Objective
To describe the clinical features, genotype, and treatment in a series of subjects with confirmed adenosine deaminase 2 (ADA2) deficiency.
Methods
All symptomatic subjects were referred for ...genetic testing for suspected ADA2 deficiency; relatives of index cases were also screened. Demographic, clinical, and laboratory characteristics and treatments were recorded. Genetic analyses included whole‐exome sequencing in 4 subjects and Sanger sequencing of CECR1 (the gene for cat eye syndrome chromosome region candidate 1) in all subjects. Assays for ADA2 enzyme activity and quantitative polymerase chain reaction analysis of CECR1 messenger RNA (mRNA) were also performed.
Results
We identified 15 subjects with ADA2 deficiency, 5 of whom were asymptomatic (relatives of index cases; ages 5–42 years). Homozygous or compound heterozygous mutations in CECR1 were identified in all subjects. Phenotypic manifestations in the patients with symptomatic ADA2 deficiency included livedo racemosa (73.3%), neurologic involvement (53.3%), and immunodeficiency (46.7%). CECR1 mRNA expression in 8 subjects, including 5 who were presymptomatic, was significantly lower than in healthy controls (P = 0.0016). Subjects with ADA2 deficiency (with or without symptoms) also had lower ADA2 enzyme activity compared to healthy pediatric controls (P < 0.0001) and patients with sporadic (nonfamilial) childhood polyarteritis nodosa (PAN) without CECR1 mutation (P = 0.0108). Anti−tumor necrosis factor therapy was required in 9 of the 10 symptomatic subjects.
Conclusion
The clinical manifestations of ADA2 deficiency ranged in severity from limited cutaneous involvement to severe multisystemic vasculitis; one‐third of our cases (5 of 15) were currently asymptomatic, and required close monitoring. We recommend CECR1 screening for unaffected siblings of index cases, cases of familial vasculitis, and cases of PAN that is resistant to standard treatment.
Overexpression of TOP2A is associated with risk of systemic progression in prostate cancer patients, and higher levels of TOP2A were found in hormone-resistant cases. To elucidate the mechanism by ...which high levels of TOP2A contribute to tumor progression we generated TOP2A overexpressing prostate cancer cell lines. We show that TOP2A promotes tumor aggressiveness by inducing chromosomal rearrangements of genes that contribute to a more invasive phenotype. Anti-androgen treatment alone was ineffective in killing TOP2A overexpressing cells due to activation of an androgen receptor network. TOP2A poisons killed tumor cells more efficiently early in the progression course, while at later stages they provided greater benefit when combined with anti-androgen therapy. Mechanistically, we find that TOP2A enhances androgen signaling by facilitating transcription of androgen responsive genes, thereby promoting tumor cell growth. These studies revealed a relationship between TOP2A and androgen receptor signaling pathway that contributes to prostate cancer progression and confers sensitivity to treatments.
Summary
Competition is a major type of interaction between fungi and bacteria in soil and is also an important factor in suppression of plant diseases caused by soil‐borne fungal pathogens. There is ...increasing attention for the possible role of volatiles in competitive interactions between bacteria and fungi. However, knowledge on the actual role of bacterial volatiles in interactions with fungi within soil microbial communities is lacking. Here, we examined colonization of sterile agricultural soils by fungi and bacteria from non‐sterile soil inoculums during exposure to volatiles emitted by soil‐derived bacterial communities. We found that colonization of soil by fungi was negatively affected by exposure to volatiles emitted by bacterial communities whereas that of bacteria was barely changed. Furthermore, there were strong effects of bacterial community volatiles on the assembly of fungal soil colonizers. Identification of volatile composition produced by bacterial communities revealed several compounds with known fungistatic activity. Our results are the first to reveal a collective volatile‐mediated antagonism of soil bacteria against fungi. Given the better exploration abilities of filamentous fungi in unsaturated soils, this may be an important strategy for bacteria to defend occupied nutrient patches against invading fungi. Another implication of our research is that bacterial volatiles in soil atmospheres can have a major contribution to soil fungistasis.
