Search Results (8)

Background/Objectives: Achromobacter xylosoxidans and Achromobacter insuavis are emerging opportunistic pathogens. Several Resistance-Nodulation-cell Division (RND) efflux systems are involved in intrinsic or acquired antibiotic resistance (AxyABM, AxyXY-OprZ, and AxyEF-OprN). The aim of this study was to explore the resistance mechanisms in one-step mutants in which the efflux systems described to date are not involved: one mutant of A. insuavis AXX-A (AXX-A-Do1) and two mutants of A. xylosoxidans CIP102236 (CIP102236-El9 and CIP102236-Eo4) selected on fluoroquinolones. Methods: In vitro mutants were compared to parental isolates by WGS. RT–qPCR and gene inactivation were used to explore the role of the new efflux systems detected. Results: In the A. insuavis AXX-A mutant (AXX-A-Do1), WGS showed a substitution in the putative regulator of the new RND efflux system AinCDJ. The transporter gene ainD was 79-fold overexpressed in AXX-A-Do1, compared to its parental strain. The inactivation of ainD in AXX-A-Do1 led to a decrease in MICs of ciprofloxacin (8-fold), levofloxacin (8-fold), cefepime (≥8-fold), meropenem (4-fold), doripenem (4-fold), doxycycline (4-fold), minocycline (4-fold), tigecycline (4-fold) and chloramphenicol (≥8-fold). The MICs values obtained were similar to those of the parental strain AXX-A. The same approach allowed the detection of the new efflux system AxySUV in A. xylosoxidans CIP102236 mutants, in which substitutions in the putative AxySUV regulator were associated with the overexpression of the transporter gene axyU. axyU inactivation in the mutants led to a decrease in MICs of ciprofloxacin (8- to 16-fold), levofloxacin (4- to 8-fold), doripenem (4-fold), doxycycline (4-fold), minocycline (4-fold), and chloramphenicol (≥4-fold). Interestingly, axySUV is present in only about 50% of available A. xylosoxidans genomes, whereas ainCDJ is detected in all A. insuavis genomes. Conclusions: This study demonstrated that AinCDJ overproduction is involved in the acquired resistance of A. insuavis to cefepime, meropenem, doripenem, fluoroquinolones, minocycline, doxycycline, tigecycline, and chloramphenicol and that AxySUV overproduction is involved in the acquired resistance of A. xylosoxidans to meropenem, fluoroquinolones, minocycline, doxycycline, and chloramphenicol. Full article

Vulvar carcinoma is a rare cancer affecting the genital tract, constituting 4% of gynecological tumors. Vulvar squamous cell carcinoma (VSCC) is the most common type. Diagnosis relies on biopsy during vulvoscopy, plus imaging such as ultrasonography (USG), magnetic resonance imaging (MRI) and positron emission tomography (PET). This review aims to lay out a thorough overview as to the current preoperative management of VSCC, both in case of vulvar and lymph node involvement. The data research was conducted using the following databases: MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID and Cochrane Library from 2010 to 2024. The selection criteria included only original articles. Seventeen studies were assessed for eligibility. A concordance rate of 62.3% for vHSIL and 65.2% for carcinoma at vulvoscopy, with a sensitivity of 98%, specificity of 40%, PPV (Positive Predictive Value) of 37% and NPV (Negative Predictive Value) of 98% in identifying malignant lesions was found. Regarding the reliability of PET for staging and assessing lymph node involvement, a mean SUV (Standardized Uptake Value) for malignant vulvar lesions of 8.4 (range 2.5–14.7) was reported. In the case of MRI, useful for the evaluation of loco-regional infiltration and lymph node involvement, the ratio of the short-to-long-axis diameter and the reader’s diagnostic confidence for the presence of lymph node metastasis yielded accuracy of 84.8% and 86.9%, sensitivity of 86.7% and 87.5%, specificity of 81.3% and 86.2%, PPV of 89.7% and 87.5% and NPV of 76.5% and 86.2%, respectively. A long lymph node axis >10 mm and a short diameter >5.8 mm were found to be predictors of malignancy. At USG, instead, the two main characteristics of potentially malignant lymph nodes are cortical thickness and short axis length; the combination of these ultrasound parameters yielded the highest accuracy in distinguishing between negative and positive lymph nodes. Despite the heterogeneity of the included studies and the lack of randomized clinical trials, this review provides a broad overview of the three imaging tools used for the presurgical management of VSCC. Nowadays, although MRI and PET represent the gold standard, ultrasound evaluation is taking on a growing role, as long as it is carried out by expert sonographer. The management of this rare disease should be always performed by a multidisciplinary team in order to precisely stage the tumor and determine the most suitable treatment approach. Full article

