Growth and differentiation factor 15 and NF-κB expression in benign prostatic biopsies and risk of subsequent prostate cancer detection

Growth and differentiation factor 15 (GDF-15), also known as macrophage inhibitory cytokine 1 (MIC-1), may act as both a tumor suppressor and promotor and, by regulating NF-κB and macrophage signaling, promote early prostate carcinogenesis. To determine whether expression of these two inflammation-related proteins affect prostate cancer susceptibility, dual immunostaining of benign prostate biopsies for GDF-15 and NF-κB was done in a study of 503 case-control pairs matched on date, age, and race, nested within a historical cohort of 10,478 men. GDF-15 and NF-κB expression levels were positively correlated (r = 0.39; p \u3c 0.0001), and both were significantly lower in African American (AA) compared with White men. In adjusted models that included both markers, the odds ratio (OR) for NF-κB expression was statistically significant, OR =0.87; p = 0.03; 95% confidence interval (CI) =0.77-0.99, while GDF-15 expression was associated with a nominally increased risk, OR =1.06; p = 0.27; 95% CI =0.96-1.17. When modeling expression levels by quartiles, the highest quartile of NF-κB expression was associated with almost a fifty percent reduction in prostate cancer risk (OR =0.51; p = 0.03; 95% CI =0.29-0.92). In stratified models, NF-κB had the strongest negative association with prostate cancer in non-aggressive cases (p = 0.03), older men (p = 0.03), and in case-control pairs with longer follow-up (p = 0.02). Risk associated with GDF-15 expression was best fit using nonlinear regression modeling where both first (p = 0.02) and second (p = 0.03) order GDF-15 risk terms were associated with significantly increased risk. This modeling approach also revealed significantly increased risk associated with GDF-15 expression for subsamples defined by AA race, aggressive disease, younger age, and in case-control pairs with longer follow-up. Therefore, although positively correlated in benign prostatic biopsies, NF-κB and GDF-15 expression appear to exert opposite effects on risk of prostate tumor development

Prenatal Course and Sonographic Features of Congenital Mesoblastic Nephroma

Background: Congenital mesoblastic nephroma (CMN) is the most common renal tumor among fetuses and infants before the age of 6 months. It usually behaves as a benign tumor. The prenatal features and outcomes of pregnancies with fetal CMN have never been systematically reviewed and analyzed, whereas neonatal or pediatric series have been published several times. The aims of this study are to (1) describe the prenatal natural course and prenatal sonographic char-acteristics of CMN; (2) determine the outcomes of pregnancies with fetal CMN; and (3) demonstrate typical sonographic images together with video clips of prenatal CMN, as an educational example based on our index case presented here. Methods: Studies focused on fetal CMN, including those consecutively published on PubMed from 1980 to June 2022 as well as the index case presented here, were identified and validated to perform a systematic review. The data of fetal imaging and the prenatal course of pregnancies were extracted for analysis. Results: The findings derived from 41 cases of review are as follows: (1) No single case has been diagnosed in the first half of pregnancy. No cases were detected during routine anomaly screening at mid-pregnancy. All cases were de-tected in the third trimester or late second trimester. (2) Polyhydramnios is very common and is the first clinical manifestation in most cases, leading to detailed ultrasound in the second half of pregnancy. (3) Preterm birth and low birth weight are the most common adverse pregnancy out-comes, resulting in neonatal morbidity. (4) Hydrops fetalis, though relatively rare, can be associated with CMN and is a grave sign. (5) Prenatal diagnosis is essential since it is critical for the antenatal plan, comprising either referral to a tertiary care center or proper surveillance to prevent serious obstetric complications, especially preterm birth. (6) Ultrasound is the primary tool for prenatal diagnosis of CMN, whereas MRI can be used as an adjunct if some other tumors are suspicious or sonographic features are not typical for CMN. Conclusion: In contrast to CMN in neonates, fetal CMN is much more serious since it significantly impacts adverse pregnancy outcomes and perinatal morbidity and mortality. The typical prenatal course and the sonographic features of CMN are described

Peripheral antinociceptive effects of a bifunctional μ and δ opioid receptor ligand in rat model of inflammatory bladder pain.

