miRNA-21表达上调作为子宫颈癌患者疾病诊断标志物探讨

目的 本文旨在探讨miRNA-21表达上调作为子宫颈癌患者疾病诊断标志物的可行性.方法 提取30例子宫颈癌患者新鲜肿瘤样本和临近非肿瘤样本的总RNA,以U6为内参基因,采用定量PCR方法检测样本中miR-21-3p和miR-21-5p的表达水平,分析miR-21-3p和miR-21-5p的表达与子宫颈癌患者临床病理学特征的关系.结果 与临近非肿瘤组织相比,HPV阳性的子宫颈癌患者miR-21-3p和miR-21-5p的表达水平上调(P＜0.05).多重变量分析结果表明miR-21表达相关的临床病理学因素包括肿瘤侵入深度和淋巴结转移.结论 本研究结果表明,miRNA-21表达上调与子宫颈癌的侵袭和患者预后不良有关,miRNA-21表达检测可以作为子宫颈癌患者疾病预后的独立肿瘤标志物.     

Nineteen-year single-center experience in 76 patients with penile cancer treated with high-dose-rate brachytherapy

PURPOSETo report the outcomes for 76 patients with penile cancer treated with high-dose-rate brachytherapy (HDR-BT) at a single institution.METHODSSeventy-six patients with penile cancer treated with HDR-BT in our department between October 1998 and September 2018 were analyzed. Seventy underwent interstitial HDR-BT (fractionation dose range of 3–3.5 Gy given twice a day with an interval of at least six hours between the fractions), and six underwent superficial treatment with mold applicators (fractionation dose range of 4–7 Gy given once or twice a week).RESULTSMedian follow-up was 76 months (7–204 months). In the whole group, 22/76 local failures (28.9%) were observed: 14/76 (18.4%) local recurrences and 8/76 (10.5%) cases of persistent disease. Median time to recurrence was 24 months (9–54 months). Inguinal lymph node metastases were observed in 18/76 cases (23.7%). Distant metastases occurred in 12/76 (15.8%) cases. Patients with local recurrence and persistent disease underwent salvage penectomies, except four who refused surgery and underwent a second course of interstitial HDR-BT. Five- and 10-year cause-specific survival were 85.0% and 77.8%, respectively. Local control at 5 and 10 years was 65.6%. Five- and 10-year penile preservation were 69.5% and 66.9%, respectively. There was no G3 or G4 acute toxicity. One urethral stenosis (1.3%) occurred in a patient with a T3 tumor and was treated successfully with dilatation.CONCLUSIONSHDR-BT provides good local control of penile cancer and is a good option for penis preservation therapy and in our experience achieves a penile preservation rate at 10 years of 66.9%.     

大孔树脂纯化柽柳总黄酮工艺的研究

目的 研究D-101大孔吸附树脂分离纯化柽柳总黄酮的工艺条件. 方法 以柽柳总黄酮为指标,对上样量、吸附时间、洗脱速度、乙醇浓度和上样药液pH进行考察. 结果大孔树脂分离柽柳总黄酮的最佳工艺条件为上样量15 mL,pH 6～7,吸附30 min,流速3 BV.h^-1,乙醇浓度70%,乙醇用量3 BV. 结论 D-101大孔吸附树脂能有效分离纯化柽柳总黄酮.     

苯丙氨酸二肽类化合物Y101对刀豆蛋白A致小鼠免疫性肝损伤的保护作用

目的:观察苯丙氨酸二肽类化合物Y101(简称Y101)对刀豆蛋白A(CnoA)致小鼠免疫性肝损伤的保护作用,并探讨其可能的作用机制。方法:将昆明种小鼠随机分为生理盐水组、CnoA模型组、Y101低、中、高(25,50,100 mg.kg-1)剂量组和联苯双酯组(LB,150 mg.kg-1)。除生理盐水组外,CnoA模型组和各给药组均于d 5和d 7给药1 h后尾静脉注射20 mg.kg-1 CnoA溶液使之中毒(按0.1 mL/10 g体重)。末次中毒后禁食不禁水,8 h后眼球取血,并迅速取肝脏备检。检测其血清中谷丙转氨酶(ALT)、谷草转氨酶(AST)含量。取肝脏,称重,检测肝脏中丙二醛(MDA)、一氧化氮(NO)、超氧化物歧化酶(SOD)、谷胱甘肽(GSH)的含量;另取肝脏做病理组织学检查。结果:与正常组比较,模型组小鼠血清中ALT、AST活性,肝内MDA、NO含量及肝脾指数显著升高(P<0.01),肝内SOD、GSH水平及胸腺指数明显降低(P<0.01)。低、中、高剂量Y101对肝损伤大鼠上述指标均有不同程度的改变,且呈良好的剂量关系。给予Y101治疗后,中、高剂量组的肝组织病理变化均明显轻于模型组。结论:Y101对CnoA致小鼠免疫性肝损伤具有保护作用,其作用机制可能与其抗氧化作用有关。     

Selective PI3Kδ inhibitors,a review of the patent literature

Introduction: Phosphatidylinositol 3-kinase (PI3K), a lipid kinase, is the first kinase involved in, and a key component of, the PI3K/Akt/mTOR signalling pathway, and is significantly upregulated in many cancers. However, four distinct isoforms of PI3K are known with different expression patterns and different pathophysiological roles. The PI3Kδ isoform is expressed in leukocytes and has been implicated as a potential target in the development of selective inhibitors for the treatment of haematological malignancies and various inflammatory diseases.

