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Supplementary Figure 1 to 7, Supplementary Table 1

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Immunotherapy treatments with anti-PD-1 boost recovery in less than 30% of treated cancer patients, indicating the complexity of the tumor microenvironment. Expression of HLA-E is linked to poor clinical outcomes in mice and human patients. However, the contributions to immune evasion of HLA-E, a ligand for the inhibitory CD94/NKG2A receptor, when expressed on tumors, compared with adjacent tissue and peripheral blood mononuclear cells, remains unclear. In this study, we report that epithelial-derived cancer cells, tumor macrophages, and CD141+ conventional dendritic cells (cDC) contributed to HLA-E enrichment in carcinomas. Different cancer types showed a similar pattern of enrichment. Enrichment correlated to NKG2A upregulation on CD8+ tumor-infiltrating T lymphocytes (TIL) but not on CD4+ TILs. CD94/NKG2A is exclusively expressed on PD-1high TILs while lacking intratumoral CD103 expression. We also found that the presence of CD94/NKG2A on human tumor–specific T cells impairs IL2 receptor–dependent proliferation, which affects IFNγ-mediated responses and antitumor cytotoxicity. These functionalities recover following antibody-mediated blockade in vitro and ex vivo. Our results suggest that enriched HLA-E:CD94/NKG2A inhibitory interaction can impair survival of PD-1high TILs in the tumor microenvironment.

The use of immune checkpoint inhibitors in malignant tumors improves patient outcomes. Because single-agent immune checkpoint blockade has a low objective response rate, it is meaningful to explore combined blockade of immune checkpoint receptors. We aimed to investigate the co-expression of TIM-3 with TIGIT or 2B4 on peripheral blood CD8+ T cells from patients with locally advanced nasopharyngeal carcinoma. The correlation between co-expression level and clinical characteristics and prognosis was studied to provide a basis for immunotherapy for nasopharyngeal carcinoma. Flow cytometry was used to detect TIM-3/TIGIT and TIM-3/2B4 co-expression on CD8+ T cells. The differences in co-expression between patients and healthy controls were analyzed. The correlation between co-expression of TIM-3/TIGIT or TIM-3/2B4 and the patient clinical characteristics and prognosis was examined. Also, the correlation between the TIM-3/TIGIT or 2B4 co-expression and other common inhibitory receptors was analyzed. We further validated our results using mRNA data from the Gene Expression Omnibus (GEO) database. TIM-3/TIGIT and TIM-3/2B4 co-expression was upregulated on peripheral blood CD8+ T cells from patients with nasopharyngeal carcinoma. They were both correlated with poor prognosis. There was a correlation between TIM-3/TIGIT co-expression and patient age and pathological stage, whereas TIM-3/2B4 co-expression correlated with age and sex. CD8+ T cells with elevated mRNA levels of TIM-3/TIGIT and TIM-3/2B4 also showed increased expression of multiple inhibitory receptors, indicating T cell exhaustion in locally advanced nasopharyngeal carcinoma. TIM-3/TIGIT or TIM-3/2B4 can be used as potential targets for combination immunotherapy in locally advanced nasopharyngeal carcinoma.

Presence of mucus layer and inlet air temperature variations can significantly affect the extent of particle transport and deposition in the mouth-throat airway for aerosol drug delivery applications. In addition, higher inlet air temperature can lead to thermal injuries as well. The main goal of the present paper is to investigate these effects in a highly idealized mouth-throat geometry in detail. Large eddy simulation was performed to accurately predict the air flow-fields and a Lagrangian particle tracking model has been employed to capture the particle deposition efficiencies and patterns. The effects of three different inlet air temperatures (15 °C, 26.7 °C and 45 °C) and three different particle sizes (3 μm, 5 μm and 6 μm) have been studied for inlet flow rates of 15 L/min and 30 L/min with and without mucus layer in the present investigation. Detailed velocity and temperature fields, as well as, particle deposition efficiencies and patterns were analyzed and it has been found out that (a) the particle deposition efficiencies varied significantly with changes in inlet air temperature and flow rates, particle diameters and in the presence of mucus layer, (b) the presence of recirculation zones and secondary vortices determined the rate of particle deposition at different inhalation flow rates and inlet air temperatures, and (c) the changes in temperature distribution near the mouth-throat wall in the presence of mucus layer have a dominant effect on particle deposition as compared to inertial deposition. The findings of the present work will provide useful information in understanding the heat transfer effects on particle transport and deposition for the design of pulmonary drug delivery devices under the influence of various environmental and human factors.

For patients with lung disease, dry powder inhalers (DPI) are profoundly beneficial. The current study introduces and develops a series of dry powder inhalers (DPIs). A capsule-based (size 0) active DPI was considered. The study aims to investigate whether swirling flow and outlet capillary diameter (dc_out) affect the percentage of emitted doses (ED) released from the capsule. Spiral vanes were added to the capillary inlet to produce a swirling flow. Computational fluid dynamics (CFD) was applied to simulate the problem. The results were compared with previous in vitro and numerical studies to validate the results. Based on the derived results, the small swirl parameter (SP) enhances the secondary flow and recirculation zone. It increases the central jet flow, which increases the ED value by about 5-20% compared to no-swirl flow. However, as the airflow rate increases, the recirculation zone enlarges, vorticities become dominant, and asymmetrical flow patterns emerge. Consequently, ED % drops significantly (more than 50%). As dc_out decreases, the vorticities around the outlet capillary become more potent, which is undesirable. Indeed, the emptying of the capsule does not happen ideally. The research provides a perspective on the device's design and DPI performance.

