Genomic aberrations of the PTEN tumour suppressor gene are among the most common in prostate cancer. Inactivation of PTEN by deletion or mutation is identified in ∼20% of primary prostate tumour ...samples at radical prostatectomy and in as many as 50% of castration-resistant tumours. Loss of phosphatase and tensin homologue (PTEN) function leads to activation of the PI3K-AKT (phosphoinositide 3-kinase-RAC-alpha serine/threonine-protein kinase) pathway and is strongly associated with adverse oncological outcomes, making PTEN a potentially useful genomic marker to distinguish indolent from aggressive disease in patients with clinically localized tumours. At the other end of the disease spectrum, therapeutic compounds targeting nodes in the PI3K-AKT-mTOR (mechanistic target of rapamycin) signalling pathway are being tested in clinical trials for patients with metastatic castration-resistant prostate cancer. Knowledge of PTEN status might be helpful to identify patients who are more likely to benefit from these therapies. To enable the use of PTEN status as a prognostic and predictive biomarker, analytically validated assays have been developed for reliable and reproducible detection of PTEN loss in tumour tissue and in blood liquid biopsies. The use of clinical-grade assays in tumour tissue has shown a robust correlation between loss of PTEN and its protein as well as a strong association between PTEN loss and adverse pathological features and oncological outcomes. In advanced disease, assessing PTEN status in liquid biopsies shows promise in predicting response to targeted therapy. Finally, studies have shown that PTEN might have additional functions that are independent of the PI3K-AKT pathway, including those affecting tumour growth through modulation of the immune response and tumour microenvironment.
We present a novel copolymer-based, uniform porous carbon microfiber (PCMF) formed via wet-spinning for significantly improved electrochemical detection. Carbon fiber (CF), fabricated from a ...polyacrylonitrile (PAN) precursor, is commonly used in batteries or for electrochemical detection of neurochemicals due to its biplanar geometry and desirable edge plane sites with high surface free energy and defects for enhanced analyte interactions. Recently, the presence of pores within carbon materials has presented interesting electrochemistry leading to detection improvements; however, there is currently no method to uniformly create pores on a carbon microfiber surface impacting a broad range of electrochemical applications. Here, we synthesized controllable porous carbon fibers from a spinning dope of the copolymers PAN and poly(methyl methacrylate) (PMMA) in dimethylformamide via wet spinning for the first time. PMMA serves as a sacrificial block introducing macropores of increased edge-plane character on the fiber. Methods were optimized to produce porous CFs at similar dimensions to traditional CF. We prove that an increase in porosity enhances the degree of disorder on the surface, resulting in significantly improved detection capabilities with fast-scan cyclic voltammetry. Local trapping of analytes at porous geometries enables electrochemical reversibility with improved sensitivity, linear range of detection, and measurement temporal resolution. Overall, we demonstrate the utility of a copolymer synthetic method for PCMF fabrication, providing a stable, controlled macroporous fiber framework with enhanced edge plane character. This work will significantly advance fundamental investigations of how pores and edge plane sites influence electrochemical detection.
Background
The rapidly expanding clinical adaptation of prostate-specific membrane antigen (PSMA)-targeted PET imaging in the evaluation of patients with prostate cancer has placed an increasing onus ...on understanding both the potential pearls of interpretation as well as limitations of this new technique. As with any new molecular imaging modality, accurate characterization of abnormalities on PSMA-targeted PET imaging can be accomplished only if one is aware of the normal distribution pattern, physiological variants of radiotracer uptake, and potential sources of false-positive and false-negative imaging findings. In recent years, a growing number of reports have come to light describing incidental non-prostatic benign or malignant pathologies with high uptake on PSMA-targeted PET imaging. In this review, we have summarized the published literature regarding the potential pearls and technical and interpretive pitfalls of this imaging modality. Knowledge of these limitations can increase the confidence of interpreting physicians and thus improve patient care.
Conclusions
As PSMA-targeted PET is expected to be evaluated in larger prospective trials, the dissemination of potential diagnostic pitfalls and the biologic underpinning of those findings will be of increased importance.
