Combining whole exome sequencing, transcriptome profiling, and T cell repertoire analysis, we investigate the spatial features of surgically-removed biopsies from multiple loci in tumor masses of 15 ...patients with non-small cell lung cancer (NSCLC). This revealed that the immune microenvironment has high spatial heterogeneity such that intratumoral regional variation is as large as inter-personal variation. While the local total mutational burden (TMB) is associated with local T-cell clonal expansion, local anti-tumor cytotoxicity does not directly correlate with neoantigen abundance. Together, these findings caution against that immunological signatures can be predicted solely from TMB or microenvironmental analysis from a single locus biopsy.
Impaired immunity in patients with late-stage cancer is not limited to antitumor responses, as demonstrated by poor vaccination protection and high susceptibility to infection
. This has been largely ...attributed to chemotherapy-induced impairment of innate immunity, such as neutropenia
, whereas systemic effects of tumors on hematopoiesis and adoptive immunity remain incompletely understood. Here we observed anemia associated with severe deficiency of CD8
T cell responses against pathogens in treatment-naive mice bearing large tumors. Specifically, we identify CD45
erythroid progenitor cells (CD71
TER119
; EPCs) as robust immunosuppressors. CD45
EPCs, induced by tumor growth-associated extramedullary hematopoiesis, accumulate in the spleen to become a major population, outnumbering regulatory T cells (T
s) and myeloid-derived suppressor cells (MDSCs). The CD45
EPC transcriptome closely resembles that of MDSCs, and, like MDSCs, reactive oxygen species production is a major mechanism underlying CD45
EPC-mediated immunosuppression. Similarly, an immunosuppressive CD45
EPC population was detected in patients with cancer who have anemia. These findings identify a major population of immunosuppressive cells that likely contributes to the impaired T cell responses commonly observed in patients with advanced cancer.
Applying the distance sum rule in strong gravitational lensing (SGL) and SN Ia observations, one can provide an interesting cosmological model-independent method to determine the cosmic curvature ...parameter k. In this paper, with the newly compiled data sets including 161 galactic-scale SGL systems and 1048 SN Ia data, we place constraints on k within the framework of three types of lens models extensively used in SGL studies. Moreover, to investigate the effect of different mass lens samples on the results, we divide the SGL sample into three subsamples based on the center velocity dispersion of intervening galaxies. In the singular isothermal sphere (SIS) and extended power-law lens models, a flat universe is supported with an uncertainty of about 0.2, while a closed universe is preferred in the power-law lens model. We find that the choice of lens models and the classification of SGL data actually can influence the constraints on k significantly.
Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation of histone 3 lysine 27 (H3K27Me3) is critical for immune regulation. However, evidence is lacking to address the effect of EZH2 enzyme's ...activity on intestinal immune responses during inflammatory bowel disease (IBD). Here we report that suppressing EZH2 activity ameliorates experimental intestinal inflammation and delayed the onset of colitis-associated cancer. In addition, we identified an increased number of functional MDSCs in the colons, which are essential for EZH2 inhibitor activity. Moreover, inhibition of EZH2 activity promotes the generation of MDSCs from hematopoietic progenitor cells in vitro, demonstrating a previously unappreciated role for EZH2 in the development of MDSCs. Together, these findings suggest the feasibility of EZH2 inhibitor clinical trials for the control of IBD. In addition, this study identifies MDSC-promoting effects of EZH2 inhibitors that may be undesirable in other therapeutic contexts and should be addressed in a clinical trial setting.
Objective:
To evaluate the neglect of left-behind children (LBC) in China.
Method:
Participants: Children separated from one or both parents for at least 6 months. Intervention: Trauma of separation. ...Comparison: Non-left-behind children (NLBC). Outcomes: Neglect rates and severity. Only case–control studies were included.