Deciphering the relationships between genes and complex traits could help us better understand the biological mechanisms leading to phenotypic variations and disease onset. Univariate gene-based analyses are widely used to characterize gene-phenotype relationships, but are subject to the influence of confounders. Furthermore, while some genes directly contribute to traits variations, others may exert their effects through other genes. How to quantify individual genes’ direct and indirect effects on complex traits remains an important yet challenging question. We presented a novel framework (BN-GWAS) to decipher the total and direct causal effects of individual genes using imputed gene expression data from GWAS and raw gene expression from GTEx. The study was partially motivated by the quest to differentiate “core” genes (genes with direct causal effect on the phenotype) from “peripheral” ones. Our proposed framework is based on a Bayesian network (BN) approach, which produces a directed graph showing the relationship between genes and the phenotype. The approach aims to uncover the overall causal structure, to examine the role of individual genes and quantify the direct and indirect effects by each gene. An important advantage and novelty of the proposed framework is that it allows gene expression and disease trait(s) to be evaluated in different samples, significantly improving the flexibility and applicability of the approach. It uses IDA and jointIDA incorporating a novel p-value-based regularization approach to quantify the causal effects (including total causal effects, direct causal effects, and medication effects) of genes. The proposed approach can be extended to decipher the joint causal network of 2 or more traits, and has high specificity and precision (a.k.a., positive predictive value), making it particularly useful for selecting genes for follow-up studies. We verified the feasibility and validity of the proposed framework by extensive simulations and applications to 52 traits across 14 tissues in the UK Biobank (UKBB). Split-half replication and stability selection analyses were performed to demonstrate the accuracy and efficiency of our proposed method to identify causally relevant genes. The identified (direct) causal genes were found to be significantly enriched for genes highlighted in the OpenTargets database, and the enrichment was stronger than achieved by conventional univariate gene-based tests. Encouragingly, many enriched pathways were supported by the literature, and some of the enriched drugs have been tested or used to treat patients in clinical practice. Our proposed framework provides a powerful way to prioritize genes with large direct or indirect causal effects and to estimate the ‘variable importance’ of such genes.

Killer cell lectin-like receptor G1 (KLRG1) and 2B4 play important roles in the immune regulation and immune tolerance to tumor cells by inhibiting T cell function. However, the clinical relevance of KLRG1 and 2B4 to cervical cancer remains to be understood.We measured the frequency of KLRG1+ or 2B4+ cells in CD4+ or CD8 + T cells derived from peripheral blood or tumour biopsies in cervical cancer patients by flow cytometry.Compared with healthy controls, the level of KLRG1 and 2B4 on CD8 + T cells in the blood of the patients increased significantly (KLRG1 level on T cells was related to age and HPV in patients with cervical cancer, while 2B4 level on T cells was related to age, underlying their roles in the host immune response to cervical cancer. Radiotherapy can improve the immune function of patients.

Images captured in the sand-dust weather often suffer from serious colour cast and poor contrast, and this has serious implications for outdoor computer vision systems. To address these problems, a normalised gamma transformation-based contrast-limited adaptive histogram equalisation (CLAHE) with colour correction in Lab colour space for sand-dust image enhancement is proposed in this study. This method consists of image contrast enhancement and image colour correction. To avoid producing new colour deviation, the input sand-dust images are first transformed from red, green, and blue colour space into Lab colour space. Then, the contrast of the lightness component (L channel) of the sand-dust image is enhanced using CLAHE. To avoid unbalanced contrast, as well as to reduce the overincreased brightness caused by CLAHE, a normalised gamma correction function is introduced to CLAHE. After that, the a and b chromatic components are recovered by a grey-world-based colour correction method. Experiments on real sand-dust images demonstrate that the proposed method can obtain the highest percentage of new visible edges for all testing images. The contrast restoration exhibits good colour fidelity and proper brightness.

To investigate the impacts of upper airway deformation on the airflow structures, the airflow fields in the trachea are simulated using three geometrical models considering three different levels of airway deformations. Structured grids are used to create the high-quality grids. Large eddy simulation with the Smagorinsky sub-grid model is adopted to solve the three-dimensional in-compressible Navier–Stokes equations using the solver pisoFoam in the open-source CFD software OpenFOAM. The numerical results demonstrate that the airway deformation influences the main airflow structures depending on the deformation level. Particularly, it slightly impacts on the laryngeal jet such as the profile and the strength of laryngeal jet. The strength of the laryngeal jet increases slightly for the heavy deformation. In contrast, it impacts on the recirculation zone, secondary vortices, and turbulent kinetic energy more obviously. The increasing airway deformation will produce stronger secondary flow, smaller recirculation zone, and weaker turbulent kinetic energy. The turbulence intensity distribution varies as well. The obviously impacted flow region is mainly within the region of one to six tracheal diameters downstream the glottis.

