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In this study, the wear behavior of a physical vapor deposition (PVD) AlTiN coated on the titanium alloy was investigated. Response surface methodology (RSM) was used to analyze input factors, such as load (A), sliding speed (B), and sliding distance (C), while wear mass loss (WML) and coefficient of driction (COF) were considered as the response parameters. The statistical analysis shows that main factors, that is, interaction of AC and pure quadratic terms B2 and C2, have maximum influences on WML. However, COF was highly affected by load, sliding speed, and interaction of AB and quadratic term A2. The present work attempts to carry out empirical modeling to predict output response on WML and COF. Desirability-based optimization technique was employed to obtain minimum WML and COF. Microscopy images of the wear tracks reveal visible grooves and scratches that confirm abrasive wear to be the primary wear mechanism accompanied by adhesive wear. The investigation concluded that AlTiN has better wear resistance properties and can be used to coat titanium implants for biomedical application. The result shows that the minimum WML and COF have been found at applied load 15 N, sliding speed at 0.5 m/s, and sliding distance 500 m.

The International Reference Ionosphere (IRI) is a widely used empirical ionospheric model based on observations from a worldwide network of ionospheric stations. Therefore, it would be reasonable to expect it to capture long-term changes in key ionospheric parameters, such as foF2 and hmF2 linked to trend forcings like greenhouse gas increasing concentrations and the Earth's magnetic field secular variation. Despite the numerous reported trends in foF2 and hmF2 derived from experimental data and model results, there are inconsistencies that require continuous refinement of trend estimation methods and regular data updates. This ongoing effort is crucial to address the difficulties posed by the weak signal-to-noise ratio characteristic of ionospheric long-term trends. Furthermore, the experimental verification of these trends remains challenging, primarily due to time and spatial coverage limitations of measured data series. Achieving these needs for accurate detection of long-term trends requires extensive global coverage and high resolution of ionospheric measurements together with long enough periods spanning multiple solar cycles to properly filter out variations of shorter terms than the sought trend. Considering these challenges, IRI-modeled foF2 and hmF2 parameters offer a valuable alternative for assessing trends and obtaining a first approximation of a plausible global picture representative of experimental trends. This work presents these global trend patterns, considering the period 1960–2022 using the IRI-Plas 2020 version, which are consistent with other model predictions. While IRI explicitly takes into account the Earth's magnetic field variations, the increase in the concentrations of greenhouse gases appears indirectly through the Ionospheric Global index (IG) which is derived from ionospheric measurements. F2-region trends induced by the first mechanism should be important only around the magnetic equator at the longitudinal range with the strongest displacement, and it should be negligible out of this region. Conversely, trends induced by the greenhouse effect, which are the controversial ones, should be dominant away from the geomagnetic equator and should globally average to negative values in both cases, i.e., foF2 and hmF2. Effectively, these negative global means are verified by trends based on IRI-Plas, even though not for the correct reasons in the hmF2 case. In addition, a verification was performed for more localized foF2 trend values, considering data from nine mid-latitude stations, and a reasonable level of agreement was observed. It is concluded that the IRI model can be a valuable tool for obtaining preliminary approximations of the Earth's magnetic-field-induced long-term changes in foF2 and hmF2, as well as of experimental trends only in the foF2 case. The latter does not hold for hmF2, even if the trends obtained are close to the expected values.

Four extreme ultraviolet (EUV) solar radiation proxies (Magnesium II core-to-wing ratio (MgII), Lyman α flux (Fα), 10.7-cm solar radio flux (F10.7), and sunspot number (Rz)) were analyzed during the last four consecutive solar activity minima to investigate how they differ during minimum periods and how well they represent solar EUV radiation. Their variability within each minimum and between minima was compared by considering monthly means. A comparison was also made of their role in filtering the effect of solar activity from the critical frequency of the ionospheric F2 layer, foF2, which at mid to low latitudes depends mainly on EUV solar radiation. The last two solar cycles showed unusually low EUV radiation levels according to the four proxies. Regarding the connection between the EUV “true” variation and that of solar proxies, according to the foF2 filtering analysis, MgII and Fα behaved in a more stable and suitable way, whereas Rz and F10.7 could be overestimating EUV levels during the last two minima, implying they would both underestimate the inter-minima difference of EUV when compared with the first two minima.

