Dietary AGEs as Exogenous Boosters of Inflammation

Most chronic modern non-transmissible diseases seem to begin as the result of low-grade inflammation extending over prolonged periods of time. The importance of diet as a source of many pro-inflammatory compounds that could create and sustain such a low-grade inflammatory state cannot be ignored, particularly since we are constantly exposed to them during the day. The focus of this review is on specific components of the diet associated with inflammation, specifically advanced glycation end products (AGEs) that form during thermal processing of food. AGEs are also generated in the body in normal physiology and are widely recognized as increased in diabetes, but many people are unaware of the potential importance of exogenous AGEs ingested in food. We review experimental models, epidemiologic data, and small clinical trials that suggest an important association between dietary intake of these compounds and development of an inflammatory and pro-oxidative state that is conducive to chronic diseases. We compare dietary intake of AGEs with other widely known dietary patterns, such as the Mediterranean and the Dietary Approaches to Stop Hypertension (DASH) diets, as well as the Dietary Inflammation Index (DII). Finally, we delineate in detail the pathophysiological mechanisms induced by dietary AGEs, both direct (i.e., non-receptor-mediated) and indirect (receptor-mediated).     

25‐OH‐Vitamin D Deficiency and Cellular Alloimmunity as Measured by Panel of Reactive T Cell Testing in Dialysis Patients

Primed antidonor alloreactive T cells are detrimental to transplant outcome, but factors that impact the strength of this immune response prior to transplantation are unknown. We tested peripheral blood mononuclear cells from dialysis patients, against panels of allogeneic, primary B‐cell lines in a newly standardized IFNγ ELISPOT panel of reactive T cell (PRT) assay. Results were correlated with known alloantibody‐sensitizing events and other clinical parameters. As 25‐OH‐vitamin D deficiency is associated with enhanced cellular immunity, is common in dialysis patients and is correctable, we assessed the relationship between serum 25‐OH‐vitamin D and the PRT. Using independent test and validation cohorts we found that low serum levels of 25‐OH‐vitamin D (<26 ng/mL) correlated with high‐PRT values (in the upper 50th percentile, OR 0.02, p = 0.01) independent of age, sex, race, previous transplant, transfusion, pregnancy, time on dialysis, panel of reactive antibody, iPTH, and treatment with 1,25‐OH‐vitamin D. The data provide a potential mechanism for the possible relationship between vitamin D deficiency and poor posttransplant outcome, and support studies to test the impact of 25‐OH‐vitamin D repletion on alloimmunity and allograft injury in kidney transplant candidates.     

Prognostic significance of performing universal HER2 testing in cases of advanced gastric cancer

Background

Trastuzumab significantly improves overall survival (OS) when added to cisplatin and fluoropyrimidine as a treatment for HER2-positive advanced gastric cancers (AGC). The aim of this study was to evaluate the impact of the gradual implementation of HER2 testing on patient prognosis in a national registry of AGC.

Methods

This Spanish National Cancer Registry includes cases who were consecutively recruited at 28 centers from January 2008 to January 2016. The effect of missing HER2 status was assessed using stratified Cox proportional hazards (PH) regression.

Results

The rate of HER2 testing increased steadily over time, from 58.3 % in 2008 to 92.9 % in 2016. HER2 was positive in 194 tumors (21.3 %). In the stratified Cox PH regression, each 1 % increase in patients who were not tested for HER2 at the institutions was associated with an approximately 0.3 % increase in the risk of death: hazard ratio, 1.0035 (CI 95 %, 1.001–1.005), P = 0.0019. Median OS was significantly lower at institutions with the highest proportions of patients who were not tested for HER2.

Conclusion

Patients treated at centers that took longer to implement HER2 testing exhibited worse clinical outcomes. The speed of implementation behaves as a quality-of-care indicator. Reviewed guidelines on HER2 testing should be used to achieve this goal in a timely manner.