BackgroundVaccines for COVID-19 represent a breakthrough in the fight against the pandemic. However, worries about adverse effects led to vaccine hesitancy in some people. On the other hand, as COVID-19 may be associated with various sequelae, the vaccine may protect against these diseases.MethodsWe leveraged a large prospective cohort, the UK-Biobank(UKBB), and studied associations of at least one dose of COVID-19 vaccination(BioNTech-BNT162b2 or Oxford-AstraZeneca-ChAdOx1) with hospitalization from cardiovascular and other diseases (N=393,544; median follow-up of 54 days in vaccinated). Multivariable Cox and Poisson regression was conducted controlling for main confounders. Besides all hospitalizations, we also conducted separate analysis for new-onset and recurrent cases. We also performed other sensitivity analyses, including adjustment for prior event rate ratio (PERR) to reduce residual confounding.ResultsWe observed that COVID-19 vaccination(at least one dose) was associated with lower risks of hospitalizations from stroke (hazard ratio[HR]=0.178, 95% CI: 0.127-0.250, p=1.50e-23), VTE (HR=0.426, 95% CI: 0.270-0.673, p=2.51e-4), dementia (HR=0.114, 95% CI 0.060-0.216; p=2.24e-11), non-COVID-19 pneumonia (NCP) (HR=0.108, 95% CI 0.0.080-0.145; p=2.20e-49), CAD (HR=0.563, 95% CI: 0.416-0.762; p=2.05e-4), COPD (HR=0.212, 95% CI 0.126-0.357; p=4.92e-9), T2DM (HR= 0.216, 95% CI: 0.096 - 0.486, p=2.12e-4), heart failure (HR=0.174, 95% CI, 0.118-0.256, p=1.34e-18) and renal failure (HR=0.415, 0.255-0.677, p=4.19e-4).After adjusting for HRs of hospitalization between the two groupsbeforethe introduction of vaccination, COVID-19 vaccination was still significantly associated with reduced hazards of hospitalization due to CAD (HR=0.517, 95% CI: 0.327-0.817; p=4.70e-03), COPD (HR=0.317, 95% CI: 0.138-0.726; p=6.60e-03), dementia (HR=0.406, 95% CI: 0.180-0.919; p=3.06e-02), heart failure (HR=0.305, 95% CI: 0.179-0.519; p=1.18e-05), NCP (HR=0.191, 95% CI: 0.123-0.295; p=1.02e-13) and stroke (HR=0.222, 95% CI: 0.130-0.382; p=4.94e-08), although the estimated protective effects were weaker.ConclusionsTaken together, this study provides further support to the safety and benefits of COVID-19 vaccination, and such benefits may extend beyond reduction of infection risk or severity per se. As an observational study, causal relationship cannot be concluded and further studies are required to verify the findings.

Despite the expansion of PD-1 checkpoint blockade to multiple types of cancer, whether the programmed cell death 1 (PD-1) expression status on CD8+ tumour infiltrating lymphocytes (TILs) could be a prognostic factor in cervical cancer is still unclear. In this study, we performed ex vivo phenotypic analysis of PD-1 expression on CD8+ TILs by flow cytometry from 47 treatment-naïve cervical cancer patients. With a median follow-up of 26.1 months (95% confidence interval [CI], 24-28.2 months), we then linked the quantitative cellular expression results to progression-free survival and overall survival. Based on the intensity of PD-1 expression, we further categorised the cervical cancer patients into PD-1high expressers (29.8%, 14/47) and PD-1low expressers (70.2%, 33/47). Multivariate analysis revealed that PD-1high expressers are correlated with early recurrence (HR, 5.91; 95% CI, 1.03-33.82; P= 0.046). Univariate analysis also demonstrated that PD-1high expressers are associated with poor overall survival in cervical cancer (HR, 5.365; 95% CI, 1.55-18.6; P=0.008). Moreover, our study also demonstrated that CD8+/CD4+ TIL ratio and HPV infection status are risk factors for early relapse and mortality in cervical cancer patients. In conclusion, this study confirms that PD-1 expression status is an independent prognostic factor for progression free survival in cervical cancer. These findings could be important in predicting the relapse of cervical cancer as a cellular diagnosis method and could be important knowledge for the selection of prospective PD-1 blockade candidates.

In rainy conditions, especially at night with low illumination, the visual of images obtained by outdoor computer vision systems is degraded significantly, leading to a significant negative effect on the work of the outdoor computer vision system. In this paper, we develop a new rainy image model to describe rain scenes at night with low illumination. From this model, we propose a joint deep neural network-based method for single nighttime rainy image enhancement. First, a decom-net based on Retinex theory is employed for image decomposition, and the purpose of this sub-net is to extract the reflection image and the illumination image from the input image. Then, an enhancement net is proposed for illumination adjustment. The goal of this sub-net is to remove the negative effect (low visual) caused by low illumination. Finally, a symmetric sub-net termed multi-stream network-based contextual autoencoder is developed, where rain features are directly learned from the enhanced nighttime rainy images in a recurrent way. The goal of this sub-net is to effectively remove rain streaks from the illumination-enhanced image. The experimental results show the advantage and effectiveness of the proposed method, and evident improvements over existing state-of-the-art methods are obtained with the proposed method.

