A virtual-pinhole PET device for improving contrast recovery and enhancing lesion detectability of a one-meter-long PET scanner: a simulation study.

This paper presents a simulation study to demonstrate that the contrast recovery coefficients (CRC) and detectability of small lesions of a one-meter-long positron emission tomography (PET) scanner can be further enhanced by the integration of high resolution virtual-pinhole (VP) PET devices. The scanner under investigation is a Siemens Biograph Vision Quadra which has an axial field-of-view (FOV) of 106 cm. The VP-PET devices contain two high-resolution flat panel detectors, each composed of 2 × 8 detector modules each of which consists of 32 × 64 lutetium-oxyorthosilicate crystals (1.0 × 1.0 × 10.0 mm3each). Two configurations for the VP-PET device placement were evaluated: (1) place the two flat-panel detectors at the center of the scanner's axial FOV below the patient bed; (2) place one flat-panel detector at the center of the first and the last quarter of the scanner's axial FOV below the patient bed. Sensitivity profiles were measured by moving a point22Na source stepwise across the scanner's FOV axially at different locations. To assess the improvement in CRC and lesion detectability by the VP-PET devices, an elliptical torso phantom (31.6 × 22.8 × 106 cm3) was first imaged by the native scanner then subsequently by the two VP-PET geometry configurations. Spherical lesions (4 mm in diameter) having 5:1 lesion-to-background radioactivity concentration ratio were grouped and placed at nine regions in the phantom to analyze the dependence of the improvement in plane. Average CRCs and their standard deviations of the 7 tumors in each group were computed and the receiver operating characteristic (ROC) curves were drawn to evaluate the improvement in lesion detectability by the VP-PET device over the native long axial PET scanner. The fraction of coincidence events between the inserts and the scanner detectors was 13%-16% (out of the total number of coincidences) for VP-PET configuration 1 and 2, respectively. The VP-PET systems provide higher CRCs for lesions in all regions in the torso, with more significant enhancement at regions closer to the inserts, than the native scanner does. For any given false positive fraction, the VP-PET systems offer higher true positive fraction compared to the native scanner. This work provides a potential solution to further enhance the image resolution of a long axial FOV PET scanner to maximize its lesion detectability afforded by its super high effective sensitivity.

Rare Variants and Polymorphisms of FBN1 Gene May Increase the Risk of Non-Syndromic Aortic Dissection.

Aortic dissection (AD) is a cardiovascular disease characterized by high mortality and poor prognosis. Although FBN1 is associated with syndromic AD, its association with non-syndromic AD remains unclear. In this study, DNA samples from 90 Chinese individuals with non-syndromic AD (60 Stanford A, 30 Stanford B types) were analyzed to determine the relationship between diverse genotypes of the FBN1 gene and non-syndromic AD. Eleven pathogenic/likely pathogenic variants (1 novel) were identified in 12.2% of patients with non-syndromic AD. Patients with positive variants suffered from AD at a younger age than those in the negative variant group. Among the six positive missense mutations associated with cysteine residue hosts, four (66.7%) were Stanford A AD, whereas two (33.3%) were Stanford B AD. Three (100%) positive splicing/truncation variant hosts were Stanford A AD. The splicing/truncation variants and missense variants involving cysteine residues in the FBN1 gene increased the risk of Stanford A AD. Ten common SNPs that increased susceptibility to AD were identified. In particular, five SNPs were detected significantly in Stanford A AD, whereas another four SNPs were significantly detected in Stanford B AD. These significant variants can function as biomarkers for the identification of patients at risk for AD. Our findings have the potential to broaden the database of positive mutations and common SNPs of FBN1 in non-syndromic AD among the Chinese population.

Genetic inhibition of nuclear factor of activated T-cell c2 prevents atrial fibrillation in CREM transgenic mice.

