RANK ligand inhibition plus docetaxel improves survival and reduces tumor burden in a murine model of prostate cancer bone metastasis

Tumor cells induce excessive osteoclastogenesis, mediating pathologic bone resorption and subsequent release of growth factors and calcium from bone matrix, resulting in a "vicious cycle" of bone breakdown and tumor proliferation. RANK ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. In metastatic prostate cancer models, RANKL inhibition directly prevents osteolysis via blockade of osteoclastogenesis and indirectly reduces progression of skeletal tumor burden by reducing local growth factor and calcium concentrations. Docetaxel, a well-established chemotherapy for metastatic hormone-refractory prostate cancer, arrests the cell cycle and induces apoptosis of tumor cells. Suppression of osteoclastogenesis through RANKL inhibition may enhance the effects of docetaxel on skeletal tumors. We evaluated the combination of the RANKL inhibitor osteoprotegerin-Fc (OPG-Fc) with docetaxel in a murine model of prostate cancer bone metastasis. Tumor progression, tumor area, and tumor proliferation and apoptosis were assessed. OPG-Fc alone reduced bone resorption (P < 0.001 versus PBS), inhibited progression of established osteolytic lesions, and reduced tumor area (P < 0.0001 versus PBS). Docetaxel alone reduced tumor burden (P < 0.0001 versus PBS) and delayed the development of osteolytic lesions. OPG-Fc in combination with docetaxel suppressed skeletal tumor burden (P = 0.0005) and increased median survival time by 16.7% (P = 0.0385) compared with docetaxel alone. RANKL inhibition may enhance docetaxel effects by increasing tumor cell apoptosis as evident by increased active caspase-3. These studies show that inhibition of RANKL provides an additive benefit to docetaxel treatment in a murine model of prostate cancer bone metastasis and supports clinical evaluation of this treatment option in patients.     

Antileishmanial activity of parthenolide, a sesquiterpene lactone isolated from Tanacetum parthenium

The in vitro activity of parthenolide against Leishmania amazonensis was investigated. Parthenolide is a sesquiterpene lactone purified from the hydroalcoholic extract of aerial parts of Tanacetum parthenium. This isolated compound was identified through spectral analyses by UV, infrared, (1)H and (13)C nuclear magnetic resonance imaging, DEPT (distortionless enhancement by polarization transfer), COSY (correlated spectroscopy), HMQC (heteronuclear multiple-quantum coherence), and electron spray ionization-mass spectrometry. Parthenolide showed significant activity against the promastigote form of L. amazonensis, with 50% inhibition of cell growth at a concentration of 0.37 microg/ml. For the intracellular amastigote form, parthenolide reduced by 50% the survival index of parasites in macrophages when it was used at 0.81 microg/ml. The purified compound showed no cytotoxic effects against J774G8 macrophages in culture and did not cause lysis in sheep blood when it was used at higher concentrations that inhibited promastigote forms. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis with gelatin as the substrate showed that the enzymatic activity of the enzyme cysteine protease increased following treatment of the promastigotes with the isolated compound. This finding was correlated with marked morphological changes induced by parthenolide, such as the appearance of structures similar to large lysosomes and intense exocytic activity in the region of the flagellar pocket, as seen by electron microscopy. These results provide new perspectives on the development of novel drugs with leishmanicidal activities obtained from natural products.     

GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS-induced lung cancer

Protein geranylgeranyltransferase type I (GGTase-I) is responsible for the posttranslational lipidation of CAAX proteins such as RHOA, RAC1, and cell division cycle 42 (CDC42). Inhibition of GGTase-I has been suggested as a strategy to treat cancer and a host of other diseases. Although several GGTase-I inhibitors (GGTIs) have been synthesized, they have very different properties, and the effects of GGTIs and GGTase-I deficiency are unclear. One concern is that inhibiting GGTase-I might lead to severe toxicity. In this study, we determined the effects of GGTase-I deficiency on cell viability and K-RAS-induced cancer development in mice. Inactivating the gene for the critical beta subunit of GGTase-I eliminated GGTase-I activity, disrupted the actin cytoskeleton, reduced cell migration, and blocked the proliferation of fibroblasts expressing oncogenic K-RAS. Moreover, the absence of GGTase-I activity reduced lung tumor formation, eliminated myeloproliferative phenotypes, and increased survival of mice in which expression of oncogenic K-RAS was switched on in lung cells and myeloid cells. Interestingly, several cell types remained viable in the absence of GGTase-I, and myelopoiesis appeared to function normally. These findings suggest that inhibiting GGTase-I may be a useful strategy to treat K-RAS-induced malignancies.     

