MicroRNA-125a-3p Modulate Amyloid ß-Protein through the MAPK Pathway in Alzheimer's Disease.

BACKGROUND: MicroRNA (miR)-125a-3p is reported to play an important role in some central nervous system diseases, such as Alzheimer's disease (AD). However, a study has not been conducted on the mechanism of miR-125a-3p in the pathological process of AD. METHODS: First, we assessed the expression of miR-125a-3p in AD cohort. Subsequently, we altered the expressions of miR-125a-3p to assess its role in cell viability, cell apoptosis, amyloid-ß (Aß) metabolism, and synaptic activity. Finally, we identified its potential mechanism underlying AD pathology. RESULTS: This study unveiled the potential function of miR-125a-3p through modulating amyloid precursor protein processing. Additionally, miR-125a-3p influenced cell survival and activated synaptic expression through the modulation of Aß metabolism in the mitogen-activated protein kinase (MAPK) pathway via fibroblast growth factor receptor 2. CONCLUSION: Our study indicates that targeting miR-125a-3p may be an applicable therapy for AD in the future. However, more in vitro and in vivo studies with more samples are needed to confirm these results.

A Thompson Sampling Algorithm With Logarithmic Regret for Unimodal Gaussian Bandit.

In this article, we propose a Thompson sampling algorithm with Gaussian prior for unimodal bandit under Gaussian reward setting, where the expected reward is unimodal over the partially ordered arms. To exploit the unimodal structure better, at each step, instead of exploration from the entire decision space, the proposed algorithm makes decisions according to posterior distribution only in the arm's neighborhood with the highest empirical mean estimate. We theoretically prove that the asymptotic regret of our algorithm reaches O(logT) , i.e., it shares the same regret order with asymptotic optimal algorithms, which is comparable to extensive existing state-of-the-art unimodal multiarm bandit (U-MAB) algorithms. Finally, we use extensive experiments to demonstrate the effectiveness of the proposed algorithm on both synthetic datasets and real-world applications.

Noah: Reinforcement-Learning-Based Rate Limiter for Microservices in Large-Scale E-Commerce Services.

Modern large-scale online service providers typically deploy microservices into containers to achieve flexible service management. One critical problem in such container-based microservice architectures is to control the arrival rate of requests in the containers to avoid containers from being overloaded. In this article, we present our experience of rate limit for the containers in Alibaba, one of the largest e-commerce services in the world. Given the highly diverse characteristics of containers in Alibaba, we point out that the existing rate limit mechanisms cannot meet our demand. Thus, we design Noah, a dynamic rate limiter that can automatically adapt to the specific characteristic of each container without human efforts. The key idea of Noah is to use deep reinforcement learning (DRL) that automatically infers the most suitable configuration for each container. To fully embrace the advantages of DRL in our context, Noah addresses two technical challenges. First, Noah uses a lightweight system monitoring mechanism to collect container status. In this way, it minimizes the monitoring overhead while ensuring a timely reaction to system load changes. Second, Noah injects synthetic extreme data when training its models. Thus, its model gains knowledge on unseen special events and hence remains highly available in extreme scenarios. To guarantee model convergence with the injected training data, Noah adopts task-specific curriculum learning to train the model from normal data to extreme data gradually. Noah has been deployed in the production of Alibaba for two years, serving more than 50000 containers and around 300 types of microservice applications. Experimental results show that Noah can well adapt to three common scenarios in the production environment. It effectively achieves better system availability and shorter request response time compared with four state-of-the-art rate limiters.

Radiotherapy plus camrelizumab and irinotecan for oligometastatic esophageal squamous cell carcinoma patients after first-line immunotherapy plus chemotherapy failure: An open-label, single-arm, phase II trial.