AIMS: Abnormal intracellular calcium (Ca2+) handling contributes to the progressive nature of atrial fibrillation (AF), the most common sustained cardiac arrhythmia. Evidence in mouse models suggests that activation of the nuclear factor of activated T-cell (NFAT) signalling pathway contributes to atrial remodelling. Our aim was to determine the role of NFATc2 in AF in humans and mouse models. METHODS AND RESULTS: Expression levels of NFATc1-c4 isoforms were assessed by quantitative reverse transcription-polymerase chain reaction in right atrial appendages from patients with chronic AF (cAF). NFATc1 and NFATc2 mRNA levels were elevated in cAF patients compared with those in normal sinus rhythm (NSR). Western blotting revealed increased cytosolic and nuclear levels of NFATc2 in AF patients. Similar findings were obtained in CREM-IbΔC-X transgenic (CREM) mice, a model of progressive AF. Telemetry ECG recordings revealed age-dependent spontaneous AF in CREM mice, which was prevented by NFATc2 knockout in CREM:NFATc2-/- mice. Programmed electrical stimulation revealed that CREM:NFATc2-/- mice lacked an AF substrate. Morphometric analysis and histology revealed increased atrial weight and atrial fibrosis in CREM mice compared with wild-type controls, which was reversed in CREM:NFATc2-/- mice. Confocal microscopy showed an increased Ca2+ spark frequency despite a reduced sarcoplasmic reticulum (SR) Ca2+ load in CREM mice compared with controls, whereas these abnormalities were normalized in CREM:NFATc2-/- mice. Western blotting revealed that genetic inhibition of Ca2+/calmodulin-dependent protein kinase II-mediated phosphorylation of S2814 on ryanodine receptor type 2 (RyR2) in CREM:RyR2-S2814A mice suppressed NFATc2 activation observed in CREM mice, suggesting that NFATc2 is activated by excessive SR Ca2+ leak via RyR2. Finally, chromatin immunoprecipitation sequencing from AF patients identified Ras and EF-hand domain-containing protein (Rasef) as a direct target of NFATc2-mediated transcription. CONCLUSION: Our findings reveal activation of the NFAT signalling pathway in patients of Chinese and European descent. NFATc2 knockout prevents the progression of AF in the CREM mouse model.

Visible photon avalanche up-conversion of Yb3+ and Ho3+ doped NaBi(WO4)2 phosphors under excitation at 980 nm.

Avalanche phenomenon uses critical pump power to produce extreme nonlinear behavior from small disturbances, and has gradually become known. Here, it is reported that the strong green up-conversion emission produced in NaBi(WO4)2 phosphor by the positive feedback enhancement of the energy transfer process. The power dependence indicates that the photon avalanche process has occurred. Contrary to other up-conversion mechanisms, photon avalanche (PA) is a bifurcation phenomenon: avalanches occur above the critical excitation power. The experimental results are analyzed using the rate equation model. The high-response photon avalanche process produced by Yb and Ho ions is discussed in detail. The results show that PA can not only improve the brightness and efficiency of up-conversion, but also has a wider range of applications than traditional up-conversion materials, especially in the detection material of temperature sensor plays an important role.

Association of Angiotensin II Type 1 Receptor Agonistic Autoantibodies With Outcomes in Patients With Acute Aortic Dissection.

Importance: Angiotensin II is significantly associated with the pathogenesis of acute aortic dissection. Angiotensin II type 1 receptor agonistic autoantibodies (AT1-AAs) can mimic the effect of angiotensin II. Objective: To investigate the association between AT1-AAs and all-cause and cause-specific mortality risk in patients with acute aortic dissection. Design, Setting, and Participants: A total of 662 patients with clinically suspected aortic dissection from 3 medical centers in Wuhan, China, were enrolled in this cohort study from August 1, 2014, to July 31, 2016. Of these, 315 patients were included in the 3-year follow-up study. Follow-up was mainly performed via telephone interviews and outpatient clinic visits. Data analysis was conducted from March 1 to May 31, 2020. Main Outcomes and Measures: The primary outcomes of interest were all-cause mortality, death due to aortic dissection, and late aortic-related adverse events. Results: The full study cohort included 315 patients with AAD (mean [SD] age, 56.2 [12.7] years; 230 men [73.0%]). Ninety-two patients (29.2%) were positive for AT1-AAs. The mortality of AT1-AA-positive patients was significantly higher than that of AT1-AA-negative patients (40 [43.5%] vs 37 [16.6%]; P < .001). The mortality risk in AT1-AA-positive patients was always significantly higher than that in AT1-AA-negative patients in patients with both type A and type B dissection. Multivariable analysis showed that the risk of AT1-AA-positive patients for type A dissection was significantly higher than that of AT1-AA-negative patients (odds ratio [OR], 1.88; 95% CI, 1.12-3.13; P = .02). The Cox proportional hazards regression model showed a significant increase of all-cause mortality risk (OR, 2.27; 95% CI, 1.44-3.57; P < .001) and late aortic-related adverse events (OR, 1.58; 95% CI, 1.06-2.36; P = .03) among AT1-AA-positive patients during the follow-up period compared with AT1-AA-negative patients. Conclusions and Relevance: This cohort study first detected AT1-AAs in patients with acute aortic dissection. The presence of AT1-AAs was associated with significantly higher all-cause and cause-specific mortality during a follow-up period of 3 years. The antibodies may be a risk factor for aortic dissection.

