Notes

Adoptive transfer of GRP78-treated dendritic tissue relieves insulitis throughout NOD these animals.
undation, Finnish Eye Foundation, Finska Läkaresällskapet, The Finnish Society of Sciences and Letters, Magnus Ehrnrooth Foundation and Sigrid Jusélius Foundation.The molecular implications of food consumption on cancer etiology are poorly defined. The rate of nutrition associated non-enzymatic glycoxidation, a reaction that occurs between reactive carbonyl groups on linear sugars and nucleophilic amino, lysyl and arginyl groups on fats and proteins, is rapidly increased by food cooking and manufacturing processes. In this study, we assign nutrition-associated glycoxidation with significant oncogenic potential, promoting prostate tumor growth, progression, and metastasis in vivo. Advanced glycation end products (AGEs) are the final irreversible product of non-enzymatic glycoxidation. Exogenous treatment of prostate tumor cells with a single AGE peptide replicated glycoxidation induced tumor growth in vivo. Mechanistically, receptor for AGE (RAGE) deficiency in the stroma inhibited AGE mediated tumor growth. Functionally, AGE treatment induced RAGE dimerization in activated fibroblasts which sustained and increased the migratory potential of tumor epithelial cells. These data identify a novel nutrition associated pathway that can promote a tissue microenvironment conducive for aggressive tumor growth. Targeted and/or interventional strategies aimed at reducing AGE bioavailability as a consequence of nutrition may be viewed as novel chemoprevention initiatives.Sepsis-induced cardiac injury leads to the high rate of mortality, the therapeutics for this disorder are limited. Disulfiram (DSF) is an FDA-approved treatment for chronic alcohol addiction, and its cardio-protection is gradually discovered in recent years. In present study, mice were injected with lipopolysaccharide (LPS, 15 mg/kg) to induce a septic cardiac injury model, and aimed to investigate the protective effect of DSF on sepsis-induced cardiac injury and the underlying mechanisms. Results showed that DSF treatment alleviated the lowered left heart function and myocardial cell apoptosis induced by LPS. Moreover, we found that LPS increased myocardium lipid peroxidation, DNA damage and the activation of NLRP3 inflammasome, which were significantly reduced by DSF. These results suggested the protective role of DSF in LPS-induced cardiac injury, and the mechanism involved the inhibition on the oxidative stress and NLRP3 inflammasome activation. Given the potent cardiac protection effect of DSF, repurposing DSF in the clinic would represent a new strategy to protect and treat sepsis-induced cardiac injury.We have recently reported the discovery of a series of oxazolidinone hydroxamic acid derivatives that are potent inhibitors of 5-lipoxygenase (5-LO) [arachidonate 5-lipoxygenase; EC 1.13.11.34]. We now report that one of the most active members of this series, compound PH-251, [(R)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl) methyl)-N-hydroxyoctanamide], also possesses a unique and strong ability to concurrently inhibit mast cell degranulation. PH-251 inhibited the biosynthesis of leukotriene C4 (LTC4), as well as degranulation of IgE/allergen-activated bone marrow-derived mouse mast cells (BMMC) in vitro. In contrast, zileuton (the prototype 5-LO inhibitor) inhibited leukotriene generation, but not degranulation. Consistent with its dual activity, compound PH-251 also significantly inhibited both the early and the late anaphylactic contractions of guinea pig lung parenchymal strip, whereas zileuton inhibited only the late (leukotriene-dependent) contractions. Comparative structure-activity analysis of PH-251 and its structural analogues showed that the anti-degranulation effect appeared to be dependent on the length of the straight-chain hydrocarbon substitution on the hydroxamic acid moiety. In the in vivo studies, PH-251 (3-30 mg/kg s.c.) strongly inhibited various components of zymosan-induced peritonitis - a typical non-allergic LT-dependent animal model of inflammation. In the mouse allergic asthma model, the compound significantly inhibited allergen-induced bronchial eosinophilic inflammation and airway hyper-responsiveness to inhaled methacholine. These results show that PH-251 is a unique dual inhibitor of 5-LO and mast cell degranulation, with in vivo activity in animal models of disease and may therefore offer potential advantages over single-target drugs in the treatment of asthma and other allergic and inflammatory diseases.Cancer is caused by abnormal cell growth and metastasis to other tissues. Development of cancers is complex and underlining mechanisms are mostly unknown. Disco-interacting protein 2 homolog B (DIP2B) is a member of Dip2. There have been reports suggesting that Dip2B may participate in tumor growth and development. However, direct link between DIP2B and cancer development is missing. In this study, Dip2btm1a/+ heterozygous knockout mouse model was used to investigate tumor growth and metastasis. Results show that one allele knockout of Dip2B significantly promoted tumor growth and metastasis, decreased tumor cell apoptosis and reduced immune cell infiltration in tumors, most likely by altering immune system that includes reduction of macrophage and cytotoxic T-cells infiltration into tumor microenvironment.Post-ischemic peripheral immunosuppression increases vulnerability to infection which is a common complication and worsens outcome in ischemic stroke patients. Hypothalamic-pituitary-adrenal (HPA) axis plays a key role in post-ischemic immunosuppression. Astragaloside IV (ASIV), isolated from Astragalus membranaceus, possesses immunomodulatory and neuroprotective effects against cerebral ischemic injury. This study investigated the effect of ASIV on cerebral ischemia-induced peripheral immunosuppression and the underlying mechanism in a mouse model of middle cerebral artery occlusion (MCAO). Our results showed that ASIV significantly prevented the atrophy of spleen and the reduction of splenic cell count. Meanwhile, ASIV preserved cell numbers of splenic NK, T, and B cells in the spleen. ASIV also suppressed apoptosis of splenic cells and preserved their proliferation ability. In addition, ASIV robustly reduced the mRNA expression of TNF-α, IL-1β, IL-6 and CRH in the hypothalamus, as well as the enlargement of adrenal gland and the increase of corticosterone in blood, indicating the inhibition of HPA axis by ASIV. Furthermore, ASIV did not enhance the effect of HPA inhibition on reducing splenic atrophy and preserving splenic NK, T, and B cell numbers in MCAO mice. Of note, ASIV did not attenuate splenic cell apoptosis induced by prednisolone, suggesting that ASIV may ameliorate splenic apoptosis through reducing peripheral glucocorticoid level. Our findings demonstrate that ASIV ameliorates post-ischemic peripheral immunosuppression through inhibiting the activation of HPA axis and targeting HPA activation to ameliorate peripheral immunosuppression may be a promising strategy to improve clinical outcomes of ischemic stroke.
This study examined whether ritualistic behaviors characteristic of obsessive-compulsive disorder (OCD) are a product of dysfunctional goal-directed behavior leading to habitual behavior (Gillan & Robbins, 2014). We used an explicit motor sequence learning task to investigate the repetition of chunked action sequences across the OC spectrum. As sequential motor behavior is practiced, action movements appear to get bundled together, and the initial movement of the sequence activates the entire sequence, leaving it relatively insensitive to change. Therefore, compulsive behavior in OCD may be a result of failing to inhibit the full activation of an extensively learned action sequence.