The images that are captured in sand storms often suffer from low contrast and serious color cast that are caused by sand dust, and these issues will have significant negative effects on the performance of an outdoor computer vision system. To address these problems, a method based on halo-reduced dark channel prior (DCP) dehazing for sand dust image enhancement is proposed in this paper. It includes three components in sequence: color correction in the LAB color space based on gray world theory, dust removal using a halo-reduced DCP dehazing method, and contrast stretching in the LAB color space using a Gamma function improved contrast limited adaptive histogram equalization (CLAHE), in which a guided filter is used to improve the artifacts of the histogram equalization. Experiments on a large number of real sand dust images demonstrate that the proposed method can well remove the overall yellowing tone and dust haze effect and obtain normal visual colors and a detailed clear image.

Auxin is the earliest discovered plant hormone, which plays important roles in each aspect of plant growth and development. There are two main pathways for auxin to be transported from the synthetic site (such as young leaves and terminal buds) to the active site. First, auxin is transported over long distances through phloem in an unfixed direction throughout the whole plant. Second, short-distance polar transport between cells requires the participation of auxin carriers, including unidirectional transport from stem tip to root and local unidirectional transport between tissues. Polar transport is critical to the establishment and maintenance of the auxin concentration gradient, which specifically regulates plant growth and development and responds to environmental changes. In this article, we reviewed the research progress of auxin transporters AUX1/LAX, PIN, and ABCB families, and some potential auxin transporters in rice growth and development, which provide information for the interpretation of biological functions of polar auxin transport families and lay a foundation for the genetic improvement of important agronomic traits in rice.

Face shield is a common personal protection equipment for pandemic. In the present work, three-dimensional computational fluid dynamic (CFD) method is used to simulate a cough jet from an emitter who wears a face shield. A realistic manikin model with a simplified mouth cavity is employed. A large eddy simulation with a dynamic structure subgrid scale model is applied to model the turbulence. An Eulerian-Lagrangian approach is adopted to model the two-phase flows, with which the droplets are represented by a cloud of particles. The droplet breakup, evaporation, dispersion, drag force, and wall impingement are considered in this model. An inlet velocity profile that is based on a variable mouth opening area is considered. Special attentions have been put the vortex structure and droplet re-distribution induced by the face shield. It is found that the multiple vortices are formed when the cough jet impinges on the face shield. Some droplets move backward and others move downward after the impinging. It is also found that a small modification of the face shield significantly modifies the flow field and droplet distribution. We conclude that face shield significantly reduces the risk factor in the front of the emitter, meanwhile the risk factor in the back of the emitter increases. When the receiver standing in front of the emitter is shorter than the emitter, the risk is still very high. More attentions should be paid on the design of the face field, clothes cleaning and floor cleaning of the emitters with face shields. Based on the predicted droplet trajectory, a conceptual model for droplet flux is proposed for the scenario with the face shield.

It is critical to understand the airflow structures in the respiratory system toward increasing the drug delivery efficiency via inhalation. A whole-lung airway model is created by connecting a three-dimensional cast-based mouth–throat model and a one-dimensional conduit describing the other lung airways according to the literature. Constant displacement of the bottom surface in the geometrical model is used to simulate the respiratory process. Large eddy simulation with the dynamic structure sub-grid scale model is used to model the turbulent flow via a commercial computational fluid dynamics software, ConvergeTM. The innovative findings are as follows: (1) shear layer as well as vortical flow is observed in the lower airway at the inspiration phase; (2) the main airflow structures in the upper airway of this model are close to the case using the mouth–throat model; (3) the airflow structures, in particular the reversed laryngeal jet, are highly unsteady during the expiration phase. It is shown that this whole-lung airway model is suitable to analyze the airflow field in the upper airway but not in the lower airway, although it has been used a lot by a few researchers. More investigations should be carried out to study the dynamics of airflow structures during the expiration phase toward understanding airflow properties of human respiratory process.

