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ABSTRACTT cell immunity is critical for human defensive immune response. Exploring the key molecules during the process provides new targets for T cell-based immunotherapies. CMC1 is a mitochondrial electron transport chain (ETC) complex IV chaperon protein. By establishing in-vitro cell culture system and Cmc1 gene knock out mice, we evaluated the role of CMC1 in T cell activation and differentiation. The B16-OVA tumor model was used to test the possibility of targeting CMC1 for improving T cell anti-tumor immunity. We identified CMC1 as a positive regulator in CD8+T cells activation and terminal differentiation. Meanwhile, we found that CMC1 increasingly expressed in exhausted T (Tex) cells. Genetic lost of Cmc1 inhibits the development of CD8+T cell exhaustion in mice. Instead, deletion of Cmc1 in T cells prompts cells to differentiate into metabolically and functionally quiescent cells with increased memory-like features and tolerance to cell death upon repetitive or prolonged T cell receptor (TCR) stimulation. Further, the in-vitro mechanistic study revealed that environmental lactate enhances CMC1 expression by inducing USP7, mediated stabilization and de-ubiquitination of CMC1 protein, in which a mechanism we propose here that the lactate-enriched tumor microenvironment (TME) drives CD8+TILs dysfunction through CMC1 regulatory effects on T cells. Taken together, our study unraveled the novel role of CMC1 as a T cell regulator and its possibility to be utilized for anti-tumor immunotherapy.

Abstract Metabolic abnormalities represent one of the pathological features of chronic obstructive pulmonary disease (COPD). Glutamic pyruvate transaminase 2 (GPT2) is involved in glutamate metabolism and lipid synthesis pathways, whilst the exact roles of GPT2 in the occurrence and development of COPD remains uncertain. This study aims at investigating how GPT2 and the associated genes modulate smoking‐induced airway epithelial metabolism and damage by reprogramming lipid synthesis. The circulating or human airway epithelial metabolomic and lipidomic profiles of COPD patients or cell‐lines explored with smoking were assessed to elucidate the pivotal roles of GPT2 in reprogramming processes. We found that GPT2 regulate the reprogramming of lipid metabolisms caused by smoking, especially phosphatidylcholine (PC) and triacylglycerol (TAG), along with changes in the expression of lipid metabolism‐associated genes. GPT2 modulated cell sensitivities and survival in response to smoking by enhancing mitochondrial functions and maintaining lipid and energy homeostasis. Our findings provide evidence for the involvement of GPT2 in the reprogramming of airway epithelial lipids following smoking, as well as the molecular mechanisms underlying GPT2‐mediated regulation, which may offer an alternative of therapeutic strategies for chronic lung diseases.

IntroductionAlthough multiple targeted treatments have appeared, hepatocellular carcinoma (HCC) is still one of the most common causes of cancer-related deaths. The immunosuppressive tumor microenvironment (TME) is a critical factor in the oncogenesis and progression of HCC. The emerging scRNA-seq makes it possible to explore the TME at a high resolution. This study was designed to reveal the immune-metabolic crosstalk between immune cells in HCC and provide novel strategies to regulate immunosuppressive TME.MethodIn this study, we performed scRNA-seq on paired tumor and peri-tumor tissues of HCC. The composition and differentiation trajectory of the immune populations in TME were portrayed. Cellphone DB was utilized to calculate interactions between the identified clusters. Besides, flow cytometry, RT-PCR and seahorse experiments were implemented to explore potential metabolic and epigenetic mechanisms of the inter-cellular interaction.ResultA total of 19 immune cell clusters were identified and 7 were found closely related to HCC prognosis. Besides, differentiation trajectories of T cells were also presented. Moreover, a new population, CD3+C1q+ tumor-associated macrophages (TAM) were identified and found significantly interacted with CD8+ CCL4+T cells. Compared to the peri-tumor tissue, their interaction was attenuated in tumor. Additionally, the dynamic presence of this newly found cluster was also verified in the peripheral blood of patients with sepsis. Furthermore, we found that CD3+C1q+TAM affected T cell immunity through C1q signaling-induced metabolic and epigenetic reprogramming, thereby potentially affecting tumor prognosis.ConclusionOur study revealed the interaction between CD3+C1q+TAM and CD8+ CCL4+T cells and may provide implications for tackling the immunosuppressive TME in HCC.

