SKA3 Expression as a Prognostic Factor for Patients with Pancreatic Adenocarcinoma.

The spindle and kinetochore-associated complex subunit 3 (SKA3) is a protein essential for proper chromosome segregation during mitosis and thus responsible for maintaining genome stability. Although its involvement in the pathogenesis of various cancer types has been reported, the potential clinicopathological significance of SKA3 in pancreatic ductal adenocarcinoma (PDAC) has not been fully elucidated. Therefore, this study aimed to assess clinicopathological associations and prognostic value of SKA3 in PDAC. For this purpose, in-house immunohistochemical analysis on tissue macroarrays (TMAs), as well as a bioinformatic examination using publicly available RNA-Seq dataset, were performed. It was demonstrated that SKA3 expression at both mRNA and protein levels was significantly elevated in PDAC compared to control tissues. Upregulated mRNA expression constituted an independent unfavorable prognostic factor for the overall survival of PDAC patients, whereas altered SKA3 protein levels were associated with significantly better clinical outcomes. The last observation was particularly clear in the early-stage tumors. These findings render SKA3 a promising prognostic biomarker for patients with pancreatic ductal adenocarcinoma. However, further studies are needed to confirm this conclusion.

Variations in chemical composition of common buckwheat (Fagopyrum esculentum Moench) as a result of different environmental conditions.

BACKGROUND: Common buckwheat (Fagopyrum esculentum Moench) is a pseudo cereal that is gaining interest in the world. The chemical profile of common buckwheat determines its high nutritional and health-promoting value. The accumulation of these valuable ingredients depends on many factors, such as: variety, location of cultivation and related weather and agrotechnical conditions. Due to the growing interest in common buckwheat as a natural plant material for food production, it is important to know the factors affecting the quantitative and qualitative composition of its grains. The aim of the research was to determine the effect of the genotype (G), environment (E) and G × E interaction on the content of nutrients (protein, starch, ash, lipids) and bioactive components [dietary fiber (DF), total phenolic content (TPC)] in the common buckwheat grains. The study covered four cultivars grown in three locations for three consecutive vegetation seasons (2016/2017, 2017/2018, 2018/2019). RESULTS: Based on the obtained results, a significant influence of the environment and G × E interaction on the content of the studied parameters was found. The greatest impact on the diversity of the content of nutrients had environmental conditions, which in the case of protein and ash determined these features in more than 80%, and in the case of starch, 70%. With regard to bioactive compounds, the greatest influence of the environment was observed for the amount of TPC (78%), lignin (51%) and the DF complex (56%). CONCLUSION: The obtained results are useful for breeders working on expanding the pool of common buckwheat genotypes, stable in changing environmental conditions. © 2023 Society of Chemical Industry.

Can Ashwagandha Benefit the Endocrine System?-A Review.

Withania somnifera, also known as Ashwagandha, has been used in traditional medicine for thousands of years. Due to the wide range of its activities, there has been interest in its possible beneficial effects on the human body. It is proved that, among others, Ashwagandha has anti-stress, anti-inflammatory, antimicrobial, anti-cancer, anti-diabetic, anti-obesity, cardioprotective, and hypolipidemic properties. Particularly interesting are its properties reported in the field of psychiatry and neurology: in Alzheimer's disease, Parkinson's disease, multiple sclerosis, depression, bipolar disorder, insomnia, anxiety disorders and many others. The aim of this review is to find and summarize the effect that Ashwagandha root extract has on the endocrine system and hormones. The multitude of active substances and the wide hormonal problems faced by modern society sparked our interest in the topic of Ashwagandha's impact on this system. In this work, we also attempted to draw conclusions as to whether W. somnifera can help normalize the functions of the human endocrine system in the future. The search mainly included research published in the years 2010-2023. The results of the research show that Ashwagandha can have a positive effect on the functioning of the endocrine system, including improving the secretory function of the thyroid gland, normalizing adrenal activity, and multidirectional improvement on functioning of the reproductive system. The main mechanism of action in the latter appears to be based on the hypothalamus-pituitary-adrenal (HPA) axis, as a decrease in cortisol levels and an increase in hormones such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in men were found, which results in stress level reduction and improvement in fertility. In turn, other studies prove that active substances from W. somnifera, acting on the body, cause an increase in the secretion of triiodothyronine (T3) and thyroxine (T4) by the thyroid gland and a subsequent decrease in the level of thyroid-stimulating hormone (TSH) in accordance with the hypothalamus-pituitary-thyroid (HPT) axis. In light of these findings, it is clear that Ashwagandha holds significant promise as a natural remedy for various health concerns, especially those related to the endocrine system. Future research may provide new insights into its mechanisms of action and expand its applications in both traditional and modern medicine. The safety and toxicity of Ashwagandha also remain important issues, which may affect its potential use in specific patient groups.

