To investigate prospectively the trade-off between temporal and spatial resolution in dynamic contrast material-enhanced bilateral magnetic resonance (MR) imaging of the breast.
Informed consent and ...institutional review board approval were obtained. An intraindividual comparative study was performed in 30 patients (mean age, 53 years; age range, 27-70 years) with a total of 54 enhancing lesions (28 benign and 26 malignant) who underwent dynamic MR imaging of the breast twice, once with a standard dynamic protocol (256 x 256 matrix, 69 seconds per acquisition) and once on a separate day with a modified dynamic protocol (400 x 512 matrix, 116 seconds per acquisition). Systematic qualitative analysis of morphologic features and region-of-interest-based analysis of enhancement kinetics were performed.
A statistically significant difference (generalized linear modeling) in enhancement rates of benign versus malignant lesions was lost when moving from the standard to the modified dynamic protocol. Kinetic information on signal intensity time course patterns was preserved. Delineation of lesion margins and internal architecture was clearly superior with the modified dynamic protocol, which allowed identification of lesion features associated with high positive predictive value or high negative predictive value for breast cancer. Ten benign lesions classified as Breast Imaging Reporting and Data System (BI-RADS) category 3 with the standard protocol were correctly downgraded to BI-RADS category 2 with the modified protocol owing to visualization of internal septations. Thirteen malignant lesions categorized as BI-RADS category 3 or 4 with the standard protocol were correctly upgraded to BI-RADS category 4 or 5 with the modified protocol owing to visualization of spicules or rim enhancement. Receiver operating characteristic analysis revealed a significantly larger area under the curve for results obtained with the modified dynamic protocol.
Increased spatial resolution significantly improves diagnostic confidence and accuracy at dynamic MR imaging, even if this improvement occurs at the expense of temporal resolution. Loss of kinetic information regarding enhancement rates proved to be not diagnostically relevant because enhancement rates showed broad overlap between benign and malignant lesions and were therefore of only limited diagnostic use in the individual patient. Kinetic information regarding time course pattern was preserved and confirmed as having high specificity and high positive predictive value.
Gram-negative bacteria release outer membrane vesicles into the external milieu to deliver effector molecules that alter the host and facilitate virulence. Vesicle formation is driven by phospholipid ...accumulation in the outer membrane and regulated by the phospholipid transporter VacJ/Yrb. We use the facultative human pathogen Vibrio cholerae to show that VacJ/Yrb is silenced early during mammalian infection, which stimulates vesiculation that expedites bacterial surface exchange and adaptation to the host environment. Hypervesiculating strains rapidly alter their bacterial membrane composition and exhibit enhanced intestinal colonization fitness. This adaptation is exemplified by faster accumulation of glycine-modified lipopolysaccharide (LPS) and depletion of outer membrane porin OmpT, which confers resistance to host-derived antimicrobial peptides and bile, respectively. The competitive advantage of hypervesiculation is lost upon pre-adaptation to bile and antimicrobial peptides, indicating the importance of these adaptive processes. Thus, bacteria use outer membrane vesiculation to exchange cell surface components, thereby increasing survival during mammalian infection.
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•Phospholipid transport of Vibrio cholerae is silenced upon host entry•Reduced transporter activity triggers OMV release and increases colonization fitness•Increased vesiculation accelerates modulation of cell surface composition•Hypervesiculation leads to faster adaptation to host defense mediators
Upon infection, Vibrio cholerae must alter its surface profile to evade host defenses and adapt to the gastrointestinal environment. Zingl et al. show that increased release of outer membrane vesicles upon host entry allows the bacteria to rapidly modify their cell surface, thus increasing in vivo adaptation and colonization fitness.
Objective:
Robin sequence (RS) consists of micrognathia and glossoptosis that result in upper airway obstruction (UAO). In RS patients who undergo tracheostomy, long-term goals include natural ...decannulation (ND) without further surgical airway intervention. The objective of this study was to identify long-term trends in the rate and length of time to ND.