Integrating Network Pharmacology and Experimental Validation to Decipher the Mechanism of Action of Huanglian Jiedu Decoction in Treating Atherosclerosis.

BACKGROUND: This study used network pharmacology, molecular docking and experimental validation to assess the effects of Huanglian Jiedu Decoction (HLJDD) on atherosclerosis (AS). METHODS: The components and targets of HLJDD were analyzed using the Traditional Chinese Medicine Systems Pharmacology database, and information on the genes associated with AS was retrieved from the GeneCards and OMIM platforms. Protein-protein interactions were analyzed using the STRING platform. A component-target-disease network was constructed using Cytoscape. GO and KEGG analyses were performed to identify molecular biological processes and signaling pathways, and the predictions were verified experimentally. Molecular docking was conducted with ChemOffice software, PyMOL software and Vina to verify the correlation of targets and compounds. RESULTS: HLJDD contained 31 active compounds, with quercetin, kaempferol, moupinamide and 5-hydroxy-7-methoxy-2-(3,4,5-trimethoxyphenyl)chromone as the core compounds. The most important biotargets of HLJDD in AS were ICAM-1, CD31 and RAM-11. The molecular docking results showed that the molecular docking interaction energy between the 3 key targets and the 4 high-degree components were much less than -5 kJ∙mol-1. The experimental validation results showed that HLJDD might treat AS mainly by reducing TC, TG and LDL-C and increasing HDL-C, upregulating CD31 expression, reducing ICAM-1 and RAM-11 expression, and downregulating inflammatory factors, including CRP, IL-6 and TNF-α. These results support the network pharmacology data and demonstrate that HLJDD affects the expression of core genes and alters the leukocyte transendothelial migration signaling pathway. CONCLUSION: Based on network pharmacology and experimental validation, our study indicated that HLJDD exerted anti-AS effect through upregulating CD31 expression and reducing the expression of ICAM-1 and RAM-11. HLJDD may be a potential therapeutic drug to the prevention of AS.

Spontaneous Pneumothorax: A Complication of Coronavirus Disease 2019 (COVID-19) Patients.

BACKGROUND: At present, the coronavirus disease 2019 (COVID-19) is spreading all over the world. The occurrence of spontaneous pneumothorax in these patients might be higher than the fact, and we should pay high clinical attention to them. METHOD: Data regarding clinical investigation, laboratory investigation, diagnosis, and treatment measures of 21 COVID-19 patients with spontaneous pneumothorax from January to March of 2020 were collected and analyzed in this study. RESULTS: Seven patients had a history of basic lung diseases. All patients used different methods of oxygen therapy before the occurrence of spontaneous pneumothorax according to the severity of the COVID-19, including 18 patients with ventilator-assisted breathing, 2 patients with bilevel positive airway pressure assisted breathing, and 1 patient with mask oxygen inhalation. All patients were confirmed cases of COVID-19 by chest CT (computed tomography) and virus nucleic acid detection and were found to have spontaneous pneumothorax through physical examination, bedside X-ray, and/or bedside ultrasound. 13 of 21 patients combined with pleural effusion at the same time. All the patients underwent closed thoracic drainage for spontaneous pneumothorax and the pleural effusion, if any. Nine patients died, and 12 patients recovered smoothly. CONCLUSION: Spontaneous pneumothorax might be an overlooked complication of COVID-19 patients and may be associated with poor prognosis.

End-of-life passenger vehicles recycling decision system in China based on dynamic material flow analysis and life cycle assessment.

