CD4+CD57+ senescent T cells as promoters of systemic lupus erythematosus pathogenesis and the therapeutic potential of senolytic BCL-2 inhibitor.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by persistent activation of immune cells and overproduction of autoantibodies. The accumulation of senescent T and B cells has been observed in SLE and other immune-mediated diseases. However, the exact mechanistic pathways contributing to this process in SLE remain incompletely understood. In this study, we found that in SLE patients: (1) the frequency of CD4+CD57+ senescent T cells was significantly elevated and positively correlated with disease activity; (2) the expression levels of B-lymphoma-2 (BCL-2) family and interferon-induced genes (ISGs) were significantly upregulated; and (3) in vitro, the cytokine IL-15 stimulation increased the frequency of senescent CD4+ T cells and upregulated the expression of BCL-2 family and ISGs. Further, treatment with ABT-263 (a senolytic BCL-2 inhibitor) in MRL/lpr mice resulted in decreased: (1) frequency of CD4+CD44hiCD62L-PD-1+CD153+ senescent CD4+ T cells; (2) frequency of CD19+CD11c+T-bet+ age-related B cells; (3) level of serum antinuclear antibody; (4) proteinuria; (5) frequency of Tfh cells; and (6) renal histopathological abnormalities. Collectively, these results indicated a dominant role for CD4+CD57+ senescent CD4+ T cells in the pathogenesis of SLE and senolytic BCL-2 inhibitor ABT-263 may be the potential treatment in ameliorating lupus phenotypes.

Single-cell transcriptome profiling of primary tumors and paired organoids of pancreatobiliary cancer.

Single-cell RNA-seq (scRNA-seq) and cancer organoid model have shown promise in investigating tumor microenvironment heterogeneity and facilitating chemotherapeutic drug testing to inform treatment selection. It is still unknown whether the scRNA-seq results based on organoid can faithfully reflect the heterogeneity of primary pancreatobiliary cancer. To reveal the similarities and differences between primary tumors and their matched organoids at transcriptome level, we conducted scRNA-seq for paired primary tumors and organoids from one cholangiocarcinoma (CCA) and two pancreatic ductal adenocarcinoma (PDAC) patients. We identified inter-patient and intra-tumor heterogeneity and found that the organoids retained copy number variation (CNV) patterns of primary tumors. There was no significant difference in cancer stem cell (CSC) properties between the primary tumors and the organoids, whereas organoid from one PDAC case had increased mesenchymal-score and decreased epithelial-score compared with the primary tumors. All organoids showed a transition tendency from the classical subtype to the basal-like subtype in the transcriptional level. Organoids and primary tumors differed in metabolic and unfolded protein response (UPR) signatures. In addition, we revealed the heterogeneity of cancer associated fibroblasts (CAFs) and T cells, and explored the developmental trajectory of T cells. Our findings facilitate further understanding of organoid model and confirm its application prospects in pancreatobiliary cancer.

Single-cell RNA-seq reveals characteristics in tumor microenvironment of PDAC with MSI-H following neoadjuvant chemotherapy with anti-PD-1 therapy.

Accumulating evidence suggests the minority of patients with advanced pancreatic ductal adenocarcinoma (PDAC) that have microsatellite instability high (MSI-H) can benefit from immune checkpoint inhibitors (ICIs). However, the effects of ICIs on the tumor microenvironment (TME) of PDAC remain elusive. We conducted single-cell RNA-seq (scRNA-seq) analysis on a residual lesion from a MSI-H PDAC patient who received a radical operation after eight cycles of neoadjuvant treatment (nab-paclitaxel/gemcitabine plus pembrolizumab). Multiple tumor subclusters were identified in residual lesion after neoadjuvant treatment, one of which was mainly composed of cells in the S and G2M phases. This subcluster also had enriched expression of MKI67 and PCNA and cell cycle-related signatures and was thus defined as a proliferating tumor subcluster. This subcluster had higher S_score, Fatty acid_score, UPR_score, and Glycolysis_score than others. We also identified characteristics of the TME after neoadjuvant treatment by comparing the excised primary tumors form nontreated PDAC and the residual lesion. The residual lesion was characterized with activated pancreatic stellate cells (PSCs) and exhausted T cells (Tex). We compared the receptor-ligand interactions between the two groups, and found that no checkpoint receptor-ligand pairs between T cells and tumor cells were identified in the residual lesion, while there were many checkpoint receptor-ligand pairs in the nontreated primary PDAC. In conclusion, our findings revealed the characteristics of residual lesion of advanced PDAC with MSI-H upon combination treatment of chemotherapy and immunotherapy, which might provide some valuable clues for solving the puzzle of ICI in PDAC.

