Tumoural infiltration of T lymphocytes is determined by local patterns of specific chemokine expression. In this report, we examined the roles of CCL4 and CCL20 in the accumulation of CD8(+) ...cytotoxic T lymphocytes (CTLs) and regulatory T (Treg) lymphocytes in oesophageal squamous cell carcinoma (ESCC), and determined the correlations between chemokine expressions and ESCC patients' survival.
Reverse transcriptase-PCR and immunohistochemistry (IHC) staining were performed to examine the expressions of interested genes. Flow cytometry was adopted to check the expressions of CCL4- and CCL6-specific receptors, CCR5 and CCR6, on CTLs and Treg cells. In addition, transwell assay was carried on.
The CCL4 expression was significantly correlated with the expression of CTL markers (CD8 and Granzyme B), whereas CCL20 was positively correlated with Treg markers (FoxP3 and IL-10). Consistently, CCR5 was found to be mainly expressed on CD8(+) T lymphocytes, while CCR6 showed prevalence on Treg lymphocytes and the frequencies of CCR5(+)CD8(+) CTLs and CCR6(+) Treg cells were higher in TIL compared with PBMC. Respectively, CCL4 and CCL20 recruited CD8(+) and regulatory T cells in vitro. Importantly, high levels of CCL4 in the lesions of ESCC patients predicted prolonged survival. Furthermore, CCL4(high)/CCL20(low) group demonstrated better overall survival, whereas CCL4(low)/CCL20(low) and CCL4(low)/CCL20(high) groups showed the worst overall survival.
Our data showed that CCL4 and CCL20 recruit functionally different T lymphocyte subsets into oesophageal carcinoma, indicating CCL4 and CCL20 are potential predictors of ESCC patients' survival.
It is known that women develop alcoholic liver injury more rapidly and have a lower alcohol toxic threshold than men. However, the detailed molecular mechanisms remain unclear. The precise mechanism ...responsible for the sex difference needs to be determined. Female and male mice were given ethanol by intragastric infusion every day for 4 weeks. The pathological changes were detected by hematoxylin–eosin, Sirius red, oil red O, periodic acid–Schiff, and Hochest33258 staining in the liver of female and male mice. The related gene and protein expression of hepatocytes stress, proliferation and apoptosis, glycogen synthesis, lipid metabolism, and hepatic fibrosis were also systematically analyzed in the female and male mice. Livers from ethanol-treated female mice had more serious hepatocyte necrosis, liver fibrosis (P < 0.01), substantial micro/macrovesicular steatosis (p < 0.01), glycogen consumption (p < 0.05), and hepatocytes apoptosis (p < 0.05) than ethanol-treated male mice. The expression of heat shock protein 27 (HSP27), HSP70, proliferating cell nuclear antigen, B-cell lymphoma/leukemia-2 (Bcl-2), and phosphorylated signal transducer and activators of transcription 3 (p-STAT3) was higher in ethanol-treated male mice than ethanol-treated female mice (P < 0.05 or P < 0.01). But, the expression of Bax (Bcl-2-associated X protein), Caspase 3, CYP2E1 (cytochrome P4502E1), and transforming growth factor βl had the contrary results. Our study suggested that ethanol treatment induced more expression of HSP27 and HSP70, faster hepatocyte proliferation, higher level of glycogen, and interleukin-6 signaling pathway activation, but less hepatocyte apoptosis and CYP2E1 expression in male mice than female mice, which could be helpful to understand the molecular mechanism for the influence of sex difference on alcoholic liver injury.
Frontal lobe epilepsy (FLE) is the second-most common focal epilepsy syndrome, and seizures are medically refractory in many patients. Although various studies have examined rates and predictors of ...seizure freedom after resection for FLE, there is significant variability in their results due to patient diversity, and inadequate follow-up may lead to an overestimation of long-term seizure freedom.
In this paper the authors report a systematic review and meta-analysis of long-term seizure outcomes and predictors of response after resection for intractable FLE. Only studies of at least 10 patients examining seizure freedom after FLE surgery with postoperative follow-up duration of at least 48 months were included.
Across 1199 patients in 21 studies, the overall rate of postoperative seizure freedom (Engel Class I outcome) was 45.1%. No trend in seizure outcomes across all studies was observed over time. Significant predictors of long-term seizure freedom included lesional epilepsy origin (relative risk RR 1.67, 95% CI 1.36-28.6), abnormal preoperative MRI (RR 1.64, 95% CI 1.32-2.08), and localized frontal resection versus more extensive lobectomy with or without an extrafrontal component (RR 1.71, 95% CI 1.26-2.43). Within lesional FLE cases, gross-total resection led to significantly improved outcome versus subtotal lesionectomy (RR 1.99, 95% CI 1.47-2.84).
These findings suggest that FLE patients with a focal and identifiable lesion are more likely to achieve seizure freedom than those with a more poorly defined epileptic focus. While seizure freedom can be achieved in the surgical treatment of medically refractory FLE, these findings illustrate the compelling need for improved noninvasive and invasive localization techniques in FLE.
