Despite molecular selection, patients (pts) with RAS wildtype mCRC represent a heterogeneous population including diversity in metastatic spread. We investigated metastatic patterns for their ...prognostic and predictive impact on maintenance therapy with 5‐fluorouracil/folinic acid ± panitumumab. The study population was stratified according to (1) number of involved metastatic sites (single vs multiple organ metastasis), liver‐limited disease vs (2) liver metastasis plus one additional site, and (3) vs liver metastasis plus ≥two additional sites. Kaplan‐Meier method and Cox regressions were used to correlate efficacy endpoints. Single organ metastasis was observed in 133 pts (53.6%) with 102 pts (41.1%) presenting with liver‐limited disease, while multiple organ metastases were reported in 114 pts (46.0). Multiple compared to single organ metastases were associated with less favorable PFS (HR 1.48, 95% CI 1.13‐1.93; P = .004) and OS (HR 1.37, 95% CI 0.98‐1.93; P = .068) of maintenance therapy. While metastatic spread involving one additional extrahepatic site was not associated with clearly impaired survival compared to liver‐limited disease, pts with liver metastasis plus ≥two additional sites demonstrated less favorable PFS (HR 1.92, 95% CI 1.30‐2.83; P < .001), and OS (HR 2.38, 95% CI 1.51‐3.76; P < .001) of maintenance therapy. Pmab‐containing maintenance therapy appeared active in both pts with multiple (HR 0.58; 95% CI, 0.39‐0.86; P = .006) as well as to a lesser numerical extent in pts with single organ metastasis (HR 0.83; 95% CI, 0.57‐1.21; P = .332; Interaction P = .183). These data may support clinical decisions when EGFR‐based maintenance therapy is considered.
What's new?
A variety of patterns in metastasis can occur in RAS wildtype metastatic colorectal cancer (mCRC). Heterogeneity in metastatic spread, however, challenges prognostic evaluation for patients with these tumors. Here, the prognostic and therapeutic significance of different metastatic patterns in RAS wildtype mCRC was investigated in patients on maintenance therapy with 5‐fluorouracil/folinic acid, with or without panitumumab. In patients who presented with liver‐limited disease, spread to one additional organ had limited impact on survival. Survival was less favorable for metastasis to multiple organs. Maintenance therapy involving panitumumab had greater effect in RAS wildtype mCRC patients with multiple organ metastasis.
Understanding of Alzheimer's disease (AD) pathophysiology requires molecular assessment of how key pathological factors, specifically amyloid β (Aβ) plaques, influence the surrounding ...microenvironment. Here, neuronal lipids have been implicated in Aβ plaque pathology, though the lipid microenvironment in direct proximity to Aβ plaques is still not fully resolved. A further challenge is the microenvironmental molecular heterogeneity, across structurally polymorphic Aβ features, such as diffuse, immature, and mature, fibrillary aggregates, whose resolution requires the integration of advanced, multimodal chemical imaging tools. Herein, we used matrix‐assisted laser desorption/ionization trapped ion mobility spectrometry time‐of‐flight based mass spectrometry imaging (MALDI TIMS TOF MSI) in combination with hyperspectral confocal microscopy to probe the lipidomic microenvironment associated with structural polymorphism of Aβ plaques in transgenic Alzheimer's disease mice (tgAPPSWE). Using on tissue and ex situ validation, TIMS MS/MS facilitated unambiguous identification of isobaric lipid species that showed plaque pathology‐associated localizations. Integrated multivariate imaging data analysis revealed multiple, Aβ plaque‐enriched lipid patterns for gangliosides (GM), phosphoinositols (PI), phosphoethanolamines (PE), and phosphatidic acids (PA). Conversely, sulfatides (ST), cardiolipins (CL), and polyunsaturated fatty acid (PUFA)‐conjugated phosphoserines (PS), and PE were depleted at plaques. Hyperspectral amyloid imaging further delineated the unique distribution of PA and PE species to mature plaque core regions, while PI, LPI, GM2 and GM3 lipids localized to immature Aβ aggregates present within the periphery of Aβ plaques. Finally, we followed AD pathology‐associated lipid changes over time, identifying plaque‐ growth and maturation to be characterized by peripheral accumulation of PI (18:0/22:6). Together, these data demonstrate the potential of multimodal imaging approaches to overcome limitations associated with conventional advanced MS imaging applications. This allowed for the differentiation of both distinct lipid components in a complex micro‐environment as well as their correlation to disease‐relevant amyloid plaque polymorphs.