The benefits of neoadjuvant therapy for patients with resectable pancreatic cancer: an updated systematic review and meta-analysis.

Neoadjuvant therapy (NAT) was effective in improving overall survival (OS) of borderline resectable pancreatic cancer. However, its application in resectable pancreatic cancer remains controversial. This study aimed to determine whether NAT has a greater advantage over conventional upfront surgery (US) in terms of resection rate, R0 resection rate, positive lymph node rate, and OS. We identified articles before October 7, 2022, by searching four electronic databases. The studies included in the meta-analysis all met the inclusion and exclusion criteria. The Newcastle-Ottawa scale was used to evaluate the quality of the articles. OS, DFS, resection rate, R0 resection rate and positive lymph nodes rate were extracted. Odds ratio (OR), hazard ratio (HR) and 95% confidence intervals (CI) were calculated, and sensitivity analysis and publication bias were used to assess the sources of heterogeneity. In total, 24 studies, involving 1384 (35.66%) patients assigned to NAT and 2497 (64.43%) patients assigned to US, were included in the analysis. NAT could effectively prolong OS (HR 0.73, 95% CI 0.65-0.82, P < 0.001) and DFS (HR 0.72, 95% CI 0.62-0.84, P < 0.001). Subgroup analysis results of 6 randomized controlled trials (RCTs) also showed that RPC patients could benefit from NAT in the long term (HR 0.72, 95% CI 0.58-0.90, P = 0.003). NAT decreased resection rate (OR 0.43, 95% CI 0.33-0.55, P < 0.001), but was associated with increased R0 resection rate (OR 2.05, 95% CI 1.47-2.88, P < 0.001) and decreased positive lymph node rate (OR 0.38, 95% CI 0.27-0.52, P < 0.001). Although the application of NAT increases the risk of patients not being able to undergo surgical resection, it can prolong the OS and delay tumor progression in RPC. Therefore, we still expect larger and higher-quality RCTs to confirm the effectiveness of NAT.

Widening educational inequalities in mortality in more recent birth cohorts: a study of 14 European countries.

BACKGROUND: Studies of period changes in educational inequalities in mortality have shown important changes over time. It is unknown whether a birth cohort perspective paints the same picture. We compared changes in inequalities in mortality between a period and cohort perspective and explored mortality trends among low-educated and high-educated birth cohorts. DATA AND METHODS: In 14 European countries, we collected and harmonised all-cause and cause-specific mortality data by education for adults aged 30-79 years in the period 1971-2015. Data reordered by birth cohort cover persons born between 1902 and 1976. Using direct standardisation, we calculated comparative mortality figures and resulting absolute and relative inequalities in mortality between low educated and high educated by birth cohort, sex and period. RESULTS: Using a period perspective, absolute educational inequalities in mortality were generally stable or declining, and relative inequalities were mostly increasing. Using a cohort perspective, both absolute and relative inequalities increased in recent birth cohorts in several countries, especially among women. Mortality generally decreased across successive birth cohorts among the high educated, driven by mortality decreases from all causes, with the strongest reductions for cardiovascular disease mortality. Among the low educated, mortality stabilised or increased in cohorts born since the 1930s in particular for mortality from cardiovascular diseases, lung cancer, chronic obstructive pulmonary disease and alcohol-related causes. CONCLUSIONS: Trends in mortality inequalities by birth cohort are less favourable than by calendar period. In many European countries, trends among more recently born generations are worrying. If current trends among younger birth cohorts persist, educational inequalities in mortality may further widen.

Non-monotonic changes in Asian Water Towers' streamflow at increasing warming levels.

Previous projections show consistent increases in river flows of Asian Water Towers under future climate change. Here we find non-monotonic changes in river flows for seven major rivers originating from the Tibetan Plateau at the warming levels of 1.5 °C, 2.0 °C, and 3.0 °C based on an observation-constrained hydrological model. The annual mean streamflow for seven rivers at 1.5 °C warming level decreases by 0.1-3.2% relative to the present-day climate condition, and increases by 1.5-12% at 3.0 °C warming level. The shifting river flows for the Yellow, Yangtze, Brahmaputra, and Ganges are mostly influenced by projected increases in rainfall, but those for the Mekong, Salween, and Indus are dictated by the relative changes in rainfall, snowmelt and glacier melt. Reduced river flows in a moderately warmed climate threaten water security in riparian countries, while elevated flood risks are expected with further temperature increases over the Tibetan Plateau.

