A Recipe for Successful Metastasis: Transition and Migratory Modes of Ovarian Cancer Cells.

One of the characteristic features of ovarian cancer is its early dissemination. Metastasis and the invasiveness of ovarian cancer are strongly dependent on the phenotypical and molecular determinants of cancer cells. Invasive cancer cells, circulating tumor cells, and cancer stem cells, which are responsible for the metastatic process, may all undergo different modes of transition, giving rise to mesenchymal, amoeboid, and redifferentiated epithelial cells. Such variability is the result of the changing needs of cancer cells, which strive to survive and colonize new organs. This would not be possible if not for the variety of migration modes adopted by the transformed cells. The most common type of metastasis in ovarian cancer is dissemination through the transcoelomic route, but transitions in ovarian cancer cells contribute greatly to hematogenous and lymphatic dissemination. This review aims to outline the transition modes of ovarian cancer cells and discuss the migratory capabilities of those cells in light of the known ovarian cancer metastasis routes.

Spectroscopic Analysis of the Effect of Ibuprofen Degradation Products on the Interaction between Ibuprofen and Human Serum Albumin.

BACKGROUND: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are one of the most commonly used groups of medicinal compounds in the world. The wide access to NSAIDs and the various ways of storing them due to their easy accessibility often entail the problem with the stability and durability resulting from the exposure of drugs to external factors. The aim of the research was to evaluate in vitro the mechanism of competition between ibuprofen (IBU) and its degradation products, i.e., 4'-isobutylacetophenone (IBAP) and (2RS)-2-(4- formylphenyl)propionic acid (FPPA) during transport in a complex with fatted (HSA) and defatted (dHSA) human serum albumin. METHODS: The research was carried out using spectroscopic techniques, such as spectrophotometry, infrared spectroscopy and nuclear magnetic resonance spectroscopy. RESULTS: The comprehensive application of spectroscopic techniques allowed, among others, for the determination of the binding constant, the number of classes of binding sites and the cooperativeness constant of the analyzed systems IBU-(d)HSA, IBU-(d)HSA-FPPA, IBU-(d)HSA-IBAP; the determination of the effect of ibuprofen and its degradation products on the secondary structure of albumin; identification and assessment of interactions between ligand and albumin; assessment of the impact of the presence of fatty acids in the structure of albumin and the measurement temperature on the binding of IBU, IBAP and FPPA to (d)HSA. CONCLUSION: The conducted research allowed us to conclude that the presence of ibuprofen degradation products and the increase in their concentration significantly affect the formation of the IBU-albumin complex and thus, the value of the association constant of the drug, changing the concentration of its free fraction in the blood plasma. It was also found that the presence of an ibuprofen degradation product in a complex with albumin affects its secondary structure.

The Complex Network of Cytokines and Chemokines in Pediatric Patients with Long-Standing Type 1 Diabetes.

Type 1 diabetes (T1D) is a progressive disorder leading to the development of microangiopathies and macroangiopathies. Numerous cytokines and chemokines are involved in the pathogenesis of T1D complications. The study aimed to assess the presence of complications in patients with long-standing T1D and its relationship with serum biomarker concentrations. We examined 52 T1D subjects, with a disease duration ≥4 years and 39 healthy controls. The group of T1D patients was further divided into subgroups based on the duration of the disease (<7 years and ≥7 years) and the metabolic control assessed by the HbAlc level (<8% and ≥8%). We used Luminex Technology to assess a wide range of biomarker concentrations. A 24 h urine test was done to evaluate the rate of albuminuria. Optical coherence tomography (OCT) was conducted to detect early retinopathic changes. Subclinical atherosclerosis was assessed by measuring the carotid intima-media thickness (IMT). T1D patients showed remarkably higher concentrations of EGF, eotaxin/CCL11, MDC/CCL22, sCD40L, TGF-α, and TNF-α. Moreover, we reported statistically significant correlations between cytokines and IMT. Biomarker concentrations depend on numerous factors such as disease duration, metabolic control, and the presence of complications. Although the majority of pediatric T1D patients do not present signs of overt complications, it is indispensable to conduct the screening for angiopathies already in childhood, as its early recognition may attenuate the further progression of complications.

Osteosarcoma's genetic landscape painted by genes' mutations.

