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.     

Hepatotoxicity of cantharidin is associated with the altered bile acid metabolism

Cantharidin (CTD) is an effective antitumor agent. However, it exhibits significant hepatotoxicity, the mechanism of which remains unclear. In this study, biochemical and histopathological analyses complemented with ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS)-based targeted metabolomic analysis of bile acids (BAs) were employed to investigate CTD-induced hepatotoxicity in rats. Sixteen male and female Sprague–Dawley rats were randomly divided into two groups: control and CTD (1.0 mg/kg) groups. Serum and liver samples were collected after 28 days of intervention. Biochemical, histopathological, and BA metabolomic analyses were performed for all samples. Further, the key biomarkers of CTD-induced hepatotoxicity were identified via multivariate and metabolic pathway analyses. In addition, metabolite–gene–enzyme network and Kyoto Encyclopedia of Genes and Genomes pathway analyses were used to identify the signaling pathways related to CTD-induced hepatotoxicity. The results revealed significantly increased levels of biochemical indices (alanine aminotransferase, aspartate aminotransferase, and total bile acid). Histopathological analysis revealed that the hepatocytes were damaged. Further, 20 endogenous BAs were quantitated via UHPLC-MS/MS, and multivariate and metabolic pathway analyses of BAs revealed that hyocholic acid, cholic acid, and chenodeoxycholic acid were the key biomarkers of CTD-induced hepatotoxicity. Meanwhile, primary and secondary BA biosynthesis and taurine and hypotaurine metabolism were found to be associated with the mechanism by which CTD induced hepatotoxicity in rats. This study provides useful insights for research on the mechanism of CTD-induced hepatotoxicity.     

Experimental study on the biocompatibility and osteogenesis induction ability of PLLA/DDM scaffolds

Odontology - To investigate the characterization and function of a novel porous osteogenic material (PLLA / DDM) containing polylactic acid and demineralized dentin matrix. The surface morphology...     

Patient navigation across the cancer care continuum: An overview of systematic reviews and emerging literature

Patient navigation is a strategy for overcoming barriers to reduce disparities and to improve access and outcomes. The aim of this umbrella review was to identify, critically appraise, synthesize, and present the best available evidence to inform policy and planning regarding patient navigation across the cancer continuum. Systematic reviews examining navigation in cancer care were identified in the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, Cumulative Index of Nursing and Allied Health (CINAHL), Epistemonikos, and Prospective Register of Systematic Reviews (PROSPERO) databases and in the gray literature from January 1, 2012, to April 19, 2022. Data were screened, extracted, and appraised independently by two authors. The JBI Critical Appraisal Checklist for Systematic Review and Research Syntheses was used for quality appraisal. Emerging literature up to May 25, 2022, was also explored to capture primary research published beyond the coverage of included systematic reviews. Of the 2062 unique records identified, 61 systematic reviews were included. Fifty-four reviews were quantitative or mixed-methods reviews, reporting on the effectiveness of cancer patient navigation, including 12 reviews reporting costs or cost-effectiveness outcomes. Seven qualitative reviews explored navigation needs, barriers, and experiences. In addition, 53 primary studies published since 2021 were included. Patient navigation is effective in improving participation in cancer screening and reducing the time from screening to diagnosis and from diagnosis to treatment initiation. Emerging evidence suggests that patient navigation improves quality of life and patient satisfaction with care in the survivorship phase and reduces hospital readmission in the active treatment and survivorship care phases. Palliative care data were extremely limited. Economic evaluations from the United States suggest the potential cost-effectiveness of navigation in screening programs.     

癫痫发作后状态及其临床意义

癫痫发作后状态(PIS)是指癫痫发作停止到恢复至发病前水平的异常状态,包括认知、运动、感觉、自主神经和精神行为等异常,症状多样,严重程度不一,持续数秒至数天不等,对患者的健康和生活质量产生很大影响。然而,目前国内外相关的研究较少,临床医生对此缺乏正确认识,容易误诊误治。本文将从PIS的定义、病理生理机制、临床表现、诊断和鉴别诊断、临床意义以及干预策略等进行综述,以提高临床医生的认识,并为今后临床研究提供参考。     

三阴性乳腺癌治疗的研究进展

三阴性乳腺癌（triple negative breast cancer，TNBC）是雌激素受体(estrogen receptor，ER)、孕激素受体（progesterone receptor，PR）及人类表皮生长因子受体（human epidermal growth factor-2,HER-2）均不表达的乳腺癌。按其功能特征可归纳为5类分子分型:以DNA修复缺陷或生长因子为途径的基底细胞样三阴性乳腺癌；以上皮-间充质转化和肿瘤干细胞为特征的间质样三阴性乳腺癌；免疫调节型三阴性乳腺癌；雄激素受体过表达的管腔／分泌型三阴性乳腺癌；HER-2富集型三阴性乳腺癌。三阴性乳腺癌恶性程度高且异型性较大，其治疗困难且预后较差，内分泌治疗及靶向治疗不敏感。目前很多学者对于三阴性乳腺癌的治疗各有研究，并有临床试验证实下述治疗有效。     

健脾生血片治疗慢性心力衰竭伴贫血的临床效果

目的:探索健脾生血片治疗慢性心力衰竭伴贫血的疗效、安全性和作用机制。方法:选取2016年5月至2017年2月同济医院收治的慢性心力衰竭贫血患者144例,按照随机数字表法分为观察组和对照组,每组72例。观察组给予健脾生血片治疗,3片/次,3次/d,疗程3个月;对照组给予生血宝合剂治疗,15 m L/次,3次/d,3个月为1个疗程。比较2组患者治疗前与治疗后血红蛋白、红细胞计数、网织红细胞、血清铁、转铁蛋白饱和度、血清铁蛋白、血清铁调素(Hepcidin)、血清IL-1β、血清肿瘤坏死因子-α(TNF-α)、血清C反应蛋白(CRP)、左室射血分数(LVEF)、6 min步行距离、明尼苏达心力衰竭生命质量量表(MLHFQ)和不良事件。并随访2组心血管事件次数,住院次数与全因死亡率。结果:观察组72例患者完成了前3个月的治疗,随访期间脱失2例;对照组治疗期间1例患者退出研究,随访期间脱失4例。2组一般资料比较,差异无统计学意义(P 0. 05),具有可比性。观察组贫血有效率98. 6%,对照组有效率11. 3%,差异有统计学意义(P0. 05)。治疗后观察组红细胞计数和网织红细胞、均显著高于对照组(P 0. 05)。观察组血清铁、转铁蛋白饱和度水平均高于对照组,差异有统计学意义(P 0. 05),但血清铁调素水平显著低于对照组,差异有统计学意义(P 0. 05),血清铁蛋白水平2组差异无统计学意义(P 0. 05)。观察组IL-1β、血清TNF-α、血清CRP均显著低于对照组,差异有统计学意义(P 0. 05)。观察组LVEF、6 min步行距离、明尼苏达心力衰竭生命质量量表(MLHFQ)均显著高于对照组,差异有统计学意义(P 0. 05)。2组不良事件总发生率比较,差异无统计学意义(P 0. 05),但对照组4例患者出现血清肌酐、尿素氮水平异常,发生率高于观察组,差异有统计学意义(P 0. 05)。经1年随访,观察组心血管事件人均发生次数显著少于对照组(P 0. 05),但2组住院次数和全因死亡率比较,差异无统计学意义(P 0. 05)。结论:健脾生血片可有效治疗心力衰竭伴贫血,减少心血管发生次数,并且安全性良好,其作用机制与提供准确足量铁元素、抑制铁调素表达,抑制慢性炎性反应有关。