Impact of Hearing Aid Use on Falls and Falls-Related Injury: Results From the Health and Retirement Study.

OBJECTIVES: Falls are considered a significant public health issue and falls risk increases with age. There are many age-related physiologic changes that occur that increase postural instability and the risk for falls (i.e., age-related sensory declines in vision, vestibular, somatosensation, age-related orthopedic changes, and polypharmacy). Hearing loss has been shown to be an independent risk factor for falls. The primary objective of this study was to determine if hearing aid use modified (reduced) the association between self-reported hearing status and falls or falls-related injury. We hypothesized that hearing aid use would reduce the impact of hearing loss on the odds of falling and falls-related injury. If hearing aid users have reduced odds of falling compared with nonhearing aid users, then that would have an important implications for falls prevention healthcare. DESIGN: Data were drawn from the 2004-2016 surveys of the Health and Retirement Study (HRS). A generalized estimating equation approach was used to fit logistic regression models to determine whether or not hearing aid use modifies the odds of falling and falls injury associated with self-reported hearing status. RESULTS: A total of 17,923 individuals were grouped based on a self-reported history of falls. Self-reported hearing status was significantly associated with odds of falling and with falls-related injury when controlling for demographic factors and important health characteristics. Hearing aid use was included as an interaction in the fully-adjusted models and the results showed that there was no difference in the association between hearing aid users and nonusers for either falls or falls-related injury. CONCLUSIONS: The results of the present study show that when examining self-reported hearing status in a longitudinal sample, hearing aid use does not impact the association between self-reported hearing status and the odds of falls or falls-related injury.

The Association Between Hearing Loss and Surgical Complications in Older Adults.

OBJECTIVES: In this study, we sought to evaluate whether older patients with hearing loss who underwent surgery were at greater risk of postsurgical complications, increased inpatient length-of-stay (LOS), and hospital readmission. DESIGN: This was a retrospective cohort study of patients receiving surgery at a tertiary medical center. Utilizing electronic health record data from two merged datasets, we identified patients 65 years and older, undergoing major surgery between January 1, 2014 and January 31, 2017, and who had audiometric evaluation before surgery. Patients were classified as having either normal hearing or hearing loss based on pure-tone average in the better ear. A Generalized Estimating Equations approach was used to fit multivariable regression models for outcome variables of interest. RESULTS: Of patients ≥65 years undergoing major surgery in our time frame, a total of 742 surgical procedures were performed on 621 patients with available audiometric data. After adjusting for age, sex, race, and comorbidities, hearing loss was associated with an increase in the odds of developing postoperative complications. Every 10 dB increase in hearing loss was associated with a 14% increase in the odds of developing a postoperative complication (odds ratio = 1.14, 95% confidence interval = 1.01-1.29, p = 0.031). Hearing loss was not significantly associated with increased hospital LOS, 30-day readmission, or 90-day readmission. CONCLUSIONS: Hearing loss was significantly associated with developing postoperative complications in older adults undergoing major surgery. Screening for hearing impairment may be a useful addition to the preoperative assessment and perioperative management of older patients undergoing surgery.

A three-tier system for evaluation of organ procurement organizations' willingness to pursue and utilize nonideal donor lungs.

Lungs from "nonideal," but acceptable donors are underutilized; however, organ procurement organization (OPO) metrics do not reflect the extent to which OPO-specific practices contribute to these trends. We developed a comprehensive system to evaluate nonideal lung donor avoidance, or risk aversion among OPOs. Adult donors in the UNOS registry who donated ≥1 organ for transplantation between 2007 and 2018 were included. Nonideal donors had any of age>50, smoking history ≥20 pack-years, PaO2 /FiO2 ratio ≤350, donation after circulatory death, or increased risk status. OPO-level risk aversion in donor pursuit, consent attainment, lung recovery, and transplantation was assessed. Among 83916 donors, 70372 (83.9%) were nonideal. Unadjusted OPO-level rates of nonideal donor pursuit ranged from 81 to 100%. In a three-tier system of overall risk aversion, tier 3 OPOs (least risk-averse) had the highest rates of nonideal donor pursuit, consent attainment, lung recovery, and transplantation. Tier 1 OPOs (most risk-averse) had the lowest rates of donor pursuit, consent attainment, and lung recovery, but higher rates of transplantation compared to tier 2 OPOs (moderately risk-averse). Risk aversion varies among OPOs and across the donation process. OPO evaluations should reflect early donation process stages to best differentiate over- and underperforming OPOs and encourage optimal OPO-specific performance.

