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Improving Detection of Somatic Mutations 改进体细胞突变的检测
Pub Date : 2019-01-01 DOI: 10.17303/jcrto.2019.7.101
T. Moorthy
J Cancer Res Therap Oncol 2019 | Vol 7: 101 Interest in this topic originated from studies on the detection of Braf p. V600E/K mutations using Allele Specific Multiplex Sequencing (ASMS) technology, which was compared to detection of Braf p. V600E by either SNapShot or Ion Torrent. Although there was no discordance among the positives, there was significant discordance among the negatives, indicative of potential false negatives by the latter two methods [1]. A similar pattern was observed when ASMS Braf p. V600E/K mutations was compared to an FDA approved Braf Test (ThxID) (unpublished data). Is there any clinical significance to such discordant results? If so, can testing protocols of somatic mutations be improved to accommodate for potential discrepancies among the test methods so that the results generated could be graded for meaningful clinical interpretation? There are at least four areas that could be affected by such discordant results;
对该主题的兴趣源于使用等位基因特异性多重测序(ASMS)技术检测Braf p. V600E/K突变的研究,并将其与SNapShot或Ion Torrent检测Braf p. V600E进行了比较。虽然阳性结果之间没有不一致,但阴性结果之间存在显著不一致,表明后两种方法可能存在假阴性[1]。当asm Braf p. V600E/K突变与FDA批准的Braf Test (ThxID)进行比较时,也观察到类似的模式(未发表的数据)。这种不一致的结果是否有临床意义?如果是这样,是否可以改进体细胞突变的测试方案,以适应测试方法之间的潜在差异,以便产生的结果可以分级,以进行有意义的临床解释?至少有四个领域可能受到这种不一致结果的影响;
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引用次数: 0
Pilot Study of the Antitumor Efficacy and Tolerability of Orally Administered Rrx-001 in Normal and Tumor-Bearing Mice 口服Rrx-001对正常小鼠和荷瘤小鼠抗肿瘤疗效和耐受性的初步研究
Pub Date : 2019-01-01 DOI: 10.17303/jcrto.2018.6.102
S. Knox
Purpose RRx-001 is a novel anticancer drug that will be entering Phase III clinical trials as a pre-sensitizer or resensitizer to chemotherapy and radiotherapy. To date, it has been very well tolerated, with the main adverse event being infusion-related reactions, consisting primarily of discomfort, itching and tingling at the site of infusion. The purpose of this preclinical pilot study was to study the antitumor efficacy and tolerability of oral administration of RRx-001 in a preclinical mouse model. Methods The maximum tolerated dose (MTD) of oral administration of RRx-001 was studied in normal C3H mice. For antitumor efficacy study, mice bearing SCC VII tumors were administered by oral gavage with RRx-001 either alone or in combination with external beam radiation therapy. Tumor growth delay time and body weight were used as the endpoints for antitumor efficacy and systemic toxicity. Results The estimated MTD for oral RRx-001 in 10% dimethyl sulfoxide (DMSO) daily for 5 days was 10-20 mg/kg. In tumor-bearing mice, oral dosing of RRx-001 at a total equivalent dose of 60 mg/kg, given either daily, or every other day, or as a single dose, significantly inhibited tumor growth (p < 0.01 vs. vehicle control). There were no statistically significant differences in tumor growth delay time among three treatment regimens (P > 0.05). However, a single dose of 60 mg/kg caused a 28% modality (2 death among 7 treated mice). When combined with local tumor radiation therapy, oral RRx-001 significantly increased the antitumor efficacy of radiation therapy (p = 0.02, combination vs. radiation alone). There were no obvious systemic or additional toxicities for combination of oral RRx-001 (10-20 mg/kg) and radiation therapy. Conclusion Oral administration of RRx-001 was safe and effective in the SCC VII tumor model in mice, and merits further study.
