Correlation between serum prolactin levels and hepatocellular tumorigenesis induced by 3'-methyl-4-dimethylaminoazobenzene in mice.

Ovariectomy at 1 month of age promotes development of hepatocellular adenomatous nodules in female C57BL/6 x DS-F1 mice treated neonatally with 3''-methyl-4-dimethylaminoazobenzene (3''-Me-DAB). Implantation of oestradiol-17 beta (E2) pellets at 1 month of age suppresses nodule development. Since E2 increases serum levels of prolactin, high serum levels of prolactin in mice that have received implants of E2 pellets may play a role in the suppression of hepatocellular tumorigenesis. Therefore, to investigate the role of prolactin in hepatocellular tumorigenesis, we examined development of adenomatous nodules in female mice that had been treated neonatally with 3''-Me-DAB and had undergone ovariectomy at 1 month of age, under various serum levels of prolactin. Treatment of these mice with perphenazine (dopamine antagonist) from 6 months of age or transplantation of pituitary glands under the renal capsule at 6 months of age markedly increased serum levels of prolactin and significantly suppressed the incidence of adenomatous nodules at 12 months of age. Implantation of E2 pellets at 1 month of age increased serum levels of prolactin to a greater extent and further decreased the incidence of adenomatous nodules. Treatment of mice that had received implants of E2 pellets at 1 month of age with bromocriptine (dopamine agonist) from 6 months of age decreased serum levels of prolactin, and was accompanied by an increase in the incidence of nodules. The present results showed that an increase in serum levels of prolactin was accompanied by a decrease in incidence of liver tumours induced by 3''-Me-DAB in mice, suggesting a suppressive effect of prolactin on liver tumorigenesis in mice. Thus, it is possible that the suppressive effect of oestrogen on liver tumorigenesis in mice is mediated, at least in part, by prolactin.     

Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin

Interference with mitochondrial calcium regulation is proposed to be a primary causative event in the mechanism of doxorubicin-induced cardiotoxicity. We previously reported disruption of mitochondrial calcium homeostasis after chronic doxorubicin administration (Solen et al. Toxicol. Appl. Pharmacol, 129: 214-222, 1994). The present study was designed to characterize the dose-dependent and cumulative interference with mitochondrial calcium regulation and to assess the reversibility of this functional lesion. Sprague Dawley rats were treated with 2 mg/kg/week doxorubicin s.c. for 4-8 weeks. With succinate as substrate, cardiac mitochondria isolated from rats after 4 weeks of treatment with doxorubicin expressed a lower calcium loading capacity compared with control. This suppression of calcium loading capacity increased with successive doses to 8 weeks of treatment (P < 0.05) and persisted for 5 weeks after the last doxorubicin injection, and was corroborated by dose-dependent and irreversible histopathological changes. Preincubation of mitochondria with tamoxifen, DTT, or monobromobimane did not reverse the diminished calcium loading capacity caused by doxorubicin. In contrast, incubation with cyclosporin A abolished any discernible difference in mitochondrial calcium loading capacity between doxorubicin-treated and saline-treated rats. The decrease in cardiac mitochondrial calcium loading capacity was not attributable to bioenergetic changes in the electron transport chain, because the mitochondrial coupling efficiency was not altered by doxorubicin treatment. However, the ADP/ATP translocase content was significantly lower in mitochondria from rats that received 8 weeks of doxorubicin treatment. These data indicate that doxorubicin treatment in vivo causes a dose-dependent and irreversible decrease in mitochondrial calcium loading capacity. Suppression of adenine nucleotide translocase content may be a key factor altering the calcium-dependent regulation of the mitochondrial permeability transition pore, which may account for the cumulative and irreversible loss of myocardial function in patients receiving doxorubicin chemotherapy.     

Protective effect of L-carnitine on cardiac metabolic damage induced by doxorubicin in vitro

Carnitine, a naturally occurring compound which is an important cofactor in the transport of fatty acids within inner mitochondria, aids myocardial cells in efficiently meeting energy requirements. L-Carnitine has been texted in this study as a possible protective agent against doxorubicin-induced cardiac toxicity. Rat heart slices were incubated with doxorubicin (14 micrograms/ml), L-carnitine (600 micrograms/ml), and L-carnitine plus doxorubicin for 60 min at 38 degrees C. Cellular oxygen uptake, ATP, intracellular Ca2+, and 14C-Leucine incorporation were measured. L-carnitine pre-incubation significantly reduced (p less than 0.001) the metabolic cardiac impairment due to doxorubicin. The inhibition of oxygen uptake declined from 38% to 7%; of ATP cellular concentration from 78% to 27%; and that of protein synthesis from 11% to 6%. L-carnitine moreover acts to eliminate completely the Ca2+ increase induced by doxorubicin. Thus, it appears L-carnitine may be useful in the prevention of doxorubicin-induced cardiac toxicity.     

