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• W2395632397 abstract "Prenatal hydronephrosis is a common condition that may spontaneously resolve after birth. However, this condition can result in renal damage and requires surgical correction in a number of cases. Preventing renal damage is paramount, but existing diagnostic technology is invasive, exposes infants to radiation, is costly, and is often indeterminate. A better understanding of the pathophysiology of renal obstruction as reflected in the urinary proteome may provide new insights into the disease that could potentially alter the clinical management of hydronephrosis. We performed a quantitative proteomics study of urine that was surgically obtained from eight clinically significant, unilaterally obstructed infants versus eight healthy controls, with the goal of identifying quantitatively varying proteins and the biological networks associated with them. Notably, urine was obtained from both the obstructed kidney and the bladder. Over 1100 proteins were identified, and a total of 76 quantitatively varying proteins were identified. Proteins involved in oxidative stress, inflammation, and renal disease pathways showed the most significant abundance differences. This study gives a deeper understanding of the critical proteomic changes associated with renal obstruction and represents the deepest proteomic profile of renal obstruction to date. Prenatal hydronephrosis is a common condition that may spontaneously resolve after birth. However, this condition can result in renal damage and requires surgical correction in a number of cases. Preventing renal damage is paramount, but existing diagnostic technology is invasive, exposes infants to radiation, is costly, and is often indeterminate. A better understanding of the pathophysiology of renal obstruction as reflected in the urinary proteome may provide new insights into the disease that could potentially alter the clinical management of hydronephrosis. We performed a quantitative proteomics study of urine that was surgically obtained from eight clinically significant, unilaterally obstructed infants versus eight healthy controls, with the goal of identifying quantitatively varying proteins and the biological networks associated with them. Notably, urine was obtained from both the obstructed kidney and the bladder. Over 1100 proteins were identified, and a total of 76 quantitatively varying proteins were identified. Proteins involved in oxidative stress, inflammation, and renal disease pathways showed the most significant abundance differences. This study gives a deeper understanding of the critical proteomic changes associated with renal obstruction and represents the deepest proteomic profile of renal obstruction to date. Currently 1–5% of all pregnancies are diagnosed prenatally with hydronephrosis or dilation of the kidney (1.Lee R.S. Cendron M. Kinnamon D.D. Nguyen H.T. Antenatal hydronephrosis as a predictor of postnatal outcome: A meta-analysis.Pediatrics. 2006; 118: 586-593Crossref PubMed Scopus (323) Google Scholar). Although many cases of hydronephrosis resolve, persistent hydronephrosis is often caused by a ureteropelvic junction obstruction (UPJO) 1The abbreviations used are:UPJOureteropelvic junction obstructionBUbladder urineKUkidney urineCUcontrol urinePSMpeptide spectral match.. UPJO or renal obstruction can result in abnormal renal development and loss of kidney function. Although renal obstruction always results in hydronephrosis, hydronephrosis does not always indicate clinically significant obstruction. Appropriately timed postnatal surgical intervention of clinically significant UPJO may prevent additional renal damage; however, identifying which children require surgical intervention versus observation is extremely clinically challenging. ureteropelvic junction obstruction bladder urine kidney urine control urine peptide spectral match. The current clinical diagnostic workflow utilizes serial ultrasound and diuretic renography, which is invasive and exposes the infant or child to ionizing radiation. Furthermore, the current tests are subjective and inaccurate (2.Taylor A. Garcia E.V. Binongo J.N. Manatunga A. Halkar R. Folks R.D. Dubovsky E. Diagnostic performance of an expert system for interpretation of 99mTc MAG3 scans in suspected renal obstruction.J. Nucl. Med. 2008; 49: 216-224Crossref PubMed Scopus (18) Google Scholar, 3.Bao J. Manatunga A. Binongo J.N. Taylor A.T. Key variables for interpreting 99mTc-mercaptoacetyltriglycine diuretic scans: Development and validation of a predictive model.AJR Am. J. Roentgenol. 