An In Vivo Screen Identifies PYGO2 as a Driver for Metastatic Prostate Cancer

Advanced prostate cancer displays conspicuous chromosomal instability and rampant copy number aberrations, yet the identity of functional drivers resident in many amplicons remain elusive. Here, we implemented a functional genomics approach to identify new oncogenes involved in prostate cancer progression. Through integrated analyses of focal amplicons in large prostate cancer genomic and transcriptomic datasets as well as genes upregulated in metastasis, 276 putative oncogenes were enlisted into an in vivo gain-of-function tumorigenesis screen. Among the top positive hits, we conducted an in-depth functional analysis on Pygopus family PHD finger 2 (PYGO2), located in the amplicon at 1q21.3. PYGO2 overexpression enhances primary tumor growth and local invasion to draining lymph nodes. Conversely, PYGO2 depletion inhibits prostate cancer cell invasion in vitro and progression of primary tumor and metastasis in vivo In clinical samples, PYGO2 upregulation associated with higher Gleason score and metastasis to lymph nodes and bone. Silencing PYGO2 expression in patient-derived xenograft models impairs tumor progression. Finally, PYGO2 is necessary to enhance the transcriptional activation in response to ligand-induced Wnt/β-catenin signaling. Together, our results indicate that PYGO2 functions as a driver oncogene in the 1q21.3 amplicon and may serve as a potential prognostic biomarker and therapeutic target for metastatic prostate cancer.Significance: Amplification/overexpression of PYGO2 may serve as a biomarker for prostate cancer progression and metastasis. Cancer Res; 78(14); 3823-33. ©2018 AACR

A Review of Full-endoscopic Interlaminar Discectomy for Lumbar Disc Disease: A Historical and Technical Overview

Lumbar disc disease is an age or trauma-related disc injury with the clinical symptoms such as lower back pain or sciatica. Surgical treatment is the reliable and effective solution only if the symptoms grow progressively worse and conservative treatments fail. The purpose of spinal surgery is to remove the real pain generator and maintain physiological spinal alignment. Traditionally, patients after discectomy tend to experience the risk of postoperative intervertebral disc degeneration with intractable low back pain. Therefore, the minimally invasive techniques have rapidly developed in the past decades and brought revolutionary progress on techniques modification. Herein, we report the historical overview of the interlaminar full-endoscopic lumbar discectomy and technical evolution based on the review of literature

Is it reliable to assess visual attention of drivers affected by Parkinson's disease from the backseat?—a simulator study

BACKGROUND: Current methods of determining licence retainment or cancellation is through on-road driving tests. Previous research has shown that occupational therapists frequently assess drivers' visual attention while sitting in the back seat on the opposite side of the driver. Since the eyes of the driver are not always visible, assessment by eye contact becomes problematic. Such procedural drawbacks may challenge validity and reliability of the visual attention assessments. In terms of correctly classified attention, the aim of the study was to establish the accuracy and the inter-rater reliability of driving assessments of visual attention from the back seat. Furthermore, by establishing eye contact between the assessor and the driver through an additional mirror on the wind screen, the present study aimed to establish how much such an intervention would enhance the accuracy of the visual attention assessment. METHODS: Two drivers with Parkinson's disease (PD) and six control drivers drove a fixed route in a driving simulator while wearing a head mounted eye tracker. The eye tracker data showed where the foveal visual attention actually was directed. These data were time stamped and compared with the simultaneous manual scoring of the visual attention of the drivers. In four of the drivers, one with Parkinson's disease, a mirror on the windscreen was set up to arrange for eye contact between the driver and the assessor. Inter-rater reliability was performed with one of the Parkinson drivers driving, but without the mirror. RESULTS: Without mirror, the overall accuracy was 56% when assessing the three control drivers and with mirror 83%. However, for the PD driver without mirror the accuracy was 94%, whereas for the PD driver with a mirror the accuracy was 90%. With respect to the inter-rater reliability, a 73% agreement was found. CONCLUSION: If the final outcome of a driving assessment is dependent on the subcategory of a protocol assessing visual attention, we suggest the use of an additional mirror to establish eye contact between the assessor and the driver. The clinicians' observations on-road should not be a standalone assessment in driving assessments. Instead, eye trackers should be employed for further analyses and correlation in cases where there is doubt about a driver's attention

Human Influenza A (H5N1) Cases, Urban Areas of People’s Republic of China, 2005–2006

