Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of ...rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10
): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10
. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) that causes substantial morbidity and diminished quality of life. Evidence highlights the ...central role of myeloid lineage cells in the initiation and progression of MS. However, existing imaging strategies for detecting myeloid cells in the CNS cannot distinguish between beneficial and harmful immune responses. Thus, imaging strategies that specifically identify myeloid cells and their activation states are critical for MS disease staging and monitoring of therapeutic responses. We hypothesized that positron emission tomography (PET) imaging of triggering receptor expressed on myeloid cells 1 (TREM1) could be used to monitor deleterious innate immune responses and disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We first validated TREM1 as a specific marker of proinflammatory, CNS-infiltrating, peripheral myeloid cells in mice with EAE. We show that the
Cu-radiolabeled TREM1 antibody-based PET tracer monitored active disease with 14- to 17-fold higher sensitivity than translocator protein 18 kDa (TSPO)-PET imaging, the established approach for detecting neuroinflammation in vivo. We illustrate the therapeutic potential of attenuating TREM1 signaling both genetically and pharmacologically in the EAE mice and show that TREM1-PET imaging detected responses to an FDA-approved MS therapy with siponimod (BAF312) in these animals. Last, we observed TREM1
cells in clinical brain biopsy samples from two treatment-naïve patients with MS but not in healthy control brain tissue. Thus, TREM1-PET imaging has potential for aiding in the diagnosis of MS and monitoring of therapeutic responses to drug treatment.
The effect of ketogenic diets (KD) on body composition in different populations has been investigated. More recently, some have recommended that athletes adhere to ketogenic diets in order to ...optimize changes in body composition during training. However, there is less evidence related to trained women. We aimed to evaluate the effect of a KD on body composition and strength in trained women following an eight-week resistance training (RT) program.
Twenty-one strength-trained women (27.6 ± 4.0 years; 162.1 ± 6.6 cm; 62.3 ± 7.8 kg; 23.7 ± 2.9 kg·m
) were randomly assigned to either a non-KD group (n = 11, NKD) or a KD group (n = 10, KD). Study outcomes included body composition as measured by dual-energy X-ray absorptiometry (DXA), strength levels measured using one maximum repetition (RM) in back squat and bench press (BP), and countermovement jump (CMJ) measured on a force plate.
A significant reduction in fat mass was observed in KD (- 1.1 ± 1.5 kg; P = 0.042; d = - 0.2) but not in NDK (0.3 ± 0.8 kg; P = 0.225; d = 0.1). No significant changes in fat-free mass were observed in KD (- 0.7 ± 1.7 kg; P = 0.202; d = - 0.1) or NKD (0.7 ± 1.1 kg; P = 0.074; d = 0.2), but absolute changes favored NKD. No significant changes in BP were observed in KD (1.5 ± 4.6 kg; P = 0.329; d = 0.2), although significant changes were noted in the squat and CMJ (5.6 ± 7.6 kg; P = 0.045; d = 0.5 and 2.2 ± 1.7 kg; P = 0.022; d = 0.6, respectively). In contrast, NKD showed significant increases in BP (4.8 ± 1.8; P < 0.01; d = 0.7), squat (15.6 ± 5.4 kg; P = 0.005; d = 1.4) and CMJ (22.0 + 4.2 cm; P = 0.001; d = 0.5).
Findings indicate that a KD may help to decrease fat mass and maintain fat-free mass after eight 8 weeks of RT in trained-women but is suboptimal for increasing fat-free mass.
To evaluate the response to cabergoline (CBG) treatment in patients with non-functioning pituitary adenomas (NFPA).
Retrospective, single tertiary care center study. A total of 44 patients were ...treated with 3 mg/week of CBG, 32 after surgical treatment (transsphenoidal surgery TSS in 27 and TC in 5 patients) and 12 as primary therapy. Mean age was 59.2 ± 12 years and 23 (52.2%) were women. Response to therapy was ascertained by serial magnetic resonance imaging. The median duration of CBG therapy was 30 months (IQR 24-48). Response to CBG therapy was defined as a greater than 20% reduction in tumor size and volume.
A significant reduction in tumor size was documented in 29 patients (66%), whereas in 11 patients (25%) the tumor increased in size and in 4 (9%), it remained stable. Significant tumor shrinkage was documented in 4 (33.3%) of 12 patients treated primarily and in 23 (71.8%) of those treated secondarily. The three-year progression-free survival was 0.61.
Cabergoline therapy is effective in reducing tumor growth in over two thirds of patients with NFPA, however 16% of patients will escape to this beneficial effect and will require alternative forms of treatment to halt tumor progression.
