MR-guided focused ultrasound (MRgFUS), in combination with intravenous microbubble administration, has been applied for focal temporary BBB opening in patients with neurodegenerative disorders and ...brain tumors. MRgFUS could become a therapeutic tool for drug delivery of putative neurorestorative therapies. Treatment for Parkinson's disease with dementia (PDD) is an important unmet need. We initiated a prospective, single-arm, non-randomized, proof-of-concept, safety and feasibility phase I clinical trial (NCT03608553), which is still in progress. The primary outcomes of the study were to demonstrate the safety, feasibility and reversibility of BBB disruption in PDD, targeting the right parieto-occipito-temporal cortex where cortical pathology is foremost in this clinical state. Changes in β-amyloid burden, brain metabolism after treatments and neuropsychological assessments, were analyzed as exploratory measurements. Five patients were recruited from October 2018 until May 2019, and received two treatment sessions separated by 2-3 weeks. The results are set out in a descriptive manner. Overall, this procedure was feasible and reversible with no serious clinical or radiological side effects. We report BBB opening in the parieto-occipito-temporal junction in 8/10 treatments in 5 patients as demonstrated by gadolinium enhancement. In all cases the procedures were uneventful and no side effects were encountered associated with BBB opening. From pre- to post-treatment, mild cognitive improvement was observed, and no major changes were detected in amyloid or fluorodeoxyglucose PET. MRgFUS-BBB opening in PDD is thus safe, reversible, and can be performed repeatedly. This study provides encouragement for the concept of BBB opening for drug delivery to treat dementia in PD and other neurodegenerative disorders.
Due to the growing demand of enantiomerically pure compounds, as well as the increasing strict safety, quality and environmentally requirements of industrial synthetic processes, the development of ...more sustainable, healthy and economically attractive strategies for the synthesis of chiral biologically active molecules is still an open challenge in the pharmaceutical industry. In this context, the biotransformations field has emerged as a real alternative to traditional synthetic routes, because of the exquisite chemo-, regio- and enantioselectivities commonly displayed by enzymes; thus, biocatalysis is becoming a widespread methodology for the synthesis of chiral compounds, not only at laboratory scale, but also at industrial scale. As hydrolases and oxido-reductases are the most employed enzymes, this review is focused on describing several industrial processes based on the use of these enzymes for obtaining chiral compounds useful for the pharmaceutical industry.
Summary
Patients infected with HIV are at increased risk for cardiovascular disease despite successful antiretroviral therapy. Likewise, chronic hepatitis C virus (HCV) infection is associated with ...extrahepatic complications, including cardiovascular disease. However the risk of cardiovascular disease has not been formally examined in HIV/HCV‐coinfected patients. A retrospective study was carried out to assess the influence of HCV coinfection on the risk of cardiovascular events in a large cohort of HIV‐infected patients recruited since year 2004. A composite event of cardiovascular disease was used as an endpoint, including myocardial infarction, angina pectoris, stroke or death due to any of them. A total of 1136 patients (567 HIV‐monoinfected, 70 HCV‐monoinfected and 499 HIV/HCV‐coinfected) were analysed. Mean age was 42.7 years, 79% were males, and 46% were former injection drug users. Over a mean follow‐up of 79.4 ± 21 months, 3 patients died due to cardiovascular disease, whereas 29 suffered a first episode of coronary ischaemia or stroke. HIV/HCV‐coinfected patients had a greater incidence of cardiovascular disease events and/or death than HIV‐monoinfected individuals (4% vs 1.2%, P = 0.004) and HCV‐monoinfected persons (4% vs 1.4%, P = 0.5). After adjusting for demographics, virological parameters and classical cardiovascular disease risk factors (smoking, hypertension, diabetes, high LDL cholesterol), both HIV/HCV coinfection (HR 2.91; CI 95%: 1.19–7.12; P = 0.02) and hypertension (HR 3.65; CI 95%: 1.34–9.94; P = 0.01) were independently associated with cardiovascular disease events and/or death in HIV‐infected patients. Chronic hepatitis C and hypertension are independently associated with increased cardiovascular disease risk in HIV‐infected patients. Therefore, treatment of chronic hepatitis C should be prioritized in HIV/HCV‐coinfected patients regardless of any liver fibrosis staging.
