Miracle-dz/UniFAR-FTUs huggingface dataset:
Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Simple Summary Chronic myeloid leukemia (CML) is a myeloproliferative neoplasia associated with a molecular alteration, the fusion gene BCR-ABL1, that encodes the tyrosine kinase oncoprotein BCR-ABL1. This led to the development of tyrosine kinase inhibitors (TKI), with Imatinib being the first TKI approved. Although the vast majority of CML patients respond to Imatinib, resistance to this targeted therapy contributes to therapeutic failure and relapse. Here we review the molecular mechanisms and other factors (e.g., patient adherence) involved in TKI resistance, the methodologies to access these mechanisms, and the possible therapeutic approaches to circumvent TKI resistance in CML. Abstract Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.
Comparison of Compass Suprathreshold Screening Strategies

Screening programs may be useful to reduce the rate of undetected glaucoma. Compass (CMP, CenterVue, Padova, Italy) Standard Suprathreshold strategy (SST) analyses the visual function at 52 retinal locations. A new Quick Suprathreshold strategy (QST) reduces the number of tested locations to 24. With both tests, the CMP also provides an image of the central retina and a detail of the optic nerve head. The aim of this paper is to measure the performances of SST and QST compared with clinical diagnosis. 63 consecutive healthy subjects and 60 consecutive patients with perimetric defects from glaucoma in both eyes were recruited. They received one test per eye (SST or QST in randomized order); results were classified into normal, suspect and abnormal according to a global index provided in the report and called SupraThreshold Response (STR). Agreement between clinical diagnosis and test output were calculated, and test time was also measured. The agreement with the clinical diagnosis was 95.7% for SST and 95.1% for QST. When two suspect tests were excluded, agreement for QST increased to 96.7%. Test duration was 164 ± 82 s for SST and 71 ± 41 s for QST (p < 0.0001). Such a difference was similar in both glaucoma patients (respectively 231 ± 65 s vs. 105 ± 33 s, p < 0.0001) and normal subjects (98 ± 17 and 39 ± 9 s, p < 0.0001). In conclusion, SST and QST showed similar, high agreement with clinical judgement. Morphological analysis is potentially helpful in further improving the clinical usefulness of suprathreshold tests. QST is characterized by a strong time saving compared with SST.
Weight Loss Barriers and Dietary Quality of Intermittent and Continuous Dieters in Women with a History of Gestational Diabetes

Weight-loss after gestational diabetes (GDM) lowers the risk of type-2 diabetes (T2DM). Intermittent energy restriction (IER) produces comparable weight-loss to continuous energy restriction (CER), but long-term adherence remains difficult in this population. This exploratory secondary analysis of a 12-month trial comparing IER to CER following GDM examined weight-loss and dietary quality associated with barriers to weight-loss or T2DM risk perception as assessed in a Likert scale questionnaire at baseline. The participants had a median (IQR) BMI of 32.6 (9.4) kg/m2 and 3 (4) years postpartum (n = 121). Forty-five percent (n = 54) of the participants thought they were at a high risk of developing T2DM. Greater affordability of healthy food was related with greater weight-loss at 3 months (p = 0.044, n = 85). At 12 months, there was no significant relationship between weight-loss and the barriers to weight-loss (p > 0.05). CER had superior improvement in dietary quality at 12 months (CER 11 ± 10, IER 6 ± 5.6, n = 42, p = 0.05). Under the Theoretical Domains Framework, the barriers were predominantly related to behavioral regulation (n = 83, 69%; n = 76, 63%) and environmental context and resources (n = 67, 56%). Interventions for diabetes prevention in this population should include behavioral regulation strategies, consider the family home environment, and ensure that the risk of T2DM is conveyed. Women choosing IER may benefit from education to improve their dietary quality.
Mindfulness Awareness Practice (MAP) to Prevent Dementia in Older Adults with Mild Cognitive Impairment: Protocol of a Randomized Controlled Trial and Implementation Outcomes