The removal of three emerging contaminants (ECs) (amitriptyline hydrochloride (AH), methyl salicylate (MS) and 2-phenoxyethanol (PE)) dissolved in several water matrices by means of their adsorption ...onto powdered activated carbon (PAC) and granular activated carbon (GAC) has been investigated. When dissolved in ultrapure water, adsorption of the ECs followed the trend of AH > MS > PE, with a positive effect of the adsorbent dose. According to the analysis of the adsorption isotherms and adsorption kinetics, PAC showed strongly higher adsorption efficiency in both capacity and velocity of the adsorption, in agreement with its higher mesoporosity. Equilibrium isotherm data were fitted by Langmuir and Freundlich models. Pseudo-second order kinetics modeled very successfully the adsorption process. Finally, the effect of the presence of dissolved organic matter (DOM) in the water matrices (ultrapure water, surface water and two effluents from wastewater treatment plants) on the adsorption of the selected ECs onto PAC was established, as well as its performance on the removal of water quality parameters. Results show a negative effect of the DOM content on the adsorption efficiency. Over 50% of organic matter was removed with high PAC doses, revealing that adsorption onto PAC is an effective technology to remove both micro-pollutants and DOM from water matrices.
► The reaction with bromine of some selected pharmaceuticals is studied. ► The main influence on the bromination reaction is exerted by the pH. ► The proposed reaction mechanism allows to evaluate ...the intrinsic rate constants. ► The elimination by bromine of the pharmaceuticals is determined in natural waters.
The bromination of five selected pharmaceuticals (metoprolol, naproxen, amoxicillin, phenacetin, and hydrochlorothiazide) was studied with these compounds individually dissolved in ultra-pure water. The apparent rate constants for the bromination reaction were determined as a function of the pH, obtaining the sequence amoxicillin
>
naproxen
≫
hydrochlorothiazide
≈
phenacetin
≈
metoprolol. A kinetic mechanism specifying the dissociation reactions and the species formed for each compound according to its p
K
a value and the pH allowed the intrinsic rate constants to be determined for each elementary reaction. There was fairly good agreement between the experimental and calculated values of the apparent rate constants, confirming the goodness of the proposed reaction mechanism.
In a second stage, the bromination of the selected pharmaceuticals simultaneously dissolved in three water matrices (a groundwater, a surface water from a public reservoir, and a secondary effluent from a WWTP) was investigated. The pharmaceutical elimination trend agreed with the previously determined rate constants. The influence of the main operating conditions (pH, initial bromine dose, and characteristics of the water matrix) on the degradation of the pharmaceuticals was established. An elimination concentration profile for each pharmaceutical in the water matrices was proposed based on the use of the previously evaluated apparent rate constants, and the theoretical results agreed satisfactorily with experiment. Finally, chlorination experiments performed in the presence of bromide showed that low bromide concentrations slightly accelerate the oxidation of the selected pharmaceuticals during chlorine disinfection.
Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, ...is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-β
oligomer-induced bioenergetic changes, suggesting that amyloid-β
oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APP
mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1
cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.
Mutations in the ATP4A proton pump prevent gastric acidification and explain the chronic autoimmune gastritis scenario that conducts the gastric neuroendocrine tumor (gNET) formation. Here, we wanted ...to investigate the co-occurrence cytomegalovirus (CMV) infection and intestinal inflammation that presented all members of a family affected with gNET and carrying an
mutation. Intestinal inflammation persisted after CMV eradication and anemia treatment. The inflammation was compatible with a ileitis/Crohn's disease and was originated by the same autoimmune mechanism described in the tumorigenesis of gNETS. The same secondary disease but no the CMV infection was observed in all members affected with gNET and carrying the ATP4A mutation. Our results suggest that the
malfunction not only explained gNETs but also the co-occurring disease and opportunistic infections, which allowed to link autoimmune pathologies and gNETs in a unique mechanism. Our results open a new window to better understand not only gastric neoplasms formation but the co-occurring autoimmune disorders and the inflammatory mechanism that compose a premalignant scenario for other tumor formation. Our findings are important since contribute to describe the genetic landscape of the Inflammatory Bowel/Crohn's disease and alert clinicians to monitor patients with gastric neoplasms mediated by achlorhydria mechanisms for concomitant secondary pathologies.
Chemical degradation of the pharmaceuticals and personal care products (PPCPs) amitriptyline hydrochloride, methyl salicylate, and 2-phenoxyethanol by means of several advanced oxidation processes, ...including 254 nm UV radiation and Fenton’s reagent, has been studied in different water matrixes, such as ultrapure (UP) and surface waters and two secondary effluents from wastewater treatment plants. The influence of the operating variables on the elimination of these compounds in UP water was established, and kinetic parameters for their degradation, such as quantum yields along a pH range of 3–11 and second-order rate constants for their oxidation by hydroxyl radicals, were determined. Specifically, for the reactions of oxidation of the three PPCPs with hydroxyl radicals, the use of a competition kinetic model in Fenton’s reagent experiments allowed evaluation of their rate constants, whose values were (10.3 ± 0.3) × 109 M–1·s–1 for amitriptyline hydrochloride, (7.1 ± 0.1) × 109 M–1·s–1 for methyl salicylate, and (4.3 ± 0.1) × 109 M–1·s–1 for 2-phenoxyethanol. Furthermore, the simultaneous oxidation of these selected PPCPs in three different water systems (surface water from a reservoir and two secondary effluents) was studied, and the influence of the operating conditions on the removal efficiency was established. Finally, a kinetic model was proposed for the prediction of the elimination of these compounds by UV radiation and a UV/H2O2 system in these water matrixes, with theoretical results that agreed well with the experimental ones.
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