Abstract Invasive breast cancer is the most common malignancy in women. Its most common site of metastasis is represented by the lymph nodes of axilla, and the sentinel lymph node (SLN) is the first ...station of nodal metastasis. Axillary SLN biopsy accurately predicts axillary lymph node status and has been accepted as standard of care for nodal staging in breast cancer. To date, the morphologic aspects of SLN metastasis have not been considered by the oncologic staging system. Extranodal extension (ENE) of nodal metastasis, defined as extension of neoplastic cells through the nodal capsule into the peri-nodal adipose tissue, has recently emerged as an important prognostic factor in several types of malignancies. It has also been considered as a possible predictor of non-sentinel node tumor burden in SLN-positive breast cancer patients. We sought out to clarify the prognostic role of ENE in SLN-positive breast cancer patients in terms of overall and disease-free survival by conducting a systematic review and meta-analysis. Among 172 screened articles, 5 were eligible for the meta-analysis; they globally include 624 patients (163 ENE+ and 461 ENE-) with a median follow-up of 58 months. ENE was associated with a higher risk of both mortality (RR= 2.51; 95% CI: 1.66-3.79, p<0.0001, I2 =0%) and recurrence of disease (RR=2.07, 95%CI: 1.38-3.10, p<0.0001, I2 =0%). These findings recommend the consideration of ENE from the gross sampling to the histopathological evaluation, in perspectives to be validated and included in the oncologic staging.
The conversion of toluene and o-, m- and p-xylene to their respective side-chain and ring monohydroxylated metabolites by human liver microsomes was investigated. Methyl hydroxylation, to form a ...benzylalcohol, was the major metabolic pathway for all four methylbenzenes. With the exception of 2,4-dimethylphenol formation from m-xylene, ring hydroxylation accounted for < 5% of total metabolite formation. However, regioselectivity of ring hydroxylation was apparent, with hydroxylation occurring only at positions ortho and/or para to a methyl substituent. Toluene and each xylene isomer exhibited biphasic methylhydroxylation kinetics in human liver microsomes. The high-affinity component of each methylhydroxylation was selectively inhibited by diethyldithiocarbamate and correlated significantly with cytochrome P-4502E1 (CYP2E1) content and activities in a panel of human liver microsomes. cDNA-expressed CYP2E1 was shown to catalyze the formation of each benzylalcohol, with apparent Km values similar to those of the high affinity microsomal reactions. In contrast, the conversion of m-xylene to 2,4-dimethylphenol followed single enzyme Michaelis-Menten kinetics, was inhibited selectively by furafylline, and correlated significantly with known CYP1A2 catalyzed reactions. cDNA-expressed CYP1A2 converted m-xylene to 2,4-dimethylphenol, with an apparent Km similar to that of the microsomal reaction. Although CYP1A2 appears to be responsible for the formation of the minor (phenolic) metabolites of toluene and the xylene isomers, CYP2E1 catalyzed methylhydroxylation will be the major determinant of the clearance of these compounds in humans.
Accumulating evidence suggests that the immune system may be an important target for new treatment approaches in schizophrenia. Positron emission tomography and radioligands binding to the ...translocator protein (TSPO), which is expressed in glial cells in the brain including immune cells, represents a potential method for patient stratification and treatment monitoring. This study examined whether patients with first-episode psychosis and schizophrenia had altered TSPO levels compared with healthy control subjects.
PubMed was searched for studies comparing patients with psychosis with healthy control subjects using second-generation TSPO radioligands. The outcome measure was total distribution volume (VT), an index of TSPO levels, in frontal cortex, temporal cortex, and hippocampus. Bayes factors (BFs) were applied to examine the relative support for higher, lower, or no difference in patients’ TSPO levels compared with healthy control subjects.