PURPOSE: Osteosarcoma (OS) is one of the most common primary bone tumors. Direct pathogenesis remains unknown, however, genes' mutations are proven to participate in the process. This study aimed to examine the most frequently mutated genes in OS to appoint candidates for the cancer markers. METHODS: Using the COSMIC Catalogue twenty the most frequently mutated genes were selected leading to an up-to-date genetic OS landscape summary. The genes can be classified into four categories: suppressor genes (TP53, RB1, NCOR1, SMAD2, NF1, TSC2, KMT2C), proto-oncogenes (GNAS, BRAF, MLLT3), epigenetic and post-translational modification-related genes (SMARCA4, ARID1A, ATRX, BCOR, H3F3A) and cell growth and survival regulating genes (EGFR, CAMTA1, LRP1B, PDE4DIP, MED12). RESULTS AND CONCLUSIONS: Their role in cancerogenesis was confirmed by the analysis of available articles published previously. The results of the study indicate that examination of selected genes' mutations might help to identify patients' predisposition to OS development, as well as monitor the disease progression, and establish prognosis. However, to fully understand the pathogenesis of OS further studies are required.

Choroid Plexus Volume Change-A Candidate for a New Radiological Marker of MS Progression.

(1) Background: Multiple sclerosis (MS) is an auto-immune, chronic, neuroinflammatory, demyelinating disease that affects mainly young patients. This progressive inflammatory process causes the chronic loss of brain tissue and results in a deterioration in quality of life. To monitor neuroinflammatory process activity and predict the further development of disease, it is necessary to find a suitable biomarker that could easily be used. In this research, we verify the usability of choroid plexus (CP) volume, a new MS biomarker, in the monitoring of the progression of multiple sclerosis disease. (2) Methods: A single-center, prospective study with three groups of patients was conducted based on the following groups: MS patients who received experimental cellular therapy (Treg), treatment-naïve MS patients and healthy controls. (3) Results: This study concludes that there is a correlation between the CPV/TIV (choroid plexus/total intracranial volume) ratio and the progress of multiple sclerosis disease-patients with MS (MS + Treg) had larger volumes of choroid plexuses. CPV/TIV ratios in MS groups were constantly and significantly growing. In the Treg group, patients with relapses had larger plexuses in comparison to the group with no relapses of MS. A similar correlation was observed for the GD+ group (patients with postcontrast enhancing plaques) compared against the non-GD group (patients without postcontrast enhancing plaques). (4) Conclusion: Choroid plexus volume, due to its immunological function, correlates with the inflammatory process in the central nervous system. We consider it to become a valuable radiological biomarker of MS activity.

Cancer Stem Cell Markers-Clinical Relevance and Prognostic Value in High-Grade Serous Ovarian Cancer (HGSOC) Based on The Cancer Genome Atlas Analysis.

Cancer stem cells (CSCs) may contribute to an increased risk of recurrence in ovarian cancer (OC). Further research is needed to identify associations between CSC markers and OC patients' clinical outcomes with greater certainty. If they prove to be correct, in the future, the CSC markers can be used to help predict survival and indicate new therapeutic targets. This study aimed to determine the CSC markers at mRNA and protein levels and their association with clinical presentation, outcome, and risk of recurrence in HGSOC (High-Grade Serous Ovarian Cancer). TCGA (The Cancer Genome Atlas) database with 558 ovarian cancer tumor samples was used for the evaluation of 13 CSC markers (ALDH1A1, CD44, EPCAM, KIT, LGR5, NES, NOTCH3, POU5F1, PROM1, PTTG1, ROR1, SOX9, and THY1). Data on mRNA and protein levels assessed by microarray and mass spectrometry were retrieved from TCGA. Models to predict chemotherapy response and survival were built using multiple variables, including epidemiological data, expression levels, and machine learning methodology. ALDH1A1 and LGR5 mRNA expressions indicated a higher platinum sensitivity (p = 3.50 × 10-3; p = 0.01, respectively). POU5F1 mRNA expression marked platinum-resistant tumors (p = 9.43 × 10-3). CD44 and EPCAM mRNA expression correlated with longer overall survival (OS) (p = 0.043; p = 0.039, respectively). THY1 mRNA and protein levels were associated with worse OS (p = 0.019; p = 0.015, respectively). Disease-free survival (DFS) was positively affected by EPCAM (p = 0.004), LGR5 (p = 0.018), and CD44 (p = 0.012). In the multivariate model based on CSC marker expression, the high-risk group had 9.1 months longer median overall survival than the low-risk group (p < 0.001). ALDH1A1, CD44, EPCAM, LGR5, POU5F1, and THY1 levels in OC may be used as prognostic factors for the primary outcome and help predict the treatment response.

Measuring Integrated Care - Methodological Reflections from Monitoring and Evaluation Process of the PHC Plus Pilot Program in Poland.