BACKGROUND AND PURPOSE: Immunotherapy has revolutionized the treatment of advanced and metastatic esophageal squamous cell carcinoma (ESCC), but most patients eventually developed disease progression. Immuno-resistance is becoming an unavoidable clinical problem. Oligometastasis is a limited-metastatic state, and patients at this stage should be evaluated for the addition of metastasis-directed local intervention, which may be associated with improved prognosis. As an immunomodulator, radiotherapy may exhibit synergistic effect when added to immunotherapy. This study assessed the efficacy and safety of low-dose radiotherapy plus immunotherapy and second-line chemotherapy in oligometastatic ESCC. MATERIALS AND METHODS: In this phase II trial (ChiCTR2000040533), oligometastatic ESCC patients after first-line immunotherapy plus chemotherapy failure were treated with low dose radiotherapy plus camrelizumab and second-line irinotecan chemotherapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and safety. Abscopal response rate (ARR) and abscopal control rate (ACR) were also been explored. RESULTS: Between November 19, 2018 and March 17, 2021, 49 patients were enrolled. With a median follow-up of 12.8 months, median PFS and OS were 6.9 months (95%CI, 4.6-9.3) and 12.8 months (95%CI, 10.1-15.5), respectively. ORR was 40.8% (95%CI, 27.3-55.7). DCR was 75.5% (95%CI, 60.8-86.2). ARR was 34.7% (95%CI, 22.1-49.7). ACR was 69.4% (95%CI, 54.4-81.3). The most common adverse effects of any grade were myelosuppression, weight loss and fatigue. Grade 3 or 4 treatment-related adverse events occurred in 31 (63.3%) patients, with the most common being leukopenia (30.6%). No treatment-related deaths occurred. CONCLUSION: Low dose radiotherapy plus camrelizumab and irinotecan exhibited survival benefit with manageable safety for oligometastatic ESCC patients after first-line immunotherapy plus chemotherapy failure. It deserves to be validated in a larger trial.

Metallomic profiling and natural copper isotopic signatures of childhood autism in serum and red blood cells.

Excessive exposure to metals directly threatens human health, including neurodeve lopment. Autism spectrum disorder (ASD) is a neurodevelopmental disorder, leaving great harms to children themselves, their families, and even society. In view of this, it is critical to develop reliable biomarkers for ASD in early childhood. Here we used inductively coupled plasma mass spectrometry (ICP-MS) to identify the abnormalities in ASD-associated metal elements in children blood. Multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS) was applied to detect isotopic differences in copper (Cu) for further assessment on account of its core role in the brain. We also developed a machine learning classification method for unknown samples based on a support vector machine (SVM) algorithm. The results indicated significant differences in the blood metallome (chromium (Cr), manganese (Mn), cobalt (Co), magnesium (Mg), and arsenic (As)) between cases and controls, and a significantly lower Zn/Cu ratio was observed in the ASD cases. Interestingly, we found a strong association of serum copper isotopic composition (δ65Cu) with autistic serum. SVM was successfully applied to discriminate cases and controls based on the two-dimensional Cu signatures (Cu concentration and δ65Cu) with a high accuracy (94.4%). Overall, our findings revealed a new biomarker for potential early diagnosis and screening of ASD, and the significant alterations in the blood metallome also helped to understand the potential pathogenesis of ASD in terms of metallomics.

CircleBase: an integrated resource and analysis platform for human eccDNAs.

Rapid advances in high-throughput sequencing technologies have led to the discovery of thousands of extrachromosomal circular DNAs (eccDNAs) in the human genome. Loss-of-function experiments are difficult to conduct on circular and linear chromosomes, as they usually overlap. Hence, it is challenging to interpret the molecular functions of eccDNAs. Here, we present CircleBase (http://circlebase.maolab.org), an integrated resource and analysis platform used to curate and interpret eccDNAs in multiple cell types. CircleBase identifies putative functional eccDNAs by incorporating sequencing datasets, computational predictions, and manual annotations. It classifies them into six sections including targeting genes, epigenetic regulations, regulatory elements, chromatin accessibility, chromatin interactions, and genetic variants. The eccDNA targeting and regulatory networks are displayed by informative visualization tools and then prioritized. Functional enrichment analyses revealed that the top-ranked cancer cell eccDNAs were enriched in oncogenic pathways such as the Ras and PI3K-Akt signaling pathways. In contrast, eccDNAs from healthy individuals were not significantly enriched. CircleBase provides a user-friendly interface for searching, browsing, and analyzing eccDNAs in various cell/tissue types. Thus, it is useful to screen for potential functional eccDNAs and interpret their molecular mechanisms in human cancers and other diseases.

