Using Joint Models for Longitudinal and Time-to-Event Data to Investigate the Causal Effect of Salvage Therapy after Prostatectomy

Prostate cancer patients who undergo prostatectomy are closely monitored for recurrence and metastasis using routine prostate-specific antigen (PSA) measurements. When PSA levels rise, salvage therapies are recommended to decrease the risk of metastasis. However, due to the side effects of these therapies and to avoid over-treatment, it is important to understand which patients and when to initiate these salvage therapies. In this work, we use the University of Michigan Prostatectomy registry Data to tackle this question. Due to the observational nature of this data, we face the challenge that PSA is simultaneously a time-varying confounder and an intermediate variable for salvage therapy. We define different causal salvage therapy effects defined conditionally on different specifications of the longitudinal PSA history. We then illustrate how these effects can be estimated using the framework of joint models for longitudinal and time-to-event data. All proposed methodology is implemented in the freely-available R package JMbayes2

A Whole-Body Model for Glycogen Regulation Reveals a Critical Role for Substrate Cycling in Maintaining Blood Glucose Homeostasis

Timely, and sometimes rapid, metabolic adaptation to changes in food supply is critical for survival as an organism moves from the fasted to the fed state, and vice versa. These transitions necessitate major metabolic changes to maintain energy homeostasis as the source of blood glucose moves away from ingested carbohydrates, through hepatic glycogen stores, towards gluconeogenesis. The integration of hepatic glycogen regulation with extra-hepatic energetics is a key aspect of these adaptive mechanisms. Here we use computational modeling to explore hepatic glycogen regulation under fed and fasting conditions in the context of a whole-body model. The model was validated against previous experimental results concerning glycogen phosphorylase a (active) and glycogen synthase a dynamics. The model qualitatively reproduced physiological changes that occur during transition from the fed to the fasted state. Analysis of the model reveals a critical role for the inhibition of glycogen synthase phosphatase by glycogen phosphorylase a. This negative regulation leads to high levels of glycogen synthase activity during fasting conditions, which in turn increases substrate (futile) cycling, priming the system for a rapid response once an external source of glucose is restored. This work demonstrates that a mechanistic understanding of the design principles used by metabolic control circuits to maintain homeostasis can benefit from the incorporation of mathematical descriptions of these networks into “whole-body” contextual models that mimic in vivo conditions

Correlation between cribriform/intraductal prostatic adenocarcinoma and percent Gleason pattern 4 to a 22‐gene genomic classifier

BackgroundThe Decipher test measures expression of 22 RNA biomarkers associated with aggressive prostate cancer used to improve risk stratification of patients to help guide management. To date, Decipher’s genomic classification has not been extensively correlated with specific histologic growth patterns in prostatic adenocarcinoma. With a growing understanding of the clinical aggressiveness associated with cribriform growth pattern (CF), intraductal carcinoma (IDC), and percent Gleason pattern 4 (G4%), we sought to determine if their presence was associated with an increased genomic risk as measured by the Decipher assay.DesignClinical use of the Decipher assay was performed on the highest Gleason score (GS) tumor nodule of prostatectomy specimens from a prospective cohort of 48 patients, with GS varying from 7 through 9 to help guide clinical risk stratification. The tumors were reviewed for CF, IDC, and G4%, which were then compared to the Decipher score (0‐1) and risk stratification (high vs not high).ResultsThe presence of CF/IDC was significantly associated with Decipher risk score (P = .007), with a high‐risk Decipher score in 22% vs 56% of patients without or with CF/IDC. On binary logistic regression analysis, G4% (odds ratio [OR] 1.04 per percent increase [95% confidence interval [CI], 1.02‐1.06]; P = .0004) and CF predominant (OR, 9.60 [95%CI, 1.48‐62.16]; P = .02) were significantly associated with a high‐risk GC score. IDC did not reach significance (OR, 1.92 [95%CI, 0.65‐5.67]; P = .24).ConclusionsOur findings add to an expanding knowledge base that supports G4% and CF/IDC as molecularly unique and clinically relevant features in prostatic adenocarcinoma. These histologic features should be standardly reported as they are associated with more aggressive prostate cancer. Future work should determine the independent information of these histologic findings that are relative to genomic assessment on long‐term outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153011/1/pros23926.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153011/2/pros23926_am.pd

The Use of Social Media in Endourology: An Analysis of the 2013 World Congress of Endourology Meeting

