Spatiotemporal association of rapid urbanization and water-body distribution on hemorrhagic fever with renal syndrome: A case study in the city of Xi’an, China

Hemorrhagic fever with renal syndrome (HFRS) is a zoonosis characterized by clinical features of high fever, hemorrhage, and renal damage. China has the largest number of HFRS cases worldwide, accounting for over 90% of the total reported cases. In this paper, we used surveyed HFRS data and satellite imagery to conduct geostatistical analysis for investigating the associations of rapid urbanization, water bodies, and other factors on the spatiotemporal dynamics of HFRS from year 2005 to 2018 in Xi’an City, Northwest China. The results revealed an evident epidemic aggregation in the incidence of HFRS within Xi’an City with a phenomenal fluctuation in periodic time series. Rapid urbanization was also found to greatly affect the HFRS incidence in two different time phases. HFRS caused by urbanization influences farmers to a lesser extent than it does to non-farmers. The association of water bodies with the HFRS incidence rate was found to be higher within the radii of 696.15 m and 1575.39 m, which represented significant thresholds. The results also showed that geomatics approaches can be used for spatiotemporally investigating the HFRS dynamic characteristics and supporting effective allocations of resources to formulate strategies for preventing epidemics.

The Pharmacology of Botulinum Toxin Type A

The aim of this chapter is to structure current information clarifying the most disputable issues of botulinum neurotoxin type A (BoNT/A) pharmacology after systemic (botulism) impact and local medical application. Botulinum neurotoxin (BoNT) pharmacological features evaluated open ways to study factors affecting its biological activity: to extend/shorten its effect duration, to increase/decrease BoNT sensitivity in specific patient populations. The chapter presents unique molecular mechanisms underlying BoNT/A pharmacokinetics and pharmacodynamics: entering the body, distribution, receptor binding, translocation, mediator release suppression, zinc metabolism as well as factors affecting body sensitivity to BoNT at each of those stages. The specific biological effects of BoNT/A, which may underlie its analgesic, anticancer and anti-inflammatory effects, are described. Botulinum neurotoxin pharmacokinetics and pharmacodynamics features discussed herein represent significant clinical relevance since they determine botulinum treatment safety and effectiveness. And also they open ways to develop both BoNT-based therapies and anti-botulinic agents.

Tracking Radiolabeled Endothelial Microvesicles Predicts Their Therapeutic Efficacy: A Proof-of-Concept Study in Peripheral Ischemia Mouse Model Using SPECT/CT Imaging

Microvesicles, so-called endothelial large extracellular vesicles (LEVs), are of great interest as biological markers and cell-free biotherapies in cardiovascular and oncologic diseases. However, their therapeutic perspectives remain limited due to the lack of reliable data regarding their systemic biodistribution after intravenous administration. Methods: Applied to a mouse model of peripheral ischemia, radiolabeled endothelial LEVs were tracked and their in vivo whole-body distribution was quantified by microSPECT/CT imaging. Hindlimb perfusion was followed by LASER Doppler and motility impairment function was evaluated up to day 28 post-ischemia. Results: Early and specific homing of LEVs to ischemic hind limbs was quantified on the day of ischemia and positively correlated with reperfusion intensity at a later stage on day 28 after ischemia, associated with an improved motility function. Conclusions: This concept is a major asset for investigating the biodistribution of LEVs issued from other cell types, including cancer, thus partly contributing to better knowledge and understanding of their fate after injection.

Tumor-Targeted Drug Delivery as a Successful Approach for Reducing Doxorubicin–Induced Cardiotoxicity

Doxorubicin (DOX) is an effective chemotherapy drug used to treat many malignancies, including breast cancer. However, its clinical application is severely limited by cardiotoxicity. This study investigated if using thermo/pHsensitive magnetic nanoparticles decorated with folate (folate-poly-MNPs) as tumor-targeted drug delivery systems (DDSs) could reduce the cardiotoxicity and inflammatory properties of DOX in a rat model of breast cancer. In this study, forty rats were intravenously administered the control, DOX, DOX-poly-MNPs, and DOXfolate-poly-MNPs every 48 hours for 12 days. The cardiac health monitoring following breast cancer therapy confirmed that the novel smart DDS improved ECG pattern, left ventricular function, blood pressure parameters, and heart weight index. Moreover, it could decrease myocardial cell death by decreasing the protein levels of BAX, c-PARP1, and c-caspase-3, with concomitant downregulation of the BAX/Bcl-2 ratio, compared to the commercial DOX. In addition, the DOXfolate-poly-MNPs treatment significantly reduced NLRP3 inflammasome activation in cardiomyocytes, which was mediated by caspase-1 inhibition, and suppressed upregulation of IL-1β and IL18 protein expression to prevent myocardial damage. In this regard, the developed folatepolyMNPs could be represented as a new potential drug delivery system for breast cancer chemotherapy due to the combination of passive and active targeting aimed at preventing nonspecific body distribution, inhibiting NLRP3 inflammasome activation, and consequently reducing DOX cardiotoxicity as its main adverse effect.

