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Prostaglandins, the bioactive lipids generated from the metabolism of arachidonic acid through cyclooxygenases, have potent effects on many constituents of tumor microenvironments. In this review, we will describe the formation and activities of prostaglandins in the context of the tumor microenvironment. We will discuss the regulation of cancer-associated fibroblasts and immune constituents by prostaglandins and their roles in immune escapes during tumor progression. The review concludes with future perspectives on improving the efficacy of immunotherapy through repurposing non-steroid anti-inflammatory drugs and other prostaglandin modulators.

Arm movement kinematics may provide a more sensitive way to assess neurorehabilitation outcomes than existing metrics. However, measuring arm kinematics in people with stroke can be challenging for traditional optical tracking systems due to non-ideal environments, expense, and difficulty performing required calibration. Here, we present two open-source methods, one using inertial measurement units (IMUs) and another using virtual reality (Vive) sensors, for accurate measurements of wrist position with respect to the shoulder during reaching movements in people with stroke. We assessed the accuracy of each method during a 3D reaching task. We also demonstrated each method’s ability to track two metrics derived from kinematics-sweep area and smoothness-in people with chronic stroke. We computed correlation coefficients between the kinematics estimated by each method when appropriate. Compared to a traditional optical tracking system, both methods accurately tracked the wrist during reaching, with mean signed errors of 0.09 ± 1.81 cm and 0.48 ± 1.58 cm for the IMUs and Vive, respectively. Furthermore, both methods’ estimated kinematics were highly correlated with each other (p < 0.01). By using relatively inexpensive wearable sensors, these methods may be useful for developing kinematic metrics to evaluate stroke rehabilitation outcomes in both laboratory and clinical environments.

PurposeMegestrol acetate is a synthetic progestogen used to treat some cancers and cancer-associated cachexia, but its potential interactions with other drugs are not well known. This study aims to determine the regulation of drug metabolizing enzymes by megestrol acetate.MethodsPrimary human hepatocytes were treated and analyzed by PCR array to identify genes involved in drug metabolism that are impacted by megestrol acetate. P450 3A4 (CYP3A4) reporter gene assay and HPLC analyses of nifedipine metabolites were used to determine CYP3A4 gene expression and activities. Competitive ligand binding assay was used to determine the affinity of megestrol acetate toward human pregnane x receptor (hPXR). Electrophoretic mobility shift assay and mammalian two hybrid assay were used to determine the mechanism of megestrol to activate hPXR.ResultsThe levels and activities of CYP3A4 were significantly induced (> 4-folds) by megestrol acetate in human hepatocytes and HepG2 cells. Megestrol treatment induced CYP3A4 through the activation of hPXR, a ligand-activated transcription factor that plays a role in drug metabolism and transport. Other tested nuclear receptors showed no response. The mechanism studies showed that megestrol activated hPXR by binding to the ligand binding domain (LBD) of hPXR and increasing the recruitment of the cofactors such as steroid receptor cofactor (SRC-1).ConclusionThe results suggest that megestrol acetate is a specific inducer of CYP3A4 mediated by hPXR and therefore has the potential to cause drug interactions, especially in the co-administration with drugs that are substrates of CYP3A4.

Purpose In our center, five Gamma Knife proceduralists differed in opioid administration practices prior to Leksell frame removal, providing the opportunity to improve the care of patients with brain metastases by studying whether opioid medications improve pain scores and patient satisfaction during Gamma Knife treatment in a prospective, pseudorandomized fashion. Methods We prospectively administered a questionnaire to patients undergoing Gamma Knife Radiosurgery for metastases between November, 2017 and July, 2018. Using multivariable methods, we assessed whether opioid pain medication administration influenced the change in pain scores after frame removal, and whether they influenced patient satisfaction on how often their pain was controlled, and their overall satisfaction. Results We included 142 patients. Mean age was 65.2 ± 10.8 years and 52.7% were female. Morphine was the most commonly administered medication. Pain increases were greater around frame removal than placement. Opioids were not associated with any difference in the change in pain scores before and after frame removal, or patient satisfaction. Patients with higher pre-removal pain scores had smaller increases in pain scores after removal; they also had worse pain control and overall satisfaction with their treatment. Conclusion Morphine administration prior to frame removal did not improve pain scores or pain control satisfaction. Absence of efficacy may be related to delayed onset of action, and stronger and faster-acting agents should be explored. Pre-removal pain scores were associated with decreased pain control and overall satisfaction, further identifying earlier and stronger pain treatment as a potential area for improvement.

