Serum interleukin-6 level is associated with response to infliximab in ulcerative colitis.

OBJECTIVES: Infliximab is effective in patients with ulcerative colitis (UC); however, one-third of patients do not respond and require additional therapies such as other biologic agents. Therefore, the aim of this study was to analyze the association between pro-inflammatory molecules and clinical efficacy to elucidate possible mechanisms for the non-response to infliximab to aid in treatment selection. MATERIALS AND METHOD: Patients with moderate-to-severe active UC receiving infliximab in our hospital between 2010 and 2016 for whom pre-treatment serum samples were available were retrospectively evaluated. We analyzed the association between serum interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) and the clinical efficacy of infliximab. The primary endpoint was clinical response at the end of the induction period. RESULTS: Forty-one patients were included in this study. After induction therapy, 27 patients (65.9%) showed a clinical response. Serum IL-6 levels were significantly lower in responders than in non-responders (p = .012), whereas no significant differences were noted in other factors including sMAdCAM-1 and TNF-α. Multivariate analysis identified that serum IL-6 level (odds ratio = 0.72; 95% confidence interval, 0.54-0.96; p = .027) was independently associated with response to infliximab. CONCLUSIONS: Serum IL-6 level is associated with response to infliximab in UC. Elevated concentrations of IL-6 may provide insight to the mechanism of non-response to infliximab.

Predictors of the efficacy of vedolizumab in patients with ulcerative colitis.

Vedolizumab is a treatment option for ulcerative colitis but data on predictors of treatment response remain insufficient to establish personalized treatment strategies. We aimed to investigate the real-world effectiveness of vedolizumab in adult patients with ulcerative colitis and explore factors involved in predicting treatment response. This single-center, single-arm, prospective observational study included 26 patients with clinically active ulcerative colitis patients' characteristics at baseline, epidemiological information, existing treatment, clinical activity index score, endoscopic score, and blood test data were collected. Serum levels of tumor necrosis factors alpha, interferon gamma, interleukin-4, interleukin-6, interleukin-10, interleukin-17, soluble mucosal addressin cell adhesion molecule 1, and soluble vascular cell adhesion molecule 1 were measured. Patient characteristics in the remission and non-remission groups were compared based on these parameters. Clinical remission at 6 weeks of treatment occurred in 9 (35%) of the 26 patients. At 14 weeks, clinical remission was observed in 11 patients (42%). There were no significant differences pertaining to age, sex, duration of disease, extent of disease, steroid resistance, or prior treatment with biological agents among the two groups after 14 weeks of treatment. Hemoglobin ≥ 11.5 g/dL (odds ratio, 15.0; 95% confidence interval, 1.50-149; P=0.014) and soluble mucosal addressin cell adhesion molecule 1 ≥ 765 pg/mL (odds ratio, 17.3; 95% confidence interval, 2.36-127; P=0.004) were significant factors. In conclusion, hemoglobin and serum soluble mucosal addressin cell adhesion molecule 1 levels are factors correlated with the therapeutic efficacy of vedolizumab.

Anterior gradient protein 2 is a marker of tumor aggressiveness in breast cancer and favors chemotherapy­induced senescence escape.

Among the different chemotherapies available, genotoxic drugs are widely used. In response to these drugs, particularly doxorubicin, tumor cells can enter into senescence. Chemotherapy­induced senescence (CIS) is a complex response. Long described as a definitive arrest of cell proliferation, the present authors and various groups have shown that this state may not be complete and could allow certain cells to reproliferate. The mechanism could be due to the activation of new signaling pathways. In the laboratory, the proteins involved in these pathways and triggering cell proliferation were studied. The present study determined a new role for anterior gradient protein 2 (AGR2) in vivo in patients and in vitro in a senescence escape model. AGR2's implication in breast cancer patients and proliferation of senescent cells was assessed based on a SWATH­MS proteomic study of patients' samples and RNA interference technology on cell lines. First, AGR2 was identified and it was found that its concentration is higher in the serum of patients with breast cancer and that this high concentration is associated with metastasis occurrence. An inverse correlation between intratumoral AGR2 expression and the senescence marker p16 was also observed. This observation led to the study of the role of AGR2 in the CIS escape model. In this model, it was found that AGR2 is overexpressed in cells during senescence escape and that its loss considerably reduces this phenomenon. Furthermore, it was shown that the extracellular form of AGR2 stimulated the reproliferation of senescent cells. The power of proteomic analysis based on the SWATH­MS approach allowed the present study to highlight the mammalian target of rapamycin (mTOR)/AKT signaling pathway in the senescence escape mechanism mediated by AGR2. Analysis of the two signaling pathways revealed that AGR2 modulated RICTOR and AKT phosphorylation. All these results showed that AGR2 expression in sera and tumors of breast cancer patients is a marker of tumor progression and metastasis occurrence. They also showed that its overexpression regulates CIS escape via activation of the mTOR/AKT signaling pathway.