Methods:
Retrospective chart review on 144 patients with RS treated from 1995 to 2020 at a pediatric tertiary care center. Patients were grouped by year of tracheostomy. Demographic data, UAO management, postoperative care, complications, and time to decannulation were recorded.
Results:
Thirty-six patients met the inclusion criteria. Tracheostomy was performed at a median age of 45.5 days. 19 (53%) patients experienced ND at a median time of 66.1 months. ND rate was higher in non-syndromic patients (93% non-syndromic vs 27% syndromic; P < .0001) and during the first study period (1995-2006: 78%, 2007-2020: 28%; P = .003). Cox proportional-hazard regression demonstrated that white race aHR 0.15 (0.03-0.8); P = .023 and higher birthweight aHR 0.9 (0.8-0.98); P = .018 were associated with a higher likelihood of ND while a syndromic diagnosis had a negative association with ND aHR 12.5 (3.3-50.0); P < .001.
Conclusions:
Our study documented that ND in patients with RS who underwent tracheostomy was significantly associated with ethnicity, birthweight, and syndromic status. The negative impact on successful ND was most observed in patients with syndromic associations. Additionally, ND rates are lower in the 2007 to 2020 subgroup. We suspect this is because alternative management techniques such as tongue lip adhesion and mandibular distraction osteogenesis became primary surgical treatment in severe RS upper airway obstruction at our institution starting in 2007.
The heat shock protein Gp96 has been shown to induce specific immune responses. On one hand, this phenomenon is based on the specific interaction with CD91 that mediates endocytosis and results in ...major histocompatibility complex class I-restricted representation of the Gp96-associated peptides. On the other hand, Gp96 induces activation of professional antigen-presenting cells, resulting in the production of pro-inflammatory cytokines and up-regulation of costimulatory molecules by unknown mechanisms. In this study, we have analyzed the consequences of Gp96 interaction with cells expressing different Toll-like receptors (TLRs) and with bone marrow-derived dendritic cells from mice lacking functional TLR2 and/or TLR4 molecules. We find that the Gp96-TLR2/4 interaction results in activation of nuclear factor κB-driven reporter genes and mitogen- and stress-activated protein kinases and induces IκBα degradation. Bone marrow-derived dendritic cells of C3H/HeJ and more pronounced C3H/HeJ/TLR2−/− mice fail to respond to Gp96. Interestingly, activation of bone marrow-derived dendritic cells depends on endocytosis of Gp96 molecules. Our results provide, for the first time, the molecular basis for understanding the Gp96-mediated activation of antigen-presenting cells by describing the simultaneous stimulation of the innate and adaptive immune system. This feature explains the remarkable ability of Gp96 to induce specific immune responses against tumors and pathogens.
To investigate the association between external beam radiotherapy (EBRT) dose and biochemical failure (BcF) of prostate cancer in patients who received salvage prostate bed EBRT for a rising ...prostate-specific antigen (PSA) level after radical prostatectomy.
We evaluated patients with a rising PSA level after prostatectomy who received salvage EBRT between July 1987 and October 2007. Patients receiving pre-EBRT androgen suppression were excluded. Cox proportional hazards models were used to investigate the association between EBRT dose and BcF. Dose was considered as a numeric variable and as a categoric variable (low, <64.8 Gy; moderate, 64.8-66.6 Gy; high, >66.6 Gy).
A total of 364 men met study selection criteria and were followed up for a median of 6.0 years (range, 0.1-19.3 years). Median pre-EBRT PSA level was 0.6 ng/mL. The estimated cumulative rate of BcF at 5 years after EBRT was 50% overall and 57%, 46%, and 39% for the low-, moderate-, and high-dose groups, respectively. In multivariable analysis adjusting for potentially confounding variables, there was evidence of a linear trend between dose and BcF, with risk of BcF decreasing as dose increased (relative risk RR, 0.77 5.0-Gy increase; p = 0.05). Compared with the low-dose group, there was evidence of a decreased risk of BcF for the high-dose group (RR, 0.60; p = 0.04), but no difference for the moderate-dose group (RR, 0.85; p = 0.41).