Objective: To examine the use of social media within Endourology by reporting on its utilization during the 2013 World Congress of Endourology (WCE) annual meeting. Materials and Methods: Two social media platforms were analyzed for this study: Twitter (San Francisco, CA) and LinkedIn (Mountain View, CA). For Twitter, a third-party analysis service (Tweetreach) was used to quantitatively analyze all tweets with the hashtags #WCE2013 and #WCE13 during a 7-day period surrounding the WCE. Two reviewers independently classified tweet content using a predefined Twitter-specific classification system. Tweet sentiment was determined using sentiment analysis software (Semantria, Inc., Amherst, MA). Finally, the penetration of Twitter and LinkedIn within the WCE faculty was assessed by means of a manual search. Results: During the study period, 335 tweets had the hashtag #WCE2013 or #WCE13. Content originated from 68 users resulting in a mean of 47 tweets/day and 4.9 tweets/contributor. Conference-related tweets had a reach of 38,141 unique Twitter accounts and an online exposure of 188,629 impressions. Physicians generated the majority of the content (63%), of which 55.8% were not attending the meeting. More tweets were informative (56.7%) versus uninformative (43.3%), and 17.9% had links to an external web citation. The mean sentiment score was 0.13 (range ?0.90 to 1.80); 13.1%, 57.0%, and 29.9% of tweets were negative, neutral, and positive in sentiment, respectively. Of 302 WCE meeting faculty, 150 (49.7%) had registered LinkedIn accounts while only 52 (17.2%) had Twitter accounts, and only 19.2% tweeted during the meeting. Conclusions: Despite a relatively low number of Twitter users, tweeting about the WCE meeting dramatically increased its online exposure with dissemination of content that was mostly informative including engagement with physicians not attending the conference. While half of faculty at WCE 2013 had LinkedIn accounts, their social media footprint in Twitter was limited.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140078/1/end.2014.0329.pd

Accreting coral reefs in a highly urbanized environment

Globally, many coral reefs have fallen into negative carbonate budget states, where biological erosion exceeds carbonate production. The compounding effects of urbanization and climate change have caused reductions in coral cover and shifts in community composition that may limit the ability of reefs to maintain rates of vertical accretion in line with rising sea levels. Here we report on coral reef carbonate budget surveys across seven coral reefs in Singapore, which persist under chronic turbidity and in highly disturbed environmental conditions, with less than 20% light penetration to 2 m depth. Results show that mean net carbonate budgets across Singapore’s reefs were relatively low, at 0.63 ± 0.27 kg CaCO3 m−2 yr−1 (mean ± 1 SE) with a range from − 1.56 to 1.97, compared with the mean carbonate budgets across the Indo-Pacific of 1.4 ± 0.15 kg CaCO3 m−2 yr−1, and isolated Indian Ocean reefs pre-2016 bleaching (~ 3.7 kg CaCO3 m−2 yr−1). Of the seven reefs surveyed, only one reef had a net negative, or erosional budget, due to near total loss of coral cover (\u3c 5% remaining coral). Mean gross carbonate production on Singapore’s reefs was dominated by stress-tolerant and generalist species, with low-profile morphologies, and was ~ 3 kg m−2 yr−1 lower than on reefs with equivalent coral cover elsewhere in the Indo-Pacific. While overall these reefs are maintaining and adding carbonate structure, their mean vertical accretion potential is below both current rates of sea level rise (1993–2010), and future predictions under RCP 4.5 and RCP 8.5 scenarios. This is likely to result in an increase of 0.2–0.6 m of water above Singapore’s reefs in the next 80 yr, further narrowing the depth range over which these reefs can persist

Performance of PCA3 and TMPRSS2:ERG urinary biomarkers in prediction of biopsy outcome in the Canary Prostate Active Surveillance Study (PASS).

BackgroundFor men on active surveillance for prostate cancer, biomarkers may improve prediction of reclassification to higher grade or volume cancer. This study examined the association of urinary PCA3 and TMPRSS2:ERG (T2:ERG) with biopsy-based reclassification.MethodsUrine was collected at baseline, 6, 12, and 24 months in the multi-institutional Canary Prostate Active Surveillance Study (PASS), and PCA3 and T2:ERG levels were quantitated. Reclassification was an increase in Gleason score or ratio of biopsy cores with cancer to ≥34%. The association of biomarker scores, adjusted for common clinical variables, with short- and long-term reclassification was evaluated. Discriminatory capacity of models with clinical variables alone or with biomarkers was assessed using receiver operating characteristic (ROC) curves and decision curve analysis (DCA).ResultsSeven hundred and eighty-two men contributed 2069 urine specimens. After adjusting for PSA, prostate size, and ratio of biopsy cores with cancer, PCA3 but not T2:ERG was associated with short-term reclassification at the first surveillance biopsy (OR = 1.3; 95% CI 1.0-1.7, p = 0.02). The addition of PCA3 to a model with clinical variables improved area under the curve from 0.743 to 0.753 and increased net benefit minimally. After adjusting for clinical variables, neither marker nor marker kinetics was associated with time to reclassification in subsequent biopsies.ConclusionsPCA3 but not T2:ERG was associated with cancer reclassification in the first surveillance biopsy but has negligible improvement over clinical variables alone in ROC or DCA analyses. Neither marker was associated with reclassification in subsequent biopsies

Differential Responses of Progesterone Receptor Membrane Component-1 (Pgrmc1) and the Classical Progesterone Receptor (Pgr) to 17β-Estradiol and Progesterone in Hippocampal Subregions that Support Synaptic Remodeling and Neurogenesis