赫赛汀与多西他赛联合应用治疗HER-2阳性转移性乳腺癌疗效分析

目的分析赫赛汀与多西他赛联合应用治疗人类表皮生长因子受体-2(HER-2)过表达的转移性乳腺癌的临床疗效。方法随机选取2011年1月至2013年12月期间收治的39例HER-2阳性的转移性乳腺癌患者,分成观察组和对照组。观察组给予赫赛汀联合多西他赛方案化疗,对照组给予赫赛汀联合长春瑞滨方案化疗。观察对比两组临床疗效及不良反应。结果观察组总有效为21例(78.8%),患者临床受益为23例(85.2%);对照组总有效为5例(41.7%),患者临床受益为7例(58.3%)。观察组总有效率显著优于对照组,差异具有统计学意义(P0.05);两组临床受益率对比,差异无统计学意义(P0.05)。两组患者临床不良反应均不明显,主要不良反应表现为发热、皮疹、骨髓抑制以及胃肠道不适。结论赫赛汀与多西他赛联合应用治疗HER-2阳性转移性乳腺癌具有良好的临床疗效及安全性,值得临床推广应用。     

重组人血管内皮抑素联合人参皂甙Rg3抑制裸鼠乳腺癌新生血管的动物实验研究

目的探讨重组人血管内皮抑素(Endostar,YH-16,恩度)联合人参皂甙Rg3抑制裸鼠乳腺癌的作用。方法取20只雌性裸小鼠,建立荷瘤鼠模型,随机分成4组,每组5只。Rg3单药组、重组人血管内皮抑素单药组、两药联合组、生理盐水对照组。隔日一次,腹腔注射,治疗时间为d1~d21。用药期间隔2 d测量裸鼠体重、计算瘤体积。用药结束3 d后处死动物,解剖瘤块称重,计算抑瘤率。免疫组化法测定肿瘤血管内皮生长因子(VEGF)、基质金属蛋白酶9(MMP-9)的表达水平。结果两药联合组体重增加,与生理盐水对照组相比,裸鼠的体重差异有统计学意义(P=0.047);各用药组均可抑制肿瘤的生长,两药联合组的抑瘤率最高,分别为(12.5±1.13)%、(11.76±1.08)%和(32.35±2.45)%;两药联合组与重组人血管内皮抑素单药组及Rg3单药组相比,VEGF及MMP-9表达水平差异有统计学意义(P<0.05)。结论 重组人血管内皮抑素与人参皂甙Rg3联合应用对抑制裸鼠乳腺癌的血管生成具有协同作用,可有效抑制肿瘤生长。     

Photodynamic therapy reduces metastasis of breast cancer by minimizing circulating tumor cells

Cancer metastasis after traditional surgery introduces a high barrier to therapy efficacy. Photodynamic therapy (PDT) for cancer is based on a photochemical process of photosensitizers that concentrate in tumors and release oxidant species under light excitation to destroy cells. Compared with traditional surgery, PDT provides minimal invasion and targeted therapy. In this in vivo study, we monitor the real-time and long-term dynamics of circulating tumor cells (CTCs) after a single round of PDT and after surgical resection in a breast cancer animal model. The CTC level is low after PDT treatment, and the recurrence of the primary tumor is postponed in the PDT group compared with the resection group. We find that metastasis is correlated with the CTC level, and the PDT-treated mice show no metastasis in the lung or liver. Our results suggest PDT can effectively reduce metastasis by minimizing CTCs after treatment and is a great technology for breast cancer therapy.     

多西紫杉醇、表阿霉素、环磷酰胺联合化疗与序贯化疗对乳腺癌患者空腹血糖的影响

目的:比较乳腺癌患者术后应用TEC方案与EC-T方案化疗对空腹的血糖影响.方法:回顾性研究TEC方案患者114例,EC-T方案患者99例,统计每例患者每周期化疗前空腹血糖,分析两种化疗方案对患者血糖的影响.结果:EC-T方案组有4例患者空腹血糖水平异常增高,TEC组有12例患者空腹血糖水平异常增高,两者比较差异有显著性.结论:EC-T方案升高患者空腹血糖水平的作用小于TEC方案,在病情允许情况下,尽可能将TEC方案改为EC-T方案,以降低患者化疗导致血糖升高甚至糖尿病的风险.     

Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock

Objective Current therapies of sepsis and septic shock require administration of a large volume of fluid to maintain hemodynamic stability. The vasoregulatory peptide adrenomedullin has been shown to prevent the transition to the fatal hypocirculatory septic state by poorly understood mechanisms. We tested the hypothesis that therapeutic administration of adrenomedullin would reduce vascular hyperpermeability, thereby contributing to improved hemodynamics and survival. Design Prospective randomized controlled animal study. Subjects Male Sprague–Dawley rats (270 g). Interventions We used 4.8 × 10³ U/kg of Staphylococcus aureus α-toxin, a pore-forming exotoxin, to induce vascular leakage and circulatory shock in rats. The infusion rate was 24 μg/kg per hour. Adrenomedullin was started 1 h after α-toxin administration. Measurement and results Infusion of α-toxin in rats induced cardiocirculatory failure resulting in a 6-h mortality of 53%. α-Toxin provoked massive vascular hyperpermeability, which was indicated by an enrichment of Evans blue dye albumin in the tissues of lung, liver, ileum and kidney. Plasma fluid loss led to a significant hemoconcentration. Hemodynamic impairment observed after α-toxin infusion was closely correlated to vascular hyperpermeability. Therapeutic administration of 24 μg/kg per hour adrenomedullin reduced 6-h mortality from 53% to 7%. Stabilization of the endothelial barrier by adrenomedullin was indicated by reduced extravasation of albumin and plasma fluid and may have contributed to hemodynamic improvement. Conclusions These data suggest that adrenomedullin-related reduction of vascular hyperpermeability might represent a novel and important mechanism contributing to the beneficial effects of this endogenous vasoregulatory peptide in sepsis and septic shock. Electronic supplementary material The online version of this article () contains supplementary material, which is available to authorized users. Bettina Temmesfeld-Wollbrück and Bernhard Brell contributed equally to this study     

Androstenetriol improves survival in a rodent model of traumatic shock

Trauma results in activation of the hypothalamic-pituitary-adrenal axis to mediate a cascade of neurohormonal changes as a defensive mechanism. Its prolongation, however, leads to a hypermetabolic, hypoperfused, and immunosuppressed state, setting the stage for subsequent sepsis and organ failure. Androstenetriol (5-androstene-3beta, 7beta, 17betatriol - AET), a metabolite of dehydroepiandrosterone, up-regulates the host immune response markedly, prevents immune suppression and controls inflammation, leading to improved survival after lethal infections by several diverse pathogens and lethal radiation. Such actions may be useful in improving survival from traumatic shock. HYPOTHESIS: The neurosteroid AET will increase survival following traumatic shock. METHODS: A combat relevant model of traumatic shock was used. Male Sprague-Dawley rats were anesthetized, catheterized and subjected to soft tissue injury (laparotomy). Animals were allowed to regain consciousness over the next 0.5 h and then bled 40% of their blood volume over 15 min. Forty-five minutes after the onset of hemorrhage animals were randomized to receive either a single subcutaneous dose of AET (40 mg/kg, sc) or vehicle (methylcellulose). Volume resuscitation consisted of l-lactated Ringer's (three times the shed blood volume), followed by packed red blood cells (one-third shed red cell volume). Animals were observed for three days. RESULTS: A total of 24 animals were studied. Of the 12 animals randomized to receive AET, all (100%) survived compared to 9 of 12 animals (75%) randomized to receive the vehicle (p < 0.05). CONCLUSION: AET significantly improved survival when administered subcutaneously in a single dose in this rodent model of traumatic shock. Further survival and mechanism studies are warranted.     

VEGF-C反义多肽对乳腺癌裸鼠移植瘤影响的实验研究

目的观察血管内皮生长因子C（VEGF—C）反义多肽对乳腺癌裸鼠皮下移植瘤的影响,探讨以VEGF—C反义多肽用于乳腺癌基因治疗的应用前景。方法制备靶向VEGF—C的反义多肽,构建乳腺癌细胞MCF-7裸鼠皮下移植瘤模型,瘤体内注射VEGF—C反义多肽,观察其对乳腺癌细胞的抑制作用;免疫印迹（Western Blot）检测VEGF—C在瘤组织的表达情况。结果VEGF—C反义多肽具有较强的生物学活性,瘤组织内给予VEGF-C反义多肽后,Western blot分析VEGF—C在瘤组织中的表达降低,肿瘤生长受制,抑瘤率为52％（P〈0．05）。结论 制备出的VEGF—C具有良好的生物学活性,有抗乳腺癌作用。     