Background: It is worthwhile to identify more epitopes as target to design T cell-based therapeutic interventions that can benefit cervical cancer patients whose disease cannot be well controlled with current treatment modalities. This study investigated T cell response to HPV16 E6 and E7 in patients with cervical squamous cell carcinoma (CSCC). Also, the human leukocyte antigen (HLA)-A allele distribution was compared among patients and evaluated as factors to predict prognosis in these patients.Materials and Methods: This study recruited a total of 76 patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IIB–IIIB CSCC. Mononuclear cells were isolated from the peripheral blood before any treatment and then enzyme-linked immunosorbent spot (ELISpot) assay was employed to measure the E6 and E7-specific T cell response. HLA‐A alleles were typed using Sanger sequence‐based typing techniques with DNA extracted from the peripheral blood. The correlation between the T cell responses, HLA‐A allele distribution and patient prognosis were analysed using the Kaplan–Meier method, univariate and multivariate Cox proportional hazard models.Results: The frequency of HPV E6-specific T cell responses in patients with pelvic lymph node metastasis was lower than that in patients without metastasis (P=0.022). The 5-year overall survival (OS) rates of patients were 87.5% for the multiple overlapping peptide group, 72.7% for the 1–2 overlapping peptide group, and 47.7% for the negative group (P=0.032). Cox regression analysis indicated that the presence of HLA*A02:07 was independently associated with worse OS (hazard ratio [HR] 3.042; 95% confidence interval [CI]: 1.348–6.862; P=0.007), while concurrent chemoradiation therapy (CCRT) was independently associated with better OS (HR 0.475; 95% CI: 0.232–0.975; P= 0.042).Conclusion: The results of our study demonstrated that the level of HPV16 E6-specific T cell response and HLA*A02:07 were correlated with prognosis in patients with advanced CSCC.

Polygenic risk scores (PRS) have the potential to identify individuals at risk of diseases, optimizing treatment, and predicting survival outcomes. Here, we construct and validate a genome-wide association study (GWAS) derived PRS for nasopharyngeal carcinoma (NPC), using a multi-center study of six populations (6 059 NPC cases and 7 582 controls), and evaluate its utility in a nested case-control study. We show that the PRS enables effective identification of NPC high-risk individuals (AUC = 0.65) and improves the risk prediction with the PRS incremental deciles in each population (Ptrend ranging from 2.79 × 10−7 to 4.79 × 10−44). By incorporating the PRS into EBV-serology-based NPC screening, the test’s positive predictive value (PPV) is increased from an average of 4.84% to 8.38% and 11.91% in the top 10% and 5% PRS, respectively. In summary, the GWAS-derived PRS, together with the EBV test, significantly improves NPC risk stratification and informs personalized screening.

Rain image enhancement is important for outdoor computer vision applications. In this study, the authors propose a multi-stage filtering method for single rainy image enhancement. It is based on their new rainy image model, and consists of two main operations: rain streaks removal and rain fog removal. For rain streaks removal, based on one key observation that the low-pass version of a rainy image and that of a non-rainy image of the same scene are almost the same after appropriate low-pass filtering, they remove rain streaks from rainy images by decomposing an input rainy image (or a rainy component image) into the low-frequency (LF) part and the high-frequency (HF) part via an LF smooth filter, i.e. the traditional Gaussian filter with a simple subtraction operation in multiple different stages. After rain streaks removal, dark channel prior-based method was employed for rain fog removal. Experimental results show that the proposed algorithm generated comparable outputs with most of the state-of-the-art algorithms with low computation cost.

Background: Development of innovative immunotherapy is imperative to improve the poor survival of the nasopharyngeal carcinoma (NPC ) patients. In this study, we evaluated the T cell response to melanoma-associated antigen (MAGE)-A1, MAGE-A3, or synovial sarcoma X-2 (SSX-2) in the peripheral blood of treatment-naive NPC patients. The relationship of responses among the three proteins and the human leukocyte antigen (HLA)-A types were analyzed to provide evidence of designing novel therapy. Methods: Sixty-one NPC patients admitted into the Tumor Hospital affiliated to the Xinjiang Medical University between March 2015 and July 2016 were enrolled. Mononuclear cells were isolated from the peripheral blood before any treatment. HLA-A alleles were typed with Sanger sequence-based typing technique. The T cell response to the MAGE-A1, MAGE-A3, or SSX-2 was evaluated with the Enzyme-Linked ImmunoSpot assay. Mann-Whitney U-test was used to compare the T cell responses from different groups. Spearman’s rank correlation was used to analyze the relationship of T cell responses. Results: HLA-A*02:01, A*02:07, and A*24:02 were the three most frequent alleles (18.9%, 12.3%, and 11.5%, respectively) among the 22 detected alleles. 31.1%, 19.7%, and 16.4% of the patients displayed MAGE-A1, MAGE-A3, or SSX-2-specific T cell response, respectively. The magnitudes of response to the three proteins were 32.5, 38.0, and 28.7 SFC/106 peripheral blood mononuclear cells, respectively. The T cell response against the three proteins correlated with each other to different extent. The percentage of A*02:01 and A*24:02 carriers were significantly higher in patients responding to any of the three proteins compared to the nonresponders. Conclusion: MAGE-A1, MAGE-A3, or SSX-2-specific T cell responses were detectable in a subgroup of NPC patients, the frequency and magnitude of which were correlated. Key words: Human Leukocyte Antigen-A; Melanoma-Associated Antigen-A; Nasopharyngeal Carcinoma; Synovial Sarcoma X-2; T Cell Response

Mimetics of antibody-binding sites represent particularly interesting targets, however they are difficult to identify. In most cases, naturally derived CDR3 peptides show a much lower activity and affinity. In this study, we identified a CDR3 domain antibody with framework 3 (FR3) and FR4 in the flank by screening a lysozyme-immunized phage display VHH library. This antibody has a potent enzyme inhibiting activity and high thermal stability. With sequence alignment and site-directed mutagenic analysis, we found that the cysteine residue at amino acid position 88 in FR3 might play a key role in maintaining the stability of the CDR3 antibody. The small-sized CDR3 domain antibody might act as a new scaffold for affinity transfer, hence making a useful contribution to the understanding of antigen-antibody interactions.