Correlation between changes in prolactin and melatonin serum levels after radical mastectomy

Both prolactin (PRL) and melatonin (MLT) (the most important pineal hormone) have been shown to play a role in regulating breast cancer growth. The present study was carried out to investigate the relationship between PRL and MLT secretions in human breast cancer. Twenty-four women with breast cancer, at clinical stage T1-2 N0-2 M0, were evaluated before and after radical mastectomy. As controls, 14 women who underwent surgery for reasons other than neoplastic disease were included in the study. PRL and MLT serum levels were measured by RIA before and 15 days after surgery. There were no significant differences in mean PRL serum levels between patients and controls; mean MLT serum values were significantly higher in patients than in controls. In no control subject was PRL affected by surgery. In contrast, 13/24 breast cancer women showed high PRL levels after mastectomy; the PRL rise induced by surgery was significantly higher in patients without axillary node involvement. MLT was not affected by mastectomy in 13 patients, whereas it was enhanced in 5 women and decreased in the last 6 cases. No significant correlation was seen between PRL and MLT changes induced by mastectomy. The present study shows that radical mastectomy influences PRL and MLT secretions, however, its clinical significance remains to be established.     

血清维生素水平与肺鳞癌转移特征的相关性

目的:检测并分析血清中九种维生素水平与肺鳞癌转移特征的关系。方法:回顾性分析2016年01月至2018年08月,就诊于我院的肺鳞癌患者,按照纳入及排除标准,共78例肺鳞癌患者纳入本研究,在初始抗肿瘤治疗时检测其血清中九种维生素水平,记录并比较血清中九种维生素水平在非转移组及转移组中分布特征;对肺鳞癌转移组进一步分析,按照转移部位及数目分为寡转移组与多发转移组,按照是否发生肝转移分为肝转移组与非肝转移组,比较血清维生素营养状态在肺鳞癌不同转移特征中的差异。结果:在肺鳞癌患者中,血清维生素营养状态水平在非转移组与转移组两组之间无统计学差异;对肺鳞癌转移组进一步分析,结果显示,寡转移组与多发转移组在血清维生素A、维生素D等方面存在差异,且具有统计学意义,而在维生素B族、维生素C、维生素E等方面无显著性差异;对于转移组中是否发生肝转移分组分析中,结果显示,肝转移组与非肝转移组,在维生素A、维生素B族等方面无差异,但在血清维生素D水平之间存在显著性差异。结论:对于肺鳞癌患者,血清维生素D水平在多发转移组中低于寡转移组,同时结果提示,对于伴有肝转移组,其血清维生素D水平亦低于非肝转移组;而对于肺鳞癌患者,发生多发转移与肝转移者具有更差预后,提示维生素D可能在肺鳞癌转移中起到一定抑制作用,对于肺鳞癌患者补充维生素D水平或许有助于抑制其转移,但限于为单中心研究,其结论有待进一步多中心研究证实。     

Correlation between serum tumor marker levels and tumor proliferation in small cell lung cancer

We analyzed serum lactate dehydrogenase (LDH), neuron-specific enolase (NSE) and thymidine kinase (TK) levels in 22 patients with small cell lung cancer. Tumor proliferation was expressed as the proportion of S-phase cells (SPF), determined by DNA flow cytometry, from concomitantly taken biopsy samples. A positive correlation between serum NSE (r = 0.41) or LDH (r = 0.65, p = 0.05) levels and tumor SPF was noted, but was not found between serum TK levels and the SPF. The correlation between NSE and SPF was even more pronounced if only patients with extensive disease were considered (r = 0.77). The serum NSE and LDH, but not TK levels, were significantly greater in the patients with extensive disease (NSE 50.4 ng/ml, LDH 621 U/ml) compared to the patients with limited disease (NSE 21.0 ng/ml, LDH 272 U/ml, p = 0.05). Our results suggest that the combined determination of serum LDH and NSE levels gives valuable data on the primary tumor mass and its proliferative activity in small cell lung cancer.     