Cover Image for this issue:
https://doi.org/10.1111/jnc.15390
Lipid species have long been implicated in Alzheimer’s disease pathology and beta‐amyloid (Aβ) plaque formation. Using trapped ion mobility spectrometry‐based mass spectrometry imaging (TIMS MSI) allowed us to resolve and unambiguously identify isobaric lipid species in situ that showed distinct localization patterns towards Aβ plaques. TIMS MSI was integrated with hyperspectral, confocal microscopy using conformation‐sensitive amyloid probes. Multivariate modeling of multimodal chemical imaging data identified lipid accumulations towards structurally distinct Aβ plaque pathology. These patterns were found to generally persist with progressing plaque pathology, while distinct polyunsaturated fatty acid‐conjugated phosphoinositol showed increased deposition with Aβ plaque maturation.
Cover Image for this issue:
https://doi.org/10.1111/jnc.15390
Organic short and medium chain fatty acids are used in diets for piglets because they have an impact on the digestive processes and the intestinal microbiota. In this study, 48 pens (2 piglets/pen) ...were assigned randomly to 4 diets, without additive (control), with organic acids (OA; 0.416% fumaric and 0.328% lactic acid), with medium chain fatty acids (MCFA; 0.15% caprylic and capric acid), and a combination of OA and MCFA, to assess changes in the gastrointestinal microbiota with 12 pens per diet. Eight to nine piglets from each group were euthanized after 4 wk. Organic acids, MCFA, and pH in the digesta were determined and the intestinal microbiota was quantified by real-time PCR. The different diets had no effect on the growth performance. Concentration of added fumaric acid was below the detection limit in the upper small intestine whereas the concentration of lactic acid in the digesta was not affected by the treatments. The added MCFA was recovered in the MCFA treated groups in the stomach, but the concentrations declined in the upper small intestine. Concentration of short chain fatty acids was reduced in the colon digesta in piglets fed diets with OA compared with those fed unsupplemented diets (P = 0.029). The MCFA resulted in a pH reduction of the digesta, likely because of the effect on bacterial acid production. The addition of OA increased cell counts of Bacteroides-Porphyromonas-Prevotella group and clostridial clusters XIVa, I, and IV in the stomach, the clostridial cluster XIVa in the jejunum, and Bacteroides-Porphyromonas-Prevotella in the ileum and reduced counts of Streptococcus spp. in the colon (P < 0.05). The MCFA induced only minor changes in the gastrointestinal microbiota but increased cell counts for the Escherichia-Hafnia-Shigella group in the jejunum and the clostridial cluster XIVa in the colon digesta (P < 0.05). In the colon of piglets fed diets with organic OA, reduced mean cell counts of STb (est-II) positive Escherichia coli were found. In conclusion, OA and MCFA had effects on the intestinal microecology in piglets. The decrease of the intestinal pH and the reduction of E. coli virulence genes by OA could make the combination of short chain fatty acids and MCFA as interesting gut flora modifiers, which can eventually prevent postweaning diarrhea.