Targeting cancer stem cells via integrin ß4.

Integrins mediate cell-cell interactions and communication with the extracellular matrix (ECM). These transmembrane protein receptors allow binding between a cell and its surroundings, initiating a breadth of intracellular signaling resulting in proliferation, differentiation, survival, or migration. Such responses have made integrins an attractive target for cancer therapy. Self-renewing and highly tumorigenic cancer stem cells (CSCs) are most resistant to traditional radiation treatment and chemotherapy, and therefore may contribute directly to the metastasis and relapse of the disease. In both the 4T1 mouse metastatic mammary tumor model and SCC7 head and neck squamous cell carcinoma model, integrin ß4 (ITGB4) was expressed on ALDHhigh 4T1 and SCC7 CSCs. Using two immunological approaches, we targeted ITGB4 through 1) ITGB4 protein-pulsed dendritic cell (ITGB4-DC) vaccination or 2) via anti-CD3/anit-ITGB4 bispecific antibody (ITGB4 BiAb)-armed T cell adoptive transfer. These two therapies reduced ITGB4-expressing CSCs and inhibited local tumor growth and lung metastasis through ITGB4 specific cellular and humoral immune responses. Additionally, the combination of anti-PD-L1 immunotherapy with our two ITGB4-targeted approaches significantly improved treatment efficacy. We also found increased concentrations of serum IFN-γ and IL-6 in the 4T1 and SCC7 models which may help define future directions of this ITGB4-targeted study. Together, these results emphasize ITGB4 as a practical CSC immunological target with possible therapeutic benefits across tumor types with high ITGB4 expression.

Explore the role of CR1 genetic variants in late-onset Alzheimer's disease susceptibility.

BACKGROUND: Complement component (3b/4b) receptor 1 (CR1) is an interesting candidate gene which has a close connection with Alzheimer's disease, and its polymorphisms have been reported to link to the late-onset Alzheimer's disease (LOAD) susceptibility. However, the findings of these related studies are inconsistent. Objective To explore the effect of CR1 genetic variants in LOAD susceptibility. MethodsWe searched relevant studies for the period up to 1 November 2020. And odds ratios (ORs) and their 95% confidence intervals (CIs) were utilized to assess the strength of the association. In addition, we carried out a case-control association study to assess their genetic association. RESULTS: Finally, a total of 30 articles with 30108 LOAD cases and 37895 controls were included. Significant allele frequency between LOAD patients and controls was observed in rs3818361 and rs6656401 (rs3818361, T vs. C: OR,1.18; 95% CI, 1.13-1.23; rs6656401, A vs. G: OR, 1.23; 95% CI, 1.10-1.36). Moreover, these results remain significant in subgroup of rs3818361 in Asia or America (OR,1.26; 95% CI,1.06-1.45; OR, 1.18; 95% CI, 1.13-1.24, respectively) and rs6656401 in Europe (OR = 1.26; 95% CI, 1.09-1.42). In addition, the two single nucleotide polymorphisms were proved to significantly increase LOAD risk in the overall population under the dominant model (OR = 1.12; 95% CI, 1.02-1.21; OR = 1.18, 95% CI, 1.15-1.22, respectively). Our case-control study showed that the distribution of rs6656401 genotype was significant (P = 0.000; OR, 6.889; 95% CI, 2.709-17.520), suggesting the A allele of rs6656401 is the risk allele. CONCLUSION: These available data indicate that rs6656401 in CR1 is significant to increase LOAD risk.

Transcriptomic signatures and repurposing drugs for COVID-19 patients: findings of bioinformatics analyses.