China's automobile industry is developing rapidly, but the recycling rate of end-of-life vehicles has been low. In 2018, the recovery rate of end-of-life passenger vehicles was less than 18% of the scrapped amount. Dynamic material flow analysis can predict the amount of end-of-life passenger cars in China in the future, and analyze the flow of materials in recycling system. Life cycle assessment can be used to quantify greenhouse gas emissions. Therefore, this paper integrates these two methods into the model construction of recycling decision system. Meanwhile, sensitivity analysis of the important factors affecting the efficiency of the recovery system is carried out. Finally, the main recovery indexes of the system are predicted under three scenarios: low-speed, medium speed and high-speed development, which are set based on scrap volume, standard recovery rate, proportion of assembly into remanufacturing and carbon tax price. The research results show that in 2018, 656.9 kg/vehicle of iron, 150.2 kg/vehicle of aluminum and 7.9 kg/vehicle of copper are recovered from end-of-life passenger car in China, and the carbon emission during the recovery process is 651.1 kg of CO2eq/vehicle, with a total emission reduction of 3816.1 kgCO2eq/vehicle compared with the original production, and the economic benefit is about 5055.5 yuan/vehicle. The scenario prediction results show that by 2050, from the low-speed development scenario to the high-speed development scenario, the total amount of iron, aluminum and copper recovered rise from 3.96 million tons, 915 thousand tons and 46 thousand tons to 697 thousand tons, 1.61 million tons and 80 thousand tons respectively throughout the year. The carbon emission in the recovery process rise from 4.98 thousand tons to 9.32 million tons. Compared with the original production, the carbon emission reduction increases from 2.21 million tons to 38.3 million tons, the economic benefit increases from 58.9 billion yuan to 118.8 billion yuan, and the comprehensive benefit increases from 57 billion yuan to 111.6 billion yuan.

Exploring the genetic pathogenicity of aortic dissection from 72 Han Chinese individuals using next-generation sequencing.

Aortic dissection (AD) is a heterogeneous genetic disease with high morbidity and mortality. Although many genes predispose patients to AD, the pathogenic spectrum remains incomplete. This study aims to (a) investigate whether genotype differences exist between Stanford A and B AD individuals, and (b) broaden the pathogenic genetic spectrum of AD and reported novel variants of AD-associated genes. The DNA of 72 unrelated Han Chinese individuals with AD was tested by whole-exome sequencing. Of 142 AD-associated genes, 10 pathogenic variants, and 48 likely pathogenic variants in 36 genes were identified among 39 cases. The diagnostic yield was 54.2%. Of the 58 positive variants, 27 were novel. FBN1 was the most frequently positive gene in both Stanford A and Stanford B. Twenty-seven positive variants from 18 COL family genes were distributed in 36.8% of Stanford A and 6.7% of Stanford B cases. We emphasize that positive variants of COL family genes show distribution predominance and strong pathogenicity in Stanford A, while positive variants of smooth muscle cell pathway genes present distribution advantages mainly in Stanford B cases. Our findings provide a new perspective for both the pathogenic mechanism and the treatment of AD.

Long non-coding RNA LINC00467 drives hepatocellular carcinoma progression via inhibiting NR4A3.

Hepatocellular carcinoma (HCC) is a main cause of cancer-related deaths globally. Long non-coding RNAs (lncRNAs) play important roles in diverse cancers. Our previous microarray-based lncRNA profiling showed that LINC00467 was highly expressed in HCC. Here, we further explored the expression, role and functional mechanism of lncRNA LINC00467 in HCC. Our findings revealed that LINC00467 was up-regulated in HCC tissues and HCC cell lines. Increased expression of LINC00467 was positively associated with tumour size and vascular invasion. In vitro functional experiments revealed that LINC00467 accelerated HCC cell proliferation, cell cycle progression and migration and reduced HCC cell apoptosis. In vivo functional assays revealed that LINC00467 drove HCC xenograft growth and HCC cell proliferation and repressed HCC cell apoptosis in vivo. Moreover, LINC00467 inhibited NR4A3 post-transcriptionally via interacting with NR4A3 mRNA to form double-stranded RNA, which was further degraded by Dicer. The expression of NR4A3 was inversely associated with LINC00467 in HCC tissues. Functional rescue assays found that restore of NR4A3 expression blocked the oncogenic roles of LINC00467 in HCC. Taken together, our results demonstrated that lncRNA LINC00467 was a novel highly expressed and oncogenic lncRNA in HCC via inhibiting NR4A3. Targeting LINC00467 or enhancing NR4A3 may be potential therapeutic strategies against HCC.

Patients with idiopathic recurrent miscarriage have abnormally high TGFß+ blood NK, NKT and T cells in the presence of abnormally low TGFß plasma levels.

