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Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF. 相似文献
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《Anais brasileiros de dermatologia》2021,96(2):148-154
BackgroundThe pathophysiology of urticaria is still poorly understood. Recent studies demonstrate that the activation of coagulation is correlated with the clinical activity of Chronic Spontaneous Urticaria. Coagulation and inflammation are strongly linked.ObjectivesTo correlate the severity and activity of Chronic Spontaneous Urticaria with the levels of D-dimer, C-reactive protein, and autologous serum test in patients with Chronic Spontaneous Urticaria.MethodsThe study included 55 patients diagnosed with chronic spontaneous urticaria. D-dimer levels were measured using enzyme-linked fluorescent assay and C-reactive protein levels were measured using the nephelometric method; autologous serum testing was performed on patients who discontinued antihistamine therapy. The severity of the disease was assessed using the urticaria activity score.Resultspatients with severe, spontaneous, and difficult-to-control chronic urticaria had elevated serum levels of D-dimer, as well as a positive autologous serum test. Little correlation was demonstrated between the severity of chronic spontaneous urticaria and the levels of C-reactive protein.ConclusionThe authors concluded that patients with severe Chronic Spontaneous Urticaria showed signs of activated fibrinolysis. Most patients with high clinical scores had high D-dimer values. Patients with positive results for the autologous serum test also had more severe Chronic Spontaneous Urticaria and needed more drugs to control the disease. Finally, little correlation was found between C-reactive protein levels and disease severity.Study limitationsThe main limitation was the small sample of patients. In the present patients, it was demonstrated that serum D-dimer levels and the autologous serum test can act as predictive markers of severity and activity of Chronic Spontaneous Urticaria. 相似文献
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J. Oliveira-Santos R. Santos C. Moreira S. Abreu L. Lopes C. Agostinis-Sobrinho G. Stratton J. Mota 《Nutrition, metabolism, and cardiovascular diseases : NMCD》2019,29(8):783-792
Background and aimsThe long-term relations between excessive adiposity in early childhood and unfavourable cardiometabolic profiles in later ages are not yet completely understood. We aimed to assess the associations between birth weight (BW) and BMI from 6 months to 6 years of age, with biomarkers indicative of low-grade inflammation, insulin resistance and lipid profiles in adolescence.Methods and resultsRetrospective school-based study with 415 Portuguese adolescents (220 girls), mean age of 14.08 ± 1.6 years old. Anthropometric data from birth to 6 years old was extracted from individual child health book records. Actual weight and height were measured and BMI calculated. Participants were classified at each time point as normal weight or overweight according to WHO reference values. Biomarkers were obtained from venous blood samples. Linear regressions were used to explore the associations between the biomarkers and early life anthropometric indicators. From 2 years onwards, BMI associated positively with the inflammatory score and HOMA-IR in adolescence. Children who were overweight/obese from 2 to 6 years of age presented significantly higher inflammatory score and HOMA-IR later in adolescence. TC/HDL ratio was also positively associated with BMI from the age of 5 years onwards. The associations between BMI and cardiometabolic outcomes remained positive in adolescence, with overweight adolescents presenting a higher inflammatory score, HOMA-IR and TC/HDL than normal weight adolescents.ConclusionA high BMI from an early age was consistently associated with worse inflammatory and lipid profiles and insulin resistance in adolescence. No associations were found between BW and the same studied outcomes. 相似文献
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