Manual development and efficacy of Mindful Living Group activities to promote trauma healing during the COVID-19 pandemic in China.

Introduction: Disasters can be traumatic with a profound and lasting impact on individuals. During the COVID-19 pandemic, our team developed the Mindful Living Group (MLG) activities manual based on Eastern body-mind wisdom and Western trauma healing theory to provide psychological assistance for trauma healing. Methods: In this study, we introduce a framework developed for the 10-session MLG activities manual, which consists of three core modules. Thirty-one participants living all over the country who had experienced traumatic stress resulting from the COVID-19 pandemic received the MLG intervention. This single-arm intervention study offered psychological assistance during the pandemic. The MLG intervention included 10 weekly 2-h sessions held online. Participants completed the initial interview, pre-test, post-test, and 1-month follow-up interviews. The effectiveness of the MLG activities manual was evaluated using psychological measures, including Self-Rating Depression Scale, Self-Rating Anxiety Scale, Mindful Attention Awareness Scale, Post-traumatic Growth Inventory, General Self-Efficacy Scale, and the Perceived Social Support Scale. Results: Compared with the pretest level, the post-test levels of depression (F = 42.78, p < 0.001, η 2 = 0.59) and anxiety (F = 23.40, p < 0.001, η 2 = 0.44) were significantly lower; and mindfulness (F = 12.98, p =0.001, η 2 =0.30), posttraumatic growth (F = 27.06, p < 0.001, η 2 = 0.48), general self-efficacy (F = 13.20, p = 0.001, η 2 = 0.31), and perceived social support (F = 16.27, p < 0.001, η 2 = 0.35) were significantly higher (ANOVA). Further correlation analysis revealed a significant negative relationship of mindfulness with both depression (r = -0.43, p = 0.015) and anxiety (r = -0.35, p = 0.053), and significant positive relationships of mindfulness with posttraumatic growth (r = 0.40, p = 0.025), general self-efficacy (r = 0.52, p = 0.003), and perceived social support (r = 0.40, p = 0.024). Discussion: These preliminary findings showed the effectiveness of MLG activities for trauma healing. The mechanisms underlying mindfulness promoting trauma healing are discussed based on both Eastern body-mind wisdom and Western theories of trauma healing. Clinical trial registration: Identifier, ChiCTR2000034164.

Bach2 in CD4+ T cells from SLE patients modulates B-cell differentiation and IgG production.

T and B cells participate in the development of systemic lupus erythematosus (SLE). BTB and CNC homology 2 (Bach2) is an irreplaceable regulator in the T and B lineages that helps to maintain immune homeostasis. However, the function of Bach2 in the pathogenesis of SLE has not been studied in depth. Flow cytometry and qRT-PCR were used to assess Bach2 levels, bisulfite sequencing PCR was used to measure the methylation level, and silencing by electroporation and stimulation with a cytokine concentration gradient were used to investigate the effect of Bach2 on T cells. Bach2 expression was elevated in the helper T-cell subsets (T follicular helper, Th1, Th2, Th17, and Treg cells) of SLE patients and negatively correlated with disease severity and autoantibody levels. CD4+ T cells from SLE patients had decreased methylation levels in the Bach2 promoter region. Silencing Bach2 in CD4+ T cells induced increases in the CD19+ B-cell count, plasmablasts, and secretion of IgG by prompting the secretion of cytokines. The activation signals CD3/CD28, IL-6, and IL-21 upregulated Bach2 expression in CD4+ T cells. The regulation of Bach2 by cytokines and T-cell activation signals in CD4+ T cells was shown to act on B cells and play a protective role against SLE.

ORLNC1 Suppresses Cell Growth in HER2-Positive Breast Cancer via miRNA-296 Sponging.