Hemophagocytic lymphohistiocytosis (HLH) is a rare life‐threatening hyperinflammatory disease. This study aimed to investigate the frequencies and distributions of inherited variants in PRF1, UNC13D, ...STX11, STXBP2, SH2D1A, and XIAP genes in Chinese patients with HLH. A total of 265 patients diagnosed with HLH from January, 2010 to December, 2016 were recruited and analyzed for the 6 genes. Genetic variants were observed in 87 (32.83%) patients. 36 (13.58%) exhibited variants in UNC13D, 18 (6.79%) exhibited PRF1 variants, 10 (3.77%) had variants in XIAP, 9 (3.40%) exhibited variants in STXBP2, 6 (2.26%) carried variants in SH2D1A, 1 (0.38%) had STX11 variant, and 7 (2.64%) exhibited digenic variants. Monoallelic variants were the most common, which accounted for 49.43% of all cases with variants. All variants were confirmed to be germline‐derived. The present study describes a distinct variant spectrum in Chinese patients with HLH, whereby UNC13D is the most frequently mutated gene with missense variants that are the most common molecular defects. The variant profile of Chinese HLH patients is quite different from that of Western cohorts but similar to that of Korean patients, yet showing its own uniqueness. This racial difference shows the role of genetic background in the occurrence of HLH.
We demonstrate a wavelength-tunable, passively mode-locked erbium-doped fiber laser based on graphene and chirped fiber Bragg grating. The saturable absorber used to enable passive mode-locking in ...the fiber laser is a section of microfiber covered by graphene film, which allows light-graphene interaction via the evanescent field of the microfiber. The wavelength of the laser can be continuously tuned by adjusting the chirped fiber Bragg grating, while maintaining mode-locking stability. Such a system has high potential in tuning the mode-locked laser pulses across a wide wavelength range.
Respiratory syncytial virus (RSV) is a seasonal infectious disease, with epidemics occurring annually from October to March in the UK. It is a very common infection in infants and young children and ...can lead to hospitalisation, particularly in those who are premature or who have chronic lung disease (CLD) or congenital heart disease (CHD). Palivizumab (Synagis®, MedImmune) is a monoclonal antibody designed to provide passive immunity against RSV and thereby prevent or reduce the severity of RSV infection. It is licensed for the prevention of serious lower respiratory tract infection caused by RSV in children at high risk. While it is recognised that a policy of using palivizumab for all children who meet the licensed indication does not meet conventional UK standards of cost-effectiveness, most clinicians feel that its use is justified in some children.
To use systematic review evidence to estimate the cost-effectiveness of immunoprophylaxis of RSV using palivizumab in different subgroups of children with or without CLD or CHD who are at high risk of serious morbidity from RSV infection.
A systematic review of the literature and an economic evaluation was carried out. The bibliographic databases included the Cochrane Library Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) and five other databases, from inception to 2009. Research registries of ongoing trials including Current Controlled Trials metaRegister, Clinical Trials.gov and the National Institute for Health Research Clinical Research Network Portfolio were also searched.
Searches were conducted for prognostic and hospitalisation studies covering 1950-2009 (the original report searches conducted in 2007 covering the period 1950-2007 were rerun in August 2009 to cover the period 2007-9) and the database of all references from the original report was sifted to find any relevant studies that may have been missed. The risk factors identified from the systematic review of included studies were analysed and synthesised using stata. The base-case decision tree model developed in the original HTA journal publication Health Technol Assess 2008;12(36) was used to derive the cost-effectiveness of immunoprophylaxis of RSV using palivizumab in different subgroups of pre-term infants and young children who are at high risk of serious morbidity from RSV infection. Cost-effective spectra of prophylaxis with palivizumab compared with no prophylaxis for children without CLD/CHD, children with CLD, children with acyanotic CHD and children with cyanotic CHD were derived.
Thirteen studies were included in this analysis. Analysis of 16,128 subgroups showed that prophylaxis with palivizumab may be cost-effective at a willingness-to-pay threshold of £30,000/quality-adjusted life-year (QALY) for some subgroups. For example, for children without CLD or CHD, the cost-effective subgroups included children under 6 weeks old at the start of the RSV season who had at least two other risk factors that were considered in this report and were born at 24 weeks gestational age (GA) or less, but did not include children who were > 9 months old at the start of the RSV season or had a GA of > 32 weeks. For children with CLD, the cost-effective subgroups included children < 6 months old at the start of the RSV season who were born at 28 weeks GA or less, but did not include children who were > 21 months old at the start of the RSV season. For children with acyanotic CHD, the cost-effective subgroups included children < 6 months old at the start of the RSV season who were born at 24 weeks GA or less, but did not include children who were > 21 months old at the start of the RSV season. For children with cyanotic CHD, the cost-effective subgroups included children < 6 weeks old at the start of the RSV season who were born at 24 weeks GA or less, but did not include children who were > 12 months old at the start of the RSV season.
