Targeting cancer stemness mediated by BMI1 and MCL1 for non‐small cell lung cancer treatment

Lung cancer is the leading cause of cancer‐associated death, with a global 5‐year survival rate <20%. Early metastasis and recurrence remain major challenges for lung cancer treatment. The stemness property of cancer cells has been suggested to play a key role in cancer plasticity, metastasis and drug‐resistance, and is a potential target for drug development. In this study, we found that in non‐small cell lung cancer (NSCLC), BMI1 and MCL1 play crucial roles of cancer stemness including invasion, chemo‐resistance and tumour initiation. JNK signalling serves as a link between oncogenic pathway or genotoxicity to cancer stemness. The activation of JNK, either by mutant EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3‐ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small‐molecule, BI‐44, was developed, which effectively suppressed BMI1/MCL1 expressions and inhibited tumour formation and progression in preclinical models. Targeting cancer stemness mediated by BMI1/MCL1 with BI‐44 provides the basis for a new therapeutic approach in NSCLC treatment.     

不同光源对K562细胞ALA-PDT作用的实验研究

目的:利用532 nm脉冲激光、532 nm连续激光和氙灯对K562细胞进行基于5-氨基乙酰丙酸的光动力疗法(ALA-PDT),研究在不同光照条件下细胞抑制率的变化情况,为实现体外ALA-PDT的高效率选择合适的光源。方法:在其他条件相同的情况下,采用不同的光源、不同的光剂量对ALA-PDT组细胞进行辐照,利用O-LYMPUS倒置荧光显微镜和显微镜数码相机系统观察细胞的形态学变化并拍照,利用光学显微镜进行台盼兰拒染法检测细胞的抑制率变化情况。结果:532 nm连续激光和脉冲激光对K562细胞的ALA-PDT抑制率均较低,增加光剂量也不能有效提高ALA-PDT的抑制率;氙灯在功率密度为350 mW/cm2、光照5 min时就能达到最佳的光剂量,此时单纯光照对K562细胞的光损伤作用很小且ALA-PDT效率很高。结论:宽光谱、高功率的氙灯对K562细胞的ALA-PDT效果远优于532 nm激光,对体外ALA-PDT实验比较适用。     

益生菌联合抗幽门螺杆菌治疗对消化性溃疡患者的疗效

目的 探讨益生菌联合抗幽门螺杆菌（H. pylori）治疗对消化性溃疡患者的疗效及其对患者肠道菌群的影响。方法 将120例经14C呼气试验（14C-UBT）检测确定为H. pylori感染阳性的消化性溃疡患者随机分为观察组和对照组,每组60例。其中,对照组采用四联疗法（奥美拉唑+阿莫西林+克拉霉素+铋剂）治疗,观察组采用四联疗法联合益生菌治疗;比较两组患者H. pylori根除情况、溃疡愈合质量及不良反应情况。治疗前后留取全部患者的新鲜粪便标本进行细菌培养,比较两组患者肠道菌群数量和肠道微生物定植抗力（B/E值）。结果 观察组患者H. pylori根除率和溃疡愈合率分别为88.3%、95.0%,显著高于对照组的70.0%和76.7%（P＜0.05）,不良反应率为3.3%,显著低于对照组的20.0%（P＜0.05）。与治疗前比,对照组患者治疗后肠道内产气荚膜梭菌、双歧杆菌及乳杆菌数量显著减少（P＜0.05）,肠杆菌、肠球菌及酵母菌数量显著增加（P＜0.05）,B/E值显著降低（P＜0.05）;观察组患者治疗后双歧杆菌和乳杆菌均显著增加（P＜0.05）,产气荚膜梭菌显著减少（P＜0.05）,肠杆菌、肠球菌及酵母菌无明显变化（P＞0.05）,B/E值显著升高（P＜0.05）。结论 常规抗H. pylori治疗易引起消化性溃疡患者肠道菌群紊乱,降低肠道定植抗力。益生菌联合治疗可有效改善患者肠道微生态,提高H. pylori根除率和溃疡愈合质量,减少不良反应。     