     

White matter involvement on DTI-MRI in Cushing’s syndrome relates to mood disturbances and processing speed: a case-control study

Purpose

Cushing’s syndrome (CS) is an endocrine disorder due to prolonged exposure to cortisol. Recently, microstructural white matter (WM) alterations detected by diffusion tensor imaging (DTI) have been reported in CS patients, and related to depression, but other functional significances. remain otherwise unclear. We aimed at investigating in more depth mood symptoms in CS patients, and how these relate to cognition (information processing speed), and to WM alterations on DTI.

Methods

The sample comprised 35 CS patients and 35 healthy controls. Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, State-Trait Anxiety Inventory (STAI) to assess anxiety, and processing speed was measured by the Symbol Digit Modalities Test (SDMT). DTI studies were acquired using a 3-Tesla Philips-Achieva MR-facility. Voxelwise statistical analysis of fractional anisotropy (FA), mean, axial and radial diffusivities (MD, AD, RD) data were performed using FMRIB Software Library. Correlation analysis were obtained between mood and processing speed variables, and FA, MD, AD and RD values, taking both CS patients and healthy controls.

Results

Active, controlled and cured CS patients showed greater depression (F?=?12.4, p?<?0.001), anxious state (F?=?4.8, p?=?0.005) and anxious trait (F?=?9.6, p?<?0.001) scores, than controls. Using the entire sample, depression scores correlated negatively to FA and positively to RD values. Although there were no differences in processing speed between groups, SDMT scores correlated positively to both FA and AD values.

Conclusions

There were greater depressive and anxious symptoms in CS patients than in healthy controls, but no difference in processing speed. However, DTI is related to depression and information processing speed in CS.

     

All-or-none amyloid disassembly via chaperone-triggered fibril unzipping favors clearance of α-synuclein toxic species

α-synuclein aggregation is present in Parkinson’s disease and other neuropathologies. Among the assemblies that populate the amyloid formation process, oligomers and short fibrils are the most cytotoxic. The human Hsc70-based disaggregase system can resolve α-synuclein fibrils, but its ability to target other toxic assemblies has not been studied. Here, we show that this chaperone system preferentially disaggregates toxic oligomers and short fibrils, while its activity against large, less toxic amyloids is severely impaired. Biochemical and kinetic characterization of the disassembly process reveals that this behavior is the result of an all-or-none abrupt solubilization of individual aggregates. High-speed atomic force microscopy explicitly shows that disassembly starts with the destabilization of the tips and rapidly progresses to completion through protofilament unzipping and depolymerization without accumulation of harmful oligomeric intermediates. Our data provide molecular insights into the selective processing of toxic amyloids, which is critical to identify potential therapeutic targets against increasingly prevalent neurodegenerative disorders.

