To differential diagnosis of esophageal cancer and other diseases with the similar clinical symptoms, by using traditional X-ray study

The principal purpose of the paper is to assess the role of the X-ray section of current radiation diagnosis in obtaining objective information and interpreting it in esophageal cancer. The study was methodically based on its serial studies, by comparing the data of clinical, radiation, and endoscopic diagnosis with those of morphological studies of the biopsy specimens taken at resection for cancer of the esophagus and the upper stomach, and histologically examined them in diseases running with the similar clinical symptoms. The complex of radiation techniques included traditional X-ray study (compact filling, double contrasting). A specially developed procedure that allowed physicians the opportunity to examine the cardioesophageal area in the fragmentary fashion was used during morphological studies. In cancer of the upper stomach, the lower esophageal segments were also involved in the process in 79.9%. It should be also noted that this number of observations includes some cases that clinical symptomatology and endoscopy strongly suggest cancer of the lower third of the esophagus. The authors have arrived at the conclusion that the present-day X-ray semiotics of esophageal diseases running with the similar clinical symptomatology permits their differential diagnosis just before the use of endoscopy and histology of biopsy specimens and that the unique advantage of radiation diagnosis over endoscopy is to specify the initial site of a tumor, namely, to detect primary gastric damage in cardioesophageal carcinoma.     

全数字化乳腺X线摄影诊断临床隐匿型乳腺癌的价值

目的：探讨全数字化乳腺X线摄影对临床隐匿性乳癌的诊断价值。方法：回顾性分析临床扪诊阴性,手术病理证实乳腺癌12例。全部病例均使用全数字化乳腺X线摄影。结果：12例病例发现病灶12个,其中单纯钙化7例,微结节或结构紊乱伴微钙化3例,微结节伴毛刺11例。局部结构紊乱1例。结论：全数字化乳腺X线摄影能清晰显示乳房各个层次结构,尤其发现恶性钙化敏感性高,对发现临床隐匿型乳腺癌具有重大价值。     

Cardiac involvement in central lung cancer

An x-ray picture of central lung cancer was analyzed in 34 operated patients in whom tumors had infiltrated the myocardium (left atrial infiltration in 33, right atrial infiltration in one, ventricular infiltration in 2). The comparison of x-ray findings with gross specimens of the removed lungs showed that tumor mass consisted of a primary tumor and metastatic bronchopulmonary lymph nodes that made impossible the differentiation of separate elements of the root x-ray image. Angiography was performed in 15 patients with suspected infiltration of the heart by a tumor on the basis of x-ray findings. Cardiac affection which was characterized on x-ray by change in the shape of the chambers, irregularity of their outlines or a filling defect at the site of tumor infiltration. Suspected cardiac infiltration by a tumor can be based on indirect x-ray signs: the presence of a large tumor mass in the area of the root, a shift of the deflated lung regions to the heart, the absence of an image of heart borders and pulmonary veins on tomograms, and a confluent image of the affected lung and cardiac shadow. These signs serve an indication for angiography.     

Resistance of cancer cells to the TRAIL-induced apoptosis in confluent cultures

TRAIL (TNF-alpha Related Apoptosis-Inducing Ligand) is an attractive candidate for anticancer therapy. TRAIL selectively kills tumor cells, without damaging normal cells. It is known that cancer cells can acquire resistance to chemotherapeutic drugs, oxidative stress in high density culture. This phenomenon appears as a multi-cell resistance, cell adhesion-dependent resistance, or density-dependent resistance of tumor cells. However, it is unclear whether such resistance appears in TRAIL-induced apoptosis. We observed that the resistance to izTRAIL of all tumor cell lines used was considerably increased in confluent cultures. The increase in tumor cell resistance in dense populations is not related to their proliferative status. It was shown that the dissociation of calcium-dependent cell-cell contacts with EGTA did not suppress tumor cell resistance to izTRAIL in confluent cultures. This phenomenon of cancer cells resistance to TRAIL-induced apoptosis should be considered in the development of methods of anticancer therapy.     

The determination of the sequences present in the shadow bands of a dinucleotide repeat PCR.

A Polymerase Chain Reaction (PCR) of a DNA sequence containing a CA repeat produces a main band but also several shadow bands that differ by 2 base pairs below the main band. In the experiments described in this paper, these shadow bands were excised from a DNA sequencing gel and directly sequenced. It was found that the sequence in the CA repeat was ambiguous. However, the sequence 5' and 3' to the CA repeat was clear and unambiguous. It is proposed that the shadow bands are generated by 2 base pair random deletions in the CA repeat region. During this process the sequence becomes 'scrambled' only in the CA repeat region. The shadow bands were shown to occur during the PCR since the genomic DNA template did not contain the shadow bands. It is probable that the shadow bands arise by slippage during the PCR. It is predicted that a thermostable DNA polymerase with a high processivity would greatly reduce the occurrence of shadow bands.     