Worsening functional status in nephrogeriatrics needs to be accounted for when clinically assessing CKD advancement in addition to GFR; supporting evidence based on the practical application of theoretical modelling.

The incidence of chronic kidney disease (CKD) has been found to increase with age. This has resulted in an increase in the number of elderly patients undergoing renal replacement therapy. There is a significant risk of error in making treatment decisions in patients with advanced CKD based solely on biochemical parameters of renal function, if the changes in the functional status of patients' health are not taken into account.AimTo determine the interrelated dependencies between chronic kidney disease with the functional status of patients aged over 65 years and to elucidate differences in functional status between CKD patients and controls.MethodsPatient subjects were qualified according to their assessed outcomes from the study protocol, which were achieved by: geriatric interview, assessing functional status by the IADL, Barthel and Tinetti tests together with assessing kidney function by performing laboratory tests of glomerular filtration rate (GFR), creatinine and urea. Subjects were divided into two groups: method 1-according to GFR and method 2-according to GFR and functional test results. The data were statistically analysed by structural equation modelling and k-means.ResultsPositive relationships were found between the CKD stage and comorbidity (ß = 0.55, p < 0.01), along with the number of medications taken and age (respectively ß = 0.19, p = 0.001 and ß = 0.30, p < 0.001). A highly negative relationship was observed between the CKD stage and the Tinetti test results (ß = -0.71, p < 0.001), whilst more moderate ones were found with the IADL and Barthel scores (respectively ß = -0.49, p < 0.001 and ß = -0.40, p < 0.001). The patient groups demonstrated differences in health status when selected by method-2 for: age, comorbidity, number of medications taken, fitness test outcomes (Tinetti, Barthel and IADL tests at p < 0.005). Those groups divided according to GFR, however only showed differences in age, comorbidity and the number of medication taken (p < 0.005).ConclusionsThe functional status worsens in geriatric patients suffering from CKD. It may thus be important to also account for disruptions to functional status when assessing CKD advancement in the elderly in addition to the GFR. The biggest problems for the over 80 s suffering from CKD are gait and balance disorders, leading to a high risk of falls. Another common problem is polypharmacy, found in both the geriatric population and particularly in those suffering from CKD.

Kallikrein-Related Peptidase 14 Activates Zymogens of Membrane Type Matrix Metalloproteinases (MT-MMPs)-A CleavEx Based Analysis.