Aberrant aggregation of α-synuclein (α-syn) into amyloid fibrils and subsequent accumulation into intracellular inclusions is a hallmark of neurodegenerative disorders such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy (1–3). In these diseases, soluble α-syn monomers misfold and self-assemble, forming small oligomeric species that retain the highly disordered structure of the monomeric state (4). These species are rather unstable and can undergo structural rearrangements, including a gain in β-sheet structure that generates more stable species (4, 5). β-structured oligomers can grow further through monomer addition or self-association, finally giving rise to well-defined amyloid fibrils (4–6). Despite the controversial evidence about the relationship between the different species that populate the aggregation process and cellular toxicity, the prevalent view is that both intermediate oligomers and small fibrils are neurotoxic (7). Due to their abnormal interactions with cellular components, certain types of oligomers are key pathogenic agents in the development of the disease (8–10). In particular, they can disrupt membranes, induce oxidative stress, dysregulate calcium homeostasis, cause mitochondria dysfunction, or impair the proteasome system (11). Furthermore, α-syn oligomers have been implicated in the spreading of the disease, as these aggregates can be transmitted between cells (12, 13). Small fibrils have also been related to intercellular spreading and propagation of neurodegeneration (14–18). In contrast, large amyloid aggregates are believed to be relatively inert, as their highly ordered packing and slow diffusion reduces undesired interactions with cellular components. Even so, large aggregates can generate intermediate species that contribute to cytotoxicity through secondary processes such as fragmentation or nucleation on the aggregate surface (19, 20).To counteract the toxic effect of protein aggregates, cells have evolved a sophisticated protein homeostasis network that coordinates protein synthesis, folding, disaggregation and degradation (21). This network is composed of the translational machinery, molecular chaperones and cochaperones, the ubiquitin-proteasome system, and the autophagy machinery. The way this network tackles amyloid aggregates remains poorly understood. It has been previously reported that the constitutive human Hsp70 (Hsc70) in collaboration with its Hsp40 cochaperone (Hdj1 or DnaJB1) slowly disassembles preformed α-syn fibrils (22). This activity was further stimulated by adding the NEF Hsp110 (Apg2). HspB5, a small heat shock protein also known as αB-crystallin, potentiated α-syn fibril disassembly by the ternary chaperone mixture. Although this chaperone combination was able to disaggregate fibrils, they did it in a timescale of weeks through a depolymerization process. Only when Hsp104, a yeast representative of the Hsp100 family able of fragmenting fibrils, was added to the mixture, disassembly occurred within hours (22). The lack of Hsp104 homologs in metazoans questioned whether this activity was physiologically relevant in humans. A later study revealed that a chaperone complex composed solely of members of the Hsp70, Hsp40, and Hsp110 families was able to efficiently reverse α-syn amyloid fibrils through both fragmentation and depolymerization, generating smaller fibrils, oligomers, and, ultimately, monomers (23). Despite the importance of this emerging disaggregase functionality, its mechanism of action remains largely unknown. Recently, the same chaperone mixture has been reported to also disaggregate tau and Htt fibrils (24–26), pointing to this Hsp70-based machinery as a potential human amyloid disaggregase.The two-fold aim of this work is, firstly, to test whether human disaggregase remodels with the same efficiency the different aggregates that populate the complex process of amyloid formation and, secondly, to shed light on the key mechanisms involved in the disassembly of amyloids. We show that the human disaggregase system disassembles toxic oligomers and short fibrils much better than large, less toxic fibrils, and that it does so by an enhanced destabilization of the small aggregated forms. Explicitly, fibril disassembly involves destabilization of the fibril ends and unzipping of the protofilaments, which allow depolymerization. The fast propagation of protofilament depolymerization toward the opposite fibril end is consistent with entropic pulling forces exerted by Hsc70 upon binding the fibril surface.     

Amorphous FeCoCrSiB Ribbons with Tailored Anisotropy for the Development of Magnetic Elements for High Frequency Applications

The ferromagnetic resonance (FMR) in the frequency range of 0.5 to 12.5 GHz has been investigated as a function of external magnetic field for rapidly quenched Fe₃Co₆₇Cr₃Si₁₅B₁₂ amorphous ribbons with different features of the effective magnetic anisotropy. Three states of the ribbons were considered: as-quenched without any treatment; after relaxation annealing without stress at the temperature of 350 °C during 1 h; and after annealing under specific stress of 230 MPa at the temperature of 350 °C during 1 h. For FMR measurements, we adapted a technique previously proposed and tested for the case of microwires. Here, amorphous ribbons were studied using the sample holder based on a commercial SMA connector. On the basis of the measurements of the reflection coefficient S_11, the total impedance including its real and imaginary components was determined to be in the frequency range of 0.5 to 12.5 GHz. In order to confirm the validity of the proposed technique, FMR was also measured by the certified cavity perturbation technique using a commercial Bruker spectrometer operating at X-band frequency of 9.39 GHz. As part of the characterization of the ribbons used for microwave measurements, comparative analysis was performed of X-ray diffraction, optical microscopy, transmission electron microscopy, inductive magnetic hysteresis loops, vibrating sample magnetometry, magneto-optical Kerr effect (including magnetic domains) and magnetoimpedance data for of all samples.