Summary Background and objective We aimed to investigate the effects of microRNA-214 (miR-214) on peritoneal metastasis as well as to elucidate its regulatory mechanism in gastric cancer (GC). Methods The expression levels of miR-214 in human GC cell lines MKN-28NM, MKN-28M, GC9811 and GC9811-P were analyzed by quantitative real-time PCR. Lentiviral miR-214, lentiviral miR-214 inhibitor, and empty lentiviral vector were transfected to GC cell lines, respectively. The roles of miR-214 in cell invasion, migration, proliferation and colony-forming ability were then analyzed. Besides, the expression levels of PTEN in different transfected cells were determined by western blot analysis. Results We found that miR-214 was up-regulated in GC9811-P cells with high metastatic potential to the peritoneum compared with that in GC9811 cells. In addition, in vitro overexpression of miR-214 promoted cell invasion, migration, proliferation and colony-forming ability of GC9811 cells, while down-regulation of miR-214 had opposite effects in GC9811-P cells. Besides, overexpression of miR-214 in GC9811 cells markedly down-regulated PTEN expression, whereas down-regulation of miR-214 in GC9811-P cells significantly increased PTEN expression. Conclusions Our findings indicate that miR-214 may promote peritoneal metastasis of GC cells via down-regulation of PTEN, thus leading to the progression of GC.

Background: Cancer patients often display dysfunctional antitumor T-cell responses. Because noteworthy benefits of immune checkpoint pathway blockade, such as programmed cell death protein 1 (PD-1) inhibitors, have been achieved in multiple advanced cancers, the next critical question is which mono-blockade or combinatorial blockade regimens may reinvigorate antitumor T-cell immunity in those cancer patients while limiting immune-related adverse effects. Method: This study recruited, in total, 172 primary cancer patients (131 were blood-tumor-matched patients) who were treatment-naïve prior to the surgeries or biopsies covering the eight most prevalent types of cancer. With access to fresh surgical samples, this study simultaneously investigated the ex vivo expression level of eight known immune checkpoint receptors [PD-1, cytotoxic T-lymphocyte antigen-4 [CTLA-4], T-cell immunoglobulin and mucin-domain containing-3 [Tim-3], 2B4, killer cell lectin like receptor G1 [KLRG-1], TIGIT, B- and T-lymphocyte attenuator [BTLA], and CD160] on tumor-infiltrating T cells (TILs) and paired circulating T cells in blood from a 131-patient cohort. Results: We found increased an expression of PD-1 and Tim-3 but a decreased expression of BTLA on TILs when compared with peripheral blood from multiple types of cancer. Moreover, our co-expression analysis of key immune checkpoint receptors delineates “shared” subsets as PD-1+Tim-3+TIGIT+2B4+KLRG-1–CTLA-4– and PD-1+TIGIT+2B4+Tim-3–KLRG-1–CTLA-4– from bulk CD8 TILs. Furthermore, we found that a higher frequency of advanced differentiation stage T cells (CD27–CCR7–CD45RA–) among the “shared” subset (PD-1+Tim-3+TIGIT+2B4+KLRG-1–CTLA-4–) in bulk CD8 TILs was associated with poorly differentiated cancer type in cervical cancer patients. Conclusions: To our knowledge, our study is the first comprehensive analysis of key immune checkpoint receptors on T cells in treatment-naïve, primary cancer patients from the eight most prevalent types of cancer. These findings might provide useful information for future design of mono-blockade/combinatorial blockades and/or genetically modified T-cell immunotherapy.

Gastric cancer is a type of cancer with increasing incidence and high mortality rates, but molecular biomarkers of diagnostic and therapeutic value are currently lacking. The aim of the present study was to examine the expression pattern of the interleukin 1 receptor-like 1 (ST2) protein and assess its clinicopathological significance in gastric cancer. Western blot analysis of 12 gastric cancer specimens and paired adjacent tissues demonstrated that the protein levels of 2 isoforms of ST2, soluble secreted ST2 and the ST2 variant without the third immunoglobulin motif and splicing in the C-terminal, were markedly decreased in cancer tissues compared with non-cancerous tissues. Immunohistochemical analysis demonstrated that ST2 protein expression was markedly decreased in primary gastric cancer tissues (39.1%, 90/230) compared with adjacent non-cancerous tissues (60.7%, 54/89) (P

Immunotherapy treatments with anti-PD-1 boost recovery in less than 30% of treated cancer patients, indicating the complexity of the tumor microenvironment. Expression of HLA-E is linked to poor clinical outcomes in mice and human patients. However, the contributions to immune evasion of HLA-E, a ligand for the inhibitory CD94/NKG2A receptor, when expressed on tumors, compared with adjacent tissue and peripheral blood mononuclear cells, remains unclear. In this study, we report that epithelial-derived cancer cells, tumor macrophages, and CD141

