血清和胸水中CA125在结核性和癌性胸水中的表达及临床意义

目的:探讨血清和胸水中CA125在结核性和癌性胸水中的表达及鉴别诊断意义。方法:抽选我院确诊的结核性胸水病人85例(结核组)和癌性胸水病人71例(癌症组),检测两组患者血清和胸水中CA125表达,并以胸水/血清中CA125比值10(p-CA125/s-CA12510)为临界值,观察其对癌性胸水的鉴别特异度、灵敏度及准确性。结果:癌症组胸水中CA125表达及p-CA125/s-CA125比值均显著高于结核组(P0.05);但血清中两组CA125表达比较差异无显著性(P0.05);两组胸水中,以35U/ml为临界值,两组患者阳性率92.9%(79/85)、100%(71/71)比较差异无显著性(X2=7.0718,P=0.0078)。癌症组中p-CA125/sCA125比值10的比率(84.5%VS 17.6%)明显高于结核组(X2=66.6244,P=0.0000);并以其为诊断癌性胸水的临界值,鉴别诊断特异度、灵敏度及准确性分别为82.3%、84.5%、83.3%。结论:血清和胸水中CA125表达对于鉴别结核性或者是癌性胸水的临床意义不大,但是p-CA125/s-CA125比值对于鉴别结核性和癌性胸水具有一定临床价值。     

Elevated levels of interleukin-8 in serum are associated with hepatitis C virus infection and resistance to interferon therapy

Hepatitis C virus (HCV), a major cause of liver disease worldwide, is frequently resistant to the antiviral alpha interferon (IFN). We have recently found that the HCV NS5A protein induces expression of the proinflammatory chemokine IL-8 to partially inhibit the antiviral actions of IFN in vitro. To extend these observations, in the present study we examined the relationship between levels of IL-8 in serum, HCV infection, and biochemical response to IFN therapy. Levels of IL-8 were significantly elevated in 132 HCV-infected patients compared to levels in 32 normal healthy subjects and were also significantly higher in patients who did not respond to IFN therapy than in patients who did respond to therapy. This study suggests that HCV-induced changes in levels of chemokine and cytokine expression may be involved in HCV antiviral resistance, persistence, and pathogenesis.     

Vascular endothelial growth factor in malignant pleural effusion associated with lung cancer

The presence of vascular endothelial growth factor (VEGF) was examined by enzyme immunoassay in 60 cytology-documented malignant pleural effusions associated with primary lung cancer and 51 other benign and malignant pleural effusions. Exudative pleural effusions contained significantly higher amounts of VEGF than transudative pleural effusions. Among exudative pleural effusions, levels of VEGF in malignant pleural effusions associated with lung cancer were significantly higher than those of benign exudative pleural effusions. There was no significant difference in pleural VEGF in patients with different histological types or clinical stages of lung cancer. Serial measurement of pleural VEGF levels was performed in six lung cancer patients treated with intrapleural instillation of recombinant interferon γ, and reduction of pleural effusion was associated with decreasing pleural VEGF levels. These findings suggest that VEGF has a role in the accumulation of exudative pleural effusions, especially that of malignant pleural effusion associated with lung cancer. Received: 14 April 1999 / Accepted: 10 June 1999     

α-2-HS-glycoprotein is a potential marker predicting hepatitis B e antigen seroconversion in patients with chronic hepatitis B during treatment with pegylated interferon alfa-2b

The efficacy of interferon (IFN) is limited in about 1/3 of patients with chronic hepatitis B (CHB). We used two-dimensional electrophoresis (2-DE)-based proteomic strategies to identify potential serum markers predicting hepatitis B e antigen (HBeAg) seroconversion in these patients during IFN therapy. Two groups of patients were enrolled: training and validation. In the training group, 2-DE experiments and subsequent identification of altered levels of proteins showed that α-2-HS-glycoprotein, leucine-rich α-2-glycoprotein, and haptoglobin were significantly upregulated as compared with baseline levels in the HBeAg seroconversion group, whereas apolipoprotein C-III precursor, leucine-rich α-2-glycoprotein, and α-albumin were downregulated in the non-seroconversion group. For patients with HBeAg seroconversion in the training group, Western blot analyses showed that α-2-HS-glycoprotein levels in 75% of patients were significantly upregulated at the end of the treatment as compared with baseline levels. Subsequent experiments in the validation group showed that α-2-HS-glycoprotein levels were significantly increased at week 4 in 83.33% of patients in the HBeAg seroconversion group. Dynamic changes in the serum level of α-2-HS-glycoprotein may be a potential early marker for predicting HBeAg seroconversion during IFN treatment for CHB.     