2011; 197: 325-333Crossref PubMed Scopus (21) Google Scholar) in determining clinically significant obstruction. These inaccuracies have resulted in a lack of clinical consensus on how to best identify which patients with hydronephrosis would benefit from surgical intervention.(1.Lee R.S. Cendron M. Kinnamon D.D. Nguyen H.T. Antenatal hydronephrosis as a predictor of postnatal outcome: A meta-analysis.Pediatrics. 2006; 118: 586-593Crossref PubMed Scopus (323) Google Scholar) Due to current challenges in UPJO patient stratification, there is a dire need for a sensitive, specific, and noninvasive standardized test that can identify the at-risk patients in need of surgical intervention. Using urine as a reflection of the pathologic changes associated with UPJO and hydronephrosis has numerous advantages. Urine is readily available and may be obtained noninvasively and longitudinally. Urine is the proximal fluid of UPJO, as well as other urological diseases. Proximal fluids possess many potential advantages for revealing new pathology networks and insights into potential future biomarkers (4.Teng P.N. Bateman N.W. Hood B.L. Conrads T.P. Advances in proximal fluid proteomics for disease biomarker discovery.J. Proteome Res. 2010; 9: 6091-6100Crossref PubMed Scopus (65) Google Scholar). In healthy individuals, urine obtained from the bladder is a combination of urine derived from both kidneys. However, in unilateral severe UPJO the “true” proximal fluid (urine directly from the obstructed kidney) will likely be significantly diluted in the bladder by the contribution from the nonobstructed kidney. We circumvent this issue by analyzing urine that was surgically obtained directly from the obstructed kidney, as well as urine from the bladder of UPJO patients representing the normal nonobstructed (contralateral) kidney. Although a test based on urine from the kidney would not be clinically feasible, studying the kidney-specific urinary proteome may provide new pathologic insights into UPJO that would not be obtainable on a study based on urine obtained from the bladder. Previous studies have demonstrated that the urinary proteome may contain clinically significant biomarkers of UPJO (5.Decramer S. Wittke S. Mischak H. Zürbig P. Walden M. Bouissou F. Bascands J.L. Schanstra J.P. Predicting the clinical outcome of congenital unilateral ureteropelvic junction obstruction in newborn by urinary proteome analysis.Nat. Med. 2006; 12: 398-400Crossref PubMed Scopus (218) Google Scholar, 6.Decramer S. Bascands J.L. Schanstra J.P. Non-invasive markers of ureteropelvic junction obstruction.World J. Urol. 2007; 25: 457-465Crossref PubMed Scopus (47) Google Scholar, 7.Caubet C. Lacroix C. Decramer S. Drube J. Ehrich J.H. Mischak H. Bascands J.L. Schanstra J.P. Advances in urinary proteome analysis and biomarker discovery in pediatric renal disease.Pediatr. Nephrol. 2010; 25: 27-35Crossref PubMed Scopus (62) Google Scholar, 8.Mesrobian H.G. Mitchell M.E. See W.A. Halligan B.D. Carlson B.E. Greene A.S. Wakim B.T. Candidate urinary biomarker discovery in ureteropelvic junction obstruction: A proteomic approach.J. Urol. 2010; 184: 709-714Crossref PubMed Scopus (31) Google Scholar, 9.Madsen M.G. Norregaard R. Frøkiaer J. Jørgensen T.M. Urinary biomarkers in prenatally diagnosed unilateral hydronephrosis.J. Pediatr. Urol. 2011; 7: 105-112Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). However, these studies either focused on the low molecular weight peptidome or achieved limited proteomic depth. In this work, we use large-scale proteomic methods to quantify the urinary proteomes of clinically unequivocal significant unilateral obstructed UPJO patients and compare them to healthy age- and sex-matched controls. Our goal was to perform an initial discovery study on this well-defined clinical cohort to identify potential pathologic mechanisms reflected in the urinary proteome. The unique advantage of our study was access to urine taken directly from a kidney undergoing surgical repair for UPJO. By surgically