Abstract In this study, aqueous spinach extract was used for the green synthesis of iron nanoparticles. The surface of iron oxide nanoparticles was coated with spermine. The physicochemical properties of nanoparticles were investigated using UV-Vis, TGA, FTIR, VSM, TEM, and DLS. The results showed that the nanoparticles had a spherical structure. The surface charge of the Fe3O4-NPs increased from −3.2 to 18.42 (mV) after Fe3O4 coating by spermine. In order to investigate the effect of nanoparticles on physicochemical properties of rosemary under drought stress conditions, an experiment was carried out in a completely randomized design. The results showed that the amount of antioxidant enzymes and secondary metabolites increased significantly under drought stress. Moreover, the use of spermine-coated iron nanoparticles can be useful in increasing resistance to drought stress in plants by increasing the activity of some antioxidant enzymes and secondary metabolites. The biocompatibility of Nanoparticles in cell suspension was investigated. the ability of Fe3O4-SM NPs to interact with DNA and protect it against DNaseI and ultrasonic waves using agarose gel electrophoresis was studied. The ability of Fe3O4-SM to neutralize the negative charge of DNA and protect it against DNaseΙ and ultrasonic waves was confirmed using an agarose gel electrophoresis assay.

Abstract This meta-analysis aimed to estimate and compare sensitivity, specificity, positive- (PPV) and negative predictive value (NPV) of magnetic resonance imaging (MRI) for predicting pathological complete remission (pCR) after neoadjuvant chemotherapy (NAC) in patients with early-stage breast cancer. We stratified for molecular subtype by immunohistochemistry (IHC) and explored the impact of other factors. Two researchers systematically searched PUBMED and EMBASE to select relevant studies and extract data. For meta-analysis of sensitivity and specificity, we used bivariate random-effects models. Twenty-six included studies contained 4497 patients. There was a significant impact of IHC subtype on post-NAC MRI accuracy (p = 0.0082) for pCR. The pooled sensitivity was 0.67 [95% CI 0.58–0.74] for the HR−/HER2−, 0.65 [95% CI 0.56–0.73] for the HR−/HER2+, 0.55 [95% CI 0.45–0.64] for the HR+/HER2− and 0.60 [95% CI 0.50–0.70] for the HR+/HER2+ subtype. The pooled specificity was 0.85 [95% CI 0.81–0.88] for the HR−/HER2−, 0.81 [95% CI 0.74–0.86] for the HR−/HER2+, 0.88[95% CI 0.84–0.91] for the HR+/HER2− and 0.74 [95% CI 0.63–0.83] for the HR+/HER2+ subtype. The PPV was highest in the HR-/HER2- subtype and lowest in the HR+/HER2− subtype. MRI field strength of 3.0 T was associated with a higher sensitivity compared to 1.5 T (p = 0.00063). The accuracy of MRI for predicting pCR depends on molecular subtype, which should be taken into account in clinical practice. Higher MRI field strength positively impacts accuracy. When intervention trials based on MRI response evaluation are designed, the impact of IHC subtype and field strength on MR accuracy should be considered.

BackgroundPoor prognosis in colon cancer is associated with a high content of cancer-associated fibroblasts (CAFs) and an immunosuppressive tumor microenvironment. The relationship between these two features is incompletely understood. Here, we aimed to generate a model system for studying the interaction between cancer cells and CAFs and their effect on immune-related cytokines and T cell proliferation.MethodsCAFs were isolated from colon cancer liver metastases and were immortalized to prolong lifespan and improve robustness and reproducibility. Established medium and matrix compositions that support the growth of patient-derived organoids were adapted to also support CAF growth. Changes in growth pattern and cellular re-organization were assessed by confocal microscopy, live cell imaging, and immunofluorescence. Single cell RNA sequencing was used to study CAF/organoid co-culture-induced phenotypic changes in both cell types. Conditioned media were used to quantify the production of immunosuppressive factors and to assess their effect on T cell proliferation.ResultsWe developed a co-culture system in which colon cancer organoids and CAFs spontaneously organize into superstructures with a high capacity to contract and stiffen the extracellular matrix (ECM). CAF-produced collagen IV provided a basement membrane supporting cancer cell organization into glandular structures, reminiscent of human cancer histology. Single cell RNA sequencing analysis showed that CAFs induced a partial epithelial-to-mesenchymal-transition in a subpopulation of cancer cells, similar to what is observed in the mesenchymal-like consensus molecular subtype 4 (CMS4) colon cancer. CAFs in co-culture were characterized by high expression of ECM components, ECM-remodeling enzymes, glycolysis, hypoxia, and genes involved in immunosuppression. An expression signature derived from CAFs in co-culture identified a subpopulation of glycolytic myofibroblasts specifically residing in CMS1 and CMS4 colon cancer. Medium conditioned by co-cultures contained high levels of the immunosuppressive factors TGFβ1, VEGFA and lactate, and potently inhibited T cell proliferation.ConclusionCo-cultures of organoids and immortalized CAFs recapitulate the histological, biophysical, and immunosuppressive features of aggressive mesenchymal-like human CRC. The model can be used to study the mechanisms of immunosuppression and to test therapeutic strategies targeting the cross-talk between CAFs and cancer cells. It can be further modified to represent distinct colon cancer subtypes and (organ-specific) microenvironments.