Progesterone (P4) and estradiol (E2) modulate neurogenesis and synaptic remodeling in the hippocampus during the rat estrous cycle and in response to deafferenting lesions, but little is known about the steroidal regulation of hippocampal progesterone receptors associated with these processes. We examined the neuronal expression of progesterone receptor membrane component-1 (Pgrmc1) and the classical progesterone receptor (Pgr), by in situ hybridization and immunohistochemistry. Pgr, a transcription factor, has been associated with synaptic remodeling and other major actions of P4, whereas Pgrmc1 is implicated in P4-dependent proliferation of adult neuroprogenitor cells and with rapid P4 effects on membranes. Ovariectomized adult rats were given E2, P4, or E2+P4 on two schedules: a 4-d model of the rodent estrous cycle and a 30-d model of postmenopausal hormone therapy. Pgr was hormonally responsive only in CA1 pyramidal neurons, and the induction of Pgr by E2 was partly antagonized by P4 only on the 30-d schedule. In CA3 pyramidal and dentate gyrus (DG) neurons, Pgr was largely unresponsive to all hormone treatments. In contrast to Pgr, Pgrmc1 was generally induced by E2 and/or P4 throughout the hippocampus in CA1, CA3, and DG neurons. In neuroprogenitor cells of the DG (immunopositive for bromodeoxyuridine and doublecortin), both Pgrmc1 and Pgr were detected. The differential regulation of hippocampal Pgrmc1 and Pgr by E2 and P4 may guide drug development in hormonal therapy for support of neurogenesis and synaptic regeneration.This work was supported by National Institute on Aging Grants 1PO1 AG026572 (to R.D.B.); Project 4 (to C.E.F. and T.E.M.), Animal Core A (to T.E.M.), and Analytic Core C (to L.Z.)

Growth and carbonate production of crustose coralline algae on a degraded turbid reef system

Crustose coralline algae (CCA) and other encrusting calcifiers drive carbonate production on coral reefs. However, little is known about the rates of growth and calcification of these organisms within degraded turbid reef systems. Here we deployed settlement cards (N = 764) across seven reefs in Singapore for two years to examine spatio-temporal variation in encrusting community composition and CCA carbonate production. Our results showed that CCA was the dominant encrusting taxa (63.7% ± 18.3SD) across reefs. CCA carbonate production rates (0.009–0.052 g cm−2 yr−1) were less than half of those reported for most Indo-Pacific reefs, but similar to other turbid reef systems. Highest CCA carbonate production rates were observed furthest from Singapore\u27s main shipping port, due to a relative increase in CCA cover on the offshore reefs. Our results suggest that proximity to areas of high industrialisation and ship traffic may reduce the cover of encrusting calcifying organisms and CCA production rates which may have negative, long-term implications for the stabilisation of nearshore reefs in urbanised settings

Growth Arrest‐Specific 6 (GAS6) Promotes Prostate Cancer Survival by G1 Arrest/S Phase Delay and Inhibition of Apoptosis During Chemotherapy in Bone Marrow

Prostate cancer (PCa) is known to develop resistance to chemotherapy. Growth arrest‐specific 6 (GAS6), plays a role in tumor progression by regulating growth in many cancers. Here, we explored how GAS6 regulates the cell cycle and apoptosis of PCa cells in response to chemotherapy. We found that GAS6 is sufficient to significantly increase the fraction of cells in G1 and the duration of phase in PCa cells. Importantly, the effect of GAS6 on G1 is potentiated during docetaxel chemotherapy. GAS6 altered the levels of several key cell cycle regulators, including the downregulation of Cyclin B1 (G2/M phase), CDC25A, Cyclin E1, and CDK2 (S phase entry), while the upregulation of cell cycle inhibitors p27 and p21, Cyclin D1, and CDK4. Importantly, these changes became further accentuated during docetaxel treatment in the presence of GAS6. Moreover, GAS6 alters the apoptotic response of PCa cells during docetaxel chemotherapy. Docetaxel induced PCa cell apoptosis is efficiently suppressed in PCa cell culture in the presence of GAS6 or GAS6 secreted from co‐cultured osteoblasts. Similarly, the GAS6‐expressing bone environment protects PCa cells from apoptosis within primary tumors in vivo studies. Docetaxel induced significant levels of Caspase‐3 and PARP cleavage in PCa cells, while GAS6 protected PCa cells from docetaxel‐induced apoptotic signaling. Together, these data suggest that GAS6, expressed by osteoblasts in the bone marrow, plays a significant role in the regulation of PCa cell survival during chemotherapy, which will have important implications for targeting metastatic disease. J. Cell. Biochem. 117: 2815–2824, 2016. © 2016 Wiley Periodicals, Inc.We explored how GAS6, expressed by osteoblasts, regulates the cell cycle and apoptosis in PCa cells during chemotherapy in the bone marrow. We demonstrate that GAS6 significantly increases the number of G1 arrested cells by altering signaling networks associated with G1 arrest and S phase delay. Our results suggest that GAS6 contributes to the regulation of PCa cell survival during chemotherapy in the bone marrow microenvironment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134410/1/jcb25582_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134410/2/jcb25582.pd