Intrapleural instillation of interferon γ in patients with malignant pleurisy due to lung cancer

 The effect of intrapleural instillation of recombinant human interferon γ (IFNγ) at increasing doses of (1–12) × 10⁶ U was examined in six patients with cytologically positive pleural effusion due to lung cancer. Intrapleural instillation was repeated up to three times. Clinically, no reaccumulation of pleural effusion was observed in one patient and disappearance of lung cancer cells from the pleural effusion was seen in two other patients. No severe side-effects were observed. Considerable levels of IFNγ remained in the pleural effusion as well as in patients’ serum up to 7 days after instillation of 2 × 10⁶ U and higher doses. The total cell number showed a transient decrease on day 1 of therapy. Levels of pro-inflammatory cytokines, such as tumor necrosis factor α, interleukin(IL)-1β and IL-6, in the pleural effusion remained almost stable after IFNγ instillation. On the other hand, intrapleural IL-1 receptor antagonist levels were remarkably elevated by the instillation of IFNγ. IL-2- and IL-12-inducible killer activity of pleural mononuclear cells tended to increase slightly. Despite the inability of IFNγ to control pleural effusion in this treatment schedule, IFNγ instilled by an intrapleural route had a potential local antitumor activity. Moreover, since IFNγ persists in pleural effusions for a long time after a single instillation, such a therapy in combination with other fibrogenic biological response modifiers can be promising. Received: 28 February 1997 / Accepted: 23 July 1997     

Combination biotherapy utilizing interleukin-2 and alpha interferon in patients with advanced cancer: a National Biotherapy Study Group Trial.

The National Biotherapy Study Group (NBSG) conducted a broad phase II trial using interleukin-2 (IL-2) by continuous infusion and alpha interferon (IFN) subcutaneously in 267 patients with a variety of advanced cancers, including 29 with breast cancer, 89 with renal cancer, and 69 with melanoma. IL-2 [18 million international units (MIU)/m2] was given by continuous infusion for 108 hours with 3 mu/m2 subcutaneous IFN every other day during the IL-2 infusion. The patients were treated for 1 week followed by a 2-week rest. After two cycles of treatment, patients were evaluated for response. Of the 237 patients evaluable for response, 20 (8%) had a complete or partial response and 128 (54%) were stable. Therefore, 62% of the evaluable patients were nonprogressive during the first 90 days of IL-2/IFN therapy. The objective response rate was 11% in melanoma, 7% in renal cancer, 14% in breast cancer, and 3% in patients with a variety of malignancies for an overall response rate of 7% in these patients with advanced cancer. The patients were treated on a general medical ward and tolerated treatment well with fatigue and fever being nearly universal. Dyspnea, pruritus, chills, and elevated creatinines were frequent but less common. This combination biotherapy regimen has minimal activity in a variety of advanced cancers and must be compared with the best existing chemotherapy for each cancer type in randomized, prospective trials.     

Analysis of serum copper and zinc concentrations in cancer patients

Several studies have shown that plasma copper concentrations are increased in various carcinomas. Zinc acts as a cellular growth protector, including growth of neoplastic cells, and its deficiency was demonstrated to be involved in several stages of malignant transformation. However, the usefulness of the serum zinc and copper determinations in cancer prevention, detection, monitoring treatment, and prognosis requires further investigations. The aim of the present study was to compare the serum copper and zinc levels in patients with cancer of the lung (PC), breast (BC), gastrointestinal tract (GIC), and gynecological (GYNC) malignancy with progress of the disease. The results of the study have shown a significant increase in the mean total serum Cu levels and the serum Cu/Zn ratio in all patient groups with cancer compared to a control group. Increased mean serum concentrations and Cu/Zn ratios were found in the whole group (ALLC), and for the GIC and GYNC groups with local as well as metastasized (Meta) disease in comparison with the control group. The mean serum concentrations of Zn were decreased only in metastasized ALLC and GYNC groups.     

Enhancement of intravesical delivery with Syn3 potentiates interferon-alpha2b gene therapy for superficial bladder cancer

Intravesical administration of interferon alpha-2b protein (IFN) has been successfully used in the treatment of patients with superficial bladder tumors. Local dosing of IFN minimizes well-known systemic side effects of the drug, but exposure to bladder tumors is limited by the duration of instillation and transient concentrations achieved in the urothelium. Intravesical delivery of the gene encoding interferon results in an alternative strategy for IFN-based therapy of the disease, enabling sustained exposure of IFN protein that results from production by tumor and non-tumor cells in the urothelium. Efficient gene delivery and expression of IFN has been achieved using a recombinant adenovirus gene delivery system (rAd-IFN) in conjunction with the novel small molecule excipient Syn3. Studies with rAd-IFN/Syn3 in animal models result in urine concentrations of IFN that persisted for weeks and correlated with potent anti-tumor effects. The objective of this review is to communicate the rationale and preclinical findings that support ongoing clinical investigation of intravesical rAd-IFN/Syn3 in superficial bladder cancer.     

