SPINK1 (Serine Peptidase Inhibitor, Kazal Type 1)

Review on SPINK1, with data on DNA, on the protein encoded, and where the gene is implicated

Tumor expression of human chorionic gonadotropin beta mRNA and prognosis of prostate cancer treated by radical prostatectomy

The beta subunit of human chorionic gonadotropin (hCG beta) is encoded by six genes (CGB) classified as type I and type II. CGB mRNA is produced in large amounts by trophoblastic tissues and in small amounts by several cancerous tissues including prostate cancer and by a few benign tissues, including the prostate. Quantitative reverse-transcription polymerase chain reaction (RT-qPCR) was used to study the expression levels of all CGB mRNAs together (total CGB mRNA) and the two types of CGB mRNA separately in non-cancerous (n = 74) and cancerous prostatic tissue obtained by radical prostatectomy (n = 193). RNA was isolated from formalin-fixed paraffin-embedded (FFPE) samples and mRNA levels of CGB were correlated with disease-specific survival. Total CGB mRNA concentrations were significantly lower (p <.0001) in cancerous than non-cancerous prostatic tissue. Separate analysis of type I CGB and type II CGB mRNA showed that both type I CGB (p <.0001) and type II CGB mRNA (p = .007) are lower in cancerous tissue than in non-cancerous tissue. Low type II CGB mRNA level in cancerous tissue was associated with shorter cancer-specific survival (p = .001) of prostate cancer patients treated by radical prostatectomy.Peer reviewe

Characterizing urinary hCG beta cf patterns during pregnancy

Objective: Elevated concentrations of hCG beta core fragment (hCG beta cf) are known to cause false-negative results in qualitative urine pregnancy test devices, but the pattern of urinary hCG beta cf during normal pregnancy has not been well characterized. Here, we evaluate the relationship between urine hCG, hCG beta cf, and hCG free beta subunit (hCG beta) during pregnancy. Design and methods: Banked second trimester urine specimens from 100 pregnant women were screened for high concentrations of hCG beta cf using a qualitative point-of-care device known to demonstrate false-negative results in the presence of elevated hCG beta cf concentrations. Additional first and third trimester specimens from the same pregnancy were obtained from 10 women who generated negative/faint positive results, 5 women who generated intermediate positive results, and 10 women who generated strong positive results on the point-of care device. Intact hCG, hCG beta cf, hCG beta, and specific gravity were quantified in these 75 specimens. Results: Urinary hCG beta cf concentrations were greater than intact hCG concentrations at all times. A strong correlation (r(2) = 0.70) was observed between urine intact hCG and hCG beta cf concentrations. A poor correlation was observed between specific gravity and intact hCG (r(2) = 0.32), hCG beta (r(2) = 0.32), and hCG beta cf (r(2) = 0.32). The highest hCG beta cf concentrations were observed between 10 and 16 weeks gestation but individual women demonstrated very different patterns of hCG beta cf excretion. Conclusions: Urine specimens with elevated hCG beta cf are frequently encountered during pregnancy but hCG beta cf excretion patterns are unpredictable. Manufacturers and clinicians must appreciate that hCG beta cf is the major immunoreactive component in urine during pregnancy and must design and interpret qualitative urine hCG test results accordingly. (C) 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.Peer reviewe

No Tissue Expression of KRAS or BRAF Mutations in 61 Adult Patients Treated for Esophageal Atresia in Early Childhood

Background Previous studies have reported an association among esophageal atresia (EA), Barrett's esophagus, and esophageal adenocarcinoma later in life. Objective The objective of the article is to evaluate KRAS and BRAF mutations as potential genetic markers for early detection of malignant transformation, we used an ultrasensitive technique to detect tissue expression of KRAS and BRAF mutations in endoscopic biopsies from 61 adult patients under follow-up after treatment for EA. Materials and Methods RNA was extracted from 112 fresh-frozen endoscopic tissue biopsies from 61 adult patients treated for EA in early childhood. RNA was reverse transcribed using the extendable blocking probe reverse transcription method. KRAS codons 12 and 13, as well as BRAF mutations were detected by quantitative polymerase chain reaction. Results No mutations of KRAS codon 12, KRAS codon 13, or BRAF were found in 112 endoscopic biopsy samples from 61 patients. Conclusion Despite the presence of histological findings indicating long-standing gastroesophageal reflux in 25%, as well as symptomatic gastroesophageal reflux in more than 40%, there was no detectable tissue expression of KRAS or BRAF mutations in this cohort of patients.Peer reviewe

The Relationship between the Tissue Expression of TLR2, TLR4, TLR5, and TLR7 and Systemic Inflammatory Responses in Colorectal Cancer Patients