The novel coronavirus SARS-CoV-2 is damaging the world's social and economic fabrics seriously. Effective drugs are urgently needed to decrease the high mortality rate of COVID-19 patients. Unfortunately, effective antiviral drugs or vaccines are currently unavailable. Herein, we systematically evaluated the effect of SARS-CoV-2 on gene expression of both lung tissue and blood from COVID-19 patients using transcriptome profiling. Differential gene expression analysis revealed potential core mechanism of COVID-19-induced pneumonia in which IFN-α, IFN-ß, IFN-γ, TNF and IL6 triggered cytokine storm mediated by neutrophil, macrophage, B and DC cells. Weighted gene correlation network analysis identified two gene modules that are highly correlated with clinical traits of COVID-19 patients, and confirmed that over-activation of immune system-mediated cytokine release syndrome is the underlying pathogenic mechanism for acute phase of COVID-19 infection. It suggested that anti-inflammatory therapies may be promising regimens for COVID-19 patients. Furthermore, drug repurposing analysis of thousands of drugs revealed that TNFα inhibitor etanercept and γ-aminobutyric acid-B receptor (GABABR) agonist baclofen showed most significant reversal power to COVID-19 gene signature, so we are highly optimistic about their clinical use for COVID-19 treatment. In addition, our results suggested that adalimumab, tocilizumab, rituximab and glucocorticoids may also have beneficial effects in restoring normal transcriptome, but not chloroquine, hydroxychloroquine or interferons. Controlled clinical trials of these candidate drugs are needed in search of effective COVID-19 treatment in current crisis.

OncoVar: an integrated database and analysis platform for oncogenic driver variants in cancers.

The prevalence of neutral mutations in cancer cell population impedes the distinguishing of cancer-causing driver mutations from passenger mutations. To systematically prioritize the oncogenic ability of somatic mutations and cancer genes, we constructed a useful platform, OncoVar (https://oncovar.org/), which employed published bioinformatics algorithms and incorporated known driver events to identify driver mutations and driver genes. We identified 20 162 cancer driver mutations, 814 driver genes and 2360 pathogenic pathways with high-confidence by reanalyzing 10 769 exomes from 33 cancer types in The Cancer Genome Atlas (TCGA) and 1942 genomes from 18 cancer types in International Cancer Genome Consortium (ICGC). OncoVar provides four points of view, 'Mutation', 'Gene', 'Pathway' and 'Cancer', to help researchers to visualize the relationships between cancers and driver variants. Importantly, identification of actionable driver alterations provides promising druggable targets and repurposing opportunities of combinational therapies. OncoVar provides a user-friendly interface for browsing, searching and downloading somatic driver mutations, driver genes and pathogenic pathways in various cancer types. This platform will facilitate the identification of cancer drivers across individual cancer cohorts and helps to rank mutations or genes for better decision-making among clinical oncologists, cancer researchers and the broad scientific community interested in cancer precision medicine.

Clinical considerations for the management of cancer patients in the mitigation stage of the COVID-19 pandemic.

The ongoing outbreak of the coronavirus disease 2019 (COVID-19) has become an unprecedented threat to public health around the world. The crisis has also brought great challenges to the routine diagnosis and treatment of cancer patients, especially given the urgency and continuity of cancer care. Cancer patients need to be more prudently and individually managed to combat COVID-19. At present, the COVID-19 epidemic in some countries has moved from the outbreak phase to the remission phase. How to preserve high-quality anti-tumor therapy for cancer patients while maintaining strict prevention and control of COVID-19 is a matter of concern. Here, we summarized essential data about COVID-19 and cancer and provided the clinical recommendations for the management of cancer patients during the COVID-19 pandemic based on our practical experience and relevant literatures.

Clinical features and short-term outcomes of elderly patients with COVID-19.

BACKGROUND: The outbreak of Coronavirus Disease 2019 (COVID-19) has become a global public health emergency. METHODS: 204 elderly patients (≥60 years old) diagnosed with COVID-19 in Renmin Hospital of Wuhan University from January 31st to February 20th, 2020 were included in this study. Clinical endpoint was in-hospital death. RESULTS: Of the 204 patients, hypertension, diabetes, cardiovascular disease, and chronic obstructive pulmonary disease (COPD) were the most common coexisting conditions. 76 patients died in the hospital. Multivariate analysis showed that dyspnea (hazards ratio (HR) 2.2, 95% confidence interval (CI) 1.414-3.517; p < 0.001), older age (HR 1.1, 95% CI 1.070-1.123; p < 0.001), neutrophilia (HR 4.4, 95% CI 1.310-15.061; p = 0.017) and elevated ultrasensitive cardiac troponin I (HR 3.9, 95% CI 1.471-10.433; p = 0.006) were independently associated with death. CONCLUSION: Although so far the overall mortality of COVID-19 is relatively low, the mortality of elderly patients is much higher. Early diagnosis and supportive care are of great importance for the elderly patients of COVID-19.