Clinical breast cancer, new developments in selection and endocrine treatment of patients.

Breast cancer is the most common malignant tumor among women, comprising an estimated 24% of all cancer cases and 18% of all cancer deaths. At least half of the patients with primary breast cancer will ultimately die by metastatic disease. The tumor characteristics, the natural course of the disease and the response to therapy vary strongly. A number of recently detected cell biological parameters such as oncogenes/suppressor genes, growth factors and secretory proteins are more or less important prognostic factors, because they influence the characteristics and behavior of a tumor with respect to metastatic pattern, extent of cellular differentiation, growth rate and response to treatment. However, there is no clear consensus how best to identify patients at high or low risk. In our experience c-myc amplification and pS2 protein are strong prognosticators for relapse rate, while in advanced disease (apart from a negative estrogen/progesterone receptor/pS2 status) amplification of HER2/neu is a good prognosticator for failure to endocrine therapy. In the diagnosis of breast cancer, in vivo imaging of tumors by labeled hormones or other factors also forms a new development which might have implications for treatment too. With respect to treatment both endocrine and chemotherapy can cure a minority of patients with micrometastases, but in patients with advanced disease only a prolongation of (progression-free) survival can be reached. Response rates decrease with increasing tumor load. In the past decade a number of interesting new endocrine agents has been developed such as new (pure) (anti)steroidal agents, vitamins, aromatase inhibitors, analogs of peptide hormones, prolactin inhibitors and growth factor antagonists. However, less is known on the (potential) interaction between hormones, chemotherapeutic agents, retinoids, cytokins, growth factor antagonists and irradiation. Rapid detection of new powerful combination therapies are needed to improve treatment results during the nineties.     

Hormonal regulation of MUC1 expression.

Several circulating mucinous markers, including CA 15.3, MCA, CA 459, CASA, and Truquant BR, are secreted products of the polymorphic MUC1 gene, and are used as diagnostic tools in patients with breast cancer. In clinical practice the measurement of the levels of these markers in the blood can give important information on the tumor's response to treatment and its biological behavior during disease monitoring. Since the marker levels reflect the activity of the tumor, it is important to know all factors influencing the production/secretion and the blood concentrations of MUC1 mucin. Recent findings suggest that MUC1 gene expression is regulated by steroid hormones and other substances present in the serum. Such observations are very important not only because of their biological significance but also for their clinical implications, as one approach to breast cancer therapy is based on chemical hormone manipulation. Nevertheless, we have preliminarily demonstrated that endocrine treatment in breast cancer patients does not influence the circulating CA 15.3 serum levels, so changes in marker levels are related only to the clinical evolution of the tumor.     

STAT3与在肿瘤耐药中的研究进展

STAT3是信号转导与转录活化蛋白(STATs)家族的重要一员,是一种存在于胞浆并在激活后能够转入核内与DNA结合的蛋白家族,具有信号转导和转录调控双重功能。STAT3在多种肿瘤组织与细胞系中异常表达,并与肿瘤的增殖分化、细胞凋亡密切相关。肿瘤耐药是其治疗失败的重要原因,STAT3能够通过多种途径介导肿瘤耐药。因而,STAT3在近年的抗肿瘤研究中备受关注,成为肿瘤治疗的良好靶点,由传统药物与STAT3抑制剂组成的新型治疗方案使得肿瘤患者大大受益。然而,STAT3介导肿瘤耐药的机制还不是很明确,需要进一步研究。本文就近年来一些化疗药物和靶向药物耐药的发生,对STAT3介导耐药的作用进行综述。     

Regulation of IkappaB kinase epsilon expression by the androgen receptor and the nuclear factor-kappaB transcription factor in prostate cancer

Although several genes have been associated with prostate cancer progression, it is clear that we are far from understanding all the molecular events implicated in the initiation and progression of the disease to a hormone-refractory state. The androgen receptor is a central player in the initiation and proliferation of prostate cancer and its response to hormone therapy. Nuclear factor-kappaB has important proliferative and antiapoptotic activities that could contribute to the development and progression of cancer cells as well as resistance to therapy. In this study, we report that IkappaB kinase epsilon (IKKepsilon), which is controlled by nuclear factor-kappaB in human chondrocytes, is expressed in human prostate cancer cells. We show that IKKepsilon gene expression is stimulated by tumor necrosis factor-alpha treatment in LNCaP cells and is inhibited by transfection of a dominant-negative form of IkappaBalpha, which prevents the nuclear translocation of p65. Furthermore, we found that tumor necrosis factor-alpha-induced IKKepsilon expression is inhibited by an androgen analogue (R1881) in androgen-sensitive prostate cancer cells and that this inhibition correlates with the modulation of IkappaBalpha expression by R1881. We also noted constitutive IKKepsilon expression in androgen-independent PC-3 and DU145 cells. To our knowledge, this is the first report of an IkappaB kinase family member whose expression is modulated by androgen and deregulated in androgen receptor-negative cells.     