Introduction: Integrated care is an important strategy for increasing health system performance. Despite its growing significance, detailed evidence on the measurement properties of integrated care instruments remains vague and limited. This article aims to present the Monitoring and Evaluation Framework (M&EF) used in the pilot program of coordinated primary care in Poland. It can serve as an example of Monitoring and Evaluation (M&E) concept for the countries taking their first steps in the care integration implementation or establishing PHC reforms. This article belongs to the series of publications entitled: "Highway to hell or stairway to heaven - evaluating complex integrated care models - lessons from the Primary Healthcare Plus pilot program (PHC Plus) in Poland". Methods: The M&EF of the PHC Plus was based on the Theory of Change within which a shift was to take place in the following 4 aspects: (1) change in health outcomes among participating patients; (2) change in health care experience among participating patients; (3) change in the fragmentation of care provided for chronic diseases among participating patients; (4) change in overall spending on health services for the patients in the PHC Plus facilities. Data for the M&EF of the PHC Plus came from two main sources: the National Health Fund (national insurer) database and the results survey questionnaires. Results: Based on the established M&EF of PHC Plus it was possible to monitor and evaluate the change in patients' health outcomes, health experience and health literacy, fragmentation of care index, and overall spending on healthcare services offered in the pilot. Some of the analyzes planned could not be carried out due errors in data reporting systems, the lack of data of adequate quality or the pandemic. However, M&E implementation process provided many insightful information supporting broader PHC reform in Poland. Inclusive process of information and data sharing, discussions with the country health stakeholders and solid analytical background allowed for better informed policy making and scaling up the pilot. Conclusion: M&E process was put in place to help identify interventions, processes and approaches that could be scaled up and implemented at the country level. This approach resulted in broader understanding and acceptance of the proposed reforms in the PHC in Poland, following PHC Plus pilot implementation. Tools and approaches available and used to evaluate care integration in the PHC setting may not fully respond to the PHC and care integration system characteristic and country capacity. Therefore, revised M&E approach should be an integral part of the health policy interventions and further development of the PHC. Care integration specific measurement tools should be considered. Integration is a complex, multidimensional concept that requires measurement at multiple levels, including the patient level, the provider (professional) level, organizational and systems level. The M&E system of care integration requires use of multidimensional approach, complexed data systems, but also active sharing process of key findings. A phased approach is recommended to help researchers define clearly where they are in the research process and show progress on the outcomes' achievement. Some simplification of the M&EF used in the PHC Plus is recommended to increase its sustainability without loosing key analytics.

A distinct septal pattern of late gadolinium enhancement specific for COVID-induced myocarditis: A multicenter cardiovascular magnetic resonance study.

BACKGROUND: COVID-19 is a great medical challenge as it provokes acute respiratory distress and has pulmonary manifestations and cardiovascular (CV) consequences. AIMS: This study compared cardiac injury in COVID-19 myocarditis patients with non-COVID-19 myocarditis patients. METHODS: Patients who recovered from COVID-19 were scheduled for cardiovascular magnetic resonance (CMR) owing to clinical myocarditis suspicion. The retrospective non-COVID-19 myocarditis (2018-2019) group was enrolled (n = 221 patients). All patients underwent contrast-enhanced CMR, the conventional myocarditis protocol, and late gadolinium enhancement (LGE). The COVID study group included 552 patients at a mean (standard deviation [SD]) age of 45.9 (12.6) years. RESULTS: CMR assessment confirmed myocarditis-like LGE in 46% of the cases (68.5% of the segments with LGE <25% transmural extent), left ventricular (LV) dilatation in 10%, and systolic dysfunction in 16% of cases. The COVID-19 myocarditis group showed a smaller median (interquartile range [IQR]) LV LGE (4.4% [2.9%-8.1%] vs. 5.9% [4.4%-11.8%]; P <0.001), lower LV end-diastolic volume (144.6 [125.5-178] ml vs. 162.8 [136.6-194] ml; P <0.001), limited functional consequence (left ventricular ejection fraction, 59% [54.1%-65%] vs. 58% [52%-63%]; P = 0.01), and a higher rate of pericarditis (13.6% vs. 6%; P = 0.03) compared to non-COVID-19 myocarditis. The COVID-19-induced injury was more frequent in septal segments (2, 3, 14), and non-COVID-19 myocarditis showed higher affinity to lateral wall segments (P <0.01). Neither obesity nor age was associated with LV injury or remodeling in subjects with COVID-19 myocarditis. CONCLUSIONS: COVID-19-induced myocarditis is associated with minor LV injury with a significantly more frequent septal pattern and a higher pericarditis rate than non-COVID-19 myocarditis.