Background: Colorectal cancer (CRC) is the third most commonly diagnosed malignancy globally. CRC patients with elevated plasma C-reactive protein (CRP) levels exhibit compromised prognoses. Toll-like receptors (TLRs), activating the innate and adaptive immune systems, may contribute to pro- and antitumorigenic inflammatory responses. We aimed to identify a possible link between local and systemic inflammatory responses in CRC patients by investigating the association between tissue TLRs and plasma CRP. Methods: Tissue expressions of TLR2, TLR4, TLR5, and TLR7 were assessed using immunohistochemistry of tissue microarray slides from 549 CRC patients surgically treated between 1998 and 2005. Blood samples were drawn preoperatively, centrifuged, aliquoted, and stored at -80 degrees C until analysis. Plasma CRP was determined through high-sensitivity time-resolved immunofluorometric assay. We investigated the association of TLRs to clinicopathologic variables, plasma CRP, and survival. Results: High TLR2 expression (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.41-0.85; p = 0.005), high TLR5 expression (HR 0.60; 95% CI 0.45-0.83; p = 0.002), positive TLR7 expression (HR 0.49; 95% CI 0.33-0.72; p < 0.001), and low CRP (HR 1.48; 95% CI 1.08-2.11; p = 0.017) were associated with a better prognosis. A high TLR2 immunoexpression was associated with a better prognosis among low-CRP patients (HR 0.53; 95% CI 0.35-0.80; p = 0.002), high TLR4 expression among high-CRP patients (HR 2.04; 95% CI 1.04-4.00; p = 0.038), high TLR5 expression among low-CRP patients (HR 0.059; 95% CI 0.37-0.92; p = 0.021), and positive TLR7 expression among low-CRP patients (HR 0.53; 95% CI 0.28-1.00; p = 0.049). In multivariate analyses, no biomarkers emerged as significant independent variables. Conclusions: High tissue TLR2, TLR5, and TLR7 levels were associated with a better prognosis. Among low-CRP patients, those with high TLR2, TLR5, and TLR7 immunoexpressions exhibited a better prognosis. Among high CRP patients, a high TLR4 immunoexpression was associated with a better prognosis.Peer reviewe

Gender has to be taken into account in diagnosing adult growth hormone deficiency by the GHRH plus arginine test

Objective: Data on the effect of gender on the interpretation of the GHRH plus arginine stimulation test (GHRH + ARG test) is controversial. We validated the GHRH + ARG stimulation test in control subjects and patients with organic or idiopathic pituitary disease and a suspicion of adult growth hormone deficiency (AGHD) using the Immulite 2000 XPi GH assay. Design: We studied 126 apparently healthy adults (median age 38.8 years) and 34 patients with a suspicion of AGHD (median age 42.2 years). Identification of AGHD with the GHRH + ARG test was investigated with commonly accepted BMI-related consensus cut-off limits for peak GH concentrations. Serum samples collected during the GHRH + ARG test were analysed for GH in 2014-2015. Serum IGF-1 concentrations were studied as a reference. Results: In 14 of 65 (22%) control males the GH peak value was below the BMI-related cut-off limits for GH sufficiency indicating a false diagnosis of AGHD. All control females had a normal GHRH + ARG response. Median peak GH response was significantly (p <0.001) higher in female (39.3 mu g/L) than in male controls (21 mu g/L). According to consensus cut-offs all but one young female patient had a deficient response compatible with a diagnosis of AGHD. Conclusions: The GH response to stimulation by GHRH + ARG is gender-dependent, being lower in healthy males than in females. Gender should be considered when defining cut-off limits for peak GH concentrations in the GHRH + ARG test. The presently used BMI-related cut-off levels will lead to a significant misclassification of males as GH deficient.Peer reviewe

Pancreatic cancer survival prediction via inflammatory serum markers

Background For prognostic evaluation of pancreatic ductal adenocarcinoma (PDAC), the only well-established serum marker is carbohydrate antigen CA19-9. To improve the accuracy of survival prediction, we tested the efficacy of inflammatory serum markers. Methods A preoperative serum panel comprising 48 cytokines plus high-sensitivity CRP (hs-CRP) was analyzed in 173 stage I-III PDAC patients. Analysis of the effect of serum markers on survival utilized the Cox regression model, with the most promising cytokines chosen with the aid of the lasso method. We formed a reference model comprising age, gender, tumor stage, adjuvant chemotherapy status, and CA19-9 level. Our prognostic study model incorporated these data plus hs-CRP and the cytokines. We constructed time-dependent ROC curves and calculated an integrated time-averaged area under the curve (iAUC) for both models from 1 to 10 years after surgery. Results Hs-CRP and the cytokines CTACK, MIF, IL-1 beta, IL-3, GRO-alpha, M-CSF, and SCF, were our choices for the prognostic study model, in which the iAUC was 0.837 (95% CI 0.796-0.902), compared to the reference model's 0.759 (95% CI 0.691-0.836, NS). These models divided the patients into two groups based on the maximum value of Youden's index at 7.5 years. In our study model, 60th percentile survival times were 4.5 (95% CI 3.7-NA) years (predicted high-survival group, n = 34) and 1.3 (95% CI 1.0-1.7) years (predicted low-survival group, n = 128), log rank p < 0.001. By the reference model, the 60th percentile survival times were 2.8 (95% CI 2.1-4.4) years (predicted high-survival group, n = 44) and 1.3 (95% CI 1.0-1.7) years (predicted low-survival group, n = 118), log rank p < 0.001. Conclusion Hs-CRP and the seven cytokines added to the reference model including CA19-9 are potential prognostic factors for improved survival prediction for PDAC patients.Peer reviewe