RRx-001是一种新型抗癌药物,将作为化疗和放疗的预增敏剂或再增敏剂进入III期临床试验。迄今为止,该药耐受性良好,主要不良事件是输注相关反应,主要包括输注部位的不适、瘙痒和刺痛。本临床前先导研究的目的是在临床前小鼠模型中研究口服RRx-001的抗肿瘤疗效和耐受性。方法对正常C3H小鼠口服RRx-001的最大耐受剂量进行研究。为了进行抗肿瘤疗效研究,我们将携带SCC VII肿瘤的小鼠单独或联合外束放射治疗灌胃RRx-001。肿瘤生长延迟时间和体重作为抗肿瘤疗效和全身毒性的终点。结果RRx-001在10%二甲亚砜(DMSO)中每日口服5 d,估计MTD为10 ~ 20 mg/kg。在荷瘤小鼠中,口服总当量剂量为60mg /kg的RRx-001,每天给药,或每隔一天给药,或单次给药,显著抑制肿瘤生长(与对照相比p < 0.01)。3个治疗方案间肿瘤生长延迟时间比较,差异均无统计学意义(P > 0.05)。然而,单次剂量60mg /kg引起28%的模式(7只治疗小鼠中2只死亡)。当联合局部肿瘤放疗时,口服RRx-001显著提高了放疗的抗肿瘤疗效(p = 0.02,联合放疗与单独放疗相比)。口服RRx-001 (10- 20mg /kg)和放疗联合使用没有明显的全身或额外的毒性。结论口服RRx-001对小鼠SCC - VII肿瘤模型安全有效,值得进一步研究。
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引用次数: 1
Retrospective Analysis of 5-Year Survival Rate of Nasopharyngeal Carcinoma: Correlation with Clinical Features and Prognosis 鼻咽癌5年生存率与临床特征及预后的相关性分析
Pub Date : 2019-01-01 DOI: 10.17303/jcrto.2019.7.102
Zhonglin Mu
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引用次数: 2
Treatment of Metastatic Sweat Gland Carcinomas: Response in Two Cases 转移性汗腺癌的治疗:两例疗效
Pub Date : 2019-01-01 DOI: 10.17303/jcrto.2019.7.104
L. Liqiong
Sweat gland carcinomas are a rare group of tumors with the potential of destructing local tissue infiltration as well as regional and distant metastasis. Due to the limited availability of reference from the literature, the management of sweat gland carcinomas is both complex and cumbersome. Sweat gland carcinomas can be divided into eccrine and apocrine categories and occur primarily in adult patients, with a peak incidence during the fifth and sixth decades [1-2]. The majority of sweat gland carcinomas occur in the genital skin and perineum, followed by the trunk, head, neck and lower extremities. Regional and distant lymph node metastases frequently occur in a certain number of patients, but visceral metastases are seldom found. The metastasis sites mainly include lymph nodes, lungs and bone [3-5]. According to the available literature, radical surgical excision is the prior and standard treatment with the clearance of draining lymph nodes [6]. Some chemotherapeutic drugs, such as fluoropyrimidines, taxanes and cisplatin, have been reported to be active agents for metastatic sweat gland carcinomas [2,7-8]. However, the effect of adjuvant chemotherapy and radiotherapy remain elusive, and classical standards of diagnosis and therapy are still not clarified. Here, we report two cases of metastatic sweat gland carcinomas. In one case, the remission of nearly 6 months was achieved through chemotherapy of GP regimen; while in another case, the size of draining axillary lymph nodes was effectively controlled by oral administration of tamoxifen.
汗腺癌是一种罕见的肿瘤,具有破坏局部组织浸润以及区域和远处转移的潜力。由于文献的可用性有限,汗腺癌的治疗既复杂又繁琐。汗腺癌可分为汗腺癌和大汗腺癌,主要发生于成年患者,发病率高峰在五、六十岁[1-2]。大多数汗腺癌发生在生殖器皮肤和会阴,其次是躯干、头部、颈部和下肢。局部和远端淋巴结转移常发生在一定数量的患者中,但内脏转移很少发现。转移部位主要包括淋巴结、肺和骨[3-5]。根据现有文献,根治性手术切除是清除引流淋巴结的首选和标准治疗方法[6]。一些化疗药物,如氟嘧啶、紫杉烷和顺铂,已被报道为转移性汗腺癌的活性药物[2,7-8]。然而,辅助化疗和放疗的效果仍然难以捉摸,经典的诊断和治疗标准仍然不明确。在此,我们报告两例转移性汗腺癌。1例通过GP方案化疗,缓解期近6个月;另一例腋窝淋巴结的引流大小通过口服他莫昔芬得到有效控制。
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引用次数: 0
Cancer as an Emergent Phenomenon? 癌症是一种突发现象?