Frequency of Effector Memory Cells Expressing Integrin α4ß7 Is Associated With TGF-ß1 Levels in Therapy Naïve HIV Infected Women With Low CD4+ T Cell Count.

Integrin α4ß7 expressing CD4+ T cells are preferred targets for HIV infection and are thought to be predictors of disease progression. Concurrent analysis of integrin α4ß7 expressing innate and adaptive immune cells was carried out in antiretroviral (ART) therapy naïve HIV infected women in order to determine its contribution to HIV induced immune dysfunction. Our results demonstrate a HIV infection associated decrease in the frequency of integrin α4ß7 expressing endocervical T cells along with an increase in the frequency of integrin α4ß7 expressing peripheral monocytes and central memory CD4+ T cells, which are considered to be viral reservoirs. We report for the first time an increase in levels of soluble MAdCAM-1 (sMAdCAM-1) in HIV infected individuals as well as an increased frequency and count of integrin ß7Hi CD8+ memory T cells. Correlation analysis indicates that the frequency of effector memory CD8+ T cells expressing integrin α4ß7 is associated with levels of both sMAdCAM-1 and TGF-ß1. The results of this study also suggest HIV induced alterations in T cell homeostasis to be on account of disparate actions of sMAdCAM-1 and TGF-ß1 on integrin α4ß7 expressing T cells. The immune correlates identified in this study warrant further investigation to determine their utility in monitoring disease progression.

sMAdCAM: IL-6 Ratio Influences Disease Progression and Anti-Viral Responses in SARS-CoV-2 Infection.

The role of sMAdCAM, an important gut immune migratory marker, remains unexplored in COVID-19 pathogenesis considering recent studies positing the gut as a sanctuary site for SARS-CoV-2 persistence. Thus, assimilating profiles of systemic inflammatory mediators with sMAdCAM levels may provide insights into the progression of COVID-19 disease. Also, the role of these markers in governing virus specific immunity following infection remains largely unexplored. A cohort (n = 84) of SARS-C0V-2 infected individuals included a group of in-patients (n = 60) at various stages of disease progression together with convalescent individuals (n = 24) recruited between April and June 2020 from Mumbai, India. Follow-up of 35 in-patients at day 7 post diagnosis was carried out. Th1/Th2/Th17 cytokines along with soluble MAdCAM (sMAdCAM) levels in plasma were measured. Also, anti-viral humoral response as measured by rapid antibody test (IgG, IgM), Chemiluminescent Immunoassay (IgG), and antibodies binding to SARS-CoV-2 proteins were measured by Surface Plasmon Resonance (SPR) from plasma. IL-6 and sMAdCAM levels among in-patients inversely correlated with one another. When expressed as a novel integrated marker-sMIL index (sMAdCAM/IL-6 ratio)-these levels were incrementally and significantly higher in various disease states with convalescents exhibiting the highest values. Importantly, sMAdCAM levels as well as sMIL index (fold change) correlated with peak association response units of receptor binding domain and fold change in binding to spike respectively as measured by SPR. Our results highlight key systemic and gut homing parameters that need to be monitored and investigated further to optimally guide therapeutic and prophylactic interventions for COVID-19.

Correlation of AGR2 expression with the incidence of metastasis in luminal breast cancer.

