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- Fischer, C, et al.
(författare)
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A miR-327-FGF10-FGFR2-mediated autocrine signaling mechanism controls white fat browning
- 2017
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1, s. 2079-
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the molecular mechanisms regulating beige adipocyte formation may lead to the development of new therapies to combat obesity. Here, we report a miRNA-based autocrine regulatory pathway that controls differentiation of preadipocytes into beige adipocytes. We identify miR-327 as one of the most downregulated miRNAs targeting growth factors in the stromal-vascular fraction (SVF) under conditions that promote white adipose tissue (WAT) browning in mice. Gain- and loss-of-function experiments reveal that miR-327 targets FGF10 to prevent beige adipocyte differentiation. Pharmacological and physiological β-adrenergic stimulation upregulates FGF10 levels and promotes preadipocyte differentiation into beige adipocytes. In vivo local delivery of miR-327 to WATs significantly compromises the beige phenotype and thermogenesis. Contrarily, systemic inhibition of miR-327 in mice induces browning and increases whole-body metabolic rate under thermoneutral conditions. Our data provide mechanistic insight into an autocrine regulatory signaling loop that regulates beige adipocyte formation and suggests that the miR-327–FGF10–FGFR2 signaling axis may be a therapeutic targets for treatment of obesity and metabolic diseases.
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| 31. |
- Gao, R, et al.
(författare)
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Resetting histone modifications during human prenatal germline development
- 2023
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Ingår i: Cell discovery. - : Springer Science and Business Media LLC. - 2056-5968. ; 9:1, s. 14-
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Tidskriftsartikel (refereegranskat)abstract
- Histone modifications play critical roles in regulating gene expression and present dynamic changes during early embryo development. However, how they are reprogrammed during human prenatal germline development has not yet been elucidated. Here, we map the genome-wide profiles of three key histone modifications in human primordial germ cells (hPGCs) from weeks 8 to 23 of gestation for the first time by performing ULI-NChIP-seq. Notably, H3K4me3 exhibits a canonical promoter-enriched pattern, though with relatively lower enrichment, and is positively correlated with gene expression in globally hypomethylated hPGCs. In addition, H3K27me3 presents very low enrichment but plays an important role in not only dynamically governing specific bivalent promoters but also impeding complete X chromosome reactivation in female hPGCs. Given the activation effects of both global DNA demethylation and H3K4me3 signals, repressive H3K9me3 and H3K27me3 marks are jointly responsible for the paradoxical regulation of demethylation-resistant regions in hPGCs. Collectively, our results provide a unique roadmap of three core histone modifications during hPGC development, which helps to elucidate the architecture of germ cell reprogramming in an extremely hypomethylated DNA environment.
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| 33. |
- He, YQ, et al.
(författare)
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A polygenic risk score for nasopharyngeal carcinoma shows potential for risk stratification and personalized screening
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1, s. 1966-
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRS) have the potential to identify individuals at risk of diseases, optimizing treatment, and predicting survival outcomes. Here, we construct and validate a genome-wide association study (GWAS) derived PRS for nasopharyngeal carcinoma (NPC), using a multi-center study of six populations (6 059 NPC cases and 7 582 controls), and evaluate its utility in a nested case-control study. We show that the PRS enables effective identification of NPC high-risk individuals (AUC = 0.65) and improves the risk prediction with the PRS incremental deciles in each population (Ptrend ranging from 2.79 × 10−7 to 4.79 × 10−44). By incorporating the PRS into EBV-serology-based NPC screening, the test’s positive predictive value (PPV) is increased from an average of 4.84% to 8.38% and 11.91% in the top 10% and 5% PRS, respectively. In summary, the GWAS-derived PRS, together with the EBV test, significantly improves NPC risk stratification and informs personalized screening.
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| 35. |
- Hosaka, K, et al.
(författare)
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Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 3704-
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Tidskriftsartikel (refereegranskat)abstract
- FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2+ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2+ pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2+ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2+ breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers.
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| 36. |
- Hu, XH, et al.
(författare)
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Neogenin suppresses tumor progression and metastasis via inhibiting Merlin/YAP signaling
- 2023
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Ingår i: Cell death discovery. - : Springer Science and Business Media LLC. - 2058-7716. ; 9:1, s. 47-
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Tidskriftsartikel (refereegranskat)abstract
- From in situ growth to invasive dissemination is the most lethal attribute of various tumor types. This transition is majorly mediated by the dynamic interplay between two cancer hallmarks, EMT and cell cycle. In this study, we applied nonlinear association analysis in 33 cancer types and found that most signaling receptors simultaneously associating with EMT and cell cycle are potential tumor suppressors. Here we find that a top co-associated receptor, Neogenin (NEO1), inhibits colorectal cancer (CRC) and Glioma in situ growth and metastasis by forming a complex with Merlin (NF2), and subsequent simultaneous promoting the phosphorylation of YAP. Furthermore, Neogenin protein level is associated with good prognosis and correlates with Merlin status in CRC and Glioma. Collectively, our results define Neogenin as a tumor suppressor in CRC and Glioma that acts by restricting oncogenic signaling by the Merlin-YAP pathway, and suggest Neogenin as a candidate therapeutic agent for CRC and Glioma.