BACKGROUND: Accumulating research has demonstrated that aberrant levels of long noncoding RNAs (LncRNAs) are related to cancer progression. The effects of ORLNC1 in HER2+ breast cancer have yet to be explored. METHODS: Real-time PCR was used to examine the expression of LncRNA ORLNC1 in HER+ breast cancer. CCK-8, wound healing and cell invasion assays were used to examine the effect of LncRNA ORLNC1 on HER+ breast cancer cells. Luciferase reporter assay was utilized to determine the regulatory relationship between LncRNA ORLNC1 and miR-296. Western blotting was used to measure the expression of PTEN. Xenograft mouse model was used to examine the effect of LncRNA ORLNC1 on tumor progression in vivo. RESULTS: In this study, our findings revealed downregulation of ORLNC1 in HER2+ breast cancer specimens and cell lines. Low levels of ORLNC1 were related to poor prognosis and advanced cancer stage. Using gain- and loss-of-function assays, the ability of these tumor cells to proliferate was found to be inhibited by ORLNC1 in vitro and in vivo. Further analyses revealed that miR-296/PTEN axis is directly targeted by ORLNC1. Consequently, over-expression of miR-296 efficiently abrogated the upregulation of PTEN induced by ORLNC1, suggesting that ORLNC1 positively regulates PTEN expression by competitively binding to miR-296. CONCLUSION: Our results indicate that lncRNA ORLNC1 acts as a tumor suppressor by regulating the miR-296/PTEN axis in HER2+ breast cancer.

The state and fate of lake ice thickness in the Northern Hemisphere.

Lake ice thickness (LIT) is important for regional hydroclimate systems, lake ecosystems, and human activities on the ice, and is thought to be highly susceptible to global warming. However, the spatiotemporal variability in LIT is largely unknown due to the difficulty in deriving in situ measurements and the lack of an effective remote sensing platform. Despite intensive development and applications of lake ice models driven by general circulation model output, evaluation of the global LIT is mostly based on assumed "ideal" lakes in each grid cell of the climate forcing data. A method for calculating the actual global LIT is therefore urgently needed. Here we use satellite altimetry to retrieve ice thickness for 16 large lakes in the Northern Hemisphere (Lake Baikal, Great Slave Lake, and others) with an accuracy of ∼0.2 m for almost three decades. We then develop a 1-D lake ice model driven primarily by remotely sensed data and cross-validated with the altimetric LIT to provide a robust means of estimating LIT for lakes larger than 50 km2 across the Northern Hemisphere. Mean LIT (annual maximum ice thickness) for 1313 simulated lakes and reservoirs covering ∼840,000 km2 for 2003-2018 is 0.63 ± 0.02 m, corresponding to ∼485 Gt of water. LIT changes are projected for 2071-2099 under RCPs 2.6, 6.0, and 8.5, showing that the mean LIT could decrease by ∼0.35 m under the worst concentration pathway and the associated lower ice road availability could have a significant impact on socio-economic activities.

Anxiety, depression, and social connectedness among the general population of eight countries during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic affected the mental health of the general population through multiple pathways. The aim of this study was to examine anxiety, depression, self-confidence, and social connectedness among the general population of eight countries during the COVID-19 pandemic, their underlying factors, and vulnerable groups. METHODS: A web-based survey was administered to persons from the general population of China, Greece, Italy, Netherlands, Russia, Sweden, the United Kingdom, and the United States. The survey included the Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9) and items on self-confidence, social connectedness, and socio-demographics. Data were analyzed with descriptive statistics, exploratory factor analysis and regression analysis. RESULTS: Twenty-three thousand six hundred twenty-two respondents completed the survey. Overall, 42% of the total sample had mild to severe anxiety symptoms and 43% had mild to severe depression symptoms. 14% to 38% reported suboptimal ratings in self-confidence, social participation, contact with family and friends, and feeling connected to others. In the exploratory factor analyses, in most countries, one dominant factor had a high influence on GAD-7, PHQ-9 sum scores and self-confidence with eigenvalue (% variance) above 3.2 (53.9%). One less dominant factor had a high influence on social connectedness scores with eigenvalue (% variance) ranging above 0.8 (12.8%). Being younger, female, having chronic conditions, perceived as risky to COVID-19 infection, and feeling not very well protected against COVID-19 were significantly associated with the two underlying factors. CONCLUSIONS: Anxiety, depression, and problems with self-confidence and social connectedness were highly prevalent in the general population of eight countries during the early phase of the COVID-19 pandemic. This highlights the importance of the allocation of additional resources to implement policies to mitigate the impact of the pandemic on mental health.

Health-Related Quality of Life and Mental Well-Being during the COVID-19 Pandemic in Five Countries: A One-Year Longitudinal Study.