African Americans' discussions about living-donor kidney transplants with family or friends: Who, what, and why not?

BACKGROUND: Although discussions with family or friends can improve access to living-donor kidney transplantation (LDKT), they remain an understudied step in the LDKT process. METHODS: Among 300 African American transplant candidates, we examined how sociodemographic, clinical, LDKT-related, and psychosocial characteristics related to the occurrence of LDKT discussions with family or friends. We also analyzed the relation between discussion occurrence and donor activation on transplant candidates' behalves (at least one donor inquiry or completed donor evaluation in the medical record). We assessed associations of discussion characteristics (context, content, and perceptions) with donor activation among discussants, and we identified discussion barriers among non-discussants. RESULTS: Most candidates (90%) had discussed LDKT. Only family functioning was statistically significantly associated with discussion occurrence. Specifically, family dysfunction was associated with 62% lower odds of discussion than family function. Family functioning, discussion occurrence, and different discussion characteristics were statistically significantly related to donor activation. The most prevalent discussion barrier was never having thought about discussing LDKT. CONCLUSIONS: Family functioning affected the likelihood of discussing LDKT, and family functioning, discussion occurrence, and discussion characteristics were associated with donor activation. Advancing understanding of how family functioning and LDKT discussions affect progression to LDKT may benefit interventions to increase LDKT.

Exploring Factors Associated With Morbidity and Mortality in Patients With Do-Not-Resuscitate Orders: A National Surgical Quality Improvement Program Database Analysis Within Surgical Groups.

BACKGROUND: Anesthesiologists caring for patients with do-not-resuscitate (DNR) orders may have ethical concerns because of their resuscitative wishes and may have clinical concerns because of their known increased risk of morbidity/mortality. Patient heterogeneity and/or emphasis on mortality outcomes make previous studies among patients with DNR orders difficult to interpret. We sought to explore factors associated with morbidity and mortality among patients with DNR orders, which were stratified by surgical subgroups. METHODS: Exploratory retrospective cohort study in adult patients undergoing prespecified colorectal, vascular, and orthopedic surgeries was performed using the American College of Surgeons National Surgical Quality Improvement Program Participant Use File data from 2010 to 2013. Among patients with preoperative DNR orders (ie, active DNR order written in the patient's chart before surgery), factors associated with 30-day mortality, increased length of stay, and inpatient death were determined via penalized regression. Unadjusted and adjusted estimates for selected variables are presented. RESULTS: After selection as above, 211,420 patients underwent prespecified procedures, and of those, 2755 (1.3%) had pre-existing DNR orders and met above selection to address morbidity/mortality aims. By specialty, of these patients with a preoperative DNR, 1149 underwent colorectal, 870 vascular, and 736 orthopedic surgery. Across groups, 36.2% were male and had a mean age 79.9 years (range 21-90). The 30-day mortality was 15.4%-27.2% and median length of stay was 6-12 days. Death at discharge was 7.0%, 13.1%, and 23.0% in orthopedics, vascular, and colorectal patients with a DNR, respectively. The strongest factors associated with increased odds of 30-day mortality were preoperative septic shock in colorectal patients, preoperative ascites in vascular patients, and any requirement of mechanical ventilation at admission in orthopedic patients. CONCLUSIONS: In patients with DNR orders undergoing common surgical procedures, the association of characteristics with morbidity and mortality varies in both direction and magnitude. The DNR order itself should not be the defining measure of risk.

Associations of perceived information adequacy and knowledge with pursuit of live donor kidney transplants and living donor inquiries among African American transplant candidates.

