The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

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.     

Evaluation of serum levels of C-reactive protein,D-Dimer and Autologous Serum Skin Test in patients with Chronic Spontaneous Urticaria in a Brazilian tertiary center : a cross-sectional study

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.     

Development of an IgG-Fc fusion COVID-19 subunit vaccine,AKS-452

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.     

RNA相关的低剂量辐射响应标志物

电离辐射会对人体造成损伤,根据受照剂量、时间等因素的不同可诱发多种生物效应。目前对于低剂量辐射产生的健康效应仍有争议,筛选对低剂量敏感的辐射响应生物标志物,对于完善低剂量辐射生物效应机制、拓宽低剂量辐射在临床中的应用均具有重要理论意义。综述探讨各核糖核酸(RNA)在低剂量辐射反应中的变化及其对辐射敏感性的调节作用,同时评估各RNA作为低剂量辐射响应标志物的潜力。     

补肾壮督方联合阿仑膦酸钠及骨水泥分期灌注椎体后凸成形术对kummell病远期临床疗效和血清标志物的影响＊

目的 探讨补肾壮督方联合阿仑膦酸钠及骨水泥分期灌注椎体后凸成形术对kummell病远期临床疗效和血清标志物的影响。方法 选取90例2019年1月-2020年3月因kummell病住院手术治疗的患者，随机分为试验组45例和对照组45例。对照组给予骨水泥分期灌注椎体后凸成形术，术后口服阿仑膦酸钠治疗，试验组术后加用补肾壮督方口服治疗。记录两组术中骨水泥注入量。采用VAS疼痛评分标准评估术后疼痛改善情况，采用ODI评分评估功能障碍改善情况。采用伤椎前缘高度比值和伤椎椎体楔形角评估脊柱稳定性。采用碱性磷酸酶（ALP），骨钙素（OC），骨保护素（OPG）评估治疗前后血清骨形成情况。结果 与对照组比较，试验组术后第3天VAS疼痛评分明显低于对照组，差异有统计学意义（P<0.05）；试验组术后第3天、术后6个月和术后12个月ODI评分明显低于对照组，差异有统计学意义（P<0.05）；试验组术后6个月和术后12个月伤椎前缘高度比值明显高于对照组，差异有统计学意义（P<0.05）；试验组术后6个月和术后12个月伤椎椎体楔形角明显低于对照组，差异有统计学意义（P<0.05）。试验组术后6个月和术后12个月碱性磷酸酶（ALP），骨钙素（OC），骨保护素（OPG）明显高于对照组，差异有统计学意义（P<0.05）。结论 补肾壮督方联合阿仑膦酸钠及骨水泥分期灌注椎体后凸成形术治疗kummell病可加快术后患者疼痛改善和功能恢复，促进骨形成，有效抑制患者中远期椎体压缩塌陷，维持脊柱稳定性。     

前列腺癌早期诊断的研究进展北大核心

前列腺癌(prostate cancer, PCa)是中老年男性常见恶性肿瘤之一,目前尚缺乏有效的晚期癌症治疗方法,因此早期诊断对于降低PCa死亡率至关重要。近年来,较多研究开发出多种新型诊断方法以改善对PCa诊断的准确性,同时避免过度诊疗,但其有效性及实用性尚需进一步验证。本文对目前新型生物标志物、联合成像技术及风险预测模型等的早期诊断技术进行总结,以期为临床研究提供指导作用。     

丹青胶囊联合他扎罗汀倍他米松治疗银屑病的临床研究

目的 探讨丹青胶囊联合他扎罗汀倍他米松治疗银屑病的临床疗效.方法 选取2019年6月—2021年6月在天津市职业病防治院门诊皮肤科就诊治疗的114例银屑病患者,根据随机数字法分为对照组和治疗组,每组各57例.对照组患者给予他扎罗汀倍他米松乳膏,洗净患处,待皮肤干爽后,将适量本品均匀涂抹于患处,1次/d.治疗组患者在对照组治疗基础上口服丹青胶囊,4粒/次,3次/d.两组患者均连续治疗7 d.观察两组患者的临床疗效和临床症状好转时间,比较两组治疗前与治疗1、4、8周的皮损面积和严重程度指数(PASI)评分和血清炎性因子水平.结果 治疗后,治疗组总有效率是98.25％,显著高于对照组的82.46％(P<0.05).治疗后,治疗组患者皮损暗红、皮损肥厚、皮肤瘙痒、皮肤疼痛等症状好转时间均显著短于对照组(P<0.05).治疗后,两组PASI评分均较治疗前显著降低(P<0.05);治疗1、4、8周治疗组PASI评分显著低于对照组(P<0.05).治疗后,两组患者血清炎性因子白细胞介素6(IL-6)、白细胞介素17(IL-17)、肿瘤坏死因子α(TNF-α)、干扰素-γ(IFN-γ)水平均较治疗前显著降低(P<0.05);治疗后,治疗组血清炎性因子水平显著低于对照组(P<0.05).结论 丹青胶囊联合他扎罗汀倍他米松治疗银屑病效果明显,能显著降低炎性因子水平,并有助于改善皮损情况,值得临床推广应用.