Chunling Xu

BACKGROUND: Cancer has become a global health problem. China still suffers continuous increasing cancer mortality. To study the trend of cancer mortality in rural China, this paper established an Age-Period-Cohort model to discuss the age effect, period effect and cohort effect on cancer mortality in rural China. METHODS: The data were collected from the "China Health Statistical Yearbook" from 1990 to 2010. Collected data were analyzed by Age-Period-Cohort model and Intrinsic Estimation method. RESULTS: The age effect on the total cancer mortality represented a V trend. Compared with Group 0-4, Group 5-9 showed 71.87% lower cancer mortality risk. Compared with Group 5-9, Group 75-79 showed 38 times higher cancer mortality risk. The period effect on the total cancer mortality risk weakened firstly but then increased. It increased by 35.70% from 1990 to 2010, showing an annual average growth of 1.79%. The cohort effect on the total cancer mortality risk weakened by totally 84.94% from 1906-1910 to 2005-2010. Three "deterioration periods" and three "improvement periods" were witnessed during this period. The malignant cancer mortality varied similarly with the total cancer mortality, while benign cancer mortality and other cancer mortality represented different variation laws. CONCLUSIONS: Although the total cancer mortality risk is increasing at an accelerated rate, cancer mortality risk in recent born year is decreasing, indicating very important impact of social change on the cancer mortality in rural China.

Cancer immunotherapy has produced impressive clinical results in recent years. Despite the success of the checkpoint blockade strategies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1), a large portion of cancer patients have not yet benefited from this novel therapy. T cell immunoglobulin and mucin domain 3 (TIM-3) has been shown to mediate immune tolerance in mouse models of infectious diseases, alloimmunity, autoimmunity, and tumor Immunity. Thus, targeting TIM-3 emerges as a promising approach for further improvement of current immunotherapy. Despite a large amount of experimental data showing an immune suppressive function of TIM-3 in vivo, the exact mechanisms are not well understood. To enable effective targeting of TIM-3 for tumor immunotherapy, further in-depth mechanistic studies are warranted. These studies will also provide much-needed insight for the rational design of novel combination therapy with other checkpoint blockers. In this review, we summarize key evidence supporting an immune regulatory role of TIM-3 and discuss possible mechanisms of action.

Mitochondrial dysfunction underlies many prevalent diseases including heart disease arising from acute ischemia/reperfusion (I/R) injury. Here, we demonstrate that mitophagy, which selectively removes damaged or unwanted mitochondria, regulated mitochondrial quality and quantity in vivo . Hypoxia induced extensive mitochondrial degradation in a FUNDC1-dependent manner in platelets, and this was blocked by in vivo administration of a cell-penetrating peptide encompassing the LIR motif of FUNDC1 only in wild-type mice. Genetic ablation of Fundc1 impaired mitochondrial quality and increased mitochondrial mass in platelets and rendered the platelets insensitive to hypoxia and the peptide. Moreover, hypoxic mitophagy in platelets protected the heart from worsening of I/R injury. This represents a new mechanism of the hypoxic preconditioning effect which reduces I/R injury. Our results demonstrate a critical role of mitophagy in mitochondrial quality control and platelet activation, and suggest that manipulation of mitophagy by hypoxia or pharmacological approaches may be a novel strategy for cardioprotection.

Hypoxic pulmonary hypertension (PH) is a progressive disease characterized by hyper-proliferation of pulmonary vascular cells including pulmonary artery smooth muscle cells (PASMCs) and can lead to right heart failure and early death. Selective degradation of mitochondria by mitophagy during hypoxia regulates mitochondrial functions in many cells, however, it is not clear if mitophagy is involved in the pathogenesis of hypoxic PH. By employing the hypoxic mitophagy receptor Fundc1 knockout (KO) and transgenic (TG) mouse models, combined hypoxic PH models, the current study found that mitophagy is actively involved in hypoxic PH through regulating PASMC proliferation. In the pulmonary artery medium from hypoxic PH mice, mitophagy was upregulated, accompanied with the increased active form of FUNDC1 protein and the enhanced binding affinity of FUNDC1 with LC3B. In PASMCs, overexpression of FUNDC1 increased mitophagy and cell proliferation while knockdown of FUNDC1 inhibited hypoxia-induced mitophagy and PASMC proliferation. Stimulation of mitophagy by FUNDC1 in PASMCs elevated ROS production and inhibited ubiquitination of hypoxia inducible factor 1α (HIF1α), and inhibition of mitophagy by FUNDC1 knockdown or knockout abolished hypoxia-induced ROS-HIF1α upregulation. Moreover, Fundc1 TG mice developed severe hemodynamics changes and pulmonary vascular remodeling, and Fundc1 KO mice were much resistant to hypoxic PH. In addition, intraperitoneal injection of a specific FUNDC1 peptide inhibitor to block mitophagy ameliorated hypoxic PH. Our results reveal that during hypoxic PH, FUNDC1-mediated mitophagy is upregulated which activates ROS-HIF1α pathway and promotes PASMC proliferation, ultimately leads to pulmonary vascular remodeling and PH.

BACKGROUND: Progressive cardiac fibrosis leads to ventricular wall stiffness, cardiac dysfunction, and eventually heart failure, but the underlying mechanism remains unexplored. PDCD5 (programmed cell death 5) ubiquitously expresses in tissues, including the heart; however, the role of PDCD5 in cardiac fibrosis is largely unknown. Therefore, this study aims at exploring the possible role and underlying mechanisms of PDCD5 in the pathogenesis of cardiac fibrosis. METHODS AND RESULTS: PDCD5 levels were found to be elevated in the serum obtained from patients with cardiac fibrosis, in fibrotic mice heart tissues after myocardial infarction, and in cardiac fibroblasts stimulated by Ang II (angiotensin II)- or TGF-β1 (transforming growth factor-β1). Overexpression of PDCD5 in cardiac fibroblasts or treatment with PDCD5 protein reduced the expression of profibrogenic proteins in response to TGF-β1 stimulation, while knockdown of PDCD5 increased fibrotic responses. It has been demonstrated that SMAD3, a protein that is also known as mothers against decapentaplegic homolog 3, directly upregulated PDCD5 during cardiac fibrosis. Subsequently, the increased PDCD5 promoted HDAC3 (histone deacetylase 3) ubiquitination, thus, inhibiting HDAC3 to reduce fibrotic responses. Fibroblast-specific knock-in of PDCD5 in mice ameliorated cardiac fibrosis after myocardial infarction and enhanced cardiac function, and these protective effects were eliminated by AAV9-mediated HDAC3 overexpression. CONCLUSIONS: The findings of this study demonstrated that PDCD5 is upregulated by SMAD3 during cardiac fibrosis, which subsequently ameliorated progressive fibrosis and cardiac dysfunction through HDAC3 inhibition. Thus, this study suggests that PDCD5 functions as a negative feedback factor on fibrotic signaling pathways and might serve as a potential therapeutic target to suppress the progression of fibrotic responses.