obtaining the most proximal fluid of UPJO (kidney urine), we were able to perform two comparisons to the control (1) from obstructed kidney urine and (2) urine from the bladder that represents the nonobstructed normal kidney and the systemic response to congenital unilateral UPJO. We hypothesized that the quantitation of proteomic changes in the urines of UPJO patients will enable patient stratification via the identification of biomarkers specific to patients in need of surgical intervention. Most importantly, identifying specific quantitative changes in the UPJO urinary proteome on a kidney-specific basis will lend further insight into the underlying pathological processes. All patients were identified using an IRB-approved protocol. We created a clinically defined, select infant cohort ≤ 2 yo with clinically significant severe unilateral UPJO and no other known medical history. Diseased patients had two inclusion criteria: (1) Society of Fetal Urology Grade 4 (scale 0–4) severe hydronephrosis on at least two serial kidney ultrasounds (US), and (2) a washout curve t1/2 ≥ 50 min (considered clinically definitive for obstruction) on a 99mTc mercaptoacetyltriglycine (MAG3) diuretic renography scan with furosemide delivered at F+20. Patients had negative voiding cystograms and no active or history of urinary tract infection. Cohort demographics are depicted in Table I. Normal controls were sex and age matched to each UPJO subject. Controls were identified from infants who were undergoing screening cystogram for a family history of vesicoureteral reflux. All normal controls had a normal kidney US, negative cystogram, no history of urinary tract infection, and no other comorbid condition. Each patient's clinical demographics are summarized in Table I.Table IA summary of the relevant clinical measurements for this cohort selection. Age in months, laterality of obstruction, grade of hydronephrosis by ultrasound (US), % function in each kidney, and t1/2 time on 99mTc mercaptoacetyltriglycine (MAG3) diuretic renogram are listed. A t1/2 is the measure of time it takes for of the radioisotope to be cleared from the kidney. A t1/2 > 20 minutes is considered to be pathologic for obstruction. UPJO patients selected for these studies all had significantly elevated t1/2 and persistent high grade hydronephrosis on serial US. Normal controls had no evidence of hydronephrosis. The patients studied were, based on current clinical parameters, unequivocally in need of surgical interventionIEF STRIPSampleGenderAge (mos)LateralityHydronephrosis grade (0–4)% Function R% Function Lt1/2 MAG3B1,K1D1F6R4465454C1C1F1-0---B2,K2D2M8L4604059C2C2M8-0---B3,K3D3F7L45050100C3C3F11-0---B4,K4D4M9R45149100C4C4M9-0---B5,K5D5M3R45347100C5C5M5-0---B6,K6D6M16L4722874C6C6M8-0---B7,K7D7M10L4514968C7C7M10-0---B8,K8D8M4R4485257C8C8M5-0--- Open table in a new tab At the time of surgery using standard sterile technique, urine was collected by catheterization of the bladder (sample name = BU, n = 8). During surgical correction of the kidney, urine was atraumatically aspirated directly from the renal pelvis of the obstructed kidney prior to relief of the obstruction (sample name = KU, n = 8). Patients in this cohort were not on prophylactic antibiotics but received intravenous antibiotics at the time of surgery prior to incision. All patients had no solid food 6 h and no clear liquids 2 h prior to surgery. During the screening cystogram, a urine sample was obtained at the time of catheterization of the bladder (sample name = CU, n = 8). No patients received anesthesia during the procedure. All patients were on low dose prophylactic antibiotics prior to the catheterization. Samples were analyzed by urinalysis using a Siemens CLINITEK® status automated analyzer (Tarrytown, NY) to ensure there was no blood contamination or evidence of proteinuria. Furthermore, as part of standard clinical practice, an aliquot of all samples are cultured to ensure no evidence of infection. All samples were negative for infection, blood, and protein. All samples were centrifuged at 4500 g for 20 min to remove cellular debris, aliquoted, and frozen at -80 C in 1.5 ml centrifuge tubes (Eppendorf) until sample preparation by our previously published protocol (10.Vaezzadeh A.R. Briscoe A.C. Steen H. Lee R.S. One-step sample concentration, purification, and