages in vitro, and reduced the tumor weight and lung metastatic niche formation in a 4T1-TNBC mouse model. We further demonstrated that the in vivo antitumor efficacy of 15w was accompanied by a multifaceted remodeling of tumor immune environment reflecting not only the suppression of M2-type macrophages but also diminished levels of regulatory T cells and myeloid-derived suppressor cells leading to a dramatically improved infiltration of antitumor CD8 + T lymphocytes. Collectively, our results reveal a novel and important role of SMS2 in the protumorigenic function and may offer a new strategy for macrophage-targeted anticancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis, particularly in the presence of liver metastases. The mechanisms by which metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), influences PDAC progression and metastasis remain poorly understood. This study investigates the role of MASLD in fostering an immunosuppressive microenvironment conducive to PDAC liver metastases and identifies the macrophage migration inhibitory factor (MIF)-CD44 axis as a key mediator of this process. Utilizing data from the UK Biobank (450,754 participants, median follow-up 14.5 years), we observed an overall increased risk of PDAC in the MASLD population (HR: 3.48; 95% CI: 2.69–4.50; P < 0.0001). Clinical cohorts confirmed the strong association between MASLD and hepatic metastases (OR: 7.06; 95% CI: 4.62–10.78; P < 0.0001). Experimental mouse models demonstrated that MASLD enhances tumor cell stemness, immune evasion, and focal adhesion in metastatic liver tissues. Mechanistically, MASLD-induced MIF secretion promotes CD44-positive PDAC cell migration, stemness, and adhesion. Targeting MIF, either genetically or pharmacologically using the MIF tautomerase inhibitor IPG1576 significantly attenuated liver metastasis in preclinical models. Validation in patient samples revealed elevated hepatic MIF and CD44 expression in MASLD-associated PDAC liver metastases. This study highlights the MIF-CD44 axis as a promising therapeutic target and underscores the importance of tailoring treatments for PDAC patients with concurrent MASLD.

How pathological livers shape tumors, thereby driving pancreatic ductal adenocarcinoma (PDAC) metastasis to the liver, is poorly understood. In the present study, we focus on examining key molecules implicated in this process and assessing their translational significance. We demonstrated that patients with combined non-alcoholic fatty liver disease (NAFLD) have approximately a ninefold increased risk of developing liver metastasis compared to those without NAFLD. In mice model, NAFLD fosters an immunosuppressive microenvironment with increased tumor cell pluripotency and focal adhesion. Mechanistically, NAFLD-induced MIF mediated the progression of PDAC liver metastasis by attracting CD44 positive pancreatic cells. Hepatic MIF knockdown significantly reduced metastases burden with decreased stem-like cancer cells, tumor associated macrophages (TAMs) infiltration and focal adhesion. Targeting the MIF-CD44 axis by either a MIF tautomerase inhibitor, IPG1576, or by CD44 knockdown in tumor cells significantly attenuate liver metastasis of PDAC within the NAFLD context. Patients with PDAC liver metastasis and NAFLD had elevated hepatic MIF expression and increased number of stem-cell like cancer cells. Collectively, our study highlights a pivotal role for MIF-CD44 axis in cancer stemness and offer novel avenues for tailoring therapeutic strategies to individual patients with NAFLD as an underlying condition.

Correlated errors may devastate quantum error corrections that are necessary for the realization of fault-tolerant quantum computation. Recent experiments with superconducting qubits indicate that they can arise from quasiparticle (QP) bursts induced by cosmic-ray muons and γ -rays. Here, we use charge-parity jump and bit flip for monitoring QP bursts and two muon detectors in the dilution refrigerator for detecting muon events. We directly observe QP bursts leading to correlated errors that are induced solely by muons and separate the contributions of muons and γ -rays. We further investigate the dynamical process of QP burst and the impact of QP trapping on correlated errors and particle detection. The proposed method, which monitors multiqubit simultaneous charge-parity jumps, has high sensitivity to QP bursts and may find applications for the detection of cosmic-ray particles, low-mass dark matter, and far-infrared photons. The correlated errors in superconducting qubits have been linked to high-energy particle impacts from cosmic rays, but a direct observation has been lacking. Here, the authors measure the quasiparticle bursts and correlated errors and separate the contributions of cosmic-ray muons and γ -rays in a 63-qubit processor.