Kallikrein-related peptidases (KLKs) and matrix metalloproteinases (MMPs) are secretory proteinases known to proteolytically process components of the extracellular matrix, modulating the pericellular environment in physiology and in pathologies. The interconnection between these families remains elusive. To assess the cross-activation of these families, we developed a peptide, fusion protein-based exposition system (Cleavage of exposed amino acid sequences, CleavEx) aiming at investigating the potential of KLK14 to recognize and hydrolyze proMMP sequences. Initial assessment identified ten MMP activation domain sequences which were validated by Edman degradation. The analysis revealed that membrane-type MMPs (MT-MMPs) are targeted by KLK14 for activation. Correspondingly, proMMP14-17 were investigated in vitro and found to be effectively processed by KLK14. Again, the expected neo-N-termini of the activated MT-MMPs was confirmed by Edman degradation. The effectiveness of proMMP activation was analyzed by gelatin zymography, confirming the release of fully active, mature MT-MMPs upon KLK14 treatment. Lastly, MMP14 was shown to be processed on the cell surface by KLK14 using murine fibroblasts overexpressing human MMP14. Herein, we propose KLK14-mediated selective activation of cell-membrane located MT-MMPs as an additional layer of their regulation. As both, KLKs and MT-MMPs, are implicated in cancer, their cross-activation may constitute an important factor in tumor progression and metastasis.

Development of Chemical Tools to Monitor Human Kallikrein 13 (KLK13) Activity.

Kallikrein 13 (KLK13) was first identified as an enzyme that is downregulated in a subset of breast tumors. This serine protease has since been implicated in a number of pathological processes including ovarian, lung and gastric cancers. Here we report the design, synthesis and deconvolution of libraries of internally quenched fluorogenic peptide substrates to determine the specificity of substrate binding subsites of KLK13 in prime and non-prime regions (according to the Schechter and Berger convention). The substrate with the consensus sequential motive ABZ-Val-Arg-Phe-Arg-ANB-NH2 demonstrated selectivity towards KLK13 and was successfully converted into an activity-based probe by the incorporation of a chloromethylketone warhead and biotin bait. The compounds described may serve as suitable tools to detect KLK13 activity in diverse biological samples, as exemplified by overexpression experiments and targeted labeling of KLK13 in cell lysates and saliva. In addition, we describe the development of selective activity-based probes targeting KLK13, to our knowledge the first tool to analyze the presence of the active enzyme in biological samples.

Detection of somatic mutations in ctDNA derived from adenocarcinoma patients - EGFR tyrosine kinase inhibitor monitoring preliminary study.

AIM OF THE STUDY: The main purpose of this study was to assess detection of mutations in the epidermal growth factor receptor (EGFR) gene in circulating tumor DNA (ctDNA) as a tool for EGFR tyrosine kinase inhibitor (TKI) monitoring therapy. MATERIAL AND METHODS: The study was conducted using 20 samples from 7 adenocarcinoma patients treated with TKIs. Blood samples for ctDNA analysis were collected in 2015-2016. ctDNA was isolated using the QIAamp Circulating Nucleic Acid Kit (Qiagen) and analyzed using the ctEGFR Mutation Detection Kit (EntroGen). RESULTS: The most common exon 19 deletion and p.Leu858Arg mutation in exon 21 of the EGFR gene were detected. We observed a correlation between stabilization of patient condition and the lack of p.Thr790Met mutation detection in ctEGFR during TKI treatment (2 out of 7 patients). We also observed a correlation between progression of the disease and p.Thr790Met mutation detection in ctEGFR (3 out of 7 cases). We did not detect ctDNA p.Thr790Metp in two patients in whom progression occurred shortly thereafter. Last but not least, we noticed that good organization during plasma collection and transportation (average time of 6 minutes and 30 seconds) allows to use K2EDTA tubes. CONCLUSIONS: When tissue is limited or insufficient, analysis of the ctEGFR mutational status can be considered as an alternative tool for qualifying patients with non-small cell lung cancer (NSCLC) for TKI therapy, also as a potential monitoring tool. The plasma p.Thr790Met-negative result needs to be verified for the presence of p.Thr790Met-positive tumor tissue.

Analysis of the causes of false negative and false positive results of preoperative axillary ultrasound in patients with early breast cancer - a single-centre study.

