HRAS mutation positive multiple myeloma in the type 2 CALR mutation positive essential thrombocythemia: A case report.

Out of BCR-ABL negative myeloproliferative neoplasm (MPNPh- ) patients, 3%-14% display a concomitant monoclonal gammopathy of unknown significance (MGUS). In most cases, the diagnosis of plasma cell dyscrasia is either synchronous with that of MPNPh- or occurs later on. We present a 50-year-old patient with type 2 CALR Lys385Asnfs*47 mutation positive essential thrombocythemia (ET) who developed symptomatic multiple myeloma (MM) 13 years after the diagnosis of ET during PEG-INF2α treatment. The NGS study performed at the time of the MM diagnosis revealed the HRAS Val14Gly/c.41T〉G mutation and the wild type CALR, JAK2 and MPL gene sequence. In the presented case, the complete molecular remission of ET was achieved after 16 months of PEG-INF2α treatment. The origin of MM cells in MPNPh- patients remains unknown. Published data suggests that type 2 CALRins5 up-regulate the ATF6 chaperone targets in hematopoietic cells and activate the inositol-requiring enzyme 1α-X-box-binding protein 1 pathway of the unfolded protein response (UPR) system to drive malignancy. It cannot be excluded that endoplasmic reticulum stress induced by the increased ATF6 resulted in an abnormal redox homeostasis and proteostasis, which are factors linked to MM. The presented case history and the proposed mechanism of mutant CALR interaction with UPR and/or ATF6 should initiate the discussion about the possible impact of the mutant CALR protein on the function and genomic stability of different types of myeloid cells, including progenitor cells.

Temporal changes in regulatory T cell subsets defined by the transcription factor Helios in stroke and their potential role in stroke-associated infection: a prospective case-control study.

BACKGROUND: Regulatory T cells (Tregs) are involved in the systemic immune response after ischemic stroke. However, their role remains unclear, and the effect appears to be both neuroprotective and detrimental. Treg suppressor function may result in immunodepression and promote stroke-associated infection (SAI). Thus we assume that the bidirectional effects of Tregs may be in part attributed to the intracellular transcription factor Helios. Tregs with Helios expression (H+ Tregs) constitute 70-90% of all Treg cells and more frequently than Helios-negative Tregs (H- Tregs) express molecules recognized as markers of Tregs with suppressor abilities. METHODS AND RESULTS: We prospectively assessed the circulating Treg population with flow cytometry in 52 subjects on days 1, 3, 10 and 90 after ischemic stroke and we compared the results with those obtained in concurrent age-, sex- and vascular risk factor-matched controls. At all studied time points the percentage of H+ Tregs decreased in stroke subjects-D1: 69.1% p < 0.0001; D3: 62.5% (49.6-76.6), p < 0.0001; D10: 60.9% (56.5-72.9), p < 0.0001; D90: 79.2% (50.2-91.7), p = 0.014 vs. controls: 92.7% (81.9-97.0) and the percentage of H- Tregs increased accordingly. In patients with SAI the percentage of pro-suppressor H+ Tregs on post-stroke day 3 was higher than in those without infection (p = 0.03). After adjustment for confounders, the percentage of H+ Tregs on day 3 independently correlated with SAI [OR 1.29; CI 95%: 1.08-1.27); p = 0.02]. Although the percentage of H+ Tregs on day 3 correlated positively with NIHSS score on day 90 (rS = 0.62; p < 0.01) and the infarct volume at day 90 (rS = 0.58; p < 0.05), in regression analysis it was not an independent risk factor. CONCLUSIONS: On the first day after stroke the proportion of H+ vs. H- Tregs changes in favor of pro-inflammatory H- Tregs, and this shift continues toward normalization when assessed on day 90. A higher percentage of pro-suppressive H+ Tregs on day 3 independently correlates with SAI and is associated positively with NIHSS score, but it does not independently affect the outcome and stroke area in the convalescent phase of stroke.

Generation of Inducible BCL11B Knockout in TAL1/LMO1 Transgenic Mouse T Cell Leukemia/Lymphoma Model.