Pub Date : 2018-06-01 DOI: 10.17303/JCRTO.2018.6.103
Anderson Km
Many biological events exhibit major features of emergent phenomena in which the detailed behavior of a collective ensemble of entities or agents is not predictable from summing their individual behaviors. The relationship between the emergent phenomena of evolution, including the development of cancer cells expressing apparently “random” genetic / epigenetic events and the influence of “scale” are also not yet widely understood or well defined. Presumably this uncertainty is also subject to further influence from non-oncologic random genetic and epigenetic events. A forward or a retrogressive evolution of individual cancer cells could be viewed as subsets of emergent phenomena in which random genetic / epigenetic events can also meld with other ongoing, underlying emergent processes, contributing to unpredictable outcomes. The extent to which such an interplay may subvert attempts at cancer therapy is not presently well identified nor are conditions that might promote or retard the incidence of random responses during the process. The rare reports of what may have included occasional random reversals of established cancers is another subject of interest. Some discussion of these questions seems merited.
许多生物事件表现出突现现象的主要特征,在这些现象中,实体或主体的集体集合的详细行为不能通过汇总它们的个体行为来预测。出现的进化现象,包括表达明显“随机”遗传/表观遗传事件的癌细胞的发展,与“规模”的影响之间的关系也尚未得到广泛理解或明确定义。据推测,这种不确定性还受到非肿瘤随机遗传和表观遗传事件的进一步影响。单个癌细胞的向前或倒退进化可以被视为突现现象的子集,其中随机遗传/表观遗传事件也可以与其他正在进行的潜在突现过程融合,导致不可预测的结果。这种相互作用在多大程度上可能会破坏癌症治疗的尝试,目前还没有很好地确定,也没有很好地确定在这一过程中可能促进或延缓随机反应发生率的条件。另一个有趣的话题是罕见的报告,其中可能包括已确定癌症的偶尔随机逆转。对这些问题进行一些讨论似乎是值得的。
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引用次数: 1
Primary Cultures Derived From Bovine Papillomavirus-Infected Lesions As Model To Study Metabolic Deregulation 牛乳头瘤病毒感染病变原代培养物作为研究代谢失调的模型
Pub Date : 2016-09-01 DOI: 10.17303/JCRTO.2016.4.103
R. C. Stocco
Bovine papillomavirus (BPV) is the etiological agent of bovine papillomatosis, disease characterized by the presence of multiple papillomas that can regress or to progress to malignances. Due to the pathological similarities with the human papillomavirus (HPV), BPV is considered a prototype to study the papillomavirus-associated oncogenic process. Although it is clear that both BPV and HPV can interact with host chromatin, the interaction of these viruses with cell metabolism remains understudied due to the little attention given to primary cultures derived from papillomavirus-infected lesions. Thus, this study analyzed the energy metabolism, including the mitochondrial membrane potential (ΔΨm) and Reactive Oxygen Species (ROS) of cells derived from cutaneous papilloma, fibropapilloma and Esophageal Carcinoma (EC) as model to evaluate the cell metabolism. These cells were cultivated until sixth passage and subjected to BPV DNA sequences identification by PCR using specific primers to BPV-1, 2 and 4. PCR results showed the presence and maintenance of at least one BPV type along the six passages analyzed. Cells derived from normal skin, without BPV DNA sequences were used as control. Results of energy metabolism showed the loss of ΔΨm in fibropapilloma and EC cells, suggesting a metabolic switch compatible to the activation of aerobic glycolysis. Cutaneous papilloma and normal skin cells showed the maintenance of ΔΨm. Paradoxically, cutaneous papilloma and fibropapilloma presented high levels of ROS production, while the EC cells reduced the ROS levels, reinforcing the activation of glycolytic metabolism. Our results suggest that the metabolic switch is mediated by BPV E6 oncoprotein, since the addition of this oncoprotein in normal cells promoted the oxidative stress. The oxidative stress showed able to activate the STAT3 nuclear factor in papilloma and fibropapilloma cells, contributing to metabolic deregulation. These data suggest that primary cultures are useful model to study the interaction between BPV and cell metabolism.