In nature, solar energy is captured by different types of light harvesting protein-pigment complexes. Two of these photoactivatable proteins are bacteriorhodopsin (bR), which utilizes a retinal ...moiety to function as a proton pump, and photosystem I (PSI), which uses a chlorophyll antenna to catalyze unidirectional electron transfer. Both PSI and bR are well characterized biochemically and have been integrated into solar photovoltaic (PV) devices built from sustainable materials. Both PSI and bR are some of the best performing photosensitizers in the bio-sensitized PV field, yet relatively little attention has been devoted to the development of more sustainable, biocompatible alternative counter electrodes and electrolytes for bio-sensitized solar cells. Careful selection of the electrolyte and counter electrode components is critical to designing bio-sensitized solar cells with more sustainable materials and improved device performance. This work explores the use of poly (3,4-ethylenedioxythiophene) (PEDOT) modified with multi-walled carbon nanotubes (PEDOT/CNT) as counter electrodes and aqueous-soluble bipyridine cobalt
complexes as direct redox mediators for both PSI and bR devices. We report a unique counter electrode and redox mediator system that can perform remarkably well for both bio-photosensitizers that have independently evolved over millions of years. The compatibility of disparate proteins with common mediators and counter electrodes may further the improvement of bio-sensitized PV design in a way that is more universally biocompatible for device outputs and longevity.
The vulnerability of some cancer cells to oxidative signals is a therapeutic target for the rational design of new anticancer agents. In addition to their well characterized effects on cell division, ...many cytotoxic anticancer agents can induce oxidative stress by modulating levels of reactive oxygen species (ROS) such as the superoxide anion radical, hydrogen peroxide and hydroxyl radicals. Tumour cells are particularly sensitive to oxidative stress as they typically have persistently higher levels of ROS than normal cells due to the dysregulation of redox balance that develops in cancer cells in response to increased intracellular production of ROS or depletion of antioxidant proteins. In addition, excess ROS levels potentially contribute to oncogenesis by the mediation of oxidative DNA damage. There are several anticancer agents in development that target cellular redox regulation. The overall cellular redox state is regulated by three systems that modulate cellular redox status by counteracting free radicals and ROS, or by reversing the formation of disulfides; two of these are dependent on glutathione and the third on thioredoxin. Drugs targeting S-glutathionylation have direct anticancer effects via cell signalling pathways and inhibition of DNA repair, and have an impact on a wide range of signalling pathways. Of these agents, NOV-002 and canfosfamide have been assessed in phase III trials, while a number of others are undergoing evaluation in early phase clinical trials. Alternatively, agents including PX-12, dimesna and motexafin gadolinium are being developed to target thioredoxin, which is overexpressed in many human tumours, and this overexpression is associated with aggressive tumour growth and poorer clinical outcomes. Finally, arsenic derivatives have demonstrated antitumour activity including antiproliferative and apoptogenic effects on cancer cells by pro-oxidant mechanisms, and the induction of high levels of oxidative stress and apoptosis by an as yet undefined mechanism. In this article we review anticancer drugs currently in development that target cellular redox activity to treat cancer.