Despite significant developments in its clinical treatment, the reported incidence and mortality of gastric cancer have exhibited marked increases. The molecular mechanisms of gastric cancer initiation and progression remain to be fully elucidated. The aim of the present study was to identify novel microRNAs (miRNAs/miRs) with a role in the peritoneal metastasis of gastric cancer by comparing the miRNA expression in the gastric cancer cell line GC9811 with that in its variant GC9811-P, a sub-cell line with a high potential for peritoneal metastasis. A miRNA microarray analysis identified 153 dysregulated miRNAs, including 74 upregulated and 79 downregulated miRNAs. Of these, four significantly upregulated miRNAs (miR-181a-5p, miR-106b-5p, miR-199a-3p and miR-148a-3p) and four downregulated miRNAs (miR-146a-5p, miR-21-5p, miR-222-3p and miR-221-3p) were selected and further confirmed by reverse transcription-quantitative polymerase chain reaction analysis. Furthermore, knockdown of miR-21-5p promoted the migration and invasion of GC9811 cells. Collectively, the results suggested that the miRNA expression profile in GC9811-P vs. GC9811 cells was altered to favor disease progression, and the dysregulated miRNAs, including miR-21-5p, may therefore provide novel biomarkers and potential therapeutic targets for gastric cancer metastasis.

Background: This study was conducted to investigate the distribution of human leukocyte antigen (HLA)-A alleles in advanced squamous cell cervical cancer patients (IIb–IVb SCC) and their relationship to human papillomavirus (HPV) status and clinical outcome. Methods: From May 2012 to March 2016, 231 advanced SCC patients (169 Uyghur and 62 Han individuals) and 197 control subjects (101 Uyghur and 96 Han individuals) from Xinjiang province were genotyped for HLA-A by polymerase chain reaction sequence-based typing (PCR-SBT). The frequencies of HLA-A alleles were compared among the different groups and the correlation of HLA-A frequencies with HPV status and clinical outcome were analyzed. Results: (I) Uyghur patients were more likely to be infected with HPV16 or other types of HPV than Han patients (P=0.001). Han patients responded better to systematic treatment than Uyghur patients (P=0.001); (II) Significantly higher frequencies of HLA-A*01:01, A*03:01 and A*03:02, and lower frequencies of HLA-A*11:01, A*24:02 and A*30:01 were observed in the Uyghur control subjects compared with the Han control subjects (P0.05); (IV) There was no significant association between HLA-A alleles and HPV16 status (P>0.05); (V) FIGO stage and treatment condition were potential independent predictors for disease-specific survival (DSS) (P=0.027 and P=0.004) while only FIGO stage was an independent predictor for DFS (P=0.001). A*30:01 showed a tendency to be an independent protective predictor for DSS (P=0.050; HR=0.132; 95% CI: 0.017–0.996). Conclusions: Women from two ethnic groups displayed varied HLA-A allele distributions. HLA-A*01:01 and A*68:01 alleles increase susceptibility to advanced SCC patients while HLA-A*33:01 serves as a protective allele. HLA-A*30:01 might be an independent predictor for DSS of advanced SCC.

Because there is no temporal information available, rain removal with a single image is more challenging than that with a video. In this paper, we present a weighted median guided filtering method for rain removal with a single image. It consists of two filtering operations. Firstly, a weighted median filter is convoluted with an input rainy image to obtain a coarse rain-free image; then, guided filter is employed to obtain a refined rain-free image, where the coarse rain-free image is used as a guided image and convoluted with the input rainy image via guided filter. Experimental results show that the proposed method generated comparable results to the state-of-the-art algorithms with low computation cost.

Five kinds of organic rectorite (OREC)-reinforced Epoxy Resin (EP) composites (OREC/EP) were prepared by using different ORECs as modifiers. The curing process of EP, the functional groups of OREC and its interlayer distance (d-spacing) are demonstrated by Fourier Transform Infrared Radiation (FTIR) and XRD (X-Ray Diffraction). The morphologies of OREC/EP composites and the dispersion of OREC in the cured EP matrix were investigated using XRD and scanning electron microscopy (SEM). The mechanical properties, thermal deformed temperature (HDT), hot-wet resistance, alkali resistance and water adsorption of the resulting OREC/EP composites were evaluated. It is found that the addition of OREC can improve the comprehensive properties of EP. The maximum mechanical properties of OREC/EP can be obtained by OREC3/EMI-2, 4/E-51 due to the high stiffness and uniform dispersion of OREC in matrixes. The most desirable properties of OREC/EP composites were obtained with impact strength of 9.5 kJ/m2, bent strength of 8...

Composites with high flame-retardant behavior based on room temperature vulcanizing silicone rubber (RTV), decabromodiphenyloxide (DBDPO) and decabromodiphenylethane (DBDPE)/Sb2O3 as fire retardant were fabricated employing reactive solution mixing process and the method of three-roller milling. The influences of DBDPO and DBDPE/Sb2O3 on the morphologies, mechanical properties, flame-retardant properties, OI, insulating properties, hot properties of RTV were systematically investigated. It has been discovered that both kinds of doping agents can significantly improve the property characteristics of RTV matrix composites. Also, DBDPE/Sb2O3/RTV were of better comprehensive performances than DBDPO/RTV. We report final performances as follows: tear strength was 13.68 kN/m; elongation at break was 233.4%; tensile strength was 2.18 Mpa; the level of flame-retardant property was FV-0; OI was 46; Volume electric resistivity was 6.9 × 1014Ω · m; the range of decomposition temperature was 300°C to 690°C and the end...