The epidemiology of invasive fungal disease (IFD) due to filamentous fungi other than Aspergillus may be changing. We analysed clinical, microbiological and outcome data in Australian patients to ...determine the predisposing factors and identify determinants of mortality. Proven and probable non-Aspergillus mould infections (defined according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria) from 2004 to 2012 were evaluated in a multicentre study. Variables associated with infection and mortality were determined. Of 162 episodes of non-Aspergillus IFD, 145 (89.5%) were proven infections and 17 (10.5%) were probable infections. The pathogens included 29 fungal species/species complexes; mucormycetes (45.7%) and Scedosporium species (33.3%) were most common. The commonest comorbidities were haematological malignancies (HMs) (46.3%) diabetes mellitus (23.5%), and chronic pulmonary disease (16%); antecedent trauma was present in 21% of cases. Twenty-five (15.4%) patients had no immunocompromised status or comorbidity, and were more likely to have acquired infection following major trauma (p <0.01); 61 (37.7%) of cases affected patients without HMs or transplantation. Antifungal therapy was administered to 93.2% of patients (median 68 days, interquartile range 19–275), and adjunctive surgery was performed in 58.6%. The all-cause 90-day mortality was 44.4%; HMs and intensive-care admission were the strongest predictors of death (both p <0.001). Survival varied by fungal group, with the risk of death being significantly lower in patients with dematiaceous mould infections than in patients with other non-Aspergillus mould infections. Non-Aspergillus IFD affected diverse patient groups, including non-immunocompromised hosts and those outside traditional risk groups; therefore, definitions of IFD in these patients are required. Given the high mortality, increased recognition of infections and accurate identification of the causative agent are required.
Ion chromatography was used to investigate the stability of LiTFSI in water at various temperatures. The addition of HNO3, LiOH and HTFSI as pH adjustment measures was studied and the long-term ...stability of the electrolytes at different pH values stored at 60°C investigated. A minor degradation product was found upon the addition of HNO3 to the electrolyte and identified via electrospray ionization mass spectrometry. The compound was formed only in traces immediately after the acidification and the concentration is not increasing over time. Electrochemical stability window investigations, using two different methods, indicate the wide applicable potential range of the aqueous LiTFSI electrolyte, which, combined with the high stability of the TFSI anion vs. hydrolysis and elevated temperature, smoothens the path for a possible application in aqueous lithium-ion systems.
Background
Recombinant allergens offer a tool for improving specific immunotherapy (SIT).
Objective
To find the optimal dose of a new hypoallergenic folding variant of recombinant Bet v 1 (rBet v ...1‐FV) as SIT for patients with birch pollen allergy.
Methods
Before SIT, thirty‐seven adult patients were exposed for eight hours in an environmental exposure chamber (EEC) to birch pollen at an average concentration of 3500 ± 500 grains/m3, then randomized to four maintenance dose groups of rBet v 1‐FV and one placebo group: 20 μg (n = 7), 80 μg (n = 8), 160 μg (n = 7), 320 μg (n = 8), and placebo (n = 7). Patients were treated for 10 weeks with weekly injections and then re‐exposed in the EEC. The optimal dose for SIT was assessed using efficacy results from the EEC, IgG responses, and tolerability.
Results
Thirty‐six patients were evaluable for efficacy assessment. The total symptom score significantly decreased in all active groups compared with placebo (−18.8% for placebo patients; −71.9%, P = 0.0022 for 20 μg; −75.6%, P = 0.0007 for 80 μg; −81.8%, P = 0.0009 for 160 μg; −78.3%, P = 0.0003 for 320 μg). IgG1 increased significantly in all active groups compared to placebo. All four active doses were well tolerated, no serious adverse event occurred; two Grade II reactions, according to EAACI classification, were observed, one in each of the 160‐ and 320‐μg groups.
Conclusions
Considering efficacy, immunological response, and tolerability, a maintenance dose of 80 μg of rBet v 1‐FV appears to be the ideal dose for allergen immunotherapy in birch pollen allergic patients.
The co-chaperone FKBP5 is a stress-responsive protein-regulating stress reactivity, and its genetic variants are associated with T2D related traits and other stress-related disorders. Here we show ...that FKBP51 plays a role in energy and glucose homeostasis. Fkbp5 knockout (51KO) mice are protected from high-fat diet-induced weight gain, show improved glucose tolerance and increased insulin signaling in skeletal muscle. Chronic treatment with a novel FKBP51 antagonist, SAFit2, recapitulates the effects of FKBP51 deletion on both body weight regulation and glucose tolerance. Using shorter SAFit2 treatment, we show that glucose tolerance improvement precedes the reduction in body weight. Mechanistically, we identify a novel association between FKBP51 and AS160, a substrate of AKT2 that is involved in glucose uptake. FKBP51 antagonism increases the phosphorylation of AS160, increases glucose transporter 4 expression at the plasma membrane, and ultimately enhances glucose uptake in skeletal myotubes. We propose FKBP51 as a mediator between stress and T2D development, and potential target for therapeutic approaches.
