CD147 supports paclitaxel resistance via interacting with RanBP1

Though the great success of paclitaxel, the variable response of patients to the drug limits its clinical utility and the precise mechanisms underlying the variable response to paclitaxel remain largely unknown. This study aims to verify the role and the underlying mechanisms of CD147 in paclitaxel resistance. Immunostaining was used to analyze human non-small-cell lung cancer (NSCLC) and ovarian cancer tissues. RNA-sequencing was used to identify downstream effectors. Annexin V-FITC/propidium iodide and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to detect apoptosis. Co-immunoprecipitation (Co-IP), fluorescence resonance energy transfer (FRET) and surface plasmon resonance (SPR) were performed to determine protein interactions. Fluorescence recovery after photobleaching (FRAP) was performed to measure the speed of microtubule turnover. Xenograft tumor model was established to evaluate sensitivity of cancer cells to paclitaxel in vivo. In vitro and in vivo assays showed that silencing CD147 sensitized the cancer cells to paclitaxel treatment. CD147 protected cancer cells from paclitaxel-induced caspase-3 mediated apoptosis regardless of p53 status. Truncation analysis showed that the intracellular domain of CD147 (CD147ICD) was indispensable for CD147-regulated sensitivity to paclitaxel. Via screening the interacting proteins of CD147ICD, Ran binding protein 1 (RanBP1) was identified to interact with CD147ICD via its C-terminal tail. Furthermore, we showed that RanBP1 mediated CD147-regulated microtubule stability and dynamics as well as response to paclitaxel treatment. These results demonstrated that CD147 regulated paclitaxel response by interacting with the C-terminal tail of RanBP1 and targeting CD147 may be a promising strategy for preventing paclitaxel resistant.

Pulse Methylprednisolone with Oral Prednisolone versus Adrenocorticotropic Hormone in Children with West Syndrome: a Randomized Controlled Trial

Background and Purpose: West syndrome is an epileptic encephalopathy of infancy. According to guidelines, adrenocorticotrophic hormone (ACTH) is probably effective for the short-term management of infantile spasm, but there is little uniformity in treatment due to variable response. This study has been done to evaluate the efficacy of pulse methylprednisolone as compared to ACTH in children with West syndrome.Methods: Children between 3 months to 24 months with the diagnosis of West syndrome were included and ACTH and pulse methyl prednisolone followed by oral prednisolone were given after randomization. Total duration of treatment was 6 weeks in both groups.Results: Total 87 children were enrolled; 12 patients lost in follow up. Finally, 43 received ACTH and 32 received pulse methylprednisolone. In pulse methylprednisolone group, 28.13% showed 50-80% response, 28.13% showed 80-99% response and 21.87% patients showed 100% response. In ACTH group, 41.86% showed 50-80% response, 25.58% showed 80-99% response and only 3 (6.97%) patients showed 100% response. Methylprednisolone treatment regimen did not cause significant or persistent adverse effects.Conclusions: Pulse methylprednisolone followed by oral prednisolone for 6 weeks is as effective as ACTH. Thus, methylprednisolone therapy can be an important alternative to ACTH.

Methotrexate Disposition, Anti-Folate Activity, and Metabolomic Profiling to Identify Molecular Markers of Disease Activity and Drug Response in the Collagen-Induced Arthritis Mouse Model

Methotrexate (MTX) is widely used in the treatment of autoimmune arthritis but is limited by its unpredictable and variable response profile. Currently, no biomarkers exist to predict or monitor early therapeutic responses to MTX. Using a collagen-induced arthritis (CIA) mouse model, this study aimed to identify biochemical pathways and biomarkers associated with MTX efficacy in autoimmune arthritis. Following arthritis disease induction, DBA/1J mice were treated with subcutaneous MTX (20 mg/kg/week) and disease activity was assessed based on disease activity scores (DAS) and paw volume (PV) measurements. Red blood cell (RBC) and plasma samples were collected at the end of the study and were assessed for folate and MTX content. Plasma samples were analyzed by semitargeted global metabolomic profiling and analyzed by univariate and multivariate analysis. Treatment with MTX was associated with significant reductions in disease activity based on both DAS (p = 0.0006) and PV (p = 0.0006). MTX therapy resulted in significant reductions in 5-methyltetrahydrofolate (5mTHF) levels in plasma (p = 0.02) and RBCs (p = 0.001). Reductions in both RBC and plasma 5mTHF were associated with lower DAS (p = 0.0007, p = 0.01, respectively) and PV (p = 0.001, p = 0.005, respectively). Increases in RBC MTX were associated with lower DAS (p = 0.003) but not PV (p = 0.23). Metabolomic analysis identified N-methylisoleucine (NMI) and quinolone as metabolites significantly altered in disease mice, which were corrected towards healthy control levels in mice treated with MTX. Reductions in plasma NMI were associated with lower DAS (p = 0.0002) and PV (p = 9.5 × 10−6). Increases in plasma quinolone were associated with lower DAS (p = 0.02) and PV (p = 0.01). Receiver-operating characteristic curve analysis identified plasma NMI (AUC = 1.00, p = 2.4 × 10−8), RBC 5mTHF (AUC = 0.99, p = 2.4 × 10−5), and plasma quinolone (AUC = 0.89, p = 0.01) as top discriminating metabolites of MTX treatment. Our data support a relationship between MTX efficacy and its effect on circulating folates and identified 5mTHF, NMI, and quinolone as potential therapeutic biomarkers of disease activity and MTX response in the CIA mouse model of autoimmune arthritis.

