Case Report: Metagenomic Next-Generation Sequencing in Diagnosis of Legionella pneumophila Pneumonia in a Patient After Umbilical Cord Blood Stem Cell Transplantation

We report a case of hospital-acquired Legionella pneumonia that was detected by metagenomic next-generation sequencing (mNGS) of blood from a 7-year-old girl after umbilical cord blood stem cell transplantation (UCBT) with myelodysplastic syndrome. UCBT is traditionally associated with an increased risk of infection, particularly during the first 3 months after transplantation. Controlling interstitial pneumonia and severe infection is the key to reducing patient mortality from infection. Legionella pneumophila can cause a mild cough to rapidly fatal pneumonia. After mNGS confirmed that the pathogen was L. pneumophila, azithromycin, cefoperazone sulbactam, and posaconazole were used for treatment, and the patient's temperature decreased and remained normal. The details of this case highlight the benefits of the timely use of metagenomic NGS to identify pathogens for the survival of immunocompromised patients

Activation and genotoxic consequences of the PremarinRTM equine estrogen metabolites to reactive quinones.

Activation and genotoxic consequences of the PremarinRTM equine estrogen metabolites to reactive quinones

Intelligent Mining of Urban Ventilation Corridors Based on High-Precision Oblique Photographic Images

With the advancement of urbanization and the impact of industrial pollution, the issue of urban ventilation has attracted increasing attention. Research on urban ventilation corridors is a hotspot in the field of urban planning. Traditional studies on ventilation corridors mostly focus on qualitative or simulated research on urban climate issues such as the intensified urban heat island effect, serious environmental pollution, and insufficient climate adaptability. Based on the high-precision urban remote sensing image data obtained by aeromagnetic oblique photography, this paper calculates the frontal area density of the city with reference to the urban wind statistics. Based on the existing urban patterns, template matching technology was used to automatically excavate urban ventilation corridors, which provides scientific and reasonable algorithmic support for the rapid construction of potential urban ventilation corridor paths. It also provides technical methods and decision basis for low-carbon urban planning, ecological planning and microclimate optimization design. This method was proved to be effective through experiments in Deqing city, Zhejiang Province, China

Intelligent Mining of Urban Ventilated Corridor Based on Digital Surface Model under the Guidance of K-Means

With the acceleration of urbanization, climate problems affecting human health and safe operation of cities have intensified, such as heat island effect, haze, and acid rain. Using high-resolution remote sensing mapping image data to design scientific and efficient algorithms to excavate and plan urban ventilation corridors and improve urban ventilation environment is an effective way to solve these problems. In this paper, we use unmanned aerial vehicle (UAV) tilt photography technology to obtain high-precision remote sensing image digital elevation model (DEM) and digital surface model (DSM) data, count the city’s dominant wind direction in each season using long-term meteorological data, and use building height to calculate the dominant wind direction. The projection algorithm calculates the windward area density of this dominant direction. Under the guidance of K-means, the binarized windward area density map is used to determine each area and boundary of potential ventilation corridors within the threshold range, and the length and angle of each area’s fitted elliptical long axis are calculated to extract the ventilation corridors that meet the criteria. On the basis of high-precision stereo remote sensing data from UAV, the paper uses image classification, segmentation, fitting, and fusion algorithms to intelligently mine potential urban ventilation corridors, and the effectiveness of the proposed method is demonstrated through a case study in Zhuji City, Zhejiang Province

Intelligent Labeling of Tumor Lesions Based on Positron Emission Tomography/Computed Tomography

Positron emission tomography/computed tomography (PET/CT) plays a vital role in diagnosing tumors. However, PET/CT imaging relies primarily on manual interpretation and labeling by medical professionals. An enormous workload will affect the training samples’ construction for deep learning. The labeling of tumor lesions in PET/CT images involves the intersection of computer graphics and medicine, such as registration, a fusion of medical images, and labeling of lesions. This paper extends the linear interpolation, enhances it in a specific area of the PET image, and uses the outer frame scaling of the PET/CT image and the least-squares residual affine method. The PET and CT images are subjected to wavelet transformation and then synthesized in proportion to form a PET/CT fusion image. According to the absorption of 18F-FDG (fluoro deoxy glucose) SUV in the PET image, the professionals randomly select a point in the focus area in the fusion image, and the system will automatically select the seed point of the focus area to delineate the tumor focus with the regional growth method. Finally, the focus delineated on the PET and CT fusion images is automatically mapped to CT images in the form of polygons, and rectangular segmentation and labeling are formed. This study took the actual PET/CT of patients with lymphatic cancer as an example. The semiautomatic labeling of the system and the manual labeling of imaging specialists were compared and verified. The recognition rate was 93.35%, and the misjudgment rate was 6.52%

In Vitro Metabolism of Oprozomib, an Oral Proteasome Inhibitor: Role of Epoxide Hydrolases and Cytochrome P450s.