Synergistic and attenuated effect of HSS in combination treatment with docetaxel plus cisplatin in human non-small-cell lung SPC-A-1 tumor xenograft

Platinum based combination regimens are first-line treatment option in treatment of non-small cell lung cancer (NSCLC) but the clinical utility has been limited because of their toxicities. Many reports indicated that patients with tumors can benefit from adjuvant chemotherapy drugs. The aim of this study was to confirm adjuvant chemotherapy of HSS with docetaxel plus cisplatin (DP) against NSCLC by evaluating antitumor activity and attenuated effect. In vivo SPC-A-1 xenograft model was established to evaluate antitumor activity and toxicity of HSS along or combination with DP. Evaluation indexes include the relative tumor proliferation rate, tumor growth inhibition rate, body weight, food consumption, hematological and biochemical analysis. HSS treatment showed inhibited tumor growth and increased tumor inhibition of DP treatment at doses of 250 mg/kg and 500 mg/kg. No significant toxicity was found in HSS-treated mice, but significant toxicity was found in DP-treated mice. HSS combination with DP could reduce toxicity of DP treatment by improving body weight and food consumption, and increasing the number of WBC and PLT, decreasing the level of ALT, AST and BUN. HSS combined with DP treatment has additive effect which contributes to enhance tumor growth inhibition of DP treatment and attenuated effect which contributes to reduce toxicity of DP treatment. These findings indicate potential benefit for use of HSS adjuvant chemotherapy for NSCLC treatment.     

Vasopressin improves survival in a pig model of hypothermic cardiopulmonary resuscitation

OBJECTIVE: During hypothermic cardiopulmonary resuscitation with a body core temperature <30 degrees C administration of a vasopressor to support coronary perfusion pressure is controversial. The purpose of the current study was to assess the effects of a single 0.4-unit/kg dose of vasopressin on coronary perfusion pressure, defibrillation success, and 1-hr survival in a pig model of hypothermic closed-chest cardiopulmonary resuscitation combined with rewarming. DESIGN: Prospective, randomized study in an established pig model. SETTING: University hospital research laboratory. SUBJECTS: Fifteen 12- to 16-wk-old domestic pigs. INTERVENTIONS: Pigs were surface cooled to a body core temperature of 26 degrees C and ventricular fibrillation was induced. After 15 mins of untreated cardiac arrest, manual closed-chest cardiopulmonary resuscitation and thoracic lavage with 40 degrees C warmed tap water were started. After 3 mins of external chest compression, animals were assigned randomly to receive vasopressin (0.4 units/kg, n = 8; or saline placebo, n = 7). Defibrillation was attempted 10 mins after drug administration. MEASUREMENTS AND MAIN RESULTS: Compared with saline placebo treated-animals, coronary perfusion pressure in vasopressin-treated pigs was significantly higher 90 secs (36 +/- 5 mm Hg vs. 7 +/- 4 mm Hg, p =.000) to 10 mins (24 +/- 4 mm Hg vs. 8 +/- 4 mm Hg, p =.000) after drug administration. Restoration of spontaneous circulation and 1 hr survival were significantly higher in vasopressin animals compared with saline placebo (8 of 8 vasopressin pigs vs. 0 of 7 placebo pigs, p <.001). CONCLUSIONS: A single 0.4-unit/kg dose of vasopressin administered at a body core temperature <30 degrees C significantly improved defibrillation success and 1-hr survival in a pig model of hypothermic cardiopulmonary resuscitation.     

Vasopressin improves survival in a porcine model of abdominal vascular injury

Introduction  

We sought to determine and compare the effects of vasopressin, fluid resuscitation and saline placebo on haemodynamic variables and short-term survival in an abdominal vascular injury model with uncontrolled haemorrhagic shock in pigs.     

