Serum soluble interleukin-2 receptor level as a prognostic indicator in gastric cancer

T lymphocytes, activated by interleukin 2 during an anti-tumour response, release soluble interleukin 2 receptors (sIL-2R) into the bloodstream. We analysed the prognostic value of the serum sIL-2R level in gastric cancer. Serum concentration of sIL-2R in 96 gastric cancer patients and 100 healthy control subjects' was measured by enzyme-linked immunosorbent assay. All survivors were followed for more than 50 months. Serum sIL-2R level was considered with respect to prognosis, clinicopathological factors, other tumour markers and peripheral blood cell count. Stage III and IV patients had significantly higher sIL-2R levels than lower stage patients and control subjects. Stage III and IV gastric cancer patients were divided into 'high' and 'low' slL-2R groups based upon the control subjects' serum sIL-2R mean value plus one standard deviation. The high group had a significantly worse prognosis than the low group, although clinicopathological features and treatments were similar. Multivariate analysis demonstrated that the serum sIL-2R level is an independent indicator. The sIL-2R level did not correlate with carbohydrate antigen 19-9, however it did correlate with carcinoembryonic antigen (r = 0.22) and with numbers of peripheral blood monocytes (r = 0.54). In conclusion, serum sIL-2R may predict the outcome of gastric cancer patients with stage III or IV disease.     

Soluble interleukin-2 receptor (sIL-2R) is a marker of disease activity in psoriasis: a comparison of sIL-2R, sCD27, sCD4, sCD8 and sICAM-1

The fine structure of the cell surface of seven enterotoxemic Escherichia coli (ETEEC) O139:K12 strains isolated from piglets with edema disease were examined electron microscopically using both the negative-staining method and the freeze-substitution fixation method. Densely packed, fine fibers were observed; they consisted of a capsule layer approximately 25 nm thick around the cell surfaces of strains 107/86, IW-2, ED-3, ED-43, and ED-61, all of which have a capacity to adhere strongly to HEp-2 cells. In contrast, no such structure was observed on the surface of strains RK-O139 or ED-1, both of which adhere only weakly to HEp-2 cells. These results suggest that the capsule structure might be associated with the ability to adhere to HEp-2 cells and, as a result, also potentially play some role in ETEEC infection.     

Level of interleukin-6 (IL-6), soluble interleukin-6 receptors (sIL-6R) and tumor necrosis factor alpha (TNF-alpha) in untreated and progressing multiple myeloma]

The effect of original analogues of the 6-9 C-terminal AVP fragment, D-MRP and D-MPRG, on the active avoidance behaviour of rats was studied using intranasal administration in a wide range of doses. The dose in 0.1 mcg/kg was the most efficient for D-MPR and 0.01 mcg/kg for D-MPRG, which for the tripeptide was ten times, and for the tetrapeptide hundred times lower than the corresponding dose of AVP used in the similar experiments. The tri- and tetrapeptide were shown to facilitate the active avoidance behaviour affecting both the formation of the reaction and consolidation of memory trace. The peptides mostly affect the perception processes, i.e., the detection of a specific stimulus from the environment, the estimation and memorizing of its biological significance.     

The significance of soluble interleukin-2 receptor in monitoring disease relapse in patients with nasopharyngeal cancer

