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Purpose: Cerebral cavernous malformations (CCMs) are vascular anomalies predominantly in the central nervous system but may include lesions in other tissues, such as the retina, skin and liver. The main clinical manifestations include seizures, hemorrhage, recurrent headaches and focal neurological deficits. Previous studies of familial CCMs (FCCMs) have mainly reported in Hispanic and Caucasian cases. Here, we report on FCCMs in a Chinese family further characterized by a novelCCM1gene mutation.Materials and methods: We investigated clinical and neuroradiological features of a Chinese family of 30 members. Furthermore, we used exome capture sequencing to identify the causing gene. TheCCM1mRNA expression level in three patients of the family and 10 wild-type healthy individuals were detected by real-time quantitative polymerase chain reaction (real-time RT-PCR).Results: Brain magnetic resonance imaging demonstrated multiple intracranial lesions in seven members. The clinical manifestation of CCM was found in five of these cases, including recurrent headaches, weakness, hemorrhage and seizures. Moreover, we identified a novel nonsense mutation c.1159G>T (p. E387*) in theCCM1gene in the pedigree. Based on real-time RT-PCR results, we have found that theCCM1mRNA expression level in three patients was reduced by 35% than that in wild-type healthy individuals.Conclusions: Our finding suggests that the novel nonsense mutation c.1159G>T inCCM1gene is associated with FCCM, and thatCCM1haploinsufficiency may be the underlying mechanism of CCMs. Furthermore, it also demonstrates that exome capture sequencing is an efficient and direct diagnostic tool to identify causes of genetically heterogeneous diseases. [ABSTRACT FROM PUBLISHER]

In recent years immune checkpoint inhibitors have garnered attention as being one of the most promising types of immunotherapy on the horizon. There has been particular focus on the immune checkpoint molecules, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) which have been shown to have potent immunomodulatory effects through their function as negative regulators of T cell activation. CTLA-4, through engagement with its ligands B7-1 (CD80) and B7-2 (CD86), plays a pivotal role in attenuating the activation of naïve and memory T cells. In contrast, PD-1 is primarily involved in modulating T cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. The discovery of these negative regulators of the immune response was crucial in the development of checkpoint inhibitors. This shifted the focus from developing therapies that targeted activation of the host immune system against cancer to checkpoint inhibitors, which aimed to mediate tumor cell destruction through the removal of coinhibitory signals blocking anti-tumor T cell responses.

Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses (TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1 (PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.

Objective: To evaluate the antitumor efficacy of Ad-TD-RFP for human nasopharyngeal carcinoma cells (C666-1) in vitro and in vivo., Methods: The oncolytic effects of Ad-TD-RFP and control virus dl11520 on C666-1 cells were determined by cytotoxicity assay (MTS assay). Viral replication of Ad-TD-RFP and dl11520 was detected at different time points (24 h, 48 h, 72 h and 96 h) by tissue culture infective dose (TCID(50)) in C666-1 cells implanted subcutaneously into the flank in each of BALB/c nude mice. The xenografts were injected intratumorally with Ad-TD-RFP or dl1520 to investigate their effects on tumor growth., Results: The concentration for 50% of maximal effect (EC(50)) values of Ad-TD-RFP and dl1520 were (107.6 ± 3.2) pt/cell and (174.1 ± 4.0) pt/cell, respectively (t = 22.6, P < 0.001). The Ad-TD-RFP replication was 3-14 folds more than dl1520 replication at four time points (24 h, 48 h, 72 h and 96 h) in C666-1 cells (t values were 33.6, 23.4, 20.8 and 17.3, respectively, P < 0.001). The average tumor volumes of PBS group, dl1520 group and Ad-TD-RFP group were (1765.5 ± 713.9) mm(3), (1036.9 ± 623.8) mm(3), and (420.8 ± 238.7) mm(3), respectively (F = 12.0, P < 0.05) on day 67 after treatment., Conclusions: The antitumour efficacy of the novel oncolytic adenovirus Ad-TD-RFP for human nasopharyngeal carcinoma C666-1 cells is superior to that of dl1520 in vitro and in vivo. The outcome of this study provides an experimental basis for the treatment of human nasopharyngeal carcinoma by viral gene therapy.