The aim of this work was to develop and validate a rapid and low cost method for estimation of ibuprofen in pharmaceutical suspensions using Reverse-Phase High Performance Liquid Chromatography. The proposed method was conducted and validated according to International Conference on Harmonization (ICH) requirements. The chromatographic parameters were as follows: column of octyldecylsilyl C18 with dimensions (150 × 4.6) mm, mobile phase composed of acetonitrile with phosphoric acid with a ratio of 50 to 50 each using isocratic mode, flow rate of 1.5 mL/min and injection volume of 5 μL. The detection was carried out using UV detector at 220 nm. The method was validated and showed short retention time for ibuprofen peak at 7.651 min, with linearity in the studied range of 0.4 - 1.6 mg/mL (R2 = 0.9999) and with great accuracy ]percent recovery was (100.48%), percent relative error(-1.511-1.465)%[ and repeatability (RSD% = 0.112 for Retention time). The detection and quantitation limits were determined to be 0.036 and 0.110 mg/mL, respectively. This method was applied successfully to determine the content of ibuprofen in three commercial pharmaceutical products. Looking at the short time of analysis and the low limit detection, we recommend this method for routine assays in the quality control laboratories and as a good method for stability studies of ibuprofen.

Purpose: To assess whether contralateral parenchymal enhancement (CPE) on MRI is associated with gene expression pathways in ER+/HER2-breast cancer, and if so, whether such pathways are related to survival. Methods: Preoperative breast MRIs were analyzed of early ER+/HER2-breast cancer patients eligible for breast-conserving surgery included in a prospective observational cohort study (MARGINS). The contralateral parenchyma was segmented and CPE was calculated as the average of the top-10% delayed enhancement. Total tumor RNA sequencing was performed and gene set enrichment analysis was used to reveal gene expression pathways associated with CPE (N = 226) and related to overall survival (OS) and invasive disease-free survival (IDFS) in multivariable survival analysis. The latter was also done for the METABRIC cohort (N = 1355). Results: CPE was most strongly correlated with proteasome pathways (normalized enrichment statistic = 2.04, false discovery rate = .11). Patients with high CPE showed lower tumor proteasome gene expression. Proteasome gene expression had a hazard ratio (HR) of 1.40 (95% CI = 0.89, 2.16; P = .143) for OS in the MARGINS cohort and 1.53 (95% CI = 1.08, 2.14; P = .017) for IDFS, in METABRIC proteasome gene expression had an HR of 1.09 (95% CI = 1.01, 1.18; P = .020) for OS and 1.10 (95% CI = 1.02, 1.18; P = .012) for IDFS. Conclusion: CPE was negatively correlated with tumor proteasome gene expression in early ER+/HER2-breast cancer patients. Low tumor proteasome gene expression was associated with improved survival in the METABRIC data.

Climate change is characterized by global surface warming associated with the increase of greenhouse gas population since the start of the industrial era. Growing evidence shows that the upper atmosphere is experiencing appreciable cooling over the last several decades. The seminal modeling study by Roble and Dickinson (1989) suggested potential effects of increased greenhouse gases on the ionosphere and thermosphere cooling which appear consistent with some observations. However, several outstanding issues remain regarding the role of CO2, other important contributors, and impacts of the cooling trend in the ionosphere and thermosphere: for example, (1) what is the regional variability of the trends? (2) the very strong ionospheric cooling observed by multiple incoherent scatter radars that does not fit with the prevailing theory based on the argument of anthropogenic greenhouse gas increases, why? (3) what is the effect of secular changes in Earth’s main magnetic field? Is it visible now in the ionospheric data and can it explain some of the regional variability in the observed ionospheric trends? (4) what is the impact of long-term cooling in the thermosphere on operational systems? (5) what are the appropriate strategic plans to ensure the long-term monitoring of the critical space climate?

