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71.
《Genetics in medicine》2022,24(12):2501-2515
PurposeThe study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH).MethodsA cohort of 1387 probands with IHH underwent exome sequencing and de novo, familial, and cohort-wide investigations. Functional studies were performed on 2 p190 Rho GTPase–activating proteins (p190 RhoGAP), ARHGAP35 and ARHGAP5, which involved in vivo modeling in larval zebrafish and an in vitro p190A-GAP activity assay.ResultsRare protein-truncating variants (PTVs; n = 5) and missense variants in the RhoGAP domain (n = 7) in ARHGAP35 were identified in IHH cases (rare variant enrichment: PTV [unadjusted P = 3.1E-06] and missense [adjusted P = 4.9E-03] vs controls). Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a, the predominant ARHGAP35 paralog in the zebrafish brain, display decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant [ARHGAP35 p.(Arg1284Trp)] had decreased GAP activity. Rare PTVs (n = 2) also were discovered in ARHGAP5, a paralog of ARHGAP35; however, arhgap5 zebrafish mutants did not display significant GnRH3-GFP+ abnormalities.ConclusionThis study identified ARHGAP35 as a new autosomal dominant genetic driver for IHH and ARHGAP5 as a candidate gene for IHH. These observations suggest a novel role for the p190 RhoGAP proteins in GnRH neuronal development and integrity. 相似文献
72.
《Immunobiology》2022,227(3):152205
BackgroundEarly biomarkers allowing effective treatment stratification in adult T-cell acute lymphoblastic leukemia (T-ALL) patients remain elusive.Materials and methodsThe mutation spectrum of 116T-ALL adult patients enrolled in the Shanghai Institute of Hematology (SIH)-based hospital network or Multicenter Hematology-Oncology Protocols Evaluation System (M-HOPES) in China were studied by using RNA-sequencing or targeted next generation sequencing. A comprehensive survival analysis based on clinical characteristics, immunophenotype and oncogenetic classifier was performed.ResultsEarly T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has higher mutation rates of N/K-RAS and lower mutation rates of FBXW7 compared to non-ETP ALL, but the survival probability of ETP-ALL patients is similar to that of non-ETP ALL patients. T-ALLs with a NOTCH1/FBXW7 (N/F) mutation in the absence of RAS or PTEN abnormalities (NFRP class I) show a more favorable outcome compared to T-ALLs with no N/F mutation and/or with the presence of RAS/PTEN alterations (NFRP class II). A survival analysis of T-ALL, taking into account both the ETP-ALL/non-ETP T-ALL groups and the NFRP oncogenetic classifier, demonstrates that, within the non-ETP T-ALL subtype, NFRP class II identifies a group with poor prognosis and significant decreases of both OS (14.8% versus 50.9%, P = 0.019) and EFS (11.4% versus 42.4%, P = 0.001). In contrast, no survival difference is observed within ETP-ALL between the NFRP class I or class II (OS: 37.9% versus 33%, P = 0.876; EFS: 39.8% versus 33.7%, P = 0.969).ConclusionIn summary, the oncogenetic classifier based on the NFRP classes is particularly useful to improve the stratification of non-ETP ALL. 相似文献
73.
In this study, we have screened the six most relevant forensic body fluids / tissues, namely blood, semen, saliva, vaginal secretion, menstrual blood and skin, for miRNAs using a whole miRNome massively parallel sequencing approach. We applied partial least squares (PLS) and linear discriminant analysis (LDA) to predict body fluids based on the expression of the miRNA markers. We estimated the prediction accuracy for models including different subsets of miRNA markers to identify the minimum number of markers needed for sufficient prediction performance. For one selected model consisting of 9 miRNA markers we calculated their importance for prediction of each of the six different body fluid categories. 相似文献
74.
Hung-Chang Shih Tze-Kiong Er Tien-Jye Chang Ya-Sian Chang Ta-Chih Liu Jan-Gowth Chang 《Clinical biochemistry》2009,42(16-17):1667-1676
ObjectiveThis study was undertaken to identify HBB gene mutation.Design and methodsHerein we evaluated high-resolution melting analysis in the identification of HBB mutations.ResultsWe have successfully established a diagnostic strategy for identifying HBB gene mutations including c.? 78A > G, c.? 79A > G, c.2T > G, c.79_80insT, c.84_85insC, c.123_124insT, c.125_128delTCTT, c.130 G > T, c.170G > A, c.216_217ins A and c.316–197 C > T from wild-type DNA using HRM analysis. The results of HRM analysis were confirmed by direct DNA sequencing.ConclusionsIn summary, we report that HRM analysis is an appealing technique for the identification of HBB mutations. We also believe that HRM can be used as a method for prenatal diagnosis of β-thalassemia. 相似文献
75.