Our results suggest a dose response for salvage EBRT. Doses higher than 66.6 Gy result in decreased risk of BcF.
Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th17 cells. Herein, we report that IRF4 is also crucial for the development and function of an ...interleukin-9 (IL-9)-producing CD4
+ T cell subset designated Th9. IRF4-deficient CD4
+ T cells failed to develop into IL-9-producing Th9 cells, and IRF4-specific siRNA inhibited IL-9 production in wild-type CD4
+ T cells. Chromatin-immunoprecipitation (ChIP) analyses revealed direct IRF4 binding to the
Il9 promoter in Th9 cells. In a Th9-dependent asthma model, neutralization of IL-9 substantially ameliorated asthma symptoms. The relevance of these findings is emphasized by the fact that the induction of IL-9 production also occurs in human CD4
+ T cells accompanied by the upregulation of IRF4. Our data clearly demonstrate the central function of IRF4 in the development of Th9 cells and underline the contribution of this T helper cell subset to the pathogenesis of asthma.
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► IRF4 crucially contributes to the development and function of Th9 cells ► IRF4 binds to and transactivates the
Il9 promoter in Th9 cells ► IL-9 production of human Th9 cells is accompanied by the expression of IRF4 ► Th9 cells crucially contribute to the pathogenesis of asthma
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•70% of Zn2+ adsorption on BioSeNPs was completed in first minute of the reaction.•Adsorption of Zn2+ on BioSeNPs follows two-step mechanism at near-neutral pH.•Adsorption of Zn2+ on ...BioSeNPs follows ligand-like (type II) mechanism at low pH.•BioSeNPs loaded with Zn2+ have lower colloidal stability vis-a-vis BioSeNPs without Zn2+.
The adsorption of Zn2+ ions onto biogenic elemental selenium nanoparticles (BioSeNPs) was investigated. BioSeNPs were produced by reduction of selenite (SeO32−) in the presence of anaerobic granules from a full scale upflow anaerobic sludge blanket (UASB) reactor treating paper mill wastewater. The BioSeNPs have an iso-electric point at pH 3.8 at 5mM background electrolyte concentration. X-ray photoelectron spectroscopy showed the presence of a layer of extracellular polymeric substances on the surface of BioSeNPs providing colloidal stability. Batch adsorption experiments showed that the uptake of Zn2+ ions by BioSeNPs was fast and occurred at a pH as low as 3.9. The maximum adsorption capacity observed was 60mg of zinc adsorbed per g of BioSeNPs. The Zn2+ ions adsorption on the BioSeNPs was largely unaffected by the presence of Na+ and Mg2+, but was impacted by the presence of Ca2+ and Fe2+ ions. The colloidal stability of BioSeNPs decreased with the increasing Zn2+ ions loading on BioSeNPs (increase in mg of zinc adsorbed per g of BioSeNPs), corresponding to the neutralization of the negative surface charge of the BioSeNPs, suggesting gravity settling as a technique for solid–liquid separation after adsorption. This study proposes a novel technology for removal of divalent cationic heavy metals by their adsorption on the BioSeNPs present in the effluent of an UASB reactor treating selenium oxyanions containing wastewaters.