Effect of Chronic Psychological Stress on Liver Metastasis of Colon Cancer in Mice

Metastasis to the liver is a main factor in colorectal cancer mortality. Previous studies suggest that chronic psychological stress is important in cancer progression, but its effect on liver metastasis has not been investigated. To address this, we established a liver metastasis model in BALB/c nude mice to investigate the role of chronic stress in liver metastasis. Our data suggest that chronic stress elevates catecholamine levels and promotes liver metastasis. Chronic stress was also associated with increased tumor associated macrophages infiltration into the primary tumor and increased the expression of metastatic genes. Interestingly, β-blocker treatment reversed the effects of chronic stress on liver metastasis. Our results suggest the β-adrenergic signaling pathway is involved in regulating colorectal cancer progression and liver metastasis. Additionally, we submit that adjunctive therapy with a β-blocker may complement existing colorectal cancer therapies.     

The Role of Platelet-Derived Endothelial Cell Growth Factor/Thymidine Phosphorylase in Tumor Behavior

Platelet-derived endothelial cell growth-factor (PD-ECGF) is similar to the pyrimidine enzyme thymidine phosphorylase (TP). A high TP expression at tumor sites is correlated with tumor growth, induction of angiogenesis, and metastasis. Therefore, high TP is most likely associated with a poor prognosis. TP is not only expressed in tumor cells but also in tumor surrounding tissues, such as tumor infiltrating macrophages. TP catalyzes the conversion of thymidine to thymine and doxyribose-1-phosphate (dR-1-P). The latter in its parent form or in its sugar form, deoxyribose (dR) may play a role in the induction of angiogenesis. It may modulate cellular energy metabolism or be a substrate in a chemical reaction generating reactive oxygen species. L-deoxyribose (L-dR) and thymidine phosphorylase inhibitor (TPI) can reverse these effects. The mechanism of TP induction is not yet completely clear, but TNF, IL10 and other cytokines have been clearly shown to induce its expression. The various complex interactions of TP give it an essential role in cellular functioning and, hence, it is an ideal target in cancer therapy.     

The role of platelet-derived endothelial cell growth factor/thymidine phosphorylase in tumor behavior

Platelet-derived endothelial cell growth-factor (PD-ECGF) is similar to the pyrimidine enzyme thymidine phosphorylase (TP). A high TP expression at tumor sites is correlated with tumor growth, induction of angiogenesis, and metastasis. Therefore, high TP is most likely associated with a poor prognosis. TP is not only expressed in tumor cells but also in tumor surrounding tissues, such as tumor infiltrating macrophages. TP catalyzes the conversion of thymidine to thymine and doxyribose-1-phosphate (dR-1-P). The latter in its parent form or in its sugar form, deoxyribose (dR) may play a role in the induction of angiogenesis. It may modulate cellular energy metabolism or be a substrate in a chemical reaction generating reactive oxygen species. L-deoxyribose (L-dR) and thymidine phosphorylase inhibitor (TPI) can reverse these effects. The mechanism of TP induction is not yet completely clear, but TNF, IL10 and other cytokines have been clearly shown to induce its expression. The various complex interactions of TP give it an essential role in cellular functioning and, hence, it is an ideal target in cancer therapy.     

Selection of microRNA for providing tumor specificity of transgene expression in cancer gene therapy

The use of tumor-specific microRNA loss to inhibit transgene expression in normal cells is considered as a way to increase the specificity of gene-therapeutic antitumor drugs. This method assumes the introduction of recognition sites of suppressed in tumor cells microRNAs into transgene transcipt. In the presented work, the efficiency of the strategy for providing the tumor specificity of transgene expression depending on parameters of microRNA expression in normal and tumor cells was studied. It was established that microRNA suppression in tumor cells and the determination of absolute microRNA levels in tumor and normal cells are not sufficient for the adequate estimation of the possibility of specific microRNA usage in the scheme of cancer gene therapy, and particularly do not allow to exclude a significant decrease in the efficiency of the gene-therapeutic drug upon the introduction of microRNA recognition sites. These parameters are only suitable for the preliminary selection of microRNA. The effect of introduction of microRNA recognition sites on transgene expression level in target tumor cells should be validated experimentally. It is suggested that this should be done directly in the cancer gene therapy scheme with monitoring of the therapeutic transgene activity.     