Cytopathology of alpha chain disease involving the central nervous system and pleura

Alpha chain disease, a lymphomatous disorder characterized by the synthesis and secretion of an abnormal IgA immunoglobulin devoid of light chains, involves mainly the gastrointestinal tract. This paper presents the cytologic and histologic findings in two cases of alpha chain disease involving the central nervous system and pleura. Most of the cell populations in the cerebrospinal fluid (CSF) and pleural fluid resembled immature plasma cells (immunoblasts); many of these cells were degenerated, with well-preserved plasma cells seen more rarely. While the definitive diagnosis of alpha chain disease depends on immunochemical analysis of serum proteins, cytology can play a role by the identification of malignant cells in CSF and pleural fluid specimens. A positive staining of such cells by the methyl green pyronin reaction may permit the correct diagnosis to be suggested.     

Enhancement of intravesical delivery with Syn3 potentiates interferon-α2b gene therapy for superficial bladder cancer

Intravesical administration of interferon alpha-2b protein (IFN) has been successfully used in the treatment of patients with superficial bladder tumors. Local dosing of IFN minimizes well-known systemic side effects of the drug, but exposure to bladder tumors is limited by the duration of instillation and transient concentrations achieved in the urothelium. Intravesical delivery of the gene encoding interferon results in an alternative strategy for IFN-based therapy of the disease, enabling sustained exposure of IFN protein that results from production by tumor and non-tumor cells in the urothelium. Efficient gene delivery and expression of IFN has been achieved using a recombinant adenovirus gene delivery system (rAd-IFN) in conjunction with the novel small molecule excipient Syn3. Studies with rAd-IFN/Syn3 in animal models result in urine concentrations of IFN that persisted for weeks and correlated with potent anti-tumor effects. The objective of this review is to communicate the rationale and preclinical findings that support ongoing clinical investigation of intravesical rAd-IFN/Syn3 in superficial bladder cancer.     

Proteomic identification of glycosylphosphatidylinositol anchor-dependent membrane proteins elevated in breast carcinoma

The glycosylphosphatidylinositol (GPI) anchor is a lipid and glycan modification added to the C terminus of certain proteins in the endoplasmic reticulum by the activity of a multiple subunit enzyme complex known as the GPI transamidase (GPIT). Several subunits of GPIT have increased expression levels in breast carcinoma. In an effort to identify GPI-anchored proteins and understand the possible role of these proteins in breast cancer progression, we employed a combination of strategies. First, alpha toxin from Clostridium septicum was used to capture GPI-anchored proteins from human breast cancer tissues, cells, and serum for proteomic analysis. We also expressed short interfering RNAs targeting the expression of the GPAA1 and PIGT subunits of GPIT in breast cancer cell lines to identify proteins in which membrane localization is dependent on GPI anchor addition. Comparative membrane proteomics using nano-ESI-RPLC-MS/MS led to the discovery of several new potential diagnostic and therapeutic targets for breast cancer. Furthermore, we provide evidence that increased levels of GPI anchor addition in malignant breast epithelial cells promotes the dedifferentiation of malignant breast epithelial cells in part by increasing the levels of cell surface markers associated with mesenchymal stem cells.     

Anti‐cancer therapy with TNFα and IFNγ: A comprehensive review

Tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ) were originally found to be produced by inflammatory cells and play important roles in the immune system and surveillance of tumour growth. By activating distinct signalling pathways of nuclear factor‐κB (NF‐κB), mitogen‐activated protein kinase (MAPK), and JAK/STAT, TNFα and IFNγ were reported to effectively trigger cell death and perform powerful anti‐cancer effects. In this review, we will discuss the new advancements of TNFα and IFNγ in anti‐cancer therapy.     

MN/CA9: a potential gene marker for detection of malignant cells in effusions.