BACKGROUND: Soluble interleukin-2 receptor alpha (sIL-2R alpha) is a well-known indicator of T-cell activation noted to be increasing in nasopharyngeal cancer. However, the significance of sIL-2R alpha in monitoring disease relapse is unclear. This study was initiated to address this issue. METHODS: Serum of 56 patients with NPC, which underwent either primary, salvage, or palliative treatments, from 1992 to 1993 at the Cancer Center, Veterans General Hospital-Taipei, were collected from our serum bank. According to their disease status at the time of study, at least two years after last treatments, the 56 patients were divided into four groups. The remission group represented those in remission at the time of study (n = 24). The metastasis group represented those with distant metastasis present at the time of study (n = 17). The recurrence group represented those with locoregional recurrence present at the time of study (n = 11). The combined group represented those with locoregional recurrence as well as distant metastasis (n = 4). The seral sIL-2R alpha concentrations of the 56 NPC patients were determined with enzyme-linked immunoabsorbent assay. The combined group was excluded in our statistical analysis. We performed statistical analysis on the differences of paired serum sIL-2R alpha concentrations between different periods of the diseases. The first analysis was on the differences of sIL-2R alpha concentrations between diagnosis and post-radiotherapy periods for 13 out of 24 patients in the remission group and 7 out of 11 patients in the recurrence group. The second analysis was on the differences of sIL-2R alpha concentration between follow-up before detection-of-relapse and after detection-of-relapse for 5 out of 17 patients in the metastasis group and six out of 11 patients in the recurrence group. RESULTS: The first statistical analysis revealed no significant differences of sIL-2R alpha concentrations for the remission group (P = 0.946) and the recurrence group (P = 0.156) between diagnosis and post-radiotherapy periods. The second statistical analysis revealed no significant differences of sIL-2R alpha concentrations between before and after detection-of-relapse for the recurrence group, neither (P = 0.438). The results for the metastasis group were different. The sIL-2R alpha concentrations were shown to increase after the detection of metastasis for the 5 paired samples from the metastasis group, although the Wilcoxon signed ranks test on the differences only showed borderline significance (P = 0.063). CONCLUSIONS: Our findings show that sIL-2R alpha would be of no value in monitoring the development of locoregional recurrence but might be useful in monitoring distant metastasis. Although our current limited data did not provide strong support for the role of sIL-2R alpha in monitoring metastasis, it might be delineated in the future by collecting more data.     

Serum concentrations of neopterin, soluble interleukin 2 receptor, and soluble tumor necrosis factor receptor in Wegener's granulomatosis

OBJECTIVE: To investigate the possible relationship between serum levels of neopterin, soluble tumor necrosis factor-55 receptor (sTNF-55R), and soluble interleukin 2 receptor (sIL-2R) with disease activity in patients with Wegener's granulomatosis (WG). METHODS: Serum neopterin was measured by radioimmunoassay, sTNF-55R and sIL-2R were measured by ELISA in 26 patients with WG. RESULTS: Serum neopterin, sTNF-55R, and sIL-2R were significantly elevated in patients with generalized WG compared with healthy controls. Concentrations of the analytes correlated with disease activity indices in patients without infectious complications. The highest elevations of all 3 variables were observed in patients with intercurrent infections. CONCLUSION: The increased serum levels of neopterin, sTNF-55R, and sIL-2R suggest activation of cellular immunity in WG.     

Changes in interleukin-1 beta and soluble interleukin-2 receptor levels in CSF and serum of schizophrenic patients

Some evidence points towards a possible autoimmune role in the aetiology of schizophrenia. Experimental findings provide contradictory results regarding abnormalities in cytokine production in this disorder. In the present study we tested the production of cytokines in CSF and serum in 16 schizophrenic patients and 10 healthy controls (tumor necrosis factor alpha - TNF alpha; interleukins IL-1 beta, IL-2, IL-6, soluble IL-2 receptor). Cytokine levels were evaluated by radioactively-labeled antibodies (IL-1 beta, IL-2, IL-6), by enzyme-linked immunoassay (TNF) and by a sandwich enzyme immunoassay (soluble IL-2 receptor). No significant differences were found in either CSF fluid or serum levels of TNF and IL-2 or IL-6. Interleukin-1 beta was significantly decreased in patients' CSF and serum as compared to controls. Soluble interleukin-2 receptor levels were decreased in CSF of patients, but highly increased in their serum in comparison with controls. Changes in various cytokine levels in CSF fluid and serum of schizophrenic patients probably reflect interrelated process of growth, degeneration or neuroimmunological abnormalities, which may all play a role in the pathophysiology of schizophrenia. The present study supports evidence for change in immune activation, probably of peripheral origin, in schizophrenic patients.     

