Using Copy Number Variation Data and Neural Networks to Predict Cancer Metastasis Origin Achieves High Area under the Curve Value with a Trade-Off in Precision.

The accurate identification of the primary tumor origin in metastatic cancer cases is crucial for guiding treatment decisions and improving patient outcomes. Copy number alterations (CNAs) and copy number variation (CNV) have emerged as valuable genomic markers for predicting the origin of metastases. However, current models that predict cancer type based on CNV or CNA suffer from low AUC values. To address this challenge, we employed a cutting-edge neural network approach utilizing a dataset comprising CNA profiles from twenty different cancer types. We developed two workflows: the first evaluated the performance of two deep neural networks-one ReLU-based and the other a 2D convolutional network. In the second workflow, we stratified cancer types based on anatomical and physiological classifications, constructing shallow neural networks to differentiate between cancer types within the same cluster. Both approaches demonstrated high AUC values, with deep neural networks achieving a precision of 60%, suggesting a mathematical relationship between CNV type, location, and cancer type. Our findings highlight the potential of using CNA/CNV to aid pathologists in accurately identifying cancer origins with accessible clinical tests.

Susceptibility to Pentylenetetrazole-Induced Seizures in Mice with Distinct Activity of the Endogenous Opioid System.

Currently, pharmacotherapy provides successful seizure control in around 70% of patients with epilepsy; however, around 30% of cases are still resistant to available treatment. Therefore, effective anti-epileptic therapy still remains a challenge. In our study, we utilized two mouse lines selected for low (LA) and high (HA) endogenous opioid system activity to investigate the relationship between down- or upregulation of the opioid system and susceptibility to seizures. Pentylenetetrazole (PTZ) is a compound commonly used for kindling of generalized tonic-clonic convulsions in animal models. Our experiments revealed that in the LA mice, PTZ produced seizures of greater intensity and shorter latency than in HA mice. This observation suggests that proper opioid system tone is crucial for preventing the onset of generalized tonic-clonic seizures. Moreover, a combination of an opioid receptor antagonist-naloxone-and a GABA receptor agonist-diazepam (DZP)-facilitates a significant DZP-sparing effect. This is particularly important for the pharmacotherapy of neurological patients, since benzodiazepines display high addiction risk. In conclusion, our study shows a meaningful, protective role of the endogenous opioid system in the prevention of epileptic seizures and that disturbances in that balance may facilitate seizure occurrence.

Investigation of the Molecular Evolution of Treg Suppression Mechanisms Indicates a Convergent Origin.

Regulatory T cell (Treg) suppression of conventional T cells is a central mechanism that ensures immune system homeostasis. The exact time point of Treg emergence is still disputed. Furthermore, the time of Treg-mediated suppression mechanisms' emergence has not been identified. It is not yet known whether Treg suppression mechanisms diverged from a single pathway or converged from several sources. We investigated the evolutionary history of Treg suppression pathways using various phylogenetic analysis tools. To ensure the conservation of function for investigated proteins, we augmented our study using nonhomology-based methods to predict protein functions among various investigated species and mined the literature for experimental evidence of functional convergence. Our results indicate that a minority of Treg suppressor mechanisms could be homologs of ancient conserved pathways. For example, CD73, an enzymatic pathway known to play an essential role in invertebrates, is highly conserved between invertebrates and vertebrates, with no evidence of positive selection (w = 0.48, p-value < 0.00001). Our findings indicate that Tregs utilize homologs of proteins that diverged in early vertebrates. However, our findings do not exclude the possibility of a more evolutionary pattern following the duplication degeneration−complementation (DDC) model. Ancestral sequence reconstruction showed that Treg suppression mechanism proteins do not belong to one family; rather, their emergence seems to follow a convergent evolutionary pattern.

Investigation of Mutated in Colorectal Cancer (MCC) Gene Family Evolution History Indicates a Putative Role in Th17/Treg Differentiation.