albumin depletion method for urinary proteomics.J. Proteome Res. 2010; 9: 6082-6089Crossref PubMed Scopus (24) Google Scholar). An overview of the sample preparation is shown in Fig. 1. In brief, aliquots were thawed, desalted, and concentrated on 5000 mw cutoff filters. Samples were reduced and alkylated with iodoacetamide, and albumin was depleted with anti-HSA resin (Sartorius). Depleted samples were then quantified by the Bradford method, and an identical amount of protein from each sample was digested with sequencing-grade trypsin overnight (Promega). Peptides were labeled with the Tandem Mass Tag (TMT-6) kits (Thermo) according to manufacturer's protocols. Peptides were then purified on Oasis HLB SPE cartridges. We mixed six labeled samples (two matched BU, KU, CU triplets) to create one study group. Each group was then separated into 24 fractions by IEF using an OFFGEL (Agilent) and dried using an SPD1010 speedvac (Thermo). Fractionated, dried peptides were reconstituted in 5% FA/5% ACN, transferred to HPLC vials, and loaded onto an autosampler coupled to an LTQ-Orbitrap classic (Thermo) with a nanoflow UPLC system (Eksigent). The LC columns (15 cm × 100 μm inner diameter) were packed in house (Magic C18, 5 μm, 100 Å, Michrom BioResources, into PicoTips, New Objective, Woburn, MA). Samples were analyzed with a 60 min linear gradient (0–35% ACN with 0.2% formic acid) and a top six data-dependent acquisition method was utilized, with pulsed-Q dissociation. Normalized collision energy was 29%, and two microscans were averaged per MS/MS spectrum. MGF files consisting of the 200 most intense fragment ions of each raw product ion spectrum were generated by an in-house script. MGFs were searched against the IPI Homo sapiens database (version 3.69, 87,130 target sequences) using Mascot version 2.2.04 (Matrix Science). The following search parameters were applied: Default charge states of 2+, 3+, and 4+ were used; trypsin (fully specific with one missed cleavage) was the protease utilized. A peptide mass tolerance of 10 ppm and a fragment ion search tolerance of 0.8 Dalton (Da) was permitted. Fixed modification on cysteine was carbamidomethyl and variable modifications were deamidation (N and Q), oxidation (M), TMT: 6-plex at N terminus and lysine residues and pyro-glutamic acid formation (Q). All data were searched against a combined target and decoy database. Peptide identifications were filtered to a 1% false discovery rate by the target-decoy approach, and all identified proteins were matched by two or more spectra. IPI listings were converted to UniGene IDs using an online tool (http://www.uniprot.org/), and protein isoforms were combined into a single UniGene ID for quantification. All raw data have been deposited in the MassIVE repository, with accession number MSV000079553. The log2 values of the BU:CU and KU:CU reporter ions for each peptide spectral match (PSM) from a unique peptide were calculated. Individual PSM ratios were then normalized by the sample-wide mixing ratio. PSM ratios were grouped by gene ID, and the means of each gene were compared by one-way ANOVA to the remaining peptide mean. Globally, the quantitative PSM ratios were approximately normally distributed. The resulting p values for each gene ID were determined cohort-wide based on eight samples. p values were adjusted by the Benjamini–Hochberg correction, and the family-wise error rate (Q-value) was controlled at 5%. Furthermore, all statistically significant hits required a fold-change of 1.5 for BU:CU and 3.0 for KU:CU for further evaluation by pathway analysis. Statistically enriched pathways, toxicology results, and networks were identified by Ingenuity Pathways analysis software of identified proteins. Proteins of interest passing the above fold-changes from BU and KU quantification were analyzed separately to identify unique biological processes associated with BU and KU separately. Protein from urine samples was purified via Amicon 4–10K Centrifugal Filter Unit Clean-up (Millipore, Bedford, MA) and quantified using the Micro BCATM Assay Kit (Thermo Scientific, Rockford, IL). Equal amounts of protein from urine were used for each validated target (5 μg for HSP70 blots and 15 μg for GSTM1 blots) and were separated on NuPAGE 4–12% Bis-Tris gels (Life Technologies, Carlsbad, CA) at 