Prognostic marker

Background Cytokines play multiple roles during neuro-inflammatory processes and several cytokines have been studied in the context of specific diseases. This study provides a comprehensive picture of cerebrospinal fluid (CSF) changes during neuro-inflammation by analyzing multiple cytokines in combination with immune cell subsets and standard CSF parameters. Methods Using multiplex assays, we simultaneously measured 36 cytokines (CCL1–3, CCL7, CCL8, CCL11, CCL13, CCL19, CCL20, CCL22–27, CXCL1, CXCL2, CXCL5, CXCL6, CXCL8, CXCL9, CXCL11–13, CXCL16, CX3CL1, IL2, IL4, IL6, IL10, IL16, GM-CSF, IFNγ, MIF, TNFα, and MIB1β) in the CSF and serum of 75 subjects. Diagnoses included clinically isolated syndrome and relapsing-remitting multiple sclerosis (MS, n = 18), secondary progressive MS (n = 8), neuro-syphilis (n = 6), Lyme neuro-borreliosis (n = 13), bacterial and viral meningitis (n = 20), and patients with non-inflammatory neurological diseases (NIND, n = 10). Cytokine concentrations w...

Aims:  To investigate survivin expression in laryngeal squamous cell carcinoma (LSCC), its prognostic significance and relation to p53 status. Survivin is an inhibitor of apoptosis protein that is overexpressed in cancer. It has been implicated in both prevention of apoptosis and cell cycle regulation. It has been suggested that wild‐type p53 represses survivin expression.Methods and results:  Expression of survivin and p53 was analysed in 68 archival biopsy specimens of LSCC by immunohistochemistry. Survivin was detected in 67 of 68 LSCC cases; the proportion of survivin‐positive cells varied from 8.2% to 100%. It was localized in the nucleus and/or cytoplasm of tumour cells. Of LSCC cases, 31.8% were p53+. The number of survivin‐positive cells was significantly higher in the p53+ group. A high level of survivin expression and a supraglottic site of the tumour were two independent adverse prognostic factors in LSCC.Conclusions:  Survivin is expressed in a varying proportion of cell...

Peptides play important roles in cell regulation and signaling in many tissues and are regulated by peptidases, most of which are highly expressed in the kidney. Several peptide convertases have a function in different tumor stages, and some have been clearly characterized as diagnostic and prognostic markers for solid tumors, including renal cancer; however, little is known about their in vivo role in kidney tumors. The present study compares the activity of a range of peptidases in human tumor samples and nontumor tissue obtained from clear cell renal cell carcinoma (CCRCC) patients. To cover the complete spectrum and subcellular distribution of peptide-converting activity, acid, neutral, basic, and omega activities were selected. CCRCC displays a selective and restricted pattern of peptidase activities. Puromycin-sensitive aminopeptidase activity in the tumor increases [tumor (t) = 10,775 vs. nontumor (n) = 7,635 units of peptidase (UP)/mg protein; P < 0.05], whereas aminopept...

BACKGROUND: Despite a strong association of schwannomin/merlin gene mutations with vestibular schwannoma formation, the regulatory mechanisms and biologic pathways involved are still largely unknown. The hypothesis of this study is that the genesis and growth characteristics of neurofibromatosis type 2 (NF2)-associated vestibular schwannomas are determined by genetic alterations that vary in gene transcript expression; this transcript expression includes oncogenic gene products that may be identified by construction and sequencing of a cDNA library from NF2-associated vestibular schwannoma. METHODS: Approximately 3 mL of fresh tumor was obtained during resection of a 4-cm vestibular schwannoma from a patient with NF2. Poly(A)+ mRNA was isolated, synthesized into double-stranded cDNA, and unidirectionally inserted into Uni-Zap XR (Stratagene, La Jolla, CA) bacteriophage vectors. Bacteriophage vectors containing cDNA inserts were processed into phagemids according to Uni-Zap XR protoc...

BACKGROUNDThe recently described reversion‐inducing cysteine‐rich protein with Kazal motifs (RECK) inhibits membrane Type 1 matrix metalloproteinase (MMP‐14), MMP‐2, and MMP‐9 secretion and enzymatic activity. Its expression is essential for normal vasculogenesis. Down‐regulation of RECK has been implicated in tumor angiogenesis and progression.METHODSThe authors assessed the prognostic value of RECK expression in tumor tissue specimens from 278 breast carcinoma patients with a median follow‐up time of 75 months (range, 2–169 months). RECK mRNA levels were measured by real‐time quantitative reverse transcriptase–polymerase chain reaction.RESULTSExpression levels of RECK were lower in tumor tissue specimens than in adjacent normal breast tissue specimens from 10 patients (P = 0.028). No relevant associations of RECK with established clinicopathologic factors or treatment regimens were found. RECK expression predicted a longer recurrence‐free survival time (RFS; P = 0.037) at the opti...