Five studies, with 75 participants with first-episode psychosis or schizophrenia and 77 healthy control subjects, were included. BFs showed strong support for lower VT in patients relative to no difference (all BFs > 32), or relative to higher VT (all BFs > 422), in all brain regions. From the posterior distributions, mean patient–control differences in standardized VT values were −0.48 for frontal cortex (95% credible interval CredInt = −0.88 to 0.09), −0.47 for temporal cortex (CredInt = −0.87 to −0.07), and −0.63 for hippocampus (CredInt = −1.00 to −0.25).
The lower levels of TSPO observed in patients may correspond to altered function or lower density of brain immune cells. Future studies should focus on investigating the underlying biological mechanisms and their relevance for treatment.
The Brain Imaging Data Structure (BIDS) is a standard for organizing and describing neuroimaging datasets, serving not only to facilitate the process of data sharing and aggregation, but also to ...simplify the application and development of new methods and software for working with neuroimaging data. Here, we present an extension of BIDS to include positron emission tomography (PET) data, also known as PET-BIDS, and share several open-access datasets curated following PET-BIDS along with tools for conversion, validation and analysis of PET-BIDS datasets.
Plant resistance to disease is controlled by the combination of defense response pathways that are activated depending on the nature of the pathogen. We identified the Arabidopsis thaliana ...BOTRYTIS-INDUCED KINASE1 (BIK1) gene that is transcriptionally regulated by Botrytis cinerea infection. Inactivation of BIK1 causes severe susceptibility to necrotrophic fungal pathogens but enhances resistance to a virulent strain of the bacterial pathogen Pseudomonas syringae pv tomato. The response to an avirulent bacterial strain is unchanged, limiting the role of BIK1 to basal defense rather than race-specific resistance. The jasmonate- and ethylene-regulated defense response, generally associated with resistance to necrotrophic fungi, is attenuated in the bik1 mutant based on the expression of the plant defensin PDF1.2 gene. bik1 mutants show altered root growth, producing more and longer root hairs, demonstrating that BIK1 is also required for normal plant growth and development. Whereas the pathogen responses of bik1 are mostly dependent on salicylic acid (SA) levels, the nondefense responses are independent of SA. BIK1 is membrane-localized, suggesting possible involvement in early stages of the recognition or transduction of pathogen response. Our data suggest that BIK1 modulates the signaling of cellular factors required for defense responses to pathogen infection and normal root hair growth, linking defense response regulation with that of growth and development.
It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and ...created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.
The vascular wilt fungi Verticillium dahliae and V. albo-atrum infect over 200 plant species, causing billions of dollars in annual crop losses. The characteristic wilt symptoms are a result of ...colonization and proliferation of the pathogens in the xylem vessels, which undergo fluctuations in osmolarity. To gain insights into the mechanisms that confer the organisms' pathogenicity and enable them to proliferate in the unique ecological niche of the plant vascular system, we sequenced the genomes of V. dahliae and V. albo-atrum and compared them to each other, and to the genome of Fusarium oxysporum, another fungal wilt pathogen. Our analyses identified a set of proteins that are shared among all three wilt pathogens, and present in few other fungal species. One of these is a homolog of a bacterial glucosyltransferase that synthesizes virulence-related osmoregulated periplasmic glucans in bacteria. Pathogenicity tests of the corresponding V. dahliae glucosyltransferase gene deletion mutants indicate that the gene is required for full virulence in the Australian tobacco species Nicotiana benthamiana. Compared to other fungi, the two sequenced Verticillium genomes encode more pectin-degrading enzymes and other carbohydrate-active enzymes, suggesting an extraordinary capacity to degrade plant pectin barricades. The high level of synteny between the two Verticillium assemblies highlighted four flexible genomic islands in V. dahliae that are enriched for transposable elements, and contain duplicated genes and genes that are important in signaling/transcriptional regulation and iron/lipid metabolism. Coupled with an enhanced capacity to degrade plant materials, these genomic islands may contribute to the expanded genetic diversity and virulence of V. dahliae, the primary causal agent of Verticillium wilts. Significantly, our study reveals insights into the genetic mechanisms of niche adaptation of fungal wilt pathogens, advances our understanding of the evolution and development of their pathogenesis, and sheds light on potential avenues for the development of novel disease management strategies to combat destructive wilt diseases.