Abstract Immune checkpoint inhibitors or anti‐cancer immunotherapy using cellular transfer have emerged as new therapies in this field. These therapies work to overcome or alleviate tumour‐induced immunosuppression, resulting in immune‐mediated tumour clearance. Cellular therapies have the largest number of active agents and clinical trials. More targets have been explored, more trials have been opened and more patients have been recruited for trials as a result of recent advancements. In this article, we describe the latest developments and major obstacles in cell therapy for cancer treatment, starting with tumour‐infiltrating T cells.

Lipids and lipid metabolism play crucial roles in regulating T cell function and are tightly related to the establishment of immune memory. It is reported that tumor-infiltrating CD8+T lymphocytes (CD8+TILs) burn fats to restore their impaired effector function due to the lack of glucose. Conversely, fatty acids (FAs) and cholesterol in the tumor microenvironment (TME) drive the CD8+ TILs dysfunction. The origin of dysfunctional CD8+ TILs shares important features with memory T cell’s precursor, but whether lipids and/or lipid metabolism reprogramming directly influence the memory plasticity of dysfunctional CD8+ TILs remains elusive. It is necessary to understand the interplay between cellular lipid metabolism and dysfunction of CD8+ TILs in the case of targeting T cell’s metabolism to synergize cancer immunotherapy. Therefore, in this review, we summarize the latest research on CD8+ TILs lipid metabolism, evaluate the impacts of lipids in the TME to CD8+ TILs, and highlight the significance of promoting memory phenotype cell formation by targeting CD8+ T cells lipid metabolism to provide longer duration of cancer immunotherapy efficacy.

BackgroundMetagenomics next-generation sequencing (mNGS) has been increasingly used in the clinic, which provides a powerful tool for the etiological diagnosis of infectious diseases. Precise treatment can be carried out according to the positive mNGS results. However, the role of negative results of mNGS remains poorly defined in clinical practice.MethodsThe results of 1,021 samples from patients who received the mNGS test at Zhongshan Hospital, Fudan University, between January 2019 and December 2019 were analyzed.ResultsThere were 308 samples (30.17%) of negative results included in the current study. The top 2 types of negative samples were blood (130/308) and tissue (63/308), which also accounted for the highest negative proportion in diseases. Sputum and bronchoalveolar lavage fluid (BALF) were more likely to have positive results. In false-negative results (defined as negative in mNGS test but reported positive in other sample types or assays), 118 samples were found when compared to regular microbiological assays. The negative predictive value (NPV) of mNGS was 95.79% [95%CI, 93.8%–97.8%] as compared to culture and smear. Mycobacterium, Aspergillus, and Mycoplasma ranked as the top 3 microorganisms on the undetected pathogen list.ConclusionsThe present data indicate that when the mNGS test is negative, the negative prediction accuracy rate of the original specimen is significant. However, other laboratory assays results and clinical presentations should always be carefully considered prior to drawing a diagnosis.