A Potential Objective Sign of Central Sensitization: Referred Pain Elicited by Manual Gluteus Minimus Muscle Exploration is Coincident with Pathological Autonomic Response Provoked by Noxious Stimulation.

Referred pain/sensation provoked by trigger points suits the nociplastic pain criteria. There is a debate over whether trigger points are related to a peripheral phenomenon or central sensitization (CS) processes. Referred pain is considered a possible sign of CS, which occurs probably mainly due to the abnormal activity of the immune and autonomic nervous systems. To confirm abnormal autonomic reactivity within the referred pain zone of active trigger points, a new diagnostic tool, the Skorupska Protocol® (the SP test®), was applied. The test uses noxious stimulation (10 minutes of dry needling under infrared camera control) as a diagnostic tool to confirm abnormal autonomic nervous system activity. A response to the SP test® of healthy subjects with referred pain sensations provoked by latent trigger points (LTrPs) stimulation was not explored before. The study aims at examining if LTrPs can develop an autonomic response. Methods. Two groups of healthy subjects, (i) gluteus minimus LTrPs with referred pain (n = 20) and (ii) control (n = 27), were examined using the SP test®. Results. Abnormal autonomic activity within the referred pain zone was confirmed for all analyzed LTrPs subjects. 70% of control subjects had no feature of vasodilatation and others presented minor vasomotor fluctuations. The size of vasomotor reactivity within the referred pain zone was LTrPs 11.1 + 10.96% vs. control 0.8 + 0.6% (p < 0.05). Conclusions. Noxious stimulation of latent TrPs induces abnormal autonomic nervous system activity within the referred pain zone. The observed phenomenon supports the concept of central nervous system involvement in the referred pain patomechanizm.

The diagnosis of multiple sclerosis: what has changed in diagnostic criteria?

Multiple sclerosis (MS) is a chronic, demyelinating disease affecting the central nervous system. Diagnosis of MS is based on the proof of disease dissemination in time (DIT) and dissemination in space (DIS) and excluding other disorders that can mimic multiple sclerosis in laboratory tests and clinical manifestation. Over the years the diagnostic criteria have evolved; the introduction of magnetic resonance in the McDonald's 2001 criteria was revolutionary. Since then, the criteria have been modified up to the currently used McDonald 2017. The aim of this review is to analyse the 2017 McDonald criteria, assess what has changed from the 2010 criteria, and present the impact of revised criteria on rapid and accurate diagnosis of MS. The main differences are as follows: inclusion of oligoclonal bands in cerebrospinal fluid as a DIT criterion, and symptomatic and cortical lesions in magnetic resonance imaging are counted in the determination of DIS and DIT. We present also the newest recommendations of the Polish Medical Society of Radiology and the Polish Society of Neurology and international group of North American Imaging in Multiple Sclerosis and Consortium of Multiple Sclerosis Centers, as well as future directions for further investigations. A proper diagnosis is crucial for the patient's quality of life, to give the possibility of early treatment, and to help avoid misdiagnosis and unnecessary therapy.

The Role of Circulating Tumor Cells in Ovarian Cancer Dissemination.

Metastatic ovarian cancer is the main reason for treatment failures and consequent deaths. Ovarian cancer is predisposed to intraperitoneal dissemination. In comparison to the transcoelomic route, distant metastasis via lymph vessels and blood is less common. The mechanisms related to these two modes of cancer spread are poorly understood. Nevertheless, the presence of tumor cells circulating in the blood of OC patients is a well-established phenomenon confirming the significant role of lymphatic and hematogenous metastasis. Thus, the detection of CTCs may provide a minimally invasive tool for the identification of ovarian cancer, monitoring disease progression, and treatment effectiveness. This review focuses on the biology of ovarian CTCs and the role they may play in cancer diagnosis and therapy.

The Hemisphere of the Brain in Which a Stroke Has Occurred Visible in the Heart Rate Variability.