Results:
Thirteen studies were included; there were 18,688 LBC in a large sample (N = 42,003) of children aged 0–18 years in China. The overall neglect rate was significantly higher in LBC compared to NLBC (odds ratio OR = 1.58, 95% confidence interval CI = 1.50, 1.67, p < .01) based on the Chinese Rural Child Neglected Evaluation Model (CRCNEM) and the Parents–Child Conflict Tactics Scales (OR = 1.44, 95% CI 1.35, 1.54, p < .01). The overall neglect severity in LBC was also significantly higher than NLBC (SMD = 0.31, 95% CI 0.28, 0.33, p < .01). The same trends were observed in sex subgroups. With regard to subtypes, LBC were significantly more likely to have emotional neglect (OR = 2.29, 95% CI 1.88, 2.78, p < .01), medical neglect (OR = 1.79, 95% CI 1.62, 1.98, p < .01), physical neglect (OR = 1.75, 95% CI 1.60, 1.91, p < .01), security neglect (OR = 1.52, 95% CI 1.32, 1.75, p < .01), educational neglect (OR = 1.50, 95% CI 1.31, 1.72, p < .01), and social neglect (OR = 1.33, 95% CI 1.18, 1.51, p < .01). Furthermore, LBC had significantly higher severity in medical neglect (SMD = 0.31, 95% CI 0.27, 0.35, p < .01), emotional neglect (SMD = 0.28, 95% CI 0.24, 0.32, p < .01), physical neglect (SMD = 0.24, 95% CI 0.18, 0.29, p < .01), security neglect (SMD = 0.26, 95% CI 0.23, 0.29, p < .01), educational neglect (SMD = 0.25, 95% CI 0.20, 0.31, p < .01), and social neglect (SMD = 0.25, 95% CI 0.10, 0.40, p < .01).
Conclusion:
The neglect rates and severity in LBC in China were both significantly higher than those in NLBC. There was a strong association between neglect and LBC. Public policy changes are urgently needed to improve the dire situation and the well-being of the LBC.
ABSTRACT
Although the cosmic curvature has been tightly constrained in the standard cosmological model using observations of cosmic microwave background anisotropies, it is still of great importance ...to independently measure this key parameter using only late-Universe observations in a cosmological model-independent way. The distance sum rule in strong gravitational lensing (SGL) provides such a way, provided that the three distances in the sum rule can be calibrated by other observations. In this paper, we propose that gravitational waves (GWs) can be used to provide the distance calibration in the SGL method, which can avoid the dependence on distance ladder and cover a wider redshift range. Using the simulated GW standard siren observation by the Einstein Telescope as an example, we show that this scheme is feasible and advantageous. We find that ΔΩk ≃ 0.17 with the current SGL data, which is slightly more precise than the case of using SN to calibrate. Furthermore, we consider the forthcoming LSST survey that is expected to observe many SGL systems, and we find that about 104 SGL data could provide the precise measurement of ΔΩk ≃ 10−2 with the help of GWs. In addition, our results confirm that this method of constraining Ωk is strongly dependent on lens models. However, obtaining a more accurate phenomenological model for lens galaxies is highly predictable as future massive surveys observe more and more SGL samples, which will significantly improve the constraint of cosmic curvature.
Objective
Major depressive disorder (MDD) and bipolar disorder (BD) are considered whole‐brain disorders with some common clinical and neurobiological features. It is important to investigate neural ...mechanisms to distinguish between the two disorders. However, few studies have explored the functional dysconnectivity between the two disorders from the whole brain level.
Methods
In this study, 117 patients with MDD, 65 patients with BD, and 116 healthy controls completed resting‐state functional magnetic resonance imaging (R‐fMRI) scans. Both edge‐based network construction and large‐scale network analyses were applied.
Results
Results found that both the BD and MDD groups showed decreased FC in the whole brain network. The shared aberrant network across patients involves the visual network (VN), sensorimotor network (SMN), dorsal attention network (DAN), and ventral attention network (VAN), which is related to the processing of external stimuli. The default mode network (DMN) and the limbic network (LN) abnormalities were only found in patients with MDD. Furthermore, results showed the highest decrease in edges of patients with MDD in between‐network FC in SMN–VN, whereas in VAN–VN of patients with BD.
Conclusions
Our findings indicated that both MDD and BD are extensive abnormal brain network diseases, mainly aberrant in those brain networks correlated to the processing of external stimuli, especially the attention network. Specific altered functional connectivity also was found in MDD and BD groups, respectively. These results may provide possible trait markers to distinguish the two disorders.