牛乳头状瘤病毒(BPV)是牛乳头状瘤病的病原,这种疾病的特征是存在多个乳头状瘤,可以退化或进展为恶性肿瘤。由于与人乳头瘤病毒(HPV)的病理相似,BPV被认为是研究乳头瘤病毒相关致癌过程的原型。虽然很明显BPV和HPV都可以与宿主染色质相互作用,但由于对乳头瘤病毒感染病变的原代培养物很少关注,这些病毒与细胞代谢的相互作用仍未得到充分研究。因此,本研究分析了皮肤乳头状瘤、纤维乳头状瘤和食管癌(EC)来源细胞的能量代谢,包括线粒体膜电位(ΔΨm)和活性氧(ROS)作为模型来评估细胞代谢。将这些细胞培养至第六代,利用BPV-1、2和4的特异性引物进行BPV DNA序列的PCR鉴定。PCR结果显示,在所分析的6个传代中至少存在并维持一种BPV型。无BPV DNA序列的正常皮肤细胞作为对照。能量代谢结果显示纤维乳头瘤细胞和EC细胞中ΔΨm的缺失,表明代谢开关与有氧糖酵解的激活相兼容。皮肤乳头瘤和正常皮肤细胞维持ΔΨm。矛盾的是,皮肤乳头瘤和纤维乳头瘤表现出高水平的ROS产生,而EC细胞降低了ROS水平,加强了糖酵解代谢的激活。我们的研究结果表明,代谢开关是由BPV E6癌蛋白介导的,因为在正常细胞中添加这种癌蛋白会促进氧化应激。氧化应激能够激活乳头状瘤和纤维乳头状瘤细胞中的STAT3核因子,促进代谢失调。这些数据表明,原代培养是研究BPV与细胞代谢相互作用的有效模型。
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引用次数: 6
Immunomodulatory Response Triggered by the Alkaloids, 3-Amino-7-Benzylbenzimidazo[3,2-a] Quinolinium Chloride (ABQ-48) and 3-Nitro-7-Benzylbenzimidazo [3,2-a] Quinolinium Chloride (NBQ-48). 生物碱3-氨基-7-苄基苯并咪唑[3,2-a]氯化喹啉(ABQ-48)和3-硝基-7-苄基苯并咪唑[3,2-a]氯化喹啉(NBQ-48)引发的免疫调节反应
Pub Date : 2015-05-04 DOI: 10.17303/jcrto.2015.103
Miguel Otero, Beatriz Zayas, Eric Miranda, Christian Velez, Wigberto J Hernandez, Luis A Rivera, Osvaldo Cox

ABQ-48 (3-amino-7-benzylbenzimidazo[3,2-a]quinolinium chloride) and NBQ-48 (3-nitro-7-benzylbenzimidaw[3,2-a] quinolinium chloride) are un-natural alkaloids containing a planar heteroaromatic systems characterized by quaternized nitrogen fused to benzothiazole nucleus. Both compounds are structurally related to naturally occurring substances such as elliptine (from Ochrosia), and berberine (from Berberis). Previous in vitro studies have shown these agents to control tumor-cell proliferation indicating that both BQS are active but especially ABQ-48 at a 1 OuM dose with over 80% control of the proliferation of multiple cancer cell lines from various etiologies including colon, melanoma, CNS and ovarian cells. Mechanism of action studies have also been conducted however this is the first approach to evaluate immune modulatory activity of these novel BQS. Immune-based therapy is an increasing field in which scientists identify how the immunomodulatory activity of known and newly discovered compounds elicits an immune response that could be used against diseases. In this study, our main objective was to apply an in vitro model to show the immunomodulatory effects of ABQ-48 and NBQ-48 by analyzing the cytokine profile resulting after extracted murine spleen cells were treated with both BQS using a fluorescence-based multiplex ELISA approach. Screened cytokines included: G-CSF, GM-CSF, IL-1a, IL-2, IL-3, IL-5, IL-6, IL-7, IL-10, IL-12p70, IL-13, IL-15, IL-17, IL-21, IL-23, IFN-γ, and TNF-α. Our study results show ABQ 48 and NBQ-48 to stimulate the release of G-CSF, IL-2, IL-6, and, IFN-γ when mouse splenocytes are incubated with serial dilutions of these agents. Our finding opens new possibilities of potentially using ABQ-48 and NBQ-48 as immunomodulatory agents; with intend to activate the immune system such as the production of neutrophils against cancer or reducing chemotherapy side effects.