BACKGROUND: Previously, we demonstrated up-regulated activated CD4+ and CD8+ T lymphocytes as well as up-regulated cytotoxic NK cells in the blood of patients with idiopathic recurrent miscarriage. In the present study, we tried to identify deficiencies in counter-regulating immune mechanisms of these patients. METHOD: Cytokines were determined in NK cells and in plasma samples of 35 healthy controls, 33 patients with idiopathic recurrent miscarriage, 34 patients with end stage renal disease, 10 transplant patients early and 37 transplant patients late post-transplant using flow-cytometry and luminex. In addition, cytokines were studied in supernatants of cell cultures with peripheral blood mononuclear cells stimulated in-vitro with tumor cell line K562. RESULTS: Patients with idiopathic recurrent miscarriage exhibited the highest absolute cell counts of circulating TGFß1+ NK, NKT and T lymphocytes and the lowest TGFß1 plasma levels of all study groups (for all p < 0.050). In-vitro, peripheral blood mononuclear cells of patients with idiopathic recurrent miscarriage showed high spontaneous TGFß1 production that could not be further increased by stimulation with K562, indicating increased consumption of TGFß1 by activated cells in the cell culture. Moreover, patients with idiopathic recurrent miscarriage had abnormally high IL4+ as well as abnormally high IFNy+ NK cells (p < 0.010) but similar IL10+ NK cell numbers as female healthy controls and showed the lowest plasma levels of IL10, TGFß3, IL1RA, IL1ß, IL5, IL6, IL8, IL17, TNFα, GM-CSF, TPO and VEGF and the highest plasma levels of G-CSF, FGF-basic, CCL3 and CXCL5 as compared to female HC and female transplant recipients (for all p < 0.050). CONCLUSIONS: Patients with idiopathic recurrent miscarriage show an activated immune system that can hardly be stimulated further and cannot be efficiently down-regulated by up-regulated TGFß1+ and IL4+ NK, NKT and T lymphocytes which are present concomitantly in these patients. The strongly decreased TGFß and IL10 plasma levels indicate deficient down-regulation and reflect a dysbalance of the immune system in patients with idiopathic recurrent miscarriage. These findings may be relevant for explaining the pathogenesis of idiopathic recurrent miscarriage.

The surgical treatment strategy and perioperative management of patients with heart valve disease complicated with severe chronic heart failure / 中国胸心血管外科临床杂志

@#Objective    To summarize the individualized selection of surgical treatment strategies and the key points of perioperative management for patients with heart valve disease complicated with severe chronic heart failure. Methods    The clinical characteristics of 5 male patients with valvular heart disease complicated with severe chronic heart failure (CHF) were analyzed retrospectively from June 2017 to October 2018 in Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, with an average age of 60.21 years. Results    Five patients were given angiotensin receptor and neprilysin inhibitor (ARNI)-based anti-heart failure treatment after admission. The operation mode of these patients was decided to be valve replacement under cardiopulmonary bypass after individualized evaluation of patients’ improving symptoms. Three patients were treated with intra-aortic balloon pump (IABP) and continuous renal replacement therapy (CRRT) early after operation to assist patients in improving cardiac function. Five patients recovered oral anti-heart failure after awakening. All patients were discharged smoothly 2 weeks after operation. Conclusion    Individualized evaluation is needed for the choice of operation timing and mode, standardized preoperative treatment for heart failure, shortening the aortic blocking time during cardiopulmonary bypass, and early application of left ventricular adjuvant drugs or instruments are all important measures to help patients recover smoothly.

Long non-coding RNA CRNDE promotes the proliferation, migration and invasion of hepatocellular carcinoma cells through miR-217/MAPK1 axis.

Hepatocellular carcinoma (HCC) is an invasive malignant tumour and the second major cause of cancer-related deaths over the world. CRNDE and miR-217 are non-coding RNAs which play critical roles in cell growth, proliferation, migration. Mitogen-activated protein kinase 1 (MAPK1) also participates in cancer cell process. Hence, this study aimed at investigating the effect of CRNDE on migration and invasion of HCC and figuring out the role of miR-217 and MAPK1 in this process. The overexpression of CRNDE was demonstrated by a microarray-based lncRNA profiling study. CRNDE expression in HCC was verified by qRT-PCR. MTT assay and BrdU staining were applied to detect cell proliferation level. Transwell assay was utilized to examine cell migration and invasiveness abilities. Wound healing assay was performed for further exploration of cell migration capacity. MiR-217 was predicted by bioinformatics. The dual luciferase reporter assay was performed to corroborate the targeting relationship between CRNDE, miR-217 and MAPK1. MAPK1, the downstream target of miR-217, was predicted using bioinformatics and was further confirmed by qRT-PCR and Western blot. The interaction between CRNDE, miR-217 and MAPK1 was studied by qRT-PCR, Western blot, MTT, BrdU, transwell assay and wound healing assay. CRNDE was up-regulated in HCC tissues and HCC cell lines. The high expression of CRNDE facilitated cell proliferation, migration and invasion, while the inhibited one affected on the contrary. MiR-217, negatively correlated with CRNDE expression, was the target of CRNDE and was more lowly expressed in HCC. With the high expression of miR-217, HCC cell proliferation, migration and invasion were suppressed. MAPK1, the possible target of miR-217, was negatively correlated with miR-217 but positively correlated with CRNDE and had the same effect in HCC formation process as CRNDE. Long non-coding RNA CRNDE promotes the proliferation, migration and invasion of HCC cells through miR-217/MAPK1 axis.