The B-cell CLL/lymphoma 11B gene (BCL11B) plays a crucial role in T-cell development, but its role in T-cell malignancies is still unclear. To study its role in the development of T-cell neoplasms, we generated an inducible BCL11B knockout in a murine T cell leukemia/lymphoma model. Mice, bearing human oncogenes TAL BHLH Transcription Factor 1 (TAL1; SCL) or LIM Domain Only 1 (LMO1), responsible for T-cell acute lymphoblastic leukemia (T-ALL) development, were crossed with BCL11B floxed and with CRE-ER/lox mice. The mice with a single oncogene BCL11Bflox/floxCREtg/tgTAL1tg or BCL11Bflox/floxCREtg/tgLMO1tg were healthy, bred normally, and were used to maintain the mice in culture. When crossed with each other, >90% of the double transgenic mice BCL11Bflox/floxCREtg/tgTAL1tgLMO1tg, within 3 to 6 months after birth, spontaneously developed T-cell leukemia/lymphoma. Upon administration of synthetic estrogen (tamoxifen), which binds to the estrogen receptor and activates the Cre recombinase, the BCL11B gene was knocked out by excision of its fourth exon from the genome. The mouse model of inducible BCL11B knockout we generated can be used to study the role of this gene in cancer development and the potential therapeutic effect of BCL11B inhibition in T-cell leukemia and lymphoma.

Immune profile of children diagnosed with multisystem inflammatory syndrome associated with SARS-CoV-2 infection (MIS-C).

Introduction: The pathophysiology of multisystem inflammatory syndrome associated with SARS-CoV-2 infection (MIS-C) remains poorly understood. This study aimed to define peripheral blood immune features in patients with MIS-C. Material and methods: We analyzed seven children diagnosed with MIS-C between April 1 and May 15, 2021, in St. Joseph's Children's Hospital in Poznan (Poland). Results: All patients had elevated inflammatory markers, IgG antibodies against SARS-CoV-2, and lymphopenia with a marked decrease in CD4+ and CD8+ T cells. The majority of CD4+ T cells were naive cells. Almost all (6/7) of the analyzed patients had a higher CD4+/CD8+ T cell ratio than average values. B cells were within the normal range - the majority were non-memory cells. Conclusions: Children with MIS-C do not resemble adults during COVID-19 recovery. The immune profile of the studied patients differs from that of children with Kawasaki disease (KD), but it is similar to that of adults with severe COVID-19. The proposed explanation is a profound lymphopenia caused by SARS-CoV-2 infection - which persists for weeks - as a result leading to uncontrolled inflammation. In COVID-19 patients the T cell level returns to normal after the second week of the disease. Our data suggest that in children prolonged lymphopenia after COVID-19 can be a practical marker for possible MIS-C alert. If there is a continuum from lymphopenia to MIS-C, there is room for screening and prevention. Further studies are needed to determine whether steroid treatment introduced in a child with prolonged lymphopenia could stop the inflammatory process.

Lithium toxicity and the kidney with special focus on nephrotic syndrome associated with the acute kidney injury: A case-based systematic analysis.

Despite the progress made in treating bipolar and unipolar affective disorders, lithium carbonate is still a common drug in psychiatric practice. Lithium-related renal side effects include nephrogenic diabetes insipidus, chronic tubulointerstitial nephropathy, and acute kidney injury (AKI). Nephrotic syndrome (NS) is an uncommon but severe complication of lithium treatment. We present a 49-year-old female treated with lithium carbonate due to a recurrent depressive disorder who developed NS during this therapy. NS spontaneously remitted after the drug withdrawal. Since her lithium serum levels were within the recommended values, we performed a retrospective analysis of lithium-induced NS cases trying to determine causes predisposing to the NS development, underlying histopathology, and preservation or irreversible loss of kidney function. This analysis revealed that in lithium-induced NS with AKI, lithium serum level was the key determinant of AKI development (the ß coefficient = 0.8499 with a confidence interval ranging from 0.7452 to 0.9546 and p value < 0.0001). In these cases, the underlying pathology was mainly minimal change disease (MCD), which was quickly reversible upon the drug withdrawal. The development of chronic kidney disease (CKD) seemed to be associated with lithium therapy duration. However, the multiple regression analysis for CKD as the dependent variable showed that the decisive factor was focal segmental glomerulosclerosis (FSGS) as the underlying pathology (the ß coefficient = 0.7866 with a confidence interval ranging from 0.600 to 0.9704 and the p value < 0.0001). Thus, we conclude that in lithium-induced NS/AKI, serum lithium levels contribute to these complications, while FSGS lesions are responsible for CKD's disease progression.