125V along with HepG2 cell lysate in RIPA buffer as a positive control. Separated proteins were then transferred to a 0.45 μm InvitrolonTM PVDF membrane (Life Technologies, Carlsbad, CA). Membranes were blocked for 2 h using 5% dried nonfat milk in phosphate buffered serum/.05% Tween (PBS-T). Protein expression was determined by the following antibodies: HSP70 at a 1:10,000 dilution and GSTM1 at a 1:1,000 dilution (AbCam, Cambridge, MA) overnight at 4 °C in 5% bovine serum albumin (BSA) in PBS-T. Membranes were washed for 1 h with PBS-T and secondary goat anti-rabbit horseradish peroxidase (HRP) (Bio-Rad, Hercules, CA) was incubated with the membranes at room temperature for 1 h in 5% dried nonfat milk. The expression of each protein was determined by ECL Western Lightning (PerkinElmer Life and Analytical Sciences, Waltham, MA), and bands of interest corresponding to target proteins (HSP70 and GSTM1) were evaluated via quantitative densitometry (Image J, NIH). Considering the limited dynamic range of WB, we set a maximum fold-change of eightfold for calculations. A total of 1113 unique proteins were identified (Table II), with similar numbers of proteins identified in each study group. Over 750 genes were quantifiable with three or more PSMs. Of those, 267 showed abundance differences that were statistically significant. As shown in supplementary materials, 74 were statistically significant in both KU and BU relative to CU. Furthermore, over 75% of all statistically significant proteins were identified in all samples (supplementary materials), meaning the varying proteins are commonly expressed.Table IIA summary of the proteomic identifications per sample group. Sample groups averaged 660 proteins, 2165 unique peptides, and 6174 spectral matches. Two disease and control triplets were pooled per sample groupSample groupProteinsGenesPeptidesSpectra1–2650539209257273–4666546220357625–6628491197864427–869555223876768TOTALS (unique)1,113810409724699 Open table in a new tab The relationship between fold-change and q-value was visualized in volcano plots (Fig. 2) for each sample. BU samples are shifted toward higher q-values and lower fold-changes overall. Each of these shifts (larger fold-changes and smaller q-values) suggest that KU is more altered by UPJO than BU. It is clear that the KU proteome has been substantially altered by this disease, as expected for a proximal fluid. This finding highlights the value of analyzing urine directly from the obstructed kidney, as changes in KU are more apparent than those in BU. A total of 74 proteins were statistically significant in both KU:CU and BU:CU. The fold-changes of these proteins were plotted in Fig. 3 to visualize the quantitative relationship observed in these samples. While several of these proteins lie near the diagonal (e.g. similar fold-change in BU versus CU and KU versus CU), several others are off the diagonal, suggesting a preferential enrichment in one sample. For example, APOA1 is far more enriched in KU (4.4-fold enriched) than it is in BU (1.27-fold). These entries, although statistically significant in both samples, have pronounced differences in their regulation. In addition, a total of three proteins were up-/down-regulated in contrasting manner between the KU and BU samples. These included retinal dehydrogenase 1, heat shock 70 kDa protein 1A/1B, and ganglioside GM2 activator (GM2A), which are discussed in detail below. Heat shock 70 kDa protein 1A/1B and GM2A did not meet the initially applied fold cutoff for inclusion in the proteins of interest list. However, because of this unique quantitative relationship, these proteins were added to the proteins of interest list. In total, 76 proteins comprise the proteins of interest list. To determine the potential biological significance of the enriched and depleted proteins, we performed a bioinformatic analysis of the identified proteins with a specific focus on the statistically significant enriched or depleted markers using Ingenuity Pathways analysis software. Overall, several pathways were overrepresented among quantitatively varying proteins (supplementary materials). The overrepresented biological processes include oxidative stress/reactive oxygenated species (ROS) processing, fibrosis, and acute-phase inflammation reaction. Many of the proteins of interest are highly networked (Fig. 4). The KU content of two proteins (GSTM1 and HSP70) were evaluated by Western blotting in order to validate the quantitative MS measurements and pathway analysis findings (Fig. 5). In correlation to the proteomic quantitative data and pathway analysis identifying ROS species activation, total (11.Hornby J.A. Luo J.K. Stevens J.M. Wallace L.A. Kaplan W. Armstrong R.N. Dirr H.W. Equilibrium folding of dimeric class mu glutathione transferases involves a stable monomeric intermediate.Biochemistry. 