Eur J Clin Invest 2010; 40 (4): 288–293Objectives  Osteopontin (OPN) is a glycoprotein, which may play a major role in the regulation of biological phenomena. Increased levels of OPN have been linked to the presence and to the severity of atherosclerosis. This study was undertaken to assess the prognostic significance of plasma OPN levels in patients with stable ischaemic heart disease (IHD).Methods  In 101 patients with stable IHD and angiographically documented significant coronary artery stenosis, plasma OPN levels were measured at baseline (time of coronary arteriography). Patients were prospectively followed for a median time of 3 years (minimum 2·25, maximum 3·9 years). The primary study endpoint was the composite of cardiovascular death, non‐fatal myocardial infarction, need for revascularization and hospitalization for cardiovascular reasons.Results  Baseline lnOPN levels were directly related to age (r = 0·27, P < 0·001) and inversely to left ventricular ejection fractio...

qRT-PCR (real-time reverse transcription-PCR) has become the benchmark for the detection and quantification of RNA targets and is being utilized increasingly in novel clinical diagnostic assays. Quantitative results obtained by this technology are not only more informative than qualitative data, but simplify assay standardization and quality management. qRT-PCR assays are most established for the detection of viral load and therapy monitoring, and the development of SARS (severe acute respiratory syndrome)-associated coronavirus qRT-PCR assays provide a textbook example of the value of this technology for clinical diagnostics. The widespread use of qRT-PCR assays for diagnosis and the detection of disease-specific prognostic markers in leukaemia patients provide further examples of their usefulness. Their value for the detection of disease-associated mRNA expressed by circulating tumour cells in patients with solid malignancies is far less apparent, and the clinical significance of ...

The tumor microenvironment plays a critical role in modulating cancer cell migration, metabolism, and malignancy, thus, highlighting the need to develop in vitro culture systems that can recapitulate its abnormal properties. While a variety of stiffness-tunable biomaterials, reviewed here, have been developed to mimic the rigidity of the tumor extracellular matrix, culture systems that can recapitulate the broader extracellular context of the tumor microenvironment (including pH and temperature) remain comparably unexplored, partially due to the difficulty in independently tuning these parameters. Here, we investigate a self-assembled polypeptide network hydrogel as a cell culture platform and demonstrate that the culture parameters, including the substrate stiffness, extracellular pH and temperature, can be independently controlled. We then use this biomaterial as a cell culture substrate to assess the effect of stiffness, pH and temperature on Suit2 cells, a pancreatic cancer cell...

A systematic review was undertaken to examine the evidence for B-type natriuretic peptides (BNP and NT-proBNP) as independent predictors of mortality, morbidity, or combined mortality and morbidity outcomes in persons with acute decompensated heart failure (ADHF). Electronic databases (Medline(®), Embase™, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL) were searched from 1989 to June 2012. Reference lists of included articles, systematic reviews, and the gray literature were also searched. English language studies were eligible if they included subjects with ADHF and measured BNP/NT-proBNP using FDA approved assays. Standardized forms were used to select studies, extract data, and assess risk of bias. Seventy-nine studies, ranging over followup intervals from 14 days to 7 years, evaluating levels of BNP (n = 38), NT-proBNP (n = 35), or both (n = 6) were eligible. The majority of studies predicted mortality outcomes for admi...

Background ZAP-70 is an independent negative prognostic marker in chronic lymphocytic leukemia (CLL). Usually, its expression is investigated by flow cytometric protocols in which the percentage of ZAP-70 positive CLL cells is determined in respect to isotypic control (ISO-method) or residual ZAP-70 positive T cells (T-method). These methods, however, beside suffering of an inherent subjectivity in their application, may give discordant results in some cases. The aim of this study was to assess the prognostic significance of these methods in comparison with another in which ZAP-70 expression was evaluated as a Mean-Fluorescence-Intensity Ratio between gated T and CLL cells (T/B Ratio-method). Methods Cytometric files relative to ZAP-70 determination according to the three readouts were retrospectively reviewed on a cohort of 173 patients (test set), all with complete clinical and biological prognostic assessment and time-to-treatment (TTT) available. Findings were then validated in ...

Wilms tumor 1 (WT1) mutations have recently been identified in approximately 10% of adult acute myeloid leukemia (AML) with normal cytogenetics (CN-AML) and are associated with poor outcome. Using array-based comparative genome hybridization in pediatric CN-AML samples, we detected a WT1 deletion in one sample. The other WT1 allele was mutated. This prompted us to further investigate the role of WT1 aberrations in childhood AML. Mutations were found in 35 of 298 (12%) diagnostic pediatric AML samples. In 19 of 35 (54%) samples, more than one WT1 aberration was found: 15 samples had 2 different mutations, 2 had a homozygous mutation, and 2 had a mutation plus a WT1 deletion. WT1 mutations clustered significantly in the CN-AML subgroup (22%; P < .001) and were associated with FLT3/ITD (43 vs 17%; P < .001). WT1 mutations conferred an independent poor prognostic significance (WT1 mutated vs wild-type patients: 5-year probability of overall survival [pOS] 35% vs 66%, P = .002; pro...

