Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis.

遗传性 α 胰蛋白酶血症是肥大细胞增多症中严重介质相关症状的有效遗传生物标志物。

  • 影响因子:7.27
  • DOI:10.1182/blood.2020006157
  • 作者列表:"Greiner G","Sprinzl B","Górska A","Ratzinger F","Gurbisz M","Witzeneder N","Schmetterer KG","Gisslinger B","Uyanik G","Hadzijusufovic E","Esterbauer H","Gleixner KV","Krauth MT","Pfeilstöcker M","Keil F","Gisslinger H","Nedoszytko B","Niedoszytko M","Sperr WR","Valent P","Hoermann G
  • 发表时间:2021-01-14

:Mastocytosis is a hematopoietic neoplasm characterized by expansion of KIT D816V-mutated clonal mast cells in various organs and severe or even life-threatening anaphylactic reactions. Recently, hereditary α-tryptasemia (HαT) has been described as a common genetic trait with increased copy numbers of the α-tryptase encoding gene, TPSAB1, and associated with an increased basal serum tryptase level and a risk of mast cell activation. The purpose of our study was to elucidate the clinical relevance of HαT in patients with mastocytosis. TPSAB1 germline copy number variants were assessed by digital polymerase chain reaction in 180 mastocytosis patients, 180 sex-matched control subjects, 720 patients with other myeloid neoplasms, and 61 additional mastocytosis patients of an independent validation cohort. α-Tryptase encoding TPSAB1 copy number gains, compatible with HαT, were identified in 17.2% of mastocytosis patients and 4.4% of the control population (P < .001). Patients with HαT exhibited higher tryptase levels than patients without HαT (median tryptase in HαT+ cases: 49.6 ng/mL vs HαT- cases: 34.5 ng/mL, P = .004) independent of the mast cell burden. Hymenoptera venom hypersensitivity reactions and severe cardiovascular mediator-related symptoms/anaphylaxis were by far more frequently observed in mastocytosis patients with HαT than in those without HαT. Results were confirmed in an independent validation cohort. The high prevalence of HαT in mastocytosis hints at a potential pathogenic role of germline α-tryptase encoding TPSAB1 copy number gains in disease evolution. Together, our data suggest that HαT is a novel emerging robust biomarker in mastocytosis that is useful for determining the individual patient´s risk of developing severe anaphylaxis.


: 肥大细胞增多症是一种造血肿瘤,其特征是KIT D816V-mutated克隆性肥大细胞在各种器官中扩增,出现严重甚至危及生命的过敏反应。最近,遗传性 α-胰蛋白酶血症 (h α t) 被描述为 α-类胰蛋白酶编码基因TPSAB1拷贝数增加的常见遗传性状,并与基础血清类胰蛋白酶水平升高和肥大细胞活化风险相关。我们研究的目的是阐明肥大细胞增生症患者中h α t的临床相关性。在独立验证队列的180例肥大细胞增生症患者、180例性别匹配的对照受试者、720例其他髓系肿瘤患者和61例其他肥大细胞增生症患者中,通过数字聚合酶链反应评估了TPSAB1种系拷贝数变异。在17.2% 的肥大细胞增多症患者和4.4% 的对照人群中鉴定出编码TPSAB1拷贝数增加的 α-类胰蛋白酶,与h α t相容 (P <.001)。具有h α t的患者表现出比不具有h α t的患者更高的类胰蛋白酶水平 (h α t + 病例中的类胰蛋白酶中值: 49.6 ng/mL vs h α t-病例: 34.5 ng/mL,P = .004),独立于肥大细胞负荷。在患有h α t的肥大细胞增多症患者中,观察到的超敏反应和严重的心血管介质相关症状/过敏反应的频率远远高于未患有h α t的患者。结果在独立的验证队列中得到证实。肥大细胞增多症中h α t的高流行率提示生殖系 α-类胰蛋白酶编码的TPSAB1拷贝数增加在疾病进化中的潜在致病作用。总之,我们的数据表明,h α t是肥大细胞增生症中一种新出现的稳健生物标志物,可用于确定个体患者发生严重过敏反应的风险。



作者列表:["Juan-Carlos PM","Perla-Lidia PP","Stephanie-Talia MM","Mónica-Griselda AM","Luz-María TE"]

METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.

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作者列表:["Sawada H","Oeda T","Kohsaka M","Tomita S","Umemura A","Park K","Yamamoto K","Kiyohara K"]

METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.

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作者列表:["Louvrier A","Terranova L","Meyer C","Meyer F","Euvrard E","Kroemer M","Rolin G"]

METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.

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