Background MicroRNAs are the endogenous small non-coding RNA molecules capable of silencing protein coding genes at the posttranscriptional level. Based on computer-aided predictions, a single microRNA could have over a hundred of targets. On the other hand, a single protein-coding gene could be targeted by many potential microRNAs. However, only a relatively small number of these predicted microRNA/mRNA interactions are experimentally validated, and no systematic validation has been carried out using a reporter system. Methods In this study, we used luciferease reporter assays to validate microRNAs that can silence cyclin D1 (CCND1) because CCND1 is a well known proto-oncogene implicated in a variety of types of cancers. We chose miRanda http://www.microRNA.org as a primary prediction method. We then cloned 51 of 58 predicted microRNA precursors into pCDH-CMV-MCS-EF1-copGFP and tested for their effect on the luciferase reporter carrying the 3'-untranslated region (UTR) of CCND1 gene. Results Real-time PCR revealed the 45 of 51 cloned microRNA precursors expressed a relatively high level of the exogenous microRNAs which were used in our validation experiments. By an arbitrary cutoff of 35% reduction, we identified 7 microRNAs that were able to suppress Luc-CCND1-UTR activity. Among them, 4 of them were previously validated targets and the rest 3 microRNAs were validated to be positive in this study. Of interest, we found that miR-503 not only suppressed the luciferase activity, but also suppressed the endogenous CCND1 both at protein and mRNA levels. Furthermore, we showed that miR-503 was able to reduce S phase cell populations and caused cell growth inhibition, suggesting that miR-503 may be a putative tumor suppressor. Conclusion This study provides a more comprehensive picture of microRNA/CCND1 interactions and it further demonstrates the importance of experimental target validation.

Aim： To investigate the effects of punicalagin, a polyphenol isolated from Punica granatum, on human U87MG glioma cells in vitro. Methods： The viability of human U87MG glioma cells was evaluated using MTT assay. Cell cycle was detected with flow cytometry analysis. The levels of Bcl-2, cleaved caspase-9, cleaved poly（ADP-ribose） polymerase （PARP）, phosphor-AMPK and phosphor-p27 at Thr198 were measured using immunoblot analyses. Caspase-3 activity was determined with spectrophotometer. To determine autopha~Lv, LC3 cleavage and punctate patterns were examined. Results： Punicalagin （1-30 pp=VmL） dose-dependently inhibited the cell viability in association with increased cyclin E level and decreased cyclin B and cyclin A levels. The treatment also induced apoptosis as shown by the cleavage of PARP, activation of caspase-9, and increase of caspase-3 activity in the cells. However, pretreatment of the cells with the pan-caspase inhibitor z-DEVD- fmk （50 pmol/L） did not completely prevent the cell death. On the other hand, punicalagin treatment increased LC3-11 cleavage and caused GFP-LC3-11-stained punctate pattern in the cells. Suppressing autopha~, of cells with chloroquine （1-10 pmol/L） dose- dependently alleviated the cell death caused by punicalagin. Punicalagin （1-30 pp=VmL） also increased the levels phosphor-AMPK and phosphor-p27 at Thr198 in the cells, which were correlated with the induction of autophagic cell death. Conclusion： Punicalagin induces human U87MG glioma cell death through both apoptotic and autophagic pathways.