We studied associations between perceived adequacy of live donor kidney transplant (LDKT) information or knowledge with pursuit of LDKT or receipt of live donor inquiries among 300 African American kidney transplant candidates. Participants reported via questionnaire how informed or knowledgeable they felt regarding LDKT. Participants also reported their pursuit of LDKT, categorized as "low" (no discussion with family or friends about LDKT and no identified donor), "intermediate" (discussed LDKT with family but no identified donor) or "high" (discussed LDKT with family and identified a potential donor). We reviewed participants' electronic health records to identify potential donors' transplant center inquiries on participants' behalves. A minority of participants reported they felt "very" or "extremely" well informed about LDKT (39%) or had "a great deal" of LDKT knowledge (38%). Participants perceiving themselves as "very" or "extremely" (vs "not" or "slightly") well informed about LDKT had statistically significantly greater odds of intermediate or high (vs low) pursuit of LDKT (odds ratio [95% confidence interval] 2.71 [1.02-7.17]). Perceived LDKT knowledge was not associated with pursuit of LDKT. Neither perceived information adequacy nor knowledge was associated with living donor inquiries. Efforts to better understand the role of education in the pursuit of LDKT among African American transplant candidates are needed.

Adding the Team into T1 Translational Research: A Case Study of Multidisciplinary Team Science in the Evaluation of Biomarkers of Prostate Cancer Risk and Prognosis.

BACKGROUND: Given translational research challenges, multidisciplinary team science is promoted to increase the likelihood of moving from discovery to health effect. We present a case study documenting the utility of multidisciplinary team science in prostate cancer tissue biomarker validation. METHODS: We used primary data generated by a team consisting of a pathologist, cancer biologists, a biostatistician, and epidemiologists. We examined their contributions by phase of biomarker evaluation to identify when, through the practice of team science, threats to internal validity were recognized and solved. Next, we quantified the extent of bias avoided in evaluating the association of Ki67 (immunohistochemistry), stromal cell telomere length (fluorescence in situ hybridization), and microRNA (miRNA) (miR-21, miR-141, miR-221; quantitative RT-PCR) with prostate cancer risk or recurrence in nested case-control studies. RESULTS: Threats to validity were tissue storage time (Ki67, miRNA) and laboratory equipment maintenance (telomeres). Solutions were all in the data analysis phase and involved using tissue storage-time specific cutpoints and/or batch-specific cutpoints. Bias in the regression coefficient for quantiles of each biomarker ranged from 24% to 423%, and the coefficient for the test for trend ranged from 15% to 910%. The interpretation of the associations changed as follows: Ki67, null to positive; stromal cell telomere length, null to positive; miR-21 and miR-141 remained null; miR-221, weak to moderate inverse. CONCLUSIONS: In this case study, we documented the inferential benefits of multidisciplinary team science when the team's collaboration and coordination led to the identification of threats to validity and the implementation of appropriate solutions.

The Impact of Ergonomics on Recruitment to Surgical Fields: A Multi-Institutional Survey Study.

BACKGROUND: Awareness of ergonomics in surgery is growing, but whether musculoskeletal (MSK) injuries in surgery influence trainee career choices remains unknown. This study aimed to characterize medical students' MSK pain during surgical rotations and determine whether ergonomics influence student interest in surgical fields. METHODS: An online survey was administered to medical students in North Carolina. Students were asked about specialty interest, MSK pain on surgical rotations, and deterrents from surgical fields. Students were exposed to literature about ergonomics in surgery then queried again about relative specialty interest (medical versus surgical). Differences in specialty interest before and after the exposure were compared using a Wilcoxon signed-rank test. RESULTS: Of 243 participants, 44.0% were interested in pursuing a surgical specialty. Overall, 75.3% reported MSK pain during their surgical rotation, with the average daily pain score highest during surgery rotations compared to all other clinical rotations. The worst pain was reported in the feet and low back while "standing in the operating room" (81.2%) or "retracting" (59.4%). Among students initially interested in surgery but whose interest changed to a medical specialty during medical school, "physical demands of the field" was a common deterrent (36.4%). After exposure to literature regarding the incidence of MSK injuries in surgery, student interest in surgical fields on a 10-point scale significantly decreased (average -0.5 points; P < 0.01). CONCLUSIONS: High incidence of MSK injury among surgeons may be one factor deterring medical students from surgical careers. Ergonomic interventions may be important both to improve surgeon longevity and maintain the surgical workforce.