Background: Melanoma is a highly malignant and aggressive tumor. The search for new and effective biomarkers facilitates early diagnosis and treatment, ultimately improving the prognosis of melanoma patients. Although the transmembrane protein TMEM176B has been linked to a number of cancers, its role in cancer immunity remains unknown.Methods: Expression levels of TMEM176B in normal tissues and several cancers, including Skin Cutaneous Melanoma (SKCM), were collected from TCGA and GTEx. We used Receiver operating characteristic and Kaplan–Meier survival curves and performed regression analysis to elucidate the link between TMEM176B and clinicopathological features of SKCM in order to determine the prognostic significance of TMEM176B in SKCM. We then used the GEPIA and STRING websites to search for proteins and associated top genes that may interact with TMEM176B and enriched them for analysis. The link between TMEM176B and immune cells infiltration was then investigated using TIMER, CIBERSORT algorithm and GSVA package of R (v3.6.3). Finally, animal tests were conducted to confirm the expression of Tmem176b and its influence on T-cell immune infiltration.Results:TMEM176B expression was considerably elevated in SKCM compared to normal tissues. Particularly, TMEM176B expression was also linked to pathological stage, tumor ulceration and radiation therapy. Patients with elevated TMEM176B expression had a better prognosis, according to the survival analysis. The majority of tumor infiltrating lymphocytes (TILs) especially T cells in SKCM was positively linked with TMEM176B expression. Our animal experiments also verified that the T-cell infiltration was significantly inhibited in local melanoma tissue of Tmem176b knockout mice. At the same time deleting Tmem176b accelerated tumor progress and impaired T cells effector function.Conclusion: Upregulated expression of TMEM176B in SKCM is associated with a better prognosis and it has the potential to serve as a diagnostic and prognostic marker for the disease. It may serve as a target for SKCM immunotherapy by regulating CD8+ T cells although it requires more evidence.

Background. Recent studies show that myeloid-derived suppressor cells (MDSCs) and M2-like macrophages are involved in the treatment of tumors; however, their therapeutic response role is rarely known in non-small cell lung cancer (NSCLC) during radiotherapy. We aim to explore the dynamic alteration of the circulating MDSCs and M2-like macrophages, to examine their relationship, and to evaluate their therapeutic response value for NSCLC patients in radiotherapy. Methods. Peripheral blood mononuclear cells from healthy controls and NSCLC patients with different radiotherapy phases were isolated to examine the circulating MDSCs and M2-like macrophages by flow cytometry. 40 plasma inflammatory cytokines were measured by multiplex ELISA. Results. In comparison with healthy controls, the percentages of MDSCs and CD68+CD163+M2-like macrophages of NSCLC patients were significantly elevated and were distinctly higher in radiotherapy than in preradiotherapy. MDSCs were correlated positively with CD68+CD163+M2-like macrophages in NSCLC patients in radiotherapy and postradiotherapy. Especially, we found that in comparison with those in the poor group, the percentages of two cells in the good response group were markedly increased during radiotherapy and they had a significantly positive correlation. During radiotherapy, the proportions of MDSCs were clearly increased in adenocarcinoma patients and the percentages of CD68+CD163+M2-like macrophages were markedly elevated in squamous carcinoma patients. We found that after radiotherapy, the expressions of eotaxin, MIP-1β, MCP-1, and BLC were significantly increased in NSCLC patients. Further results showed that the low levels of eotaxin and TNF RII expression before radiotherapy could predict a good therapeutic response. IL-1ra and MIP-1β had a positive relation with MDSCs or CD68+CD163+M2-like macrophages in NSCLC patients during radiotherapy, and eotaxin was correlated with CD68+CD163+M2-like macrophages but not MDSCs in NSCLC patients after radiotherapy. Conclusions. MDSCs and CD68+CD163+M2-like macrophages serve as therapeutic response biomarkers and are associated with the expressions of plasma inflammatory cytokines for NSCLC patients during radiotherapy.

Abstract Objectives Immune thrombocytopenia (ITP) is an autoimmune disease characterised by impaired platelet production and increased platelet destruction. However, the involvement of neutrophils in ITP is yet to be explored. Methods B‐cell activating factor (BAFF) expression and activation markers of neutrophils, as well as activation of platelets in ITP patients and healthy controls were measured. The interaction of CD62P on platelets and BAFF in neutrophils was analysed by correlation analysis and verified by co‐culture. The effects of neutrophils on apoptosis of acquired immune cells were evaluated in co‐culture systems with or without belimumab. Results The BAFF expression and activation of neutrophils were increased in active ITP patients. BAFF levels in neutrophils were positively correlated with CD62P+ platelets and neutrophils produced increased BAFF by interfering with CD62P on platelets. Neutrophils inhibited the apoptosis of CD4+, CD8+ and CD19+ cells dependent on BAFF levels, and belimumab could interrupt the effects of neutrophils. Conclusions Neutrophils were overactivated in ITP patients and participated in the progression of disease by producing excessive BAFF, which could be regulated by CD62P on platelets. Targeting BAFF by belimumab may be a novel potential therapy for ITP.