BACKGROUND: AGR2 expression is associated with luminal breast cancer. Overexpression of AGR2 is a predictor of poor prognosis. Several studies have found correlations between AGR2 in disseminated tumor cells (DTCs) in breast cancer patients. OBJECTIVE: This study aims to determine the correlation between anterior Gradient2 (AGR2) expression with the incidence of distant metastases in luminal breast cancer. METHODS: This study was an observational study using a cross-sectional method and was conducted at Wahidin Sudirohusodo Hospital and the network. ELISA methods examine AGR2 expression from blood serum of breast cancer patients. To compare the AGR2 expression in metastatic patients and the non-metastatic patient was tested with Mann Whitney test. The correlation of AGR2 expression and metastasis was tested with the Rank Spearman test. RESULTS: The mean value of AGR2 antibody expression on ELISA in this study was 2.90 ± 1.82 ng/dl, and its cut-off point was 2.1 ng/dl. Based on this cut-off point value, 14 subjects (66.7%) had overexpression of AGR2 serum ELISA, and 7 subjects (33.3%) had not. The mean value AGR2 was significantly higher in metastatic than not metastatic, 3.77 versus 1.76 (p < 0.01). The Spearman rank test obtained a p-value for the 2 tail test of 0.003 (p < 0.05), which showed a significant correlation of both, while the correlation coefficient of 0.612 showed a strong positive correlation of AGR2 overexpression and metastasis. CONCLUSIONS: AGR2 expression is correlated with metastasis in Luminal breast cancer.

Evidence for a role of uromodulin in chronic kidney disease progression.

BACKGROUND: Uromodulin (also known as Tamm-Horsfall protein) is the most abundant urinary protein in healthy individuals and exhibits diverse functions including prevention of ascending urinary tract infections by binding type I-fimbriated Escherichia coli. Although uromodulin is targeted to the apical membrane of thick ascending limb (TAL) cells and secreted into the lumen, detectable levels are also found in venous blood. Uromodulin has been shown to interact with and activate specific components of the immune system, and thus, may act as a signalling molecule for renal tubular damage. METHODS: In order to investigate the potential involvement of uromodulin in chronic kidney disease (CKD), we quantified uromodulin in paired urine and serum from 14 healthy volunteers and 77 CKD patients. Clinical parameters such as estimated GFR (eGFR), proteinuria and urinary N-acetyl-beta-D-glucosaminidase (NAG) were measured. Mean infiltration and atrophy score were assessed in patient biopsies. Additionally, tumour necrosis factor-alpha, interleukin-6 (IL-6), IL-8 and IL-1 beta were measured in serum samples. RESULTS: eGFR correlated positively with urinary uromodulin and negatively with serum uromodulin. Patients with abnormally low urinary uromodulin showed a broader range of serum uromodulin. Patients with both very low urinary and serum uromodulin had the highest tubular atrophy scores. There was a positive correlation of serum uromodulin with all cytokines measured. Additionally, in in vitro experiments, uromodulin caused a dose-dependent increase in pro-inflammatory cytokine release from whole blood. CONCLUSIONS: Our data suggest that TAL damage, or damage distal to the TAL, results in an elevated interstitial uromodulin, which stimulates an inflammatory response. Persistent chronic TAL damage reduces TAL cell numbers and attenuates urinary and serum uromodulin concentrations. The combined analysis of serum and urinary uromodulin provides new insights into the role of uromodulin in CKD and suggest that uromodulin may be an active player in CKD progression.

Population Pharmacokinetics and Pharmacodynamics of Ontamalimab (SHP647), a Fully Human Monoclonal Antibody Against Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1), in Patients With Ulcerative Colitis or Crohn's Disease.

