Associations of gut microbiota alterations with clinical, metabolic, and immune-inflammatory characteristics of chronic schizophrenia.

The present study had the following aims: 1) to compare gut microbiota composition in patients with schizophrenia and controls and 2) to investigate the association of differentially abundant bacterial taxa with markers of inflammation, intestinal permeability, lipid metabolism, and glucose homeostasis as well as clinical manifestation. A total of 115 patients with schizophrenia during remission of positive and disorganization symptoms, and 119 controls were enrolled. Altogether, 32 peripheral blood markers were assessed. A higher abundance of Eisenbergiella, Family XIII AD3011 group, Eggerthella, Hungatella, Lactobacillus, Olsenella, Coprobacillus, Methanobrevibacter, Ligilactobacillus, Eubacterium fissicatena group, and Clostridium innocuum group in patients with schizophrenia was found. The abundance of Paraprevotella and Bacteroides was decreased in patients with schizophrenia. Differentially abundant genera were associated with altered levels of immune-inflammatory markers, zonulin, lipid profile components, and insulin resistance. Moreover, several correlations of differentially abundant genera with cognitive impairment, higher severity of negative symptoms, and worse social functioning were observed. The association of Methanobrevibacter abundance with the level of negative symptoms, cognition, and social functioning appeared to be mediated by the levels of interleukin-6 and RANTES. In turn, the association of Hungatella with the performance of attention was mediated by the levels of zonulin. The findings indicate that compositional alterations of gut microbiota observed in patients with schizophrenia correspond with clinical manifestation, intestinal permeability, subclinical inflammation, lipid profile alterations, and impaired glucose homeostasis. Subclinical inflammation and impaired gut permeability might mediate the association of gut microbiota alterations with psychopathological symptoms and cognitive impairment.

Variation in the gene encoding the co-inhibitory molecule BTLA is associated with survival in patients treated for clear cell renal carcinoma - results of a prospective cohort study.

Introduction: The successful introduction of immune checkpoint blockade approaches to renal-cell carcinoma (RCC) treatment indicates the importance of molecules regulating the T cell response to RCC risk and progression. Material and methods: In this study, we evaluate the association of variations in the CTLA-4, BTLA and CD28 genes with overall survival (OS) of RCC patients and specifically clear cell RCC (ccRCC) patients. The following single nucleotide polymorphisms (SNPs) previously genotyped using the RFLP method or TaqMan SNP Genotyping Assays were analyzed: CTLA-4 gene: c.49A>G (rs231775), g.319C>T (rs5742909), g.*6230G>A (CT60; rs3087243), g.*10223G>T (Jo31; rs11571302); CD28 gene: c.17+3T>C (rs3116496), c.-1042G>A (rs3181098); BTLA gene: rs2705511, rs1982809, rs9288952, rs9288953, rs2705535 and rs1844089. Results: During long term observation (6.5 years) we discovered that possessing the A allele at BTLA rs1844089 SNP, together with advanced disease (stage ≥ 3, tumor grade > 3, tumor diameter ≥ 70 mm), is an independent risk factor of death which increases the hazard ratio (HR) of death by more than two-fold (HR = 2.21, 95% CI: 1.28-3.83). Furthermore, the OS of patients bearing this allele is 6 months shorter than for homozygous (GG) patients (42.5 vs. 48.2 months). Conclusions: Our results indicate for the first time that genetic variation within the gene encoding BTLA is significantly associated with overall survival in clear cell renal cell carcinoma patients.

Incidence of different types of cancer in the follow-up period after primary diagnosis and treatment of melanoma. Single-centre 4-year follow-up on a population of 709 patients.