Single cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation

The human endometrium experiences repetitive cycles of tissue wounding characterised by piecemeal shedding of the surface epithelium and rapid restoration of tissue homeostasis. In this study we used a validated mouse model of endometrial repair in combination with three transgenic lines of mice to investigate whether epithelial cells that become incorporated into the newly formed luminal epithelium have their origins in one or more of the mesenchymal cell types present in the stromal compartment of the cycling endometrium. Using scRNAseq we identified a novel population of PDGFRb+ cells that arose in the endometrium in response to endometrial breakdown/repair. These cells expressed genes usually considered specific to epithelial cells and in silico trajectory analysis suggested they arose from stromal fibroblasts and were in transition to becoming epithelial cells. To confirm our hypothesis we used a lineage tracing strategy to compare the fate of stromal fibroblasts (PDGFRa+) and stromal perivascular cells (NG2+). We demonstrate for the first time that stromal fibroblasts can undergo a mesenchyme to epithelial transformation and become incorporated into the re-epithelialised luminal surface of the repaired tissue. This study is the first to discover a novel population of wound-responsive, plastic endometrial stromal fibroblasts that contribute to restoration of tissue integrity during endometrial repair. These findings form a platform for comparisons both to endometrial pathologies which involve a fibrotic response (Ashermans syndrome, endometriosis) as well as other mucosal tissues which have a variable response to wounding.

Response Surface Methodology (RSM)-Based Prediction and Optimization of the Fenton Process in Landfill Leachate Decolorization

As an advanced oxidative processes, the Fenton process is receiving popularity as a wastewater treatment technique that can be used for hazardous landfill leachate. The treatment is simple, yet involves complex interactions between the affecting parameters including reaction time, H2O2/Fe2+ ratio, pH, and iron (II) ion concentration. Hence, the purpose of this present study was to analyze the factors affecting landfill leachate treatment as well as their interaction by means of response surface methodology (RSM) with central composite design. The independent variables were reaction time, H2O2/Fe2+ ratio, iron (II) ion concentration, and pH, and the dependent variable (response) was color-removal percentage. The optimum treatment conditions for pH, H2O2/Fe2+ ratio, Fe2+ concentration, and reaction time were 8.36, 3.32, 964.95 mg/L, and 50.15 min, respectively. The model predicted 100% color removal in optimum conditions, which was close to that obtained from the experiment (97.68%). In conclusion, the optimized Fenton process using the RSM approach promotes efficient landfill leachate treatment that is even higher than that already reported.

Current Therapeutics and Future Perspectives to Ocular Melanocytic Neoplasms in Dogs and Cats

Neoplasms of melanocytic origin are diseases relevant to dogs and cats’ ophthalmic oncology due to their incidence, potential visual loss, and consequent decrease in life quality and expectancy. Despite its non-specific clinical presentation, melanocytic neoplasms can be histologically distinguished in melanocytomas, which present benign characteristics, and malignant melanomas. The diagnosis often occurs in advanced cases, limiting the therapeutic options. Surgery, cryotherapy, radiotherapy, photodynamic therapy (PDT), and laser are currently available therapeutic strategies. As no clinical guidelines are available, the treatment choice is primarily based on the clinician’s preference, proficiency, and the owner’s financial constraints. While surgery is curative in benign lesions, ocular melanomas present a variable response to treatments, besides the potential of tumour recurrences or metastatic disease. This review presents the currently available therapies for ocular melanocytic neoplasms in dogs and cats, describing the therapeutic, indications, and limitations. Additionally, new therapeutics being developed are presented and discussed, as they can improve the current treatment options.

Analysis of predictive capabilities of metacognitive strategies in the expression of professional thinking of military personnel

The article examines professional thinking in relation to the conditions of military activity. The goal is to identify a model of cadets’ metacognitive competence, contributing to the successful formation of professional thinking in the conditions of military activity. The construction of two regression models is carried out by means of multiple stepwise regression analysis with inclusion. In the first model, the variable response was the over-situational style of thinking of servicemen, determined by the questionnaire «Determination of the dominant level of problematicity in solving service-professional problem situations.» In the second model of the variable, the response was the type of professional thinking determined on the basis of the case method. Cadets’ metacognitive strategies were used as variable predictors. It was possible to establish that both regression models are statistically significant, the level of error probability is less than 0.01% and explain more than 40% of the variability of the variable responses. All metacognitive strategies (six variable predictors) in the first model have a statistically significant relationship with variable responses (p≤0.05). The predictive influence on the dominance of a certain type of professional thinking among cadets has the character of structural interaction. Metacognitive strategies such as information acquisition, concentration, time management and the level of reflection are facilitators for the formation of a supra-situational level of cadets’ professional thinking. Whereas metacognitive knowledge and metacognitive activity act as inhibitors.