There is a need to develop a novel analgesic for pain associated with interstitial cystitis/painful bladder syndrome (IC/PBS). The use of the conventional μ-opioid receptor agonists to manage IC/PBS pain is controversial due to adverse CNS effects. These effects are attenuated in benzylideneoxymorphone (BOM), a low-efficacy μ-opioid receptor agonist/δ-opioid receptor antagonist that attenuates thermal pain and is devoid of reinforcing effects. We hypothesize that BOM will inhibit bladder pain by attenuating responses of urinary bladder distension (UBD)-sensitive afferent fibers. Therefore, the effect of BOM was tested on responses of UBD-sensitive afferent fibers in L6 dorsal root from inflamed and non-inflamed bladder of rats. Immunohistochemical (IHC) examination reveals that following the induction of inflammation there were significant high expressions of μ, δ, and μ-δ heteromer receptors in DRG. BOM dose-dependently (1-10 mg/kg, i.v) attenuated mechanotransduction properties of these afferent fibers from inflamed but not from non-inflamed rats. In behavioral model of bladder pain, BOM significantly attenuated visceromotor responses (VMRs) to UBD only in inflamed group of rats when injected either systemically (10 mg/kg, i.v.) or locally into the bladder (0.1 ml of 10 mg/ml). Furthermore, oxymorphone (OXM), a high-efficacy μ-opioid receptor agonist, attenuated responses of mechanosensitive bladder afferent fibers and VMRs to UBD. Naloxone (10 mg/kg, i.v.) significantly reversed the inhibitory effects of BOM and OXM on responses of bladder afferent fibers and VMRs suggesting μ-opioid receptor-related analgesic effects of these compounds. The results reveal that a low-efficacy, bifunctional opioid-based compound can produce analgesia by attenuating mechanotransduction functions of afferent fibers innervating the urinary bladder

Racial Disparities in Expression of GDF15 and NFκB in Prostate Cancer and Benign Prostatic Epithelium

Prostate cancer (PC) outcomes are more adverse for African-American (AA) than white (W) men. Growth differentiation factor 15 (GDF15, PDF, NAG-1) is a stress-induced anti-inflammatory cytokine with immunosuppressive and tumor growth-promoting functions. GDF15 inversely regulates NFκB, a transcription factor enabling pro-inflammatory gene expression and becomes constitutively activated in androgen-independent PC. Tissue microarrays (TMAs), prepared from prostatectomy tissue at three institutions, comprised 688 cases (364 W and 324 AA). Each case included ≥3 tumor punches plus ≥3 non-neoplastic punches. TMAs were stained separately for GDF15 and NFκB and evaluated by two pathologists, using the 0-3+ scale. PC, compared to benign epithelium, had elevated mean GDF15 expression (1.93 vs. 0.99) and also, NFκB (1.18 vs. 0.96, both P<0.0001). Only in AA men did PC show gradewise or stagewise altered expression of these markers. In AA men, GDF15 expression fell as stage rose in PC (P=0.007) and also in benign epithelium (P =0.003). In W men, GDF15 expression in benign epithelium fell as stage (P=0.01) and grade (P=0.01) rose. NFκB expression was higher in AA than W men only in high-grade PC (P =0.01). NFκB expression rose with increasing tumor grade only in AA men (P =0.027) and in the benign prostate component only in W men (P=0.007). Benign and tumor NFκB expression did not vary with stage. PC showed significant alterations in GDF15 and NFκB expression in accord with cancer aggressiveness in AA men only: stagewise decrease in GDF15, and gradewide increase in NFκB.  Findings suggest a disparity for immune response by race in prostate carcinogenesis

Radio-pathomic mapping model generated using annotations from five pathologists reliably distinguishes high-grade prostate cancer.

Purpose: Our study predictively maps epithelium density in magnetic resonance imaging (MRI) space while varying the ground truth labels provided by five pathologists to quantify the downstream effects of interobserver variability. Approach: Clinical imaging and postsurgical tissue from 48 recruited prospective patients were used in our study. Tissue was sliced to match the MRI orientation and whole-mount slides were stained and digitized. Data from 28 patients ( n = 33 slides) were sent to five pathologists to be annotated. Slides from the remaining 20 patients ( n = 123 slides) were annotated by one of the five pathologists. Interpathologist variability was measured using Krippendorffs alpha. Pathologist-specific radiopathomic mapping models were trained using a partial least-squares regression using MRI values to predict epithelium density, a known marker for disease severity. An analysis of variance characterized intermodel means difference in epithelium density. A consensus model was created and evaluated using a receiver operator characteristic classifying high grade versus low grade and benign, and was statistically compared to apparent diffusion coefficient (ADC). Results: Interobserver variability ranged from low to acceptable agreement (0.31 to 0.69). There was a statistically significant difference in mean predicted epithelium density values ( p < 0.001 ) between the five models. The consensus model outperformed ADC (areas under the curve = 0.80 and 0.71, respectively, p < 0.05 ). Conclusion: We demonstrate that radiopathomic maps of epithelium density are sensitive to the pathologist annotating the dataset; however, it is unclear if these differences are clinically significant. The consensus model produced the best maps, matched the performance of the best individual model, and outperformed ADC

Multi-Site Concordance of Diffusion-Weighted Imaging Quantification for Assessing Prostate Cancer Aggressiveness

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172844/1/jmri27983.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172844/2/jmri27983_am.pd