This study aimed to investigate socioeconomic and health-related determinants and recent life events and their relation to changes in health-related quality of life (HRQoL) and mental well-being during the first year of the COVID-19 pandemic. A web-based survey was administered repeatedly to participants from Greece, Italy, the Netherlands, the United Kingdom, and the United States. Primary outcome measures were HRQoL (measured by EQ-5D-5L) and mental well-being (measured by WHO-5). Linear regression analyses were performed to estimate the impact of determinants on HRQoL and well-being. In total, 6765 respondents completed the questionnaire at T1 (April-May 2020) and T2 (May-June 2021). Regarding results, 33% showed improved HRQoL at T2, whereas 31% deteriorated. In terms of mental well-being, 44% improved and 41% deteriorated. The greatest deterioration in HRQoL and mental well-being from T1 to T2 was observed with an increasing number of chronic conditions. The effect of negative life events on HRQoL and mental well-being was larger than the effect of positive life events. We conclude that slightly more respondents showed improved rather than deteriorated HRQoL and mental well-being, with some variation by outcome measure and country.

Reconstructed eight-century streamflow in the Tibetan Plateau reveals contrasting regional variability and strong nonstationarity.

Short instrumental streamflow records in the South and East Tibetan Plateau (SETP) limit understanding of the full range and long-term variability in streamflow, which could greatly impact freshwater resources for about one billion people downstream. Here we reconstruct eight centuries (1200-2012 C.E.) of annual streamflow from the Monsoon Asia Drought Atlas in five headwater regions across the SETP. We find two regional patterns, including northern (Yellow, Yangtze, and Lancang-Mekong) and southern (Nu-Salween and Yarlung Zangbo-Brahmaputra) SETP regions showing ten contrasting wet and dry periods, with a dividing line of regional moisture regimes at ~32°-33°N identified. We demonstrate strong temporal nonstationarity in streamflow variability, and reveal much greater high/low mean flow periods in terms of duration and magnitude: mostly pre-instrumental wetter conditions in the Yarlung Zangbo-Brahmaputra and drier conditions in other rivers. By contrast, the frequency of extreme flows during the instrumental periods for the Yangtze, Nu-Salween, and Yarlung Zangbo-Brahmaputra has increased by ~18% relative to the pre-instrumental periods.

Single cell RNA-seq reveals the CCL5/SDC1 receptor-ligand interaction between T cells and tumor cells in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the complex tumor microenvironment (TME), consisting of an abundance of stromal cells. Among them, tumor infiltrating T cells play a pivotal role in tumor progress. To identify the full spectrum and developmental trajectory of T cells and their crosstalk with tumor cells in PDAC, we conducted scRNA-seq analysis based on multiple datasets from our institution and open databases. We delineated the cellular landscape and transcriptional dynamics of T cells in PDAC. Through the inferCNV analysis and known tumor markers, the malignant ductal cells were identified. The inter-patients heterogeneity of tumor cells was also identified. After integrating T cells and malignant ductal cells, we found the CCL5-SDC1/4 receptor-ligand interactions between them. Furthermore, we demonstrated that CCL5 promoted tumor cells migration via interacting with SDC1 in vitro. Our findings pave the way for characterizing the heterogeneity and development trajectory of T cells, and cell-to-cell communications in TME of PDAC, which might provide a new target for immunotherapy.

Health inequities as measured by the EQ-5D-5L during COVID-19: Results from New York in healthy and diseased persons.

INTRODUCTION: The effects of the COVID-19 pandemic caused considerable psychological and physical effects in healthy and diseased New Yorkers aside from the effects in those who were infected. We investigated the relationship between known risk-enhancing and health-promoting factors (social and medical), comorbidity indicators, and, as the primary outcome, health-related quality of life (HRQoL). METHODS: Between April 22 and May 5, 2020, a market research agency (Dynata) administered a digital survey including the EQ-5D-5L and items related to individual characteristics, social position, occupational and insurance status, living situation, exposures (smoking and COVID-19), detailed chronic conditions, and experienced access to care to an existing internet panel representative of New Yorkers. RESULTS: 2684 persons completed the questionnaire. The median age was 48 years old, and most respondents were non-Hispanic white (74%) and reported at least higher vocational training or a university education (83%). During COVID-19, mean HRQoL scores were 0.82 for the EQ-5D-5L index and 79.3 for the EQ VAS. Scores varied for healthy and diseased respondents differently by the above determinants. Lower age, impaired occupational status, loss of health insurance, and limited access to care exerted more influence on EQ-5D-5L scores of diseased persons compared to healthy persons. Among diseased persons, the number of chronic conditions and limited access to health care had the strongest association with EQ-5D-5L scores. While EQ-5D-5L scores improved with increasing age, gender had no noticeable effect. Deprivation factors showed moderate effects, which largely disappeared in (stratified) multivariable analysis, suggesting mediation through excess chronic morbidity and poor healthcare access. Generally, modifying effects were larger in the EQ-5D-5L as compared to the EQ VAS. CONCLUSIONS: Almost all factors relating to a disadvantaged position showed a negative association with HRQoL. In diseased respondents, pre-existing chronic comorbidity and experienced access to health care are key factors.