Introduction: Follow-up plays a key role in melanoma management, especially in the first years after diagnosis. During this period it is crucial to assess possible recurrence, progression of the disease or treatment complications. An important aspect is also the possibility of formation of new primary foci or other skin cancers. Aim: To assess the coincidence of skin lesions and cancers among the melanoma patients. Material and methods: Patients treated in the Comprehensive Cancer Centre between 2019 and 2022 were retrospectively analysed for occurrence of skin lesions diagnosed during the follow-up, and confirmed by biopsy. The lesions considered included skin cancers, dysplastic nevus and actinic keratosis. Results: In 100 (14%) out of 709 enrolled patients, 184 lesions were diagnosed. In 7 patients it was melanoma, in 49 BCC, and in 16 SCC. Dysplastic nevus and actinic keratosis were excised in 28 and 14 patients, respectively. More than one site of the skin lesion was observed in 39 patients, and more than one type of the lesion in 13 patients. Patients with lesions were on average 8.6 years older (p < 0.001), had less advanced tumours (p = 0.010), and primary melanoma was more often located on the head and neck (p = 0.056). Conclusions: Among melanoma patients, particular attention must be paid to, apart from early detection of melanoma recurrence and progression, the occurrence of new primary foci or independent skin cancers.

The deficit subtype of schizophrenia is associated with a pro-inflammatory phenotype but not with altered levels of zonulin: Findings from a case-control study.

There is evidence that subclinical inflammation and increased gut permeability might be involved in the pathophysiology of schizophrenia. Less is known about these phenomena in patients with the deficit subtype of schizophrenia (D-SCZ) characterized by primary and enduring negative symptoms. Therefore, in the present study we aimed to compare the levels of zonulin (the marker of gut permeability) and immune-inflammatory markers in patients with D-SCZ, those with non-deficit schizophrenia (ND-SCZ) and healthy controls (HCs). A total of 119 outpatients with schizophrenia and 120 HCs were enrolled. The levels of 26 immune-inflammatory markers and zonulin were determined in serum samples. The following between-group differences were significant after adjustment for multiple testing and the effects of potential confounding factors: 1) higher levels of interleukin(IL)- 1ß and C-reactive protein (CRP) in patients with D-SCZ compared to those with ND-SCZ and HCs; 2) higher levels of tumor necrosis factor-α and RANTES in both groups of patients with schizophrenia compared to HCs and 3) higher levels of IL-17 in patients with D-SCZ compared to HCs. No significant between-group differences in zonulin levels were found. Higher levels of IL-1ß and CRP were associated with worse performance of attention after adjustment for age, education and chlorpromazine equivalents. Also, higher levels of IL-1ß were correlated with greater severity of negative symptoms after adjustment for potential confounding factors. In conclusion, individuals with D-SCZ are more likely to show subclinical inflammation. However, findings from the present study do not support the hypothesis that this phenomenon is secondary to increased gut permeability.

Inappropriate Expression of PD-1 and CTLA-4 Checkpoints in Myeloma Patients Is More Pronounced at Diagnosis: Implications for Time to Progression and Response to Therapeutic Checkpoint Inhibitors.

Multiple myeloma (MM) is a hematologic malignancy characterized by severely profound immune dysfunction. Therefore, the efficacy of drugs targeting the immune environments, such as immune checkpoint inhibitors (ICIs), is of high clinical importance. However, several clinical trials evaluating ICIs in MM in different therapeutic combinations revealed underwhelming results showing a lack of clinical efficacy and excessive side effects. The underlying mechanisms of resistance to ICIs observed in the majority of MM patients are still under investigation. Recently, we demonstrated that inappropriate expression of PD-1 and CTLA-4 on CD4 T cells in active MM is associated with adverse clinical outcomes and treatment status. The aim of the current study was to determine the usefulness of immune checkpoint expression assessment as a predictive biomarker of the response to therapeutic inhibitors. For this purpose, along with checkpoint expression estimated by flow cytometry, we evaluated the time to progression (TTP) of MM patients at different clinical stages (disease diagnosis and relapse) depending on the checkpoint expression level; the cut-off point (dividing patients into low and high expressors) was selected based on the median value. Herein, we confirmed the defective levels of regulatory PD-1, CTLA-4 receptors, and the CD69 marker activation in newly diagnosed (ND) patients, whereas relapsed/refractory patients (RR) exhibited their recovered values and reactivity. Additionally, substantially higher populations of senescent CD4+CD28- T cells were found in MM, primarily in NDMM subjects. These observations suggest the existence of two dysfunctional states in MM CD4 T cells with the predominance of immunosenescence at disease diagnosis and exhaustion at relapse, thus implying different responsiveness to the external receptor blockade depending on the disease stage. Furthermore, we found that lower CTLA-4 levels in NDMM patients or higher PD-1 expression in RRMM patients may predict early relapse. In conclusion, our study clearly showed that the checkpoint level in CD4 T cells may significantly affect the time to MM progression concerning the treatment status. Therefore, when considering novel therapies and potent combinations, it should be taken into account that blocking PD-1 rather than CTLA-4 might be a beneficial form of immunotherapy for only a proportion of RRMM patients.