Anti asialoglycoprotein receptor antibodies and soluble interleukin-2 receptor levels as marker for inflammation in autoimmune hepatitis

Previous results using an amphibian model showed that systemic and spinal administration of opioids selective for mu, delta and kappa-opioid receptors produce analgesia. It is not known whether non-mammalian vertebrates also contain supraspinal sites mediating opioid analgesia. Thus, opioid agonists selective for mu (morphine; fentanyl), delta (DADLE, [D-Ala2, D-Leu5]-enkephalin; DPDPE, [D-Pen2, D-Pen5]-enkephalin) and kappa (U50488, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methanesulfonate; CI977, (5R)-(544alpha,744alpha,845beta)-N-methyl-N-[7-(1-p yrr olidinyl)-1-oxaspiro[4,5]dec-8yl]-4-benzofuranaceta mide++ + monohydrochloride) opioid receptors were tested for analgesia following i.c.v. administration in the Northern grass frog, Rana pipiens. Morphine, administered at 0.3, 1, 3 and 10 nmol/frog, produced a dose-dependent and long-lasting analgesic effect. Concurrent naltrexone (10 nmol) significantly blocked analgesia produced by i.c.v. morphine (10 nmol). ED50 values for the six opioids ranged from 2.0 for morphine to 63.9 nmol for U50488. The rank order of analgesic potency was morphine > DADLE > DPDPE > CI977 > fentanyl > U50488. These results show that supraspinal sites mediate opioid analgesia in amphibians and suggest that mechanisms of supraspinal opioid analgesia may be common to all vertebrates.     

A phase I study of recombinant human soluble interleukin-1 receptor (rhu IL-1R) in patients with relapsed and refractory acute myeloid leukemia

PURPOSE: The recombinant human interleukin-1 receptor (rhu IL-1R) is a soluble truncated form of the type 1 full-length membrane-bound receptor that binds IL-1 with identical affinity to that of the membrane form. As such, it may have clinical potential by sequestering IL-1, thereby preventing it from binding to its membrane-bound receptor and eliciting a biological effect. As IL-1 has been shown to regulate leukemic cell proliferation in an autocrine fashion, a phase I trial of rhu IL-1R was conducted in patients with relapsed and refractory acute myeloid leukemia (AML). METHODS: The study group comprised 11 patients who were sequentially treated on one of three dose levels, receiving a single intravenous (i.v.) bolus dose on day 1 followed by 13 days of daily subcutaneous (s.c.) injections with the option of an additional 14 days of treatment if a response of stable disease or better was achieved. Dose level 1 i.v. bolus 500 microg/m2, s.c. dose 250 microg/m2 per day (five patients); dose level 2 i.v. bolus 1000 microg/m2, s.c. dose 500 microg/m2 per day (three patients); dose level 3 i.v. bolus 2000 microg/m2, s.c. dose 1000 microg/m2 per day (three patients). Owing to limited drug availability, the study was designed to only examine these three dose levels. RESULTS: rhu IL-IR was well tolerated. There was no grade 3 or 4 non-hematological toxicity related to the study drug and the maximum tolerated dose was not reached. No IL-1R-blocking antibodies developed during the course of the study. Serum levels of IL-1beta, IL-6 and TNF were undetectable before, during and after rhu IL-IR administration. The terminal half-life after i.v. dosing was at least 7-12 h, and after s.c. dosing 2-4 days. Serum levels of rhu IL-1R up to 360- and 25-fold those of pretreatment levels were achieved after i.v. and s.c. dosing respectively. No patient had a complete, partial or minor response to treatment; four had stable disease and seven had progressive disease. CONCLUSIONS: rhu IL-1R therapy was safe but did not have any apparent antileukemic effect at the doses administered.     

