Development of EQ-6, a Novel Analogue of Ethoxyquin to Prevent Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and often dose-limiting side effect of many cancer drugs. Because the onset of neuronal injury is known, it is an ideal clinical target to develop neuroprotective strategies. Several years ago, we had identified ethoxyquin as a potent neuroprotective drug against CIPN through a phenotypic drug screening and demonstrated a novel mechanism of action, inhibition of chaperone domain of heat shock protein 90. To improve its drug-like properties we synthesized a novel analogue of ethoxyquin and named it EQ-6 (6-(5-amino)-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline hydrochloride). Here we show that EQ-6 prevents axon degeneration in primary dorsal root ganglion neurons in vitro, and this axon protection is associated with preserved levels of nicotinamide adenine dinucleotide, a key metabolite in programmed axon degeneration pathway. We also found that EQ-6 prevents loss of epidermal nerve fibers in a mouse model of CIPN induced by paclitaxel and that doses of EQ-6 that provide neuroprotection are associated with reduced tissue levels of SF3B2, a potential biomarker of target engagement. Furthermore, we show that EQ-6 is safe in vitro and in mice with daily administration for a month. We found that oral bioavailability is about 10%, partly due to rapid metabolism in liver, but EQ-6 appears to be concentrated in neural tissues. Given these findings, we propose EQ-6 as a first-in-class drug to prevent CIPN.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01093-8.     

Porcine IL‐6, IL‐1β, and TNF‐α regulate the expression of pro‐inflammatory‐related genes and tissue factor in human umbilical vein endothelial cells

Whether porcine cytokines are induced after pig‐to‐primate xenotransplantation and activate human cells remains unknown. First, we investigated the regulation of porcine IL‐6, IFN‐γ, IL‐1β, and TNF‐α in xenotransplantation using an in vitro model in which porcine aortic endothelial cells (PAECs) and porcine peripheral blood mononuclear cells (PBMCs) were stimulated with human serum. Downstream cytokines/chemokines were monitored. Pro‐inflammatory cytokines (IL‐6, IFN‐γ, and IL‐1β) and chemokines (IL‐8, MCP‐1, and CXCL2) were upregulated in the both cell types. TNF‐α was induced 10‐fold in PAECs, but not in PBMCs. Then, we assessed the role of porcine IL‐6, IFN‐γ, IL‐1β, and TNF‐α in xenotransplantation using western blotting and real‐time PCR. Human umbilical vein endothelial cells (HUVECs) were selected as the target cells. Signaling pathways and downstream genes, such as those related to adhesion, inflammation, and coagulation, and chemokines were investigated. Porcine IL‐1β and TNF‐α significantly activated NF‐κB and P38, and STAT3 was activated by porcine IL‐6 in HUVECs. The adhesion genes (E‐selectin, VCAM‐1, and ICAM‐1), inflammatory cytokines (IL‐6, IL‐1β, and TNF‐α), chemokines (MCP‐1 and IL‐8), and the pro‐coagulation gene (tissue factor) were upregulated by porcine IL‐1β and TNF‐α. Porcine IL‐6 increased the expression of ICAM‐1, IL‐6, MCP‐1, and tissue factor, but decreased IL‐8 expression slightly. Surprisingly, porcine IFN‐γ could not activate STAT1 or regulate the expression of any of the above genes in HUVECs. In conclusion, these findings suggest that porcine IL‐6, IL‐1β, and TNF‐α activate HUVECs and regulate downstream genes expression, which may promote inflammation and coagulation response after xenotransplantation.     

Influence of Recipient Race on the Outcome of Simultaneous Pancreas and Kidney Transplantation

Racial differences on the outcome of simultaneous pancreas and kidney (SPK) transplantation have not been well studied. We compared mortality and graft survival of African Americans (AA) recipients to other racial/ethnic groups (non‐AA) using the national data. We studied a total of 6585 adult SPK transplants performed in the United States between January 1, 2000 and December 31, 2007. We performed multivariate logistic regression analyses to determine risk factors associated with early graft failure and immune‐mediated late graft loss. We used conditional Kaplan–Meier survival and multivariate Cox regression analyses to estimate late death‐censored kidney and pancreas graft failure and death between the groups. Although there was no racial disparity in the first 90 days, AA patients had 38% and 47% higher risk for late death‐censored kidney and pancreas graft failure, respectively (p = 0.006 and 0.001). AA patients were twice more likely to lose the kidney and pancreas graft due to rejection (OR 2.31 and 1.86, p = 0.002 and 0.008, respectively). Bladder pancreas drainage was associated with inferior patient survival (HR 1.42, 95% CI 1.15, 1.75, p = 0.001). In the era of modern immunosuppresion, AA SPK transplant patients continue to have inferior graft outcome. Additional studies to explore the mechanisms of such racial disparity are warranted.     