BackgroundMesenchymal Consensus Molecular Subtype 4 (CMS4) colon cancer is associated with poor prognosis and therapy resistance. In this proof-of-concept study, we assessed whether a rationally chosen drug could mitigate the distinguishing molecular features of primary CMS4 colon cancer.MethodsIn the ImPACCT trial, informed consent was obtained for molecular subtyping at initial diagnosis of colon cancer using a validated RT-qPCR CMS4-test on three biopsies per tumor (Phase-1, n=69 patients), and for neoadjuvant CMS4-targeting therapy with imatinib (Phase-2, n=5). Pre- and post-treatment tumor biopsies were analyzed by RNA-sequencing and immunohistochemistry. Imatinib-induced gene expression changes were associated with molecular subtypes and survival in an independent cohort of 3232 primary colon cancer.ResultsThe CMS4-test classified 52/172 biopsies as CMS4 (30%). Five patients consented to imatinib treatment prior to surgery, yielding 15 pre- and 15 post-treatment samples for molecular analysis. Imatinib treatment caused significant suppression of mesenchymal genes and upregulation of genes encoding epithelial junctions. The gene expression changes induced by imatinib were associated with improved survival and a shift from CMS4 to CMS2.ConclusionImatinib may have value as a CMS-switching drug in primary colon cancer and induces a gene expression program that is associated with improved survival.

Introduction The response to neoadjuvant chemotherapy (NAC) in breast cancer has important prognostic implications. Dynamic prediction of tumour regression by NAC may allow for adaption of the treatment plan before completion, or even before the start of treatment. Such predictions may help prevent overtreatment and related toxicity and correct for undertreatment with ineffective regimens. Current imaging methods are not able to fully predict the efficacy of NAC. To successfully improve response prediction, tumour biology and heterogeneity as well as treatment-induced changes have to be considered. In the LIMA study, multiparametric MRI will be combined with liquid biopsies. In addition to conventional clinical and pathological information, these methods may give complementary information at multiple time points during treatment.Aim To combine multiparametric MRI and liquid biopsies in patients with breast cancer to predict residual cancer burden (RCB) after NAC, in adjunct to standard clinico-pathological information. Predictions will be made before the start of NAC, approximately halfway during treatment and after completion of NAC.Methods In this multicentre prospective observational study we aim to enrol 100 patients. Multiparametric MRI will be performed prior to NAC, approximately halfway and after completion of NAC. Liquid biopsies will be obtained immediately prior to every cycle of chemotherapy and after completion of NAC. The primary endpoint is RCB in the surgical resection specimen following NAC. Collected data will primarily be analysed using multivariable techniques such as penalised regression techniques.Ethics and dissemination Medical Research Ethics Committee Utrecht has approved this study (NL67308.041.19). Informed consent will be obtained from each participant. All data are anonymised before publication. The findings of this study will be submitted to international peer-reviewed journals.Trial registration number NCT04223492.

Abstract Effective predictive biomarkers are needed to enable personalized medicine and increase treatment efficacy and survival for cancer patients, thereby reducing toxic side effects and treatment costs. Patient-derived organoids (PDOs) enable individualized tumour response testing. Since 2018, 17 publications have examined PDOs as a potential predictive biomarker in the treatment of cancer patients. We review and provide a pooled analysis of the results regarding the use of PDOs in individualized tumour response testing, focusing on evidence for analytical validity, clinical validity and clinical utility. We identify future perspectives to accelerate the implementation of PDOs as a predictive biomarker in the treatment of cancer patients.

Abstract Background It is estimated that around 15–30% of patients with early stage colon cancer benefit from adjuvant chemotherapy. We are currently not capable of upfront selection of patients who benefit from chemotherapy, which indicates the need for additional predictive markers for response to chemotherapy. It has been shown that the consensus molecular subtypes (CMSs), defined by RNA-profiling, have prognostic and/or predictive value. Due to postoperative timing of chemotherapy in current guidelines, tumor response to chemotherapy per CMS is not known, which makes the differentiation between the prognostic and predictive value impossible. Therefore, we propose to assess the tumor response per CMS in the neoadjuvant chemotherapy setting. This will provide us with clear data on the predictive value for chemotherapy response of the CMSs. Methods In this prospective, single arm, multicenter intervention study, 262 patients with resectable microsatellite stable cT3–4NxM0 colon cancer will be treated with two courses of neoadjuvant and two courses of adjuvant capecitabine and oxaliplatin. The primary endpoint is the pathological tumor response to neoadjuvant chemotherapy per CMS. Secondary endpoints are radiological tumor response, the prognostic value of these responses for recurrence free survival and overall survival and the differences in CMS classification of the same tumor before and after neoadjuvant chemotherapy. The study is scheduled to be performed in 8–10 Dutch hospitals. The first patient was included in February 2020. Discussion Patient selection for adjuvant chemotherapy in early stage colon cancer is far from optimal. The CMS classification is a promising new biomarker, but a solid chemotherapy response assessment per subtype is lacking. In this study we will investigate whether CMS classification can be of added value in clinical decision making by analyzing the predictive value for chemotherapy response. This study can provide the results necessary to proceed to future studies in which (neo) adjuvant chemotherapy may be withhold in patients with a specific CMS subtype, who show no benefit from chemotherapy and for whom possible new treatments can be investigated. Trial registration This study has been registered in the Netherlands Trial Register (NL8177) at 11–26-2019, https://www.trialregister.nl/trial/8177 . The study has been approved by the medical ethics committee Utrecht (MEC18/712).