The MCC family of genes plays a role in colorectal cancer development through various immunological pathways, including the Th17/Treg axis. We have previously shown that MCC1 but not MCC2 plays a role in Treg differentiation. Our understanding of the genetic divergence patterns and evolutionary history of the MCC family in relation to its function, in general, and the Th17/Treg axis, in particular, remains incomplete. In this investigation, we explored 12 species' genomes to study the phylogenetic origin, structure, and functional specificity of this family. In vertebrates, both MCC1 and MCC2 homologs have been discovered, while invertebrates have a single MCC homolog. We found MCC homologs as early as Cnidarians and Trichoplax, suggesting that the MCC family first appeared 741 million years ago (Ma), whereas MCC divergence into the MCC1 and MCC2 families occurred at 540 Ma. In general, we did not detect significant positive selection regulating MCC evolution. Our investigation, based on MCC1 structural similarity, suggests that they may play a role in the evolutionary changes in Tregs' emergence towards complexity, including the ability to utilize calcium for differentiation through the use of the EFH calcium-binding domain. We also found that the motif NPSTGE was highly conserved in MCC1, but not in MCC2. The NPSTGE motif binds KEAP1 with high affinity, suggesting an Nrf2-mediated function for MCC1. In the case of MCC2, we found that the "modifier of rudimentary" motif is highly conserved. This motif contributes to the regulation of alternative splicing. Overall, our study sheds light on how the evolution of the MCC family is connected to its function in regulating the Th17/Treg axis.

The Journey of Cancer Cells to the Brain: Challenges and Opportunities.

Cancer metastases into the brain constitute one of the most severe, but not uncommon, manifestations of cancer progression. Several factors control how cancer cells interact with the brain to establish metastasis. These factors include mediators of signaling pathways participating in migration, infiltration of the blood-brain barrier, interaction with host cells (e.g., neurons, astrocytes), and the immune system. Development of novel therapies offers a glimpse of hope for increasing the diminutive life expectancy currently forecasted for patients suffering from brain metastasis. However, applying these treatment strategies has not been sufficiently effective. Therefore, there is a need for a better understanding of the metastasis process to uncover novel therapeutic targets. In this review, we follow the journey of various cancer cells from their primary location through the diverse processes that they undergo to colonize the brain. These processes include EMT, intravasation, extravasation, and infiltration of the blood-brain barrier, ending up with colonization and angiogenesis. In each phase, we focus on the pathways engaging molecules that potentially could be drug target candidates.

Adera2.0: A Drug Repurposing Workflow for Neuroimmunological Investigations Using Neural Networks.

Drug repurposing in the context of neuroimmunological (NI) investigations is still in its primary stages. Drug repurposing is an important method that bypasses lengthy drug discovery procedures and focuses on discovering new usages for known medications. Neuroimmunological diseases, such as Alzheimer's, Parkinson's, multiple sclerosis, and depression, include various pathologies that result from the interaction between the central nervous system and the immune system. However, the repurposing of NI medications is hindered by the vast amount of information that needs mining. We previously presented Adera1.0, which was capable of text mining PubMed for answering query-based questions. However, Adera1.0 was not able to automatically identify chemical compounds within relevant sentences. To challenge the need for repurposing known medications for neuroimmunological diseases, we built a deep neural network named Adera2.0 to perform drug repurposing. The workflow uses three deep learning networks. The first network is an encoder and its main task is to embed text into matrices. The second network uses a mean squared error (MSE) loss function to predict answers in the form of embedded matrices. The third network, which constitutes the main novelty in our updated workflow, also uses a MSE loss function. Its main usage is to extract compound names from relevant sentences resulting from the previous network. To optimize the network function, we compared eight different designs. We found that a deep neural network consisting of an RNN neural network and a leaky ReLU could achieve 0.0001 loss and 67% sensitivity. Additionally, we validated Adera2.0's ability to predict NI drug usage against the DRUG Repurposing Hub database. These results establish the ability of Adera2.0 to repurpose drug candidates that can shorten the development of the drug cycle. The workflow could be download online.