FOXO3a, a member of the forkhead class 'O' (FOXO) transcription factor family, controls a wide spectrum of biological processes, such as DNA damage repair, apoptosis, and cell cycle regulation. ...FOXO3a has been shown to be a tumor suppressor in various cancers. This study investigated the expression of FOXO3a in primary gastric adenocarcinomas and its prognostic value for primary gastric adenocarcinoma patients.
Real-time quantitative RT-PCR (qRT-PCR), western blotting, and immunohistochemical staining were used to detect FOXO3a expression in primary gastric cancerous surgical specimens and adjacent non-tumorous tissues.
Our data showed that the expression of FOXO3a mRNA (p = 0.03) and protein (p = 0.019) was lower in cancerous tissues compared with their adjacent non-tumorous tissues. In addition, the chi-square test revealed that low FOXO3a expression was significantly correlated with larger tumor size (p = 0.007), poor histopathological classification (p = 0.029), depth of invasion (p = 0.049), local lymph node metastasis (p = 0.013), distant metastasis (p = 0.013) and AJCC staging (p<0.001). Kaplan-Meier survival analysis demonstrated that low expression of FOXO3a was significantly correlated with a poor prognosis for gastric cancer patients (p<0.001). The multivariate analysis showed that FOXO3a expression was an independent prognostic factor of the overall survival rate of patients with primary gastric adenocarcinoma.
Our study suggested that decreased FOXO3a expression may play an important role in the progression of gastric cancer. FOXO3a could be a valuable prognostic marker as well as a potential molecular therapy target for gastric cancer patients.
Posttraumatic stress disorder (PTSD) is one of the most common psychiatric diseases, which is characterized by the typical symptoms such as re‐experience, avoidance, and hyperarousal. However, there ...are few drugs for PTSD treatment. In this study, conditioned fear and single‐prolonged stress were employed to establish PTSD mouse model, and we investigated the effects of Tanshinone IIA (TanIIA), a natural product isolated from traditional Chinese herbal Salvia miltiorrhiza, as well as the underlying mechanisms in mice. The results showed that the double stress exposure induced obvious PTSD‐like symptoms, and TanIIA administration significantly decreased freezing time in contextual fear test and relieved anxiety‐like behavior in open field and elevated plus maze tests. Moreover, TanIIA increased the spine density and upregulated synaptic plasticity‐related proteins as well as activated CREB/BDNF/TrkB signaling pathway in the hippocampus. Blockage of CREB remarkably abolished the effects of TanIIA in PTSD model mice and reversed the upregulations of p‐CREB, BDNF, TrkB, and synaptic plasticity‐related protein induced by TanIIA. The molecular docking simulation indicated that TanIIA could interact with the CREB‐binding protein. These findings indicate that TanIIA ameliorates PTSD‐like behaviors in mice by activating the CREB/BDNF/TrkB pathway, which provides a basis for PTSD treatment.
CD8(+) cytotoxic T lymphocytes (CTLs) have potent antitumor activity and therefore are leading candidates for use in tumor immunotherapy. The application of CTLs for clinical use has been limited by ...the susceptibility of ex vivo-expanded CTLs to become dysfunctional in response to immunosuppressive microenvironments. Here, we developed a microRNA-targeting (miRNA-targeting) approach that augments CTL cytotoxicity and preserves immunocompetence. Specifically, we screened for miRNAs that modulate cytotoxicity and identified miR-23a as a strong functional repressor of the transcription factor BLIMP-1, which promotes CTL cytotoxicity and effector cell differentiation. In a cohort of advanced lung cancer patients, miR-23a was upregulated in tumor-infiltrating CTLs, and expression correlated with impaired antitumor potential of patient CTLs. We determined that tumor-derived TGF-β directly suppresses CTL immune function by elevating miR-23a and downregulating BLIMP-1. Functional blocking of miR-23a in human CTLs enhanced granzyme B expression, and in mice with established tumors, immunotherapy with just a small number of tumor-specific CTLs in which miR-23a was inhibited robustly hindered tumor progression. Together, our findings provide a miRNA-based strategy that subverts the immunosuppression of CTLs that is often observed during adoptive cell transfer tumor immunotherapy and identify a TGF-β-mediated tumor immune-evasion pathway.
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