ß-Lactoglobulin affects the oxidative status and viability of equine endometrial progenitor cells via lncRNA-mRNA-miRNA regulatory associations.

The ß-lactoglobulin (ß-LG) was previously characterized as a mild antioxidant modulating cell viability. However, its biological action regarding endometrial stromal cell cytophysiology and function has never been considered. In this study, we investigated the influence of ß-LG on the cellular status of equine endometrial progenitor cells under oxidative stress. The study showed that ß-LG decreased the intracellular accumulation of reactive oxygen species, simultaneously ameliorating cell viability and exerting an anti-apoptotic effect. However, at the transcriptional level, the reduced mRNA expression of pro-apoptotic factors (i.e. BAX and BAD) was accompanied by decreased expression of mRNA for anti-apoptotic BCL-2 and genes coding antioxidant enzymes (CAT, SOD-1, GPx). Still, we have also noted the positive effect of ß-LG on the expression profile of transcripts involved in endometrial viability and receptivity, including ITGB1, ENPP3, TUNAR and miR-19b-3p. Finally, the expression of master factors of endometrial decidualization, namely prolactin and IGFBP1, was increased in response to ß-LG, while non-coding RNAs (ncRNAs), that is lncRNA MALAT1 and miR-200b-3p, were upregulated. Our findings indicate a novel potential role of ß-LG as a molecule regulating endometrial tissue functionality, promoting viability and normalizing the oxidative status of endometrial progenitor cells. The possible mechanism of ß-LG action includes the activation of ncRNAs essential for tissue regeneration, such as lncRNA MALAT-1/TUNAR and miR-19b-3p/miR-200b-3p.

Introduction of a pilot program to measure and improve the clinical care of melanoma patients in the Lower Silesian Voivodeship in Poland: a report of 20 months experience.

BACKGROUND: In recent years, benchmarking and assessment methods to improve the quality of care have become increasingly important. Such approaches allow for a uniform assessment, comparisons between centers or over time, and the identification of weaknesses. In this study, the results of a 20-month pilot program to assess, monitor and improve the quality of care in melanoma patients primarily treated surgically are presented. METHODS: The pilot program started in May 2020 at the Lower Silesian Oncology, Pulmonology and Hematology Center (LSOPHC) in Wroclaw, Poland (Lower Silesian Voivodeship, southwestern province of Poland with a population of 2,9 million). The program involved the introduction of a synoptic histopathological protocol, medical coordinators, and a set of measures to assess oncological care. In total, 11 Skin Cancer Unit (SCU) measures were introduced to analyze clinical outcomes, diagnostic quality, and duration. Data from 352 patients covered by the program were analyzed. In addition, the completeness of diagnostics from external sites was compared to our own results. Furthermore, the timeliness of the initial diagnostic tests and in-depth diagnostics were assessed and compared to the timeliness before implementation of the pilot program. RESULTS: The introduced measures assessed the mortality related to oncological treatment, the rate of complications, advanced stages of melanoma, the completeness and duration of diagnostics, the involved nodes after lymphadenectomy, and melanoma screening. During the study period, the timeliness of the initial diagnostics was maintained at 87.8%, and the timeliness of the in-depth diagnostics at 89.5%. Compared to a similar period before the program, these values were 36.1% and 67.5%, respectively. CONCLUSION: The introduced measures seem to be effective and practical tools for benchmarking clinical and diagnostic aspects. They also allowed for a sensitive assessment of individual issues and indicated sensitive points. Furthermore, the actions undertaken in this pilot program allowed for a shortening of the duration of diagnostics.