肺癌患者血清ODF和OCIF水平与骨转移的相关性研究

  目的   探讨检测破骨细胞分化因子（osteoclast differentiation factor,ODF）和破骨细胞生成抑制因子（osteo-clastogenesis inhibitory factor,OCIF）对肺癌骨转移诊断及病情评价的临床价值。   方法   分析2009年7月至2012年4月186例初诊为肺癌患者的资料。肺癌骨转移组和非骨转移组分别为104例和82例,采用ELISA法测定各组血清ODF和OCIF浓度。   结果   骨转移组患者血清ODF和OCIF分别为（32.22±6.22）ng/L、（41.23±8.13）ng/L,明显高于非骨转移组的（8.35±5.42）ng/L、（10.15±4.42）ng/L,有显著性差异（P < 0.01）。ODF和OCIF诊断肺癌骨转移ROC曲线下面积分别为0.91和0.87,具有良好的诊断价值。诊断肺癌骨转移的灵敏度、特异度,ODF分别为90.38%、86.59%;OCIF分别为86.54%、84.15%。ODF随骨转移部位数量增加而明显升高,OCIF随骨转移部位数量增加而明显降低。新发骨转移组和骨转移组血清ODF和OCIF浓度均显著高于非骨转移组,有显著性差异（P< 0.01）;新发骨转移组血清ODF和OCIF浓度与骨转移组比较,两组间无显著性差异（P>0.05）。   结论   肺癌患者发生骨转移时,血清ODF和OCIF含量明显增高,可作为判断肺癌患者骨转移及监测病情的参考指标,在临床上有广泛的应用前景。       

Skin and perivascular toxicity induced experimentally by doxorubicin

Extravasation of antitumor drugs and particularly doxorubicin (DXR) can be followed by skin ulceration and slowly evolving perivascular necrosis. DXR lesions have some characteristics in common with those induced by ionizing radiation and, with respect to gross morphology, are reminiscent of skin lesions induced by necrotizing agents. Time course and histopathology of toxic phenomena induced by intradermal or perivascular injection of various doses of either DXR or caustic chemicals have been studied in hairy outbred and hairless inbred (MF1 hr/hr) mice. The latter strain has been found to be intrinsically more sensitive to DXR induced toxic effects, particularly as far as perivascular administration is concerned. Long lasting lesions and, in a few cases, systemic involvement have been observed. On the contrary, necrotic foci induced by caustic chemicals rapidly regressed in both strains. The perivascular administration model, which has not been previously investigated, appears to be representative of what happens in clinical conditions and can be of use for assessing either skin toxicity of antitumor compound or the protective effect of candidate antidotes.     

Lack of correlation between interferon levels induced by polyribonucleotides and their antimetastatic effect.

The inhibitory effect of poly(A)poly(U) on the pulmonary metastasis of B16-F10 melanoma was examined in comparison with that of poly(I,C)-L,C and poly(I)poly(C). The correlation between interferon (IFN) level and antimetastatic effect was also investigated. Intraperitoneal injection of poly(A)poly(U) (50 mg/kg) into C57BL/6 mice 24 h before intravenous inoculation of B16-F10 melanoma (1 X 10(5] caused a significant decrease (p less than 0.01) in the number of pulmonary nodules 14 days after tumor challenge. But poly(I,C)-L,C (1 or 0.2 mg/kg) and poly(I)poly(C) (5 mg/kg or 1 mg/kg) did not. From the kinetic study of IFN levels induced by polyribonucleotides, poly(I,C)-L,C showed the most potent IFN-inducing activity, followed by poly(I)poly(C) and poly(A)poly(U), in this order. Plasma IFN reached a peak at 6 h and still continued to be detected at 24 h after intraperitoneal injection of the polyribonucleotides. Against B16-F10 melanoma, the cytotoxicity of spleen cells stimulated by poly(A)poly(U) (50 mg/kg) was significantly (p less than 0.05) higher than that of spleen cells stimulated by poly(I)poly(C) (5 mg/kg) both at 12 and 24 h after intraperitoneal injection of those agents. The above results that there is no correlation between the IFN levels induced by polyribonucleotides and their antimetastatic effect. More extensive study of poly(A)poly(U) might give more fruitful results, which will give valuable information for future clinical trials of this lowly toxic promising agent.     