•Repeat imaging has limited utility in low-risk, mild traumatic brain injury patients.•No patient with low-risk, mild traumatic brain injury had neurosurgical intervention.•Performing serial neurological examinations may be a safe, cost-effective alternative.•Transferring low-risk, mild traumatic brain injury patients may be unnecessary. Intracranial hemorrhage (ICH) is frequently found on computed tomography (CT) after mild traumatic brain injury (mTBI) prompting transfer to centers with neurosurgical coverage and repeat imaging to confirm hemorrhage stability. Studies suggest routine repeat imaging has little utility in patients with minimal ICH, no anticoagulant/antiplatelet use, and no neurological decline. Additionally, it is unclear which mTBI patients benefit from transfer for neurosurgery consultation. The authors sought to assess the clinical utility and cost effectiveness of routine repeat head CTs and transfer to tertiary centers in patients with low-risk, mTBI. Retrospective evaluation of patients receiving a neurosurgical consultation for TBI during a 4-year period was performed at a level 1 trauma center. Patients were stratified according to risk for neurosurgical intervention based on their initial clinical evaluation and head CT. Only patients with low-risk, mTBI were included. Of 531 patients, 119 met inclusion criteria. Eighty-eight (74.0 %) received two or more CTs. Direct cost of repeat imaging was $273,374. Thirty-seven (31.1 %) were transferred to our facility from hospitals without neurosurgical coverage, costing $61,384. No patient had neurosurgical intervention or mTBI-related in-hospital mortality despite enlarging ICH on repeat CT in three patients. Two patients had mTBI related 30-day readmission for seizure without ICH expansion. Routine repeat head CT or transfer of low-risk, mTBI patients to a tertiary center did not result in neurosurgical intervention. Serial neurological examinations may be a safe, cost-effective alternative to repeat imaging for select mTBI patients. A large prospective analysis is warranted for further evaluation.

Planning and executing motor behaviors requires coordinated neural activity among multiple cortical and subcortical regions of the brain. Phase-amplitude coupling between the high-gamma band amplitude and the phase of low frequency oscillations (theta, alpha, beta) has been proposed to reflect neural communication, as has synchronization of low-gamma oscillations. However, coupling between low-gamma and high-gamma bands has not been investigated. Here, we measured phase-amplitude coupling between low- and high-gamma in monkeys performing a reaching task and in humans either performing finger movements or speaking words aloud. We found significant coupling between low-gamma phase and high-gamma amplitude in multiple sensorimotor and premotor cortices of both species during all tasks. This coupling modulated with the onset of movement. These findings suggest that interactions between the low and high gamma bands are markers of network dynamics related to movement and speech generation.Competing Interest StatementThe authors have declared no competing interest.

Emerging evidence suggests that myocyte enhancer factor 2 (MEF2) transcription factors act as effectors of neurogenesis in the brain, with MEF2C the predominant isoform in developing cerebrocortex. Here, we show that conditional knockout of Mef2c in nestin-expressing neural stem/progenitor cells (NSCs) impaired neuronal differentiation in vivo, resulting in aberrant compaction and smaller somal size. NSC proliferation and survival were not affected. Conditional null mice surviving to adulthood manifested more immature electrophysiological network properties and severe behavioral deficits reminiscent of Rett syndrome, an autism-related disorder. Our data support a crucial role for MEF2C in programming early neuronal differentiation and proper distribution within the layers of the neocortex.

Androgen receptor (AR) signaling regulates the development and homeostasis of male reproductive organs, including the prostate. Deregulation of AR and AR coregulators, expression, or activity is involved in the initiation of prostate cancer and contributes to the transition of the disease to hormone-refractory stage. The ubiquitous βArrestin proteins are now recognized as bona fide adapters and signal transducers with target effectors found in both the cytosol and nucleus. Here, we provide evidence that βArrestin2 forms a complex with AR and acts as an AR corepressor in androgen-dependent prostate cancer cells. Accordingly, the forced overexpression of βArrestin2 diminishes, and knockdown of βArrestin2 expression with RNAi increases the androgen-induced prostate-specific antigen (PSA) gene expression. βArrestin2 serves as an adapter, bringing into close proximity the Mdm2 E3 ligase and AR, thereby promoting AR ubiquitylation and degradation. Human prostate tissues evidence an inverse relationship between the expression of βArrestin2 and AR activity: glands that express high levels of βArrestin2 exhibit low expression of PSA, and those glands that express low levels of βArrestin2 evidence elevated PSA levels. We conclude that βArrestin2 acts as a corepressor of AR by serving as a scaffold for Mdm2 leading to the AR ubiquitylation and degradation.

The Dark Energy Spectroscopic Instrument (DESI) survey will measure spectroscopic redshifts for millions of galaxies across roughly \\(14,000 \\, deg^2\\) of the sky. Cross-correlating targets in the DESI survey with complementary imaging surveys allows us to measure and analyze shear distortions caused by gravitational lensing in unprecedented detail. In this work, we analyze a series of mock catalogs with ray-traced gravitational lensing and increasing sophistication to estimate systematic effects on galaxy-galaxy lensing estimators such as the tangential shear \\(_t\\) and the excess surface density \\(\\). We employ mock catalogs tailored to the specific imaging surveys overlapping with the DESI survey: the Dark Energy Survey (DES), the Hyper Suprime-Cam (HSC) survey, and the Kilo-Degree Survey (KiDS). Among others, we find that fiber incompleteness can have significant effects on galaxy-galaxy lensing estimators but can be corrected effectively by up-weighting DESI targets with fibers by the inverse of the fiber assignment probability. Similarly, we show that intrinsic alignment and lens magnification are expected to be statistically significant given the precision forecasted for the DESI year-1 data set. Our study informs several analysis choices for upcoming cross-correlation studies of DESI with DES, HSC, and KiDS.