An analysis of clinical effectiveness of electrochemotherapy in the treatment of advanced metastatic malignant melanoma performed in the eastern part of Central Europe: a single-centre experience.

Introduction: Patients with cutaneous malignant melanoma (MM), in case of non-resectability of the lesions, have only a limited pool of the available treatment options. In recent years especially electrochemotherapy (ECT) has become an increasingly important therapy in locoregionally advanced MM. Aim: In this study an analysis of the ECT treatment of locoregionally advanced malignant melanoma was presented. Material and methods: Six ECT cycles in 5 patients were performed in the Wroclaw Comprehensive Cancer Centre. Treatment response, long-term observation, technical data downloaded from electroporator and photographs taken before and after the ECT were assessed in the analysis. Results: In total, 200 nodules in 5 patients were treated with ECT in palliative intent. After 5 out of 6 ECT cycles, the particular clinical response has been observed. Four patients with primary unresectable lesions underwent 11 surgeries of the cutaneous metastases. In long-term follow-up in 2 patients, of whom one died 19 months after the ECT, the disease progressed and in another two, no recurrence was observed. Conclusions: ECT is an encouraging therapy for patients in whom the recurrent cutaneous melanoma cannot be treated with other methods, however, access to this method in eastern part of Central Europe is limited. The presented study seems to confirm the usefulness of this palliative approach in a specific group of patients suffering from cutaneous MM.

The effect of population-based screening on the incidence and detection on breast cancer in woman in Lower Silesia over the period 2005-2014.

INTRODUCTION: The National Cancer Control Programme 2006-2015 (NCCP) was implemented to improve the health situation of Polish women in 2006. Its effectiveness was evaluated by analysing trends of changes in incidence rates of pre-invasive (D05) and invasive (C50) breast cancers in three age cohorts: pre-screening cohort (<50), screening cohort (50-69) and post-screening cohort (>69). MATERIAL AND METHODS: Medical data of 13,089 women with C50 and 738 women with D05 diagnosed in 2005-2014 in the Lower Silesian Voivodeship (LS) were analysed. RESULT: In 2009-2014, incidence rates of C50 (p=0.0224) and D05 (p=0.0003) were found to be higher in the LS than those recorded for Poland. During this period, there were approx. 1,400 cases of C50 and 90-100 cases of D05 per year. After the NCCP had been implemented, there was a gradual increase in the proportion of the female population included in the mammography screening, from 32% in 2007 to 45% in 2014. The age group included in the screening programme experienced a significant increase in the proportion of pre-invasive cancers - from 3% in 2005 to 7-10% in 2010-2013. In that group, cancer was statistically more frequently detected in Tis- or T1- stages (p=0.0002). Beneficial effects of screening were also observed in post-screening women. There was no similar trend in patients aged <50. CONCLUSIONS: This analysis shows positive population effects of mammography screening. The least favourable changes in the detection of early stages of breast cancer were observed in female patients aged less than 50 years. This suggests that some modifications regarding both the age range and the screening interval in the Polish population should be considered.

Regulation of ROCK1/2 by long non-coding RNAs and circular RNAs in different cancer types.

Recent breakthroughs in high-throughput technologies have enabled the development of a better understanding of the functionalities of rho-associated protein kinases (ROCKs) under various physiological and pathological conditions. Since their discovery in the late 1990s, ROCKs have attracted the attention of interdisciplinary researchers due to their ability to pleiotropically modulate a myriad of cellular mechanisms. A rapidly growing number of published studies have started to shed light on the mechanisms underlying the regulation of ROCK1 and ROCK2 via long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in different types of cancer. Detailed analyses have suggested that lncRNAs may be characteristically divided into oncogenic and tumor suppressor lncRNAs. Several exciting recent discoveries have also indicated how different lncRNAs and circRNAs modulate ROCK1/2 and mediate multistep cancer onset and progression. The present review chronicles the major advances that have been made in our understanding of the regulatory role of ROCK1/2 in different types of cancer, and how wide-ranging lncRNAs and circRNAs potentiate ROCK-driven signaling by blocking the targeting activities of tumor suppressor microRNAs.

