多种复方中药注射液治疗小鼠化疗相关白细胞减少症

目的: 比较5种常用复方中药注射液和粒细胞集落刺激因子（G-CSF）治疗化疗相关白细胞减少症小鼠的疗效,以及对小鼠多脏器及胸腺的影响。方法: 采用环磷酰胺腹腔注射法制备小鼠化疗相关白细胞减少症模型,以G-CSF为阳性对照,用5种复方中药注射液（康艾、复方苦参、参附、参麦和生脉注射液）对各治疗组小鼠分别腹腔注射给药,隔天抽取外周血测血常规,随后处死小鼠,取心脏血测血清肝、肾功能指标（ALT,AST,BUN和CR）,取重要脏器（心、肝、脾、肺、肾）及胸腺计算相应脏器指数,并比较各组病理变化,以评价各治疗组的疗效和对多脏器及胸腺的影响。结果: 5个中药治疗组小鼠的白细胞计数较模型组显著上升（P<0.01）,但低于阳性对照组（G-CSF）（P<0.05,P<0.01）。此外,5种复方中药注射液和G-CSF均有不同程度的升血小板作用（P<0.05,P<0.01）。与模型组相比,苦参治疗组（P=0.036）、参附治疗组（P=0.008）的血清AST略升高;各中药治疗组的血清ALT和肾功能指标未见明显升高,但是,脾脏指数下降（P<0.05或P<0.01）,肺脏指数增加（P<0.01）。各中药治疗组小鼠肝细胞可见不同程度的细胞变性、点状坏死和炎症反应,但组间差别不明显。除苦参治疗组外,其余中药治疗组的肝脏病理评分均显著低于模型组（P<0.05,P<0.01）,其中生脉治疗组最明显（P<0.01）。结论: 5种中药注射液均能有效治疗化疗相关白细胞减少症,其作用弱于G-CSF。5种中药注射液和G-CSF还有一定升血小板作用。除苦参外,其余4种中药注射液可能有一定护肝作用。5种中药注射液对其他脏器和胸腺的影响不明显。     

Targeting Cancer Stem Cells with Small Molecules

Cancers arise as a result of physiological imbalances and subsequent uncontrolled cell division. Cancer initiation requires a set of biochemical alterations, including some occurring at the genetic and epigenetic levels. Thus, tumors are heterogeneous in nature making it challenging to selectively target different cancer cells by means of small molecule intervention. The paradigm of cancer stem cells (CSCs) describes subpopulations of cells with high self-renewal and tumor-seeding capacity. These cells, typically refractory to conventional therapies, can give rise to relapse after treatment. Combinatorial strategies, including drugs that selectively target this population of cells, have emerged in recent years. Here, we review how discovery-based – unbiased – screening approaches 1 have helped identify small molecules that specifically target CSCs. We also highlight biological pathways characteristic of CSCs that can potentially be selectively targeted in a hypothesis-driven manner by small molecules. We describe molecules that effectively target CSCs and emphasize what is known about their biological modes of action. The diversity and complexity of biochemical processes that CSCs may be addicted to, raises the question of how selective targeting of these pathways can be achieved. This challenge may be addressed by the continuing production of structurally complex and diverse small molecules using target and diversity-oriented synthesis approaches. 2     

Structure-Based Drug Design of Phenazopyridine Derivatives as Inhibitors of Rev1 Interactions in Translesion Synthesis

Rev1 is a protein scaffold of the translesion synthesis (TLS) pathway, which employs low-fidelity DNA polymerases for replication of damaged DNA. The TLS pathway helps cancers tolerate DNA damage induced by genotoxic chemotherapy, and increases mutagenesis in tumors, thus accelerating the onset of chemoresistance. TLS inhibitors have emerged as potential adjuvant drugs to enhance the efficacy of first-line chemotherapy, with the majority of reported inhibitors targeting protein-protein interactions (PPIs) of the Rev1 C-terminal domain (Rev1-CT). We previously identified phenazopyridine (PAP) as a scaffold to disrupt Rev1-CT PPIs with Rev1-interacting regions (RIRs) of TLS polymerases. To explore the structure-activity relationships for this scaffold, we developed a protocol for co-crystallization of compounds that target the RIR binding site on Rev1-CT with a triple Rev1-CT/Rev7^R124A/Rev3-RBM1 complex, and solved an X-ray crystal structure of Rev1-CT bound to the most potent PAP analogue. The structure revealed an unexpected binding pose of the compound and informed changes to the scaffold to improve its affinity for Rev1-CT. We synthesized eight additional PAP derivatives, with modifications to the scaffold driven by the structure, and evaluated their binding to Rev1-CT by microscale thermophoresis (MST). Several second-generation PAP derivatives showed an affinity for Rev1-CT that was improved by over an order of magnitude, thereby validating the structure-based assumptions that went into the compound design.     

Potential Effects of Phytoestrogen Genistein in Modulating Acute Methotrexate Chemotherapy-Induced Osteoclastogenesis and Bone Damage in Rats

Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg) were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc) of MTX (0.75 mg/kg). MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001), increased osteoclast density on the trabecular bone surface (p < 0.05), and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001). Genistein supplementation preserved body weight gain (p < 0.05) and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001). However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage.     