The Effect of Homocysteine on the Secretion of Il-1ß, Il-6, Il-10, Il-12 and RANTES by Peripheral Blood Mononuclear Cells-An In Vitro Study.

The contemporary theory of the inflammatory-immunological pathomechanism of atherosclerosis includes the participation of interleukin-1ß (Il), Il-6, Il-10, Il-12, RANTES, and homocysteine in this process. The knowledge on the direct effect of hyperhomocysteinemia on inflammatory-state-related atherosclerosis is rather scarce. Our study is the first to account for the effects of homocysteine on the secretion of Il-10 and RANTES in vitro conditions. For this purpose, human mitogen-stimulated peripheral blood mononuclear cells (PBMNCs) were cultured in vitro and exposed to homocysteine at high concentrations. Subsequently, the concentrations of cytokines were assayed in the cell culture supernatant using flow cytofluorimetry. It has been shown that, in the presence of homocysteine, the secretion of IL-1, IL-6 and RANTES by PBMNCs was increased, whereas IL-10 concentration was significantly lower than that of the supernatant derived from a mitogen-stimulated cell culture without homocysteine. The secretion of Il-12 by PBMNCs exposed exclusively to mitogen, did not differ from homologous cells also treated with homocysteine. Therefore, in our opinion, high-concentration homocysteine affects the progression of atherosclerosis by increasing the secretion of proinflammatory cytokines secreted by PBMNCs, such as Il-1ß, Il-6, RANTES, and by attenuating the secretion of Il-10.

A case of bizarre posttransplant anti-glomerular basement membrane disease.

The non-collagenous (NC1) domain of α3 and α5 chains of type IV collagen are eminent targets of abnormal immune response in anti-glomerular basement membrane (anti-GBM) disease, which can be diagnosed by the presence of strong linear IgG staining along GBM detected by direct immunofluorescence. The presence of linear GBM fixation in renal allograft is a rare finding. We observed a 33-year-old male with de novo renal failure in a kidney transplant. An examination of a kidney biopsy specimen revealed, in light microscopy, mild mesangial hypercellularity together with mild focal interstitial fibrosis and sparse inflammatory infiltrate. In immunofluorescence microscopy strong linear IgG staining along the capillary walls was seen. Serum anti-GBM antibodies were negative and no mutation in exons coding NC1 domains of α3 and α5 chains of type IV collagen were detected. We described a rare case of a patient with atypical anti-GBM disease in renal allograft, caused probably by the same process which affected the native kidneys.

Relationship between the von Willebrand Factor Plasma Concentration and Ultrasonographic Doppler Findings in Pregnancies Complicated by Hypertensive Disorders: A Pilot Study.

BACKGROUND/AIMS: Recent evidence suggests that impaired cytotrophoblast proliferation and migration are major factors responsible for the development of hypertension in pregnancy. Studies report that von Willebrand factor (vWf) is a specific endothelial damage plasma marker. The aim of this study was to evaluate the relationship between vWf maternal plasma concentration and maternal and fetal Doppler flow measurements in pregnancies complicated by hypertension. It may provide additional insight into the pathophysiology of pregnancy-related hypertension and show the potential method for disease prevention and therapy. METHODS: We created 3 study groups: pregnant women with chronic hypertension (n = 10), gestational hypertension (n = 18), preeclampsia (n = 21), and control (22 healthy pregnant women). Every woman underwent ultrasound Doppler flow measurements performed simultaneously with venous blood collection. The vWf plasma concentrations were assessed using the commercially available enzyme-linked immunosorbent assay kit. RESULTS: The preeclampsia group had significantly higher vWf plasma concentrations in those patients with ultrasonographic features of placental insufficiency than in those without these characteristics (638 ± 208 vs. 377 ± 74 ng/mL; p < 0.017). CONCLUSION: Our results may confirm the arrangement and severity of endothelial damage in preeclamptic patients and may have identified those patients with a significantly higher risk of developing cardiovascular disease.

The impact of dapagliflozin on glucose excursions related to early proatherogenic derangement in the aortic wall.