The Moderating Role of the FKBP5 Gene Polymorphisms in the Relationship between Attachment Style, Perceived Stress and Psychotic-like Experiences in Non-Clinical Young Adults.

Numerous studies have reported that stressful life experiences increase the risk of psychosis and psychotic-like experiences (PLEs). Common variations of the FKBP5 gene have been reported to impact the risk of psychosis by moderating the effects of environmental exposures. Moreover, anxious and avoidant attachment styles have been shown to increase both the level of perceived stress and the risk for psychosis development. In the present cross-sectional study, we aimed to investigate whether variants of the FKBP5 gene moderate the effects of attachment styles and the level of perceived stress on the development of PLEs. A total of 535 non-clinical undergraduates were genotyped for six FKBP5 single nucleotide polymorphisms (SNPs) (rs3800373, rs9470080, rs4713902, rs737054, rs1360780 and rs9296158). The Psychosis Attachment Measure (PAM), the Perceived Stress Scale-10 (PSS-10) and the Prodromal Questionnaire 16 (PQ-16) were administered to assess attachment styles, the level of perceived stress and PLEs, respectively. Anxious attachment style, lower levels of perceived self-efficacy and higher levels of perceived helplessness were associated with a significantly higher number of PLEs. The main effects of attachment style on the severity of PLEs were significant in models testing for the associations with perceived self-efficacy and three FKBP5 SNPs (rs1360780, rs9296158 and rs9470080). The main effect of rs38003733 on the number of PLEs was observed, with GG homozygotes reporting a significantly higher number of PLEs in comparison to T allele carriers. In individuals with dominant anxious attachment style, there was a significant effect of the interaction between the FKBP5 rs4713902 SNP and self-efficacy on the severity of PLEs. Among rs4713902 TT homozygotes, a low level of perceived self-efficacy was associated with higher severity of PLEs. In subjects with non-dominant anxious attachment, a low level of perceived self-efficacy was associated with a higher number of PLEs, regardless of the genotype. Our results indicate that the FKBP5 gene might moderate the relationship between attachment, perceived stress and PLEs.

Confirmation Bias in the Course of Instructed Reinforcement Learning in Schizophrenia-Spectrum Disorders.

A large body of research attributes learning deficits in schizophrenia (SZ) to the systems involved in value representation (prefrontal cortex, PFC) and reinforcement learning (basal ganglia, BG) as well as to the compromised connectivity of these regions. In this study, we employed learning tasks hypothesized to probe the function and interaction of the PFC and BG in patients with SZ-spectrum disorders in comparison to healthy control (HC) subjects. In the Instructed Probabilistic Selection task (IPST), participants received false instruction about one of the stimuli used in the course of probabilistic learning which creates confirmation bias, whereby the instructed stimulus is overvalued in comparison to its real experienced value. The IPST was administered to 102 patients with SZ and 120 HC subjects. We have shown that SZ patients and HC subjects were equally influenced by false instruction in reinforcement learning (RL) probabilistic task (IPST) (p-value = 0.441); however, HC subjects had significantly higher learning rates associated with the process of overcoming cognitive bias in comparison to SZ patients (p-value = 0.018). The behavioral results of our study could be hypothesized to provide further evidence for impairments in the SZ-BG circuitry; however, this should be verified by neurofunctional imaging studies.

Deregulated Expression of Immune Checkpoints on Circulating CD4 T Cells May Complicate Clinical Outcome and Response to Treatment with Checkpoint Inhibitors in Multiple Myeloma Patients.