Background: Since most endocrine glands express ACE-2 receptors and can be infected by SARS-CoV-2 virus, this retrospective multicentre observational study aims to assess the metabolic activity of thyroid and adrenal glands of COVID-19 patients by ¹⁸F-FDG PET/CT. Methods: We retrospectively evaluated the ¹⁸F-FDG PET/CT scans of COVID-19 patients admitted by three different centres, either in a low-intensity department or in the intensive care unit (ICU). A visual assessment and a semi-quantitative evaluation of areas of interest in thyroid and adrenal glands were performed by recording SUVmax and SUVmean. The ¹⁸F-FDG PET/CT uptake in COVID-19 patients was compared with those observed in normal age-matched controls. Results: Between March 2020 and March 2022, 33 patients from three different centres (twenty-eight patients in a low-intensity department and five patients in ICU), were studied by ¹⁸F-FDG PET/CT during active illness. Seven of them were also studied after clinical remission (3–6 months after disease onset). Thirty-six normal subjects were used as age-matched controls. In the thyroid gland, no statistically significant differences were observed between control subjects and COVID-19 patients at diagnosis. However, at the follow-up PET/CT study, we found a statistically higher SUVmax and SUVmean (p = 0.009 and p = 0.004, respectively) in the thyroid of COVID-19 patients. In adrenal glands, we observed lower SUVmax and SUVmean in COVID-19 patients at baseline compared to control subjects (p < 0.0001) and this finding did not normalize after clinical recovery (p = 0.0018 for SUVmax and p = 0.002 for SUV mean). Conclusions: In our series, we observed persistent low ¹⁸F-FDG uptake in adrenal glands of patients at diagnosis of COVID-19 and after recovery, suggesting a chronic hypofunction. By contrast, thyroid uptake was comparable to normal subjects at disease onset, but after recovery, a subgroup of patients showed an increased metabolism, thus possibly suggesting the onset of an inflammatory thyroiditis. Our results should alert clinicians to investigate the pituitary–adrenal axis and thyroid functionality at the time of infection and to monitor them after recovery. Full article

Macrophages undergo different cellular states upon activation that can be hyporesponsive (tolerated) or hyperresponsive (primed or trained) to subsequent stimuli. Epigenetic modifications are known to play key roles in determining these cellular states. However, little is known about the role of signaling pathways that lead to these epigenetic modifications. Here, we examined the effects of various inhibitors targeting key signaling pathways induced by lipopolysaccharide (LPS) on tolerance and priming in murine macrophages. We found that a prolonged inhibition (>18 h) of the mitogen-activated protein kinase (MEK)1/2—extracellular signal-regulated kinase (ERK)1/2 signaling axis reversed tolerance and primed cells in expressing interleukin (IL)-1β and other inflammatory cytokines such as IL-6, tumor necrosis factor (TNF)α, and CXCL10. The ectopic expression of catalytically active and inactive MEK1 mutants suppressed and enhanced IL-1β expression, respectively. A transcriptomic analysis showed that cells primed by the MEK1/2 inhibitor U0126 expressed higher levels of gene sets associated with immune responses and cytokine/chemokine production, but expressed lower levels of genes with cell cycle progression, chromosome organization, and heterochromatin formation than non-primed cells. Of interest, the mRNA expressions of the histone 3 lysine 9 (H3K9) methyltransferase Suv39h1 and the H3K9 methylation reader Cbx5 were substantially suppressed, whereas the H3K9 demethylase Kdm7a was enhanced, suggesting a role of the MEK1/2-ERK signaling axis in H3K9 demethylation. The H3K9 trimethylation levels in the genomic regions of IL-1β, TNFα, and CXCL10 were decreased by U0126. Also, the H3K9 methyltransferase inhibitor BIX01294 mimicked the U0126 training effects and the overexpression of chromobox homolog (CBX)5 prevented the U0126 training effects in both RAW264.7 cells and bone-marrow-derived macrophages. Collectively, these data suggest that the prolonged inhibition of the MEK1/2-ERK signaling axis reverses tolerance and primed macrophages likely through decreasing the H3K9 methylation levels. Full article

Crowdsourced logistics has emerged as a delivery channel for many single-parcel packages. As a result, this logistics network has introduced personal passenger vehicles as a means to transport parcels during last mile delivery segments. To understand this network’s vibration levels and cargo capacity restraints, four vehicle types (a sedan, sports sedan, compact SUV and full-size SUV) commonly used in crowdsourced logistics deliveries were selected for measurement and analysis. This study shows that the vibration levels were significantly higher in the vertical axis and that the overall vibration energy increased as vehicle speed increased, except in the sedan. The sedan and SUV vehicles showed power spectral density peak frequencies in the low-frequency range, occurring at approximately 2 Hz, matching previous studies using similar vehicles. The vibration levels were greatest in the sports sedan and lowest in the sedan. The recorded vibration events showed a right-skewed heavy-tailed distribution and were non-Gaussian. Full article