Oprozomib is an oral proteasome inhibitor currently under investigation in patients with hematologic malignancies or solid tumors. Oprozomib elicits potent pharmacological actions by forming a covalent bond with the active site N-terminal threonine of the 20S proteasome. Oprozomib has a short half-life across preclinical species and in patients due to systemic clearance via metabolism. Potential for drug-drug interactions (DDIs) could alter the exposure of this potent therapeutic; therefore, a thorough investigation of pathways responsible for metabolism is required. In the present study, the major drug-metabolizing enzyme responsible for oprozomib metabolism was identified in vitro. A diol of oprozomib was found to be the predominant metabolite in human hepatocytes, which formed via direct epoxide hydrolysis. Using recombinant epoxide hydrolases (EHs) and selective EH inhibitors in liver microsomes, microsomal EH (mEH) but not soluble EH (sEH) was found to be responsible for oprozomib diol formation. Coincubation with 2-nonylsulfanyl-propionamide, a selective mEH inhibitor, resulted in a significant decrease in oprozomib disappearance (>80%) with concurrent complete blockage of diol formation in human hepatocytes. On the contrary, a selective sEH inhibitor did not affect oprozomib metabolism. Pretreatment of hepatocytes with the pan-cytochrome P450 (P450) inhibitor 1-aminobenzotriazole resulted in a modest reduction (∼20%) of oprozomib metabolism. These findings indicated that mEH plays a predominant role in oprozomib metabolism. Further studies may be warranted to determine whether drugs that are mEH inhibitors cause clinically significant DDIs with oprozomib. On the other hand, pharmacokinetics of oprozomib is unlikely to be affected by coadministered P450 and sEH inhibitors and/or inducers

Differential Effects of Oral Boluses of Vitamin D2 vs Vitamin D3 on Vitamin D Metabolism: A Randomized Controlled Trial.

CONTEXT: Vitamin D2 and vitamin D3 have been hypothesized to exert differential effects on vitamin D metabolism. OBJECTIVE: To compare the influence of administering vitamin D2 vs vitamin D3 on metabolism of vitamin D3. METHODS: We measured baseline and 4-month serum concentrations of vitamin D3, 25-hydroxyvitamin D3 [25(OH)D3], 25-hydroxyvitamin D2, 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3], 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], and 4β,25-dihydroxyvitamin D3 [4β,25(OH)2D3] in 52 adults randomized to receive a total of four oral bolus doses of 2.5 mg vitamin D2 (n = 28) or vitamin D3 (n = 24) over four months. Metabolite-to-parent compound ratios were calculated to estimate hydroxylase activity. Pairwise before vs after comparisons were made to evaluate effects of vitamin D2 and vitamin D3 on metabolism of vitamin D. Mean postsupplementation metabolite-to-parent ratios were then compared between groups. RESULTS: Vitamin D2 was less effective than vitamin D3 in elevating total serum 25(OH)D concentration. Vitamin D2 suppressed mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 and mean ratios of 25(OH)D3 to D3 and 1α,25(OH)2D3 to 25(OH)D3, while increasing the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Vitamin D3 increased mean four-month serum concentrations of 25(OH)D3, 24R,25(OH)2D3, 1α,25(OH)2D3, and 4β,25(OH)2D3 and the mean ratio of 24R,25(OH)2D3 to 25(OH)D3. Participants receiving vitamin D2 had lower mean postsupplementation ratios of 25(OH)D3 to vitamin D3 and 1α,25(OH)2D3 to 25(OH)D3 than those receiving vitamin D3. Mean postsupplementation ratios of 24R,25(OH)2D3 to 25(OH)D3 and 4β,25(OH)2D3 to 25(OH)D3 did not differ between groups. CONCLUSIONS: Bolus-dose vitamin D2 is less effective than bolus-dose vitamin D3 in elevating total serum 25(OH)D concentration. Administration of vitamin D2 reduces 25-hydroxylation of vitamin D3 and 1-α hydroxylation of 25(OH)D3, while increasing 24R-hydroxylation of 25(OH)D3.UK Medical Research Council (MC_UP_A100_1003, MC_U106179474, MC_UU_12015/5 and MC_UU_12015/4). US National Institutes of Health (R01 GM63666)