Background: With an aging population, developing non-pharmacological interventions (NPIs) to delay dementia has become critical. Apart from cognitive decline, dementia is associated with multiple pathophysiology, including increased oxidative stress, dysregulated gene expressions, cytokine, neurotrophin, and stress markers, telomere shortening, and deteriorations in brain connectivity. Although mindfulness practices have been proposed to ameliorate these biological changes, no empirical studies were conducted. We thus aimed to investigate the effects of mindfulness awareness practice (MAP) to prevent cognitive decline and improve peripheral biomarkers in community-dwelling older adults diagnosed with mild cognitive impairment (MCI). Methods/Design: This was a single-blinded and parallel-group randomized controlled trial with two arms (intervention and active control arms), conducted over nine months. A total of 60 consenting community-dwelling older adults diagnosed with MCI were planned to be randomized in a 1:1 ratio to either the MAP or the Health Education Program (HEP). Interventions were performed weekly for the initial 12 weeks, and monthly for the subsequent six months. Outcome measures were assessed at baseline, 3-month, and 9-month post-intervention by blinded assessors. Primary outcomes were neurocognitive tests, comprehensive peripheral biomarkers, and brain imaging scans. Secondary outcomes included basic health screening measures, affective symptoms, and measures of physical functions. Linear-mixed models were used to examine the effects of MAP on these outcome measures. Significance: This is the first randomized controlled trial to systematically investigate the effects of a mindfulness intervention in improving cognitive functions and various biomarkers in community-dwelling older adults diagnosed with MCI. Our findings have the potential to inform mindfulness intervention as a novel approach to delay dementia.
Spectral Transmission of the Human Corneal Layers

We have assessed the spectral transmittance of the different layers of the human cornea in the ultraviolet (UV), visible, and near-infrared (IR) spectral ranges. Seventy-four corneal sample donors were included in the study. Firstly, the corneal transmittance was measured using a spectrophotometer. Then, all samples were fixed for histopathological analysis, which allowed us to measure the thickness of each corneal layer. Finally, the absorption coefficients of the corneal layers were computed by a linear model reproducing total transmittance. The results show that corneal transmission was almost in unity at the visible and IR ranges but not at the UV range, in which the layer with higher transmission is Descemet’s membrane, whereas the stroma showed the lowest transmittance. Regarding the absorption coefficient, the most absorptive tissue was Bowman’s layer, followed by the endothelium. Variations on transmittance due to changes in the stroma, Bowman’s layer, or Descemet layer were simulated, and important transmission increases were found due to stroma and Bowman changes. To conclude, we have developed a method to measure the transmittance and thickness for each corneal layer. All corneal layers absorb UV light to a greater or lesser extent. The absorption coefficient is higher for Bowman’s layer, while the stroma is the layer with the lowest transmittance due to its thickness. Variations in stroma thickness or changes in the corneal tissue of Bowman’s layer or the endothelium layer due to some pathologies or surgeries could affect, to a greater or lesser degree, the total transmission of the cornea. Thus, obtaining accurate absorption coefficients for different layers would help us to predict and compensate these changes.
A New Perspective on Human Rights in the Use of Physical Restraint on Psychiatric Patients-Based on Merleau-Ponty’s Phenomenology of the Body

(1) Background: Physical restraint in psychiatric settings must be determined by health care professionals for ensuring their patients’ safety. However, when a patient cannot participate in the process of deciding what occurs in their own body, can they even be considered as a personal self who lives in and experiences the lifeworld? The purpose of this study is to review the existential capability of the body from Merleau-Ponty’s phenomenology to explore ways of promoting human rights in physical restraint. (2) Methods: A philosophical reflection was contemplated regarding notions of the body’s phenomenology. (3) Results: Merleau-Ponty’s body phenomenology can explain bodily phenomena as a source of the personal subject, who perceives and acts in the world, and not as a body alienated from the subject in health and illness. Patients, when they are physically restrained, cannot be the self as a subject because their body loses its subjecthood. They are entirely objectified, becoming objects of diagnosis, protection, and control, according to the treatment principles of health care professionals. (4) Conclusions: The foundation of human rights, human being’s dignity lies in the health professionals’ genuine understanding and response to the existential crisis of the patient’s body in relation to its surrounding environment.
Implications for Early Diagnosis and Treatment in Schizophrenia Due to Correlation between Auditory Perceptual Deficits and Cognitive Impairment

It is indicated that auditory perception deficits are present in schizophrenia and related to formal thought disorder. The purpose of the present study was to investigate the association of auditory deficits with cognitive impairment in schizophrenia. An experimental group of 50 schizophrenia patients completed a battery of auditory processing evaluation and a neuropsychological battery of tests. Correlations between neuropsychological battery scores and auditory processing scores were examined. Cognitive impairment was correlated with auditory processing deficits in schizophrenia patients. All neuropsychological test scores were significantly correlated with at least one auditory processing test score. Our findings support the coexistence of auditory processing disorder, severe cognitive impairment, and formal thought disorder in a subgroup of schizophrenia patients. This may have important implications in schizophrenia research, as well as in early diagnosis and nonpharmacological treatment of the disorder.
Association between Serum Phosphate Levels and the Development of Aortic Stenosis in Patients Undergoing Hemodialysis