INTRODUCTION: Properly planned and performed diagnostic tests allow the optimal treatment option to be chosen for the patient. They also allow qualification for the correct surgical procedure. AIM OF THE STUDY: In this study we evaluated the clinical value of preoperative ultrasound scan (USS) testing performed during primary disease staging in patients with early breast cancer qualified to sentinel lymph node biopsy (SLNB). MATERIAL AND METHODS: The group of breast cancer patients who underwent SLNB from March 2012 to May 2013. As well as the standard procedure of the preoperative diagnostics model, in each patient the USS of axillary lymph nodes was performed additionally. The results were compared with the data from postoperative pathological reports. We attempted to define the factors influencing the possibility of obtaining false positive and false negative USS results. RESULTS: The analysis comprised 172 patients. In 14.4% of cases with normal USS result the pathological result was different from the expected one (pN1). In 42.3% of patients with suspicious axillary lymph nodes the result of the pathological report was positive. The sensitivity of the USS testing was 89.3%, and the specificity was 34.4%, PPV - 85.6%, NPV - 42.3%. CONCLUSIONS: Ultrasonographic assessment of axillary lymph nodes in breast cancer patients qualified for SLNB is a test with high sensitivity and high predictive value of the positive test result. The possibility of a result contrary to the actual nodal status may result primarily from the technical limitations of USS testing.

Functional and structural properties of a novel protein and virulence factor (Protein sHIP) in Streptococcus pyogenes.

Streptococcus pyogenes is a significant bacterial pathogen in the human population. The importance of virulence factors for the survival and colonization of S. pyogenes is well established, and many of these factors are exposed to the extracellular environment, enabling bacterial interactions with the host. In the present study, we quantitatively analyzed and compared S. pyogenes proteins in the growth medium of a strain that is virulent to mice with a non-virulent strain. Particularly, one of these proteins was present at significantly higher levels in stationary growth medium from the virulent strain. We determined the three-dimensional structure of the protein that showed a unique tetrameric organization composed of four helix-loop-helix motifs. Affinity pull-down mass spectrometry analysis in human plasma demonstrated that the protein interacts with histidine-rich glycoprotein (HRG), and the name sHIP (streptococcal histidine-rich glycoprotein-interacting protein) is therefore proposed. HRG has antibacterial activity, and when challenged by HRG, sHIP was found to rescue S. pyogenes bacteria. This and the finding that patients with invasive S. pyogenes infection respond with antibody production against sHIP suggest a role for the protein in S. pyogenes pathogenesis.

Overall survival and disease-free survival in breast cancer patients treated at the Oncology Centre in Bydgoszcz - analysis of more than six years of follow-up.

AIM OF THE STUDY: Malignant breast tumours are the largest oncological problem in the developed world. In the recent years the number of new diagnoses has exceeded 16,500 per year. Published data regarding far-distant results of breast cancer treatment that take under consideration the provincial division of the country may not be representative of the therapeutic effects achieved in specific oncological centres. The goal of this article is to analyse far-distant therapeutic results in breast cancer patients treated at the Oncology Centre in Bydgoszcz in 2006. They were compared with data available for Kujawsko-Pomorskie Voivodeship and with all-Poland results. MATERIAL AND METHODS: A cohort of 667 breast cancer patients at Bydgoszcz Oncology Centre between Jan 1 and Dec 31, 2006 was studied. The majority of the studied group were patients in stage I (26.2%) and II (48.3%) according to the TNM staging system, 17.5% were in stage III, and 6.4% in stage IV. The 5-year survival and 5-year disease-free survival rates were calculated. Median observation time was 79 months. RESULTS: A total of 148 patients (22.2%) suffered a relapse. There were 168 (25.2%) deaths caused by primary disease. The 5-year survival probability was 0.761 ±0.017 and the five-year disease-free survival probability was 0.807 ±0.016. Median survival time was 76.4 months, and median disease-free survival was 19.4 months. CONCLUSIONS: The five-year survival probability for breast cancer patients undergoing treatment at Bydgoszcz Oncology Centre was higher than all-Poland median five-year survival probability. The observation needs to be continued and should include the assessment of treatment in subsequent time periods.