We investigated potential sources of infection for 6 confirmed influenza A (H5N1) patients who resided in urban areas of People’s Republic of China. None had known exposure to sick poultry or poultry that died from illness, but all had visited wet poultry markets before illness

Plasma Heme Oxygenase-1 Concentration in Relation to Impaired Glucose Regulation in a Non-Diabetic Chinese Population

Background: Our previous study has recently shown that plasma heme oxygenase-1 (HO-1), a stress-responsive protein, is elevated in individuals with type 2 diabetes. The current study aimed to examine the association between plasma HO-1 concentration and impaired glucose regulation (IGR) in non-diabetic individuals. Methods: We conducted a case-control study including a total of 865 subjects (262 IGR individuals and 603 healthy controls) in a Chinese population. Basic characteristics were collected by questionnaire and standardized anthropometric measurements. Plasma HO-1 concentration was determined by ELISA. Results: Plasma HO-1 concentration was significantly increased in IGR individuals compared with healthy controls (1.34 (0.81–2.29) ng/ml vs 0.98 (0.56–1.55) ng/ml, P,0.001). After adjustment for age, sex, and BMI, the ORs for IGR in the highest quartile of plasma HO-1 concentrations, compared with the lowest, was 3.42 (95 % CI 2.11–5.54; P for trend,0.001). The trend remained significant even after additional adjustment for smoking, alcohol drinking, hypertension, family history of diabetes, lipid profiles and C-reactive protein. In the receiver-operating characteristic curve analysis, addition of plasma HO-1 concentration to a model with known risk factors yielded significantly improved discriminative value for IGR (area under the curves 0.75 (95 % CI 0.71–0.78) vs. 0.72 (95 % CI 0.69–0.76); P for difference = 0.026)

Diammonium Glycyrrhizinate Upregulates PGC-1α and Protects against Aβ1–42-Induced Neurotoxicity

Mitochondrial dysfunction is a hallmark of beta-amyloid (Aβ)-induced neurotoxicity in Alzheimer's disease (AD), and is considered an early event in AD pathology. Diammonium glycyrrhizinate (DG), the salt form of Glycyrrhizin, is known for its anti-inflammatory effects, resistance to biologic oxidation and membranous protection. In the present study, the neuroprotective effects of DG on Aβ1–42-induced toxicity and its potential mechanisms in primary cortical neurons were investigated. Exposure of neurons to 2 µM Aβ1–42 resulted in significant viability loss and cell apoptosis. Accumulation of reactive oxygen species (ROS), decreased mitochondrial membrane potential, and activation of caspase-9 and caspase-3 were also observed after Aβ1–42 exposure. All these effects induced by Aβ1–42 were markedly reversed by DG treatment. In addition, DG could alleviate lipid peroxidation and partially restore the mitochondrial function in Aβ1–42-induced AD mice. DG also significantly increased the PGC-1α expression in vivo and in vitro, while knocking down PGC-1α partially blocked the protective effects, which indicated that PGC-1α contributed to the neuroprotective effects of DG. Furthermore, DG significantly decreased the escape latency and search distance and increased the target crossing times of Aβ1–42-induced AD mice in the Morris water maze test. Therefore, these results demonstrated that DG could attenuate Aβ1–42-induced neuronal injury by preventing mitochondrial dysfunction and oxidative stress and improved cognitive impairment in Aβ1–42-induced AD mice, indicating that DG exerted potential beneficial effects on AD

Evaluation of individual and ensemble probabilistic forecasts of COVID-19 mortality in the United States

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks

The United States COVID-19 Forecast Hub dataset

Academic researchers, government agencies, industry groups, and individuals have produced forecasts at an unprecedented scale during the COVID-19 pandemic. To leverage these forecasts, the United States Centers for Disease Control and Prevention (CDC) partnered with an academic research lab at the University of Massachusetts Amherst to create the US COVID-19 Forecast Hub. Launched in April 2020, the Forecast Hub is a dataset with point and probabilistic forecasts of incident cases, incident hospitalizations, incident deaths, and cumulative deaths due to COVID-19 at county, state, and national, levels in the United States. Included forecasts represent a variety of modeling approaches, data sources, and assumptions regarding the spread of COVID-19. The goal of this dataset is to establish a standardized and comparable set of short-term forecasts from modeling teams. These data can be used to develop ensemble models, communicate forecasts to the public, create visualizations, compare models, and inform policies regarding COVID-19 mitigation. These open-source data are available via download from GitHub, through an online API, and through R packages