Functional Comparison of Human Colonic Carcinoma Cell Lines and Primary Small Intestinal Epithelial Cells for Investigations of Intestinal Drug Permeability and First-Pass Metabolism

ABSTRACT To further the development of a model for simultaneously assessing intestinal absorption and first-pass metabolism in vitro, Caco-2, LS180, T84, and fetal human small intestinal epithelial cells (fSIECs) were cultured on permeable inserts, and the integrity of cell monolayers, CYP3A4 activity, and the inducibility of enzymes and transporters involved in intestinal drug disposition were measured. Caco-2, T84, and fSIECs all formed tight junctions, as assessed by immunofluorescence microscopy for zonula occludens-1, which was well organized into circumscribing strands in T84, Caco-2, and fSIECs but was diffuse in LS180 cells. The transepithelial electrical resistance value for LS180 monolayers was lower than that for Caco-2, T84, and fSIECs. In addition, the apical-to-basolateral permeability of the paracellular marker Lucifer yellow across LS180 monolayers was greater than in fSIECs, T84, and Caco-2 monolayers. The transcellular marker propranolol exhibited similar permeability across all cells. With regard to metabolic capacity, T84 and LS180 cells showed comparable basal midazolam hydroxylation activity and was inducible by rifampin and 1a,25(OH) 2 D 3 in LS180 cells, but only marginally so in T84 cells. The basal CYP3A4 activity of fSIECs and Caco-2 cells was much lower and not inducible. Interestingly, some of the drug transporters expressed in LS180 and Caco-2 cells were induced by either 1a,25(OH) 2 D 3 or rifampin or both, but effects were limited in the other two cell lines. These results suggest that none of the cell lines tested fully replicated the drug disposition properties of the small intestine and that the search for an ideal screening tool must continue

Dynamic Profile of CD4+ T-Cell-Associated Cytokines/Chemokines following Murine Myocardial Infarction/Reperfusion

CD4+ T-cells play crucial roles in the injured heart. However, the way in which different CD4+ T subtypes function in the myocardial infarction/reperfusion (MI/R) heart is still poorly understood. We aimed to detect the dynamic profile of distinct CD4+ subpopulation-associated cytokines/chemokines by relying on a closed-chest acute murine MI/R model. The protein levels of 26 CD4+ T-cell-associated cytokines/chemokines were detected in the heart tissues and serum of mice at day 7 and day 14 post-MI/R or sham surgery. The mRNA levels of IL-4, IL-6, IL-13, IL-27, MIP-1β, MCP-3, and GRO-α were measured in blood mononuclear cells. The protein levels of IL-4, IL-6, IL-13, IL-27, MIP-1β, MCP-3, and GRO-α increased in both injured heart tissues and serum, while IFN-γ, IL-12P70, IL-2, IL-1β, IL-18, TNF-α, IL-5, IL-9, IL-17A, IL-23, IL-10, eotaxin, MIP-1α, RANTES, MCP-1, and MIP-2 increased only in MI/R heart tissues in the day 7 and day 14 groups compared to the sham group. In serum, the IFN-γ, IL-23, and IL-10 levels were downregulated in the MI/R model at both day 7 and day 14 compared to the sham. Compared with the protein expressions in injured heart tissues at day 7, IFN-γ, IL-12P70, IL-2, IL-18, TNF-α, IL-6, IL-4, IL-5, IL-9, IL-17A, IL-23, IL-27, IL-10, eotaxin, IP-10, RANTES, MCP-1, MCP-3, and GRO-α were reduced, while IL-1β and MIP-2 were elevated at day 14. IL-13 and MIP-1β showed higher levels in the MI/R serum at day 14 than at day 7. mRNA levels of IL-4, IL-6, IL-13, and IL-27 were increased in the day 7 group compared to the sham, while MIP-1β, MCP-3, and GRO-α mRNA levels showed no significant difference between the MI/R and sham groups in blood mononuclear cells. Multiple CD4+ T-cell-associated cytokines/chemokines were upregulated in the MI/R hearts at the chronic stage. These results provided important evidence necessary for developing future immunomodulatory therapies after MI/R