Haematologica最新文献

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Venous thromboembolism (VTE) is a common and serious condition among cancer patients. The diagnostic and therapeutic strategies for cancer and VTE have improved during the last three decades. It remains unclear whether mortality after cancer-related VTE (CRVTE) has decreased in this period. Therefore, we investigated the mortality risk after CRVTE over the last three decades in a population-based cohort. In total, 111,119 participants from Tromsø4-7 (1994-2016) and HUNT2-3 (1995-2008) surveys were followed through 2019, and all firstlifetime cancer and VTE events were recorded. CRVTE patients were compared with participants neither exposed to cancer nor VTE (disease-free-group), and those with cancer. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for all-cause mortality using Cox regression with cancer and VTE as time-dependent exposures, and one-year cumulative incidence of mortality after CRVTE. Analyses were performed for three timeperiods (1994-2002, 2003-2011, 2012-2019). The age- and sex-adjusted HRs for mortality after CRVTE versus disease-free-group decreased from 25.3 (95%CI 20.5-31.3) in 1994-2002 to 22.6 (95%CI 19.2-26.6) in 2003-2011, and 16.9 (95%CI 14.3-20.0) in 2012-2019. The HRs for mortality after CRVTE versus cancer-group remained stable (about 3-fold higher) along the three time-periods. Similar estimates were obtained after further adjustments for comorbidities. The one-year cumulative incidence of mortality after CRVTE decreased from 61.8% (95%CI 52.9%-70.8%) in 1994-2002 to 55.6% (95%CI 49.0%-62.4%) in 2003-2011, and 45.5% (95%CI 39.3%-52.1%) in 2012-2019. Our results indicate a decrease in mortality risk after CRVTE over the last three decades, which might be mainly the result of considerable advances in cancer management.

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Germline loss of function (LoF) DDX41 variants predispose to late-onset hematopoietic malignancies (HMs), predominantly of myeloid lineage. Among 43 families with germline DDX41 LoF variants, bone marrow (BM) biopsies in those without (n=8) or with malignancies (n=21) revealed mild dysplasia in peripheral blood (57%) and BM (88%), long before the average age of DDX41-related HM onset. Therefore, we recommend baseline bone marrow biopsies in people with germline DDX41LoF alleles to avoid over-diagnosis of myelodysplastic syndromes. A variety of solid tumors were also observed in our cohort, with 24% penetrance by age 75. Although acquired DDX41 mutations are common in HMs, we failed to identify such alleles in solid tumors arising in those with germline DDX41LoF variants (n=15), suggesting an alternative mechanism driving solid tumor development. Furthermore, 33% of pedigrees in which >15% of first-degree relatives including the proband were diagnosed with a solid tumor had second germline deleterious variants in other cancerpredisposition genes, likely serving as primary cancer drivers. Finally, both lymphoblastoid cell lines and primary peripheral blood from individuals with germline DDX41LoF variants exhibited differential levels of inflammation-associated proteins. These data provide evidence of inflammatory dysfunction mediated by germline DDX41LoF alleles that may contribute to solid tumor growth in the context of additional germline cancer-associated variants. For those with HMs and personal/family histories of solid tumors, we recommend broad germline testing. DDX41 may be an indirect modifier of solid tumor pathogenesis compared to its tumor suppressor function within hematopoietic tissues, a hypothesis that can be addressed in future work.

Hyperadrenocorticism (HAC) leads to a hypercoagulable state and contributes to the risk of thromboembolic disease. Hypercoagulation in HAC occurs in both humans and dogs. Platelets play a major role in thrombosis and hemostasis, but no study has investigated platelet function in dogs with HAC. Thus, we aimed to characterize the platelet function and its molecular mechanism in dogs with HAC by using platelets isolated from normal dogs and dogs with HAC. This prospective crosssectional study included 7 dogs with HAC and 15 normal dogs. Various platelet functional responses including platelet aggregation and dense-granule secretion were evaluated. 2-MeSADP- and low concentration of thrombin-induced platelet aggregation and secretion were significantly inhibited in dogs with HAC compared to normal dogs. Furthermore, the pre-incubation of platelets with prednisolone inhibited 2-MeSADP- and thrombin-induced platelet aggregation and secretion only in normal dog platelets, whereas no additional inhibitory effect was shown in dogs with HAC confirming a role of excessive cortisol in platelet function. In addition, 2-MeSADP- and thrombininduced platelet aggregation and post-adrenocorticotropic hormone (ACTH) cortisol levels showed a negative correlation. Moreover, 2-MeSADP- and thrombin-induced thromboxane A2 (TxA2) generation was significantly inhibited in dogs with HAC compared to normal dogs, confirming the role of cortisol in TxA2 generation. Finally, thrombin-induced ERK and AKT phosphorylation were significantly inhibited in dogs with HAC. In conclusion, excessive cortisol in dogs with HAC affects platelet function by suppressing TxA2 generation through the regulation of ERK and AKT phosphorylation.