We recently demonstrated that human BM cells can be treated in vitro with defined growth factors to induce the rapid generation of myeloid-derived suppressor cells (MDSCs), hereafter defined as ...BM-MDSCs. Indeed, combination of G-CSF + GM-CSF led to the development of a heterogeneous mixture of immature myeloid cells ranging from myeloblasts to band cells that were able to suppress alloantigen- and mitogen-stimulated T lymphocytes. Here, we further investigate the mechanism of suppression and define the cell subset that is fully responsible for BM-MDSC–mediated immune suppression. This population, which displays the structure and markers of promyelocytes, is however distinct from physiologic promyelocytes that, instead, are devoid of immuosuppressive function. In addition, we demonstrate that promyelocyte-like cells proliferate in the presence of activated lymphocytes and that, when these cells exert suppressive activity, they do not differentiate but rather maintain their immature phenotype. Finally, we show that promyelocyte-like BM-MDSCs are equivalent to MDSCs present in the blood of patients with breast cancer and patients with colorectal cancer and that increased circulating levels of these immunosuppressive myeloid cells correlate with worse prognosis and radiographic progression.
The objective of this study was to analyze the impact of incorporating enteric methane into the breeding objective of dairy cattle in Spain, and to evaluate both genetic and economic response of ...traits in the selection index under 4 scenarios: (1) the current ICO (Spanish total merit index), used as benchmark; (2) a hypothetical penalization of methane emissions through a carbon tax; (3) considering methane as a net energy loss for the animal; and (4) desired genetic response to reduce methane production by 20% in 10 yr. A bio-economic model was developed to derive the economic values for production and methane traits in each scenario. The estimated economic values for methane were estimated at −€1.21/kg and −€0.32/kg for scenarios 2 and 3, respectively. When merged with other traits in the selection index, methane had less economic importance (1–5%) than milk protein yield (39–42%) or milk fat yield (27–28%). Under these scenarios, selection resulted in an unfavorable response in methane emissions when it was included with an economic weight, with an increase in methane estimated from 0.52 to 0.60 kg/cow per year. Small differences in total profit per cow per year were observed between indices. The incorporation of methane production into the breeding objective had a negligible effect on production, with minor reductions in the expected genetic gain for fat and protein yields and in total economic benefits. However, total methane emissions in the dairy industry in Spain were estimated to decrease between 2 and 5% in the next 10 yr due to positive genetic trends for milk yield and an expected decrease in the total number of dairy cows. Additionally, methane intensity per 1 billion liters of milk would decrease in all scenarios. The uncertainty in the genetic parameters of methane and in carbon prices were tested in a sensitivity analysis, resulting in small deviations from the benchmark scenario. A major effect was observed only under the desired genetic response scenario. In this case, it was possible to achieve a 20% reduction of methane production in 10 yr via selective breeding but at the expense of a larger ad hoc weight (33%) of methane in the selection index and decelerating the genetic gain for production traits from 6 to 18%. This study shows the potential of including environmental traits in the selection indices while retaining populations profitable for producers.
Abstract Objective To analyse the impact of liver resection (LR) in patients with Hepatocellular Carcinoma (HCC) within the Barcelona-Clinic-Liver-Cancer (BCLC)-B stage. Methods Analysis of patients ...with BCLC-B HCC treated with LR or transarterial chemoembolization (TACE) between 2007 and 2012 in our hospital. Survival/recurrence analyses were performed by log-rank tests and Cox multivariate models. Further analyses were specifically obtained for the HCC subclassification (B1–2–3–4) proposed recently. Results Eighty patients were treated (44-TACE/36-LR). Number of nodules was 1.8(1.1), being multinodular in 50% of cases. Although resected patients had a higher hospital stay than those who underwent TACE (14 ± 13 vs 7 ± 6; P = 0.004), the rate and severity of complications was lower measured by Dindo–Clavien scale (P < 0.05). Overall survival was 40% with a median follow-up of 29.5 months (0.07–96.9). Five-years survival rates were 62.9%, 28.1% and 15.4%, respectively (P = 0.004) for B1, B2 and B3–4 stages. Cox model showed that only total bilirubin OR = 2.055(1.23–3.44) and BCLC subclassification B3–4 OR = 2.439(1.04–5.7) and B2 OR = 2.79(1.35–5.77) vs B1 were independent predictors of 5-years-survival. In B1 patients, surgical approach led a significant decrease in 5-years recurrence-rate (25% vs 60%; P = 0.018). In the surgical subgroup analysis, better results were observed if well/moderate differentiation combined with no microvascular-invasion (VI) in 5-years-survival (84.6%; P = 0.001) and -recurrence (23.1%; P = 0.041), respectively. These survival and recurrence trends were remarkable in B1 stages. Conclusions Management of Intermediate BCLC-B HCC stage should be more complex and include updated criteria regarding B-stage subclassifications, VI and tumour differentiation. Modern surgical resection would offer improved survival benefit with acceptable safety in selected BCLC-B stage patients.
