Macrophage Proliferation Machinery Drives Immunosuppression and PDAC Progression (巨噬细胞增值机制抑制肿瘤免疫促进胰腺癌发展)

Tumor-associated macrophages (TAMs) are abundant in near all solid tumors and are involved in many aspects of cancer progression. The presence of TAMs is negative prognostic indicator in several cancer types including pancreatic cancer. Attempts to target this population by limiting their number in PDAC tumors have not achieved promising results, as compensatory resistance pathways have already been defined. The heterogeneity of TAMs puts another barrier into this targeting strategy, given macrophage subsets are important in maintaining tissue homeostasis and some in performing anti-tumor functions. Previous studies have shown that TAMs in PDAC tumors have dual origins – HSC-derived and embryonic-derived. Both subsets of TAMs expand during tumor development and potentially have distinct functions. However, the impact local proliferation might have on macrophage phenotype and cancer progression has not been demonstrated. Here, we utilized genetically engineered cancer models, single-cell RNA-sequencing data, and in vitro systems to show that proliferation of TAMs was driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. We further found that a negative regulator of cell-cycle machinery, p21, was also induced by CSF-1 signaling pathway. TAMs in human and mouse PDAC with high levels of p21 acquired a more inflammatory yet immunosuppressive phenotype. The p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo promoted tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression, also cause responsive to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell-cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy. 肿瘤相关的巨噬细胞 (TAM)广泛存在于几乎所有实体瘤中，并且参与癌症发生发展的许多方面。TAM的浸染和很多包括胰腺癌在内的病人存活率呈负相关。之前尝试通过抑制巨噬细胞存活信号通路减少其数量的研究并没有产生太多的临床效果，因为肿瘤会很快找到逃脱途径。巨噬细胞的异质性使得针对这个细胞类群为靶点的药物无法有效甄别和去除只是促进肿瘤生长的巨噬细胞子集。研究表明，巨噬细胞在胰腺中有两种起源，一种通过血液中的单核细胞，另外一种通过胚胎时期产生的存在于组织中的巨噬细胞的增值。这两种来源的巨噬细胞在胰腺瘤中都保持增值的能力。但是至今没有研究直接解答增值本身是否影响胰腺肿瘤中巨噬细胞的总数，以及胰腺癌的发展。这篇毕业论文作者通过新建立的小鼠模型，单细胞测序，体外细胞共培养等方式，发现肿瘤中成纤维细胞分泌的CSF1诱导巨噬细胞的增值，同时独立于巨噬细胞增值，上调细胞周期负调控因子，p21的表达。p21表达本身可以激活炎症信号以及免疫抑制信号通路。p21表达在小鼠模型中直接改变巨噬细胞表现型，同时促进胰腺癌肿瘤增长。更有趣的是，相同的p21诱导的炎症免疫抑制通路的激活增强了CD40激动剂和化疗药物连用的作用。综上所述，本文阐述了，基质或治疗诱导的细胞周期因子的表达可以调节巨噬细胞介导的免疫抑制和对先天免疫疗法的敏感性

Tetrakis[μ-3-(3-pyridyl)acrylato-κ2 O:O′]bis{(1,10-phenanthroline-κ2 N,N′)[3-(3-pyridyl)acrylato-κ2 O,O′]europium(III)} pentahydrate

The europiumIII ion in the title compound, [Eu2(C8H6NO2)6(C12H8N2)2]·5H2O, is coordinated by seven carboxyl­ate O atoms and two N atoms from one phenanthroline mol­ecule. The carboxyl­ate groups of 3-(3-pyrid­yl)acrylate link pairs of europium(III) ions, forming centrosymmetric dinuclear units, which further assemble into a sheet parallel to the (001) plane through hydrogen-bonding inter­actions involving the uncoordinated water mol­ecules. One water molecule is disordered

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International Conference on Information Systems 2011, ICIS 201131841-185

Pengaruh Implementasi Kebijakan Tambahan Penghasilan Terhadap Motivasi Kerja Pegawai Dinas Kesehatan Provinsi Sulawesi Tengah

This study was conducted to determine how much influence the implementation of additional policies on work motivation income civil servants in Central Sulawesi province. This study uses the theory of Van Meter and Van Horn with standard dimensions and policy objectives, resources, communication between the implementing agency, the implementing body characteristics, social, economic and political, disposition / attitude implementers. The method used in the study is survay analytic using cross sectional design of a study to study the dynamics of the correlation between risk factors by means of observation or data collection approach as well. The results showed that the magnitude of the effect of the implementation of additional policies on work motivation of employees earning the provincial health bureau in Central Sulawesi was the degree of correlation moderate to very low-level relations with the interval of the correlation coefficient between 0.172 up to 0.457

Post-translational modifications and immune responses in liver cancer

Post-translational modification (PTM) refers to the covalent attachment of functional groups to protein substrates, resulting in structural and functional changes. PTMs not only regulate the development and progression of liver cancer, but also play a crucial role in the immune response against cancer. Cancer immunity encompasses the combined efforts of innate and adaptive immune surveillance against tumor antigens, tumor cells, and tumorigenic microenvironments. Increasing evidence suggests that immunotherapies, which harness the immune system’s potential to combat cancer, can effectively improve cancer patient prognosis and prolong the survival. This review presents a comprehensive summary of the current understanding of key PTMs such as phosphorylation, ubiquitination, SUMOylation, and glycosylation in the context of immune cancer surveillance against liver cancer. Additionally, it highlights potential targets associated with these modifications to enhance the response to immunotherapies in the treatment of liver cancer