There is increasing awareness of an association between the uptake of the HIV integrase inhibitor, dolutegravir, in first-line antiretroviral regimens with unusual weight gain and development of the ...metabolic syndrome, particularly in African women. Although seemingly unexplored, the development of systemic inflammation linked to the putative pro-inflammatory activity of dolutegravir represents a plausible pathophysiological mechanism of this unusual weight gain. This possibility was explored in the current study undertaken to investigate the effects of dolutegravir (2.5−20 μg/mL) on several pro-inflammatory activities of neutrophils isolated from the blood of healthy, adult humans. These activities included the generation of reactive oxygen species (ROS), degranulation (elastase release) and alterations in the concentrations of cytosolic Ca2+ using chemiluminescence, spectrophotometric and fluorimetric procedures, respectively. Exposure of neutrophils to dolutegravir alone resulted in the abrupt, dose-related, and significant (p < 0.0039−p < 0.0022) generation of ROS that was attenuated by the inclusion of the Ca2+-chelating agent, EGTA, or inhibitors of NADPH oxidase (diphenyleneiodonium chloride, DPI), phospholipase C (U733122), myeloperoxidase (sodium azide) and phosphoinositol-3-kinase (wortmannin). In addition, exposure to dolutegravir augmented the release of elastase by stimulus-activated neutrophils. These pro-inflammatory effects of dolutegravir on neutrophils were associated with significant, rapid, and sustained increases in the concentrations of cytosolic Ca2+ that appeared to originate from the extracellular compartment, seemingly consistent with an ionophore-like property of dolutegravir. These findings are preliminary and necessitate verification in the clinical setting of HIV infection. Nevertheless, given the complex link between inflammation and obesity, these pro-inflammatory interactions of dolutegravir with neutrophils may contribute to unexplained weight gain, possibly via the development of insulin resistance.
The climate and environmental significance of the Deccan Traps large igneous province of west-central India has been the subject of debate in paleontological communities. Nearly one million years of ...semi-continuous Deccan eruptive activity spanned the Cretaceous-Paleogene boundary, which is renowned for the extinction of most dinosaur groups. Whereas the Chicxulub impactor is acknowledged as the principal cause of these extinctions, the Deccan Traps eruptions are believed to have contributed to extinction patterns and/or enhanced ecological pressures on biota during this interval of geologic time. We present the first coupled records of biogenic carbonate clumped isotope paleothermometry and mercury concentrations as measured from a broad geographic distribution of marine mollusk fossils. These fossils preserve evidence of simultaneous increases in coastal marine temperatures and mercury concentrations at a global scale, which appear attributable to volcanic CO
and mercury emissions. These early findings warrant further investigation with additional records of combined Late Cretaceous temperatures and mercury concentrations of biogenic carbonate.
State-of-the-art tomographic scanning techniques provide detailed pore-space geometries of natural porous media, which are central for the study of subsurface flow and transport. Due to experimental ...and computational limitations, the extraction of high-resolution images is limited to relatively small sample volumes. To reduce the amount of data and the physical complexity, pore-space geometries are routinely translated into pore network models. Subsequently, such networks are expanded in space with suitable computational methods to determine effective medium parameters at larger scales relevant in engineering applications. While existing methods can provide networks with effective flow parameters being consistent with experimental data for comparably homogeneous media such as bead packs and sandstones, these methods are inadequate for more complex heterogeneous rocks such as carbonates or become too expensive for large networks. The netflow Python library accompanying this paper extends existing methods by preserving pore clusters that are a key characteristic of heterogeneous rocks. To this end dendrograms are extracted from experimental data and perturbed when generating larger networks. Moreover, the methods included in the netflow library are implemented in computationally efficient ways and enable the generation of large periodic networks that virtually eliminate boundary effects, which interfere in existing methods.
• The netflow Python library enables the generation of large irregular networks, as it preserves pore or node clusters which are present in certain natural rock types.
• The netflow Python library allows for the generation and flow analysis of boundary-free periodic networks. It further includes methods to convert periodic networks into conventional cubical ones.
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