ABQ-48(3-氨基-7-苄基苯并咪唑[3,2-a]氯代喹啉)和NBQ-48(3-硝基-7-苄基苯并咪唑[3,2-a]氯代喹啉)是一种非天然生物碱,含有以季铵化氮与苯并噻唑核融合为特征的平面杂芳香体系。这两种化合物在结构上都与天然存在的物质有关,如椭圆素(来自黄花属)和小檗碱(来自小檗属)。先前的体外研究表明这些药物可以控制肿瘤细胞的增殖,这表明这两种BQS都是有活性的,尤其是ABQ-48在1 OuM剂量下对多种病因的多种癌细胞系的增殖有80%以上的控制,包括结肠癌、黑色素瘤、中枢神经系统和卵巢细胞。作用机制研究也进行了,但这是第一次评估这些新型BQS的免疫调节活性的方法。基于免疫的治疗是一个新兴的领域,在这个领域中,科学家们发现了已知的和新发现的化合物的免疫调节活性如何引起免疫反应,从而可以用来治疗疾病。在这项研究中,我们的主要目的是利用基于荧光的多重ELISA方法,通过分析提取的小鼠脾细胞经两种BQS处理后的细胞因子谱,应用体外模型来显示ABQ-48和NBQ-48的免疫调节作用。筛选的细胞因子包括:G-CSF、GM-CSF、IL-1a、IL-2、IL-3、IL-5、IL-6、IL-7、IL-10、IL-12p70、IL-13、IL-15、IL-17、IL-21、IL-23、IFN-γ、TNF-α。我们的研究结果表明,ABQ -48和NBQ-48可以刺激G-CSF、IL-2、IL-6和IFN-γ的释放,当这些药物被一系列稀释后孵育小鼠脾细胞时。我们的发现为ABQ-48和NBQ-48作为免疫调节剂开辟了新的可能性;与意图激活免疫系统,如生产中性粒细胞对抗癌症或减少化疗的副作用。
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引用次数: 0
Post-mastectomy Hypofractionation Radiotherapy in Breast Cancer Patients 乳腺癌患者乳腺切除术后低分割放疗
Pub Date : 2014-12-01 DOI: 10.13189/cor.2014.020701
Elsayed M Ali, Magdy Khalil Abd AlMageed
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引用次数: 10
Lymphoma Caused by Intestinal Microbiota 肠道菌群引起的淋巴瘤
Pub Date : 2014-09-01 DOI: 10.13189/cor.2014.020601
Mitsuko L. Yamamoto, Robert H. Schiestl
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引用次数: 0
Mouse Models for Radiation-Induced Breast Cancer 辐射诱发乳腺癌小鼠模型
Pub Date : 2014-09-01 DOI: 10.13189/COR.2014.020602
Leena Rivina, Michael J Davoren, R. Schiestl, C. Young
Radiation is a widely known, and prototypical, inducer of genotoxic damage. With every moment of exposure to ionizing radiation, lesions and breaks are induced in the DNA, increasing an individual's lifetime risk of developing cancer. At the same time, radiation therapy is a key part of the effective treatment of the very same disease. Radiation therapy is effective, capable of shrinking and even eliminating tumors. In conjunction with surgery, its use is extremely common for the treatment of breast cancer. Even when radiation is our ally, however, the risks remain. Therapeutic use to treat existing cancers paradoxically leads to the incidence of secondary, radiation-induced neoplasias. One strategy to reduce this secondary risk while still encouraging the use of radiotherapy to its full potential would be the development co-administered therapeutic compounds or strategies designed to preferentially protect healthy cells while leaving cancer cells vulnerable. The development and efficacy testing such agents would require not only extensive in vitro testing, but also a well investigated set of in vivo models to actively recapitulate the complex nature of radiation-induced carcinogenesis. The laboratory mouse Mus musculus is probably the best choice for this endeavor. As a cancer model it possesses a combination of favorable attributes: a well annotated genome, molecular and physiological similarities with man and other mammals, and a small size and high breeding rate for ease of use. This work will focus on the description of m. musculus inbred and F1 hybrid animal models of radiation-induced breast cancers and their associated molecular pathologies.
辐射是一种众所周知的、典型的基因毒性损伤诱导剂。每时每刻暴露在电离辐射下,DNA都会发生损伤和断裂,从而增加个体一生患癌症的风险。与此同时,放射治疗是有效治疗同一疾病的关键部分。放射治疗是有效的,能够缩小甚至消除肿瘤。与外科手术相结合,它在乳腺癌的治疗中非常普遍。然而,即使辐射是我们的盟友,风险仍然存在。治疗性使用来治疗现有的癌症矛盾地导致继发性,放射诱导的肿瘤的发生。减少这种继发性风险,同时仍鼓励充分利用放射治疗的一种策略是开发共同施用的治疗化合物或策略,旨在优先保护健康细胞,同时使癌细胞易受伤害。这些药物的开发和疗效测试不仅需要广泛的体外测试,还需要一套充分研究的体内模型,以积极概括辐射诱发致癌的复杂性质。实验用的小家鼠可能是最好的选择。作为一种癌症模型,它具有多种有利的属性:基因组注释良好,与人类和其他哺乳动物在分子和生理上相似,体积小,繁殖率高,便于使用。本工作将着重于描述肌支原体近交系和F1杂交动物模型及其相关的分子病理。
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引用次数: 0
期刊
Journal of Cancer Research and Therapeutic Oncology
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