Many cancers cause malignant effusions. The presence of malignant cells in effusions has implications in diagnosis, tumour staging and prognosis. The detection of malignant cells currently presents a challenge for cytopathologists. New adjunctive methods are needed. Although the effusions provide excellent materials for molecular assay, the available molecular markers are extremely limited, which hinders its clinical application. MN/CA9 has proved to be a valuable marker in many cancers such as lung, breast, colon, kidney, etc. The present study was to evaluate MN/CA9 as a new molecular marker for the detection of cancer cells in pleural effusions. Seventy-one pleural effusions including 59 malignant effusions from patients with cancer, and 12 patients with benign diseases as a control, were subjected to RT-PCR for detection of MN/CA9 gene expression. MN/CA9 gene expression was detected in 53/59 (89.8%) pleural effusions from cancer patients (15/16 for breast cancers, 10/11 for lung cancers, 4/4 for ovary cancers, 2/3 for colon-rectal cancers, 5/6 for cancers of unknown site, 7/8 for mesothelioma and 10/11 for other cancers). Furthermore, MN/CA9 was positive in 13/18 (72.2%) of cytologically negative effusions of cancer patients. MN/CA9 was detected in only 1/12 (8.3%) effusions from the control patients (p < 0.01). The sensitivity and specificity of MN/CA9 gene expression were, respectively, 89.8% and 91.7%. Our preliminary results suggest that MN/CA9 could be a potential marker for the detection of malignant cells in effusions. A large-scale study is needed to confirm these results.     

Ovine trophoblast protein-1 and human interferon alpha reduce prostaglandin synthesis by ovine endometrial cells

Ovine trophoblast protein-1 (oTP-1), a protein secreted by the sheep conceptus immediately prior to implantation has sequence homology with alpha interferon. We have previously shown that, in parallel with human alpha interferon (IFN), oTP-1 reduces the release of prostaglandins (PG) E and F2 alpha from cultured ovine endometrial cells. Here we have examined the time and dose dependence of these actions and the possible site of action of the peptides. The concentrations of oTP-1 and IFN required for 50% inhibition of PGE release were 92 pg/ml and 0.88 pg/ml and for PGF2 alpha release, 165 pg/ml and 1.12 pg/ml respectively. Significant effects on PG release were not measured before 12 h after addition of peptide to culture dishes. Following removal of the peptides, the cells released less PGs for a further 18 h but then recovered. A large increase in PG synthesis and release occurred from cells cultured with added serum or arachidonic acid (AA) and an interactive effect was demonstrated between them, AA having a greater stimulatory effect on PG released in the presence of serum. However, in all cases oTP-1 and IFN continued to attenuate prostaglandin release. We conclude that the IFNs act directly or indirectly on the prostaglandin synthase enzyme.     

Inactivation of interferon by serum and synovial fluids

The stability of interferons-alpha, -beta, and -gamma (IFN) in serum and synovial fluids were compared. Interferon-beta was the least stable interferon species, losing at least 75% of its activity during incubation in samples of both serum and synovial fluid. Interferon-alpha was the most stable IFN, but interferon-gamma under these conditions approached the stability of the alpha species. The inactivation of IFN-beta was found due to dialyzable factors and hence not classical antibodies.     

miR-188-5p suppresses cellular proliferation and migration via IL6ST: A potential noninvasive diagnostic biomarker for breast cancer

Previously, serum miR-188-5p is differentially expressed in breast cancer, but the diagnostic potential of circulating miR-188-5p as well as its regulatory mechanism in breast cancer remain uncertain. Herein, serum miR-188-5p was detected by real-time polymerase chain reaction in patients with breast cancer, breast fibroadenoma, and healthy subjects. Circulating miR-188-5p was abnormally elevated in patients with breast cancer as compared with these other two groups, and was reduced in patients with breast cancer following surgical treatment. Increased serum miR-188-5p corresponded to lymph node metastasis status and TNM stages of breast cancer. A receiver operating characteristic curve analysis of the ability to circulate miR-188-5p to distinguish between patients with breast cancer and either noncancerous patients or patients with breast fibroadenoma yielded corresponding areas under the curve of 0.894 and 8.814. miR-188-5p was downregulated in the highly malignant cancer line MDA-MB-231 relative to the less malignant MCF-7 cells. In vitro, functional analyses conducted via transfecting cells with mimics and inhibitors revealed miR-188-5p to suppress breast cancer cell proliferation and migration, which was mediated by its downstream target IL6ST. Comparison of intracellular and exosomal miR-188-5p levels indicated that miR-188-5p was selectively sorted into exosomes derived from MDA-MB-231 cells rather than those from MCF-7 cells. However, exosomal miR-188-5p levels in the serum of patients with breast cancer were reduced compared to healthy controls and did not differ relative to patients with breast fibroadenoma. In summary, miR-188-5p acts in a tumor-suppressive manner in breast cancer progression and may serve as a noninvasive early diagnostic biomarker and therapeutic target in breast cancer.     