Ontamalimab (SHP647) is a fully human, immunoglobulin G2 , antihuman mucosal addressin cell adhesion molecule-1 (MAdCAM-1) monoclonal antibody being developed for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). A population pharmacokinetic/pharmacodynamic (PK/PD) analysis was conducted using clinical phase 2 study data to evaluate the PK and PD of ontamalimab following subcutaneous administrations of 7.5, 22.5, 75, and 225 mg every 4 weeks in patients with moderate to severe UC or CD. A total of 440 patients with UC (n = 249; 56.6%) or CD (n = 191; 43.4%) were included in the analysis. A 2-compartment model with parallel linear and nonlinear elimination adequately characterized concentration-time profiles of ontamalimab. The apparent clearance and volume of distribution were 0.0127 L/h (0.305 L/day) and 6.53 L, respectively. Apparent clearance and volume of distribution were mainly dependent on baseline albumin and body weight, respectively. No differences in the PK properties of ontamalimab were observed between patients with UC or CD. The presence of antidrug antibodies did not impact the PK of ontamalimab. Nonlinear elimination occurred at very low concentrations and was unlikely to contribute to the elimination half-life under steady-state conditions. A linear PK/PD model described the relationship between ontamalimab and free MAdCAM-1. Minimum concentrations of ontamalimab at steady state following 75 mg every 4 weeks were associated with >95% suppression of circulating free MAdCAM-1. The PK/PD properties characterized support phase 3 testing in UC and CD.

Soluble Mucosal Addressin Cell Adhesion Molecule 1 and Retinoic Acid are Potential Tools for Therapeutic Drug Monitoring in Patients with Inflammatory Bowel Disease Treated with Vedolizumab: A Proof of Concept Study.

BACKGROUND AND AIMS: Vedolizumab [VDZ], a humanized monoclonal antibody targeting α4ß7 integrin, is effective in induction and maintenance therapy in patients with inflammatory bowel disease [IBD] who have not adequately responded to standard therapies, and high vedolizumab trough levels [VTLs] have been associated with clinical remission. The α4ß7 integrin binds to endothelial MAdCAM-1 and is upregulated by retinoic acid [RA]. The aim of this study was to determine the relationships between soluble MAdCAM-1 [sMAdCAM-1] and RA concentrations during clinical remission with VDZ maintenance therapy. METHODS: In a retrospective study performed in IBD patients treated with VDZ, we measured VTL, sMAdCAM-1 and RA concentrations. RESULTS: Among the 62 included patients [38 Crohn's disease], 24 relapsed and 38 stayed in remission from Weeks 10 to 30 after VDZ initiation. During this maintenance therapy, the median values of VTLs and RA were 15.4 µg/mL and 0.97 ng/mL, respectively, whereas sMAdCAM-1 was undetectable [<0.41 ng/mL] in 67.3% of samples. The positive predictive value [PPV] of undetectable sMAdCAM-1 for clinical remission was 80.0%, with a corresponding sensitivity of 74.6%. On multivariate analysis, undetectable sMAdCAM-1 and high VTLs [>19 µg/mL] were independently associated with clinical remission [OR = 7.5, p = 0.006 and OR = 2.2, p = 0.045, respectively]. The combination of sMAdCAM-1 < 0.41 ng/mL and VTL > 19 µg/mL was the best pharmacokinetic profile, with a PPV of 95.2%. Median values of sMAdCAM-1 and RA were significantly higher [p = 0.0001] before VDZ therapy than during the follow-up [sMAdCAM-1: 40.5 vs < 0.41 ng/mL; RA: 1.7 vs 0.97 ng/mL]. Only RA > 1.86 ng/mL before VDZ therapy was predictive of clinical remission during the follow-up (Area Under a Receiver Operating Characteristic curve [AUROC] = 80.7%). CONCLUSIONS: Undetectable sMAdCAM-1 appears strongly associated with clinical remission during VDZ maintenance therapy. Combination of undetectable sMAdCAM-1 with high VTL is also potentially interesting for therapeutic drug monitoring. Baseline RA concentrations are predictive of clinical remission. These findings need to be confirmed in further prospective studies.

Anti-MAdCAM Antibody Increases ß7+ T Cells and CCR9 Gene Expression in the Peripheral Blood of Patients With Crohn's Disease.

