Introduction
The tumor microenvironment (TME) plays a crucial role in therapy response and modulation of immunologic surveillance. Adjuvant immunotherapy has recently been introduced in post-surgery ...treatment of locally advanced esophageal cancer (EC) with residual pathological disease after neoadjuvant chemoradiotherapy (nCRT). F-18 fluorodeoxyglucose positron emission tomography/computed tomography (
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F-FDG-PET/CT) remains a valuable imaging tool to assess therapy response and to visualize metabolic TME; however, there is still a paucity in understanding the interaction between the TME and nCRT response. This systematic review investigated the potential of TME biomarkers and
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F-FDG-PET/CT features to predict pathological and clinical response (CR) after nCRT in EC.
Methods
A literature search of the Medline and Embase electronic databases identified 4190 studies. Studies regarding immune and metabolic TME biomarkers and
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F-FDG-PET/CT features were included for predicting pathological response (PR) and/or CR after nCRT. Separate analyses were performed for
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F-FDG-PET/CT markers and these TME biomarkers.
Results
The final analysis included 21 studies—10 about immune and metabolic markers alone and 11 with additional
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F-FDG-PET/CT features. High CD8 infiltration before and after nCRT, and CD3 and CD4 infiltration after nCRT, generally correlated with better PR. A high expression of tumoral or stromal programmed death-ligand 1 (PD-L1) after nCRT was generally associated with poor PR. Moreover, total lesion glycolysis (TLG) and metabolic tumor volume (MTV) of the primary tumor were potentially predictive for clinical and PR.
Conclusion
CD8, CD4, CD3, and PD-L1 are promising immune markers in predicting PR, whereas TLG and MTV are potential
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F-FDG-PET/CT features to predict clinical and PR after nCRT in EC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Forest restoration is a prime goal within the 2021–2030 UN “Decade of Ecosystem Resoration”. As part of these activities, natural regeneration has to be promoted for biological as well as ...for economic reasons. For this, the processes of seed dispersal, seed predation and germination have to be understood in the original as well as in degraded vegetation formations. We used seed removal experiments to assess post-dispersal processes that influence recruitment along a gradient of forest degradation in Madagascar analyzing seeds of three animal dispersed tree species. The percentage of seeds consumed or dispersed, declined from forest (28.6%) to degraded forest (17.2%) to savanna (10.8%). Only three out of 1080 seeds were cached and remained intact during the 14-day experiment. All three seeds were cached in the forest habitat and none in the degraded forest and savanna. The low percentage of seeds removed may be due to the lack of endemic rodents caching seeds, as only introduced rats were recorded in the area. The species-poor fauna of potential secondary seed dispersers of the region and especially in the degraded areas might represent an obstacle for diverse regeneration in degraded regions of Madagascar.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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Simulation of HME processes is a valuable tool for increased process understanding and ease of scale-up. However, the experimental determination of all required input parameters is ...tedious, namely the melt rheology of the amorphous solid dispersion (ASD) in question. Hence, a procedure to simplify the application of hot-melt extrusion (HME) simulation for forming amorphous solid dispersions (ASD) is presented. The commercial 1D simulation software Ludovic® was used to conduct (i) simulations using a full experimental data set of all input variables including melt rheology and (ii) simulations using model-based melt viscosity data based on the ASDs glass transition and the physical properties of polymeric matrix only. Both types of HME computation were further compared to experimental HME results. Variation in physical properties (e.g. heat capacity, density) and several process characteristics of HME (residence time distribution, energy consumption) among the simulations and experiments were evaluated. The model-based melt viscosity was calculated by using the glass transition temperature (Tg) of the investigated blend and the melt viscosity of the polymeric matrix by means of a Tg-viscosity correlation. The results of measured melt viscosity and model-based melt viscosity were similar with only few exceptions, leading to similar HME simulation outcomes. At the end, the experimental effort prior to HME simulation could be minimized and the procedure enables a good starting point for rational development of ASDs by means of HME. As model excipients, Vinylpyrrolidone-vinyl acetate copolymer (COP) in combination with various APIs (carbamazepine, dipyridamole, indomethacin, and ibuprofen) or polyethylene glycol (PEG 1500) as plasticizer were used to form the ASDs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Chronic fatigue, in its various manifestations, frequently co-occur with pain, sleep disturbances and depression and is a non-communicable condition which is rapidly becoming endemic worldwide. ...However, it is handicapped by a lack of objective definitions and diagnostic measures. This has prompted the World Health Organization to develop an international instrument whose intended purpose is to improve quality of life (QOL), with energy and fatigue as one domain of focus. To complement this objective, the interface between detoxification, the exposome, and xenobiotic-sensing by nuclear receptors that mediate induction of biotransformation-linked genes, is stimulating renewed attention to a rational development of strategies to identify the metabolic profiles in complex multifactorial conditions like fatigue. Here we present results from a seven-year study of a cohort of 576 female patients suffering from low to high levels of chronic fatigue, in which phase I and phase II biotransformation was assessed. The biotransformation profiles used were based on hepatic detoxification challenge tests through oral caffeine, acetaminophen and acetylsalicylic acid ingestion coupled with oxidative stress analyses. The interventions indicated normal phase I but increased phase II glucuronidation and glycination conjugation. Complementarity was indicated between a fatigue scale, medical symptoms and associated energy-related parameters by application of Chi-square Automatic Interaction Detector (CHAID) analysis. The presented study provides a cluster of data from which we propose that multidisciplinary inputs from the combination of a fatigue scale, medical symptoms and biotransformation profiles provide the rationale for the development of a comprehensive laboratory instrument for improved diagnostics and personalized interventions in patients with chronic fatigue with a view to improving their QOL.