Deep Brain Stimulation Treating Dystonia: A Systematic Review of Targets, Body Distributions and Etiology Classifications

Background: Deep brain stimulation (DBS) is a typical intervention treating drug-refractory dystonia. Currently, the selection of the better target, the GPi or STN, is debatable. The outcomes of DBS treating dystonia classified by body distribution and etiology is also a popular question.Objective: To comprehensively compare the efficacy, quality of life, mood, and adverse effects (AEs) of GPi-DBS vs. STN-DBS in dystonia as well as in specific types of dystonia classified by body distribution and etiology.Methods: PubMed, Embase, the Cochrane Library, and Google Scholar were searched to identify studies of GPi-DBS and STN-DBS in populations with dystonia. The efficacy, quality of life, mood, and adverse effects were quantitatively compared. Meta-regression analyses were also performed. This analysis has been registered in PROSPERO under the number CRD42020146145.Results: Thirty five studies were included in the main analysis, in which 319 patients underwent GPI-DBS and 113 patients underwent STN-DBS. The average follow-up duration was 12.48 months (range, 3–49 months). The GPI and STN groups were equivalent in terms of efficacy, quality of life, mood, and occurrence of AEs. The focal group demonstrated significantly better disability symptom improvement (P = 0.012) than the segmental and generalized groups but showed less SF-36 enhancement than the segmental group (P < 0.001). The primary groups exhibited significantly better movement and disability symptom improvements than the secondary non-hereditary group (P < 0.005), which demonstrated only disability symptom improvement compared with the secondary hereditary group (P < 0.005). The primary hereditary and idiopathic groups had a significantly lower frequency of AEs than the secondary non-hereditary group (P < 0.005). The correlation between disability symptom improvement and movement symptom improvement was also significant (P < 0.05).Conclusion: GPi-DBS and STN-DBS were both safe and resulted in excellent improvement in efficacy and quality of life in patients with dystonia. Compared with patients with segmental dystonia, patients with focal dystonia demonstrated better improvement in dystonia symptoms but less enhancement of quality of life. Those with primary dystonia had a better response to DBS in terms of efficacy than those with secondary dystonia. Patients who exhibit a significant improvement in movement symptoms might also exhibit excellent improvement in disability symptoms.

Target Occupancy Study and Whole-Body Dosimetry with a MAGL PET Ligand 11C-PF-06809247 in non-human Primates

BackgroundMonoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous system (CNS). To develop [11C]PF-06809247 into a clinically usable positron emission tomography (PET) radioligand, we assessed the brain target occupancy of a MAGL inhibitor using non-human primate (NHP). Additionally, we measured the whole-body distribution of [11C]PF-06809247 in NHP and estimated human effective radiation doses.MethodsSeven cynomolgus monkeys were enrolled for brain PET measurements. Two PET measurements were performed in each NHP: one baseline and one pretreatment condition with intravenous administration of PF-06818883, a selective MAGL inhibitor, (total of seven doses between 0.01-1.27 mg/kg). Kinetic parameters K1, k2 and k3 were estimated by an irreversible two tissue compartment (2TC) model using metabolite corrected plasma radioactivity as the input function. Ki by 2TC and Patlak analysis were calculated. The target occupancy was calculated using Ki at baseline and pretreatment conditions. Two cynomolgus monkeys were enrolled for whole-body PET measurements. Estimates of the absorbed radiation dose in humans were calculated with OLINDA/EXM 1.1 using the adult male reference model.ResultsRadioactivity was decreased in all brain regions following pretreatment with PF-06818883. Occupancy was measured as 25.4%-100.5% in a dose dependent manner. Whole-body PET showed high uptake values in the liver, small intestine, kidney, and brain. The effective dose was calculated as 4.3 μSv/MBq.Conclusions[11C]PF-06809247 is a promising PET ligand for further MAGL studies in human brain.