Unlike solid-tumor patients, a disappointingly small subset of multiple myeloma (MM) patients treated with checkpoint inhibitors derive clinical benefits, suggesting differential participation of inhibitory receptors involved in the development of T-cell-mediated immunosuppression. In fact, T cells in MM patients have recently been shown to display features of immunosenescence and exhaustion involved in immune response inhibition. Therefore, we aimed to identify the dominant inhibitory pathway in MM patients to achieve its effective control by therapeutic interventions. By flow cytometry, we examined peripheral blood (PB) CD4 T cell characteristics assigned to senescence or exhaustion, considering PD-1, CTLA-4, and BTLA checkpoint expression, as well as secretory effector function, i.e., capacity for IFN-γ and IL-17 secretion. Analyses were performed in a total of 40 active myeloma patients (newly diagnosed and treated) and 20 healthy controls. At the single-cell level, we found a loss of studied checkpoints' expression on MM CD4 T cells (both effector (Teff) and regulatory (Treg) cells) primarily at diagnosis; the checkpoint deficit in MM relapse was not significant. Nonetheless, PD-1 was the only checkpoint distributed on an increased proportion of T cells in all MM patients irrespective of disease phase, and its expression on CD4 Teff cells correlated with adverse clinical courses. Among patients, the relative defect in secretory effector function of CD4 T cells was more pronounced at myeloma relapse (as seen in declined Th1/Treg and Th17/Treg cell rates). Although the contribution of PD-1 to MM clinical outcomes is suggestive, our study clearly indicated that the inappropriate expression of immune checkpoints (associated with dysfunctionality of CD4 T cells and disease clinical phase) might be responsible for the sub-optimal clinical response to therapeutic checkpoint inhibitors in MM.

NF-κB1 -94del/del ATTG polymorphic variant maintains CLL at an early, mildest stage.

BACKGROUND: NF-κB is an essential player in cancer biology, especially in tumor development, due to its constitutive activation, and because a four-base deletion (ATTG) in the NF-κB1 promoter region at site -94, alters mRNA stability and regulates translation efficiency. This polymorphism is a good candidate risk marker and modulator of clinical course in chronic lymphocytic leukemia (CLL). As the effect of this NF-κB1 gene polymorphism has not been studied in patients with CLL so far, the present study was undertaken to find out whether the NF-κB1 promoter -94 ins/del ATTG polymorphism might be an essential genetic risk factor and/or modulatory disease player associated with CLL. OBJECTIVES: The NF-κB1 -94 ins/del ATTG (rs28362491) polymorphism was investigated as a potential CLL susceptibility and progression factor, along with demonstration of potential modulation of the stage of clinical disease based on Rai classification. MATERIAL AND METHODS: The associations of NF-κB1 -94 ins/del ATTG polymorphism with CLL and its clinical manifestation in 282 Polish individuals, including 156 CLL patients, were analyzed using polymerase chain reaction (PCR) with primers including a labeled forward primer, followed by capillary electrophoresis. RESULTS: A higher occurrence of the del/del homozygosity was observed among patients when compared to controls, resulting in an increase in CLL risk of more than twofold in patients carrying this homozygous genotype (OR = 2.23, p = 0.02, 95% CI = 1.14-4.37). Moreover, the del/del-positive patients more frequently presented the less aggressive disease phenotype (Rai 0), suggesting a low probability of progression to more advanced disease. CONCLUSIONS: The NF-κB1 -94 del/del genetic variant, although associated with increased risk of CLL disease, may be associated with maintenance of disease severity in the early, mildest stage. The likelihood of disease progression may increase as the frequency of wild-type (insertion) alleles for this polymorphism increases.

The Impact of the FKBP5 Gene Polymorphisms on the Relationship between Traumatic Life Events and Psychotic-Like Experiences in Non-Clinical Adults.