Decorin Concentrations in Aqueous Humor of Patients with Diabetic Retinopathy

Diabetic retinopathy (DR) is a microvascular complication of diabetes in the retina. Chronic hyperglycemia damages retinal microvasculature embedded into the extracellular matrix (ECM), causing fluid leakage and ischemic retinal neovascularization. Current treatment strategies include intravitreal anti-vascular endothelial growth factor (VEGF) or steroidal injections, laser photocoagulation, or vitrectomy in severe cases. However, treatment may require multiple modalities or repeat treatments due to variable response. Though DR management has achieved great success, improved, long-lasting, and predictable treatments are needed, including new biomarkers and therapeutic approaches. Small-leucine rich proteoglycans, such as decorin, constitute an integral component of retinal endothelial ECM. Therefore, any damage to microvasculature can trigger its antifibrotic and antiangiogenic response against retinal vascular pathologies, including DR. We conducted a cross-sectional study to examine the association between aqueous humor (AH) decorin levels, if any, and severity of DR. A total of 82 subjects (26 control, 56 DR) were recruited. AH was collected and decorin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA). Decorin was significantly increased in the AH of DR subjects compared to controls (p = 0.0034). AH decorin levels were increased in severe DR groups in ETDRS and Gloucestershire classifications. Decorin concentrations also displayed a significant association with visual acuity (LogMAR) measurements. In conclusion, aqueous humor decorin concentrations were found elevated in DR subjects, possibly due to a compensatory response to the retinal microvascular changes during hyperglycemia.

Ambient temperature and relative humidity-based drift correction in frequency domain electromagnetics using machine learning

Electromagnetic instrument responses suffer from signal drift that results in a variable response at a given location over time. If left uncorrected, spatiotemporal aliasing can manifest and global trends or abrupt changes might be observed in the data, which are independent of subsurface electromagnetic variations. By performing static ground measurements, we characterized drift patterns of different electromagnetic instruments. Next, we performed static measurements at an elevated height, approximately 4 metre above ground level, to collect a data set that forms the basis of a new absolute calibration methodology. By additionally logging ambient temperature variations, battery voltage and relative humidity, a relation between signal drift and these parameters was modelled using a machine learning (ML) approach. The results show that it was possible to mitigate the effects of signal drift; however, it was not possible to completely eliminate them. The reason is three-fold: (1) the ML algorithm is not yet sufficiently adapted for accurate prediction; (2) signal instability is not explained sufficiently by ambient temperature, relative humidity and battery voltage; and (3) the black-box internal (factory) calibration impeded direct access to raw data,which prevents accurate evaluation of the proposed methodology. However, the results suggest that these challenges are not insurmountable and thatML can form a viable approach in tackling the drift problem instrument specific in the near future.

PD-L1, Vimentin and Ki-67 Acting as Immunotherapy Predictive Biomarkers in Pulmonary Carcinomas Transthoracic and Bronchial Biopsies

Introduction: Programmed death-ligand 1 (PD-L1) expression became a routine biomarker to preview response to programmed death-1 (PD-1)/PD-L1 inhibitors, with diverging parameters concerning PD-L1 scoring and variable response to immunotherapy agents. The aim of this study was to evaluate association between PD-L1 expression and immunohistochemistry panel applied in Pathology practice, defining any of those antibodies as biomarkers concurrent in patients selection for PD-1/PD-L1 blockade therapy. Methods A total of 97 cTNM IIIb/IV staged pulmonary carcinoma biopsies were randomly selected between 2018/2020, after adequate representativeness and PD-L1 expression scored through Dako 22C3 antibody. The panel with cytokeratin 7, thyroid transcription factor 1 (TTF1), cytokeratin 5.6, cluster of differentiation 56 (CD56), periodic acid-Schiff (PAS-D), vimentin expression, and ki-67 labeling index (LI) was considered for retrieving reports and respective archival slides. Results PD-L1 expression in tumor cells (TCs) was identified in 56 samples and significantly associated with male gender (p=0.028), vimentin expression (p=0.018) and ki-67 LI>30% (p=0.029). A tendency to PD-L1 positivity came up in lymphocytic-predominant/immune-inflamed stroma (9/10), adenocarcinoma solid subtype (21/23) and CK7-negative squamous cell carcinomas (8/13). When more than 50% TCs expressed PD-L1, the risk of vimentin expression was 3.85 times higher (OR=3.85; p=0.013), and for ki-67 LI>30% the risk was 9.90 times higher (OR=9.90; p=0.033), compared with PD-L1-negative samples. Conclusion High proliferation status defined by ki-67 LI>30% and epithelial-mesenchymal transition phenotype verified by vimentin staining analysis might complement PD-L1-positive TCs percentage determination for immunotherapy prescription. These patients will more likely benefit from PD-1/PD-L1 blockade therapy, overcoming the limitations of selection based on PD-L1 immunohistochemistry status.