The oligometastatic state has been proposed as an intermediate stage of cancer spread between localized disease and widespread metastases. With improvements in diagnostic modalities such as ...functional imaging, oligometastatic prostate cancer is being diagnosed with greater frequency than ever before. Furthermore, the paradigm for treatment of advanced prostate cancers is shifting toward a more aggressive approach. Many questions surround the understanding of the process and consequences of oligometastasis, meaning that the contemporary literature offers a wide variety of definitions of oligometastatic prostate cancer. Until genomic data exist to provide a biological component to the definition of oligometastatic disease, a clinical diagnosis made on the basis of up to five extrapelvic lesions is reasonable for use. Retrospective studies suggest that interventions such as radical prostatectomy and local or metastasis-directed radiotherapy can be performed in the metastatic setting with minimal risk of toxic effects. These therapies seem to decrease the need for subsequent palliative interventions, but insufficient data are available to draw reliable conclusions regarding their effect on survival. Thus, a protocol for clinicians to manage the patient presenting with oligometastatic prostate cancer would be a useful clinical tool.
Active surveillance (AS) is a treatment option for men with very low-risk prostate cancer (PCa); however, favorable outcomes achieved for men in AS are based on cohorts that under-represent African ...American (AA) men. To explore whether race-based health disparities exist among men with very low-risk PCa, we evaluated oncologic outcomes of AA men with very low-risk PCa who were candidates for AS but elected to undergo radical prostatectomy (RP).
We studied 1,801 men (256 AA, 1,473 white men, and 72 others) who met National Comprehensive Cancer Network criteria for very low-risk PCa and underwent RP. Presenting characteristics, pathologic data, and cancer recurrence were compared among the groups. Multivariable modeling was performed to assess the association of race with upgrading and adverse pathologic features.
AA men with very low-risk PCa had more adverse pathologic features at RP and poorer oncologic outcomes. AA men were more likely to experience disease upgrading at prostatectomy (27.3% v 14.4%; P < .001), positive surgical margins (9.8% v 5.9%; P = .02), and higher Cancer of the Prostate Risk Assessment Post-Surgical scoring system (CAPRA-S) scores. On multivariable analysis, AA race was an independent predictor of adverse pathologic features (odds ratio, OR, 3.23; P = .03) and pathologic upgrading (OR, 2.26; P = .03).
AA men with very low-risk PCa who meet criteria for AS but undergo immediate surgery experience significantly higher rates of upgrading and adverse pathology than do white men and men of other races. AA men with very low-risk PCa should be counseled about increased oncologic risk when deciding among their disease management options.
17β-Estradiol (E2) is a ubiquitously expressed hormone that is active in a wide range of neuroprotective and regenerative roles throughout the brain. In particular, it is a well-known dopamine (DA) ...regulator and is responsible for modulating the expression of dopaminergic receptors and transporters. Recent studies point to E2 release occurring on a rapid time scale and having impacts on DA activity within seconds to minutes. As such, tools capable of monitoring the release of both E2 and DA in real time are essential for developing an accurate understanding of their interactive roles in neurotransmission and regulation. Currently, no analytical techniques capable of codetection of both analytes with high sensitivity, spatiotemporal resolution, extended monitoring, and minimal tissue damage exist. We describe a modified waveform using fast-scan cyclic voltammetry that is capable of low nanomolar detection of both DA and E2 on a subsecond time scale. Both analytes have limits of detection at or below 30 nM and high sensitivity: 11.31 ± 0.55 nA/μM for DA and 9.47 ± 0.36 nA/μM for E2. The waveform is validated in a tissue matrix, confirming its viability for measurement in a biologically relevant setting. This is the first method capable of codetection of fluctuations in DA and E2 with the temporal, spatial, and sensitivity requirements necessary for studying real-time neurochemical signaling.
B7 homolog 3 (B7-H3; CD276), a tumor-associated antigen and possible immune checkpoint, is highly expressed in prostate cancer (PCa) and is associated with early recurrence and metastasis. ...Enoblituzumab is a humanized, Fc-engineered, B7-H3-targeting antibody that mediates antibody-dependent cellular cytotoxicity. In this phase 2, biomarker-rich neoadjuvant trial, 32 biological males with operable intermediate to high-risk localized PCa were enrolled to evaluate the safety, anti-tumor activity and immunogenicity of enoblituzumab when given before prostatectomy. The coprimary outcomes were safety and undetectable prostate-specific antigen (PSA) level (PSA
) 1 year postprostatectomy, and the aim was to obtain an estimate of PSA
with reasonable precision. The primary safety endpoint was met with no notable unexpected surgical or medical complications, or surgical delay. Overall, 12% of patients experienced grade 3 adverse events and no grade 4 events occurred. The coprimary endpoint of the PSA
rate 1 year postprostatectomy was 66% (95% confidence interval 47-81%). The use of B7-H3-targeted immunotherapy in PCa is feasible and generally safe and preliminary data suggest potential clinical activity. The present study validates B7-H3 as a rational target for therapy development in PCa with larger studies planned. The ClinicalTrials.gov identifier is NCT02923180.