Preliminary study on change of interleukin-2 and its receptor in the elderly

We measured the interleukin-2 (IL-2) and soluble interleukin-2 receptor (SIL-2R) in 86 senile patients (aged 71.5 +/- 8.45) with various diseases in order to evaluate the cell immune function in the elderly. The results showed that serum IL-2 activity was significantly lower in the senile group than in the middle-aged and young group, but SIL-2R was significantly higher in the senile group, predominantly in the cases of tumor and diabetes. It was also noted that lowered IL-2 activity and abnormal elevation of SIL-2R in late stage and diffused metastatic tumour patients were more significant than in other groups of senile patients. The magnitude of decrease in IL-2 activity and increase in SIL-2R correlated well with the severity of spread of tumour, suggesting that the higher the SIL-2R level goes, the worse the prognosis may be.     

Detection of soluble interleukin-2 receptor in the serum of patients with non-Hodgkin''s lymphoma

Falls are the most common type of injury among the elderly, and the source of both functional and psychological morbidity. The aim of this study was to validate the Elderly Fall Screening Test (EFST). In a community primary-care clinic, the members 60 years or older who were functionally independent were screened. Of the 568 elderly persons who met these criteria, 361 were interviewed once and 283 persons were re-interviewed a year later. The EFST, a five-item test, was used to divide participants into low- and high-risk groups. Concurrent criterion validity was assessed by physical examinations conducted by physicians who were blind as to the risk designation. Using data from the follow-up interview, predictive validity was assessed on both fall-related and general health measures. Based on the results of the EFST, 28% of the respondents were designated as being at high risk for falls (i.e. having a score of two or more risk items). The results of physicians' examinations corroborated the screening test results in 75% of the cases, with 83% sensitivity and 69% specificity. In the follow-up interview, the high-risk group, as compared to the low-risk group, was more likely to have high scores on EFST, a fall in the past month or year, frequent near falls, and an injurious fall. Those with high EFST scores were more likely to report four or more sick days in the past six months, a hospitalization in the past year, poor self-rated health, a decline in health in the past 6 months, and symptoms of depression. The EFST has both criterion and predictive validity. It can be useful in community-based prevention programmes with functionally independent elderly people.     

Serum interleukin-2 receptor levels in Hodgkin disease and other solid tumors of childhood

Serum levels of interleukin-2 receptor (IL2R) were determined in children with newly diagnosed Hodgkin disease (n = 68), Wilms tumor (n = 20), osteosarcoma (n = 18), rhabdomyosarcoma (n = 18), or Ewing sarcoma (n = 15). Measurements of soluble IL2R were positively correlated with disease stage in Hodgkin disease but not in other tumors. Very high levels of soluble IL2R (> or = 5000 U/ml) were significantly associated with a poorer treatment outcome in Hodgkin disease (p = 0.006) and retained significance in a multivariate analysis (p = 0.03). The addition of soluble IL2R measurements to existing prognostic models may improve risk assignment in children with Hodgkin disease.     

Recombinant soluble interleukin-11 (IL-11) receptor alpha-chain can act as an IL-11 antagonist

We have expressed a soluble N-glycosylated form of the murine interleukin-11 (IL-11) receptor alpha-chain (sIL-11R) and examined signaling in cells expressing the gp130 molecule. In the presence of gp130 but not the transmembrane IL-11R, the sIL-11R mediated IL-11-dependent differentiation of M1 leukemic cells and proliferation in Ba/F3 cells. Early intracellular events stimulated by the sIL-11R including phosphorylation of gp130, STAT 3, and SHP-2 were similar to signaling through the transmembrane IL-11R. IL-11 bound to sIL-11R with low affinity (kd 10 to 50 nmol/L). Binding of sIL-11R to gp130 was IL-11 dependent with intermediate affinity (kd 1.5 to 3.0 nmol/L). However, the concentration of IL-11 required for signaling through the sIL-11R was 10- to 20-fold greater than that required for cells expressing the transmembrane IL-11R and gp130 in the absence of sIL-11R. Furthermore, the sIL-11R was capable of antagonizing the activity of IL-11 when tested on cells expressing the transmembrane IL-11R and gp130. We propose that the observed IL-11 antagonism by the sIL-11R may depend on limiting numbers of gp130 molecules on cells already expressing the transmembrane IL-11R.     