INTRODUCTION: Cardiovascular risk in the course of diabetes depends greatly on glycemic variability which is even more significant than chronic hyperglycemia. Optimal management of diabetes involves a multidisciplinary approach focused in particular on decreasing the risk of atherosclerosis. Therefore, our purpose was to evaluate the impact of dapagliflozin on glucose excursions and related proatherogenic changes in the aortic wall. METHODS AND MATERIALS: Animal model of type 2 diabetes rich-fat/STZ rats was used. Wistar rats were randomized into 3 groups: dapagliflozin-treated with glucose excursions, placebo-treated with glucose excursions and placebo-treated with stable diabetes. Dapagliflozin was administered once a day, 1 mg/kg, for 8 consecutive weeks. Glucose levels were measured twice a week at fasting and postprandially. The samples of aortas were taken for histopathological and immunochemistry examinations at the end of the experiment. The derangement in the aortic wall and the distribution of CD68+ cells in the aorta were considered early signs of atherosclerosis. RESULTS: Dapagliflozin reduced glucose excursion to the level characteristic for stable, well-controlled diabetes. It was related to a significant decrease in histopathological changes which were observed in the placebo-treated rats with glucose variability. Dapagliflozin significantly reduced also the accumulation of CD68+ macrophages in the aortic adventitia. CONCLUSION: Dapagliflozin provides not only mere beneficial regulation of metabolic status with the depletion of glucose variability, but is also helpful in the prevention of early atherosclerosis related to the course of diabetes type 2.

[Ibrutinib - new tool in hematologist hand, new challenges for internist].

Chronic lymphocytic leukemia is the most common cancer of the lymphatic tissue in adults. The peak incidence falls on the 65-70 year old. Therefore, the majority of patients with chronic lymphocytic leukemia (CLL) has at least one coexisting disease. Successful oncological and supportive treatment, that is common in recent years, significantly prolongs the survival. This paper presents ibrutinib - a new drug used to treat CLL. The aim of this paper is, to show an example of this drug, meaning and benefits of modern methods of pharmacotherapy in the treatment of oncology.

The Impact of Pharmacotherapy of Type 2 Diabetes Mellitus on IL-1ß, IL-6 and IL-10 Secretion.

BACKGROUND: The aim of this study was to assess the impact of pharmacotherapy of diabetes on atherosclerosis, as reflected in interleukin (IL)-1ß, IL-6 and IL-10 serum levels. METHODS: We studied patients with type 2 diabetes, treated with metformin, insulin combined with metformin and conventional insulin. IL-1ß, IL-6 and IL-10 serum levels were assayed using BD™ Cytometric Bead Array. Multivariate analysis of covariance was performed to exclude the impact of some metabolic and anthropometric factors on differences in cytokines concentrations among the participants receiving different pharmacotherapy. RESULTS: The serum concentrations of IL-1ß and IL-6 were significantly higher and IL-10 serum levels were significantly lower in the insulin-treated group than in other therapeutic groups. Covariance analysis confirmed that differences in IL-1ß and IL-6 levels were determined by pharmacotherapy and fasting plasma glucose, whereas in IL-10 levels by the therapy only. Additionally, peptide C modified differences in IL-1ß levels and HbA1c in IL-6 concentrations. CONCLUSION: This study revealed that both pharmacotherapy and glycemic control may modify some pro-atherogenic factors, such as IL-1ß and IL-6. The therapy with metformin and insulin combined with metformin seems to be much more beneficial in terms of their impact on pro-inflammatory cytokines secretion in comparison to conventional insulinotherapy.

Patterns of glomerular disease based on 4-year kidney biopsy material analyzed by light microscopy and immunofluorescence: a retrospective single-center analysis in Poland.

The aim of this study was to assess the epidemiology of different patterns of chronic glomerular diseases based on clinical, histopathological and immunofluorescent findings of glomerulonephritis patients hospitalized in the Department of Nephrology, Transplantology and Internal Diseases in Poznan between January 2009 and December 2012. We retrospectively studied 418 patients who had been subjected to renal biopsies. Data on serum creatinine concentration, 24 h proteinuria, arterial hypertension, diabetes mellitus, and histological and immunofluorescent findings were collected. The patients' mean age was 42 ±15. The male sex prevailed (53.1%). Immunoglobulin A nephropathy was the most common finding (18.9%), followed by focal segmental glomerulosclerosis (16.3%), membranous glomerulonephritis (10.1%), lupus nephritis (8.4%), extracapillary glomerulonephritis (3.3%) and membranoproliferative glomerulonephritis (2.6%). In 69 (16.5%) patients the biopsy was non-informative or non-diagnostic. Patients with membranous nephropathy presented the highest frequency of nephrotic syndrome (71.4%), followed by membranoproliferative glomerulonephritis and focal segmental glomerulosclerosis. Combined analysis of the clinical, histopathological and immunofluorescent findings in glomerulonephritis patients based on a single center's data can provide important epidemiological findings.