Guanosine and adenosine are important neuromodulators in the brain and work in cooperation to mitigate the effects of stroke, traumatic injury, and other neurological events. Both purines can act on ...slow (minutes to hours) and rapid (milliseconds to seconds) time scales. A guanosine–adenosine interaction has been proposed in which guanosine modulates adenosine levels, and the two work together to control glutamate neurotransmission. Traditional methods to codetect purines, such as HPLC with microdialysis, are robust but lack the temporal resolution necessary to quantify release in real time. Fast-scan cyclic voltammetry (FSCV) has been used to detect guanosine and adenosine independently, but codetection has not been possible. Here, we developed a novel “scalene waveform” to codetect guanosine and adenosine with nanomolar limits of detection in real time with FSCV. The scalene waveform uses a slow rate (100 V/s) on the forward scan and the conventional rate (400 V/s) on the back scan; potentials go from −0.4 to 1.45 V and back to −0.4 V. The scan rates were optimized to increase the separation of the oxidative peaks for guanosine and adenosine. The temporal separation of the primary peaks was increased (4.6 ± 0.1)-fold at the scalene waveform compared to the traditional waveform. Both exogenously applied guanosine and adenosine and endogenous transient release were detected at the scalene waveform in rat-brain slices. We show the first method for codetecting guanosine and adenosine using FSCV, which can be used to study the guanosine–adenosine interaction and better understand their cooperative therapeutic effects.
Adenosine is a neuroprotective agent that inhibits neuronal activity and modulates neurotransmission. Previous research has shown adenosine gradually accumulates during pathologies such as stroke and ...regulates neurotransmission on the minute-to-hour time scale. Our lab developed a method using carbon-fiber microelectrodes to directly measure adenosine changes on a sub-second time scale with fast-scan cyclic voltammetry (FSCV). Recently, adenosine release lasting a couple of seconds has been found in murine spinal cord slices. In this study, we characterized spontaneous, transient adenosine release in vivo, in the caudate-putamen and prefrontal cortex of anesthetized rats. The average concentration of adenosine release was 0.17±0.01 µM in the caudate and 0.19±0.01 µM in the prefrontal cortex, although the range was large, from 0.04 to 3.2 µM. The average duration of spontaneous adenosine release was 2.9±0.1 seconds and 2.8±0.1 seconds in the caudate and prefrontal cortex, respectively. The concentration and number of transients detected do not change over a four hour period, suggesting spontaneous events are not caused by electrode implantation. The frequency of adenosine transients was higher in the prefrontal cortex than the caudate-putamen and was modulated by A1 receptors. The A1 antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine, 6 mg/kg i.p.) increased the frequency of spontaneous adenosine release, while the A1 agonist CPA (N(6)-cyclopentyladenosine, 1 mg/kg i.p.) decreased the frequency. These findings are a paradigm shift for understanding the time course of adenosine signaling, demonstrating that there is a rapid mode of adenosine signaling that could cause transient, local neuromodulation.
Abstract Prostate cancer (PCa) subtypes based on ETS gene expression have been described. Recent studies suggest there are racial differences in tumor location, with PCa located anteriorly more often ...among African-American (AA) compared to Caucasian-American (CA) men. In this retrospective analysis of a multi-institutional cohort treated by radical prostatectomy (179 CA, 121 AA), we evaluated associations among molecular subtype, race, anatomic tumor location, and androgen receptor (AR) signaling. Subtype (m-ERG+ , m-ETS+ , m-SPINK1+ , or triple-negative) was determined using distribution-based outlier analysis. AR signaling was investigated using gene expression profiling of canonical AR targets. m-ERG+ was more common in CA than AA men (47% vs 22%, p < 0.001). AA men were more likely to be m-SPINK1+ (13% vs 7%; p = 0.069) and triple-negative (50% vs 37%; p = 0.043). Racial differences in molecular subtypes did not persist when tumors were analyzed by location, suggesting a biologically important relationship between tumor location and subtype. Accordingly, anterior tumor location was associated with higher Decipher scores and lower global AR signaling. Patient summary This study demonstrates associations among patient race, prostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships.
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