The poor quality of the studies feeding numerical results into this analysis means that the true cost-effectiveness may vary considerably from that estimated here. There is a risk that the relatively high mathematical precision of the point estimates of cost-effectiveness may be quite inaccurate because of poor-quality inputs.
Prophylaxis with palivizumab does not represent good value for money based on the current UK incremental cost-effectiveness ratio threshold of £30,000/QALY when used unselectively in children without CLD/CHD or children with CLD or CHD. This subgroup analysis showed that prophylaxis with palivizumab may be cost-effective (at a willingness-to-pay threshold of £30,000/QALY) for some subgroups. In summary, the cost-effective subgroups for children who had no CLD or CHD must contain at least two other risk factors apart from GA and birth age. The cost-effective subgroups for children who had CLD or CHD do not necessarily need to have any other risk factors. Future research should be directed towards conducting much larger, better powered and better reported studies to derive better estimates of the risk factor effect sizes.
This report was funded by the HTA programme of the National Institute for Health Research.
This study provides an effective surface processing technology to increase the local mechanical properties of medium carbon steel castings. Ultrafine dual-phase structure of the ferrite and the ...martensite was obtained in the processed zone with a depth of 1mm via submerged friction stir processing (FSP). Significantly enhanced yield strength (YS) of 2070MPa was achieved in the FSP steel compared to that of the base material (BM) with a relatively low YS of 590MPa, but a low uniform elongation (UE) of 3.0% was achieved compared to that of the BM (9.4%). After annealing, obvious carbide precipitation was observed in the original quenched martensite phases. Therefore, good strength-ductility synergies with high YS of 1020MPa and 925MPa, and acceptable UE of 5.9% and 9.3% were achieved in the FSP steel after annealed for 2h at 500°C and 600°C, respectively.
During transcription, RNA polymerase (RNAP) supercoils DNA as it translocates. The resulting torsional stress in DNA can accumulate and, in the absence of regulatory mechanisms, becomes a barrier to ...RNAP elongation, causing RNAP stalling, backtracking, and transcriptional arrest. Here we investigate whether and how a transcription factor may regulate both torque-induced Escherichia coli RNAP stalling and the torque generation capacity of RNAP. Using a unique real-time angular optical trapping assay, we found that RNAP working against a resisting torque was highly prone to extensive backtracking. We then investigated transcription in the presence of GreB, a transcription factor known to rescue RNAP from the backtracked state. We found that GreB greatly suppressed RNAP backtracking and remarkably increased the torque that RNAP was able to generate by 65%, from 11.2 pN·nm to 18.5 pN·nm. Variance analysis of the real-time positional trajectories of RNAP after a stall revealed the kinetic parameters of backtracking and GreB rescue. These results demonstrate that backtracking is the primary mechanism by which torsional stress limits transcription and that the transcription factor GreB effectively enhances the torsional capacity of RNAP. These findings suggest a broader role for transcription factors in regulating RNAP functionality and elongation.
Introduction
Dermatomyositis (DM) is an idiopathic inflammatory myopathy involving severe debilitation in need of diagnostics. We evaluated the proximal lower extremity musculature with diffusion ...tensor imaging (DTI), intravoxel incoherent motion (IVIM) and dynamic DTI in DM patients and controls and compared with standard clinical workup.
Methods
In this IRB-approved, HIPAA-compliant study with written informed consent, anatomical, Dixon fat/water and diffusion imaging were collected in bilateral thigh MRI of 22 controls and 27 DM patients in a 3T scanner. Compartments were scored on T1/T2 scales. Single voxel dynamic DTI metrics in quadriceps before and after 3-min leg exercise were measured. Spearman rank correlation and mixed model analysis of variance/covariance (ANOVA/ANCOVA) were used to correlate with T1 and T2 scores and to compare patients with controls.
Results
DM patients showed significantly lower pseudo-diffusion and volume in quadriceps than controls. All subjects showed significant correlation between T1 score and signal-weighted fat fraction; tissue diffusion and pseudo-diffusion varied significantly with T1 and T2 score in patients. Radial and mean diffusion exercise response in patients was significantly higher than controls.
Conclusion
Static and dynamic diffusion imaging metrics show correlation with conventional imaging scores, reveal spatial heterogeneity, and provide means to differentiate dermatomyositis patients from controls.
Key Points
• Diffusion imaging shows regional differences between thigh muscles of dermatomyositis patients and controls.
• Signal-weighted fat fraction and diffusion metrics correlate with T1/T2 scores of disease severity.
• Dermatomyositis patients show significantly higher radial diffusion exercise response than controls.
We propose an experimentally feasible scheme to achieve quantum computation based on nonadiabatic geometric phase shifts, in which a cyclic geometric phase is used to realize a set of universal ...quantum gates. Physical implementation of this set of gates is designed for Josephson junctions and for NMR systems. Interestingly, we find that the nonadiabatic phase shift may be independent of the operation time under appropriate controllable conditions. A remarkable feature of the present nonadiabatic geometric gates is that there is no intrinsic limitation on the operation time.
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