Background： Lymphocyte subsets play important roles in rejection in liver transplant recipients, and the effect of splenic function on these roles remains unknown. The aim of this study was to ...explore the feasibility to adjust immunosuppressive agents based on splenic function status through detecting the lymphocyte subsets in liver transplant recipients. Methods： The lymphocyte subsets of 49 liver transplant recipients were assessed in the 309th Hospital of Chinese People＇s Liberation Army between June 2014 and August 2015. The patients were divided into splenectomy group （n - 9）, normal splenic function group （n = 24）, and hypersplenism group （n = 16）. The percentages and counts of CD4＋ T, CD8＋ T, natural killer （NK） cell, B-cell, regulatory B-cell （Breg）, and regulatory T-cell （Treg） were detected by flow cytometer. In addition, the immunosuppressive agents, histories of rejection and infection, and postoperative time of the patients were compared among the three groups. Results： There was no significant difference of clinical characteristics among the three groups. The percentage ofCD 19＋CD24＋CD38＋ Breg was significantly higher in hypersplenism group than normal splenic function group and splenectomy group （3.29±0.97% vs. 2.12 i 1.08% and 1.90 ± 0.99%, P = 0.001）. The same result was found in CD4＋CD25＋FoxP3＋ Treg percentage （0.97 ± 0.39% vs. 0.54 ±0.31% and 0.56 ± 0.28%, P = 0.001 ）. The counts of CD8＋ T-cell, CD4＋ T-cell, and NK cell were significantly lower in hypersplenism group than normal splenic function group （254.25 ± 149.08 vs. 476.96 ± 225.52, P = 0.002; 301.69 ±154.39 vs. 532.50 ±194.42, P= 0.000; and 88.56± 63.15 vs. 188.33± 134.51, P = 0.048）. Moreover, the counts of CD4＋ T-cell and NK cell were significantly lower in hypersplenism group than splenectomy group （301.69 ± 154.39 vs. 491.89 ± 132.31, P = 0.033; and 88.56 ± 63.15 vs. 226.00± 168.85, P 0.032）. Conclusion： Splenic function status might affect the immunity of liver transplant recipients, that should be considered when we make immunosuppressive protocols.
Background: The increasing prevalence of colorectal cancer (CRC) in China and the paucity of information about relevant expenditure highlight the necessity of better understanding the financial ...burden and effect of CRC diagnosis and treatment. We performed a survey to quantify the direct medical and non-medical expenditure as well as the resulting financial burden of CRC patients in China.Methods: We conducted a multicenter, cross-sectional survey in 37 tertiary hospitals in 13 provinces across China between 2012 and 2014. Each enrolled patient was interviewed using a structured questionnaire. All expenditure data were inflated to the 2014 Chinese Yuan (CNY; 1 CNY = 0.163 USD). We quantified the overall expenditure and financial burden and by subgroup (hospital type, age at diagnosis, sex, education, occupation, insurance type, household income, clinical stage, pathologic type, and therapeutic regimen). We then performed generalized linear modeling to determine the factors associated with overall expenditure.Results: A total of 2356 patients with a mean age of 57.4 years were included, 57.1% of whom were men; 13.9% of patients had stage I cancer; and the average previous-year household income was 54,525 CNY. The overall average direct expenditure per patient was estimated to be 67,408 CNY, and the expenditures for stage I, II, III, and IV disease were 56,099 CNY, 59,952 CNY, 67,292 CNY, and 82,729 CNY, respectively. Non-medical expenditure accounted for 8.3% of the overall expenditure. The 1-year out-of-pocket expenditure of a newly diagnosed patient was 32,649 CNY, which accounted for 59.9% of their previous-year household income and caused 75.0% of families to suffer an unmanageable financial burden. Univariate analysis showed that financial burden and overall expenditure differed in almost all subgroups (P < 0.05), except for sex. Multivariate analysis showed that patients who were treated in specialized hospitals and those who were diagnosed with adenocarcinoma or diagnosed at a later stage were likely to spend more,whereas those with a lower household income and those who underwent surgery spent less (all P < 0.05).Conclusions: For patients in China, direct expenditure for the diagnosis and treatment of CRC seemed catastrophic,and non-medical expenditure was non-ignorable. The financial burden varied among subgroups, especially among patients with different clinical stages of disease, which suggests that, in China, CRC screening might be cost-effective.