Common variations of the FKBP5 gene are implicated in psychotic disorders, by modulating the hypothalamic-pituitary-adrenal axis reactivity to stress. It has been demonstrated that some of them might moderate the effects of childhood trauma on psychosis proneness. However, these associations have not been investigated with respect to traumatic life events (TLEs). Therefore, we aimed to explore whether the FKBP5 polymorphisms moderate the effects of TLEs on the level of psychotic-like experiences (PLEs). A total of 535 non-clinical adults were approached for participation, and genotyping of six FKBP5 polymorphisms (rs3800373, rs9470080, rs4713902, rs737054, rs1360780 and rs9296158) was performed. The Prodromal Questionnaire-16 (PQ-16) and the Traumatic Events Checklist (TEC) were administered to assess PLEs and TLEs, respectively. Among the rs1360780 CC homozygotes, a history of physical abuse was associated with significantly higher PQ-16 scores. This difference was not significant in the rs1360780 T allele carriers. Similarly, a history of physical abuse was associated with significantly higher PQ-16 scores in the rs9296158 GG homozygotes but not in the rs9296158 A allele carriers. Finally, emotional neglect was related to significantly higher PQ-16 scores in the rs737054 T allele carriers but not in the rs737054 CC homozygotes. The present study indicates that variation in the FKBP5 gene might moderate the effects of lifetime traumatic events on psychosis proneness.

The Significance of Toll-Like Receptors in the Neuroimmunologic Background of Alcohol Dependence.

Toll-like receptors (TLR) are a group of protein belonging to the family of Pattern Recognition Receptors (PRR) which have the ability to distinguish between an organism's own antigens and foreign ones and to induce immunological response. TLR play a significant part in non-specific immunity but at the same time they are also a vital element linking non-specific response to the specific one. A growing number of data seems to indicate that the non-specific immunity mechanisms affect the development and sustenance of alcohol addiction. Alcohol damages the organism's cells not only directly but also through an increase inintestinal permeability which induces innate immune response of peripheral blood cells. The signaling pathway of Toll-like receptors located on the surface of brain immune cells intensifies the inflammatory reaction and, through modifying gene expression of proinflammatory factors, unnaturally supports it. This overly protracted "sterile inflammatory reaction" positively correlates with alcohol craving affecting also the functioning of the reward system structures and increasing the risk of relapse of alcoholism. Recurrent alcoholic binges sensitize the microglia and cause an escalation in inflammatory reaction which also leads to neurodegeneration. The induction of innate immunity signaling pathways exposes clinical symptoms of alcohol addiction such as increased impulsivity, loss of behavioral control, depressive-anxiety symptoms and cognitive dysfunctions. Traditional methods of treating alcohol addiction have tended to focus predominantly on reducing symptoms which-given the frequency of relapses-seems insufficient. The aim of the present paper is to discuss the role of toll-like receptors as elements of the immunity system which, together with the nervous system, plays a crucial part in the pathogenesis of alcohol addiction. We also wish to present pharmacotherapeutic perspectives targeted at the neuroimmunological mechanisms of alcohol addiction.

The Role of Dopaminergic Genes in Probabilistic Reinforcement Learning in Schizophrenia Spectrum Disorders.

Schizophrenia spectrum disorders (SZ) are characterized by impairments in probabilistic reinforcement learning (RL), which is associated with dopaminergic circuitry encompassing the prefrontal cortex and basal ganglia. However, there are no studies examining dopaminergic genes with respect to probabilistic RL in SZ. Thus, the aim of our study was to examine the impact of dopaminergic genes on performance assessed by the Probabilistic Selection Task (PST) in patients with SZ in comparison to healthy control (HC) subjects. In our study, we included 138 SZ patients and 188 HC participants. Genetic analysis was performed with respect to the following genetic polymorphisms: rs4680 in COMT, rs907094 in DARP-32, rs2734839, rs936461, rs1800497, and rs6277 in DRD2, rs747302 and rs1800955 in DRD4 and rs28363170 and rs2975226 in DAT1 genes. The probabilistic RL task was completed by 59 SZ patients and 95 HC subjects. SZ patients performed significantly worse in acquiring reinforcement contingencies during the task in comparison to HCs. We found no significant association between genetic polymorphisms and RL among SZ patients; however, among HC participants with respect to the DAT1 rs28363170 polymorphism, individuals with 10-allele repeat genotypes performed better in comparison to 9-allele repeat carriers. The present study indicates the relevance of the DAT1 rs28363170 polymorphism in RL in HC participants.