Exisulind-induced apoptosis in a non-small cell lung cancer orthotopic lung tumor model augments docetaxel treatment and contributes to increased survival

We reported previously a significant increase in survival of nude rats harboring orthotopic A549 human non-small cell lung cancer tumors after treatment with a combination of exisulind (Sulindac Sulfone) and docetaxel (D. C. Chan, Clin. Cancer Res., 8: 904-912, 2002). The purpose of the current study was to determine the biochemical mechanisms responsible for the increased survival by an analysis of the effects of both drugs on A549 orthotopic lung tumors and A549 cells in culture. Orthotopic A549 rat lung tissue sections from drug-treated rats and A549 cell culture responses to exisulind and docetaxel were compared using multiple apoptosis and proliferation analyses [i.e., terminal deoxynucleotidyl transferase-mediated nick end labeling, active caspase 3, the caspase cleavage products cytokeratin 18 and p85 poly(ADP-ribose) polymerase, and Ki-67]. Immunohistochemistry was used to determine cyclic GMP (cGMP) phosphodiesterase (PDE) expression in tumors. The cGMP PDE composition of cultured A549 cells was resolved by DEAE-Trisacryl M chromatography and the pharmacological sensitivity to exisulind, and additional known PDE inhibitors were determined by enzyme activity assays. Exisulind inhibited A549 cell cGMP hydrolysis and induced apoptosis of A549 cells grown in culture. PDE5 and 1 cGMP PDE gene family isoforms identified in cultured cells were highly expressed in orthotopic tumors. The in vivo apoptosis rates within the orthotopic tumors increased 7-8-fold in animals treated with the combination of exisulind and docetaxel. Exisulind increased the in vivo apoptosis rates as a single agent. Docetaxel, but not exisulind, decreased proliferative rates within the tumors. The data indicate that exisulind-induced apoptosis contributed significantly to the increased survival in rats treated with exisulind/docetaxel. The mechanism of exisulind-induced apoptosis involves inhibition of cGMP PDEs, and these results are consistent with a cGMP-regulated apoptosis pathway.     

乳腺癌术后乳房重建病人高生存质量的生活体验

[目的]探讨乳腺癌术后乳房重建病人高生存质量的生活状态。[方法]以11例乳腺癌术后乳房重建病人为研究对象,采用质性研究中的现象学研究方法,对乳腺癌术后乳房重建病人进行半结构访谈,采用Giorgi的现象学资料分析方法分析资料。[结果]处于高生存质量的乳腺癌术后乳房重建病人的生活状态主要为重拾女性自信心、找回自尊,建立人生新态度和改变社会适应力等,健康积极的心态和生活方式对提高生存质量有积极作用。[结论]护士应深入了解乳腺癌术后乳房重建病人内心深处的感受,使她们得到身心社灵四位一体的全人照护。     

Mesenteric lymph duct ligation improves survival in a lethal shock model

The goal of this study was to test the hypothesis that factors released from the gut and carried in the mesenteric lymph contribute to mortality in a lethal gut I/R model. To test this hypothesis, a lethal splanchnic artery occlusion (SAO) shock model was used in male Sprague-Dawley rats. In the first set of experiments, ligation of the mesenteric lymph duct (LDL), which prevents gut-derived factors carried in the intestinal lymphatics from reaching the systemic circulation, significantly improved 24-h survival after a 20-min SAO insult (0% vs. 60% survival; P < 0.05). This increase in survival in the LDL-treated rats was associated with a blunted hypotensive response. Because increased iNOS-induced NO levels have been implicated in SAO-induced shock, we measured plasma nitrite/nitrate levels and liver iNOS protein levels in a second group of animals. Ligation of the mesenteric lymph duct significantly abrogated the SAO-induced increase in plasma nitrite/nitrate levels and the induction of hepatic iNOS (P < 0.05). In an additional series of studies, we documented that LDL increased not only 24-h but also long-term 7-day survival. During the course of these studies, we made the unexpected finding that Sprague-Dawley rats from different animal vendors had differential resistance to SAO, and that the time of the year that the experiments were carried out also influenced the results. Nonetheless, in conclusion, these studies support the hypothesis that factors carried in the mesenteric lymph significantly contribute to the development of irreversible shock after SAO.     

表柔比星分别联合多西紫杉醇与长春瑞滨治疗晚期乳腺癌患者的疗效观察及对患者的预后生存分析

目的 观察表柔比星分别联合多西紫杉醇与长春瑞滨治疗晚期乳腺癌患者的临床疗效及对患者预后生存影响.方法 前瞻性选取2017年1月到2020年1月在池州市人民医院接受治疗的60例晚期乳腺癌患者,按随机抽样法将其分为研究组与对照组,每组各30例.研究组给予表柔比星联合多西紫杉醇治疗,对照组给予表柔比星联合长春瑞滨治疗,2组患...