Fifty-seven participants across the range of OCD symptoms practiced one sequence and then tested on a novel sequence in which one of the middle movements was omitted. Optimal performance for the new sequence required goal-directed inhibition of the original sequence and goal-directed execution of the new sequence instead. To manipulate activation of goal-directed behavior, we added a dual-task condition with a competing auditory tonal N-Back task. Data were analyzed using mixed-effects models.

Although we did observe expected learning patterns during learning of the original sequence, slower reaction times for the new sequences, and higher errors in the dual-task condition, performance was not significantly related to either obsessive-compulsive symptoms or distress symptoms.

The current study used an analog sample; replication in a treatment seeking sample is warranted.

These findings challenge the goal-directed dysfunction model of OCD.
These findings challenge the goal-directed dysfunction model of OCD.Clonal hematopoiesis (CH) defines a population of hematopoietic cells with one or more somatic mutations/copy number alterations that can expand with time and under positive clonal selection pressures. The term CH of indeterminate potential (CHIP) operationally describes somatic mutations in leukemia-associated driver genes in hematopoietic stem cells with variant allele frequencies (VAF) of ≥ 2%, without evidence for an underlying hematological malignancy. Risk factors for CHIP include aging, inflammation, male sex, cigarette smoking, history of cancer and cancer treatments, germline predisposition states, among others. CHIP is a premalignant condition, with a low but definite risk of hematologic malignancies and is associated with increased all-cause mortality, largely due to cardiovascular disease and associated endothelial dysfunction. Here we review recent advances in CHIP, including diagnostic, prognostic, and potential therapeutic strategies.Amyloid positron emission tomography (PET) and hippocampal volume derived from magnetic resonance imaging may be useful clinical biomarkers for differentiating between geriatric depression and Alzheimer's disease (AD). Here we investigated the incremental value of using hippocampal volume and 18F-flutemetmol amyloid PET measures in tandem and sequentially to improve discrimination in unclassified participants. Two approaches were compared in 41 participants with geriatric depression and 27 participants with probable AD (1) amyloid and hippocampal volume combined in one model and (2) classification based on hippocampal volume first and then subsequent stratification using standardized uptake value ratio (SUVR)-determined amyloid positivity. Hippocampal volume and amyloid SUVR were significant diagnostic predictors of depression (sensitivity 95%, specificity 89%). 51% of participants were correctly classified according to clinical diagnosis based on hippocampal volume alone, increasing to 87% when adding amyloid data (sensitivity 94%, specificity 78%). Our results suggest that hippocampal volume may be a useful gatekeeper for identifying depressed individuals at risk for AD who would benefit from additional amyloid biomarkers when available.
We have developed a feasible method to evaluate deformable image registration using deep learning (DL)-based segmentation.

Eighty patients with nasopharyngeal carcinoma were enrolled in this study. Two sets of fixed and moving computed tomography images acquired from each patient were input into the DL segmentation model to generate nine anatomic regions of interest (ROIs) separately and automatically. CT-707 supplier The ROIs generated in moving images were transferred to the fixed images using the registration transformation metric. The registration evaluation indexes, including the Dice similarity coefficient, derived from 60 well-registrated cases were then used to develop criteria for decision making. A double-blind study was performed to test the proposed method on quality assurance (QA) for image registration on a new test data set of 20 cases.

The values of evaluation indexes generated by our automated evaluation method were quite consistent with those from the manual method; however, the proposed method could save about 116min per patient on average.
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