血管内皮生长因子在肝癌患者血清中的表达水平与肿瘤侵袭能力的相关性研究

目的探讨原发性肝癌患者血清血管内皮生长因子（VEGF）表达水平与肿瘤侵袭转移的关系。方法应用ELISA方法对30例原发性肝癌（PHC）患者、20例肝脏良性疾病患者及20例正常人血清中VEGF水平进行检测。结果PHC组与良性肝脏疾病及正常对照组中血清VEGF的含量比较,3组间有显著性差异（P〈0．01）;合并门脉瘤栓组血清VEGF含量明显高于无门脉瘤栓组血清VEGF含量（P〈0．05）;发生肝内转移组患者血清VEGF含量亦明显高于无肝内转移组患者血清VEGF含量（P〈0．05）。结论PHC患者血清中VEGF水平显著高于正常人和良性肝病患者;患者血清中VEGF的高表达预示着PHC的高侵袭转移能力,可以作为评估PHC转移潜能、预测患者预后的有效指标之一。     

Correlation between serum vascular endothelial growth factor and endostatin levels in patients with breast cancer

Serum vascular endothelial growth factor (VEGF) and endostatin levels were detected in 59 patients with breast cancer before surgery and at 3 weeks after surgery. Pre-operatively, their levels were significantly elevated and correlated with each other. Post-operatively, VEGF level decreased significantly and endostatin remained at a high level. Patients with both normalized VEGF and elevated endostatin following surgery had a lower risk of relapse than patients whose VEGF failed to normalize. Univariate and multivariate analyses showed a correlation between elevated VEGF level and short free-relapse survival. These findings suggest a new angiogenesis balance is formed in the patients after surgery and such a resultant balance may be beneficial for the prognosis of breast cancer, which deserves more extensive study.     

Relationship between serum selenium levels and patients with carcinoma.

Serum selenium levels were determined by neutron activation analysis on 110 patients with carcinoma. An attempt was made to correlate the wide range in the serum concentrations of the trace element with the parameters employed in this study. An association was noted between the serum selenium levels and patient survival time, incidence of multiple primary malignancies, rate of recurrence of the primary lesion and the extent of local and disseminated involvement.     

Correlation of serum metalloproteinase levels with lung cancer metastasis and response to therapy.

Cancer cells elaborate metalloproteinases which may play a role in invasion and metastasis. The serum level of the M(r) 72,000 type IV collagenase (MMP-2) was measured in 87 lung cancer patients. Stage IV cancer levels were significantly elevated (P less than 0.0001) compared to normal sera. A significant difference (P less than 0.01) was found between enzyme levels in the presence versus the absence of distant metastasis. For 29 patients treated with combination chemotherapy, a positive relationship was noted between response failure and elevated enzyme levels. Serum metalloproteinase levels may provide information relevant to prognosis as well as treatment decisions.     

Mitochondrial proliferation during apoptosis induced by anticancer agents: effects of doxorubicin and mitoxantrone on cancer and cardiac cells

Doxorubicin is one of the most largely prescribed antitumor drug for the treatment of breast, liver and colon cancers as well as leukemia, but the cardiotoxicity of this anthracycline derivative limits its clinical use. Although doxorubicin is toxic to both cancer and cardiac cells, there are evidences suggesting that the mechanism of cell death is different for the two cell types. To investigate further this issue, we have compared the proapoptotic effects of doxorubicin and the functionally related anthracenedione compound mitoxantrone, which is also used in the clinic for the treatment of cancer. After evaluating the toxicity of the two drugs to mammary adenocarcinoma MTLn3 cells and H9C2 cardiomyocytes, we dissected the drug-induced apoptotic machinery by measuring the effects on the cell cycle progression, DNA condensation and fragmentation, production of endogenous peroxides and caspase activation. Both doxorubicin and mitoxantrone are potent inducers of apoptosis in H9C2 cardiomyocytes and MTLn3 breast cancer cells, but there are significant differences between the two cell types in terms of kinetics and order of the events. In particular, flow cytometry measurements of drug-induced changes in mitochondrial transmembrane potential and mitochondrial mass with different fluorescent probes suggested that the two drugs induced a progressive increase in mitochondrial mass in the cancer cells but not in the cardiac cells. The hypothesis was validated by means of electron microscopy, which revealed a significant increase in the number of mitochondria in drug-treated MTLn3 but not in H9C2 cells. The mitochondrial proliferation precedes the nuclear apoptosis in doxorubicin-treated MTLn3 cells. The changes in the architecture and number of mitochondria are linked to the drug-induced perturbation of the cell cycle progression and apoptosis. The proliferation of mitochondria could explain the higher toxicity of doxorubicin to cancer cells compared to cardiac cells and this suggests novel therapeutic opportunities to better control the cardiotoxicity of anthracyclines.     