Heat shock proteins (HSPs) like glycoprotein (gp)96 (glucose-regulated protein 94 grp94) are able to induce specific cytotoxic T lymphocyte (CTL) responses against cells from which they originate. ...Here, we demonstrate that for CTL activation by gp96-chaperoned peptides, specific receptor-mediated uptake of gp96 by antigen-presenting cells (APCs) is required. Moreover, we show that in both humans and mice, only professional APCs like dendritic cells (DCs), macrophages, and B cells, but not T cells, are able to bind gp96. The binding is saturable and can be inhibited using unlabeled gp96 molecules. Receptor binding by APCs leads to a rapid internalization of gp96, which colocalizes with endocytosed major histocompatibility complex (MHC) class I and class II molecules in endosomal compartments. Incubation of gp96 molecules isolated from cells expressing an adenovirus type 5 E1B epitope with the DC line D1 results in the activation of E1B-specific CTLs. This CTL activation can be specifically inhibited by the addition of irrelevant gp96 molecules not associated with E1B peptides. Our results demonstrate that only receptor-mediated endocytosis of gp96 molecules leads to MHC class I-restricted re-presentation of gp96-associated peptides and CTL activation; non-receptor-mediated, nonspecific endocytosis is not able to do so. Thus, we provide evidence on the mechanisms by which gp96 is participating in the cross-presentation of antigens from cellular origin.
To study five radiotherapy (RT) schedules and potential prognostic factors for functional outcome in metastatic spinal cord compression (MSCC).
One thousand three hundred four patients who were ...irradiated from January 1992 to December 2003 were included in this retrospective review. The schedules of 1 x 8 Gy in 1 day (n = 261), 5 x 4 Gy in 1 week (n = 279), 10 x 3 Gy in 2 weeks (n = 274), 15 x 2.5 Gy in 3 weeks (n = 233), and 20 x 2 Gy in 4 weeks (n = 257) were compared for motor function, ambulatory status, and in-field recurrences. The following potential prognostic factors were investigated: age, sex, performance status, histology, number of involved vertebra, interval from cancer diagnosis to MSCC, pretreatment ambulatory status, and time of developing motor deficits before RT. A multivariate analysis was performed with the ordered logit model.
Motor function improved in 26% (1 x 8 Gy), 28% (5 x 4 Gy), 27% (10 x 3 Gy), 31% (15 x 2.5 Gy), and 28% (20 x 2 Gy); and posttreatment ambulatory rates were 69%, 68%, 63%, 66%, and 74% (P = .578), respectively. On multivariate analysis, age, performance status, primary tumor, involved vertebra, interval from cancer diagnosis to MSCC, pretreatment ambulatory status, and time of developing motor deficits were significantly associated with functional outcome, whereas the RT schedule was not. Acute toxicity was mild, and late toxicity was not observed. In-field recurrence rates at 2 years were 24% (1 x 8 Gy), 26% (5 x 4 Gy), 14% (10 x 3 Gy), 9% (15 x 2.5 Gy), and 7% (20 x 2 Gy) (P < .001). Neither the difference between 1 x 8 Gy and 5 x 4 Gy (P = .44) nor between 10 x 3 Gy, 15 x 2.5 Gy, and 20 x 2 Gy (P = .71) was significant.
The five RT schedules provided similar functional outcome. The three more protracted schedules seemed to result in fewer in-field recurrences. To minimize treatment time, the following two schedules are recommended: 1 x 8 Gy for patients with poor predicted survival and 10 x 3 Gy for other patients. Results should be confirmed in a prospective randomized trial.
Although cytotoxic T lymphocytes (CTLs) in people infected with human immunodeficiency virus type 1 can potentially target multiple virus epitopes, the same few are recognized repeatedly. We show ...here that CTL immunodominance in regions of the human immunodeficiency virus type 1 group-associated antigen proteins p17 and p24 correlated with epitope abundance, which was strongly influenced by proteasomal digestion profiles, affinity for the transporter protein TAP, and trimming mediated by the endoplasmatic reticulum aminopeptidase ERAAP, and was moderately influenced by HLA affinity. Structural and functional analyses demonstrated that proteasomal cleavage 'preferences' modulated the number and length of epitope-containing peptides, thereby affecting the response avidity and clonality of T cells. Cleavage patterns were affected by both flanking and intraepitope CTL-escape mutations. Our analyses show that antigen processing shapes CTL response hierarchies and that viral evolution modifies cleavage patterns and suggest strategies for in vitro vaccine optimization.
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