2000; 39: 12336-12344Crossref PubMed Scopus (59) Google Scholar) GSTM1 and HSP70 were both elevated in the KU as compared with CU by WB. This finding supports the idea of altered ROS processing in the obstructed kidney. In this study of the urinary proteome of infants with well-defined severe unilateral UPJO versus healthy age- and sex-matched controls, we identified 76 proteins of interest in UPJO from 1113 proteins identified in an unbiased quantitative discovery study of the obstructed urinary proteome. We demonstrated that (1) obstruction significantly changes the urinary proteome; (2) compensatory changes in the normal nonobstructed kidney may also be contributing to significant quantitative changes in the urinary proteome; and (3) proteins involved in oxidative stress play a critical role in the pathophysiology of UPJO and may be the basis for a clinical biomarker of UPJO. Previous work also identified the potential value of analyzing urinary proteins in UPJO patient stratification.(5.Decramer S. Wittke S. Mischak H. Zürbig P. Walden M. Bouissou F. Bascands J.L. Schanstra J.P. Predicting the clinical outcome of congenital unilateral ureteropelvic junction obstruction in newborn by urinary proteome analysis.Nat. Med. 2006; 12: 398-400Crossref PubMed Scopus (218) Google Scholar, 6.Decramer S. Bascands J.L. Schanstra J.P. Non-invasive markers of ureteropelvic junction obstruction.World J. Urol. 2007; 25: 457-465Crossref PubMed Scopus (47) Google Scholar, 8.Mesrobian H.G. Mitchell M.E. See W.A. Halligan B.D. Carlson B.E. Greene A.S. Wakim B.T. Candidate urinary biomarker discovery in ureteropelvic junction obstruction: A proteomic approach.J. Urol. 2010; 184: 709-714Crossref PubMed Scopus (31) Google Scholar, 12.Decramer S. Zürbig P. Wittke S. Mischak H. Bascands J.L. Schanstra J.P. Identification of urinary biomarkers by proteomics in newborns: Use in obstructive nephropathy.Contrib. Nephrol. 2008; 160: 127-141Crossref PubMed Scopus (30) Google Scholar) However, these studies were differently focused, exclusively analyzing the low molecular weight peptidome (< 10kDa) or had a low degree of proteomic coverage. Points of merit in the current study include: (1) very well defined, age- and sex-matched severe disease and control cohorts (Table I) to provide definitive insight into the pathophysiology of clinically significant renal obstruction; (2) unique access to urine directly from the diseased kidney (KU); and (3) the deepest profiling of the UPJO urinary proteome to date. Currently, there is less clinical controversy about the need to intervene on patients with severe hydronephrosis, but there is no definitive consensus on the timing of surgical intervention, as many cases of severe hydronephrosis may still resolve without intervention. While there is a significant clinical need for markers to help with the management of lower grades of hydronephrosis, we specifically choose to study very severe obstruction to provide the most unbiased representation of the pathologic process of UPJO for this discovery study. Studying lesser degrees of hydronephrosis, although of high merit, would likely result in a cohort with varying clinical degrees of obstruction and physiology. Subsequently, a much larger number of patients would be required to identify any statistically relevant data, which potentially could preclude the logistics of an unbiased discovery-based proteomics study. Furthermore, the severe cohort has specific advantages over all animal models that are created postnatally and typically are complete obstruction models. Although obtaining urine directly from the kidney is not clinically feasible, by studying kidney urine from patients with severe obstruction, we have the unique ability to study the most proximal body fluid for UPJO. This provides the purest insight into the pathology of UPJO and may have the highest likelihood of identifying potential clinically informative pathways or proteins when combined with deep proteomic profiling. Since diseases are often affected by an integrated pathway of proteins (13.Schadt E.E. Molecular networks as sensors and drivers of common human diseases.Nature. 