Abstract Background We assessed the effect of equivalent weight loss with or without exercise on (intra-) abdominal fat in postmenopausal women in the SHAPE-2 study. Methods The SHAPE-2 study is a three-armed randomised controlled trial conducted in 2012–2013 in the Netherlands. Postmenopausal overweight women were randomized to a diet (n = 97), exercise plus diet (n = 98) or control group (n = 48). Both intervention groups aimed for equivalent weight loss (6–7%) following a calorie-restricted diet (diet group) or a partly supervised intensive exercise programme (4 h per week) combined with a small caloric restriction (exercise plus diet group). Outcomes after 16 weeks are amount and distribution of abdominal fat, measured by magnetic resonance imaging (MRI) with the use of the three-point IDEAL Dixon method. Results The diet and exercise plus diet group lost 6.1 and 6.9% body weight, respectively. Compared to controls, subcutaneous and intra-abdominal fat reduced significantly with both diet (− 12.5% and − 12.0%) and exercise plus diet (− 16.0% and − 14.6%). Direct comparison between both interventions revealed that the reduction in subcutaneous fat was statistically significantly larger in the group that combined exercise with diet: an additional 10.6 cm2 (95%CI -18.7; − 2.4) was lost compared to the diet-only group. Intra-abdominal fat loss was not significantly larger in the exercise plus diet group (− 3.8 cm2, 95%CI -9.0; 1.3). Conclusions We conclude that weight loss of 6–7% with diet or with exercise plus diet reduced both subcutaneous and intra-abdominal fat. Only subcutaneous fat statistically significantly reduced to a larger extent when exercise is combined with a small caloric restriction. Trial register NCT01511276 (clinicaltrials.gov), prospectively registered.

Abstract Background The identification of four Consensus Molecular Subtypes (CMS1–4) of colorectal cancer forms a new paradigm for the design and evaluation of subtype-directed therapeutic strategies. The most aggressive subtype - CMS4 - has the highest chance of disease recurrence. Novel adjuvant therapies for patients with CMS4 tumours are therefore urgently needed. CMS4 tumours are characterized by expression of mesenchymal and stem-like genes. Previous pre-clinical work has shown that targeting Platelet-Derived Growth Factor Receptors (PDGFRs) and the related KIT receptor with imatinib is potentially effective against mesenchymal-type colon cancer. In the present study we aim to provide proof for the concept that imatinib can reduce the aggressive phenotype of primary CMS4 colon cancer. Methods Tumour biopsies from patients with newly diagnosed stage I-III colon cancer will be analysed with a novel RT-qPCR test to pre-select patients with CMS4 tumours. Selected patients (n = 27) will receive treatment with imatinib (400 mg per day) starting two weeks prior to planned tumour resection. To assess treatment-induced changes in the aggressive CMS4 phenotype, RNA sequencing will be performed on pre- and post-treatment tissue samples. Discussion The development of effective adjuvant therapy for primary colon cancer is hindered by multiple factors. First, new drugs that may have value in the prevention of (early) distant recurrence are almost always first tested in patients with heavily pre-treated metastatic disease. Second, measuring on-target drug effects and biological consequences in tumour tissue is not commonly a part of the study design. Third, due to the lack of patient selection tools, clinical trials in the adjuvant setting require large patient populations. Finally, the evaluation of recurrence-prevention requires a long-term follow-up. In the ImPACCT trial these issues are addressed by including newly diagnosed pre-selected patients with CMS4 tumours prior to primary tumour resection, rather than non-selected patients with late-stage disease. By making use of the pre-operative window period, the biological effect of imatinib treatment on CMS4 tumours can be rapidly assessed. Delivering proof-of-concept for drug action in early stage disease should form the basis for the design of future trials with subtype-targeted therapies in colon cancer patients. Trial registration ClinicalTrials.gov: NCT02685046 . Registration date: February 9, 2016.