Participation in Competing Strategies for Colorectal Cancer Screening: A Randomized Health Services Study (PICCOLINO Study).

BACKGROUND & AIMS: Primary colonoscopy and fecal immunochemical testing (FIT) are considered first-tier tests for colorectal cancer (CRC) screening. Although colonoscopy is considered the most efficacious test, FIT might achieve higher participation rates. It is uncertain what the best strategy is for offering population-wide CRC screening. METHODS: This was a multicenter randomized health services study performed within the framework of the Polish Colonoscopy Screening Program between January 2019 and March 2020 on screening-naïve individuals. Eligible candidates were randomly assigned in a 1:1:1 ratio to participate in 1 of 3 competing invitation strategies: control (invitation to screening colonoscopy only); sequential (invitation to primary colonoscopy and invitation for FIT for initial nonresponders); or choice (invitation offering a choice of colonoscopy or FIT). The primary outcome was participation in CRC screening within 18 weeks after enrollment into the study. The secondary outcome was diagnostic yield for advanced neoplasia. RESULTS: Overall, 12,485 individuals were randomized into the 3 study groups. The participation rate in the control group (17.5%) was significantly lower compared with the sequential (25.8%) and choice strategy (26.5%) groups (P < .001 for both comparisons). The colonoscopy rates for participants with positive FITs were 70.0% for the sequential group and 73.3% for the choice group, despite active call-recall efforts. In the intention-to-screen analysis, advanced neoplasia detection rates were comparable among the control (1.1%), sequential (1.0%), and choice groups (1.1%). CONCLUSIONS: Offering a combination of FIT and colonoscopy as a sequential or active choice strategy increases participation in CRC screening. Increased participation in strategies with FIT do not translate into higher detection of advanced neoplasia. ClinicalTrials.gov, Number NCT03790475.

CTLA-4, CD28, and ICOS gene polymorphism associations with non-small-cell lung cancer.

Polymorphisms in genes encoding CD28, ICOS, and CTLA-4 were demonstrated to be associated with susceptibility to malignancies. To the best of our knowledge, no study on this association has been performed in a Caucasian population for non-small-cell lung cancer (NSCLC). In the present work, we investigated the polymorphisms CTLA-4c.49A>G (rs231775), CTLA-4g.319C>T (rs5742909), CTLA-4g.*642AT(8_33), CTLA-4g.*6230G>A (CT60) (rs3087243), CTLA-4g.*10223G>T (Jo31) (rs11571302), CD28c.17+3T>C (rs3116496), and ICOSc.1554+4GT(8_15) in 208 NSCLC patients and 326 controls. The distributions of the allele and genotype were similar in both groups for CTLA-4, CD28, and ICOS gene polymorphisms. However, we noted a tendency toward overrepresentation of individuals possessing the CTLA-4c.49A>G[A] allele in NSCLC patients compared with controls (0.84 vs 0.79, p = 0.09). The association became significant compared with controls in women for the CTLA-4c.49A>G[A] allele and CTLA-4c.49A>G[AA] genotype (0.67 vs 0.54, p = 0.01, and 0.47 vs 0.30, p = 0.02; respectively). Moreover, the constellation of alleles CTLA-4c.49A>G[A]/CT60[G]/CD28c.17+3T>C[T]/ICOSc.1554+4GT(8_15)[>10] increased the risk of NSCLC about 2-fold (p = 0.002). The same constellation of alleles combined with smoking, CTLA-4g.319C>T[T], and ICOSc.1554+4GT(8_15)[>10] was associated with a decreased overall survival rate. In conclusion, the constellation of specific alleles in CTLA-4, CD28, and ICOS genes contributes to the susceptibility and clinical course of NSCLC.