Search

Opioids can alleviate pain and are the main drugs for clinical analgesic treatment. However, due to poor management or improper application, it may cause drug abuse, social harm, and even public health events. The United States has experienced three opioid crises in the past 20 years, which have not only adversely affected patients' health, but also caused significant economic losses and resource waste to society. This paper reviewed the process of the three opioid crises in the United States, analyzed the causes, and summarized the strategies to address the national epidemic of opioids and the enlightenment of the opioid crisis on clinical work to provide references for the management and clinical use of opioids. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by dopaminergic neurodegeneration, motor impairment and non-motor symptoms. Epidemiological and experimental investigations into potential risk factors have firmly established that dietary factor caffeine, the most-widely consumed psychoactive substance, may exerts not only neuroprotective but a motor and non-motor (cognitive) benefits in PD. These multi-benefits of caffeine in PD are supported by convergence of epidemiological and animal evidence. At least six large prospective epidemiological studies have firmly established a relationship between increased caffeine consumption and decreased risk of developing PD. In addition, animal studies have also demonstrated that caffeine confers neuroprotection against dopaminergic neurodegeneration using PD models of mitochondrial toxins (MPTP, 6-OHDA, and rotenone) and expression of α-synuclein (α-Syn). While caffeine has complex pharmacological profiles, studies with genetic knockout mice have clearly revealed that caffeine's action is largely mediated by the brain adenosine A2A receptor (A2AR) and confer neuroprotection by modulating neuroinflammation and excitotoxicity and mitochondrial function. Interestingly, recent studies have highlighted emerging new mechanisms including caffeine modulation of α-Syn degradation with enhanced autophagy and caffeine modulation of gut microbiota and gut-brain axis in PD models. Importantly, since the first clinical trial in 2003, United States FDA has finally approved clinical use of the A2AR antagonist istradefylline for the treatment of PD with OFF-time in Sept. 2019. To realize therapeutic potential of caffeine in PD, genetic study of caffeine and risk genes in human population may identify useful pharmacogenetic markers for predicting individual responses to caffeine in PD clinical trials and thus offer a unique opportunity for "personalized medicine" in PD. [ABSTRACT FROM AUTHOR]

Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors - either directly or indirectly - have now entered the clinic. However, only one adenosine receptor-specific agent - the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) - has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges. [ABSTRACT FROM AUTHOR]

Diffuse solar radiation (Rd), known as an important component of global solar radiation (Rg), is a key parameter for solar energy related applications and ecosystem photosynthesis. Some meteorological models have been developed to estimate Rd with acceptable accuracy, but their spatial scales are often small due to the limited meteorological station number. Satellite-based models provide accurate and large-scale Rg estimates. However, remote sensing estimations of Rd are often with low spatial resolutions and large uncertainties, because their methods were based on inaccurate surface and atmospheric parameters. To address these challenges, the high-spatiotemporal-resolution (half-hourly and 1-km) Rd in the United States was estimated using the top-of-atmosphere (TOA) data from the new-generation geostationary satellite Geostationary Operational Environmental Satellites (GOES-16) and the method iterative random forest (RF). The results showed that the iterative RF model had higher accuracy than the simple RF and artificial neural network (ANN) models, and using TIR (thermal infrared) bands can improve models' accuracy. The best model can estimate half-hourly Rd with the accuracy R2 = 0.88, RMSE = 37.81 W/m2, and MBE = 0.01 W/m2. Compared with the previous 0.01-degree (∼11-km) Rd product Earth Polychromatic Imaging Camera (EPIC), the GOES-16 estimated 1-km Rd had similar spatial patterns. Moreover, based on the GOES-16 estimated half-hourly and 1-km Rd in the United States, the spatiotemporal heterogeneity of Rd was quantitatively observed. The proposed approach can be used to produce more high-spatiotemporal-resolution Rd products, and these products are very helpful for many solar-related research topics and industrial applications. [Display omitted] • Diffuse solar radiation was estimated using a new satellite-based machine learning model. • Top-of-atmosphere thermal infrared information helps the estimation of diffuse solar radiation. • Half-hourly/daily 1-km diffuse solar radiation in the United States was mapped. • Spatiotemporal heterogeneity of diffuse solar radiation was quantitatively observed. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma is characterized by a poor prognosis with limited treatment and management options. Chemotherapy using gemcitabine with cisplatin is the only available first-line therapy for patients with advanced cholangiocarcinoma, although it offers only palliation and yields a median survival of < 1 year. Recently there has been a resurgence of immunotherapy studies focusing on the ability of immunotherapy to inhibit cancer growth by impacting the tumor microenvironment. Based on the TOPAZ-1 trial, the US Food and Drug Administration has approved the combination of durvalumab and gemcitabine with cisplatin as the first-line treatment of cholangiocarcinoma. However, immunotherapy, like immune checkpoint blockade, is less effective in cholangiocarcinoma than in other types of cancer. Although several factors such as the exuberant desmoplastic reaction are responsible for cholangiocarcinoma treatment resistance, existing literature on cholangiocarcinoma cites the inflammatory and immunosuppressive environment as the most common factor. However, mechanisms activating the immunosuppressive tumor microenvironment contributing to cholangiocarcinoma drug resistance are complicated. Therefore, gaining insight into the interplay between immune cells and cholangiocarcinoma cells, as well as the natural development and evolution of the immune tumor microenvironment, would provide targets for therapeutic intervention and improve therapeutic efficacy by developing multimodal and multiagent immunotherapeutic approaches of cholangiocarcinoma to overcome the immunosuppressive tumor microenvironment. In this review, we discuss the role of the inflammatory microenvironment-cholangiocarcinoma crosstalk and reinforce the importance of inflammatory cells in the tumor microenvironment, thereby highlighting the explanatory and therapeutic shortcomings of immunotherapy monotherapy and proposing potentially promising combinational immunotherapeutic strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yu, Zhu, Wang and Chen.)

After more than two decades of preclinical and clinical studies, on August 27, 2019, the US Food and Drug Administration (FDA) approved the adenosine A 2A receptor antagonist Nourianz® (istradefylline) developed by Kyowa Hakko Kirin Inc., Japan, as an add-on treatment to levodopa in Parkinson's disease (PD) with "OFF" episodes. This milestone achievement is the culmination of the decade-long clinical studies of the effects of istradefylline in more than 4000 PD patients. Istradefylline is the first non-dopaminergic drug approved by FDA for PD in the last two decades. This approval also provides some important lessons to be remembered, namely, concerning disease-specific adenosine signaling and targeting subpopulation of PD patients. Importantly, this approval paves the way to foster entirely novel therapeutic opportunities for adenosine A 2A receptor antagonists, such as neuroprotection or reversal of mood and cognitive deficits in PD and other neuropsychiatric diseases.