Skin CD4+ Trm cells distinguish acute cutaneous lupus erythematosus from localized discoid lupus erythematosus/subacute cutaneous lupus erythematosus and other skin diseases.

BACKGROUND: Although the contribution of aberrant CD4+ T cell signaling to systemic lupus erythematosus (SLE) is well established, its role in cutaneous lupus erythematosus (CLE) skin is largely unknown. Because the rate of systemic manifestations varies in each subtype, resident memory CD4+ T cells in lesions that are responsible for only skin-associated tissue responses may vary in each subtype. However, the role of CD4+ tissue-resident memory T (CD4+ Trm) cells in each CLE subtype remains unclear. OBJECTIVES: To analyze and compare CD4+ Trm cells and absent in melanoma 2 (AIM2) identified by smart RNA sequencing (Smart-seq) in CD4+ Trm cells from patients with acute CLE (ACLE), subacute CLE (SCLE), and localized discoid lupus erythematosus (localized DLE) lesions. METHODS: We performed Smart-seq to investigate differences in dermal CD4+ Trm cells between patients with ACLE and normal controls (NCs). Multicolor immunohistochemistry was utilized to measure the levels of AIM2 in CD4+ Trm cells present in the skin of 134 clinical patients, which included patients with localized DLE (n = 19), ACLE (n = 19), SCLE (n = 16), psoriasis (n = 12), rosacea (n = 17), lichen planus (n = 18), and annular granuloma (n = 15), as well as NCs (n = 18). RESULTS: The Smart-seq data showed higher AIM2 expression in skin CD4+ Trm cells from ACLE lesions than NCs (fold change >10, adjusted P < 0.05). AIM2 expression in CD4+ Trm cells did not vary according to age or sex. AIM2 expression in CD4+ Trm cells was significantly lower in patients with ACLE (6.38 ± 5.22) than localized DLE (179.41 ± 160.98, P < 0.0001) and SCLE (63.43 ± 62.27, P < 0.05). In an overall comparison of ACLE with localized DLE and SCLE, the receiver operating characteristic curve for AIM2 expression in CD4+ Trm cells had a sensitivity of 100.00% and a specificity of 82.86% at a cutoff value of 18.26. In a comparison of ACLE with localized DLE, the sensitivity was 89.47%, and the specificity was 100.00% at a cutoff value of 12.26. In a comparison of ACLE with SCLE, the sensitivity was 100.00%, and the specificity was 75.00% at a cutoff value of 18.26. CONCLUSIONS: The number of CD4+ Trm cells is increased in lesions of SCLE and localized DLE compared to ACLE, suggesting that CD4+ Trm cells may have a more crucial role in persistent lesions of SCLE and localized DLE. In addition, AIM2 expression in CD4+ Trm cells discriminates patients with ACLE from those with localized DLE and SCLE.

The IL-21-TET2-AIM2-c-MAF pathway drives the T follicular helper cell response in lupus-like disease.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that involves T follicular helper (TFH ) cell-mediated humoral immune responses. Absent in melanoma 2 (human AIM2 and murine Aim2) is a well-known component of the inflammasome in the innate immune system. Surprisingly, we observed that in SLE patients, upregulated levels of AIM2 expression were found in peripheral blood and skin lesions, with the highest levels detected in TFH -like cells. In the CD4cre Aim2fl/fl conditional knockout mice, a markedly reduced TFH cell response was observed, with significantly lower levels of serum autoantibodies and proteinuria, as well as profoundly reduced renal IgG deposition in pristane-induced lupus mice. Mechanistically, IL-21 was found to recruit hydroxymethyltransferase ten-eleven translocation 2 (TET2) to the AIM2 promoter, resulting in DNA demethylation and increased transcription of AIM2. In addition, AIM2 could regulate c-MAF expression to enhance IL-21 production, which consequently promoted TFH cell differentiation. Our results have identified a role of AIM2 in promoting the TFH cell response and further revealed that the IL-21-TET2-AIM2-c-MAF signalling pathway is dysregulated in lupus pathogenesis, which provides a potential therapeutic target for SLE.