A Reissner-Nordström black hole (BH) is superradiantly unstable against spherical perturbations of a charged scalar field enclosed in a cavity, with a frequency lower than a critical value. We use ...numerical relativity techniques to follow the development of this unstable system-dubbed a charged BH bomb-into the nonlinear regime, solving the full Einstein-Maxwell-Klein-Gordon equations, in spherical symmetry. We show that (i) the process stops before all the charge is extracted from the BH, and (ii) the system settles down into a hairy BH: a charged horizon in equilibrium with a scalar field condensate, whose phase is oscillating at the (final) critical frequency. For a low scalar field charge q, the final state is approached smoothly and monotonically. For large q, however, the energy extraction overshoots, and an explosive phenomenon, akin to a bosenova, pushes some energy back into the BH. The charge extraction, by contrast, does not reverse.
Records of methane emissions from 1,501 cows on 14 commercial farms in 4 regions of Spain were collected from May 2018 to June 2019. Methane concentrations (MeC) were measured using a nondispersive ...infrared methane detector installed within the feed bin of the automatic milking system during 14- to 21-d periods. Rumination time (RT; min/d) was collected using collars with a tag that registered time (minutes) spent eating and ruminating. The means of MeC and methane production (MeP) were 1,254.28 ppm and 182.49 g/d, respectively; mean RT was 473.38 min/d. Variance components for MeC, MeP, and RT were estimated with REML using pedigree and genomic information in a single-step model. Heritabilities for MeC and MeP were 0.11 and 0.12, respectively. Rumination time showed a slightly larger heritability estimate (0.17). The genetic correlation between MeP and MeC was high (>0.95), suggesting that selection on either trait would lead to a positive correlated response on the other. Negative correlations were estimated between RT and MeC (−0.24 ± 0.38) and MeP (−0.43 ± 0.35). Methane concentration and MeP had slightly positive correlations with milk yield (0.17 ± 0.39 and 0.21 ± 0.36), protein percentage (0.08 ± 0.32 and 0.30 ± 0.45), protein yield (0.22 ± 0.41 and 0.31 ± 0.35), fat percentage (0.02 ± 0.40 and 0.27 ± 0.36), and fat yield (0.27 ± 0.28 and 0.29 ± 0.28) from bivariate analyses. Rumination time had positive correlations with milk yield (0.41 ± 0.75) and protein yield (0.26 ± 0.57) and negative correlations with fat yield (−0.45 ± 0.32), protein percentage (−0.15 ± 0.38), and fat percentage (−0.40 ± 0.47). A positive approximated genetic correlation was estimated between fertility and MeC (0.10 ± 0.05) and MeP (0.18 ± 0.05), resulting in slightly higher CH4 production when selecting for better fertility days open estimated breeding values (EBV) are expressed with mean 100 and SD 10, inversely related to days from calving to conception; that is, greater days open EBV implies better fertility. Positive correlations were also estimated for stature with MeC and MeP (0.30 ± 0.04 and 0.43 ± 0.04, respectively). Other type traits (chest width, udder depth, angularity, and capacity) were positively correlated with methane traits, possibly because of higher milk yield and higher feed intake from these animals. Rumination time showed positive EBV correlations with production traits and type traits, and negative correlations with somatic cell count and body condition score. Based on the genetic correlations and heritabilities estimated in this study, methane is measurable and heritable, and estimates of genetic correlations suggest no strong opposition to current breeding objectives in Spanish Holsteins.
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