[The treatment of septic shock with continuous venovenous hemodialysis using high cut-off dialyzer in patient after immediate circulatory arrest]. / Ciagla zylno-zylna hemodializa z uzyciem dializatora high cut-off w leczeniu wstrzasu septycznego u chorego po naglym zatrzymaniu krazenia.

The decreased immunity which occurs frequently in severely intoxicated patients may led to sepsis. The sepsis may be caused by bacterial toxins in unconscious patients with toxic coma which generate decreased immunity. Apart from the wide spectrum antibiotic therapy, crystalloids, colloids, vasopressin and corticosteroids, the renal replacement therapy may be useful in treatment of sepsis due to its complexes pathophysiology. Taking into account the role of cytokines in sepsis pathomechanism, the trials of treatment using high cut-off (HCO) membranes were performed in the recent years. These membranes remove molecules with mass up to 60 kDa, including cytokines typical for severe sepsis. The usefulness of continuous veno-venous hemodialysis--CVVHD with HCO dialyzer in the treatment of patient in septic shock and multiorgan damage--including damage caused by cardiac arrest was presented in the study. The concentration of IL-1P, IL-2, IL-4, IL-6, IL-10, IL-12, INF-alpha, INF-gamma, TGF-alpha in blood were determined before and after the 24-hours procedure. After the procedure the most evident decrease was observed for IL-4, 6, 10, 12 (17.3%, 31.8%, 83.4% i 22.3% respectively). During the following days the general status of patient improved gradually. The patient was discharged from the hospital after 20 days of hospitalization. His general condition was good, the values of inflammatory parameters were normal and the renal function was correct. There are very few studies describing HCO membranes effectiveness and they were performed on limited populations of patients. The presented case study may contribute to the discussion on the usefulness of dialysis with HCO membranes in the treatment of severely intoxicated patients complicated by serious sepsis resistant to standard antibiotic therapy.

A study on the attitude of Polish psychotherapists towards online therapy - Polish adaptation of the UTAUT-T (Unified Theory of Acceptance and Use of Technology - Therapist version) and verification of the UTAUT-T model. / Badanie nastawienia polskich psychoterapeutów wobec terapii online ­ polska adaptacja kwestionariusza UTAUT-T (Uogólniona Teoria Akceptacji i Stosowania Technologii, wersja dla Terapeutów (Unified Theory of Acceptance and Use of Technology ­ Therapists Version) oraz weryfikacja modelu UTAUT-T.

OBJECTIVES: The aim of the study was to verify the psychometric properties of the Polish adaptation of the Unified Theory of Acceptance and Use of Technology - Therapist version (UTAUT-T) and to verify the UTAUT-T model in a group of Polish psychotherapists. METHODS: A total of 434 people aged 27-66 (M = 40.78; SD = 7.70), including 337 women and 58 men, took part in an online self-report study, which involved completing three questionnaires: UTAUT-T, the short IPIP-BFM-20 Questionnaire for measuring the Big Five, the Technology Readiness Index (TRI 2.0), as well as answers to questions about the use of digital technologies at work. The following analyses were carried out: confirmatory factor analysis (CFA), reliability analysis using Cronbach's alpha, and theoretical validity analysis - an analysis of the correlation between the subscales of the UTAUT-T instrument and questionnaires enabling the measurement of dimensions which had been indicated in previous research results as related to the acceptance of technology. RESULTS: The conducted analyses showed that the factor structure of the Polish version of UTAUT-T is the same as of the original tool, and the UTAUT-T model was confirmed in the group of Polish psychotherapists. The Cronbach's alpha reliability coefficient for individual subscales ranged from 0.57 to 0.97. The theoretical validity analysis confirmed the expected correlations between most dimensions of technology acceptance and technology readiness. In addition, there were single very weak correlations observed between technology acceptance and personality traits. CONCLUSIONS: The psychometric properties of the Polish version of UTAUT-T show satisfactory values. The scale can be used to conduct further research. The UTAUT-T model can be utilized to predict the actual use of new technologies by Polish psychotherapists.