We aimed to investigate the factors associated with the development of aortic stenosis (AS) in patients undergoing hemodialysis (HD), and to elucidate the prognosis of HD patients with AS. Patients on HD that had also undergone echocardiography at Nagasaki Renal Center between July 2011 and June 2012 were included. Patients with AS at the time of inclusion were excluded. The diagnosis of AS was based on an annual routine or additional echocardiography. The patients were followed up until June 2021. The association between patient background and AS was also evaluated. Of the 302 patients (mean age, 67.4 ± 13.3 years; male, 58%; median dialysis history, 4.7 years), 60 developed AS and 10 underwent aortic valve replacement. A Cox proportional hazards model revealed that age (hazard ratio (HR), 1.07; 95% confidential interval (CI), 1.04–1.10; p < 0.001) and serum phosphate levels (HR, 1.40; 95%CI, 1.16–1.67, p < 0.001) were independent risk factors for developing AS. Incidentally, there was no significant mortality difference between patients with AS and those without (p = 0.53). Serum phosphate levels are a risk factor for developing AS and should be controlled. Annual echocardiography may contribute to the early detection of AS and improves the prognosis of patients undergoing HD.
Differential Regulation of NAPDH Oxidases in Salt-Tolerant Eutrema salsugineum and Salt-Sensitive Arabidopsis thaliana

Reactive oxygen species (ROS) signalling is crucial in modulating stress responses in plants, and NADPH oxidases (NOXs) are an important component of signal transduction under salt stress. The goal of this research was to investigate whether the regulation of NOX-dependent signalling during mild and severe salinity differs between the halophyte Eutrema salsugineum and the glycophyte Arabidopsis thaliana. Gene expression analyses showed that salt-induced expression patterns of two NOX genes, RBOHD and RBOHF, varied between the halophyte and the glycophyte. Five days of salinity stimulated the expression of both genes in E. salsugineum leaves, while their expression in A. thaliana decreased. This was not accompanied by changes in the total NOX activity in E. salsugineum, while the activity in A. thaliana was reduced. The expression of the RBOHD and RBOHF genes in E. salsugineum leaves was induced by abscisic acid (ABA) and ethephon spraying. The in silico analyses of promoter sequences of RBOHD and RBOHF revealed multiple cis-acting elements related to hormone responses, and their distribution varied between E. salsugineum and A. thaliana. Our results indicate that, in the halophyte E. salsugineum, the maintenance of the basal activity of NOXs in leaves plays a role during acclimation responses to salt stress. The different expression patterns of the RBOHD and RBOHF genes under salinity in E. salsugineum and A. thaliana point to a modified regulation of these genes in the halophyte, possibly through ABA- and/or ethylene-dependent pathways.
Estimation of the Impact of Foodborne Salmonellosis on Consumer Well-Being in Hungary

In Hungary, salmonellosis is one of the most frequent foodborne illnesses. According to our estimation, based on a representative consumer survey with 1001 respondents, the annual number of salmonellosis cases exceeded 90,000, which was 18 times higher than the officially reported data. Salmonellosis infections impose significant direct and indirect costs to the health care system, to companies (as employers) and to households. This study focused on the cost to households by analysing well-being losses due to Salmonella infections, for which the WTP (willingness-to-pay) method was used. WTP measures the cost that an individual would pay to avoid an undesirable harm or health outcome. For estimating WTP, 456 respondents gave quantifiable answers. The average WTP to avoid salmonellosis was 86.3 EUR. Based on this data, the total consumer well-being loss could be estimated to be about 7.87 million EUR per year in Hungary. These results indicate that consumers’ well-being losses alone would necessitate further interventions for Salmonella reduction.
Host–Viral Interactions in the Pathogenesis of Ulcerative Colitis

Ulcerative colitis is characterized by relapsing and remitting colonic mucosal inflammation. During the early stages of viral infection, innate immune defenses are activated, leading to the rapid release of cytokines and the subsequent initiation of downstream responses including inflammation. Previously, intestinal viruses were thought to be either detrimental or neutral to the host. However, persisting viruses may have a role as resident commensals and confer protective immunity during inflammation. On the other hand, the dysregulation of gut mucosal immune responses to viruses can trigger excessive, pathogenic inflammation. The purpose of this review is to discuss virus-induced innate immune responses that are at play in ulcerative colitis.
Fixed-Bed Column Technique for the Removal of Phosphate from Water Using Leftover Coal