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| 42. |
- Li, SY, et al.
(författare)
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Incidental findings on brain MRI among Chinese at the age of 55-65 years: the Taizhou Imaging Study
- 2019
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 464-
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Tidskriftsartikel (refereegranskat)abstract
- Asymptomatic brain abnormalities are common incidental findings on brain MRI in the elderly population and can be regarded as imaging markers of early stroke and dementia. We initiated the Taizhou Imaging Study (TIS) to examine the prevalence and correlates of incidental findings using brain MRI among an elderly population residing in a rural area of China. A total of 562 individuals, at the age of 55 to 65 years, participated in the TIS study with a response rate of 90%. The prevalence of lacunes, white matter hyperintensity (WMH), cerebral microbleeds (CMB), perivascular space, and intracranial arterial stenosis was 26.69%, 10.68%, 18.51%, 27.76%, and 12.81%, respectively. Age and hypertension were the major correlates of these incidental findings. Per each year increase in age, the risks of WMH and CMB increased by 15% and 14%. Compared to individuals with normal blood pressure, individuals with hypertension had an increased risk of all incidental findings, with the adjusted odds ratios of 2.28 to 5.45. Correlations of age, gender and body mass index with brain gray matter fraction were also observed. The high prevalence of these findings indicates a need of preventative strategy to help prevent future stroke and dementia in this population.
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| 43. |
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| 44. |
- Liu, SW, et al.
(författare)
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Concealed conduction and dual pathway physiology of the atrioventricular node
- 2004
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Ingår i: Journal of Cardiovascular Electrophysiology. - : Wiley. - 1540-8167 .- 1045-3873. ; 15:2, s. 144-149
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Tidskriftsartikel (refereegranskat)abstract
- AV Nodal Duality and Concealment. Introduction: Both concealed conduction and dual pathway physiology are important electrophysiologic characteristics of the AV node. The interaction of AV nodal concealment and duality, however, is not clearly understood. Methods and Results: The properties of AV conduction curves in the presence and absence of a conditioning blocked impulse were prospectively studied during premature atrial stimulation in 20 patients with AV nodal reentrant tachycardia before and after slow pathway ablation and in 14 control patients. AV nodal duality in the control conduction curve in the absence of a conditioning impulse was observed in 19 (95%) of 20 patients with AV nodal reentrant tachycardia. However, AV nodal duality in the modulated conduction curve in the presence of a blocked impulse was only identified in 2 (10%) of 20 patients (2/20 vs 19/20, P < 0.0001). The modulated curve was characterized by a significantly longer AV nodal effective and functional refractory periods compared to the control curve (P < 0.0001) in both patients with and without AV nodal reentry and in AV nodal reentry patients after successful slow pathway ablation. The maximum AH interval (AH(max)) of the modulated curve was significantly shorter than the control curve in both patients with (217 +/- 74 ms vs 347 +/- 55 ms, P < 0.0001) and without AV nodal reentry (178 +/- 50 ms vs 214 +/- 54 ms, P = 0.02). AH(max) of the control curve was significantly longer in AV nodal reentry patients than in controls (P < 0.0001). AH(max) of the modulated curve, however, was not significantly different between the two groups. After slow pathway ablation, AHmax of the control curve was significantly reduced (347 +/- 55 ms vs 191 +/- 40 ms, P < 0.0001). Significant reduction in AH(max) of the modulated curve was not observed. Conclusion: An interaction of AV nodal concealed conduction and dual pathway physiology was demonstrated by our data. Slow pathway conduction of the AV node was prevented by the concealed beat in both patients with and without AV nodal reentry.
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| 45. |
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| 46. |
- Pelaz, B, et al.
(författare)
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Diverse Applications of Nanomedicine
- 2017
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Ingår i: ACS nano. - : American Chemical Society (ACS). - 1936-086X .- 1936-0851. ; 11:3, s. 2313-2381
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Tidskriftsartikel (refereegranskat)
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| 47. |
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| 48. |
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| 49. |
- Seki, T, et al.
(författare)
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Endothelial PDGF-CC regulates angiogenesis-dependent thermogenesis in beige fat
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 12152-
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Tidskriftsartikel (refereegranskat)abstract
- Cold- and β3-adrenoceptor agonist-induced sympathetic activation leads to angiogenesis and UCP1-dependent thermogenesis in mouse brown and white adipose tissues. Here we show that endothelial production of PDGF-CC during white adipose tissue (WAT) angiogenesis regulates WAT browning. We find that genetic deletion of endothelial VEGFR2, knockout of the Pdgf-c gene or pharmacological blockade of PDGFR-α impair the WAT-beige transition. We further show that PDGF-CC stimulation upregulates UCP1 expression and acquisition of a beige phenotype in differentiated mouse WAT-PDGFR-α+ progenitor cells, as well as in human WAT-PDGFR-α+ adipocytes, supporting the physiological relevance of our findings. Our data reveal a paracrine mechanism by which angiogenic endothelial cells modulate adipocyte metabolism, which may provide new targets for the treatment of obesity and related metabolic diseases.
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