血清miR-27b、miR-223水平与骨肉瘤患者化疗效果的相关性

目的:观察骨肉瘤患者血清微小RNA-27b、miR-223水平与化疗效果的相关性,指导未来临床对骨肉瘤患者实施合理的化疗。方法:选择我院2016年01月至2020年01月收治的241例骨肉瘤患者作为研究对象,均于化疗前检测血清miR-27b及miR-223水平,实施化疗治疗,分析血清miR-27b及miR-223水平与化疗效果的相关性。结果:241例骨肉瘤患者行化疗治疗后,总缓解率为59.75%;化疗后未缓解组肿瘤直径≥5 cm占比高于缓解组,化疗前血清miR-27b相对表达量高于缓解组,miR-223相对表达量低于缓解组,差异有统计学意义（P＜0.05）;两组其他基线资料比较,差异无统计学意义（P＞0.05）;经二元Logistic回归分析后建立多元回归模型,结果显示,骨肉瘤患者肿瘤直径、化疗前血清miR-27b及miR-223表达水平是化疗后未缓解的影响因素（OR＞1,P＜0.05）;绘制受试者工作曲线（ROC）发现,化疗前血清miR-27b及miR-223水平预测化疗后未缓解的曲线下面积（area under curve,AUC）均＞0.80,有一定预测性能。结论:骨肉瘤患者血清miR-27b、miR-223水平与化疗效果存在密切相关,化疗前血清miR-27b过表达及miR-223表达下调均可能提示化疗效果不佳,可将二者作为骨肉瘤患者化疗效果的有效预测因子,并根据评估结果合理调整治疗方案,可能对提高化疗整体获益意义重大。     

Correlation between preoperative serum levels of five biomarkers and relationships between these biomarkers and cancer stage in epithelial overian cancer

Objective

To examine the correlation among the preoperative serum levels of five biomarkers presumed to be useful for early detection of epithelial ovarian cancer and evaluate the relationships between serum levels of these five biomarkers and epithelial ovarian cancer stage.

Methods

We analyzed 56 newly diagnosed epithelial ovarian cancer patients. Preoperative serum levels of leptin, prolactin, osteopontin (OPN), insulin-like growth factor-II, and CA-125 were determined by ELISA. We also examined the correlation between the serum levels of the biomarkers and ovarian cancer stage. Significant differences in the mean serum levels of two proteins, leptin and CA-125, were observed between stage subsets.

Results

There was a significant negative correlation between prolactin and leptin and a significant positive correlation between prolactin and OPN. Of the five biomarkers, only the mean serum CA-125 level showed a significant positive correlation with cancer stage (Spearman ρ=0.24, p<0.01). OPN showed a marginally significant positive correlation with stage (Spearman ρ=0.14, p=0.07).

Conclusion

We demonstrated the relationship between five biomarkers in epithelial ovarian cancer. These tumor markers may be useful in screening for ovarian cancer, in characterizing disease states, and in developing therapeutic interventions targeting these marker proteins. Large-scale studies that include potential confounding factors and modifiers are necessary to more accurately define the value of these novel biomarkers in ovarian cancer.     

Correlation between tumor proliferation and serum levels of beta 2-microglobulin and thymidine kinase in malignant lymphomas

We have studied the serum beta 2-microglobulin (beta 2m) and thymidine kinase (TK) levels in 19 newly diagnosed lymphoma patients. The proportion of the S-phase cells (SPF) was determined by flow cytometry from subsequently taken tumor biopsy material. A positive correlation between SPF and TK (r = 0.4, P = 0.1), but not between SPF and beta 2m, was seen in the whole material. Sixty-three percent of the high-grade malignancy non-Hodgkin lymphomas (5/8) showed high proliferative activity in both the SPF and TK analyses. Furthermore, high tumor SPF and enhanced serum TK levels reflected equally well and consistently the clinical outcome of the underlying disease.