微生态制剂在儿童幽门螺杆菌根除治疗中应用效果的Meta分析

目的 系统评价微生态制剂联合标准三联疗法或贯序疗法在儿童幽门螺杆菌（H. pylori）治疗中应用的临床疗效及其对治疗中抗生素相关不良反应发生的改善情况。方法 计算机检索CNKI、VIP、Wan Fang Data、Pub Med、Web of science和The Cochrane Library数据库,搜集国内外公开发表的关于微生态制剂在治疗儿童H. pylori感染中应用的随机对照试验（RCT）,检索时限均为从建库至2017年10月,同时人工检索相关文献的参考文献,以补充获取研究文献。由2位研究员独立筛选文献、提取数据并对纳入研究进行质量评价,采用RevMan 5.3软件进行Meta分析。结果 共纳入17个RCT,共2 033例H. pylori 阳性的儿童患者。Meta分析结果显示,微生态制剂+标准三联或贯序疗法vs标准三联或贯序疗法：微生态制剂+标准三联或贯序疗法在儿童H. pylori根除率方面优于对照组[OR=2.66,95%CI（2.09,3.40）,P<0.00001];总不良反应发生率明显低于对照组[OR=0.28,95%CI（0.21,0.37）,P<0.00001],差异均有统计学意义。微生态制剂+标准三联或贯序疗法组的恶心呕吐（P<0.001）、腹痛（P=0.015）、腹泻（P<0.001）、便秘（P=0.023）、纳差（P<0.001）、味觉障碍或口腔炎（P<0.001）发生率明显低于对照组,差异有统计学意义。结论 与标准三联或贯序疗法相比,微生态制剂+标准三联或贯序疗法安全、有效,能提高儿童H. pylori的根除率,降低H. pylori治疗中抗生素相关不良反应的发生。受纳入研究质量的限制,上述结论尚需开展高质量的RCT 进一步验证。     

口腔微生物群和人体健康

口腔微生物群作为人体微生物群的重要组成部分,其与人体健康之间的关系已成为各领域研究的焦点。口腔微生物群种类繁多、组成复杂,涵盖了细菌、真菌、古细菌和病毒等。近年来的研究显示,口腔微生物群的组成和比例与人体健康密切相关,会影响口腔疾病如龋齿、牙周病的发生。同时口腔微生物也是全身系统性疾病如肺炎、肿瘤和糖尿病等发生的危险因素之一。大量研究认为,口腔微生物群组成的改变、口腔微生物群之间的相互作用对疾病的发生有协同促进作用。本文聚焦于口腔微生物群的组成相关研究、口腔微生物组的最新进展,并对其与人体健康之间的关系进行综述。     

HIV/AIDS的细胞治疗

获得性免疫缺陷综合征（AIDS）是由人类免疫缺陷病毒（HIV）感染引起的危险性极高的慢性传染病。高效抗逆转录病毒疗法（HAART）能够阻断正在进行的病毒复制而不能清除潜伏的病毒,目前尚无有效根治AIDS方法。免疫细胞在HIV/AIDS发展过程的不同阶段发挥着十分复杂的作用。细胞治疗是通过筛选表达抗HIV基因型的细胞或转染抗HIV基因、受体基因等方法获得抗HIV免疫细胞,并在体外进行扩增,将其转输给HIV/AIDS患者。细胞疗法与HAART等疗法有协同作用,促进HIV/AIDS的治疗。本文综述抗HIV-CAR T细胞、aTCR T细胞、负载HIV抗原的树突状细胞等在HIV/AIDS治疗中的应用及其疗效。     

Nucleic acid-based vaccine for ovarian cancer cells; bench to bedside

Ovarian cancer continues to be a difficult medical issue that affects millions of individuals worldwide. Important platforms for cancer immunotherapy include checkpoint inhibitors, chimeric antigen receptor T cells, bispecific antibodies, cancer vaccines, and other cell-based treatments. To avoid numerous infectious illnesses, conventional vaccinations based on synthetic peptides, recombinant subunit vaccines, and live attenuated and inactivated pathogens are frequently utilized. Vaccine manufacturing processes, however, are not entirely safe and carry a significant danger of contaminating living microorganisms. As a result, the creation of substitute vaccinations is required for both viral and noninfectious illnesses, including cancer. Recently, there has been testing of nucleic acid vaccines, or NAVs, as a cancer therapeutic. Tumor antigens (TAs) are genetically encoded by DNA and mRNA vaccines, which the host uses to trigger immune responses against ovarian cancer cells that exhibit the TAs. Despite being straightforward, safe, and easy to produce, NAVs are not currently thought to be an ideal replacement for peptide vaccines. Some obstacles to this strategy include selecting the appropriate therapeutic agents (TAs), inadequate immunogenicity, and the immunosuppressive characteristic of ovarian cancer. We focus on strategies that have been employed to increase NAVs' effectiveness in the fight against ovarian cancer in this review.     