We statistically evaluated the relative orientation between gas column density structures, inferred from Herschel submillimetre observations, and the magnetic field projected on the plane of sky, ...inferred from polarized thermal emission of Galactic dust observed by the Balloon-borne Large-Aperture Submillimetre Telescope for Polarimetry (BLASTPol) at 250, 350, and 500 μm, towards the Vela C molecular complex. First, we find very good agreement between the polarization orientations in the three wavelength-bands, suggesting that, at the considered common angular resolution of 3.́0 that corresponds to a physical scale of approximately 0.61 pc, the inferred magnetic field orientation is not significantly affected by temperature or dust grain alignment effects. Second, we find that the relative orientation between gas column density structures and the magnetic field changes progressively with increasing gas column density, from mostly parallel or having no preferred orientation at low column densities to mostly perpendicular at the highest column densities. This observation is in agreement with previous studies by the Planck collaboration towards more nearby molecular clouds. Finally, we find a correspondencebetween (a) the trends in relative orientation between the column density structures and the projected magnetic field; and (b) the shape of the column density probability distribution functions (PDFs). In the sub-regions of Vela C dominated by one clear filamentary structure, or “ridges”, where the high-column density tails of the PDFs are flatter, we find a sharp transition from preferentially parallel or having no preferred relative orientation at low column densities to preferentially perpendicular at highest column densities. In the sub-regions of Vela C dominated by several filamentary structures with multiple orientations, or “nests”, where the maximum values of the column density are smaller than in the ridge-like sub-regions and the high-column density tails of the PDFs are steeper, such a transition is also present, but it is clearly less sharp than in the ridge-like sub-regions. Both of these results suggest that the magnetic field is dynamically important for the formation of density structures in this region.
The common marmoset has emerged as a key model in neuroscience. Marmosets are small in size, show great potential for genetic modification and exhibit complex behaviors. Thus, it is necessary to ...develop technology that enables monitoring and manipulation of the underlying neural circuits. Here, we describe a novel approach to record and optogenetically manipulate neural activity in awake, behaving marmosets. Our design utilizes a light-weight, 3D printed titanium chamber that can house several high-density silicon probes for semi-chronic recordings, while enabling simultaneous optogenetic stimulation. We demonstrate the application of our method in male marmosets by recording multi- and single-unit data from areas V1 and V6 with 192 channels simultaneously, and show that optogenetic activation of excitatory neurons in area V6 can influence behavior in a detection task. This method may enable future studies to investigate the neural basis of perception and behavior in the marmoset.
Purpose
Acute kidney injury (AKI) frequently occurs in critically ill patients and often precipitates use of renal replacement therapy (RRT). However, the ideal circumstances for whether and when to ...start RRT remain unclear. We performed evidence synthesis of the available literature to evaluate the value of biomarkers to predict receipt of RRT for AKI.
Methods
We conducted a PRISMA-guided systematic review and meta-analysis including all trials evaluating biomarker performance for prediction of RRT in AKI. A systematic search was applied in MEDLINE, Embase, and CENTRAL databases from inception to September 2017. All studies reporting an area under the curve (AUC) for a biomarker to predict initiation of RRT were included.
Results
Sixty-three studies comprising 15,928 critically ill patients (median per study 122.5 31–1439) met eligibility. Forty-one studies evaluating 13 different biomarkers were included. Of these biomarkers, neutrophil gelatinase-associated lipocalin (NGAL) had the largest body of evidence. The pooled AUCs for urine and blood NGAL were 0.720 (95% CI 0.638–0.803) and 0.755 (0.706–0.803), respectively. Blood creatinine and cystatin C had pooled AUCs of 0.764 (0.732–0.796) and 0.768 (0.729–0.807), respectively. For urine biomarkers, interleukin-18, cystatin C, and the product of tissue inhibitor of metalloproteinase-2 and insulin growth factor binding protein-7 showed pooled AUCs of 0.668 (0.606–0.729), 0.722 (0.575–0.868), and 0.857 (0.789–0.925), respectively.
Conclusion
Though several biomarkers showed promise and reasonable prediction of RRT use for critically ill patients with AKI, the strength of evidence currently precludes their routine use to guide decision-making on when to initiate RRT.
The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. ...Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6Rα) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6Rα antibody, suppressed tumor growth
in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6Rα overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6Rα and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers.
These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers.
.
Metal negative electrodes that alloy with lithium have high theoretical charge storage capacity and are ideal candidates for developing high-energy rechargeable batteries. However, such electrode ...materials show limited reversibility in Li-ion batteries with standard non-aqueous liquid electrolyte solutions. To circumvent this issue, here we report the use of non-pre-lithiated aluminum-foil-based negative electrodes with engineered microstructures in an all-solid-state Li-ion cell configuration. When a 30-μm-thick Al
In
negative electrode is combined with a Li
PS
Cl solid-state electrolyte and a LiNi
Mn
Co
O
-based positive electrode, lab-scale cells deliver hundreds of stable cycles with practically relevant areal capacities at high current densities (6.5 mA cm
). We also demonstrate that the multiphase Al-In microstructure enables improved rate behavior and enhanced reversibility due to the distributed LiIn network within the aluminum matrix. These results demonstrate the possibility of improved all-solid-state batteries via metallurgical design of negative electrodes while simplifying manufacturing processes.