Serum interleukin-6 (IL-6) and interleukin-4 (IL-4) in patients with multiple myeloma (MM)

In this study we determined, in patients with multiple myeloma (MM), serum levels of IL-4 and IL-6 at diagnosis and during the course of the disease, seeking a correlation with disease activity and prognosis. We studied 54 MM patients, 41 of whom responded to chemotherapy whilst 11 were resistant. At diagnosis, IL-6 was increased in 66% of patients (median 35.5 pg/ml) whereas IL-4 was low (median 4 pg/ml) in 75% of patients. In responding patients, IL-4 increased in remission (median 25 pg/ml), whereas IL-6 decreased (median 4 pg/ml). In chemotherapy-resistant patients, IL-6 and IL-4 values remained stable during the course of the disease.     

Effects of cyclosporine A on serum and urinary soluble interleukin-2 receptor in patients with lupus nephritis

OBJECTIVE: To evaluate the association of the level of urine and serum soluble interleukin-2 receptor (sIL-2R) with disease activity and response to cyclosporine A (CsA) therapy in patients with lupus nephritis (LN). METHODS: Sixteen hospitalized patients with LN were studied. At admission, fifteen patients had type IV-LN and one had type V-LN. All patients received CsA 6 mg/kg per day for 6-8 weeks, then tapered off gradually to 2 mg/kg per day. The levels of urinary and serum sIL-2R were determined by enzyme-linked immunosorbent assay (ELISA). Serum antinuclear antibody (ANA), anti-dsDNA antibody (A-ds-DNA), complement C3 and C4, total IgG, creatinine, urinary red blood cells and protein excretion, and lymphocyte subpopulations in the peripheral blood were also measured before and after CsA treatment. RESULTS: In LN patients, both urinary (534 +/- 101 U/ml) and serum SIL-2R levels (326 +/- 148 U/ml) were higher than those in normal controls. These findings were associated with higher levels of peripheral blood CD4 + and CD8 + lymphocytes (29.3 +/- 4.24 and 28.6 +/- 9.12%), higher titer of serum anti-ds-DNA, lower levels of serum complement C2 and C4 (0.98 +/- 0.23 and 0.24 +/- 0.12 g/L), as well as more proteinuria (Upro 2.99 +/- 0.76 g/24 hrs) and hematuria (URBC 83.9 +/- 95.2 10(4)/ml). These abnormalities were gradually ameliorated by CSA therapy. The changes in the levels of both serum (116 +/- 58.6 U/ml) and urine (136 +/- 43.2 U/ml) SIL-2R induced by CsA (at 8 weeks) were correlated with the changes in the levels of CD4 + and CD8 + cells (23.2 +/- 3.30 and 26.7 +/- 3.54%), degrees of immune abnormalities (serum C3 and C4 1.28 +/- 0.14 and 0.42 +/- 0.06 g/L), and renal injuries (Upro 1.07 +/- 0.46 g/24 hrs, URBC 5.82 +/- 3.15 10(4)/ml). CONCLUSIONS: These results suggest that serum and urinary sIL-2R are sensitive markers for the disease activity in patients with LN. CsA, a powerful immunosuppressive agent, significantly improves both immunologic disorders and renal functional impairments, the mechanism of which on patients with LN appears to inhibit the lymphocyte activation in the peripheral blood and renal tissues as indicated by the decrease in sIL-2R levels.     