奥美拉唑在晚期非小细胞肺癌患者化疗中的疗效观察

目的观察奥美拉唑在晚期非小细胞肺癌患者化疗中的临床应用价值。方法将67例晚期非小细胞肺癌（Ⅳ期）患者按随机数字表法分为观察组（n=37）和对照组（n=30）,2组均给予含铂两药联合化疗方案进行治疗。对照组在化疗第1天给予常规止吐药恩丹西酮、地塞米松、胃复安等;观察组在化疗第1天给予常规止吐药后,另给予奥美拉唑40mg静脉注射,开始每12h1次,1～2d后改为每日1次,用至化疗结束后1～2d。对2组患者出现的胃肠道反应和原始化疗方案疗程次数进行比较。结果观察组恶心、呕吐总有效率分别为89．2％、75．7％,对照组恶心、呕吐总有效率分别为66．7％、63．3％,2组比较差异均有统计学意义（均P〈0．05）。观察组原始化疗方案疗程次数多于对照组（P〈0．05）。结论奥美拉唑对化疗药物引起的胃肠道反应有一定的预防作用,对延缓化疗药物耐药可能有一定作用。     

How to manage locally advanced primary and recurrent cancer of the uterine cervix: The surgeon's view

Locally advanced cancer of the uterine cervix covers a broad disease spectrum comprising primary tumours of >4 cm in size or FIGO stage >IIA and all local tumour relapses except the rare cases of small recurrences in a retained cervix. Treatment designs have to consider the probability of pelvic and periaortic lymph node metastases and – albeit less frequent in primary disease – distant metastases.Established treatment standards aiming to achieve pelvic and eventually periaortic tumour control are chemoradiation for locally advanced primary disease as well as post-surgical pelvic recurrences, and pelvic exenteration for post-radiation central relapses. A subset of patients with pelvic side wall relapses can now be successfully treated by laterally extended endopelvic resection as well. Based on the current results it is not evident whether neoadjuvant chemotherapy, radical hysterectomy and eventually adjuvant radiation are comparable or superior treatment alternatives for locally advanced intermediate stage cases. Likewise, the benefit of (laparoscopic) surgical staging including the exstirpation of bulky pelvic and periaortic lymph nodes has not been convincingly demonstrated to date. Both surgical treatment concepts need further well-designed prospective randomized trials for their evaluation. From the surgeon's perspective total mesometrial resection, therapeutic lymph node dissection, laterally extended endopelvic resection and new developments in restoration/substitution of pelvic functions have the potential to improve the therapeutic index for defined cohorts of patients suffering from locally advanced cancer of the uterine cervix.     

放线菌素D单日冲击疗法治疗低危妊娠滋养细胞肿瘤

目的探讨放线菌素D(Actinomycin D,Act-D)单日冲击疗法用于低危妊娠滋养细胞肿瘤(low-risk gestational trophoblastic neoplasia,LRGTN)患者的疗效及安全性。方法回顾性分析2012年1月至2015年10月北京协和医院95例接受Act-D单日冲击化疗方案治疗的LRGTN患者临床资料,对不同临床特征的疗效进行统计学分析,随诊血清人绒毛膜促性腺激素(β-human chorionic gonadotropin,β-h CG)水平评价治疗效果,并根据美国国家癌症研究所-不良事件通用术语标准评估化疗毒副反应的严重程度。结果 95例患者中,79例经Act-D单日冲击疗法治疗后达到血清学完全缓解,完全缓解率83.2%(79/95),总疗程平均(4.4±1.3)程(1~8程),不同临床特征之间完全缓解率差异无统计学意义(P>0.05);16例患者因无效或耐药更改联合化疗方案后均达到血清学完全缓解。所有患者严重毒副反应发生率仅1.1%(1/95)。患者病情完全缓解后平均随诊(11.6±9.0)个月,3例复发,复发率3.8%。结论 Act-D单日冲击化疗方案用于治疗LRGTN安全有效,且具备简便、耐受性好等优点,可作为LRGTN一线化疗方案。     

Magnetic biliary stent targeting to treat hepatoma combining with magnetic nanoparticles

To evaluate the effect of targeting to hepatoma treated by magnetic biliary stent combining with magnetic nanoparticle containing 5-fluorouracil （5-FU）, thirty-two nude mice modes with transplanted hepatoma were divided equally into four groups randomly. Experimental group received magnetic biliary stent and magnetic nanoparticles containing 5-FU. The tumor volume and pathomorphology of all groups was measured. The tumor control rate of the experimental group provided magnetic biliary stent wires and magnetic nanoparticles containing 5-FU is remarkably higher than three other control groups, showing significant curative effect. More apoptosis of tumor cells could be detected easily in experimental group. There are more apoptotic bodies and phagotrophic magnetic particle in apoptosis cells of experimental group under electron microscope. Magnetic biliary stent combining with magnetic nanoparticle containing 5-FU could inhibit the growth of hepatoma, and its curative effect is more remarkable than the traditional methods based on external magnetic fields.     

Clinically relevant cancer chemotherapy dose scheduling via mixed-integer optimization

Cancer is a class of diseases characterized by an imbalance between cell proliferation and programmed cell death. Chemotherapy is commonly employed as a treatment by clinicians, who must deliver the agent on a schedule that balances treatment efficacy with the toxic side effects. Engineers have considered the development of drug administration schedules for simulated cancer patients constrained by pharmacokinetic (PK) and pharmacodynamic (PD) models. The results typically involve mathematically elegant solutions, although the clinical utility of such results is limited by the formulation of the problem as well as the level of abstraction. At issue is the common disconnect between solutions that are mathematically vs. clinically optimal. The focus of this work is to develop a methodology which can explicitly account for the constraints clinicians consider implicitly. To demonstrate the clinical relevance of this methodology two case studies were considered: a theoretical system from the literature and a preclinical mouse model. The problem formulation is accomplished in a mixed-integer programming framework that is capable of solving problems with complex objectives and constraints yielding results that are clinically relevant.