Identification of Potential Gene Signatures Related to Sleep Deprivation.

This study aimed to identify possible therapeutic targets involved in sleep deprivation (SD) risks. GSE77393 data set was acquired from Gene Expression Omnibus database. Functional analysis and protein-protein interaction (PPI) analysis were used to extract the differentially expressed genes (DEGs) between two SD samples and control samples. Moreover, submodule network with the same function was further extracted and the functional enrichment analysis of corresponding genes was carried out. Afterward, the transcriptional regulation analysis and drug-gene interaction were also carried out to identify the essential genes associated with SD susceptibility. Totally, 121 DEGs, including 90 consistently upregulated DEGs and 31 downregulated DEGs, were screened and the results of functional analysis indicated that upregulated genes were related to learning or memory and response to drug, whereas downregulated DEGs were mainly responsible for response to UV and cell differentiation. Moreover, PPI network and submodule analysis revealed that many key genes (FOS and BDNF) were hub genes and the KEGG enrichment analysis found that these genes such as FOS and BDNF were considerably enriched in pathways such as MAPK signaling pathway, HTLV-I infection, and Hepatitis B. In addition, two genes (FOS and BDNF) with a higher degree were found to be key regulators and play important roles in the transcriptional regulator network and drug-gene interactions, suggesting that these two genes were associated with SD development. FOS and BDNF might be served as the potential targets for SD treatment.

Integrin ß4-Targeted Cancer Immunotherapies Inhibit Tumor Growth and Decrease Metastasis.

Integrin ß4 (ITGB4) has been shown to play an important role in the regulation of cancer stem cells (CSC). Immune targeting of ITGB4 represents a novel approach to target this cell population, with potential clinical benefit. We developed two immunologic strategies to target ITGB4: ITGB4 protein-pulsed dendritic cells (ITGB4-DC) for vaccination and adoptive transfer of anti-CD3/anti-ITGB4 bispecific antibody (ITGB4 BiAb)-armed tumor-draining lymph node T cells. Two immunocompetent mouse models were utilized to assess the efficacy of these immunotherapies in targeting both CSCs and bulk tumor populations: 4T1 mammary tumors and SCC7 head and neck squamous carcinoma cell line. Immunologic targeting of ITGB4 utilizing either ITGB4-DC or ITGB4 BiAb-T cells significantly inhibited local tumor growth and metastases in both the 4T1 and SCC7 tumor models. Furthermore, the efficacy of both of these ITGB4-targeted immunotherapies was significantly enhanced by the addition of anti-PD-L1. Both ITGB4-targeted immunotherapies induced endogenous T-cell cytotoxicity directed at CSCs as well as non-CSCs, which expressed ITGB4, and immune plasma-mediated killing of CSCs. As a result, ITGB4-targeted immunotherapy reduced not only the number of ITGB4high CSCs in residual 4T1 and SCC7 tumors but also their tumor-initiating capacity in secondary mouse implants. In addition, treated mice demonstrated no apparent toxicity. The specificity of these treatments was demonstrated by the lack of effects observed using ITGB4 knockout 4T1 or ITGB4-negative CT26 colon carcinoma cells. Because ITGB4 is expressed by CSCs across a variety of tumor types, these results support immunologic targeting of ITGB4 as a promising therapeutic strategy.Significance: This study identifies a novel mechanism of resistance to anti-PD-1/PD-L1 immunotherapy mediated by HPV E5, which can be exploited using the HPV E5 inhibitor rimantadine to improve outcomes for head and neck cancer patients.

OncoBase: a platform for decoding regulatory somatic mutations in human cancers.