2009; 461: 218-223Crossref PubMed Scopus (636) Google Scholar), achieving sufficient depth of proteomic data is critical to identifying the relevant pathways in a disease. With this in mind, we elected to perform an unbiased analysis of the entire urinary proteome. This study has increased the number of proteins profiled from previous urinary UPJO proteomic studies by approximately an order of magnitude. In addition, many proteins that were implicated in obstructive nephropathy in a prior study (8.Mesrobian H.G. Mitchell M.E. See W.A. Halligan B.D. Carlson B.E. Greene A.S. Wakim B.T. Candidate urinary biomarker discovery in ureteropelvic junction obstruction: A proteomic approach.J. Urol. 2010; 184: 709-714Crossref PubMed Scopus (31) Google Scholar) were also statistically significant in this study, with the same quantitative trends. Elevated proteins included angiotensin; albumin; keratin 8; keratin 9; lectin, galactoside-binding, soluble, 3 binding protein; macrophage inhibitory factor; myosin heavy chain 7; serpin peptidase inhibitor; clade A member 1; and transferrin. Epidermal growth factor was previously reported as down-regulated (14.Taha M.A. Shokeir A.A. Osman H.G. Abd El-Aziz Ael A. Farahat S.E. Pelvi-ureteric junction obstruction in children: The role of urinary transforming growth factor-beta and epidermal growth factor.BJU Int. 2007; 99: 899-903Crossref PubMed Scopus (44) Google Scholar), and our study replicated that trend although statistical significance was not achieved in this study cohort. Similarly, prior studies evaluating BU also shared trends with KU quantitation. Glutathione S-transferase pi 1; GAPDH, and heat shock 27kDa protein 1 were all elevated in KU, as in prior work. Performing research on human subjects is challenging due to extensive heterogeneity between individuals. The fact that quantitative trends for proteins remained the same between different studies despite substantial differences in study design, patient selection, and analytical methodologies is quite striking and further supports the validity of the quantification. The urine obtained directly from the obstructed kidney (KU) represents the most proximal fluid of UPJO and has the advantage of a higher concentration of the proteins of interest (15.Alatas F. Alatas O. Metintas M. Colak O. Harmanci E. Demir S. Diagnostic value of CEA, CA 15–3, CA 19–9, CYFRA 21–1, NSE and TSA assay in pleural effusions.Lung Cancer. 2001; 31: 9-16Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 16.Kishi T. Grass L. Soosaipillai A. Scorilas A. Harbeck N. Schmalfeldt B. Dorn J. Mysliwiec M. Schmitt M. Diamandis E.P. Human kallikrein 8, a novel biomarker for ovarian carcinoma.Cancer Res. 2003; 63: 2771-2774PubMed Google Scholar, 17.Rosty C. Christa L. Kuzdzal S. Baldwin W.M. Zahurak M.L. Carnot F. Chan D.W. Canto M. Lillemoe K.D. Cameron J.L. Yeo C.J. Hruban R.H. Goggins M. Identification of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein I as a biomarker for pancreatic ductal adenocarcinoma by protein biochip technology.Cancer Res. 2002; 62: 1868-1875PubMed Google Scholar). UPJO inherently retards drainage from the obstructed kidney, so BU is expected to be overrepresented in urine filtered from the contralateral kidney, particularly in the case of severe obstruction. Subsequently, the protein profile identified in the bladder may more closely represent changes in the contralateral kidney or possibly systemic responses to unilater" @default.
• W2395632397 created "2016-06-24" @default.
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• W2395632397 date "2016-08-01" @default.
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• W2395632397 title "Urinary Proteomics Yield Pathological Insights for Ureteropelvic Junction Obstruction" @default.
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• W2395632397 doi "https://doi.org/10.1074/mcp.m116.059386" @default.
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