Objective
To describe an expanded phenotypic spectrum and longitudinal outcome in 256 LGI1‐IgG–seropositive and/or CASPR2‐IgG–seropositive patients.
Methods
Patients were identified through service ...neural autoantibody evaluation. Ninety‐five had longitudinal follow‐up (7–456 months; median = 35).
Results
Among 3,910 patients tested, 196 were LGI1‐IgG positive, 51 were CASPR2‐IgG positive, and 9 were dual positive. Cerebrospinal fluid testing was less sensitive than serum testing, detecting only 24 of 38 (63%) LGI1‐IgG–positive and 5 of 6 (83%) CASPR2‐IgG–positive patients. LGI1‐IgG–positive specimens had higher voltage‐gated potassium channel–IgG immunoprecipitation values (0.33nmol/l, range = 0.02–5.14) than CASPR2‐IgG–positive specimens (0.10nmol/l, range = 0.00–0.45, p < 0.001). Of patients presenting with pain or peripheral nervous system (PNS) manifestations, 39% were LGI1‐IgG seropositive (7% had solely neuropathy or pain). Multivariate analysis identified age as the only significant predictor of central nervous system (CNS) versus PNS involvement (>50 years; odds ratio = 15, p < 0.001). Paroxysmal dizziness spells (PDS), a unique LGI1‐IgG accompaniment (14% of patients), frequently delayed the diagnosis. T2‐mesiotemporal hyperintensity was more common in LGI1‐IgG–positive (41%) than in CASPR2‐IgG–positive patients (p = 0.033). T1‐bright basal ganglia were confined to LGI1‐IgG–positive patients with faciobrachial–dystonic seizures (9 of 39, 31%). Cancer was found in 44% of LGI1‐IgG/CASPR2‐IgG dual seropositive patients (one‐third thymoma). Response to initial immunotherapy was favorable in 97%; mean modified Rankin score was 3 (range = 1–5) at onset and 1.74 (range = 0–6) at last follow‐up, with 9% having severe refractory disability, 20% being asymptomatic, 28% receiving immunotherapy, and 58% receiving antiepileptic medication.
Interpretation
Older age is a strong predictor of CNS involvement in patients seropositive for CASPR2‐IgG or LGI1‐IgG. Pain, peripheral manifestations, and stereotypic paroxysmal dizziness spells are common with LGI1‐IgG. Response to initial immunotherapy is often favorable, but some patients remain severely disabled, requiring long‐term immunotherapy and/or antiepileptic medications. Ann Neurol 2017;82:79–92
Management of Kawasaki disease Eleftheriou, D; Levin, M; Shingadia, D ...
Archives of disease in childhood,
01/2014, Letnik:
99, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Kawasaki disease (KD) is an acute self-limiting inflammatory disorder, associated with vasculitis, affecting predominantly medium-sized arteries, particularly the coronary arteries. In developed ...countries KD is the commonest cause of acquired heart disease in childhood. The aetiology of KD remains unknown, and it is currently believed that one or more as yet unidentified infectious agents induce an intense inflammatory host response in genetically susceptible individuals. Genetic studies have identified several susceptibility genes for KD and its sequelae in different ethnic populations, including FCGR2A, CD40, ITPKC, FAM167A-BLK and CASP3, as well as genes influencing response to intravenous immunoglobulin (IVIG) and aneurysm formation such as FCGR3B, and transforming growth factor (TGF) β pathway genes. IVIG and aspirin are effective therapeutically, but recent clinical trials and meta-analyses have demonstrated that the addition of corticosteroids to IVIG is beneficial for the prevention of coronary artery aneurysms (CAA) in severe cases with highest risk of IVIG resistance. Outside of Japan, however, clinical scores to predict IVIG resistance perform suboptimally. Furthermore, the evidence base does not provide clear guidance on which corticosteroid regimen is most effective. Other therapies, including anti-TNFα, could also have a role for IVIG-resistant KD. Irrespective of these caveats, it is clear that therapy that reduces inflammation in acute KD, improves outcome. This paper summarises recent advances in the understanding of KD pathogenesis and therapeutics, and provides an approach for managing KD patients in the UK in the light of these advances.
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