Aim
We aimed to assess economic burden of breast cancer (BC) diagnosis and treatment in China through a multicenter cross‐sectional study, and to obtain theoretical evidence for policy‐making.
...Methods
This survey was conducted in 37 hospital centers across 13 provinces in China from September 2012 to December 2014. We collected information on the subject characteristics. We then assessed the medical and non‐medical expenditure for BC diagnosis and treatment, factors influencing the average case expense, variations between medical and non‐medical expenditure at different clinical stages, economic impact of overall expenditure in newly diagnosed course after reimbursement to the patient's family, composition of non‐medical expenditure and time loss for the patient and family.
Results
Among 2746 women with BC (72.6% were admitted to specialized hospitals), the overall average expenditure was US $8450 (medical expenditure: $7527; non‐medical expenditure: $922). Significant differences were found among the overall expenditure in the four clinical stages (P < 0.0001); the expenditure was higher in stages III and IV than that in stages I and II, whereas the stage IV was the highest (P < 0.0001). Moreover, a higher self‐reported predicted reimbursement ratio was associated with a less economic impact on the patient's family, and the average time lost was estimated as $1529.
Conclusions
Early detection and treatment of breast cancer might be effective for decreasing the economic burden, because costs escalate as the degree of malignancy increases.
Type 2 diabetic osteoporosis (T2DOP) is a chronic bone metabolic disease. Compared with traditional menopausal osteoporosis, the long-term high glucose (HG) microenvironment increases patients’ risk ...of fracture and osteonecrosis. We were accumulating evidence that implicated ferroptosis as a pivotal mechanism of glucolipotoxicity-mediated death of osteocytes and osteoblast, a novel form of programmed cell death resulting from uncontrolled lipid peroxidation depending on iron. Vitamin K2 (VK2), a fat-soluble vitamin, is clinically applied to prevent osteoporosis and improve coagulation. This study aimed to clarify the role and mechanism of VK2 in HG-mediated ferroptosis. We established the mouse T2DOP model by intraperitoneal injection of streptozotocin solution and a high-fat and high-sugar diet. We also cultured bone marrow mesenchymal stem cells (BMSCs) in HG to simulate the diabetic environment in vitro. Based on our data, VK2 inhibited HG-mediated bone loss and ferroptosis, the latter manifested by decreased levels of mitochondrial reactive oxygen species, lipid peroxidation, and malondialdehyde and increased glutathione in vitro. In addition, VK2 treatment was capable of restoring bone mass and strengthening the expression of SIRT1, GPX4, and osteogenic markers in the distal femurs. As for further mechanism exploration, we found that VK2 could activate AMPK/SIRT1 signaling, and knockdown of SIRT1 by siRNA prevented the VK2-mediated positive effect in HG-cultured BMSCs. Summarily, VK2 could ameliorate T2DOP through the activation of the AMPK/SIRT1 signaling pathway to inhibit ferroptosis.
Vascular integrity helps maintain brain microenvironment homeostasis, which is critical for the normal development and function of the central nervous system. It is known that neural cells can ...regulate brain vascular integrity. However, due to the high complexity of neurovascular interactions involved, understanding of the neural regulation of brain vascular integrity is still rudimentary. Using intact zebrafish larvae and cultured rodent brain cells, we find that neurons transfer miR-132, a highly conserved and neuron-enriched microRNA, via secreting exosomes to endothelial cells (ECs) to maintain brain vascular integrity. Following translocation to ECs through exosome internalization, miR-132 regulates the expression of vascular endothelial cadherin (VE-cadherin), an important adherens junction protein, by directly targeting eukaryotic elongation factor 2 kinase (eef2k). Disruption of neuronal miR-132 expression or exosome secretion, or overexpression of vascular eef2k impairs VE-cadherin expression and brain vascular integrity. Our study indicates that miR-132 acts as an intercellular signal mediating neural regulation of the brain vascular integrity and suggests that the neuronal exosome is a novel avenue for neurovascular communication.