Optimize the management of urological tube-related emergencies during the coronavirus disease 2019 (COVID-19) pandemic

BackgroundTo introduce and determine the value of optimized strategies for the management of urological tube-related emergencies with increased incidence, complexity and operational risk during the global spread of coronavirus disease 2019 (COVID-19).MethodsAll emergent urological patients at Tongji Hospital, Wuhan, during the period of January 23 (the beginning of lockdown in Wuhan) to March 23, 2020, and the corresponding period in 2019 were recruited to form this study’s COVID-19 group and control group, respectively. Tongji Hospital has the most concentrated and strongest Chinese medical teams to treat the largest number of severe COVID-19 patients. Patients in the control group were routinely treated, while patients in the COVID-19 group were managed following the optimized principles and strategies. The case incidence for each type of tube-related emergency was recorded. Baseline characteristics and management outcomes (surgery time, secondary complex operation rate, readmission rate, COVID-19 infection rate) were analyzed and compared across the control and COVID-19 periods.ResultsThe total emergent urological patients during the COVID-19 period was 42, whereas during the control period, it was 124. The incidence of tube-related emergencies increased from 53% to 88% (P<0.001) during the COVID-19 period. In particular, the incidence of nephrostomy tube-related (31% vs. 15%, P=0.027) and single-J stent-related problems (19% vs. 6%, P=0.009) increased significantly. The mean surgery times across the two periods were comparable. The number of secondary complex operations increased from 12 (18%) to 14 (38%) (P=0.028) during the COVID 19-period. The number of 2-week postoperative readmission decreased from 10 (15%) to 1 (3%) (P=0.049). No participants contracted during the COVID-19 period.ConclusionsUrological tube-related emergencies have been found to have a higher incidence and require more complicated and dangerous operations during the COVID-19 pandemic. However, the optimized management strategies introduced in this study are efficient, and safe for both urologists and patients.     

弹性成像对部队官兵精索静脉曲张术后评估的初步研究

目的利用超声弹性成像组织弥散定量分析技术(UE)探讨部队官兵精索静脉曲张(VC)患者手术前后睾丸组织硬度的变化。方法选取左侧VC需行手术治疗的部队官兵58例(VC组),另以同期无VC的健康志愿者36例为对照组,术前1周及术后6个月对所有受检者进行常规超声扫查后,使用组织弹性成像技术进行组织弥散定量分析,测量感兴趣区域(ROI)内应变均值。结果 VC术前睾丸组织应变值较对照组增高(P<0.05),VC术后睾丸组织应变值较术前降低(P<0.05),与对照组比较睾丸组织应变均值无统计学差异(P>0.05)。结论睾丸组织应变值可作为评价部队官兵精索静脉曲张患者睾丸组织硬度及评估术后疗效的指标。     

奥马珠单抗治疗慢性自发性荨麻疹的疗效及安全性分析

【摘要】 目的 回顾分析奥马珠单抗治疗慢性自发性荨麻疹（CSU）的疗效、安全性及停药复发情况。方法 回顾北京大学第一医院皮肤科门诊2018年2月至2021年1月使用奥马珠单抗治疗的CSU病例,分析其临床特征,采用门诊随访形式,通过荨麻疹控制评分（UCT）、皮肤病生活质量指数（DLQI）评估疾病严重程度,监测不良事件及停药后复发情况。正态分布的计量资料组间比较采用独立样本t检验或方差分析,非正态分布的计量资料组间比较采用Mann-Whitney U检验、Wilcoxon符号秩和检验或Kruskal-Wallis H检验,计数资料组间比较采用卡方检验或Fisher 精确检验。结果 纳入59例CSU患者,奥马珠单抗治疗至少3个月,其中45例治疗达6个月,15例达12个月。经奥马珠单抗治疗,UCT从基线期3.0（1.0,6.0）分上升至第1个月11.0 （3.0,14.0）分和第3个月15.0 （12.0,16.0）分（均P < 0.05）。DLQI从基线期16.0（12.0,20.0）分下降至第1个月7.0 （1.0,13.0）分和第3个月1.0 （0.0,4.0）分（均P < 0.05）。疾病部分或完全控制的比例在基线期为0,第1个月上升至44.1%,第3个月达78.0%,第6个月达88.9%。疾病对生活质量存在重度或极重度影响的比例在基线期为84.7%,第1个月降至30.5%,第3个月降至15.3%,第6个月降至4.4%。对奥马珠单抗治疗完全反应组和部分反应组比无反应组病程更短（t = -2.894,P = 0.011;t = -2.511,P = 0.036）;完全反应组比部分反应组和无反应组治疗时间更长（t = 2.479,P = 0.039;t = 2.677,P = 0.022）。慢反应组与快反应组相比,基线DLQI更高（Z = -2.622,P = 0.009）,基线UCT更低（Z = -2.746,P = 0.006）。19例患者病情完全控制后停药,其中13例（68.4%）在停药7（5,8）周后复发,复发后UCT评分高于治疗前（Z = 3.172,P = 0.001）,复发组比未复发组病程更长（Z = -2.635,P = 0.007）。复发后5例重新开始奥马珠单抗治疗,均再次得到部分或完全控制。治疗期间报告不良反应事件均为轻中度。结论 奥马珠单抗能够有效控制CSU症状,提高患者生活质量,且安全性较好,但停药后复发率高,复发后重新开始奥马珠单抗治疗仍有效。     

难治性癫癎MRJ颞极信号特点与癫癎的相关性分析

目的探讨难治性癫癎MRI颞极信号特点与致癎区相关性。方法回顾性分析339例难治性癫癎病人MRI颞极信号特点。根据癫癎发作起始区将研究对象分为颞叶癫癎、额叶癫癎、顶叶癫癎、枕叶癫癎、岛叶癫癎、多脑叶癫癎等6类。结果颞极信号异常187例,颞极信号异常侧别与致癎区侧别一致率达98．93％,颞极信号异常与癫癎类型或致癎区有关（χ2=311．339,P〈0．001）。与颞叶外癫癎比较,颢极信号异常更常见于颞叶癫癎。结论在各类癫癎中均可出现MR／颞极信号异常,但更常见于颞叶癫癎。颞极信号异常侧常与致癎区侧别一致．特别是颞叶癫癎。