Outcomes of Prostate Cancer Screening by 5 alpha-Reductase Inhibitor Use

Purpose: Prostate cancer screening with prostate specific antigen reduces prostate cancer mortality but leads to over diagnosis of indolent prostate cancer. The use of 5 alpha-reductase inhibitors lowers prostate specific antigen and in theory could affect the performance of prostate specific antigen based screening. We evaluated the outcomes of prostate cancer screening in 5 alpha-reductase inhibitors users. Materials and Methods: The study was performed in FinRSPC (Finnish Randomized Study of Screening for Prostate Cancer). Of 80,454 men 31,866 were randomized to be screened at 4-year intervals during 1996 to 2004. Information on 5 alpha-reductase inhibitors reimbursements before prostate cancer during 1995 to 2009 was collected from the national prescription database for 78,615 men. We evaluated the effect of screening on prostate cancer risk and mortality by 5 alpha-reductase inhibitors using Cox regression. Results: Men receiving 5 alpha-reductase inhibitors had higher median prostate specific antigen and were more often screen positive than nonusers. Despite this, screening did not significantly affect prostate cancer detection (HR 0.89, 95% CI 0.7-1.01) or mortality (HR 0.82, 95% CI 0.51-1.32) compared to findings in the control arm among men on 5 alpha-reductase inhibitors. On ROC analysis prostate specific antigen and age did not predict Gleason 7-10 prostate cancer as accurately in 5 alpha-reductase inhibitors users as it did among nonusers (first screening round AUC 0.79 vs 0.88). Conclusions: Prostate specific antigen based screening among men receiving 5 alpha-reductase inhibitors did not improve the detection of high grade or metastatic prostate cancer, or prevent prostate cancer death.Peer reviewe

Dramatic increase in serum trypsinogens, SPINK1 and hCG beta in aortic surgery patients after hypothermic circulatory arrest

The concentrations of several diagnostic markers have been found to increase dramatically in critically ill patients with a severe disturbance of normal physiological homeostasis, without indication of the diseases they are normally associated with. To prevent false diagnoses and inappropriate treatments of critically ill patients, it is important that the markers aiding the selection of second-line treatments are evaluated in such patients and not only in the healthy population and patients with diseases the markers are associated with. The levels of trypsinogen isoenzymes, the trypsin inhibitor serine peptidase inhibitor Kazal type 1 (SPINK1), hCG and hCG beta, which are used as pancreatitis and cancer markers, were analyzed by immunoassays from serum samples of 17 adult patients who have undergone surgery of the ascending aorta during hypothermic circulatory arrest (HCA) with optional selective cerebral perfusion. Highly elevated levels of trypsinogen-1, -2 and -3, SPINK1 and hCG beta were observed in patients after HCA. This was accompanied by increased concentrations of S100 beta and NSE. In conclusion, this study highlights the importance of critically evaluating the markers used for aiding selection of second line of treatments in critically ill patients.Peer reviewe

Systemic Inflammatory Response and Elevated Tumour Markers Predict Worse Survival in Resectable Pancreatic Ductal Adenocarcinoma

Background Estimation of the prognosis of resectable pancreatic ductal adenocarcinoma (PDAC) currently relies on tumour-related factors such as resection margins and on lymph-node ratio (LNR) both inconveniently available only postoperatively. Our aim was to assess the accuracy of preoperative laboratory data in predicting PDAC prognosis. Methods Collection of laboratory and clinical data was retrospective from 265 consecutive patients undergoing surgery for PDAC at Helsinki University Hospital. Cancer-specific survival assessment utilized Kaplan-Meier analysis, and independent associations between factors were by the Cox regression model. Results During follow-up, 76% of the patients died of PDAC, with a median survival time of 19.6 months. In univariate analysis, CRP, albumin, CEA, and CA19-9 were significantly associated with postoperative cancer-specific survival. In multivariate analysis, taking into account age, gender, LNR, resection margins, tumour status, and adjuvant chemotherapy, the preoperative biomarkers independently associated with adverse prognosis were hypoalbuminemia ( 5 mg/L, HR 1.44, 95% CI 1.03-2.02, p = 0.036), CEA (> 5 mu g/L, HR 1.60, 95% CI 1.07-2.53, p = 0.047), and CA19-9 (>= 555 kU/L, HR 1.91, 95% CI 1.18-3.08, p = 0.008). Conclusion For patients with resectable PDAC, preoperative CRP, along with albumin and tumour markers, is useful for predicting prognosis.Peer reviewe