Ansofaxine hydrochloride inhibits tumor growth and enhances Anti-TNFR2 in murine colon cancer model.

Introduction: As psychoneuroimmunology flourishes, there is compelling evidence that depression suppresses the anti-tumor immune response, promotes the progression of cancer, and inhibits the effectiveness of cancer immunotherapy. Recent studies have reported that antidepressants can not only alleviate the depressant condition of cancer patients, but also strengthen the anti-tumor immunity, thus suppressing tumors. Tumor necrosis factor receptor 2 (TNFR2) antagonistic antibodies (Anti-TNFR2) targeting tumor-infiltrating regulatory T cells (Tregs) has achieved great results in preclinical studies, and with a favorable toxicity profile than existing immunotherapies, and is expected to become a new generation of more effective treatment strategies. Understanding the effects of combination therapy with antidepressants and Anti-TNFR2 may help design new strategies for cancer immunotherapy. Methods: We treated CT26, HCT116, MCA38 and SW620 colon cancer cells with fluoxetine (0-50 µM), ansofaxine hydrochloride (0-50 µM) and amitifadine hydrochloride (0-150 µM) to examine their effects on cell proliferation and apoptosis. We explored the antitumor effects of ansofaxine hydrochloride in combination with or without Anti-TNFR in subcutaneously transplanted CT26 cells in tumor-bearing mouse model. Antitumor effects were evaluated by tumor volume. NK cell, M1 macrophage cell, CD4+ T cell, CD8+ T cell, exhausted CD8+ T and regulatory T cell (Tregs) subtypes were measured by flow cytometry. 5-hydroxytryptamine, dopamine and norepinephrine levels were measured by ELISA. Results: Oral antidepression, ansofaxine hydrochloride, enhanced peripheral dopamine levels, promoted CD8+T cell proliferation, promoted intratumoral infiltration of M1 and NK cells, decreased the proportion of tumor-infiltrating exhausted CD8+T cells, and strengthened anti-tumor immunity, thereby inhibiting colon cancer growth. In combination therapy, oral administration of ansofaxine hydrochloride enhanced the efficacy of Anti-TNFR2, and produced long-term tumor control in with syngeneic colorectal tumor-bearing mice, which was attributable to the reduction in tumor-infiltrating Treg quantity and the recovery of CD8+ T cells function. Discussion: In summary, our data reveal the role of ansofaxine hydrochloride in modulating the anti-tumor immunity. Our results support that exhausted CD8+T is an important potential mechanism by which ansofaxine hydrochloride activates anti-tumor immunity and enhances anti-tumor effects of anti-TNFR2.

Huc-MSC-derived exosomes modified with the targeting peptide of aHSCs for liver fibrosis therapy.

BACKGROUND: Effective therapeutics to stop or reverse liver fibrosis have not emerged, because these potential agents cannot specifically target activated hepatic stellate cells (aHSCs) or are frequently toxic to parenchymal cells. Human umbilical cord mesenchymal stem cell (Huc-MSC)-derived exosomes show promise in nanomedicine for the treatment of liver fibrosis. However, systemic injection showed that unmodified exosomes were mainly taken up by the mononuclear phagocyte system. The discovery of ligands that selectively bind to a specific target plays a crucial role in clinically relevant diagnostics and therapeutics. Herein, we aimed to identify the targeting peptide of aHSCs by screening a phage-displayed peptide library, and modify Huc-MSC-derived exosomes with the targeting peptide. RESULTS: In this study, we screened a phage-displayed peptide library by biopanning for peptides preferentially bound to HSC-T6 cells. The identified peptide, HSTP1, also exhibited better targeting ability to aHSCs in pathological sections of fibrotic liver tissues. Then, HSTP1 was fused with exosomal enriched membrane protein (Lamp2b) and was displayed on the surface of exosomes through genetic engineering technology. The engineered exosomes (HSTP1-Exos) could be more efficiently internalized by HSC-T6 cells and outperformed both unmodified exosomes (Blank-Exos) and Lamp2b protein overexpressed exosomes (Lamp2b + Exos) in enhancing the ability of exosomes to promote HSC-T6 reversion to a quiescent phenotype. In vivo results showed HSTP1-Exos could specifically target to the aHSC region after intravenous administration, as demonstrated by coimmunofluorescence with the typical aHSCs marker α-SMA, and enhance the therapeutic effect on liver fibrosis. CONCLUSION: These results suggest that HSTP1 is a reliable targeting peptide that can specifically bind to aHSCs and that HSTP1-modified exosomes realize the precise treatment for aHSCs in complex liver tissue. We provide a novel strategy for clinical liver fibrosis therapy.