Cell origins and diagnostic accuracy of interleukin 27 in pleural effusions

The objective of the present study was to investigate the presence of interleukin (IL)-27 in pleural effusions and to evaluate the diagnostic significance of pleural IL-27. The concentrations of IL-27 were determined in pleural fluids and sera from 68 patients with tuberculous pleural effusion, 63 malignant pleural effusion, 22 infectious pleural effusion, and 21 transudative pleural effusion. Flow cytometry was used to identify which pleural cell types expressed IL-27. It was found that the concentrations of pleural IL-27 in tuberculous group were significantly higher than those in malignant, infectious, and transudative groups, respectively. Pleural CD4(+) T cells, CD8(+) T cells, NK cells, NKT cells, B cells, monocytes, macrophages, and mesothelial cells might be the cell sources for IL-27. IL-27 levels could be used for diagnostic purpose for tuberculous pleural effusion, with the cut off value of 1,007 ng/L, IL-27 had a sensitivity of 92.7% and specificity of 99.1% for differential diagnosing tuberculous pleural effusion from non-tuberculous pleural effusions. Therefore, compared to non-tuberculous pleural effusions, IL-27 appeared to be increased in tuberculous pleural effusion. IL-27 in pleural fluid is a sensitive and specific biomarker for the differential diagnosing tuberculous pleural effusion from pleural effusions with the other causes.     

Interferon induction by Lactobacillus bulgaricus and Streptococcus thermophilus in mice.

This study investigates the effect of intraperitoneal injection of L. bulgaricus and S. thermophilus on interferon production by Swiss mice. The serum from mice given 5 x 10(7) L. bulgaricus in 0.5 ml saline showed a maximal production of 300 U/ml of alpha/beta interferon activity six hours after injection. Cellular integrity appears to be necessary for stimulation; heat-treated bacteria had little effect, while irradiated-bacteria had a greater effect. TNF was also produced, the sera of mice with high IFN also contained 300 U/ml TNF. Streptococcus thermophilus produced no detectable increase in serum IFN, but the 2'-5' A synthetase activity of peritoneal cells was elevated suggesting that small amounts of interferon were produced. Injection of Streptococcus thermophilus plus Lactobacillus bulgaricus did not change the serum interferon response to L. bulgaricus. These observations suggest that non-pathogenic bacteria such as those used in food processing, can stimulate IFN production in mice. There is some evidence that the bacterial cell walls might be responsible for at least part of this effect.     

Effect of in vitro interferon treatment on the rapid clearance of murine leukemia cells in vivo.

Previous work showed that interferon (IFN) can protect target cells from NK mediated lysis in vitro. In the present study we investigate the effect of IFN alpha/beta or IFN gamma treatment of three different murine leukemia cell lines. For this purpose FLC-745 (susceptible to the antiproliferative activity of IFN alpha/beta and gamma), FLC-3C18 (IFN alpha/beta -resistant and IFN gamma - susceptible) of DBA/2 origin and EL-4 (IFN alpha/beta - susceptible and IFN gamma - resistant) leukemia of C57B1/6 origin were treated with IFN alpha/beta or gamma in vitro and assayed for their susceptibility to natural resistance measured in vivo as organ rapid clearance 4 hr after iv injection into syngeneic mice. Using young or Poly I:C stimulated hosts, but not mice with low levels of natural resistance (i.e. older animals or mice treated with cyclophosphamide), slower elimination of treated cells was observed with: (a) FLC-745 cells treated with IFN alpha/beta and IFN gamma and (b) FLC 3C18 treated with IFN gamma. Such a delayed clearance was not observed with: (a) FLC-3C18 cells treated with IFN alpha/beta and (b) EL-4 leukemia cells preincubated with IFN alpha/beta or IFN gamma. These results suggest that under selected conditions IFNs can protect leukemic cells from in vivo natural reactivity.     

Pleural fluid lysozyme in human disease.

A prospective study was conducted to define the content, significance, and source of lysozyme present in the pleural fluid in human diseases. The pleural fluid lysozyme activity is similar in various malignant and nonmalignant transudates and exudates, and is of limited diagnostic value. The pleural fluid activity correlated well with that of paired serum samples but it had poor correlation with the disease state, the pleural fluid granulocyte counts, and total white blood cell counts. The data suggest that the pleural fluid lysozyme may be derived primarily from the blood and that it is not the product of inflammatory or neoplastic cells in the fluid itself.