Tick exposure and prevalence of Borrelia burgdorferi antibodies among hunters and other individuals exposed to vector ticks in eastern Poland

Background: Lyme borreliosis is the most frequent tick-borne disease in Europe and North America, and the number of registered cases is on the increase. Frequent presence in the habitats of ticks enhances the risk of tick bites and possible infection with Borrelia burgdorferi spirochetes. Objective: The aim of the study was to assess the risk of B. burgdorferi infection posed to hunters and other individuals exposed to activity-related contact with ticks. Material and methods: The study was carried out in the northern part of the Lublin Province (eastern Poland) and involved 150 individuals exposed to tick bites (110 hunters and 40 individuals exposed to activity-related contact with ticks). The analysis of sera for the presence of B. burgdorferi IgM and IgG antibodies was carried out. All 150 individuals were tested with the ELISA assay, and positive and borderline results of the assay were verified with the Western blot test. All study participants completed a questionnaire, which provided information about exposure to ticks, application of prophylactic measures, and awareness of Lyme borreliosis. Results: The ELISA assay revealed a positive or borderline result in at least one of the classes of B. burgdorferi antibodies in 63.3% (95/150) of the individuals (IgM 14.0%, IgG 63.3%). Verification carried out with the Western blot test showed a positive or borderline result in at least one of the antibody classes in 38.0% (57/150) of the examined persons (IgM 2.7%, IgG 36.7%). Abdomen (56.0%) and legs (53.7%) were the most frequently bitten body regions. Tick bites on the abdomen were significantly more frequently declared by hunters. Inspection of the body after returning from natural areas was more popular prophylactic method than use of repellents. Inspection of the body was significantly more often used in the group of the hunters. Conclusions: The risk of B. burgdorferi infection among hunters and other individuals undertaking activities associated with exposure to tick bites in the study area is high.

Seroprevalence of Rubella and Cytomegalia in Young Women from Biala Podlaska District.

The aim of this study was to analyze the seroprevalence of rubella and cytomegalia among young women. The study included 175 healthy women from the Biala Podlaska District, aged 16 to 35 years. Anti-rubella and anti-CMV IgG were determined by ELISA. 172 (98.3%) study subjects tested positive for rubella antibodies, 1 (0.6%) was seroindeterminate and 2 (1.1%) were seronegative. CMV antibodies were detected in 119 (68.0%) participants; the series included also 1 (0.6%) seroindeterminate and 55 (31.4%) seronegative women. The levels of rubella and CMV antibodies were not significantly affected by age, place of residence and educational level of the study subjects.

[Risk of occupational infections caused by Borrelia burgdorferi among forestry workers and farmers]. / Ryzyko zakazen zawodowych Borrelia burgdorferi u pracowników lesnictwa i rolników.

BACKGROUND: The aim of the work was to analyze the incidence of infection with Borrelia burgdorferi in forestry workers and farmers, major groups occupationally exposed to tick bites. MATERIAL AND METHODS: The study group included 275 workers (171 foresters and 104 farmers). The control group consisted of 45 people, who have not been occupationally exposed to tick bites. The screening Elisa and Wb tests for the presence of anti-Borrelia IgM/IgG antibodies were performed in all subjects of the study and control groups. Statistical analysis was performed using the Chi2 test. RESULTS: The positive results denoting the presence of anti-Borrelia IgM/IgG antibodies were found in 55% of farmers and 28% of foresters occupationally exposed to Lyme borreliosis and coming from the area of South Podlasie Lowland and Lublin Polesie. The differences between the forestry workers and the control group (p < or = 0.00001) and between farmers and the control group (p < or = 0.001) were statistically significant. The species, such as B. spielmanii and B. bavariensis, which have not yet been reported in Poland, are significant etiologic agents of Lyme disease. CONCLUSION: The risk of occupational exposure to the B. burgdorferi infection is high for foresters and farmers, and the infection with spirochetes is frequently confirmed on the basis of positive results of the Wb test. The presence of specific antibodies against protein antigens of B. spielmanii and B. bavariensis suggest that these bacteria can cause Lyme disease both independently and in participation with other Borrelia species, which influences the development of the clinical manifestations of infection.

[Significance of circulating immune complexes (CIC) in the diagnosis of infections with Borrelia burgdorferi]. / Znaczenie krazacych kompleksów immunologicznych (CIC) w diagnostyce zakazen Borrelia burgdorferi.