CTooth+: A Large-scale Dental Cone Beam Computed Tomography Dataset and Benchmark for Tooth Volume Segmentation

Accurate tooth volume segmentation is a prerequisite for computer-aided dental analysis. Deep learning-based tooth segmentation methods have achieved satisfying performances but require a large quantity of tooth data with ground truth. The dental data publicly available is limited meaning the existing methods can not be reproduced, evaluated and applied in clinical practice. In this paper, we establish a 3D dental CBCT dataset CTooth+, with 22 fully annotated volumes and 146 unlabeled volumes. We further evaluate several state-of-the-art tooth volume segmentation strategies based on fully-supervised learning, semi-supervised learning and active learning, and define the performance principles. This work provides a new benchmark for the tooth volume segmentation task, and the experiment can serve as the baseline for future AI-based dental imaging research and clinical application development

Mindfulness for mediating the relationship between self-control and alexithymia among Chinese medical students: A structural equation modeling analysis

BackgroundsMedical students are prone to experience alexithymia due to academic work overload, which could increase the prevalence of mental illness such as anxiety and depression. The purpose of our study was to estimate the levels of alexithymia and to explore the relationships between alexithymia, self-control, and mindfulness among medical students.Materials and methodsFrom March 18th, 2021 to April 9th, 2021, a cross-sectional study with stratified sampling was carried out in China Medical University, Liaoning Province, China. A total of 1,013 medical students participated in this study. The questionnaires pertaining to the Toronto Alexithymia Scale (TAS-26), the Five Facet Mindfulness Questionnaire (FFMQ), and the Self-control Scale (SCS) were used to assess the levels of alexithymia, mindfulness and self-control. We used Hierarchical Multiple Regression (HMR) and structural equation modeling to explore the mediating role of mindfulness between self-control and alexithymia.ResultsThe mean score of alexithymia in medical students was 69.39 ± 9.9. After controlling for confounders, males were more likely to experience alexithymia. Self-control, acting with awareness, describing, and observing in mindfulness were negatively associated with alexithymia (P < 0.01). Mindfulness mediated the relationship between self-control and alexithymia (a*b = −0.06, BCa 95% CI: −0.09 to −0.031, Percentile 95% CI: −0.089 to −0.031).ConclusionChinese medical students experienced high levels of alexithymia. Self-control could directly attenuate alexithymia for medical students and indirectly affect alexithymia through the mediating path of mindfulness. Initiatives for self-control ability enhancement should be provided to medical students to combat alexithymia. And interventions on mindfulness training should be developed to prevent from alexithymia and promote their mental health

Effects of extreme drought on plant nutrient uptake and resorption in rhizomatous vs bunch grass dominated grasslands

Both the dominance and the mass ratio hypotheses predict that plant internal nutrient cycling in ecosystems is determined by the dominant species within plant communities. We tested this hypothesis under conditions of extreme drought by assessing plant nutrient (N, P and K) uptake and resorption in response to experimentally imposed precipitation reductions in two semiarid grasslands of northern China. These two communities shared similar environmental conditions, but had different dominant species-one was dominated by a rhizomatous grass (Leymus chinensis) and the other by a bunchgrass (Stipa grandis). Results showed that responses of N to drought differed between the two communities with drought decreasing green leaf N concentration and resorption in the community dominated by the rhizomatous grass, but not in the bunchgrass-dominated community. In contrast, negative effects of drought on green leaf P and K concentrations and their resorption efficiencies were consistent across the two communities. Additionally, in each community, the effects of extreme drought on soil N, P and K supply did not change synchronously with that on green leaf N, P and K concentrations, and senesced leaf N, P and K concentrations showed no response to extreme drought. Consistent with the dominance/mass ratio hypothesis, our findings suggest that differences in dominant species and their growth form (i.e., rhizomatous vs bunch grass) play an important nutrient-specific role in mediating plant internal nutrient cycling across communities within a single region

Stromal and therapy-induced macrophage proliferation promotes PDAC progression and susceptibility to innate immunotherapy

Tumor-associated macrophages (TAMs) are abundant in pancreatic ductal adenocarcinomas (PDACs). While TAMs are known to proliferate in cancer tissues, the impact of this on macrophage phenotype and disease progression is poorly understood. We showed that in PDAC, proliferation of TAMs could be driven by colony stimulating factor-1 (CSF1) produced by cancer-associated fibroblasts. CSF1 induced high levels of p21 in macrophages, which regulated both TAM proliferation and phenotype. TAMs in human and mouse PDACs with high levels of p21 had more inflammatory and immunosuppressive phenotypes. p21 expression in TAMs was induced by both stromal interaction and/or chemotherapy treatment. Finally, by modeling p21 expression levels in TAMs, we found that p21-driven macrophage immunosuppression in vivo drove tumor progression. Serendipitously, the same p21-driven pathways that drive tumor progression also drove response to CD40 agonist. These data suggest that stromal or therapy-induced regulation of cell cycle machinery can regulate both macrophage-mediated immune suppression and susceptibility to innate immunotherapy