Abstract Spatial transcriptomics is considered as an important part of spatiotemporal molecular images to bridge molecular information with clinical images. Of those potentials and opportunities, the excellent quality of human sample preparation and handling will ensure the precise and reliable information generated from clinical spatial transcriptome. The present study aims at defining potential factors that might influence the quality of spatial transcriptomics in lung cancer, para‐cancer, or normal tissues, pathological images of sections and the RNA integrity before spatial transcriptome sequencing. We categorised potential influencing factors from clinical aspects, including patient selection, pathological definition, surgical types, sample harvest, temporary preservation conditions and solutions, frozen approaches, transport and storage conditions and duration. We emphasis on the relationship between the combination of histological scores with RNA integrity number (RIN) and the unique molecular identifier (UMI), which is determines the quality of of spatial transcriptomics; however, we did not find significantly relevance between them. Our results showed that isolated times and dry conditions of sample are critical for the UMI and the quality of spatial transcriptomic samples. Thus, clinical procedures of sample preparation should be furthermore optimised and standardised as new standards of operation performance for clinical spatial transcriptome. Our data suggested that the temporary preservation time and condition of samples at operation room should be within 30 min and in ‘dry’ status. The direct cryo‐preservation within OCT media for human lung sample is recommended. Thus, we believe that clinical spatial transcriptome will be a decisive approach and bridge in the development of spatiotemporal molecular images and provide new insights for understanding molecular mechanisms of diseases at multi‐orientations.

Abstract The communication between endoplasmic reticulum (ER) and mitochondria (Mt) plays important roles in maintenance of intra‐ and extra‐cellular microenvironment, metabolisms, signaling activities and cell‐cell communication. The present review aims to overview the advanced understanding about roles of ER‐Mt structural contacts, molecular interactions and chemical exchanges, signal transmissions and inter‐organelle regulations in ER‐Mt communication. We address how the ER‐Mt communication contributes to the regulation of lipid, amino acid and glucose metabolisms by enzymes, transporters and regulators in the process of biosynthesis. We specially emphasize the importance of deep understanding about molecular mechanisms of ER‐Mt communication for identification and development of biology‐specific, disease‐specific and metabolism‐specific biomarkers and therapeutic targets for human diseases. The inhibitors and modulators of the ER‐Mt communication are categorized according to therapeutic targets. Rapid development of biotechnologies will provide new insights for spatiotemporally understanding the molecular mechanisms of ER‐Mt communication.

Abstract Increasing evidence supports a central role of the immune system in lung diseases. Understanding how immunological alterations between lung diseases provide opportunities for immunotherapy. Exhausted T cells play a key role of immune suppression in lung cancer and chronic obstructive pulmonary disease was proved in our previous study. The present study aims to furthermore define molecular landscapes and heterogeneity of systemic immune cell target proteomic and transcriptomic profiles and interactions between circulating immune cells and lung residential cells in various lung diseases. We firstly measured target proteomic profiles of circulating immune cells from healthy volunteers and patients with stable pneumonia, stable asthma, acute asthma, acute exacerbation of chronic obstructive pulmonary disease, chronic obstructive pulmonary disease and lung cancer, using single‐cell analysis by cytometry by time‐of‐flight with 42 antibodies. The nine immune cells landscape was mapped among those respiratory system diseases, including CD4+ T cells, CD8+ T cells, dendritic cells, B cells, eosinophil, γδT cells, monocytes, neutrophil and natural killer cells. The double‐negative T cells and exhausted CD4+ central memory T cells subset were identified in patients with acute pneumonia. This T subset expressed higher levels of T‐cell immunoglobulin and mucin domain‐containing protein 3 (Tim3) and T‐cell immunoreceptor with Ig and ITIM domains (TIGIT) in patients with acute pneumonia and stable pneumonia. Biological processes and pathways of immune cells including immune response activation, regulation of cell cycle and pathways in cancer in peripheral blood immune cells were defined by bulk RNA sequencing (RNA‐seq). The heterogeneity among immune cells including CD4+, CD8+ T cells and NK T cells by single immune cell RNA‐seq with significant difference was found by single‐cell sequencing. The effect of interstitial telocytes on the immune cell types and immune function was finally studied and the expressions of CD8a and chemokine C–C motif receptor 7 (CCR7) were increased significantly in co‐cultured groups. Our data indicate that proteomic and transcriptomic profiles and heterogeneity of circulating immune cells provides new insights for understanding new molecular mechanisms of immune cell function, interaction and modulation as a source to identify and develop biomarkers and targets for lung diseases.