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cultivated bacteria such as actinomycetes are a highly useful source of biomedically important natural products. However, such 'talented' producers represent only a minute fraction of the entire, ...mostly uncultivated, prokaryotic diversity. The uncultured majority is generally perceived as a large, untapped resource of new drug candidates, but so far it is unknown whether taxa containing talented bacteria indeed exist. Here we report the single-cell- and metagenomics-based discovery of such producers. Two phylotypes of the candidate genus 'Entotheonella' with genomes of greater than 9 megabases and multiple, distinct biosynthetic gene clusters co-inhabit the chemically and microbially rich marine sponge Theonella swinhoei. Almost all bioactive polyketides and peptides known from this animal were attributed to a single phylotype. 'Entotheonella' spp. are widely distributed in sponges and belong to an environmental taxon proposed here as candidate phylum 'Tectomicrobia'. The pronounced bioactivities and chemical uniqueness of 'Entotheonella' compounds provide significant opportunities for ecological studies and drug discovery.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Gums produced by trees after injuries are valuable food resources for several primate species. Yet, information on the chemical characteristics of gum is scant and inconsistent. We use gums consumed ...by lemurs (strepsirrhine primates of Madagascar) as an example to illustrate their possible nutritive and pharmaceutical properties. Exudates from 45 tree species of the dry forests of Madagascar contained 0.38–23.29% protein, 0.46–65.62% sugar, and 0.39–11.86 kJ/g of energy in dry matter. Exemplified by the lemur species Microcebus griseorufus, gum consumption increased with increasing sugar and energy content but was unrelated to protein. But lemurs also fed on gum with very low protein and energy content, suggesting that these exudates were consumed for other reasons. Disk diffusion tests with exudates from five out of 22 tree species consumed by lemurs showed antibacterial activity against Micrococcus spp. and/or Staphylococcus aureus. Exudates with antibacterial activity had lower protein, sugar, and energy contents than samples without antibacterial properties. GC-MS analyses revealed several components with antimicrobial effects that would have the potential for self-medication. This might explain the consumption of gum with very low nutritive value. Possible medicinal effects of tree exudates deserve further attention in view of their pharmaceutical applicability for animals and humans alike.
Therapy with low-dose amitriptyline is commonly used to treat painful diabetic peripheral neuropathy. There is a knowledge gap, however, regarding the role of variable CYP2D6-mediated drug metabolism ...and side effects (SEs). We aimed to generate pilot data to demonstrate that SEs are more frequent in patients with variant CYP2D6 alleles.
To that end, 31 randomly recruited participants were treated with low-dose amitriptyline for painful diabetic peripheral neuropathy and their CYP2D6 gene sequenced.
Patients with predicted normal or ultra-rapid metabolizer phenotypes presented with less SEs compared with individuals with decreased CYP2D6 activity.
Hence, CYP2D6 genotype contributes to treatment outcome and may be useful for guiding drug therapy. Future investigations in a larger patient population are planned to support these preliminary findings.
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In this study, the impact of binder distribution on the tabletability and compactibility of granules produced by twin-screw melt granulation was investigated. To this end, two grades ...of dicalcium phosphate anhydrous (fine and coarse) were used as model substances (filler) in combination with two grades of poloxamer (fine and coarse) as melt binder at three concentrations. For the fine filler, granule forming followed the immersion mechanism, whereas a distribution mechanism was observed in case of the coarse filler. Compared to the granules prepared with the coarse filler, the tabletability of granules prepared with the fine filler increased more pronouncedly compared to the corresponding physical mixtures (PM). In general, tabletability, compressibility and compactibility depended predominantly on the distribution of the binder in the tablet, and the homogeneity of distribution correlated with increased tensile strength. Binder distribution was analysed using scanning electron microscopy combined with energy-dispersive X-ray analysis (SEM/EDX) and quantified by image-analysis of the tablet surface. PMs in general varied in tabletability. However, even at tabletability similar to the granules, all PMs suffered from poor flow and/or segregation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Wines from three important wine-producing regions, Stellenbosch, Robertson, and Swartland, in the Western Cape Province of South Africa, were analyzed by ICP−MS and the elemental composition used in ...multivariate statistical analysis to classify the wines according to geographical origin. The method is based on the assumption that the provenance soil is an important contributor to the trace element composition of a wine. A total of 40 elements were determined in 40 wines. Of these, 20 elements: Li, B, Mg, Al, Si, Cl, Sc, Mn, Ni, Ga, Se, Rb, Sr, Nb, Cs, Ba, La, W, Tl, and U showed differences in their means across the three areas. In a stepwise discriminant analysis procedure, functions based on linear combinations of the log-transformed element concentrations of Al, Mn, Rb, Ba, W, and Tl were generated to correctly classify wines from each region. In an alternative approach, a pairwise discriminant analysis procedure, not previously used in wine provenance studies, was tested. In this procedure, the classification was done in three steps, with each step classifying a wine as coming from a certain region or not. The combination of elements characterizing wines from a particular region was different in each region. The discriminant functions were based on the following elements: Al, Mn, Rb, Ba, and W for Stellenbosch; Se, Rb, Cs, and Tl for Robertson; and Al, Mn, Rb, Sr, Ba, and Tl for Swartland. After this procedure, the classification of the wines into one of the groups was 100% successful. Keywords: Wine analysis; fingerprinting; multivariate statistical analysis; provenance; multi-element analysis; ICP−MS
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
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