Current or recent smoking is associated with more variable telomere length in prostate stromal cells and prostate cancer cells.

BACKGROUND: Current and recent smoking have been associated with a greater risk of prostate cancer recurrence and mortality, though the underlying mechanism is unknown. METHODS: To determine if telomere shortening, which has been associated with poor outcomes, may be a potential underlying mechanism, we prospectively evaluated the association between smoking status and telomere length in 567 participants in the Health Professionals Follow-up Study, who were surgically treated for prostate cancer. Using tissue microarrays (TMA), we measured telomere length in cancer and benign tissue, specifically stromal cells in the same TMA spot using a telomere-specific fluorescence in situ hybridization assay. Smoking status was collected via questionnaire 2-years before diagnosis. Adjusting for age, pathologic stage and grade, the median and standard deviation of the per-cell telomere signals were determined for each man for stromal cells and cancer cells by smoking categories. In sub-analyses, we restricted to men without major co-morbidities diagnosed before prostate cancer. RESULTS: Overall, there were no associations between smoking status and telomere length or variability in stromal cells or cancer cells. However, among men without comorbidities, current smokers and former smokers who quit <10 years ago had the most variable telomere length in stromal cells (29.3% more variable than never smokers; P-trend = 0.0005) and in cancer cells (27.7% more variable than never smokers; P-trend = 0.05). Among men without comorbidities, mean telomere length did not differ by smoking status in stromal cells or cancer cells. CONCLUSION: Telomere variability in prostate cells may be one mechanism through which smoking influences poor prostate cancer outcomes.

The effect of risk factor misclassification on the partial population attributable risk.

The partial population attributable risk (pPAR) is used to quantify the population-level impact of preventive interventions in a multifactorial disease setting. In this paper, we consider the effect of nondifferential risk factor misclassification on the direction and magnitude of bias of pPAR estimands and related quantities. We found that the bias in the uncorrected pPAR depends nonlinearly and nonmonotonically on the sensitivities, specificities, relative risks, and joint prevalence of the exposure of interest and background risk factors, as well as the associations between these factors. The bias in the uncorrected pPAR is most dependent on the sensitivity of the exposure. The magnitude of bias varies over a large range, and in a small region of the parameter space determining the pPAR, the direction of bias is away from the null. In contrast, the crude PAR can only be unbiased or biased towards the null by risk factor misclassification. The semiadjusted PAR is calculated using the formula for the crude PAR but plugs in the multivariate-adjusted relative risk. Because the crude and semiadjusted PARs continue to be used in public health research, we also investigated the magnitude and direction of the bias that may arise when using these formulae instead of the pPAR. These PAR estimators and their uncorrected counterparts were calculated in a study of risk factors for colorectal cancer in the Health Professionals Follow-up Study, where it was found that because of misclassification, the pPAR for low folate intake was overestimated with a relative bias of 48%, when red meat and alcohol intake were treated as misclassified risk factors that are not modified, and when red meat was treated as the modifiable risk factor, the estimated value of the pPAR went from 14% to 60%, further illustrating the extent to which misclassification can bias estimates of the pPAR.

Differential long-term stability of microRNAs and RNU6B snRNA in 12-20 year old archived formalin-fixed paraffin-embedded specimens.

BACKGROUND: The quantitative analysis of microRNA (miRNA) gene expression in archived formalin-fixed, paraffin embedded (FFPE) tissues has been instrumental to identifying their potential roles in cancer biology, diagnosis, and prognosis. However, it remains unclear whether miRNAs remain stable in FFPE tissues stored for long periods of time. METHODS: Here we report Taqman real-time RT-PCR quantification of miR-21, miR-141, miR-221, and RNU6B small nuclear RNA (snRNA) levels from 92 radical prostatectomy specimens stored for 12-20 years in FFPE blocks. The relative stability of each transcript over time was assessed using general linear models. The correlation between transcript quantities, sample age, and RNA integrity number (RIN) were determined utilizing Spearman rank correlation. RESULTS: All transcript levels linearly decreased with sample age, demonstrating a clear loss of miRNA stability and RNU6B snRNA stability over time. The most rapid rates of degradation were observed for RNU6B and miR-21, while miR-141 and miR-221 were more stable. RNA quality was not correlated with sample age or with miR-21, miR-221, or RNU6B snRNA levels. Conversely, miR-141 levels increased with RNA quality. CONCLUSIONS: MiRNA and snRNA levels gradually decreased over an eight year period in FFPE tissue blocks. Sample age was the most consistent feature associated with miRNA stability. The reference snRNA, RUN6B, was more rapidly degraded when compared to miR-141 and miR-221 miRNAs. Various miRNAs demonstrated differential rates of degradation. Quantitative miRNA studies from long-term archived FFPE tissues may therefore benefit from epidemiologic study design or statistical analysis methods that take into account differential storage-dependent transcript degradation.