Changes of NK cell subsets with time post-transplant in peripheral blood of renal transplant recipients.

BACKGROUND: There is evidence that NK cells with low cytotoxicity but strong immunoregulatory characteristics contribute to good graft outcome. We attempted to investigate which NK cell subsets increase post-transplant and might affect graft function. METHOD: Lymphocyte and NK cell subsets were determined in whole blood using eight-colour-fluorescence flow cytometry in patients pre-transplant and post-transplant. In total, 31 transplant recipients were studied. RESULTS: When cell numbers were compared in 9 patients pre- and 6 months post-transplant, post-transplant CD56dimCD16+ (p = 0.011) NK cells with the phenotype CD158a+ (p = 0.008), CD158e+ (p = 0.038), NKG2A+ (p = 0.008), NKG2D+ (p = 0.011), IFNyR+ (p = 0.008), perforin+ (p = 0.008), granzymeB+ (p = 0.008), perforin+granzymeB+ (p = 0.008) and perforin-granzymeB- (p = 0.021) were lower than those pre-transplant, indicating a post-transplant reduction of cytotoxic NK cells. In 28 patients NK cell subsets were analyzed with respect to time post-transplant (median 888 days post-transplant). CD56dimCD16+ NK cells co-expressing CD158a (p = 0.014), NKG2D (p = 0.047), IL4R (p = 0.038), IL10R (p = 0.008) and IFNy (p = 0.036) as well as CD56bright NK cells with the phenotype TGFß+ (p = 0.017), TGFR+ (p = 0.035), CD158a+ (p = 0.042) and perforin-granzymeB- (p = 0.048) increased with time post-transplant. CONCLUSION: Post-transplant, cytotoxic NK cells were lower than pre-transplant and remained low, whereas NK cell subsets with potentially immunoregulatory properties increased.

microRNA-452 exerts growth-suppressive activity against T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer. Although microRNA (miR)-452 serves as a tumor suppressor in multiple solid tumors, its expression and function in hematological cancers including T-ALL is largely unknown. We measured the expression of miR-452 in 38 T-ALL and 22 normal lymph node samples by real-time PCR analysis. The methylation levels in the promoter of miR-452 were determined using MethyLight assay. The effects of miR-452 overexpression on proliferation, cell cycle distribution, and tumorigenesis were explored. It was found that miR-452 expression levels were significantly lower in T-ALL specimens than in normal lymph node biopsies (P=0.0079). T-ALL specimens had a significantly higher methylation level in the promoter of miR-452 than normal lymph node tissues (P=0.0014). Consistently, miR-452 was downregulated in Jurkat and Molt-4 T-ALL cells, whose expression was restored after treatment with a demethylation agent 5-aza-2'-deoxycytidine. Ectopic expression of miR-452 inhibited the proliferation of Jurkat and Molt-4 cells and induced a G0/G1 cell cycle arrest. Overexpression of miR-452 suppressed the protein expression of BMI1 in T-ALL cells. Rescue experiments revealed that overexpression of BMI1 partially reversed the growth-suppressive effect of miR-452 on T-ALL cells. Xenograft tumor studies confirmed that overexpression of miR-452 suppressed tumor growth in nude mice and reduced the expression of BMI1. Collectively, miR-452 is epigenetically silenced and targets BMI1 to exert a growth suppressive activity in T-ALL. Restoration of miR-452 expression may represent a promising therapeutic strategy for this malignancy.