OBJECTIVE: To define pharmacodynamic biomarkers in the peripheral blood of patients with Crohn's disease [CD] after treatment with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody. METHODS: In this Phase 2, randomised, double-blind, controlled study [OPERA], blood samples were analysed from patients with moderate to severe active CD who received placebo or 22.5 mg, 75 mg, or 225 mg of PF-00547659 subcutaneously at baseline and at Weeks 4 and 8, with follow-up at Week 12. Soluble MAdCAM [sMAdCAM] was measured by mass spectrometry, ß7-expressing T cells by flow cytometry, and gene transcriptome by RNA sequencing. RESULTS: A slight increase in sMAdCAM was measured in the placebo group from baseline to Week 12 [6%], compared with significant decreases in all PF-00547659 groups [-87% to -98%]. A slight increase from baseline to Week 12 was observed in frequency and molecules of equivalent soluble fluorochrome for ß7+ central memory T cells in the placebo group [4%], versus statistically significant increases in the active treatment groups [48% to 81%]. Similar trends were seen for ß7+ effector memory T cells [placebo, 8%; PF-00547659, 84-138%] and ß7+ naïve T cells [8%; 13-50%]. CCR9 gene expression had statistically significant up-regulation [p = 1.09e-06; false discovery rate < 0.1] with PF-00547659 treatment, and was associated with an increase in ß7+ T cells. CONCLUSIONS: Results of the OPERA study demonstrate positive pharmacology and dose-dependent changes in pharmacodynamic biomarker measurements in blood, including changes in cellular composition of lymphocytes and corresponding CCR9 gene expression changes.

Clinical significance of fucose level in glycoprotein fraction of serum in patients with malignant tumors.

Serum fucose content in the glycoprotein fraction was determined in various patients with malignant and benign diseases. The results showed that, in contrast to benign diseases, malignant diseases were characterized by an increased fucose content in the glycoprotein fraction. However, no significant difference was noted in the fucose levels in the mucoprotein fraction. The increased fucose level in glycoprotein in malignant diseases was parallel to the increment in total fucose content in serum, which suggests that the increased levels in total fucose in malignant diseases, reported previously, are primarily due to the increase in fucose-containing glycoprotein.

Development and validation of receptor occupancy pharmacodynamic assays used in the clinical development of the monoclonal antibody vedolizumab.

BACKGROUND: Vedolizumab is a monoclonal antibody approved for use in ulcerative colitis and Crohn's disease. By specifically binding to α4 ß7 integrin, vedolizumab prevents trafficking of lymphocytes to the gut, thereby interfering with disease pathology. During the clinical development program, the pharmacodynamic effect of vedolizumab was evaluated by 2 flow cytometry receptor occupancy assays: act-1 (ACT-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Here we describe the development and validation of these assays. METHODS: The ACT-1 assay is a receptor occupancy free-site assay that uses a monoclonal antibody with the same binding epitope as vedolizumab to detect free (unbound) sites on α4 ß7 integrin. The MAdCAM-1 assay used a soluble version of the natural ligand for α4 ß7 integrin to detect free sites. The assays were validated using a fit-for-purpose approach throughout the clinical development of vedolizumab. RESULTS: Both the ACT-1 assay and the MAdCAM-1 assay demonstrated acceptable reproducibility and repeatability. The assays were sufficiently stable to allow for clinical use. During clinical testing the assays demonstrated that vedolizumab was able to saturate peripheral cells at all doses tested. CONCLUSIONS: Two pharmacodynamic receptor occupancy assays were developed and validated to assess the effect of vedolizumab on peripheral blood cells. The results of these assays demonstrated the practical use of flow cytometry to examine pharmacodynamic response in clinical trials.

Hereditary hyperuricemia and renal disease.