Are you confident enough to act? Individual differences in action control are associated with post-decisional metacognitive bias.

The art of making good choices and being consistent in executing them is essential for having a successful and fulfilling life. Individual differences in action control are believed to have a crucial impact on how we make choices and whether we put them in action. Action-oriented people are more decisive, flexible and likely to implement their intentions in the face of adversity. In contrast, state-oriented people often struggle to commit to their choices and end up second-guessing themselves. Here, we employ a model-based computational approach to study the underlying cognitive differences between action and state-oriented people in simple binary-choice decision tasks. In Experiment 1 we show that there is little-to-no evidence that the two groups differ in terms of decision-related parameters and strong evidence for differences in metacognitive bias. Action-oriented people exhibit greater confidence in the correctness of their choices as well as slightly elevated judgement sensitivity, although no differences in performance are present. In Experiment 2 we replicate this effect and show that the confidence gap generalizes to value-based decisions, widens as a function of difficulty and is independent of deliberation interval. Furthermore, allowing more time for confidence deliberation indicated that state-oriented people focus more strongly on external features of choice. We propose that a positive confidence bias, coupled with appropriate metacognitive sensitivity, might be crucial for the successful realization of intentions in many real-life situations. More generally, our study provides an example of how modelling latent cognitive processes can bring meaningful insight into the study of individual differences.

Response of Polish Psychiatric Patients to the Russian Invasion of Ukraine in February 2022-Predictive Role of Risk Perception and Temperamental Traits.

This study examined the impact of the Russian invasion of Ukraine in February 2022 on Polish patients with depression and schizophrenia. It has been hypothesized that possible changes in symptoms may be predicted by the subjective risk perception related with the Russo-Ukraine War (RUW) as well as by temperamental traits. The study was conducted with 80 patients with schizophrenia or depression. A questionnaire measuring sociodemographic characteristics, perception of risk, temperamental characteristics, and symptoms of depression and schizophrenia were used as research tools. Symptom intensity was compared with the average symptom intensity calculated on the basis of archival symptom measurements from the three consecutive months preceding the outbreak of the RUW. Predictors of change in symptoms were also analyzed, taking into account sociodemographic variables, the level of risk perception, and temperamental traits. The results indicate the specific patterns of reactions to war danger for patients with different types of psychiatric diagnosis. Depressed patients reacted with an increase in seven symptoms related to unworthiness and/or guilt, lack of interest, and/or pleasure and pessimism. The response of schizophrenic patients was related only with an increase in positive symptoms. This study highlights the need to provide more support to psychiatric patients in acute emergencies.

The Effect of Flame Retardant-Aluminum Trihydroxide on Mixed Mode I/II Fracture Toughness of Epoxy Resin.

Fire resistance is a major issue concerning composite materials for safe operation in many industrial sectors. The design process needs to meet safety requirements for buildings and vehicles, where the use of composites has increased. There are several solutions to increasing the flame resistance of polymeric materials, based on either chemical modification or physical additions to the material's composition. Generally, the used flame retardants affect mechanical properties either in a positive or negative way. The presented research shows the influence of the mixed-mode behavior of epoxy resin. Fracture toughness tests on epoxy resin samples were carried out, to investigate the changes resulting from different inorganic filler contents of aluminum trihydroxide (ATH). Three-point bending and asymmetric four-point bending tests, with different loading modes, were performed, to check the fracture behavior in a complex state of loading. The results showed that the fracture toughness of mode I and mode II was reduced by over 50%, compared to neat resin. The experimental outcomes were compared with theoretical predictions, demonstrating that the crack initiation angle for higher values of KI/KII factor had a reasonable correlation with the MTS prediction. On the other hand, for small values of the factor KI/KII, the results of the crack initiation angle had significant divergences. Additionally, based on scanning electron microscopy images, the fracturing of the samples was presented.