The aim of this study was to investigate the protective effects of Xin Mai Jia (XMJ) on atherosclerosis (AS) in rabbits and to explore the underlying mechanisms in order to provide experimental evidence for the clinical application of XMJ. An intraperitoneal injection of vitamin D3, combined with a high-fat diet and sacculus injury, was utilized to establish the AS rabbit model. Following the oral administration of lovastatin, Zhibituo and different dosages of XMJ, respectively, blood was drawn from each rabbit for the detection of blood rheological indicators, such as serum lipids. The pathological changes in the right common carotid artery were observed. Vascular function experiments and the expression detection of common carotid artery-related proteins by immunohistochemistry were conducted. XMJ was observed to decrease the blood lipid levels of the AS rabbits; increase the concentration of high-density lipoprotein and apolipoprotein A; decrease blood viscosity, erythrocyte sedimentation rate and hematocrit; elevate the levels of endothelial nitric oxide synthase (eNOS) and Na+/H+ exchanger 1 in vascular tissues and decrease the levels of angiotensin II receptor, type 1 (AT-1) and endothelin-1 (ET-1). In conclusion, XMJ was shown to lower the blood lipid levels of the experimental AS rabbits, improve the abnormal changes in hemorheology, increase the eNOS content in the vascular tissue, decrease the AT-1 and ET-1 levels and increase the endothelium-dependent vasodilation reaction. XMJ therefore has an anti-AS effect.

Objective　 To evaluate the safety and immunogenicity of the therapeutic dual-plasmid HBV DNA vaccine mediated by electroporation (EP) in vivo against the hepatitis B virus in healthy adult volunteers. Methods　The enrolled 30 healthy volunteers were randomly divided into three dosage groups (10 volunteers in each group), namely: high-dose (4mg), middle-dose (2mg) and low-dose (1mg) groups. Volunteers received four intramuscular injections of HBV DNA vaccine mediated by in vivo EP at the 0, 4th, 12th and 24th week. Each dose group was further divided into 2 sub-groups (5 persons/per group) with different EP frequencies, i.e. 36 and 60 volt. The changes in response was determined by physical diagnosis (ECG, chest X-ray, type-B ultrasound), lab findings (blood and urine routine, blood biochemistry, prothrombin time, thyroid function, tumor biomarkers), immunological variables (IFN-γ, ANA, anti-dsDNA Ab), serological variables pertaining to HBV (HBsAg, HBcAb, HBeAg, HBeAb, HBV DNA) and serum anti-HBs status in volunteers before and after receiving EP mediated HBV DNA vaccination. Results　The dual-plasmid HBV DNA vaccination mediated by in vivo EP was well tolerated in all healthy volunteers with a stable life signs. It was found that EP-mediated immunization of the therapeutic DNA vaccine against hepatitis B virus had a specific and obvious anti-HBs humoral immune response in one volunteer (17.22mU/ml). Four repeated intramuscular injections of the vaccine did not show any significant adverse effects in the receptors. Although mild elevation of serum ALT and enlarged spleen were found in one individual, the abnormalities disappeared spontaneously at the end of the trial. Conclusions　EP-mediated dual-plasmid HBV DNA vaccine is safe and well tolerated with certain degree of humoral immunogenicity.

To explore the potential of electroporation (EP)-mediated hepatitis B virus (HBV) DNA vaccination for the treatment of chronic HBV infection. BALB/c mice were vaccinated with HBV DNA vaccine encoding for the HBV preS(2)-S antigen, combined with or without EP. HBV surface antigen expression plasmid was administered into mice liver via a hydrodynamic injection to mimic HBV infection. The clearance of antigen in the serum and liver was detected by ELISA assay and immunohistochemical staining. The histopathology of the liver tissues was examined by HE staining and serum alanine aminotransferase assay. The immunogenicity of HBV DNA vaccine encoding for the HBV preS(2)- S antigen can be improved by EP-mediated vaccine delivery. The elicited immune responses can indeed reduce the expression of HBV surface antigen (HBsAg) in hepatocytes of the mouse model that was transfected to express HBsAg using the hydrodynamic injection method. The antigen clearance process did not cause significant toxicity to liver tissue, suggesting a non-cytolytic mechanism. The EP-aided DNA vaccination may have potential in mediating viral clearance in chronic hepatitis B patients.