Thymic emigration patterns in patients with type 2 diabetes treated with metformin.

Recent data suggest that thymic output, which provides the naive T cells necessary for the normal functioning of T-cell-dependent immunosurveillance cellular immunity including anti-cancer protection, can be disturbed in the course of type 2 diabetes. Metformin, an anti-diabetic drug commonly confirmed as an agent with many potential anti-cancer activities, might be helpful in this immune correction. The profile of thymic output was evaluated in the current study on the basis of the signal-joint T-cell receptor excision circle (sjTREC) concentration in peripheral blood polymorphonuclear cells and thymic emigrant content in peripheral blood evaluated from CD127 and/or CD132 antigen expression. It was revealed that recent thymic emigrants and more differentiated CD127(+) CD132(+) cell populations were decreased among naive T cells and CD8(+) T cells, whereas RTE count was increased in CD4(+) T cells, and the CD127(+) CD132(+) cell population was less numerous than in non-diabetic participants. Terminally differentiated thymic emigrants, i.e. CD127(-) CD132(+) cells, were increased in naive T cells and in CD8(+) T cells. Metformin affects mainly the early phases of thymic export, increasing CD127(+) CD132(-) and CD127(+) CD132(+) cell populations in naive T cells and the CD127(+) CD132(-) population in CD4(+) T lymphocytes. It could be concluded that type 2 diabetes deteriorates thymic immunostasis. The decreased thymic output could be compensated by metformin, especially with regard to CD4(+) naive T cells. It is the first time that therapy with metformin has been documented by us as particularly useful in the control and normalization of thymus function, regarding correction of early populations of thymic emigrants.

Statins in low doses reduce VEGF and bFGF serum levels in patients with type 2 diabetes mellitus.

BACKGROUND/AIMS: Recent experimental research revealed that statins at low doses induce angiogenesis, which in turn may be related to the course of atherosclerosis. There are no clinical studies evaluating the effect of 'low-dose' statins on serum levels of angiogenesis regulators in diabetic subjects. We aimed to explain how low doses of statins modify the serum concentrations of two potent proangiogenic factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), in patients with type 2 diabetes. METHODS: Measurements of fasting glucose level, HbA1c, 1,5-anhydro-D-glucitol and lipid profile were taken from 47 patients with type 2 diabetes treated with low doses of atorvastatin (10 mg daily) or simvastatin (10-20 mg daily), from 45 statin-free patients with type 2 diabetes and from 23 nondiabetic subjects. Measurements of VEGF and bFGF in serum were taken using the BD™ Cytometric Bead Array. RESULTS AND CONCLUSION: Statins used in low doses in patients with type 2 diabetes reduce the serum concentration of VEGF and bFGF which suggests antiangiogenic potential of these doses. Nevertheless, this effect could be neutralized by postprandial hyperglycemia.

New hopes for the breast cancer treatment: perspectives on the oncolytic virus therapy.