INTRODUCTION: The infection caused by Borrelia burgdorferi initiates a number of reactions in the human immunological system and particular behaviors of the infectious factor. The aim of work was to analyze the level of circulating immune complexes (CIC) due to infection with Borrelia burgdorferi in persons professionally exposed to tick bites. MATERIAL AND METHODS: The group of tested consisted of 275 persons, who are professionally exposed to tick bites, including 171 foresters and 104agriculturists. The controlled group consisted of 45 people, living permanently ortemporarily in Biata Podlaska, city in the South Podlasie Lowland, who have not been exposed professionally on tick bites.The screening test ELISA (Euroimmun) has been carried among all persons from the tested group towards the presence ofantibodies IgM/IgG anty-Borrelia. Among those who met positive or delimited results from screening test Elisa, another test of Western blot (Wb, Euroimmun, Virotech GmbH) has been carried in order to confirm the infection. The serum which has been taken from a group of persons being professionally exposed to infection of B. burgdorferi and persons from a controlled group, has been tested in terms of estimating levels of circulating immune complexes CIC C1q (Elisa, DRG). RESULTS AND CONCLUSION: The circulating immune complexes (CIC) are increasingly generated at persons with present IgM and/or IgG anty-Borrelia but their existence accompanied by the presence of strongly expressed humoral response does not affect the diagnostic effectiveness of infections with B. burgdorferi.

Differences in Emotional Intelligence Between Male and Female Nursing Students From a Population With a Low Percentage of Male Nurses.

Introduction: Poland has the largest shortage of nurses in Europe, as well as a low percentage of male nurses. Information relating to emotional intelligence has been explored to determine whether it predicts the characteristics and outcomes of qualified health professionals during their academic training and practice. Objective: This study aimed to measure differences in emotional intelligence between male and female nursing students. Participants and methods: In this cross-sectional study, emotional intelligence was measured using the Schutte Self-Report Emotional Intelligence Test (SSEIT) in 21 male and 127 female nursing students from John Paul II University in Biala Podlaska, Poland. Results: The raw overall scores of emotional intelligence in male and female students were similar. Differences were observed after the conversion of raw scores into normalized (sten) scores. High normalized scores (sten 8-10) of emotional intelligence had every third of male students and only 14.2% of female students. The lowest sten values of emotional intelligence in male and female students were 3 and 1, respectively. Less than 10% of male students and over 20% of female students had low normalized scores (sten ≤3) for emotional intelligence and an isolated ability to recognize emotions (factor II). Conclusions: The emotional intelligence expressed in normalized scores was higher in male nursing students than in female nursing students. This evidence may suggest that, at the stage of choosing a field of study, Polish male nursing students self-select for the nursing profession, at least in terms of emotional intelligence. The influx of men into the profession should be considered as a positive trend.

Association Between SARS-CoV-2 Vaccination and Development of Antinuclear Antibodies Among Students.

INTRODUCTION: Antinuclear antibodies (ANA) are the hallmark of many connective tissue disorders (including lupus), which comprise roughly 5% to 10% of chronic debilitating diseases causing morbidity and mortality. In society, fear of these diseases increases illness-related uncertainty because the prognosis of progression is often difficult to determine and at least some symptoms fluctuate unpredictably. In the anti-vaccination movement, the question of the possible connection between vaccination and connective tissue disorders and other autoimmune diseases has grown to rank as an important argument for rejecting vaccination. In 2021, every fifth Polish first-degree nursing student decided to not be vaccinated against COVID-19. OBJECTIVE: This study aimed to explore the prevalence of antinuclear antibodies in students vaccinated and unvaccinated against COVID-19. PARTICIPANTS AND METHODS: A single university cross-sectional study was performed in a small academic centre in Poland, where 210 students were recruited in 2022. All the participants were screened for SARS-CoV-2 IgG and antinuclear antibodies. RESULTS: The mean age of the students who rejected vaccination was higher than that of those who were vaccinated. Among nursing students, 30.0% of vaccinated and 58.3% of unvaccinated individuals had COVID-19. The frequency of antinuclear antibodies was 3 times lower in vaccinated students than in unvaccinated students (2/159 vs 2/51; P > .05). CONCLUSION: The results of our study did not confirm the rationality of rejecting vaccinations against COVID-19 for fear of developing autoimmune diseases among healthy students.