Surgical treatment of pregnancy complicated with aortic dissection / 中国胸心血管外科临床杂志

@#Objective To summarize the characteristics and management of pregnancy complicated with aortic dissection, and to explore the reasonable diagnosis and treatment plan. Methods The clinical data of 10 patients of pregnancy complicated with aortic dissection in Wuhan Tongji Hospital from January 2011 to June 2017 were collected. Their age was 25.2 (21-29) years. Results In the 10 patients, the majority (8 patients) were primipara, and most of them were in the late stages of pregnancy (5 patients) and puerperal (4 patients). Among them, 1 patient had gestational hypertension, and the blood pressure of the left and right upper extremities was significantly abnormal (initial blood pressure: left upper limb blood pressure: 90/60 mm Hg, right upper limb blood pressure: 150/90 mm Hg). The major clinical manifestations were severe chest and back pain which happened suddenly, with D-dimmer and C-creative protein increased which may be associated with inflammatory reaction. All patients were diagnosed by thoracoabdominal aortic CTA, including 5 patients of Stanford type A dissection and 5 patients of Stanford type B dissection. In the 10 patients, 1 patient refused surgery and eventually died of aortic rupture with the death of fetus before birth. And the remaining 9 patients underwent surgical treatment, 3 patients of endovascular graft exclusion for thoracic aortic stent graft, 2 patients underwent Bentall operation, 1 patient with Bentall + total aortic arch replacement + vascular thoracic aortic stent graft, 1 patient with Bentall operation combined with endovascular graft exclusion for thoracic aortic stent graft, 1 patient with Bentall + coronary artery bypass grafting, 1 patient of thoracoabdominal aortic vascular replacement. Among them, 1 patient underwent endovascular graft exclusion for thoracic aortic stent graft died of severe postoperative infection, and the remaining 8 patients were discharged from hospital. Nine patients were single birth, among them 5 newborn patients had severe asphyxia, 4 patients had mild asphyxia. Finally, 3 neonates died of severe complications, and the remaining 6 survived. Conclusion The ratio of pregnancy with Stanford type A aortic dissection is far higher than in the general population, the possibility of fetal intrauterine asphyxia is larger, but through active and effective surgical and perioperative treatment, we can effectively save the life of mother and fetus.

Decreased NK cell immunity in kidney transplant recipients late post-transplant and increased NK-cell immunity in patients with recurrent miscarriage.

BACKGROUND: There is evidence that NK-cell reactivity might affect graft outcome in transplant recipients and pregnancy in women. METHOD: NK-cell subsets were determined in whole blood using eight-colour-fluorescence flow cytometry in patients before and after renal transplantation, patients with recurrent miscarriage (RM) and healthy controls (HC). RESULTS: Patients late post-transplant (late-Tx) with functioning renal transplants showed abnormally low CD56dimCD16+ NK-cells containing both perforin and granzyme (vs HC p = 0.021) whereas RM patients exhibited abnormally high numbers of these cells (vs HC p = 0.043). CD56dimCD16+perforin+granzyme+ NK-cell counts were strikingly different between the two patient groups (p<0.001). In addition, recipients late-Tx showed abnormally low CD8+ NK-cells (vs HC p<0.001) in contrast to RM patients who showed an abnormal increase (vs HC p = 0.008). CD8+ NK-cell counts were strongly different between the two patient groups (p<0.001). Higher perforin+granzyme+CD56dimCD16+ and CD8+ NK-cells were associated with impaired graft function (p = 0.044, p = 0.032). After in-vitro stimulation, CD56dimCD16+ and CD56brightCD16dim/- NK-cells showed strong upregulation of CD107a and IFNy, whereas the content of perforin decreased dramatically as a consequence of perforin release. Recipients late post-Tx showed less in-vitro perforin release (= less cytotoxicity) than HC (p = 0.037) and lower perforin release was associated with good graft function (r = 0.738, p = 0.037). Notably, we observed strong in-vitro perforin release in 2 of 6 investigated RM patients. When circulating IL10+CD56bright NK-cells were analyzed, female recipients late post-Tx (n = 9) showed significantly higher relative and absolute cell numbers than RM patients (p = 0.002 and p = 0.018, respectively); and high relative and absolute IL10+CD56bright NK-cell numbers in transplant recipients were associated with low serum creatinine (p = 0.004 and p = 0.012) and high glomerular filtration rate (p = 0.011 and p = 0.002, respectively). Female recipients late post-Tx exhibited similar absolute but higher relative numbers of IL10+IFNy- NK-cells than RM patients (p>0.05 and p = 0.016, respectively). CONCLUSION: NK-cells with lower cytotoxicity and immunoregulatory function might contribute to good long-term graft outcome, whereas circulating NK-cells with normal or even increased cytotoxicity and less immunoregulatory capacity are observed in patients with RM.

Restoration of microRNA-212 causes a G0/G1 cell cycle arrest and apoptosis in adult T-cell leukemia/lymphoma cells by repressing CCND3 expression.