The severity and clinical course of idiopathic thrombocytopenic purpura (ITP) vary from patient to patient. The factors responsible for this variation are not well understood. In this study we attempted to evaluate the role of antiidiotypic antibodies in the immunoregulation of the disease. We investigated 114 cases of chronic ITP in adults. We determined antiidiotypic antibodies against antiplatelet antibodies using (a) idiotype-binding enzyme-linked immunosorbent assay (ELISA), (b) paratope-blocking ELISA, and (c) Western blotting. Results indicated that 80.6%, 11.2%, and 8.3% of the patients, respectively, presented with antiidiotypes against antibodies to GPIIb/IIIa, GPIb/IX, and both GPIIb/IIIa and GPIb/IX. More than 70% of the patients who showed high levels of blocking of antiidiotypic antibodies went into complete remission, compared with less than 5% of patients who showed low levels of such antibodies (P <.01). Disease severity was also found to be inversely related (P ...

Background: The human tissue kallikrein gene family (KLK1 to KLK15) encodes a group of 15 serine proteases (hK1 to hK15), several of which have been implicated in cancer-related processes.Methods: We established a specific quantitative reverse transcription-PCR assay for full-length KLK7 mRNA that excluded amplification of the exon 2 deletion splice variant (the latter does not encode a functional protease), and evaluated full-length KLK7 mRNA expression [normalized to human glucose-6-phosphate dehydrogenase (h-G6PDH)] in tumor tissue specimens from 155 breast cancer patients.Results: High KLK7 mRNA expression (continuous) was significantly associated with a better patient outcome according to both univariate (P = 0.005) and multivariate (P = 0.046) Cox survival analysis. Separation of patients by optimized dichotomization revealed a significantly better prognosis for patients with high KLK7 mRNA status (n = 89) compared with patients with low KLK7 mRNA status (n = 66) [univariate h...

Transition probabilities are the engine within many health economics decision models. However, the probabilities of progression of disability due to multiple sclerosis (MS) have not previously been estimated in Australia. To estimate annual probabilities of changing disability levels in Australians with relapsing-remitting MS (RRMS). Combining data from Ausimmune/Ausimmune Longitudinal (2003-2011) and Tasmanian MS Longitudinal (2002-2005) studies ( n = 330), annual transition probabilities were obtained between no/mild (Expanded Disability Status Scale (EDSS) levels 0-3.5), moderate (EDSS 4-6.0) and severe (EDSS 6.5-9.5) disability. From no/mild disability, 6.4% (95% confidence interval (CI): 4.7-8.4) and 0.1% (0.0-0.2) progressed to moderate and severe disability annually, respectively. From moderate disability, 6.9% (1.0-11.4) improved (to no/mild state) and 2.6% (1.1-4.5) worsened. From severe disability, 0.0% improved to moderate and no/mild disability. Male sex, age at onset, l...

Purpose: Neuroblastoma (NB) is a heterogeneous neoplasm. Detailed biological discrimination is critical for the effective treatment of this disease. Because the tumor behavior of NB is closely associated with the histologic state of differentiation, we thus aimed to identify novel differentiation-associated markers of NB with prognostic implication.Experimental Design: A human NB cell line SH-SY5Y was used as a model system to explore potential biomarkers for the differentiation of NB by proteomic analyses. Seventy-two NB tumor tissues were subsequently investigated by immunohistochemistry to validate the correlations between the expression of a novel prognostic marker, various clinicopathologic and biological factors, and patient survival.Results: Using two-dimensional differential gel electrophoresis, we found a total of 24 spots of proteins in SH-SY5Y cells whose expression was enhanced following differentiation. Glucose-regulated protein 75 (GRP75) was unambiguously identified a...

Eur J Clin Invest 2010; 40 (4): 288–293Objectives  Osteopontin (OPN) is a glycoprotein, which may play a major role in the regulation of biological phenomena. Increased levels of OPN have been linked to the presence and to the severity of atherosclerosis. This study was undertaken to assess the prognostic significance of plasma OPN levels in patients with stable ischaemic heart disease (IHD).Methods  In 101 patients with stable IHD and angiographically documented significant coronary artery stenosis, plasma OPN levels were measured at baseline (time of coronary arteriography). Patients were prospectively followed for a median time of 3 years (minimum 2·25, maximum 3·9 years). The primary study endpoint was the composite of cardiovascular death, non‐fatal myocardial infarction, need for revascularization and hospitalization for cardiovascular reasons.Results  Baseline lnOPN levels were directly related to age (r = 0·27, P < 0·001) and inversely to left ventricular ejection fractio...