Circulating total testosterone and PSA concentrations in a nationally representative sample of men without a diagnosis of prostate cancer.

BACKGROUND: The association between serum sex steroid hormones and PSA in a general population has not been described. METHODS: Included were 378 men aged 40-85 years who participated in the National Health and Nutrition Examination Survey in 2001-2004, who did not have a prostate cancer diagnosis, and had not had a recent biopsy, rectal examination, cystoscopy, or prostate infection or inflammation. Serum total PSA, total testosterone, androstanediol glucuronide (3α-diol-G), estradiol, and sex hormone binding globulin (SHBG) concentrations were previously measured. Free testosterone was estimated by mass action. We applied sampling weights and calculated geometric mean PSA concentration by hormone quintiles adjusting for age and race/ethnicity, and also for body mass index, waist circumference, smoking, diabetes, and mutually for hormones. We estimated the OR of PSA ≥2.5 ng/ml per hormone quintile using logistic regression. RESULTS: Geometric mean PSA increased across testosterone quintiles after age and race/ethnicity (Q1: 0.80, Q5: 1.14 ng/ml; P-trend = 0.002) and multivariable (Q1: 0.79, Q5: 1.16 ng/ml; P-trend = 0.02) adjustment; patterns were similar for free testosterone and 3α-diol-G. SHBG was inversely associated with PSA only after multivariable adjustment (Q1: 1.32, Q5: 0.82 nmol/L; P-trend = 0.01). Estradiol and PSA were not associated. The OR of PSA ≥2.5 ng/ml was 1.54 (95% CI 1.18-2.01) per testosterone quintile after age and race/ethnicity adjustment, and 1.78 (95% CI 1.16-2.73) after multivariable adjustment. CONCLUSIONS: In this nationally representative sample, men with higher testosterone had higher PSA even after taking into account other hormones and modifiable factors. Men with higher SHBG had lower PSA, but only after multivariable adjustment.

Prostate stromal cell telomere shortening is associated with risk of prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial.

BACKGROUND: Telomeres are repetitive nucleoproteins that help maintain chromosomal stability by inhibiting exonucleolytic degradation, prohibiting inappropriate homologous recombination, and preventing chromosomal fusions by suppressing double-strand break signals. We recently observed that men treated for clinically localized prostate cancer with shorter telomeres in their cancer-associated stromal cells, in combination with greater variation in cancer cell telomere lengths, were significantly more likely to progress to distant metastases, and die from their disease. Here, we hypothesized that shorter stromal cell telomere length would be associated with prostate cancer risk at time of biopsy. METHODS: Telomere-specific fluorescence in situ hybridization (FISH) analysis was performed in normal-appearing stromal, basal epithelial, and luminal epithelial cells in biopsies from men randomized to the placebo arm of the Prostate Cancer Prevention Trial. Prostate cancer cases (N = 32) were either detected on a biopsy performed for cause or at the end of the study per trial protocol, and controls (N = 50), defined as negative for cancer on an end-of-study biopsy performed per trial protocol (e.g., irrespective of indication), were sampled. Logistic regression was used to estimate the association between mean telomere length of the particular cell populations, cell-to-cell telomere length variability, and risk of prostate cancer. RESULTS: Men with short stromal cell telomere lengths (below median) had 2.66 (95% CI 1.04-3.06; P = 0.04) times the odds of prostate cancer compared with men who had longer lengths (at or above median). Conversely, we did not observe statistically significant associations for short telomere lengths in normal-appearing basal (OR = 2.15, 95% CI 0.86-5.39; P= 0 .10) or luminal (OR = 1.15, 95% CI 0.47-2.80; P = 0.77) cells. CONCLUSIONS: These findings suggest that telomere shortening in normal stromal cells is associated with prostate cancer risk. It is essential to extend and validate these findings, while also identifying the cellular milieu that comprises the subset of cells with short telomeres within the prostate tumor microenvironment.

PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy.

When distinguishing between indolent and potentially harmful prostate cancers, the Gleason score is the most important variable, but may be inaccurate in biopsies due to tumor under-sampling. This study investigated whether a molecular feature, PTEN protein loss, could help identify which Gleason score 6 tumors on biopsy are likely to be upgraded at radical prostatectomy. Seventy one patients with Gleason score 6 tumors on biopsy upgraded to Gleason score 7 or higher at prostatectomy (cases) were compared with 103 patients with Gleason score 6 on both biopsy and prostatectomy (controls). A validated immunohistochemical assay for PTEN was performed, followed by fluorescence in situ hybridization (FISH) to detect PTEN gene deletion in a subset. PTEN protein loss and clinical-pathologic variables were assessed by logistic regression. Upgraded patients were older than controls (61.8 vs 59.3 years), had higher pre-operative PSA levels (6.5 vs 5.3 ng/ml) and a higher fraction of involved cores (0.42 vs 0.36). PTEN loss by immunohistochemistry was found in 18% (13/71) of upgraded cases compared with 7% (7/103) of controls (P=0.02). Comparison between PTEN immunohistochemistry and PTEN FISH showed the assays were highly concordant, with 97% (65/67) of evaluated biopsies with intact PTEN protein lacking PTEN gene deletion, and 81% (13/16) of the biopsies with PTEN protein loss showing homozygous PTEN gene deletion. Tumors with PTEN protein loss were more likely to be upgraded at radical prostatectomy than those without loss, even after adjusting for age, preoperative PSA, clinical stage and race (odds ratio=3.04 (1.08-8.55; P=0.035)). PTEN loss in Gleason score 6 biopsies identifies a subset of prostate tumors at increased risk of upgrading at radical prostatectomy. These data provide evidence that a genetic event can improve Gleason score accuracy and highlight a path toward the clinical use of molecular markers to augment pathologic grading.

A group randomized controlled trial integrating obesity prevention and control for postpartum adolescents in a home visiting program.

BACKGROUND: Adolescence represents a critical period for the development of overweight that tracks into adulthood. This risk is significantly heightened for adolescents that become pregnant, many of whom experience postpartum weight retention. The aim of this study was to evaluate Balance Adolescent Lifestyle Activities and Nutrition Choices for Energy (BALANCE), a multicomponent obesity prevention intervention targeting postpartum adolescents participating in a national home visiting child development-parent education program. METHODS: A group randomized, nested cohort design was used with 1325 adolescents, 694 intervention and 490 control, (mean age = 17.8 years, 52 % underrepresented minorities) located across 30 states. Participatory methods were used to integrate lifestyle behavior change strategies within standard parent education practice. Content targeted replacement of high-risk obesogenic patterns (e.g. sweetened drink and high fat snack consumption, sedentary activity) with positive behaviors (e.g. water intake, fruit and vegetables, increased walking). Parent educators delivered BALANCE through home visits, school based classroom-group meetings, and website activities. Control adolescents received standard child development information. Phase I included baseline to posttest (12 months); Phase II included baseline to follow-up (24 months). RESULTS: When compared to the control group, BALANCE adolescents who were ≥12 weeks postpartum were 89 % more likely (p = 0.02) to maintain a normal BMI or improve an overweight/obese BMI by 12 months; this change was not sustained at 24 months. When compared to the control group, BALANCE adolescents significantly improved fruit and vegetable intake (p = .03). In stratified analyses, water intake improved among younger BALANCE teens (p = .001) and overweight/obese BALANCE teens (p = .05) when compared to control counterparts. There were no significant differences between groups in sweetened drink and snack consumption or walking. CONCLUSION: Prevention of postpartum weight retention yields immediate health benefits for the adolescent mother and may prevent the early development or progression of maternal obesity, which contributes to the intergenerational transmission of obesity to her offspring. Implementing BALANCE through a national home visiting organization may hold promise for promoting positive lifestyle behaviors associated with interruption of the progression of maternal obesity. TRIAL REGISTRATION: Clinical Trials Registry NCT01617486 .

Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome.

Prostate cancer is the second leading cause of cancer death among United States men. However, disease aggressiveness is varied, with low-grade disease often being indolent and high-grade cancer accounting for the greatest density of deaths. Outcomes are also disparate among men with high-grade prostate cancer, with upwards of 65% having disease recurrence even after primary treatment. Identification of men at risk for recurrence and elucidation of the molecular processes that drive their disease is paramount, as these men are the most likely to benefit from multimodal therapy. We previously showed that androgen-induced expression profiles in prostate development are reactivated in aggressive prostate cancers. Herein, we report the down-regulation of one such gene, Sparcl1, a secreted protein, acidic and rich in cysteine (SPARC) family matricellular protein, during invasive phases of prostate development and regeneration. We further demonstrate a parallel process in prostate cancer, with decreased expression of SPARCL1 in high-grade/metastatic prostate cancer. Mechanistically, we demonstrate that SPARCL1 loss increases the migratory and invasive properties of prostate cancer cells through Ras homolog gene family, member C (RHOC), a known mediator of metastatic progression. By using models incorporating clinicopathologic parameters to predict prostate cancer recurrence after treatment, we show that SPARCL1 loss is a significant, independent prognostic marker of disease progression. Thus, SPARCL1 is a potent regulator of cell migration/invasion and its loss is independently associated with prostate cancer recurrence.

Overexpression of α (1,6) fucosyltransferase associated with aggressive prostate cancer.

Aberrant protein glycosylation is known to be associated with the development of cancers. The aberrant glycans are produced by the combined actions of changed glycosylation enzymes, substrates and transporters in glycosylation synthesis pathways in cancer cells. To identify glycosylation enzymes associated with aggressive prostate cancer (PCa), we analyzed the difference in the expression of glycosyltransferase genes between aggressive and non-aggressive PCa. Three candidate genes encoding glycosyltransferases that were elevated in aggressive PCa were subsequently selected. The expression of the three candidates was then further evaluated in androgen-dependent (LNCaP) and androgen-independent (PC3) PCa cell lines. We found that the protein expression of one of the glycosyltransferases, α (1,6) fucosyltransferase (FUT8), was only detected in PC3 cells, but not in LNCaP cells. We further showed that FUT8 protein expression was elevated in metastatic PCa tissues compared to normal prostate tissues. In addition, using tissue microarrays, we found that FUT8 overexpression was statistically associated with PCa with a high Gleason score. Using PC3 and LNCaP cells as models, we found that FUT8 overexpression in LNCaP cells increased PCa cell migration, while loss of FUT8 in PC3 cells decreased cell motility. Our results suggest that FUT8 may be associated with aggressive PCa and thus is potentially useful for its prognosis.

Investigation of miR-21, miR-141, and miR-221 expression levels in prostate adenocarcinoma for associated risk of recurrence after radical prostatectomy.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs that regulate a broad array of cellular and disease processes. Several miRNAs are differentially expressed in cancer and many are being considered as biomarkers for predicting clinical outcomes. Here we quantified the expression of three miRNAs, miR-21, miR-141, and miR-221, from prostate cancer surgical specimens and evaluated their association with disease recurrence after primary therapy. METHODS: A pilot nested case-control study was designed from a large cohort of men who underwent radical prostatectomy between 1993 and 2001. Total RNA was extracted from malignant prostate tissue of 59 cases (recurrence) and 59 controls. Cases and controls were matched on age, race, pathologic stage, and grade. The relative expression of each miRNA was then determined for each sample by quantitative real-time RT-PCR. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of recurrence for tertiles of miRNA expression. We noted block storage time effects and thus, used separate tertile cutpoints based on the controls by calendar year of prostatectomy. RESULTS: Lower miR-221 expression was associated with a higher risk of recurrence; the ORs were 3.21 for the lowest tertile and 2.63 for the middle tertile compared with the highest tertile of expression (P-trend = 0.02). This pattern was unchanged after multivariable adjustment (P-trend = 0.05). No statistically significant trends were observed for miR-21 or miR-141 after multivariable adjustment. CONCLUSIONS: Based on this small pilot study, men with localized prostate cancers with lower miR-221 expression may have a greater risk for recurrence after surgery.