Oncolytic virus (OV) therapy has emerged as a promising frontier in cancer treatment, especially for solid tumours. While immunotherapies like immune checkpoint inhibitors and CAR-T cells have demonstrated impressive results, their limitations in inducing complete tumour regression have spurred researchers to explore new approaches targeting tumours resistant to current immunotherapies. OVs, both natural and genetically engineered, selectively replicate within cancer cells, inducing their lysis while sparing normal tissues. Recent advancements in clinical research and genetic engineering have enabled the development of targeted viruses that modify the tumour microenvironment, triggering anti-tumour immune responses and exhibiting synergistic effects with other cancer therapies. Several OVs have been studied for breast cancer treatment, including adenovirus, protoparvovirus, vaccinia virus, reovirus, and herpes simplex virus type I (HSV-1). These viruses have been modified or engineered to enhance their tumour-selective replication, reduce toxicity, and improve oncolytic properties.Newer generations of OVs, such as Oncoviron and Delta-24-RGD adenovirus, exhibit heightened replication selectivity and enhanced anticancer effects, particularly in breast cancer models. Clinical trials have explored the efficacy and safety of various OVs in treating different cancers, including melanoma, nasopharyngeal carcinoma, head and neck cancer, and gynecologic malignancies. Notably, Talimogene laherparepvec (T-VEC) and Oncorine have. been approved for advanced melanoma and nasopharyngeal carcinoma, respectively. However, adverse effects have been reported in some cases, including flu-like symptoms and rare instances of severe complications such as fistula formation. Although no OV has been approved specifically for breast cancer treatment, ongoing preclinical clinical trials focus on four groups of viruses. While mild adverse effects like low-grade fever and nausea have been observed, the effectiveness of OV monotherapy in breast cancer remains insufficient. Combination strategies integrating OVs with chemotherapy, radiotherapy, or immunotherapy, show promise in improving therapeutic outcomes. Oncolytic virus therapy holds substantial potential in breast cancer treatment, demonstrating safety in trials. Multi-approach strategies combining OVs with conventional therapies exhibit more promising therapeutic effects than monotherapy, signalling a hopeful future for OV-based breast cancer treatments.

Head and neck squamous carcinomas with exophytic and endophytic type of growth have the same prognosis after surgery and adjuvant radiotherapy.

Head and neck squamous cell carcinomas (HNSCC) are characterized by exophytic or endophytic growth. We hypothesized that the growth pattern predicts outcome and associates with distinct clinical and immunological profiles. Tumors obtained from 60 HNSCC patients treated with surgery and adjuvant radiotherapy were identified as exophytic or endophytic. Recurrence-free survival (RFS) at 42 months was determined. In a subsets of 30 patients (22 exophytic and 8 endophytic) tumor stroma and parenchyma were evaluated for infiltrating CD4(+) and CD8(+) T, dendritic, myeloid and FOXP3(+) regulatory T cells (Treg) and expression of immunosuppressive cytokines by immunohistochemistry. The localization and frequency of positive cells were determined microscopically and analyzed by hierarchical clustering to distinguish exophytic versus endophytic tumors. 34/60 patients had exophytic and 26/60 endophytic tumors. No differences in clinicopathologic data, disease progression or RFS were seen between the two cohorts. Infiltrates of CD3(+)CD8(+) T cells were larger in endophytic than exophytic tumors, while FOXP3(+) Treg, TGF-ß(+), IL-10(+), Arg-1(+), CD11b(+) cells were equally prominent in both. FOXP3(+) Treg accumulated in endophytic tumor nests, while the exophytic tumor stroma was enriched in IL-10(+) cells (both at p < 0.05). Hierarchical clustering based on immunophenotyping failed to identify different clusters in these two tumor types. However, CD68(+) macrophages and FOXP3(+) Treg showed a distinct distribution. The HNSCC growth pattern did not predict RFS. Although higher numbers and differences in localization of immunosuppressive cells in endophytic versus exophytic tumors were observed, no significant relationship was established between the growth pattern and the immune profile of infiltrating lymphocytes.

MicroRNA in lung cancer-a novel potential way for early diagnosis and therapy.

Lung cancer is the most common cause of cancer-related deaths in the world. One of the reasons of poor prognosis and high mortality of lung cancer patients is the diagnosis of the disease in its advanced stage. Despite innovative diagnostic methods and multiple completed and ongoing clinical trials aiming at therapy improvement, no significant increase in patients' long-term survival has been noted over last decades. Patients would certainly benefit from early detection of lung cancer. Therefore, it is crucial to find new biomarkers that can help predict outcomes and tumor responses in order to maximize therapy effectiveness and avoid over- or under-treating patients with lung cancer. Nowadays, scientists' attention is mainly dedicated to so-called liquid biopsy, which is fully non-invasive and easily available method based on simple blood draw. Among common liquid biopsy elements, circulating tumor nucleic acids are worth mentioning. Epigenetic biomarkers, particularly miRNA expression, have several distinct features that make them promising prognostic markers. In this review, we described miRNA's involvement in tumorigenesis and present it as a predictor of cancer development and progression, potential indicator of treatment efficacy, and most importantly promising therapeutic target.

Arginase-1 in Plasma-Derived Exosomes as Marker of Metastasis in Patients with Head and Neck Squamous Cell Carcinoma.

