Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia

Dysregulation of apoptotic machinery is one mechanism by which acute myeloid leukemia (AML) acquires a clonal survival advantage. B-cell lymphoma protein-2 (BCL2) overexpression is a common feature in hematologic malignancies. The selective BCL2 inhibitor, venetoclax (VEN) is used in combination with azacitidine (AZA), a DNAmethyltransferase inhibitor (DNMTi), to treat patients with AML. Despite promising response rates to VEN/AZA, resistance to the agent is common. One identified mechanism of resistance is the upregulation of myeloid cell leukemia-1 protein (MCL1). Pevonedistat (PEV), a novel agent that inhibits NEDD8-activating enzyme, and AZA both upregulate NOXA (PMAIP1), a BCL2 family protein that competes with effector molecules at the BH3 binding site of MCL1. We demonstrate that PEV/AZA combination induces NOXA to a greater degree than either PEV or AZA alone, which enhances VEN-mediated apoptosis. Herein, using AML cell lines and primary AML patient samples ex vivo, including in cells with genetic alterations linked to treatment resistance, we demonstrate robust activity of the PEV/VEN/AZA triplet. These findings were corroborated in preclinical systemic engrafted models of AML. Collectively, these results provide rational for combining PEV/VEN/AZA as a novel therapeutic approach in overcoming AML resistance in current therapies.     

Current apparent treatment‐resistant hypertension in patients undergoing peritoneal dialysis: A multi‐center cross‐sectional study

Apparent treatment‐resistant hypertension (aTRH) is the most commonly used term to report resistant hypertension (RH) and is considered as a common problem in dialysis population. However, few reports have focused on peritoneal dialysis (PD) hypertensive patients. The authors conducted a multi‐center cross‐sectional study involving 1789 PD patients from nine centers in Guangdong, China. The prevalence of aTRH was estimated by home blood pressure (BP) monitoring. Evaluating drug adherence through Eight‐item Morisky Medication Adherence Scale (MMAS‐8) and pill counting was performed to assess RH in one PD center. Related factors of aTRH were analyzed using logistic regression analysis. The prevalence of aTRH in PD patients was estimated at 42.2% (755 out of 1789 hypertensive patients) based on home BP. Of those, 91.4% patients were classified as uncontrolled RH, 2.0% as controlled RH, and 6.6% as refractory hypertension. The prevalence of RH was 40.6% and 41.9% among those with medium/high adherence based on the MMAS‐8 scores and the pill counting rate, respectively. PD patients who were younger, with higher body mass index, with lower serum albumin and poorer dialysis adequacy were significantly associated with higher aTRH incident. In conclusion, the present study demonstrates a high prevalence of aTRH in PD population, which occurs in about two in five treated hypertensive patients. Nutritional status and dialysis adequacy might tightly associate with aTRH.     

Should psychological distress be listed as a surgical indication for indeterminate pulmonary nodules: protocol for a prospective cohort study in real-world settings

BackgroundPulmonary nodules (PNs) are documented in up to 30% of computed tomography (CT) reports. PNs of indeterminate nature (IPN) have been reported to be associated with increased psychological distress and deterioration of the quality of life. Despite lack of solid evidence, severe anxiety or depression has been proposed to be one of the surgical indications in expert consensus for IPN management. So far, there is no established criterion to guide the decision-making process, or to ensure evidence-based management. This study aims to evaluate whether psychological distress could be a surgical indication for IPN, and to establish an evidence-based distress threshold for necessary surgical intervention.MethodsThis prospective observational study in real-world setting will involve an expected sample size of 1,253 IPN patients from the thoracic clinic of Guangdong Provincial People’s Hospital. Web-based questionnaires powered by Wen Juan Xing (WJX) platform will be delivered to the patients for baseline data collection and psychological screening. Based on our pilot study, a total of 376 IPN patients with abnormal or borderline abnormal psychological states, as assessed by the Hospital Anxiety and Depression Scale (HADS), will be followed for 1 year before proceeding to the final analysis. The planned study period is from Jan 1, 2021, to Sept 30, 2022, and will entail two HADS assessments at baseline and follow-up. Sleep quality and indicators of healthcare-seeking behavior, such as the number of unplanned clinic visits or CT scans per year, will be used as anchors of psychological state. Patients who undergo surgical resection against the follow-up plan will be enrolled into a surgical group (expected n=94), while those who adhere to their plan will be automatically classified as a follow-up group after 1-year follow-up (expected n=282). Statistical measures such as independent-samples t-test and receiver operating characteristics (ROC) analysis will be used to assess the difference in psychological changes between the groups, and to generate an optimal threshold alerting surgical need. A Chi-square test or nonparametric test will be used to compare the baseline characteristics. Contributors to psychological burden and their effect sizes will be evaluated using general linear regression.DiscussionTo date, data on the psychological benefits of surgical resection of IPN remains scanty. Evidence-based procedure of patient selection using appropriate psychological screening tools is crucial in improving the quality of care and preventing overtreatment. This protocol describes the rationale and methodology to address this unmet clinical need using real-world data, aiming to bridge the gap between clinical guidelines and real-world practice.Trial RegistrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT04857333","term_id":"NCT04857333"}}NCT04857333. Registered April 23, 2021.     