Abstract The purpose of the establishment of multidisciplinary therapy (MDT) strategy of precision medicine is to provide professional gene interpretation and consultation, combined with the expertise of clinicians, to develop personalized treatment strategies for patients. In this article, we report four typical cases to demonstrate the process and working mode of MDT strategy of precision medicine, and what it could bring to clinicians or patients is also discussed.

Background With the development and advancement of gene sequencing technologies, next generation sequencing, especially metagenomic next generation sequencing (mNGS), has been explored in infectious disease diagnosis. Aims To first introduce the standardization of each step of mNGS, the interpretation of positive and negative results and their clinic application in pathogen diagnosis. Methods A typical workflow of mNGS includes six main steps: sample collection, nucleic acid extraction, library construction, sequencing ,data analysis and report writing. Results Based on our previous work, we introduce the standardization of steps of mNGS in pathogen diagnosis and summarize the interpretation of positve and negative results and their application in clinic settings. Conclusion It is believed that this clinical standardization of mNGS could be a routine diagnostic tool for infectious diseases in coming future.

Abstract Profiling heterologous cell types within tumors is essential to decipher tumor microenvironment that shapes tumor progress and determines the outcome of therapeutic response. Here, we comprehensively characterized transcriptomes of 34,037 single cells obtained from 12 treatment‐naïve patients with colorectal cancer. Our comprehensive evaluation revealed attenuated B‐cell antigen presentation, distinct regulatory T‐cell clusters with different origin and novel polyfunctional tumor associated macrophages associated with CRC. Moreover, we identified expanded XCL1+ T‐cell clusters associated with tumor mutational burden high status. We further explored the underlying molecular mechanisms by profiling epigenetic landscape and inferring transcription factor motifs using single‐cell ATAC‐seq. Our dataset and analysis approaches herein provide a rich resource for further study of the impact of immune cells and translational research for human colorectal cancer.

Abstract Clinical and translational medicine is an ongoing opportunity and challenge to transition science from bench to patient, from patient to bench, and from patient to policy for scientists and clinicians. Of the many objectives, the most important one is to improve the quality of life in patients, including living duration, dignity, emotional well‐being, psychiatric and physical health, as well as independency. Emphasis and redefining concepts has allowed clinical and translational medicine to experience exciting and productive developments. Further discoveries, innovations, validations, and developments in clinical and translational medicine are expected in 2020. The present editorial aims to present the top three most discussed topics with high expectations for translation from clinical investigations and trials into practice and application.