The excessive discharge of phosphate from anthropogenic activities is a primary cause for the eutrophication of aquatic habitats. Several methodologies have been tested for the removal of phosphate from aqueous solutions, and adsorption in a flow-through reactor is an effective mechanism to reduce the nutrient loading of water. This research aimed to investigate the adsorption potential of leftover coal material to remove phosphate from a solution by using continuous flow fixed-bed column, and analyzes the obtained breakthrough curves. A series of column tests were performed to determine the phosphorus breakthrough characteristics by varying operational design parameters such as adsorbent bed height (5 to 8 cm), influent phosphate concentration (10–25 mg/L), and influent flow rate (1–2 mL/min). The amorphous and crystalline property of leftover coal material was studied using XRD technology. The FT-IR spectrum confirmed the interaction of adsorption sites with phosphate ions. Breakthrough time decreased with increasing flow rate and influent phosphate concentration, but increased with increasing adsorbent bed height. Breakthrough-curve analysis showed that phosphate adsorption onto the leftover coal material was most effective at a flow rate of 1 mL/min, influent phosphate concentration of 25 mg/L, and at a bed height of 8 cm. The maximal total phosphate adsorbed onto the coal material’s surface was 243 mg/kg adsorbent. The Adams–Bohart model depicted the experimental breakthrough curve well, and overall performed better than the Thomas and Yoon–Nelson models did, with correlation values (R2) ranging from 0.92 to 0.98. Lastly, leftover coal could be used in the purification of phosphorus-laden water, and the Adams–Bohart model can be employed to design filter units at a technical scale.
The Implementation of National Dementia Plans: A Multiple-Case Study on Denmark, Germany, and Italy

In a theory-driven, qualitative, multiple-case study, we examined the implementation of national dementia plans (NDPs) in Denmark, Germany, and Italy to determine how stakeholders involved in implementing the NDPs evaluate contextual factors in light of the World Health Organization’s seven action areas of dementia-focused policy. To analyse the NDPs, we used a driver diagram of large-scale change and conducted both document analysis and semi-structured interviews, after which we performed three-way open coding to analyse the methods. The results show that the implementation of NDPs has increased awareness of dementia in all three countries by positioning the disease as a national public health concern. The study also reveals that resources, the use of change theory, and the monitoring of implementation and fragmentation are crucial factors to consider for countries when implementing NDPs. Although stakeholders find the NDPs useful, many challenges remain for their successful implementation due to the highly limited means for implementation and evaluation. Moreover, present NDPs all lack a communication plan that encompasses all layers of society to address ways of achieving change. Patients with dementia, and their informal caregivers, should be included more in the design, implementation, and evaluation of NDPs in order to improve their usefulness and effectiveness.
Opioid Addiction and Opioid Receptor Dimerization: Structural Modeling of the OPRD1 and OPRM1 Heterodimer and Its Signaling Pathways

Opioid addiction is a complex phenomenon with genetic, social, and other components. Due to such complexity, it is difficult to interpret the outcome of clinical studies, and thus, mutations found in individuals with these addictions are still not indisputably classified as opioid addiction-causing variants. Here, we computationally investigated two such mutations, A6V and N40D, found in the mu opioid receptor gene OPRM1. The mutations are located in the extracellular domain of the corresponding protein, which is important to the hetero-dimerization of OPRM1 with the delta opioid receptor protein (OPRD1). The hetero-dimerization of OPRD1–OPRM1 affects the signaling pathways activated by opioids and natural peptides and, thus, could be considered a factor contributing to addiction. In this study, we built four 3D structures of molecular pathways, including the G-protein signaling pathway and the β-arrestin signaling pathway of the heterodimer of OPRD1–OPRM1. We also analyzed the effect of mutations of A6V and N40D on the stability of individual OPRM1/OPRD1 molecules and the OPRD1–OPRM1 heterodimer with the goal of inferring their plausible linkage with opioid addiction. It was found that both mutations slightly destabilize OPRM1/OPRD1 monomers and weaken their association. Since hetero-dimerization is a key step for signaling processes, it is anticipated that both mutations may be causing increased addiction risk.
Effect of Volume Tie Ratio in the Engineered Cementitious Composites Plastic Hinges on the Seismic Performance of RC Composite Bridge Columns

The feasibility that the transverse reinforcements in steel-reinforced Engineered Cementitious Composites (ECC) columns could be reduced or even totally eliminated has been experimentally demonstrated. However, due to the effect of the tie volume ratio in ECC plastic hinges on the seismic performance of RC composite bridge columns not being fully clarified as of yet, a numerical study was carried out. In this study, the analytical models based on the fiber element method, by considering the superposition of different lateral confinements resulting from ties and the ECC cover, were used to correlate with a target hybrid-loading experiment. Load-displacement hysteresis, strains in extreme fibers and longitudinal bars in analytical results correlated well with the experiments, verifying the accuracy of the analytical models proposed in this study. Based on the analytical results, it was found that the volume tie ratio had little effect on the stress-strain hysteresis of the ECC cover, but a lower volume tie ratio resulted in more significant nonlinear behavior longitudinally. Finally, the pushover analysis was conducted to investigate the effect of volume tie ratios on the seismic design parameters, and the results showed that a higher volume tie ratio resulted in a limited increase in the maximum allowable displacement for design.