The programmed cell death protein 1 (PD-1) pathway has received considerable attention due to its role in eliciting the immune checkpoint response of T cells, resulting in tumor cells capable of evading immune surveillance and being highly refractory to conventional chemotherapy. Application of anti-PD-1/PD-L1 antibodies as checkpoint inhibitors is rapidly becoming a promising therapeutic approach in treating tumors, and some of them have successfully been commercialized in the past few years. However, not all patients show complete responses and adverse events have been noted, suggesting a better understanding of PD-1 pathway mediated immunosuppression is needed to predict patient response and improve treatment efficacy. Here, we review the progresses on the studies of the mechanistic role of PD-1 pathway in the tumor immune evasion, recent clinical development and commercialization of PD-1 pathway inhibitors, the toxicities associated with PD-1 blockade observed in clinical trials as well as how to improve therapeutic efficacy and safety of cancer immunotherapy.

Dermatophytes are the most common cause of onychomycosis, counting for 90% fungal nail infection. Although dermatophyte pathogens are normally susceptible to antifungal agents, onychomycosis often results in refractory chronic disease, and the formation of biofilms frequently underlines the inadequate responses and resistance to standard antifungal treatment. Numerous in vitro and in vivo antimicrobial photodynamic therapy (aPDT) studies have shown biofilm eradication or substantial reduction, however, such investigation has not yet been expanded to the biofilms of dermatophytes involved in onychomycosis. To shed a light on the potential application of aPDT in the clinic management of onychomycosis, in particular with the manifestation of dermatophytoma, we investigated photodynamic effects on the viabilities and the drug susceptibilities of the biofilm of dermatophytes in vitro. Here, methylene blue at the concentration of 8, 16, and 32 μg/ml applied as photosensitizing agent and LED (635 ± 10 nm, 60 J/cm²) as light source were employed against six strains of Trichophyton rubrum, ten strains of Trichophyton mentagrophytes and three strains of Microsporum gypseum isolated from clinical specimens. Our results indicated highly efficient photodynamic inhibition, exhibiting CFU (colony forming unit) reduction up to 4.6 log₁₀, 4.3 log₁₀, and 4.7 log₁₀ against the biofilms formed by T. rubrum, T. mentagrophytes, and M. gypseum, respectively. Subjected biofilms displayed considerable decreases in SMICs (sessile minimum inhibitory concentrations) to multiple antifungal agents when compared with untreated groups, indicating the biofilms of dermatophytes became more susceptible to conventional antifungal drugs after aPDT. Additionally, the obliteration of biofilm after aPDT could be observed as shattered and ruptured structures being evident in SEM (Scanning Electron Microscopy) images. These findings suggest that aPDT is an attractive alternative treatment holding great promise for combating recalcitrant onychomycosis associated with the biofilm formation.

Retroviral gene therapy has emerged as a promising therapeutic modality for multiple inherited and acquired human diseases. The capability of delivering curative treatment or mediating therapeutic benefits for a long-term period following a single application fundamentally distinguishes this medical intervention from traditional medicine and various lentiviral/γ-retroviral vector-mediated gene therapy products have been approved for clinical use. Continued advances in retroviral vector engineering, genomic editing, synthetic biology and immunology will broaden the medical applications of gene therapy and improve the efficacy and safety of the treatments based on genetic correction and alteration. This review will summarize the advent and clinical translation of ex vivo gene therapy, with the focus on the milestones during the exploitation of genetically engineered hematopoietic stem cells (HSCs) tackling a variety of pathological conditions which led to marketing approval. Finally, current statue and future prospects of gene editing as an alternative therapeutic approach are also discussed.

Purpose: There is still lacking of highly sensitive and specific biomarkers for the prediction of hepatocellular carcinoma (HCC) early recurrence, which has hindered further improvement of the clinical outcomes. We aim to find highly sensitive and specific biomarkers for the prediction of HCC recurrence. Patients and methods: By using isobaric tags for relative and absolute quantitation (iTRAQ)-based multidimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS) technique, we have quantitatively investigated and monitored the proteome alterations of a series of serum after radical resection during the follow-up of 4 HCC patients. Results: A total of 27 differentially abundant proteins (DAPs) in serum were identified to be closely associated with the early recurrence of HCC, and these DAPs were particularly concentrated within ERK1/2 and nuclear factor-κ beta signaling pathways, suggesting the dysregulation of these two pathways played an important role in the pathological process of HCC early recurrence. Further investigation of a cohort of patients confirmed that the high serum level of PGK1 was closely associated with HCC early recurrence and poor prognosis. In addition, the serum level of PGK1 could be complementary with AFP to further improve the sensitivity and specificity for predicting the relapse of HCC. Conclusion: PGK1 might be an independent factor for the recurrence of HCC. And the PGK1 could be complementary with AFP to further improve the sensitivity and specificity in prognostic prediction of HCC relapse.

Antennapedia homeodomain has been shown to be able to translocate from extracellular space into the cytoplasm of cells in a receptor-independent manner. Its third α-helix domain, designated as "Penetratin", was proposed to be the functional transduction domain that is responsible for the translocation, and it is widely used for intracellular delivery of various exogenous proteins. Although Penetratin has been regarded to be the only element conferring the capacity on its parent polypeptide to penetrate through the plasma membrane, we found that the complete Antennapedia homeodomain exhibits an appreciably higher level of translocation efficiency as compared to Penetratin. Pharmacological analysis demonstrated that macropinocytic endocytosis plays a significant role underlying the process of the homeodomain internalization, and this is consistent with the observation that internalized polypeptide co-localizes with a fluid phase dye. Our results identify macropinocytosis as a major mechanism by which Antennapedia homeodomain obtains the access to the interior of cells, providing a novel perspective in the field of protein translocation and transduction.