Abstract Background Telocytes play key roles in maintenance of organ/tissue function and prevention of organ injury. However, there are great challenges to investigate telocytes functions using primary telocytes, due to the difficulties of isolation, identification, and stability. The present study aims at constructing continuous cell strain of mouse lung telocyte cell line with stable characters by gene modification and investigating biological behaviors and responses of gene-modified telocytes to inflammation. Methods Mouse primary lung telocytes were isolated and identified using immune-labeling markers and immunoelectron microscopy. Primary telocytes were transformed with Simian vacuolating virus 40 small and large T antigen (SV40). Biological characters, behaviors morphology, and proliferation of those gene-modified telocytes were defined and monitored dynamically for 50 generations, as compared with primary lung telocytes. Cell cycle of mouse primary lung telocytes or gene-modified telocytes was detected by flow cytometry. Results Gene modified telocytes of generations 5, 10, 30 and 50 were observed with telopodes and also showed CD34 and ckit positive. Multiple cellular morphology were also observed on telocyte cell-line under monitor of celliq and enhanced cell proliferation were showed. SV40 transduction was also reduced apoptosis and increased the ratio of S and G2 phases in telocyte cell-line. Conclusion We successfully constructed mouse lung telocyte cell-line which maintained the biological properties and behaviors as primary telocytes and could responses to inflammation induced by LPS. Thus, gene-modified lung telocytes, Telocyte Line, would provide a cell tool for researchers exploring the roles and applications of telocytes involved in physiological and pathological states in future.

Single-cell RNA-seq (scRNA-seq) technologies are broadly applied to dissect the cellular heterogeneity and expression dynamics, providing unprecedented insights into single-cell biology. Most of the scRNA-seq studies mainly focused on the dissection of cell types/states, developmental trajectory, gene regulatory network, and alternative splicing. However, besides these routine analyses, many other valuable scRNA-seq investigations can be conducted. Here, we first review cell-to-cell communication exploration, RNA velocity inference, identification of large-scale copy number variations and single nucleotide changes, and chromatin accessibility prediction based on single-cell transcriptomics data. Next, we discuss the identification of novel genes/transcripts through transcriptome reconstruction approaches, as well as the profiling of long non-coding RNAs and circular RNAs. Additionally, we survey the integration of single-cell and bulk RNA-seq datasets for deconvoluting the cell composition of large-scale bulk samples and linking single-cell signatures to patient outcomes. These additional analyses could largely facilitate corresponding basic science and clinical applications.

Background Regulating T-cell metabolism is crucial for their anticancer activity. Therefore, understanding the function and metabolism of human tumor-infiltrating T cells is of broad interest and clinical importance.Methods CD3+CD45+ T cells were sorted from adjacent area or tumor core of human hepatocellular carcinoma (HCC), then the clusters and heterogeneity of T cells were further interrogated by single-cell transcriptomic profiling. 118 surgical samples from patients with HCC were histologically examined for infiltration of CD8+ T cells in tumor and adjacent tissue.Results Single-cell transcriptomic profiling indicated that several exhausted T-cell (Tex) populations differentially coexisted in the tumor and adjacent tissue. CD137 identifies and enriches Tex with superior effector functions and proliferation capacity. Furthermore, enhanced fatty acid-binding protein 5 (FABP5) expression along with increased mitochondrial oxidative metabolism were evident in these CD137-enriched Tex. Inhibiting FABP5 expression and mitochondrial fatty acid oxidation impaired the anti-apoptosis and proliferation of CD137-enriched Tex. These observations have been verified by generating CD137 CART. Immunohistochemistry staining on the tissue microarray of 118 patients with HCC showed intra-tumoral FABP5 high CD8+ T-cell infiltration was linked to overall and recurrence-free survival.Conclusions The tumor microenvironment can impose metabolic restrictions on T-cell function. CD137, a costimulatory molecule highly expressed on some Tex, uses exogenous fatty acids and oxidative metabolism to mediate antitumor immunity. The immunometabolic marker FABP5 should be investigated in larger, longitudinal studies to determine their potential as prognostic biomarkers for HCC.

