Nanozyme-integrated microneedle patch for enhanced therapy of cutaneous squamous cell carcinoma by breaking the gap between H2O2 self-supplying chemodynamic therapy and photothermal therapy.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers with increasing incidence worldwide. However, it is still challenging to prevent the relapse of cSCC due to poor drug penetration across the stratum corneum. Herein, we report the design of a microneedle patch loaded with MnO2/Cu2O nanosheets and combretastatin A4 (MN-MnO2/Cu2O-CA4) for the enhanced therapy of cSCC. The prepared MN-MnO2/Cu2O-CA4 patch could effectively deliver adequate drugs locally into the tumor sites. Moreover, the glucose oxidase (GOx)-mimicking activity of MnO2/Cu2O could catalyze glucose to produce H2O2, which combined with the released Cu to induce a Fenton-like reaction to efficiently generate hydroxyl radicals for chemodynamic therapy. Meanwhile, the released CA4 could inhibit cancer cell migration and tumor growth by disrupting the tumor vasculature. Moreover, MnO2/Cu2O was endowed with the ability of photothermal conversion under the irradiation of near-infrared (NIR) laser, which could not only kill the cancer cells but also promote the efficiency of the Fenton-like reaction. Significantly, the photothermal effect did not compromise the GOx-like activity of MnO2/Cu2O, which guaranteed enough production of H2O2 for the sufficient generation of hydroxyl radicals. This work may open avenues for constructing MN-based multimodal treatment for the efficient therapy of skin cancers.

Comprehensive analysis of peripheral blood non-coding RNAs identifies a diagnostic panel for fungal infection after transplantation.

The occurrence of fungal infection seriously affects the survival and life quality of transplanted patients. The accurate diagnosis is of particular importance in the early stage of infection. To develop a novel diagnostic method for this kind of patient, we established a post-transplant immunosuppressed mice model with fungus inoculation and collected their peripheral blood at specific time points after infection. After screening by microarray, differentially expressed miRNAs and lncRNAs were selected and homologously analyzed with those of human beings from the gene database. These miRNAs and lncRNAs candidates were validated by qRT-PCR in peripheral blood samples from transplanted patients. We found that, compared with normal transplanted patients, the levels of miR-215 and miR-let-7 c were up-regulated in the plasma of patients with fungal infection (P < 0.01), while levels of miR-154, miR-193a, NR_027669.1, and NR_036506.1 were down-regulated in their peripheral blood mononuclear cells (P < 0.01). Principal component analysis shows that the expression pattern of the above RNAs was different between the two groups. A 6-noncoding-RNA detection panel was established by the support vector machine analysis, whose area under the ROC curve was 0.927. The accuracy, precision, sensitivity, and specificity of this model were 0.928, 0.919, 0.944, and 0.910, respectively. Though our detection panel has excellent diagnostic efficacy, its clinical application value still needs to be further confirmed by multi-center prospective clinical trials.

Identification of a detection panel for post-transplant virus infection through integrated analysis of non-coding RNAs in peripheral blood.

Viral infection seriously affects the survival and life quality of transplanted patients without an accurate diagnosis during the early stage. Herein, we aimed to develop a novel diagnostic method based on non-coding RNAs expression in peripheral blood. An immunosuppressive mouse model of viral infection after transplantation was established. Differentially expressed non-coding RNAs were distinguished by microarray analyses in the virus-infected group. After homology analysis, 46 miRNAs and 24 lncRNAs were further verified by qRT-PCR in the peripheral blood samples of transplanted patients. Compared with normal transplanted patients, miR-29b, miR-185, and NR_073415.2 were significantly downregulated in the PBMC of post-transplant patients with viral infection. Based on the expression of the above three RNAs, principal component analysis (PCA) identified a slight overlap between the two groups. A 3-non-coding-RNA detection panel was constructed by the support vector machine analysis (SVM), whose loss rate was 14.71%. The area under the curve of it was 0.909. With the optimal cut-off value (Y = 0.328), the sensitivity was 0.929 and the specificity was 0.781. Therefore, based on non-coding RNAs expressions, a detection panel for viral infection after organ transplantation was formed with high diagnostic specificity and sensitivity.

Cepharanthine as a Potential Novel Tumor-Regional Therapy in Treating Cutaneous Melanoma: Altering the Expression of Cathepsin B, Tumor Suppressor Genes and Autophagy-Related Proteins.

