第8卷，第3期

Sex hormone-binding globulin (SHBG), a crucial modulator of sex steroids in human blood, regulates androgen bioavailability and homeostasis. When androgen or AR signaling is known to be involved in the hepatocellular carcinoma (HCC) and SHBG plays an integral role in regulating the levels of bioavailable androgens, the concern whether SHBG might influence HCC onset or progression by modulating androgen action remains open. Our study aims to investigate the role of SHBG in HCC progression in contexts of androgen regulation and steroid independence.

1192

Mucoepidermoid carcinoma (MEC) is a common malignancy of the salivary glands, which account for approximately 30% of all malignant salivary gland neoplasms that originate in both the major and minor glands. But it is relatively rare at other organs, extremely rare in the hepatobiliary system. To the best of our knowledge, since primary MEC of the liver was first reported in 1971, no more than 20 cases have been reported worldwide. The cellular morphology of MEC can be easily misdiagnosed as adenosquamous carcinoma (ASC). In view of the poor prognosis of MEC, we herein report the morphological, histochemical, immunohistochemical, gene sequencing results and ultrastructural features, which distinguished from ASC through a misdiagnosed case.

1229

Kidney disease has become a global public health problem affecting over 750 million people worldwide and imposing a heavy economic burden on patients. The complex architecture of the human kidney makes it very difficult to study the pathophysiology of renal diseases in vitro and to develop effective therapeutic options for patients. Even though cell lines and animal models have enriched our understanding, they fail to recapitulate key aspects of human kidney development and renal disease at cellular and functional levels. Organoids can be derived from either pluripotent stem cells or adult stem cells by strictly regulating key signalling pathways. Today, these self-differentiated organoids represent a promising technology to further understand the human kidney, one of the most complex organs, in an unprecedented way. The newly established protocols improved by organ-on-chip and coculture with immune cells will push kidney organoids towards the next generation. Herein, we focus on recent achievements in the application of kidney organoids in disease modelling, nephrotoxic testing, precision medicine, biobanking, and regenerative therapy, followed by discussions of novel strategies to improve their utility for biomedical research. The applications we discuss may help to provide new ideas in clinical fields.

1185

Basement membrane proteins are known to guide cell structures, differentiation, and tissue repair. Although there is a wealth of knowledge on the functions of laminins, perlecan, and type IV collagen in maintaining tissue homeostasis, not much is known about nidogen. As a key molecule in the basement membrane, nidogen contributes to the formation of a delicate microenvironment that proves necessary for stem cell lineage-specific differentiation. In this review, the expression of nidogen is delineated at both cellular and tissue levels from embryonic to adult stages of development; the effect of nidogens is also summarized in the context of musculoskeletal development and regeneration, including but not limited to adipogenesis, angiogenesis, chondrogenesis, myogenesis, and neurogenesis. Furthermore, potential mechanisms underlying the role of nidogens in stem cell-based tissue regeneration are also discussed. This concise review is expected to facilitate our existing understanding and utilization of nidogen in tissue engineering and regeneration.

1240

Stress granules are non-membranous cytoplasmic foci induced by various stress conditions. It is a protective strategy used by cells to suppress overall translation during stress. In cancer cells, it was thought that the formation of stress granules could protect them from apoptosis and induces resistance towards anti-cancer drugs or radiation treatment which makes the stress granules a potential target for cancer treatment. However, most of our understanding of stress granules are still in the stage of molecular and cell biology, and a transitional gap for its actual effect on clinical settings remains. In this review, we summarize the mechanism and effect of stress granules formation in cancer and try to illuminate its potential applications in cancer therapy, using breast cancer as an example.

1286

Ischemic stroke resulting from atherosclerosis (particularly in the carotid artery) is one of the major subtypes of stroke and has a high incidence of death. Disordered lipid homeostasis, lipid deposition, local macrophage infiltration, smooth muscle cell proliferation, and plaque rupture are the main pathological processes of atherosclerotic ischemic stroke. Hepatocytes, macrophages, endothelial cells and vascular smooth muscle cells are the main cell types participating in these processes. By inhibiting the expression of the target genes in these cells, microRNAs play a key role in regulating lipid disorders and atherosclerotic ischemic stroke. In this article, we listed the microRNAs implicated in the pathology of atherosclerotic ischemic stroke and aimed to explain their pro-or antiatherosclerotic roles. Our article provides an update on the potential diagnostic use of miRNAs for detecting growing plaques and impending clinical events. Finally, we provide a perspective on the therapeutic use of local microRNA delivery and discuss the challenges for this potential therapy.

1223

Glioblastoma (GBM, WHO grade IV glioma) is the most common and lethal malignant brain tumor in adults with a dismal prognosis. The extracellular matrix (ECM) supports GBM progression by promoting tumor cell proliferation, migration, and immune escape. Uridine diphosphate (UDP) -glucose 6-dehydrogenase (UGDH) is the rate-limiting enzyme that catalyzes the biosynthesis of glycosaminoglycans that are the principal component of the CNS ECM. We investigated how targeting UGDH in GBM influences the GBM immune microenvironment, including tumor-associated microglia/macrophages (TAMs) and T cells. TAMs are the main immune effector cells in GBM and can directly target tumor cells if properly activated. In cocultures of GBM cells and human primary macrophages, UGDH knockdown in GBM cells promoted macrophage phagocytosis and M1-like polarization. In orthotropic human GBM xenografts and syngeneic mouse glioma models, targeting UGDH decreased ECM deposition, increased TAM phagocytosis marker expression, reduced M2-like TAMs and inhibited tumor growth. UGDH knockdown in GBM cells also promoted cytotoxic T cell infiltration and activation in orthotopic syngeneic mouse glioma models. The potent and in-human-use small molecule GAG synthesis inhibitor 4-methylumbelliferone (4-MU) was found to inhibit GBM cell proliferation and migration in vitro, mimic the macrophage and T-cell responses to UGDH knockdown in vitro and in vivo and inhibit growth of orthotopic murine GBM. Our study shows that UGDH supports GBM growth through multiple mechanisms and supports the development of ECM-based therapeutic strategies to simultaneously target tumor cells and their microenvironment.

1165

Body height, body mass index, hip and waist circumference are important risk factors or outcome variables in clinical and epidemiological research with complex underlying genetics. However, these classical anthropometric traits represent only a very limited view on the human body and other traits with potentially higher functional specificity are not yet studied to a larger extent. Participants of LIFE-Adult were assessed by three-dimensional body scanner VITUS XXL determining 99 high-quality anthropometric traits in parallel. Genotyping was performed by Axiom Genome-Wide CEU 1 Array Plate microarray technology and imputation was done using 1000 Genomes phase 3 reference panel. Combined phenotype and genetic information are available for a total of 7, 562 participants. Largest heritabilities were estimated for height traits (maximum heritability with h² = 44% for neck height) and 61 traits achieved values larger than 20%. By genome-wide analyses, we identified 16 loci associated with at least one of the 99 traits. Ten of these loci were not described for association with classical anthropometric traits so far. The strongest novel association was observed for 7p14.3 (rs11979006, P = 2.12-10^-9) for the trait Back Width with ZNRF2 as the most plausible candidate gene. Loci established for association with classical anthropometric traits were subjected to anthropometric phenome-wide association analysis. From the reported 709 loci, 211 are coassociated with body scanner traits (enrichment: OR = 1.96, P = 1.08-10^-61). We conclude that genetics of 3D laser-based anthropometry is promising to identify novel loci and to improve the functional understanding of established ones.

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