Abstract Background Exhausted T cells and regulatory T cells (Tregs) comprise diverse subsets of tumor immunosuppressive microenvironment that play key roles in tumor progress. Understanding subset diversity in T cells is a critical question for developing cancer immunotherapy. Methods A total of 235 specimens from surgical resections of hepatocellular carcinoma (HCC) patients were examined for infiltration of exhausted T cell (Tex) in tumor and adjacent tissue. We conducted deep single‐cell targeted immune profiling on CD3+ cells collected from tumor tissues, adjacent normal tissues (ANTs) and peripheral blood of HCC patients. Total 10 cell clusters were identified with distinct distributions and characteristics. Results We observed transitional differentiation of exhausted CD8+T cells and Tregs increasingly enriched in tumor tissue. The accumulation and location of Tex were related to the differences in the long‐term clinical outcome of HCC. Furthermore, data of single‐cell RNA‐seq showed that (1) cells transforming from effector CD8+ T cells to exhausted CD8+ T cells simultaneously expressed upregulated effector molecules and inhibitory receptors, (2) indicated alteration of gene expression related to stress response and cell cycle at early exhaustion stage, and (3) immunosuppressive Treg had profound activation in comparison to resting Tregs. Conclusions T cell exhaustion is a progressive process, and the gene‐expression profiling displayed T cell exhaustion and anergy are different. Accordingly, it is possible that functional exhaustion is caused by the combination effects of passive defects and overactivation in stress response. The results help to understand the dynamic framework of T cells function in cancer which is important for designing rational cancer immunotherapies.

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. T-cell infiltration and/or the presence of PD-L1 in tumors may be used as indicators of clinical response; However, recent studies reported that preexisting tumor-specific T cells may have limited reinvigoration capacity. Therefore, evaluating status of T cells of tumor-adjacent area and its impact on the prognosis are very important. Here, we examined 117 surgical samples from HCC patients for infiltration of exhausted T cell (Tex) including CD4+-Tex, CD8+-Tex and regulatory T cell (FOXP3+-Treg) in tumor and adjacent tissue. CD3+CD45RO+T cells were sorted from adjacent area or tumor core, then the clusters and heterogeneity of T cells were further interrogated by single-cell RNA sequencing. As a result, we suggested that abundance or location of T cell subsets is differentially correlate with long-term clinical outcome of HCC. In contrast with CD4+T or CD4+-Tex, the infiltration of CD8+T or CD8+-Tex cells was closely linked to overall or recurrence-free survival. FOXP3+-Treg is more predictive of early recurrence. Single-cell transcriptional analysis demonstrates the composition of CD4+-Tex, CD8+-Tex, and FOXP3+-Treg is shifted in tumor and adjacent tissue. Molecular profiles including genes coding checkpoint receptors, effector molecules are distinct between CD4+-Tex, CD8+-Tex, though some common features of CD4+ and CD8+ T cell exhaustion are revealed. In conclusion, we underline the heterogeneity and clinical relevance of Tex cells in HCC patients. A better understanding of Tex is critical for HCC monitoring and treatment.

The precise mechanisms underlying dissections, especially those without connective tissue diseases or congenital vascular diseases, are incompletely understood. This study attempted to identify both the expression profile of the dissected ascending aorta and the interactome hotspots associated with the disease, using microarray technology and gene regulatory network analysis. There were 2,737 genes differentially expressed between patients with acute Stanford type A aortic dissection and controls. Eight interactome hotspots significantly associated with aortic dissection were identified by an integrative network algorithm. In particular, we identified a JAK2-centered expression module, which was validated in an independent gene expression microarray data set, and which was characterized by over-expressed cytokines and receptors in acute aortic dissection cases, indicating that JAK2 may play a key role in the inflammatory process, which potentially contributes to the occurrence of acute aortic dissection. Overall, the analytical strategy used in this study offered the possibility to identify functional relevant network modules and subsequently facilitated the biological interpretation in the complicated disease.

Abstract Background Clinical translational medicine (CTM) is an emerging area comprising multidisciplinary research from basic science to medical applications and entails a close collaboration among hospital, academia and industry. Findings This Session focused discussing on new models for project development and promotion in translational medicine. The conference stimulated the scientific and commercial communication of project development between academies and companies, shared the advanced knowledge and expertise of clinical applications, and created the environment for collaborations. Conclusions Although strategic collaborations between corporate and academic institutions have resulted in a state of resurgence in the market, new cooperation models still need time to tell whether they will improve the translational medicine process.