Hyperuricemia and gout have long been known to run in families. As well as an apparently multifactorial genetic component to classic gout itself, 2 rather unusual sex-linked single-gene disorders of purine biosynthesis or recycling have been defined: deficiency of the enzyme hypoxanthine-guaninephosphoribosyl transferase (HPRT), and overactivity of PPriboseP synthase. Both result in overproduction of urate, hyperuricemia, and secondary overexcretion that may lead to acute or chronic renal damage. Familial juvenile hyperuricemic nephropathy (FJHN) and autosomal-dominant medullary cystic kidney disease (ADMCKD) are more common but less well-defined hyperuricemic conditions resulting from a decrease in the fractional excretion of filtered urate, with normal urate production. Although having features in common, ADMCKD is distinguished in particular by the presence of medullary cysts. One major group of both disorders is associated with mutations in the gene for uromodulin, but this accounts for only about one third of cases, and genetic heterogeneity is present. Whether the genes involved in these latter disorders contribute to the polygenic hyperuricemia and urate underexcretion of classic gout remains unexplored.

Structural and functional modification of THP on nitration: comparison with stone formers THP.

OBJECTIVE: The crucial steps involved in the lithogenic process are governed by the macromolecular components of urine, of which proteins play a major role. Structurally abnormal proteins have been reported to be present in the urine of stone formers. Free radical injury has come a long way in explaining some of the pathophysiological events of renal lithiasis. Thus, our present work was designed to study the impact of the potent oxidant peroxynitrite on the biochemical components of the urinary Tamm-Horsfall glycoprotein (THP). MATERIALS AND METHODS: Nitration on THP was carried out using peroxynitrite (ONOO(-)). After nitration, biochemical components like thiols, S-nitrosothiol, hexose, hexosamine and sialic acid were determined and these factors were compared with those of stone formers and normal THP. Crystallization behavior of control, nitrated NS-THP and stone formers THP was studied. RESULTS: There was a significant decrease in thiol, hexose, hexosamine and sialic acid contents in stone formers and nitrated NS-THP, when compared to that of the control THP. In contrast to this, S-nitrosothiol content was significantly increased in stone formers and nitrated NS-THP (p < 0.001) when compared with the control THP. NO(x) metabolites were significantly elevated in stone formers THP when compared with that of control THP. When subjected to CaOx crystallization, stone formers THP and nitrated NS-THP promoted both CaOx nucleation and aggregation, while normal THP was found to be an inhibitor of the above processes. CONCLUSION: From our results we conclude that nitration of THP could represent one of the prime events in modifying kinetic behavior of THP, thus converting THP into a heterogeneous nucleator of renal calculi formation.

Correlation between changes in the tumour markers CA-M26 and CA-M29 and standard response evaluation in patients with metastatic breast cancer.

In this study we correlated response evaluated by standard WHO criteria to strict defined criteria of tumour marker response in 63 patients with metastatic breast cancer. Pretreatment sensitivity at first evaluation was 71% and 85% for CA-M26 and CA-M29, respectively. Of the 156 evaluations for CA-M26 and 178 for CA-M29 in 26 and 30 patients with evaluable lesions 72% and 67% were concordant with the results of the clinical evaluations. When the discordant evaluations due to lead time were included the concordances were 87% for CA-M26 and 83% for CA-M29. Of the 70 evaluations for CA-M26 and 92 for CA-M29 in 19 and 24 patients with non-evaluable lesions 59% and 72% were concordant with the results of the clinical evaluations. Most importantly, progressive disease according to the changes in the marker level nearly always predicted disease progression. Such knowledge obtained in a simple way may prevent continuation of ineffective treatment in patients with metastatic breast cancer.

A sensitive and specific ELISA using a monoclonal capture antibody for detection of Tamm-Horsfall urinary glycoprotein in serum.

An enzyme-linked immunosorbent assay (ELISA) has been established using Nunc polystyrene immunoplates coated with a monoclonal antibody to human Tamm-Horsfall urinary glycoprotein (THP) to detect and measure THP in human serum. Optimal reaction conditions for both the monoclonal capture antibody and the affinity-purified rabbit anti-human THP second antibody were established to produce standard curves which showed linearity between 20-90 ng/ml with a sensitivity of 2-3 ng/ml. The plate-to-plate standard curve mean coefficient of variation (CV) was 5.9 +/- 2.9% on assays performed on the same day while day to day mean CV was 13.3 +/- 2.4%. The specificity of the ELISA was demonstrated by inhibition of binding after preincubation of both urinary THP standards and serum with monoclonal anti-THP antibody. Sera from 195 blood donors tested by the ELISA had a mean concentration of THP antigenic determinants of 260 +/- 105 ng/ml. Results from three control sera run on all plates used in the survey showed mean CV less than 7.6% while no binding was observed with sera from an anephric patient.