MTANN (Massive Training Artificial Neural Network) is a promising tool, which applied to eliminate false-positive for thoracic CT in recent years. In order to evaluate whether this method is feasible to eliminate false-positive of different CAD schemes, especially, when it is applied to commercial CAD software, this paper evaluate the performance of the method for eliminating false-positives produced by three different versions of commercial CAD software for lung nodules detection in chest radiographs. Experimental results demonstrate that the approach is useful in reducing FPs for different computer aided lung nodules detection software in chest radiographs.

Cancer, a disease which has been a serious threaten to people's health, is of great concern to scientists. But the study on it has not made substantial progress attributed to its multi-factor incidents. Specimen information in the tissue, as one of the important data sources of the translational research, plays an indispensable role in promoting the diagnosis and treatment of cancer. With the advent of the era of “big data”, it becomes extremely significant to associate the clinical information with the basic research information and to manage the information of the bio-specimen efficaciously, so that some analysis such as data-mining can be done with the follow-up information obtained. However, the existing information management systems of tissue banks only focus on the storing, importing, and exporting of the bio-specimen, while the information of the area of basic research is overlooked. Therefore, we proposed and established a tumor tissue information management system, which can associate the clinical information with the molecular experimental information, so as to establish an information database of tissue samples and to avoid the miss of experimental information. A case study for colorectal cancer research was applied by using the proposed system, which demonstrated the feasibility of our patient-centered tumor tissue information management system.

Nowadays, a growing number of researchers devote themselves to re-excavation of existing biomedical knowledge discovery, focusing on how to establish associations between clinical and genomic data. However, quantitative analysis is still inadequate for a particular disease. Colorectal cancer is the one of malignant tumors whose molecular mechanism is relatively clear, making it a more appropriate object of study. This paper proposed a quantitative measurement of clinic-genomic associations for colorectal cancer based on Google Distance, using MEDLINE database as the corpus. Our method is engineered with several technologies, including mapping clinic and genomic data to MeSH terms, modifying Normalized Google Distance using year average. Data from Electronic Medical Records (EMR), Online Mendelian Inheritance in Man (OMIM), and Genetic Association Database (GAD) were used in this study. A total of 3795 clinic-genomic associations of colorectal cancer between 67 clinical concepts and 236 genes were obtained, of which 584 associations were identified for their gene is contained in the colorectal cancer pathway using KEGG pathway analysis. Assessment and interpretation were conducted using KEGG, GeneCards, and then getting new discoveries. This method is valid in quantitative analysis using biomedical literature and achieves a good performance in measuring the clinical data and genomic data, which can be transplanted to other disease research.

The carmine spider mite, Tetranychus cinnabarinus (Boisduval), is one of the most important pests in agricultural industry. Pyrethroid insecticide has been used to control insects and mites worldwide. However, the intensive use of pyrethroid insecticide resulted in the development of resistance, which has mainly been induced by a variety of point mutations responsible for voltage-gated sodium channel (VGSC) insensitivity and has become the biggest obstacle to sustain the use of pyrethroid insecticide. In this study, we cloned cDNA full length of the para-homologous sodium channel gene from T. cinnabarinus named TC-vgsc. The complete open reading frame of TC-vgsc contains 6,579 nucleotides, encoding 2,193 amino acids. A point mutation, F1538I, was identified from both the DNA and RNA sequences of VGSC in fenpropathrin-resistant strain, which developed approximately 100-folds resistance against fenpropathrin. The result indicated the F1538I kdr mutation underwent DNA mutation events rather than RNA editing. Single nucleotide polymorphisms detection of F1538I mutation from indoor susceptible strain, fenpropathrin-resistant strain, and seven field populations found that this mutation appeared in all the strains (populations), but the frequency of mutation was closely related to the resistance level, with a r2 value of 0.665 (P0.05), that is, the higher the resistance level, the larger the mutation frequency. These results demonstrated that the F1538I mutation in the kdr gene can be used as a molecular marker for fenpropathrin-resistance monitoring in field T. cinnabarinus populations.

Due to its capability of high-speed information processing and uncertainty information processing, Feature point based Hopfield Neural Network image matching method has attracted considerable attention in recent years. However, there often exists much difference between two images, especially under the influences of distortion factors, thus the result of image matching is affected greatly. In addition, Hopfield Neural Network is often trapped in local minima, which gives an optimization solution with an unacceptable high cost. To overcome the defects mentioned above, in this paper, Hausdorff distance is used to measure the degree of the similarity of two images. Chaos is used to optimize the search process of Hopfield Neural Network, and a new energy formulation for general invariant matching is derived. Experimental results demonstrate the efficiency and the effectiveness of the proposed method.