Structural determination of functional domains in early B-cell factor (EBF) family of transcription factors reveals similarities to Rel DNA-binding proteins and a novel dimerization motif.

The early B-cell factor (EBF) transcription factors are central regulators of development in several organs and tissues. This protein family shows low sequence similarity to other protein families, which is why structural information for the functional domains of these proteins is crucial to understand their biochemical features. We have used a modular approach to determine the crystal structures of the structured domains in the EBF family. The DNA binding domain reveals a striking resemblance to the DNA binding domains of the Rel homology superfamily of transcription factors but contains a unique zinc binding structure, termed zinc knuckle. Further the EBF proteins contain an IPT/TIG domain and an atypical helix-loop-helix domain with a novel type of dimerization motif. The data presented here provide insights into unique structural features of the EBF proteins and open possibilities for detailed molecular investigations of this important transcription factor family.

Exhausted Capacity of Bicarbonate Buffer in Renal Failure Diagnosed Using Point of Care Analyzer.

BACKGROUND: Metabolic acidosis in patients with chronic kidney disease (CKD) is a common complication. A bicarbonate concentration in venous blood (V-HCO3-) is a key index for diagnosis and treatment initiation. The aim of our study is to evaluate usability of acid-base balance parameters of in blood taken simultaneously from peripheral artery and the vein. METHODS: A total of 49 patients (median age 66 years [interquartile range IQR 45-75]), with CKD stage G4 or G5 were enrolled in this cross-sectional study. All patients were qualified for arteriovenous fistula creation in pre-dialysis period. The samples were taken during surgery, directly after dissection, and evaluated in a point of care testing analyzer. The arteriovenous difference in bicarbonate levels (Δ-HCO3-) was calculated. According to glomerular filtration rate (eGFR) the group was divided into Group A eGFR ≥ 10 mL/min/1.73 m2) and Group B eGFR < 10 mL/min/1.73 m2). RESULTS: In Group A Δ-HCO3- was significantly higher compared to Group B. No such differences were observed in the case of V-HCO3-. Δ-HCO3- positively correlated with eGFR. The discriminative power of Δ-HCO3- for predicting eGFR < 10 mL/min/1.73 m2 was 0.72 (95% confidence interval [CI] = 0.551-0.88; p = 0.01) which provided 67% sensitivity and 75% specificity. The best cut-off was 0.5 mmol/L. CONCLUSIONS: The Δ-HCO3- lower than 0.5 mmol/L may be used as predictor of exhaust buffer capacity. The value of this tool should be tested in larger population.

Time-Frequency Characterization of Resting Brain in Bipolar Disorder during Euthymia-A Preliminary Study.