The aim of this study was to assess whether heart rate variability (HRV) could predict which hemisphere of the brain was affected during an acute ischemic stroke (AIS). To achieve this goal, we compared HRV between patients with a right (RH) and left hemispheric (LH) stroke. The studied group consisted of 64 patients with AIS (25 with RH and 39 with LH stroke, with a mean age of 64 ± 12 and 66 ± 13, p = 0.3, respectively) using 24 h Holter ECG records at NN intervals performed at a mean of 4.3 ± 2 days following their AIS. Standard linear methods were used to analyze HRV in the time and frequency domains, as well as nonlinear methods, including sample entropy, detrended fluctuation analysis, and asymmetry measures. Patients with an LH stroke had significantly greater values for sample entropy compared to subjects with an RH stroke (1.31 ± 0.53 vs. 0.92 ± 0.46, p = 0.003, Bonferroni-corrected p = 0.033, effect size = 0.8). The LH stroke group also had higher RMSSD (113 ± 81 vs. 76 ± 61, p = 0.06), pNN50 (33.35 ± 28.54 vs. 18.52 ± 23.75, p = 0.02), and HFnu (48.42 ± 16.41 vs. 42.66 ± 17.88, p = 0.11) values, when compared to the RH group, which was possibly related to higher activity in the parasympathetic system in the LH group. Conversely, subjects with RH stroke had higher LFnu (57.34 ± 17.88 vs. 51.58 ± 16.41, p-value = 0.11) and LF/HF ratios (2.24 ± 2.87 vs. 1.68 ± 2.50, p-value = 0.11), which were likely related to higher activity in the sympathetic nervous system, when compared to the LH stroke group. Our pilot study demonstrated that patients with RH stroke had lower HRV complexity than those with LH stroke, indicating that HRV could be useful in the discrimination of hemispheric involvement in AIS.

Heterogeneity of Cognitive Profiles in Children and Adolescents with Mild Intellectual Disability (MID).

Mild Intellectual Disability (MID) is a neurodevelopmental disorder that begins in childhood and is characterized by limitations in intellectual functioning (IQ = 55-69) and adaptive behavior that manifests in everyday living. In addition to these specific criteria, clinical practice shows that the population of children with MID has heterogeneous deficits in cognitive functioning. Thus, the aim of this study was to identify groups of homogenous cognitive profiles within a heterogeneous population of students with MID. The cognitive profiles of 16,411 participants with Mild Intellectual Disability were assessed based on their performance on the Stanford-Binet Intelligence Scales-Fifth Edition. Prior to the assessment, participants were divided into three age groups corresponding to the levels of the Polish education system: (1) 7;00-9;11, (2) 10;00-14;11, and (3) 15;00-18;11 years old. Using cluster analysis, we identified three distinct cognitive profiles (clusters) in each age group. These clusters differed from each other within and between each age group. Distinguishing cognitive profiles among children and adolescents with MID is important both in the context of diagnosis as well as the development of research-based interventions for these students.

The Advances and Challenges of Liposome-Assisted Drug Release in the Presence of Serum Albumin Molecules: The Influence of Surrounding pH.

The aim of this study is to prepare a liposomal delivery system for 5-methyl-12 (H)-quino[3,4-b]-1,4-benzothiazine chloride (5-MBT) and study the in vitro release characteristics. The release of 5-MBT from a liposomal complex with human serum albumin (HSA) [LDPPC/5-MBT]:HSA was examined using the spectrophotometric method and differential scanning calorimetry (DSC). Electronic paramagnetic resonance was used to assess the influence of the pH of the environment on the conformation of phospholipids, the latter determining the degree of release of the encapsulated compound. The applied mathematical models made it possible to determine the necessary analytical parameters to facilitate the process of potential drug release from liposomes. The complexes formed by liposomal 5-MBT with serum albumin (HSA) particles allowed for the description of the Fick process. The change in the polarity of the phospholipid membrane resulting from the changes in the pH of the surroundings, significantly influenced the percentage of 5-MBT entrapment in the liposomes. It also affected the release percentage.

Preferences of seniors living in selected Baltic Sea region countries towards the use of indoor public space furniture.

Demographic changes can be observed all over the world. The number of seniors located in the societies of well-developed countries continues to rise. Both enterprises and governments need to be prepared for such changes. Consequently, public spaces need to evolve to reduce problems related to ageism and be friendly to all. Much attention is currently being paid to finding solutions for redesigning public spaces and adjusting them to the needs and requirements of senior citizens. To identify the preferences of seniors in relation to the characteristics of furniture in indoor public spaces, a survey study with 1539 respondents aged 60+ was conducted in Denmark, Finland, Latvia, Poland, Russia and Sweden. The gathered data were coded and implemented to the unified database. The statistical grouping method was used to recognize the characteristics of the needs and attitudes of seniors related to the use of public space furniture. The main variables taken into consideration in the analysis were the age and gender of respondents and their country of living. Among the most important findings are those indicating the necessity to provide the increased number of furniture for sitting in the public spaces and making sure they are not located too far away from each other. As the main disadvantages of public space furniture respondents indicated the lack of armrests or other solutions to facilitate getting up and/or sitting down, as well as profiled backrests that constitute solid support for the spine. The implementation of these data in the process of rethinking and redesigning public spaces may support the adaptation of indoor public furniture according to the requirements of a very large group of customers, namely, seniors.