Abstracts Health systems globally face challenges and opportunities in balancing quality, access, and cost, where clinical and translational medicine (CTM) should play more important and powerful roles in the identification, development and validation of solutions and strategies. Strategic collaboration can gather global strengths and resources and improve health systems, care delivery, regulations and policies. CTM‐driven innovation and development has the potential to achieve step‐change improvements across three dimensions. Thus, we have the reasons to believe that CTM will play even more roles in the development of new diagnostics, therapies, healthcare, and policies and SAS‐CTM will become more and more important platform to obtain the latest development in CTM internationally and explore new opportunities in the international collaborations.

Hydrogen sulfide, as a novel gaseous mediator, has been suggested to play a key role in atherogenesis. However, the precise mechanisms by which H(2)S affects atherosclerosis remain unclear. Therefore, the present study aimed to investigate the potential role of H(2)S in atherosclerosis and the underlying mechanism with respect to chemokines (CCL2, CCL5 and CX3CL1) and chemokine receptors (CCR2, CCR5, and CX3CR1) in macrophages. Mouse macrophage cell line RAW 264.7 or mouse peritoneal macrophages were pre-incubated with saline or NaHS (50 µM, 100 µM, 200 µM), an H(2)S donor, and then stimulated with interferon-γ (IFN-γ) or lipopolysaccharide (LPS). It was found that NaHS dose-dependently inhibited IFN-γ or LPS-induced CX3CR1 and CX3CL1 expression, as well as CX3CR1-mediated chemotaxis in macrophages. Overexpression of cystathionine γ-lyase (CSE), an enzyme that catalyzes H(2)S biosynthesis resulted in a significant reduction in CX3CR1 and CX3CL1 expression as well as CX3CR1-mediated chemotaxis in stimulated macrophages. The inhibitory effect of H(2)S on CX3CR1 and CX3CL1 expression was mediated by modulation of proliferators-activated receptor-γ (PPAR-γ) and NF-κB pathway. Furthermore, male apoE(-/-) mice were fed a high-fat diet and then randomly given NaHS (1 mg/kg, i.p., daily) or DL-propargylglycine (PAG, 10 mg/kg, i.p., daily). NaHS significantly inhibited aortic CX3CR1 and CX3CL1 expression and impeded aortic plaque development. NaHS had a better anti-atherogenic benefit when it was applied at the early stage of atherosclerosis. However, inhibition of H(2)S formation by PAG increased aortic CX3CR1 and CX3CL1 expression and exacerbated the extent of atherosclerosis. In addition, H(2)S had minimal effect on the expression of CCL2, CCL5, CCR2 and CCR5 in vitro and in vivo. In conclusion, these data indicate that H(2)S hampers the progression of atherosclerosis in fat-fed apoE(-/-) mice and downregulates CX3CR1 and CX3CL1 expression on macrophages and in lesion plaques.

Lipids and lipid metabolism play crucial roles in regulating T cell function and are tightly related to the establishment of immune memory. It is reported that tumor-infiltrating CD8+T lymphocytes (CD8+TILs) burn fats to restore their impaired effector function due to the lack of glucose. Conversely, fatty acids (FAs) and cholesterol in the tumor microenvironment (TME) drive the CD8+ TILs dysfunction. The origin of dysfunctional CD8+ TILs shares important features with memory T cell’s precursor, but whether lipids and/or lipid metabolism reprogramming directly influence the memory plasticity of dysfunctional CD8+ TILs remains elusive. It is necessary to understand the interplay between cellular lipid metabolism and dysfunction of CD8+ TILs in the case of targeting T cell’s metabolism to synergize cancer immunotherapy. Therefore, in this review, we summarize the latest research on CD8+ TILs lipid metabolism, evaluate the impacts of lipids in the TME to CD8+ TILs, and highlight the significance of promoting memory phenotype cell formation by targeting CD8+ T cells lipid metabolism to provide longer duration of cancer immunotherapy efficacy. [ABSTRACT FROM AUTHOR]