A novel bioluminescence orthotopic mouse model for advanced lung cancer

Lung cancer is the leading cause of cancer-related death in the United States despite recent advances in our understanding of this challenging disease. An animal model for high-throughput screening of therapeutic agents for advanced lung cancer could help promote the development of more successful treatment interventions. To develop our orthotopic lung cancer model, luciferase-expressing A549 cancer cells were injected into the mediastinum of athymic nude mice. To determine whether the model would allow easy monitoring of response to therapeutic interventions, tumors were treated with 30 mg/kg Paclitaxel or were irradiated with 5 fractions of 2 Gy, and tumor burden was monitored using bioluminescence imaging. Evidence of radiation-induced lung injury was assessed using immunohistochemical staining for phospho-Smad2/3 and cleaved caspase-3. We found that tumor implantation recapitulated advanced human lung cancer as evidenced by tumor establishment and proliferation within the mediastinum. The tumor responded to Paclitaxel or radiation as shown by decreased tumor bioluminescence and improved overall survival. Immunohistochemistry revealed increased phospho-Smad2/3 and cleaved caspase-3 in irradiated lungs, consistent with radiation-induced lung injury. This orthotopic lung cancer model may help provide a method to assess therapeutic interventions in a preclinical setting that recapitulates locally advanced lung cancer.     

Identification of novel therapeutic targets in microdissected clear cell ovarian cancers

Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.     

前列腺癌的靶向治疗研究现状与展望

前列腺癌难以根治,研究雄激素非依赖型前列腺癌的靶向治疗具有实际的临床意义,涉及抗体靶向治疗、靶向抗前列腺癌药物研制、细胞生长信号转导通路抑制、微小RNA应用等多方面,而靶向清除肿瘤干细胞则是根治前列腺癌的有效策略。     

Combined immunotherapy with Listeria monocytogenes-based PSA vaccine and radiation therapy leads to a therapeutic response in a murine model of prostate cancer

Radiation therapy (RT) is an integral part of prostate cancer treatment across all stages and risk groups. Immunotherapy using a live, attenuated, Listeria monocytogenes-based vaccines have been shown previously to be highly efficient in stimulating anti-tumor responses to impact on the growth of established tumors in different tumor models. Here, we evaluated the combination of RT and immunotherapy using Listeria monocytogenes-based vaccine (ADXS31-142) in a mouse model of prostate cancer. Mice bearing PSA-expressing TPSA23 tumor were divided to 5 groups receiving no treatment, ADXS31-142, RT (10?Gy), control Listeria vector and combination of ADXS31-142 and RT. Tumor growth curve was generated by measuring the tumor volume biweekly. Tumor tissue, spleen, and sera were harvested from each group for IFN-?? ELISpot, intracellular cytokine assay, tetramer analysis, and immunofluorescence staining. There was a significant tumor growth delay in mice that received combined ADXS31-142 and RT treatment as compared with mice of other cohorts and this combined treatment causes complete regression of their established tumors in 60?% of the mice. ELISpot and immunohistochemistry of CD8+?cytotoxic T Lymphocytes (CTL) showed a significant increase in IFN-?? production in mice with combined treatment. Tetramer analysis showed a fourfold and a greater than 16-fold increase in PSA-specific CTLs in animals receiving ADXS31-142 alone and combination treatment, respectively. A similar increase in infiltration of CTLs was observed in the tumor tissues. Combination therapy with RT and Listeria PSA vaccine causes significant tumor regression by augmenting PSA-specific immune response and it could serve as a potential treatment regimen for prostate cancer.     

Assessing responses to cancer therapy using molecular imaging

Tumor responses to therapy in the clinic are still evaluated primarily from non-invasive imaging measurements of reductions in tumor size. This approach, however, lacks sensitivity and can only give a delayed indication of a positive response to treatment. Major advances in our understanding of the molecular mechanisms responsible for cancer, combined with new targeted clinical imaging technologies designed to detect the molecular correlates of disease progression and response to treatment, are set to revolutionize our approach to the detection and treatment of the disease. We describe here the imaging technologies available to image tumor cell proliferation and migration, metabolism, receptor and gene expression, apoptosis and tumor angiogenesis and vascular function, and show how measurements of these parameters can be used to give early indications of positive responses to treatment or to detect drug resistance and/or disease recurrence. Special emphasis has been placed on those applications that are already used in the clinic and those that are likely to translate into clinical application in the near future or whose use in preclinical studies is likely to facilitate translation of new treatments into the clinic.