Individual and combined usefulness of lipid associated sialic acid, mucoid proteins and hexoses as tumor markers in breast carcinoma.

Serum levels of lipid associated sialic acid (LASA), mucoid proteins (MP) and hexoses (galactose + mannose) were measured in 41 breast cancer patients, 14 patients with benign breast diseases and 36 healthy age matched female individuals. In breast carcinoma patients, we have observed significant increase in the levels of the three markers compared with the controls (P less than 0.001) and in MP and hexoses compared to the patients with benign breast diseases (P less than 0.001). LASA and hexoses levels were significantly higher in benign breast diseases with respect to controls (P less than 0.001 and P less than 0.01, respectively). We evaluated the sensitivity and specificity of the markers individually and in combination. MP were most sensitive (71.8%) and specific (71.4%). Both sensitivity and specificity were increased when combinations of the markers were studied. Combination of MP with LASA was most sensitive (97.4%) while the combination of MP and hexoses was most specific (92.9%). LASA was significantly elevated in infiltrating duct carcinoma compared to lobular carcinoma (P less than 0.001). MP and hexoses also showed higher mean value in infiltrating duct carcinoma than lobular carcinoma. The present study suggests that the combination of the markers investigated might be useful for diagnosis and classification of breast carcinoma.

The effect of serum protein concentrations on the specificity of the radioimmunoassay of carcinoembryonic antigen in malignant neoplasia and non-neoplastic disease.

Carcinoembryonic antigen (CEA) has been measured in parallel with seven serum proteins and seromucoids in the sera of patients with malignant neoplasia and non-neoplastic disease. In the total group significant correlations were found between CEA and seromucoids and between CEA and several serum proteins. However, with two exceptions, when the individual disease groups were examined no correlation was seen. It is concluded that abnormal concentrations of the specific proteins measured do not consistently interfere in the CEA radioimmunoassay and do not explain the high CEA levels in patients with non-neoplastic diseases.

Is there any association between Peyronie's disease and serum collagen markers?

Several theories regarding the pathogenesis of Peyronie's disease have been investigated under many clinical conditions. We have investigated the association of Peyronie's disease with the most common markers of collagen disease. Several serum markers of collagen disease (mucoproteins, C-reactive protein, antinuclear antibody, rheumatoid factor, lupus erythematosus cells, proteinograms) of 30 patients with Peyronie's disease were compared with those obtained from 30 patients, matched for age, with other urological conditions unrelated to the penis. Mucoproteins were altered in 66.7% of patients of the Peyronie's disease group and in 46.7% of the control patients (P>0.05). C-reactive protein was altered in 23.3% of the Peyronie's disease patients and in 13.3% of the control patients (P>0.05). Antinuclear antibody (ANA) was reactive in 16.7% of the tested group and in 6.7% of the control group (P>0.05). The rheumatoid factor was elevated in 6.7% of the patients from both groups (P>0.05). LE cells were normal in all the patients in our study. No statistical significance between the two groups was found in the protein electrophoresis test. Only the Waaler-Rose test (rheumatoid hemagglutination test) was statistically significant in our study (P<0.05). We have not found any significant association between the serum markers of collagen diseases in patients with Peyronie's disease, except the rheumatoid hemagglutination test (Waaler-Rose).

Development of a radioimmunoassay for 'Tamm-Horsfall-like' glycoprotein in serum and cerebrospinal fluid.

Affinity chromatography purification was combined with a radioimmunoassay for 'Tamm-Horsfall-like' glycoprotein. This enabled serum concentrations to be established and to demonstrate its presence in cerebrospinal fluid for the first time. This assay method used in different circumstances suggests a multifocal synthesis. Nevertheless, urinary Tamm-Horsfall glycoprotein so far must be distinguished from the serum or cerebrospinal fluid Tamm-Horsfall-like glycoprotein.