纳米递送系统线粒体靶向策略在肿瘤诊疗中的应用

肿瘤是危害人类健康的重大疾病之一。目前用于肿瘤治疗的方法有手术治疗、化学药物治疗、放射治疗等。然而,传统的治疗方法存在治疗效果不佳、易引发多药耐药、毒副作用大等缺点,仍需进一步探索新的肿瘤治疗靶点和策略。线粒体作为细胞的能量转换器,被认为是肿瘤、心血管和神经性疾病新药设计的最重要靶点之一。纳米药物递送载体具有易被主动靶向基团修饰的特点,可实现细胞乃至细胞器的精准靶向给药。本文从抑制肿瘤细胞增殖、促进肿瘤细胞凋亡、抑制肿瘤复发与转移、诱导细胞自噬等方面综述了线粒体靶向纳米载体在肿瘤诊疗中的应用。     

Algorithm-based modular psychotherapy vs. cognitive-behavioral therapy for patients with depression,psychiatric comorbidities and early trauma: a proof-of-concept randomized controlled trial

Effect sizes of psychotherapies currently stagnate at a low-to-moderate level. Personalizing psychotherapy by algorithm-based modular procedures promises improved outcomes, greater flexibility, and a better fit between research and practice. However, evidence for the feasibility and efficacy of modular-based psychotherapy, using a personalized treatment algorithm, is lacking. This proof-of-concept randomized controlled trial was conducted in 70 adult outpatients with a primary DSM-5 diagnosis of major depressive disorder, a score higher than 18 on the 24-item Hamilton Rating Scale for Depression (HRSD-24), at least one comorbid psychiatric diagnosis according to the Structured Clinical Interview for DSM-5 (SCID-5), a history of at least “moderate to severe” childhood maltreatment on at least one domain of the Childhood Trauma Questionnaire (CTQ), and exceeding the cut-off value on at least one of three measures of early trauma-related transdiagnostic mechanisms: the Rejection Sensitivity Questionnaire (RSQ), the Interpersonal Reactivity Index (IRI), and the Difficulties in Emotion Regulation Scale-16 (DERS-16). Patients were randomized to 20 sessions of either standard cognitive-behavioral therapy alone (CBT) or CBT plus transdiagnostic modules according to a mechanism-based treatment algorithm (MoBa), over 16 weeks. We aimed to assess the feasibility of MoBa, and to compare MoBa vs. CBT with respect to participants’ and therapists’ overall satisfaction and ratings of therapeutic alliance (using the Working Alliance Inventory - Short Revised, WAI-SR), efficacy, impact on early trauma-related transdiagnostic mechanisms, and safety. The primary outcome for efficacy was the HRSD-24 score at post-treatment. Secondary outcomes included, among others, the rate of response (defined as a reduction of the HRSD-24 score by at least 50% from baseline and a score <16 at post-treatment), the rate of remission (defined as a HRSD-24 score ≤8 at post-treatment), and improvements in early trauma-related mechanisms of social threat response, hyperarousal, and social processes/empathy. We found no difficulties in the selection of the transdiagnostic modules in the individual patients, applying the above-mentioned cut-offs, and in the implementation of MoBa. Both participants and therapists reported higher overall satisfaction and had higher WAI-SR ratings with MoBa than CBT. Both approaches led to major reductions of depressive symptoms at post-treatment, with a non-significant superiority of MoBa over CBT. Patients randomized to MoBa were nearly three times as likely to experience remission at the end of therapy (29.4% vs. 11.4%; odds ratio, OR = 3.2, 95% CI: 0.9-11.6). Among mechanism-based outcomes, MoBa patients showed a significantly higher post-treatment effect on social processes/empathy (p<0.05) compared to CBT patients, who presented an exacerbation on this domain at post-treatment. Substantially less adverse events were reported for MoBa compared to CBT. These results suggest the feasibility and acceptability of an algorithm-based modular psychotherapy complementing CBT in depressed patients with psychiatric comorbidities and early trauma. While initial evidence of efficacy was observed, potential clinical advantages and interindividual heterogeneity in treatment outcomes will have to be investigated in fully powered confirmation trials.     

Purinergic ATP triggers moxibustion-induced local anti-nociceptive effect on inflammatory pain model

Purinergic signalling adenosine and its A1 receptors have been demonstrated to get involved in the mechanism of acupuncture (needling therapy) analgesia. However, whether purinergic signalling would be responsible for the local analgesic effect of moxibustion therapy, the predominant member in acupuncture family procedures also could trigger analgesic effect on pain diseases, it still remains unclear. In this study, we applied moxibustion to generate analgesic effect on complete Freund’s adjuvant (CFA)-induced inflammatory pain rats and detected the purine released from moxibustioned-acupoint by high-performance liquid chromatography (HPLC) approach. Intramuscular injection of {"type":"entrez-protein","attrs":{"text":"ARL67156","term_id":"1186396857","term_text":"ARL67156"}}ARL67156 into the acupoint Zusanli (ST36) to inhibit the breakdown of ATP showed the analgesic effect of moxibustion was increased while intramuscular injection of ATPase to speed up ATP hydrolysis caused a reduced moxibustion-induced analgesia. These data implied that purinergic ATP at the location of ST36 acupoint is a potentially beneficial factor for moxibustion-induced analgesia.