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell malignancy. This study was designed to explore the expression and functional significance of microRNA (miR)-212 in ATL. The expression of miR-212 in human ATL tissues and cell lines were investigated. Gain-of-function experiments were carried out to determine the roles of miR-212 in cell proliferation, tumorigenesis, cell cycle progression, and apoptosis. We also identified and functionally characterized the target genes of miR-212 in ATL cells. Compared with normal lymph node biopsies, lymphoma samples from ATL patients displayed underexpression of miR-212 (p=0.0032). Consistently, miR-212 was downregulated in human ATL cell lines, compared with normal T lymphocytes. Restoration of miR-212 significantly (p<0.05) inhibited ATL cell proliferation and tumorigenesis in mice. Overexpression of miR-212 led to an accumulation of G0/G1-phase cells and a concomitant reduction of S-phase cells. Moreover, enforced expression of miR-212-induced significant apoptosis in ATL cells. CCND3, which encodes a cell cycle regulator cyclin D3, was identified as a direct target of miR-212 in ATL cells. Rescue experiments with a miR-212-resistant variant of CCND3 demonstrated that overexpression of CCND3 restored cell-cycle progression and attenuated apoptotic response in miR-212-overexpressing ATL cells. Taken together, miR-212 exerts growth-suppressive effects in ATL cells largely by targeting CCND3 and may have therapeutic potential in ATL.

Interferon-gamma producing regulatory T cells as a diagnostic and therapeutic tool in organ transplantation.

There is increasing evidence that IFNg plays a major role in both induction of Tregs as well as immunosuppression mediated by IFNg-producing Tregs. The present review focuses on a small subset of iTregs that produces IFNg, comprises only 0.04% of all CD4(+) T lymphocytes in the blood of healthy individuals, and increases strongly during an immune response. IFNg(+) Tregs are induced by IFNg and IL12, making them sensors for inflammatory cytokines. They develop rapidly during inflammation and represent the first line of Tregs that suppress initial immune responses. The pool of IFNg(+) Tregs consists of activated stable immunosuppressive thymus-derived nTregs as well as peripherally proliferating iTregs with in part only transient immunosuppressive function, which limits their diagnostic and therapeutic usefulness in organ transplantation. Apparently, a part of IFNg(+) Tregs dies during the immune response, whereas others, after efficient immunosuppression with resolution of the immune response, differentiate toward Th1 lymphocytes. Goals of further research are the development of appropriate diagnostic tests for rapid and exact determinination of immunosuppressive IFNg(+) iTregs, as well as the induction and propagation of stable immunosuppressive IFNg(+) Tregs that establish and maintain good long-term graft function in transplant recipients.

Plasmapheresis adjusts inflammatory responses in potential kidney transplant recipients.

BACKGROUND: Plasmapheresis (PP) has been used in the treatment of various immunologic disorders, and its efficacy has mainly been attributed to the removal of humoral factors and autoantibodies. Besides these effects, PP may induce modifications of the cellular immunologic status, contributing to the restoration of impaired immunologic function. The effect of PP on lymphocyte subpopulations, plasma neopterin, and cytokines in renal transplant recipients was investigated in this study. METHODS: We compared pre-PP and post-PP lymphocyte subpopulations and plasma neopterin in 37, and cytokine plasma levels in 30, potential renal transplant recipients. Plasma neopterin and cytokines were measured by enzyme-linked immunosorbent assay kits, lymphocyte subsets were determined using four-color fluorescence flow cytometry. RESULTS: Lymphocyte subpopulation counts and ratios including CD45:µL (P=0.005), CD3:µL (P=0.02), CD4DR:µL (P=0.002), CD8:µL (P=0.01), and CD8DR:µL (P=0.005) T cells; CD4DR:CD4 (P=0.009) and CD8DR:CD8 (P=0.0004) ratios; DR cells:µL (P=0.003); CD19 B lymphocytes:µL (P=0.001); and plasma levels of neopterin (P<;0.0001), soluble interleukin-1 receptor antagonist (P<;0.0001), IL-8 (P=0.0001), and tumor necrosis factor-α (P=0.008) were significantly decreased after PP as compared with before PP. The results indicate a decrease of activated DR, CD4, and CD8 T lymphocytes and B lymphocytes, and a decrease of monocyte and macrophage activation as a result of PP. CONCLUSION: Based on these results, we conclude that PP not only removes antibodies from the plasma but, in addition, modulates T-lymphocyte activation and the inflammatory response by decreasing plasma proinflammatory cytokines.