Association of C-peptide and leptin with prostate cancer incidence in the Health Professionals Follow-up Study.

PURPOSE: Hyperinsulinemia is hypothesized to influence prostate cancer risk. Thus, we evaluated the association of circulating C-peptide, which is a marker of insulin secretion, and leptin, which is secreted in response to insulin and influences insulin sensitivity, with prostate cancer risk. METHODS: We identified prostate cancer cases (n = 1,314) diagnosed a mean of 5.4 years after blood draw and matched controls (n = 1,314) in the Health Professionals Follow-up Study. Plasma C-peptide and leptin concentrations were measured by ELISA. Odds ratios (ORs) and 95 % confidence intervals (CI) were estimated taking into account the matching factors age and history of a PSA test before blood draw and further adjusting for body mass index, diabetes, and other factors. RESULTS: Neither C-peptide (quartile [Q]4 vs. Q1: OR 1.05, 95 % CI 0.82-1.34, p-trend = 0.95) nor leptin (Q4 vs. Q1: OR 0.85, 95 % CI 0.65-1.12, p-trend = 0.14) was associated with prostate cancer risk. Further, neither was associated with risk of advanced or lethal disease (n = 156 cases; C-peptide: Q4 vs. Q1, OR 1.18, 95 % CI 0.69-2.03, p-trend = 0.78; leptin: Q4 vs. Q1, OR 0.74, 95 % CI 0.41-1.36, p-trend = 0.34). CONCLUSIONS: In this large prospective study, circulating C-peptide and leptin concentrations were not clearly associated with risk of prostate cancer overall or aggressive disease. Well into the PSA era, our findings do not appear to be supportive of the hypothesis that hyperinsulinemia influences risk of total or aggressive prostate cancer.

The association between circulating high-sensitivity C-reactive protein concentration and pathologic measures of colonic inflammation.

PURPOSE: C-reactive protein (CRP), an inflammation marker, is associated with colorectal cancer (CRC) risk in some prospective studies. Whether increased CRP is indicative of colonic inflammation, a possible CRC cause, or of other sources of inflammation (e.g., adiposity), is unknown. Thus, we evaluated the association between CRP and colonic mucosal measures of inflammation. METHODS: 151 adults undergoing colonoscopy provided a blood sample and random left- and right-side colonic mucosal biopsies. Height and weight were measured, and lifestyle information was collected. High-sensitivity C-reactive protein (hsCRP) was measured by immunoturbidometric assay. A gastrointestinal pathologist evaluated biopsies for seven colonic inflammation measures. Of 119 participants with complete information, 24 had an inflammatory bowel disease (IBD) history and were analyzed separately. We calculated the number of colonic inflammation measures present in both biopsies, and separately for right and left biopsies. Adjusted geometric mean hsCRP was calculated using linear regression, overall, by demographic and lifestyle factors, and inflammation measures. RESULTS: Most participants had ≥ 1 colonic inflammation measure (0: 21 %, 1: 39 %, ≥ 2: 40 %). Adjusted mean hsCRP did not increase with increasing number of inflammation measures (0: 1.67; 1: 1.33; ≥ 2: 1.01 mg/L; p trend = 0.21). Obese (2.03 mg/L) and overweight (1.61 mg/L) participants had higher adjusted mean hsCRP than normal-weight participants (0.62 mg/L; p trend <0.0001). Patterns were similar for participants with a history of IBD. CONCLUSIONS: hsCRP concentration was not associated with colonic inflammation, although hsCRP increased with adiposity. The hsCRP-CRC association may be explained by residual confounding by other risk factors, such as adiposity, rather than by CRP marking colonic inflammation.