Emerging Role of Exosomal-Derived Long Noncoding RNAs in Human PDAC.

Background: The incidence and mortality of pancreatic ductal adenocarcinoma (PDAC) are increasing recently. Most patients with PDAC are diagnosed at advanced stage because of the high invasiveness of cancer cells and the lack of typical early symptoms. Therefore, early diagnosis of PDAC is very important to improve the prognosis. Exosomes play crucial role in intercellular communication and deliver the contents to recipient cells to regulate their biological behaviors. Recent evidence suggests emerging role of exosomes in the carcinogenesis of a variety of cancers including PDAC. Long noncoding RNAs (LncRNAs) have been reported to be involved in the development of PDAC. It has been proved that LncRNAs have the potential to be biomarkers and therapeutic targets for PDAC. Moreover, increasing number of studies focus on the role of exosomal LncRNAs in PDAC. Summary: In this review, we summarize the current status on our understanding of the role of exosomal-derived LncRNAs in the progression and metastasis of PDAC. Key Messages: We focus on challenges in the potential of exosomal-derived LncRNAs as novel diagnostic and prognostic markers and therapeutic targets of PDAC. In addition, we provide an overview about the demonstrated important role of exosomal LncRNAs in the progression of PDAC.

MicroRNAs as potential therapeutic targets for pancreatic cancer.

ABSTRACT: Pancreatic cancer is one of the most aggressive malignancies. The poor prognosis of pancreatic cancer patients is mainly attributed to low diagnostic rate at the early stage, highly aggressive nature coupled with the inadequate efficacy of current chemotherapeutic regimens. Novel therapeutic strategies are urgently needed for pancreatic cancer. MicroRNAs (miRNAs) play an important regulatory role in key processes of cancer development. The aberrant expression of miRNAs is often involved in the initiation, progression, and metastasis of pancreatic cancer. The discovery of tumor suppressor miRNAs provides prospects for the development of a novel treatment strategy for pancreatic cancer. We reviewed recent progress on the understanding of the role of miRNAs in pancreatic cancer, highlighted the efficient application of miRNAs-based therapies for pancreatic cancer in animal models and clinical trials, and proposed future prospects. This review focuses on the promise of integrating miRNAs into the treatment of pancreatic cancer and provides guidance for the development of precision medicine for pancreatic cancer.

Evaluating the efficacy and safety of electro-acupuncture in patients with antipsychotic-related constipation: protocol for a randomized controlled trial.

BACKGROUND: Constipation is known as a common adverse effect of antipsychotics. Advice for its management remains inadequate. This study is designed to investigate the efficacy and safety of electro-acupuncture (EA) for antipsychotic-related constipation. METHODS: This is a single-centric, parallel-group, randomized controlled trial with blinded participants, outcome assessor, and statistician. One hundred twelve participants will be randomly assigned into the EA group or sham acupuncture (SA) group in a 1:1 ratio. The study will last for 22 weeks for each participant, including a 2-week baseline assessment period, an 8-week treatment period, and a follow-up for 12 weeks. The primary outcome is the change of mean weekly complete spontaneous bowel movements (CSBMs) during weeks 1 to 8 from baseline. Secondary outcomes include the change from baseline of mean weekly CSBMs during the follow-up period, mean weekly spontaneous bowel movements (SBMs), overall CSBM response rate, scores on Bristol Stool Form Scale (BSFS), straining level, Patient Assessment of Constipation Symptoms (PAC-SYM), Patient Assessment of Constipation Quality of life questionnaire (PAC-QOL), and Brief Psychiatric Rating Scale (BPRS). Adverse events and medicine use will be recorded as well. DISCUSSION: The study is designed based on a rigorous methodology to evaluate the efficacy and safety of EA for antipsychotic-related constipation. The finding will be published in peer-reviewed journals as reliable evidence. TRIAL REGISTRATION: ClinicalTrials.gov ChiCTR2000032582. Registered May 3, 2020, with the Chinese Clinical Trial Registry.