The goal of this paper is to investigate the baseline brain activity in euthymic bipolar disorder (BD) patients by comparing it to healthy controls (HC) with the use of a variety of resting state functional magnetic resonance imaging (rs-fMRI) analyses, such as amplitude of low frequency fluctuations (ALFF), fractional ALFF (f/ALFF), ALFF-based functional connectivity (FC), and r egional homogeneity (ReHo). We hypothesize that above-mentioned techniques will differentiate BD from HC indicating dissimilarities between the groups within different brain structures. Forty-two participants divided into two groups of euthymic BD patients (n = 21) and HC (n = 21) underwent rs-fMRI evaluation. Typical band ALFF, slow-4, slow-5, f/ALFF, as well as ReHo indexes were analyzed. Regions with altered ALFF were chosen as ROI for seed-to-voxel analysis of FC. As opposed to HC, BD patients revealed: increased ALFF in left insula; increased slow-5 in left middle temporal pole; increased f/ALFF in left superior frontal gyrus, left superior temporal gyrus, left middle occipital gyrus, right putamen, and bilateral thalamus. There were no significant differences between BD and HC groups in slow-4 band. Compared to HC, the BD group presented higher ReHo values in the left superior medial frontal gyrus and lower ReHo values in the right supplementary motor area. FC analysis revealed significant hyper-connectivity within the BD group between left insula and bilateral middle frontal gyrus, right superior parietal gyrus, right supramarginal gyrus, left inferior parietal gyrus, left cerebellum, and left supplementary motor area. To our best knowledge, this is the first rs-fMRI study combining ReHo, ALFF, f/ALFF, and subdivided frequency bands (slow-4 and slow-5) in euthymic BD patients. ALFF, f/ALFF, slow-5, as well as REHO analysis revealed significant differences between two studied groups. Although results obtained with the above methods enable to identify group-specific brain structures, no overlap between the brain regions was detected. This indicates that combination of foregoing rs-fMRI methods may complement each other, revealing the bigger picture of the complex resting state abnormalities in BD.

BRAF and MEK inhibitors rechallenge as effective treatment for patients with metastatic melanoma.

Despite considerable progress made in the treatment of patients with advanced melanoma, the majority of the patients treated with BRAF and mitogen-activated protein inhibitors (BRAFi and MEKi) experience a disease progression due to acquired resistance. Currently, ongoing studies explore the possibility to overcome or reverse this process. Our multicenter retrospective analysis included 51 patients with metastatic BRAF-mutated melanoma who had previously progressed on BRAFi/MEKi than had progressed on immunotherapy (anti-progression disease-1 or anti-cytotoxic T-lymphocyte-associated protein 4) and next were rechallenged with BRAFi/MEKi. Median age at BRAFi/MEKi rechallenge was 56 (range: 31-82 y/o). Median overall survival from the start of the first BRAFi/MEKi therapy and from rechallenge BRAFi/MEKi treatment was 29.7 and 9.3 months, respectively, whereas median progression-free survival was 10.5 and 5.9 months, respectively. Six-month, annual, and 2-year overall survival rates on both treatments were: 98% and 55%, 92% and 29%, and 69% and 2%, respectively. A response rate to treatment was higher in the group receiving BRAFi/MEKi for the first time as compared with the group receiving BRAFi/MEKi rechallenge and was overall response rate 72% and 27%; disease control rate 92% and 63%. Time interval between the end of the first BRAFi/MEKi treatment and the beginning of BRAFi/MEKi rechallenge did not influence median overall survival or progression-free survival. A lower toxicity rate was noted with BRAFi/MEKi rechallenge. BRAFi/MEKi rechallenge treatment remains clinically important and is associated with the lower toxicity. BRAFi/MEKi rechallenge efficacy is higher in patients who are in good performance status, with normal lactate dehydrogenase, and without brain metastases.

A quantitative Streptococcus pyogenes-human protein-protein interaction map reveals localization of opsonizing antibodies.

A fundamental challenge in medical microbiology is to characterize the dynamic protein-protein interaction networks formed at the host-pathogen interface. Here, we generate a quantitative interaction map between the significant human pathogen, Streptococcus pyogenes, and proteins from human saliva and plasma obtained via complementary affinity-purification and bacterial-surface centered enrichment strategies and quantitative mass spectrometry. Perturbation of the network using immunoglobulin protease cleavage, mixtures of different concentrations of saliva and plasma, and different S. pyogenes serotypes and their isogenic mutants, reveals how changing microenvironments alter the interconnectivity of the interaction map. The importance of host immunoglobulins for the interaction with human complement proteins is demonstrated and potential protective epitopes of importance for phagocytosis of S. pyogenes cells are localized. The interaction map confirms several previously described protein-protein interactions; however, it also reveals a multitude of additional interactions, with possible implications for host-pathogen interactions involving other bacterial species.