Whole-exome and whole-genome sequencing have revealed millions of somatic mutations associated with different human cancers, and the vast majority of them are located outside of coding sequences, making it challenging to directly interpret their functional effects. With the rapid advances in high-throughput sequencing technologies, genome-scale long-range chromatin interactions were detected, and distal target genes of regulatory elements were determined using three-dimensional (3D) chromatin looping. Herein, we present OncoBase (http://www.oncobase.biols.ac.cn/), an integrated database for annotating 81 385 242 somatic mutations in 68 cancer types from more than 120 cancer projects by exploring their roles in distal interactions between target genes and regulatory elements. OncoBase integrates local chromatin signatures, 3D chromatin interactions in different cell types and reconstruction of enhancer-target networks using state-of-the-art algorithms. It employs informative visualization tools to display the integrated local and 3D chromatin signatures and effects of somatic mutations on regulatory elements. Enhancer-promoter interactions estimated from chromatin interactions are integrated into a network diffusion system that quantitatively prioritizes somatic mutations and target genes from a large pool. Thus, OncoBase is a useful resource for the functional annotation of regulatory noncoding regions and systematically benchmarking the regulatory effects of embedded noncoding somatic mutations in human carcinogenesis.

Expression and clinical significance of Semaphorin4D in non-small cell lung cancer and its impact on malignant behaviors of A549 lung cancer cells.

This study aimed to explore Semaphrin4D (Sema4D) expression and clinical significance in non-small cell lung cancer (NSCLC), and to define the roles and mechanisms of Sema4D in regulating the malignant behaviors of A549 cells by small interfering RNA (siRNA). Firstly, immunohistochemistry revealed that Sema4D was more frequently expressed in NSCLC than in lung benign lesion (P<0.05) and its overexpression was associated with low differentiation (P<0.05), poor pTNM staging (P<0.05) and occurrence of lymph node (LN) metastasis (P<0.05). Endogenous Sema4D expression was suppressed by Sema4D siRNA in A549 cells overexpressing Sema4D. Protein levels of Sema4D, total Akt and p-Akt were examined by Western blotting. Cell proliferation, migration and invasion abilities were measured by MTT assay and Transwell assay respectively. Results showed that Sema4D siRNA significantly suppressed phosphorylation of AKT in A549 cells, but it did not alter total AKT expression. In addition, efficient down-regulation of SemaD significantly inhibit cell proliferation (P<0.05), migration (P<0.05) and invasion (P<0.05) in A549 cells. These findings suggest that Sema4D might serve as a reliable tool for early prediction of NSCLC poor prognosis. Sema4D could play an important role in promoting tumor proliferation, migration and metastasis in the NSCLC, by influencing the Akt protein phosphorylation. Inhibition of Sema4D may be a useful approach for the treatment of NSCLC.

Fibroblasts in omentum activated by tumor cells promote ovarian cancer growth, adhesion and invasiveness.

Omentum metastasis is a common occurrence in epithelial ovarian cancer (EOC), which is often accompanied by ascites that facilitates the spread of EOC cells. A subpopulation of fibroblasts-the cancer-associated fibroblasts (CAFs) are important promoters of tumor progression. We have shown previously that CAFs exist not only in omentum with EOC metastasis but also in omentum without metastasis. In the present study, using primary human fibroblasts isolated from normal omentum (NFs) and omentum with ovarian cancer metastasis (CAFs), we established in vitro coculture models and a 3D culture model mimicking human omentum structure for investigation of interactions between fibroblasts and cancer cells. We demonstrate that EOC cells activate NFs and promote their proliferation via transforming growth factor-ß1 (TGF-ß1) signaling, and the activated fibroblasts contribute to the invasion and adhesion of EOC cells. Moreover, EOC cells and NFs coculture led to overexpression of hepatocyte growth factor (HGF) and matrix metalloproteinase-2 (MMP-2) and adhesion and invasion of EOC cells could be partially suppressed by blocking the function of HGF or MMP-2. Additionally, mouse peritoneal dissemination models of EOC confirmed the activation of fibroblasts by cancer cells and the tumor growth- and metastasis-promoting effects of activated fibroblasts in vivo. Our findings indicate that activated fibroblasts in omentum form a congenial environment to promote EOC cells implantation. It is an intriguing concept that targeting the activation of omentum fibroblast through the inhibition of TGF-ß1 signaling can be used as a new therapeutic strategy against ovarian cancer omentum metastases, which needs further study.