The incidence of primary cutaneous melanoma continues to increase annually and is one of the most aggressive malignancies in humans and need to develop more novel non-surgical therapies. Autophagy and cathepsin B targeted therapy was reported to improve melanoma treatment. Cepharanthine (CEP), a natural alkaloid extracted from the genus Cephalophyllum has been reported to have the function of inhibiting cancers. We found that CEP inhibited human primary cutaneous melanoma cells viability and proliferation in 24 h in vitro, and topical application or intra-tumoral injection of CEP decreased the growth of cutaneous melanoma in mice within 4 weeks. CEP preparations below 50% concentration did not induce skin irritation and allergy reaction on human skin in vivo. Primary cutaneous melanoma cells incubated with CEP, the expression of cathepsin B was decreased and the LC3-I and LC3-II expression changed in a dose-dependent manner, while p53, p21Cip1p, and p16Inka gene expression was up-regulated. We demonstrated the effects of CEP as a novel tumor-regional therapy for cutaneous melanoma and provided a preliminary research basis for future clinical treatment researches and the exploration of integrated treatments with systemic therapy, radiotherapy, and surgery for human primary cutaneous melanoma.

Strain Distribution and Drug Susceptibility of Invasive Fungal Infection in Clinical Patients With Systemic Internal Diseases.

BACKGROUND: Patients with systemic internal diseases present high risks for invasive fungal infections, which results in increased morbidity and mortality. Identification of high-risk departments and susceptibility systems could help to reduce the infective rate clinically. Correct selection of sensitive anti-fungal drugs not only could improve the cure rate but also could reduce the adverse reactions and complications caused by long-term antifungal drug treatment, which can be especially important in patients with serious systemic diseases. Therefore, the distribution changes of invasive fungal strains in patients with systemic internal diseases and the choice of antifungal drugs in clinical practice should be updated. OBJECTIVE: This work aimed to investigate the incidence, strain distributions, and drug susceptibility of invasive fungal strains isolated from patients with systemic internal diseases. METHODS: Samples were collected from 9,430 patients who were diagnosed with internal diseases in our hospital from January to December 2018. We then cultured and identified the fungal strains using API 20C AUX. We performed drug sensitivity analysis via the ATB Fungus-3 fungal susceptibility strip. Resistance was defined using the revised Clinical Laboratory Standardization Committee of United States breakpoints/epidemiological cutoff values to assign susceptibility or wild-type status to systemic antifungal agents. RESULTS: A total of 179 patients (49 female, 130 male) with fungal infection were included. The high-incidence departments were determined to be the respiratory department (34.64%), intensive care unit (ICU; 21.79%), and hepatology department (9.50%). The susceptible systems for infection were the respiratory tract (sputum, 68.72%, 123/179; secretion retained in the tracheal catheter, 3.35%, 6/179), urinary tract (urine, 9.50%, 17/179), and gastrointestinal tract (feces, 9.50%, 17/179). The major pathogens were Candida (90.50%), Aspergillus (8.93%), and Cryptococcus neoformans (0.56%). The infective candida subgroups were Candida albicans (70.95%), Candida krusei (6.15%), Candida glabrata (5.59%), Candida parapsilosis (3.91%), and Candida tropicalis (3.91%). The susceptibility of non-Aspergillus fungi for amphotericin B was 100.0%. The susceptibility rates of 5-fluorocytocine (5-FC) and voriconazole were 72.73 and 81.82%, respectively, for C. krusei, 98.43 and 100% for C. albicans, and 100% for both drugs for C. glabrata, C. parapsilosis, and C. tropicalis. The susceptibility rates of fluconazole and itraconazole were 0 and 54.55%, respectively, for C. krusei, 20 and 20% for C. glabrata, and 57.14 and 57.14% for C. tropicalis. The resistance rate of C. tropicalis for both fluconazole and itraconazole was 41.43%. CONCLUSION: Patients in the respiratory department, ICU, and hepatology department presented high rates of invasive fungal infections and should include special attention during clinical treatment. The respiratory tract, urinary tract, and gastrointestinal tract were the susceptible systems. Candida, especially C. albicans, was the main pathogen. From the perspective of drug sensitivity, amphotericin B should be given priority in treating the non-Aspergillus fungi infection in patients with systemic internal diseases, while the susceptibility of invasive fungal strains to azoles was variant. These data might provide clinical evidence for the prevention and treatment of invasive fungal infection in patients with systemic internal diseases.