Implantation of a dual-chamber pacemaker in a patient with dextrocardia and sick sinus syndrome: a case report.

Dextrocardia is a congenital abnormal position of the heart in which the main part of the heart is in the right chest, and the long axis of the heart points to the lower right. Cases of a combination of dextrocardia and sick sinus syndrome are rare. A 65-year-old female patient was admitted to hospital with palpitations and dizziness for 1 week. Mirror-image dextrocardia and sick sinus syndrome were diagnosed by an electrocardiogram, echocardiography, Holter monitoring, and X-rays. Finally, we successfully implanted a dual-chamber pacemaker into the patient. The patient had an uneventful recovery and was discharged when her symptoms had greatly improved 1 week later. When dextrocardia is present, using active fixation leads in the atrial and ventricular leads is easier for finding the pacing position with optimal sensing and pacing thresholds, and they reduce the incidence of falling off.

Coronary artery-left ventricular multiple microfistulas, a rare disease that is easily missed: case report and literature review.

Coronary artery-left ventricular multiple microfistulas (CALVMMFs) are a very rare type of coronary artery fistula. Because of their special anatomical structure and hemodynamics, CALVMMFs often result in no obvious symptoms and signs. Most patients are diagnosed by coronary angiography; however, as a routine noninvasive screening method, Doppler echocardiography is a potential first-choice diagnostic technique for patients with CALVMMFs. Although satisfactory results of CALVMMF closure are difficult to achieve, the clinical symptoms of these patients are not obvious, and drug therapy has a clear therapeutic effect on most patients. We herein introduce seven cases of CALVMMFs confirmed by our hospital and briefly review the related literature.

A new non-muscle-invasive bladder tumor-homing peptide identified by phage display in vivo.

Bladder cancer is common and widespread, and its incidence is increasing. Many new diagnostic methods combined with state-of-the-art technology have been introduced in cystoscopy to collect real-time images of the bladder mucosa for diagnosis, but often miss inconspicuous early-stage tumors. Fluorophore-labeled peptides with high sensitivity and specificity for cancer would be a desirable tool for the detection and treatment of tiny or residual bladder tumors. Phage display and the human non-muscle-invasive bladder cancer cell line BIU-87 were used to identify a peptide. The isolated phage display peptide (CSSPIGRHC, named NYZL1) was tested in vitro for its binding specificity and affinity. Accumulation into xenograft tumors in a nude mouse model was analyzed with FITC-labeled NYZL1. NYZL1, with strong tumor­homing ability, was identified by in vivo phage library selection in the bladder cancer model. The NYZL1 phage and synthetic FITC-labeled NYZL1 peptides bound to tumor tissues and cells, but were hardly detected in normal control organs. Notably, accumulation of FITC-NYZL1 in bladder tumor cells was time-dependent. Biodistribution studies of xenografts of BIU-87 cells showed accumulation of injected FITC-NYZL1 in the tumors, and the bound peptide could not be removed by perfusion after 24 h. The mouse model of bladder tumor showed increased fluorescence intensity in the tumor-bearing bladder in comparison with normal bladder tissues after 4-6 h. In conclusion, NYZL1 may represent a lead peptide structure applicable in the development of optical molecular imaging.