Immunoregulatory Arginase-1 (Arg-1) is present in the tumor microenvironment of solid tumors. Its association to clinicopathology and its prognostic impact are inconsistent among different tumor types and biological fluids. This study evaluated Arg-1 protein levels in tumors and the circulation of patients with head and neck squamous cell carcinoma (HNSCC) in relation to clinical stage and prognosis. Tumor Arg-1 expression was monitored via immunohistochemistry while plasma Arg-1 levels via ELISA in 37 HNSCC patients. Arg-1 presence in plasma-derived exosomes was assessed using Western blots in 20 HNSCC patients. High tumor Arg-1 expression correlated with favorable clinicopathology and longer recurrence-free survival (RFS), while high plasma Arg-1 levels were associated with unfavorable clinicopathology. All patients with low tumor and high plasma Arg-1 had nodal metastases and developed recurrence. This discrepancy was attributed to the presence of Arg-1-carrying exosomes. Arg-1 was found in plasma-derived exosomes from all HNSCC patients. High exosomal Arg-1 levels were associated with positive lymph nodes and short RFS. Circulating Arg-1+ exosomes represent a mechanism of active Arg-1 export from the tumor to the periphery. Exosomes reflected biologically relevant Arg-1 levels in metastatic HNSCC and emerged as potentially more accurate biomarkers of metastatic disease and RFS than tissue or plasma Arg-1 levels.

Chronic hyper-reactivity of platelets resulting in enhanced monocyte recruitment in patients after ischaemic stroke.

Although the platelet activation profile after stroke is a well-known issue, the platelet reactivity assessed prospectively after ischaemic stroke still remains equivocal. The aim of this study was to evaluate the reactivity of platelets in response to stimulation with thrombin receptor-activating peptide (TRAP) at 1, 10 and 90 days after ischaemic stroke and to compare it with results obtained in control groups. We determined the increment in surface expression of CD62P, CD40L and monocyte- and granulocyte-platelet aggregate formation using five-colour flow cytometry in 86 subjects after an ischaemic event, in 62 disease controls, and in 38 healthy volunteers. We assessed the plasma levels of CD62P and CD40L soluble forms. In patients after stroke a significantly lower increment in CD62P surface expression (p < 0.01) and higher increments in both CD40L platelet surface expression (p < 0.01) and monocyte-platelet aggregate percentage (p < 0.01) were found at every studied time point, as compared with the control groups. Plasma levels of soluble CD62P (sCD62P) and soluble CD40L (sCD40L) were increased in stroke subjects in both the acute and the subacute phase of the stroke and they dropped to levels observed in controls at day 90 after the ischaemic incident. In all studied groups a positive correlation was noted between plasma levels of sCD62P and sCD40L. In conclusion, while at 3-month follow-up the levels of soluble forms normalize in stroke patients, the profile of platelet reactivity in response to activation with TRAP differs from that observed in the controls despite the secondary stroke prevention.

To vaccinate or not to vaccinate - BNT162b2 seroconversion rate and side effects among Polish healthcare workers.

OBJECTIVES: The study aimed to analyze the effect of BNT162b2 vaccination among Polish healthcare workers in terms of serologic response and adverse events. MATERIAL AND METHODS: A questionnaire survey covered data in the period January 1-March 31, 2021 gathered in 2 hospitals in Wielkopolska, Poland. Additionally, serological analysis (SARS-CoV-2 anti-S protein IgG) was performed. RESULTS: A total of 617 medical workers were vaccinated with BNT162b2 (Comirnaty, Pfizer). Data from the questionnaires were received from all of the staff after the first and the second dose. No severe side effects were observed. The most common side effect following the first and second doses of vaccination was pain at the injection site. After the first dose, 3 (1.4 %) women aged 18-55 years, 5 women (3.9 %), and 3 men (8.3 %) aged >55 years had negative SARS-CoV-2 anti-S protein IgG result. After the second dose, all those who agreed to have antibodies tested responded to vaccination with positive SARS-CoV-2 anti-S protein IgG results. CONCLUSIONS: Vaccination tolerance was good in the studied population; no severe side effects were observed. After the second dose, all tested healthcare workers responded to vaccination with antibody production. Int J Occup Med Environ Health. 2022;35(6):761-66.