清胰汤点滴式保留灌肠治疗急性胰腺炎的临床观察

急性胰腺炎是一种常见的急腹症,按病理分为水肿性和出血坏死性。该病病情凶险,死亡率高。以往我院临床上以口服清胰汤治疗,患者易出现恶心、呕吐等现象,致使药物利用率低。为了寻求更好的治疗方法,我科采用清胰汤点滴式保留灌肠法治疗急性水肿性胰腺炎,并与传统灌肠方法进行对比观察,现报告如下。     

槲皮素通过p53-p21-Rb通路缓解慢性阻塞性肺疾病的肺衰老

目的 探讨槲皮素对慢性阻塞性肺疾病(COPD)小鼠肺衰老的治疗作用及机制。方法 将30只C57BL/6小鼠随机分为对照组、模型组、槲皮素组,每组10只。模型组和槲皮素组采用烟熏联合气道内滴注脂多糖(LPS)的方法构建COPD小鼠模型。造模成功后,槲皮素组给予槲皮素(50 mg/kg)灌胃,1次/d,持续4周;对照组和模型组给予等体积生理盐水。采用苏木精-伊红(HE)染色法观察小鼠肺组织病理改变,并评估肺部病理损伤;采用衰老相关β-半乳糖苷酶(SA-β-gal)染色法观察小鼠肺组织的衰老状况;采用免疫组化法检测肺组织中凋亡相关蛋白Bcl-2、Bax表达情况;采用蛋白质印迹(Western blot)法检测肺组织中衰老相关蛋白p53、p21、Rb表达水平。结果 与对照组比较,模型组小鼠肺组织病理损伤明显,SA-β-gal染色的阳性面积明显增加,肺组织中Bcl-2蛋白表达减少、Bax蛋白表达增多,衰老相关蛋白p53、p21、Rb表达水平明显升高(均P<0.05);与模型组比较,槲皮素组小鼠肺组织病理损伤减轻,SA-β-gal染色阳性面积减少,肺组织中Bcl-2蛋白表达增高、Bax蛋白表...     

急、慢性髓性白血病细胞低温冻存后诱生的树突状细胞生物特性研究

目的 观察急、慢性髓性白血病原代细胞经低温冻存后诱生的白血病源性树突状细胞的生物特性.方法 取急、慢性髓性白血病原代细胞,一部分细胞立即培养,一部分细胞用5%二甲基亚砜-6%羟乙基淀粉为保护剂,-80℃冰箱降温,液氮保存一定时间后复温培养.培养时细胞内加重组人粒-巨噬细胞集落刺激因子、白介素-4、肿瘤坏死因子-α等细胞因子,培养12 d,为白血病源性树突状细胞,观察细胞形态及免疫表型、自身混合淋巴细胞反应及细胞毒T淋巴细胞杀伤自身白血病细胞活性.结果 急、慢性髓性白血病新鲜或冻存的原代细胞,经组合细胞因子培养,细胞均不同程度地出现典型的树突状形态,细胞表面CD80、CD54、人白细胞表面抗原DR、CD1a、CD83、CD86表达上调,CD14下调;冻存原代细胞经培养生成的白血病源性树突状细胞,还表现为自体混合淋巴细胞反应和T淋巴细胞杀伤自体白血病细胞活性明显.结论 急、慢性髓性白血病新鲜或经低温冻存的原代细胞可诱生为白血病源性树突状细胞,这种细胞可诱导T淋巴细胞杀伤自身白血病细胞,为用树突状细胞免疫治疗微小残留病提供了实验依据.     

“医信校企双融合”物联网工程专业创新应用型人才培养模式研究

介绍“医信校企双融合”物联网工程专业创新应用型人才培养模式体系框架,详细阐述该模式下教学实践的技术路线及实施途径,包括建立校企协同多层次实践教学体系、建设多学科融合4级课程体系、组建多维度学习共同体和建立3重保障机制等,分析推广应用效果。     

基于工作过程的案例教学法在“网站建设与维护”课程中的应用

以济宁医学院“网站建设与维护”课程为例,分析现有案例教学法存在的问题,阐述基于工作过程的案例教学法设计思路及其具体实施,指出该教学模式打破传统教学体系,突出学生主体地位,有利于学生职业技能培养。     

A Multi-Parameter Integrated Sensor Based on Selectively Filled D-Shaped Photonic Crystal Fiber

We propose and numerically investigate a multi-parameter integrated sensor based on a selectively filled D-shaped photonic crystal fiber (PCF). The simple structure can be used to comprehensively detect refractive index, magnetic field, temperature, and voltage. According to the surface plasmon resonance and directional coupling effect, the PCF is coated with a gold nano-film to detect the refractive index of the external environment. In addition, magnetic fluid (water-based Fe₃O₄), toluene, and nematic liquid crystal (NLC E7) are selectively filled into different cladding air holes of the D-shaped PCF to realize the different sensing of the magnetic field, temperature, and voltage. The measurement of refractive index, magnetic field, temperature, and voltage are independent of each other, so these four parameters can be measured simultaneously. The sensing characteristics of the proposed structure are investigated systematically by the finite element method. The results show that the sensitivities of refractive index, magnetic field, temperature, and voltage are 4600 nm/RIU, 1.375 nm/Oe, 15.143 nm/°C, and 0.971 nm/V, respectively. The presented design based on materials selectively filled with D-shaped PCF might enable promising application in multi-parameter optical sensing.