Mounting evidence suggests that aberrations in immune-inflammatory pathways contribute to the pathophysiology of major depressive disorder (MDD), and individuals with MDD may have elevated levels of ...predominantly pro-inflammatory cytokines and C-reactive protein. In addition, previous meta-analyses suggest that antidepressant drug treatment may decrease peripheral levels of interleukin-1 beta (IL-1β) and IL-6. Recently, several new studies examining the effect of antidepressants on these cytokines have been published, and so we performed an updated meta-analysis of studies that measured peripheral levels of cytokines and chemokines during antidepressant treatment in patients with MDD. The PubMed/MEDLINE, EMBASE, and PsycInfo databases were searched from inception through March 9, 2017. Forty-five studies met inclusion criteria (
N
= 1517). Peripheral levels of IL-6, tumor necrosis factor-alpha (TNF-α), IL-1β, IL-10, IL-2, IL-4, interferon-γ, IL-8, the C-C motif ligand 2 chemokine (CCL-2), CCL-3, IL-1 receptor antagonist, IL-13, IL-17, IL-5, IL-7, and the soluble IL-2 receptor were measured in at least three datasets and thus were meta-analyzed. Antidepressant treatment significantly decreased peripheral levels of IL-6 (Hedges
g
= −0.454,
P
<0.001), TNF-α (
g
= −0.202,
P
= 0.015), IL-10 (
g
= −0.566,
P
= 0.012), and CCL-2 (
g
= −1.502,
P
= 0.006). These findings indicate that antidepressants decrease several markers of peripheral inflammation. However, this meta-analysis did not provide evidence that reductions in peripheral inflammation are associated with antidepressant treatment response although few studies provided separate data for treatment responders and non-responders.
•Human study measuring pandemic-related neuroinflammation in individuals negative to COVID-19 antibodies.•Multimodal PET/MR brain imaging shows elevation in two independent putative markers of glial ...activation.•PET signal increases are associated with physical/mental fatigue indices.•Imaging transcriptomics analyses reveal a spatial overlap with the expression of genes related to neuroimmune responses.•Marginally elevated serum inflammatory markers correlate with neuroimaging markers.
While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other “sickness behavior”-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus.
We compared fifty-seven ‘Pre-Pandemic’ and fifteen ‘Pandemic’ datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation.
Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions.
This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.
OBJECTIVE
To determine whether there is an association between osteoarthritis (OA) and incident social isolation using data from the European Project on OSteoArthritis (EPOSA) study.
DESIGN
...Prospective, observational study with 12 to 18 months of follow‐up.
SETTING
Community dwelling.
PARTICIPANTS
Older people living in six European countries.
MEASUREMENTS
Social isolation was assessed using the Lubben Social Network Scale and the Maastricht Social Participation Profile. Clinical OA of the hip, knee, and hand was assessed according to American College of Rheumatology criteria. Demographic characteristics, including age, sex, multijoint pain, and medical comorbidities, were assessed.
RESULTS
Of the 1967 individuals with complete baseline and follow‐up data, 382 (19%) were socially isolated and 1585 were nonsocially isolated at baseline; of these individuals, 222 (13.9%) experienced social isolation during follow‐up. Using logistic regression analyses, after adjustment for age, sex, and country, four factors were significantly associated with incident social isolation: clinical OA, cognitive impairment, depression, and worse walking time. Compared to those without OA at any site or with only hand OA, clinical OA of the hip and/or knee, combined or not with hand OA, led to a 1.47 times increased risk of social isolation (95% confidence interval = 1.03‐2.09).
CONCLUSION
Clinical OA, present in one or two sites of the hip and knee, or in two or three sites of the hip, knee, and hand, increased the risk of social isolation, adjusting for cognitive impairment and depression and worse walking times. Clinicians should be aware that individuals with OA may be at greater risk of social isolation. J Am Geriatr Soc 68:87–95, 2019
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