《European journal of cancer & clinical oncology》1989,25(11):1583-1588
The progression of Lewis lung carcinoma has been examined in mice under the stress of different housing and experimental conditions. The maintenance of the animals in a low stress environment decreased the weight of spontaneous lung metastases in comparison with conventional housing. The handling of mice in the low stress environment for intraperitoneal saline administration increased metastasis formation, whereas the application of a psychological stressor (spatial disorientation) to these animals increased both primary tumor growth and metastasis formation. These results indicate that psychological and experimental stressors can modulate, presumably via neuroendocrine mechanisms, the host's antitumor responses which can control metastases and primary tumor independently from each other. 相似文献
77.
Microglia, the brain-resident immune cells, play an essential role in the upkeep of brain homeostasis. They actively adapt into specific activation states based on cues from the microenvironment. One of these encompasses the activated response microglia (ARMs) phenotype. It arises along a healthy aging process and in a range of neurodegenerative diseases, including Alzheimer’s disease (AD). As the phenotype is characterized by an increased lipid metabolism, phagocytosis rate, lysosomal protease content and secretion of neuroprotective agents, it leaves to reason that the phenotype is adapted in an attempt to restore homeostasis. This is important to the conundrum of inflammatory processes. Inflammation per se may not be deleterious; it is only when microglial reactions become chronic or the microglial subtype is made dysfunctional by (multiple) risk proteins with single-nucleotide polymorphisms that microglial involvement becomes deleterious instead of beneficial. Interestingly, the ARMs up- and downregulate many late-onset AD-associated risk factor genes, the products of which are particularly active in the endolysosomal system. Hence, in this review, we focus on how the endolysosomal system is placed at the crossroad of inflammation and microglial capacity to keep pace with degradation. 相似文献
78.
79.
《Immunobiology》2022,227(3):152210
Among all the cancer-related deaths globally, pancreatic ductal adenocarcinoma (PDAC) accounts for the seventh leading cause of mortality. A dysregulated immune system disrupts anti-tumor immunity by abnormal accumulation of myeloid-derived suppressor cells (MDSCs), but the underlying mechanisms are still inconclusive. To gain new insights into the role of MDSCs in tumor settings, we aimed to determine the mechanism of expansion of various subsets of MDSCs in PDAC patients and their role in promoting invasiveness. We assessed the load of MDSCs, chemokines responsible for the recruitment of MDSCs in PDAC patients by flow cytometry. We investigated the chemokine profile of tumor tissue using qRT-PCR and the status of epithelial-mesenchymal transition (EMT) related markers E-Cadherin, N-Cadherin, Snail, and ZEB1 by qRT-PCR and immunohistochemistry. We found a higher frequency of tumor infiltrated MDSCs in PDAC patients. Chemokine ligands CCL2 and the receptor CCR4 were markedly elevated in the PDAC tumor, while CCR4+ monocytic MDSCs (M-MDSCs) were found significantly elevated in peripheral blood and tumor tissue. In tumor tissue, expression of E-Cadherin was significantly reduced, while N-Cadherin, Snail, and ZEB1 were markedly raised. The frequency of CCR4+ M-MDSCs significantly correlated with the expression of mesenchymal transition markers N-Cadherin, Snail, and ZEB1. Collectively, these results suggest that the CCL2-CCR4 axis plays a crucial role in driving the recruitment of M-MDSCs, which is associated with increased invasiveness in PDAC. This study sheds light on the expansion mechanism of MDSCs, which can serve as a crucial target of future anti-cancer strategies to inhibit tumor cell invasiveness. 相似文献
80.
S.M. Kaakinen A. Säkkinen K.-E. Wahlberg H. Hakko J. Holma P. Tienari 《European psychiatry》2012,27(5):350-357
The aim of this study was to investigate whether severe formal thought disorders and mature thinking are stable among adoptees (= 187) drawn from the Finnish adoptive family study of schizophrenia. A group of 93 adoptees genetically at high risk (HR) and 94 at low risk (LR) for schizophrenia were assessed blindly and reliably using the Index of Primitive Thought (IPT) and the Index of Integration (IOI). Two assessments of the IPT and the IOI were performed with the mean interval of 11 years. Comparisons of the IPT and the IOI mean scores were conducted both at baseline and at follow-up between adoptees at low and high genetic risk, gender, and psychiatric status. The main result was that the IOI as well as the IPT of the adoptees at the initial assessment predicted the IOI and the IPT estimated at follow-up, thus indicating the stability of severe formal thought disorders and mature thinking over time. The stability of IOI or IPT was not related to genetic risk, gender or psychiatric status or their interactions. 相似文献