Areas covered: This review briefly covers the understanding of the four PI3K isoforms and their roles and the inhibitors selective for either one or two isoforms that have been identified to date. It then focuses upon progress in the identification of selective PI3Kδ inhibitors focusing upon the original efforts at ICOS/Calistoga that led to the initial clinical candidates such as CAL-101. After assessing the patent filings from these companies, it considers filings from other players and how they have sought to explore similar, and structurally distinct, scaffolds in their search for selective inhibitors, and how different companies appear focused on either oncological or anti-inflammatory uses for their inhibitors.

Expert opinion: The impact of the work at ICOS is highlighted by the fact that prior to their disclosure of selective leads, no patent applications claiming selective PI3Kδ inhibitors had been filed by other companies. This disclosure, followed by the first filings by Piramed, led to an upsurge in interest with a large cluster of filings published in 2008 while half the relevant applications were published in 2010 or 2011. These efforts, and the initial clinical data on CAL-101, the leading PI3Kδ inhibitors, have also prompted a number of commercially significant deals. In addition to an increasing number of filings, the entry into the clinical development of more selective PI3Kδ inhibitors should stimulate a better understanding of the role of this specific kinase isoform.     

New phosphatidylinositol 3-kinase inhibitors for cancer

Introduction: Cancer treatment is moving away from conventional cytotoxic drugs and towards agents that target specific proteins important to cancer development or survival. The PI3K signaling axis is an important pathway involved in myriad human malignancies. Inhibition of this axis is a promising therapeutic approach for several cancers.

Areas covered: This article reviews current literature and recent conference proceedings to analyze the rationale for targeting PI3K and its downstream effectors in cancer. Preclinical and clinical results of several PI3K and PI3K–mammalian target of rapamycin (mTOR) inhibitors in early clinical trials, as single agents and in combination with other drugs, are discussed. Thus far, clinical results have been mixed.

Expert opinion: The clinical utility of PI3K and PI3K–mTOR inhibitors will depend on appropriate selection of patients. Mutations in the PI3K pathway may predict sensitivity to PI3K inhibition but they are not reliable biomarkers at this point. Efforts to define predictive biomarkers will probably be the key to finding therapeutic uses for this novel class of anticancer agents.     

Serotonin 2A receptor antagonists for treatment of schizophrenia

Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D₂) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia.

Areas covered: Preclinical, clinical and post-mortem studies of the serotonin 5-HT_2A system in schizophrenia are reviewed. The implications of a combined D₂ and 5-HT_2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT_2A receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT_2A receptor antagonists for the treatment of schizophrenia.

Expert opinion: 5-HT_2A receptor antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT_2A receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT_2A receptor antagonist will need substantial additional validation to be approved as a new treatment strategy against schizophrenia.     

MF101: a multi-component botanical selective estrogen receptor beta modulator for the treatment of menopausal vasomotor symptoms

Calcium channel antagonists have become popular medications for the management of hypertension. These agents belong to the diphenylalkylamine, benzothiazepine, dihydropyridine, or tetralol chemical classes. Although the medications share a common pharmacological mechanism in reducing peripheral vascular resistance, clinical differences between the sub-classes can be linked to structural profiles. This heterogeneity is manifested by differences in vascular selectivity, effects on cardiac conduction and adverse events. The lack of differentiation between calcium channel antagonists in clinical trials has contributed to uncertainty associated with their impact on morbidity and mortality. Data from more recent studies in specific patient populations underscores the importance of investigating these antihypertensives as individual agents. A proposed therapeutic classification system suggests that newer agents should share the slow onset and long-acting antihypertensive effect of amlodipine. Additionally, a favourable trough-to-peak ratio has been recommended as an objective measurement of efficacy. The newer drugs, barnidipine and lacidipine, have a therapeutic profile similar to amlodipine, but trough-to-peak ratios are not substantially greater than the recommended minimum of 0.50. Aranidipine, cilnidipine and efonidipine have unique pharmacological properties that distinguish them from traditional dihydropyridines. Although clinical significance is unconfirmed, these newer options may be beneficial for patients with co-morbid conditions that preclude use of older antagonists.