Induction of soluble IL-2 receptor in patients with myelodysplastic syndromes undergoing high-dose interleukin-3 treatment

Sera of ten healthy controls and of 15 patients with myelodysplastic syndromes (MDS) were investigated for soluble interleukin-2 receptor (sIL-2R) with a cell-free enzyme-linked immunosorbent assay (ELISA). The patients with MDS underwent treatment with IL-3: eight patients at dose levels of 250 and 500 micrograms/m2 s.c. daily for 15 days, and seven patients at the dose levels of 60 and 125 micrograms/m2 s.c. three times per week for 12 weeks. None of the patients had reported infectious episodes or been under treatment with cytotoxic drugs and/or cytokines within the preceding 2 months. sIL-2R levels were elevated in MDS patients compared with healthy controls (p < 0.001). sIL-2R increased in the high-dose treatment group from 504 +/- 68 U/ml to 731 +/- 199 U/ml (p < 0.025). The increased sIL-2R expression in MDS could be a primary event due to involvement of lymphocytes in the malignant clone or due to a secondary alteration of the cytokine network caused by chronic neutropenia. A down-regulation of the immune response caused by neutralization of free IL-2 by sIL-2R during IL-3 therapy seems possible.     

Functional expression of soluble human interleukin-11 (IL-11) receptor alpha and stoichiometry of in vitro IL-11 receptor complexes with gp130

The interleukin-6 (IL-6) family of cytokines activates signaling through the formation of either gp130 homodimers, as for IL-6, or gp130-leukemia inhibitory factor receptor (LIFR) heterodimers as for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor, oncostatinM, and cardiotrophin-1. Recent in vitro studies with IL-6 and CNTF have demonstrated that higher order hexameric receptor complexes are assembled in which signaling chain dimerization is accompanied by the dimerization of both the cytokine molecule and its specific receptor alpha subunits (IL-6Ralpha or CNTFRalpha, respectively). IL-11 is a member of the IL-6 family and known to require gp130 but not LIFR for signaling. In this study we investigate the functional and biochemical composition of the IL-11 receptor complex. The human IL-11 receptor alpha-chain was cloned from a human bone marrow cDNA library. IL-11Ralpha was shown to confer IL-11 responsiveness to human hepatoma cells either by cDNA transfection or by adding a soluble form of the receptor (sIL11Ralpha) expressed in the baculovirus system to the culture medium. In vitro immunoprecipitation experiments showed that sIL11Ralpha specifically binds IL-11 and that binding is enhanced by gp130. Similarly to IL-6 and CNTF, gp130 is able to induce dimerization of the IL-11.IL-11Ralpha subcomplex, the result of which is the formation of a pentameric receptor complex. However, in contrast to the other two cytokines, IL-11 was unable to induce either gp130 homodimerization or gp130/LIFR heterodimerization. These results strongly suggest that an as yet unidentified receptor beta-chain is involved in IL-11 signaling.     

Long-acting neuroleptics. IV. Preliminary study of clopimozide (R 29764)

Clopimozide is, in our opinion, a noteworthy neuroleptic drug. Its action is mainly ataraxic but also antidelusional, long-acting and accompanied with minimal side-effects. It is therefore particularly indicated in the maintenance therapy of psychotics, at a weekly dosage of 7.5 to 25 mg. The present conclusions are preliminary because of the limited number of patients (10) but also because of the rigidity of the trial protocol suggested to us.     

Clinicoepidemiologic study of uterine cancer. Comparative aspects of the endometrial and cervical sites

A review of all newly diagnosed cases of cervical and endometrial carcinoma in Israel during the 5-year period of 1961-1965 yielded mean annual incidence rates of 4.9/100,000 and 7.4/100,000, respectively. Cervical cancer was more prevalent in Moroccan-born women and among divorcees, while the risk of endometrial cancer was highest in older age, among the European born, and the single; it also appeared earlier in life. Postmenopausal bleeding constituted the most frequent first symptom in both sites. Fifty percent of the patients of both groups were diagnosed within 1 month, but the delay was somewhat longer in the endometrial group. Median survival was 5 years in patients with cervical cancer and above 12 years in those with cancer of the corpus. Five-year survival was 50 and 75%, respectively. Survival tended to be better in younger patients in both groups. It is expected that the gradual disappearance of intraethnic differences in Israel would lead to a decrease in the incidence of invasive cervical cancer, coupled with an increased incidence of the endometrial category.