The primary objective of a hybrid electric vehicle (HEV) is to optimize the energy consumption of the automotive powertrain. This optimization has to be applied while respecting the operating conditions of the battery. Otherwise, there is a risk of compromising the battery life and thermal runaway that may result from excessive power transfer across the battery. Such considerations are critical if factoring in the low battery capacity and the passive battery cooling technology that is commonly associated with HEVs. The literature has proposed many solutions to HEV energy optimization. However, only a few of the solutions have addressed this optimization in the presence of thermal constraints. In this paper, a strategy for energy optimization in the presence of thermal constraints is developed for P2 HEVs based on battery sizing and the application of model predictive control (MPC) strategy. To analyse this approach, an electro-thermal battery pack model is integrated with an off-axis P2 HEV powertrain. The battery pack is properly sized to prevent thermal runaway while improving the energy consumption. The power splitting, thermal enhancement and energy optimization of the complex and nonlinear system are handled in this work with an adaptive MPC operated within a moving finite prediction horizon. The simulation results of the HEV SUV demonstrate that, by applying thermal constraints, energy consumption for a 0.9 kWh battery capacity can be reduced by 11.3% relative to the conventional vehicle. This corresponds to about a 1.5% energy increase when there is no thermal constraint. However, by increasing the battery capacity to 1.5 kWh (14s10p), it is possible to reduce the energy consumption by 15.7%. Additional benefits associated with the predictive capability of MPC are reported in terms of energy minimization and thermal improvement. Full article

The aim of this research was to design a physically consistent model for the forced torsional vibrations of automotive driveshafts that considered aspects of the following phenomena: excitation due to the transmission of the combustion engine through the gearbox, excitation due to the road geometry, the quasi-isometry of the automotive driveshaft, the effect of nonuniformity of the inertial moment with respect to the longitudinal axis of the tulip–tripod joint and of the bowl–balls–inner race joint, the torsional rigidity, and the torsional damping of each joint. To resolve the equations of motion describing the forced torsional nonlinear parametric vibrations of automotive driveshafts, a variational approach that involves Hamilton’s principle was used, which considers the isometric nonuniformity, where it is known that the joints of automotive driveshafts are quasi-isometric in terms of the twist angle, even if, in general, they are considered CVJs (constant velocity joints). This effect realizes the link between the terms for the torsional vibrations between the elements of the driveshaft: tripode–tulip, midshaft, and bowl–balls–inner race joint elements. The induced torsional loads (as gearbox torsional moments that enter the driveshaft through the tulip axis) can be of harmonic type, while the reactive torsional loads (as reactive torsional moments that enter the driveshaft through the bowl axis) are impulsive. These effects induce the resulting nonlinear dynamic behavior. Also considered was the effect of nonuniformity on the axial moment of inertia of the tripod–tulip element as well as on the axial moment of inertia of the bowl–balls–inner race joint element, that vary with the twist angle of each element. This effect induces parametric dynamic behavior. Moreover, the torsional rigidity was taken into consideration, as was the torsional damping for each joint of the driveshaft: tripod–joint and bowl–balls–inner race joint. This approach was used to obtain a system of equations of nonlinear partial derivatives that describes the torsional vibrations of the driveshaft as nonlinear parametric dynamic behavior. This model was used to compute variation in the natural frequencies of torsion in the global tulip (a given imposed geometry) using the angle between the tulip–midshaft for an automotive driveshaft designed for heavy-duty SUVs as well as the characteristic amplitude frequency in the region of principal parametric resonance together the method of harmonic balance for the steady-state forced torsional nonlinear vibration of the driveshaft. This model of dynamic behavior for the driveshaft can be used during the early stages of design as well in predicting the durability of automotive driveshafts. In addition, it is important that this model be added in the design algorithm for predicting the comfort elements of the automotive environment to adequately account for this kind of dynamic behavior that induces excitations in the car structure. Full article

The standardized uptake value (SUV), an indicator of the degree of glucose uptake in ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET), has been used for predicting the clinical behavior of malignant tumors. However, its characteristics have been insufficiently explored at the genomics level. Here, we aim to identify genomic signatures reflecting prognostic SUV characteristics in breast cancer (BRC). Through integrative genomic profiling of 3710 BRC patients, including 254 patients who underwent preoperative FDG-PET, we identified an SUV signature, which showed independent clinical utility for predicting BRC prognosis (hazard ratio [HR] 1.27, 95% confidence interval [CI] = 1.12 to 1.45, p = 2.23 × 10⁻⁴). The risk subgroups classified by the signature exhibited mutually exclusive mutation patterns of TP53 and PIK3CA and showed significantly different responsiveness to immunotherapy. Experimental assays revealed that a signaling axis defined by TP53–FOXM1 and its downstream effectors in glycolysis–gluconeogenesis, including LDHA, might be important mediators in the FDG-PET process. Our molecular characterizations support an understanding of glucose metabolism and poor prognosis in BRC with a high SUV, utilizable in clinical practice to assist other diagnostic tools. Full article