A brief review of the essential role of nanovehicles for improving the therapeutic efficacy of pharmacological agents against tumours

: Cancer is the leading cause of death globally. There are several differences between cancer cells and normal cells. From all the therapies, chemotherapy is the most prominent therapy to treat cancer. However, the conventional drug delivery that is used to deliver poorly aqueous soluble chemotherapeutic agents has several obstacles such as whole-body distribution, rapid excretion, degradation before reaching the infected site, side effects, etc. Nanoformulation of these aqueous insoluble agents is the emerging delivery system for targeted and increasing solubility. Among all the three methods (physical, chemical and biological) chemical and biological methods are mostly used for the synthesis of nanovehicles (NVs) of different sizes, shapes and dimensions. A passive targeting delivery system in which NVs supports the pharmacological agents (drugs/genes) is a good way for resolving the obstacles with a conventional delivery system. It enhances the therapeutic efficacy of pharmacological agents (drugs/genes). These NVs have several specific characters like small size, large surface area to volume ratio, surface functionalization, etc. However, this delivery is not able to deliver site-specific delivery of drugs. An active targeting delivery system in which pharmacological agents are loaded on NVs to attack directly on cancer cells and tissues is a superior way for delivering the pharmacological agents compared to a passive targeting delivery system. Various targeting ligands have been investigated and applied for targeting the delivery of drugs such as sugar, vitamin, antibodies, protein, peptides, etc. These targeted ligand supports to guide the NVs accumulated directly on the cancer cells with a higher level of cellular internalization compared to passive targeting and conventional delivery system.

Achieving dendritic cell subset-specific targeting in vivo by site-directed conjugation of targeting antibodies to nanocarriers

The major challenge of nanocarrier-based anti-cancer vaccination approaches is the targeted delivery of antigens and immunostimulatory agents to cells of interest, such as specific subtypes of dendritic cells (DCs), in order to induce robust antigen-specific anti-tumor responses. An undirected cell and body distribution of nanocarriers can lead to unwanted delivery to other immune cell types like macrophages reducing the vaccine efficacy. An often-used approach to overcome this issue is the surface functionalization of nanocarriers with targeting moieties, such as antibodies, mediating cell type-specific interaction. Numerous studies could successfully prove the targeting efficiency of antibody-conjugated carrier systems in vitro, however, most of them failed when targeting DCs in vivo that is partly due to cells of the reticuloendothelial system unspecifically clearing nanocarriers from the blood stream via Fc receptor ligation. Therefore, this study shows a surface functionalization strategy to site-specifically attach antibodies in an orientated direction onto the nanocarrier surface. Different DC-targeting antibodies, such as anti-CD11c, anti-CLEC9A, anti-DEC205 and anti-XCR1, were conjugated to the nanocarrier surface at their Fc domains. Anti-mouse CD11c antibody-conjugated nanocarriers specifically accumulated in the targeted organ (spleen) over time. Additionally, antibodies against CD11c and CLEC9A proved to specifically direct nanocarriers to the targeted DC subtype, conventional DCs type 1. In conclusion, site-directed antibody conjugation to nanocarriers is essential in order to avoid unspecific uptake by non-target cells while achieving antibody-specific targeting of DC subsets. This novel conjugation technique paves the way for the development of antibody-functionalized nanocarriers for DC-based vaccination approaches in the field of cancer immunotherapy.

Extracting Local Symmetry of Mono-Atomic Systems from Extended X-Ray Absorption Fine Structure Using Deep Neural Networks

In recent years, neural networks have become a new method for the analysis of extended X-ray absorption fine structure data. Due to its sensitivity to local structure, X-ray absorption spectroscopy is often used to study disordered systems and one of its more interesting property is the sensitivity not only to pair distribution function, but also to three-body distribution, which contains information on the local symmetry. In this study, by considering the case of Ni, we show that by using neural networks, it is possible to obtain not only the radial distribution function, but also the bond angle distribution between the first nearest-neighbors. Additionally, by adding appropriate configurations in the dataset used for training, we show that the neural network is able to analyze also data from disordered phases (liquid and undercooled state), detecting small changes in the local ordering compatible with results obtained through other methods.