DJ-1 is a multifunctional protein associated with cancers and autosomal early-onset Parkinson disease. Besides the well-documented antioxidative stress activity, recent studies show that DJ-1 has ...deglycation enzymatic activity and anti-ferroptosis effect. It has been shown that DJ-1 forms the homodimerization, which dictates its antioxidative stress activity. In this study, we investigated the relationship between the dimeric structure of DJ-1 and its newly reported activities. In HEK293T cells with Flag-tagged and Myc-tagged DJ-1 overexpression, we performed deletion mutations and point mutations, narrowed down the most critical motif at the C terminus. We found that the deletion mutation of the last three amino acids at the C terminus of DJ-1 (DJ-1 ΔC3) disrupted its homodimerization with the hydrophobic L187 residue being of great importance for DJ-1 homodimerization. In addition, the ability in methylglyoxal (MGO) detoxification and deglycation was almost abolished in the mutation of DJ-1 ΔC3 and point mutant L187E compared with wild-type DJ-1 (DJ-1 WT). We also showed the suppression of erastin-triggered ferroptosis in DJ-1
mouse embryonic fibroblast cells was abolished by ΔC3 and L187E, but partially diminished by V51C. Thus, our results demonstrate that the C terminus of DJ-1 is crucial for its homodimerization, deglycation activity, and suppression of ferroptosis.
Objective： The aim of this study was to detect metastasis-associated in colon cancer-1 （MACC1） expression in Chinese gastric cancer and analyze the relationship between MACC1 expression and ...postoperative survival. Methods： The expression of MACC1 and c-MET protein in a sample of 128 gastric cancer tissues was detected by immunohistochemistry. A retrospective cohort study on the prognosis was carried out and data were collected from medical records. Results： The positive rate of MACC1 protein expression in gastric cancer was 47.66%, higher than that in adjacent noncancerous mucosa （P0.001）. MACC1 protein expression was not related to the clinicopathological variables involved. Kaplan-Meier analysis revealed that the survival of MACC1 positive group tended to be better than that of MACC1 negative group, particularly in patients with stage III carcinoma （P=0.032）. Cox regression analysis revealed that MACC1 protein over-expression in gastric cancer tended to be a protective factor with hazard ratio of 0.621 （P=0.057）. Immunohistochemical analysis showed that the positive rate of c-MET protein expression was much higher in cases with positive MACC1 expression in gastric cancer （P=0.002）, but P53 expression was not associated with MACC1 expression. Conclusion： MACC1 over-expression implies better survival and may be an independent prognostic factor for gastric cancer in Chinese patients.
Among arthropod vectors, ticks transmit the most diverse human and animal pathogens, leading to an increasing number of new challenges worldwide. Here we sequenced and assembled high-quality genomes ...of six ixodid tick species and further resequenced 678 tick specimens to understand three key aspects of ticks: genetic diversity, population structure, and pathogen distribution. We explored the genetic basis common to ticks, including heme and hemoglobin digestion, iron metabolism, and reactive oxygen species, and unveiled for the first time that genetic structure and pathogen composition in different tick species are mainly shaped by ecological and geographic factors. We further identified species-specific determinants associated with different host ranges, life cycles, and distributions. The findings of this study are an invaluable resource for research and control of ticks and tick-borne diseases.
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•Six high-quality ixodid tick genomes and 678 re-sequenced tick specimens•Insights into the genetic basis of tick hematophagy and related phenotypes•Population structure and genetic diversity of six tick species•Tick-borne pathogen composition and distribution by metagenome analyses
The high-quality genomes of six ixodid tick species and resequencing of 678 tick specimens are a resource to understand the genetic diversity, population structure, and pathogen distribution of ticks with implications for control of ticks and tick-borne diseases.
The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key enzyme, which extensively digests CoV replicase polyproteins essential for viral replication and ...transcription, making it an attractive target for antiviral drug development. However, the molecular mechanism of how Mpro of SARS-CoV-2 digests replicase polyproteins, releasing the nonstructural proteins (nsps), and its substrate specificity remain largely unknown. Here, we determine the high-resolution structures of SARS-CoV-2 Mpro in its resting state, precleavage state, and postcleavage state, constituting a full cycle of substrate cleavage. The structures show the delicate conformational changes that occur during polyprotein processing. Further, we solve the structures of the SARS-CoV-2 Mpro mutant (H41A) in complex with six native cleavage substrates from replicase polyproteins, and demonstrate that SARS-CoV-2 Mpro can recognize sequences as long as 10 residues but only have special selectivity for four subsites. These structural data provide a basis to develop potent new inhibitors against SARS-CoV-2.
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