Anti-Cancer and Anti-Inflammatory Properties of Black Garlic.

Black garlic (BG) is a fermented form of garlic (Allium sativum L.), produced at precisely defined temperatures, humidities, and time periods. Although garlic has been used for thousands of years, black garlic is a relatively new discovery. There are many bioactive compounds in black garlic that give it medicinal properties, including anti-inflammatory and anti-cancer properties. In our review article, we present scientific studies examining the anti-inflammatory and anti-cancer effects of black garlic. According to research, this effect is mainly due to the reduction in the production of pro-inflammatory cytokines, as well as the ability to scavenge free oxygen radicals and induce apoptosis. In addition, the phytochemicals contained in it have antiproliferative and antiangiogenic properties and inhibit the growth of cancer cells. Black garlic is a valuable source of biologically active substances that can support anti-inflammatory and anti-cancer therapy. Compared to Allium sativum, black garlic has fewer side effects and is easier to consume.

Influence of dietary and lifestyle factors on levels of inflammatory markers (IL-6, IFN-γ and TNF-α) in obese subjects.

Introduction: The low-grade inflammation occurring in obese individuals leads to many diseases, including cardiovascular disease (CVD). Dietary patterns, food groups or nutrients in a well-balanced diet may reduce the level of pro-inflammatory markers and the risk of obesity-related morbidities. Our study aims to describe three cytokines in obese patients in relation to dietary habits, lifestyle and body composition. Material and methods: Serum samples were collected from 84 obese adult volunteer subjects [body mass index (BMI) ≥ 30 kg/m2] to analyze the concentrations of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ). The subjects were tested by bioelectrical impedance analysis (BIA) and completed a three-day food diary and original questionnaire with the FFQ-6 food consumption frequency questionnaire. Results and conclusions: Higher serum levels of IL-6 and IFN-γ were found in patients with atherosclerosis, but the group was too small for a reliable correlation. Subcutaneous but not visceral adipose tissue correlated positively with IL-6 levels. Dietary factors such as amount of sugars, including galactose and sucrose, in the diet and the frequency of consumption of sweet flavored dairy products correlated positively with the levels of IL-6 and TNF-α, while the frequency of alcohol consumption negatively correlated with the level of IL-6. The greater the frequency of sports, the higher was the level of IL-6. In obese individuals, the level of pro-inflammatory cytokines could predispose to atherosclerosis and is associated with dietary factors and lifestyle.

Most Fractures Treated Nonoperatively in Individuals With Fibrodysplasia Ossificans Progressiva Heal With a Paucity of Flareups, Heterotopic Ossification, and Loss of Mobility.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an ultrarare genetic disorder with episodic and progressive heterotopic ossification. Tissue trauma is a major risk factor for flareups, heterotopic ossification (HO), and loss of mobility in patients with FOP. The International Clinical Council on FOP generally recommends avoiding surgery in patients with FOP unless the situation is life-threatening, because soft tissue injury can trigger an FOP flareup. Surprisingly little is known about flareups, HO formation, and loss of mobility after fractures of the normotopic (occurring in the normal place, distinct from heterotopic) skeleton when treated nonoperatively in patients with FOP. QUESTIONS/PURPOSES: (1) What proportion of fractures had radiographic evidence of union (defined as radiographic evidence of healing at 6 weeks) or nonunion (defined as the radiographic absence of a bridging callus at 3 years after the fracture)? (2) What proportion of patients had clinical symptoms of an FOP flareup because of the fracture (defined by increased pain or swelling at the fracture site within several days after closed immobilization)? (3) What proportion of patients with fractures had radiographic evidence of HO? (4) What proportion of patients lost movement after a fracture? METHODS: We retrospectively identified 36 patients with FOP from five continents who sustained 48 fractures of the normotopic skeleton from January 2001 to February 2021, who were treated nonoperatively, and who were followed for a minimum of 18 months after the fracture and for as long as 20 years, depending on when they sustained their fracture during the study period. Five patients (seven fractures) were excluded from the analysis to minimize cotreatment bias because these patients were enrolled in palovarotene clinical trials (NCT02190747 and NCT03312634) at the time of their fractures. Thus, we analyzed 31 patients (13 male, 18 female, median age 22 years, range 5 to 57 years) who sustained 41 fractures of the normotopic skeleton that were treated nonoperatively. Patients were analyzed at a median follow-up of 6 years (range 18 months to 20 years), and none was lost to follow-up. Clinical records for each patient were reviewed by the referring physician-author and the following data for each fracture were recorded: biological sex, ACVR1 gene pathogenic variant, age at the time of fracture, fracture mechanism, fracture location, initial treatment modality, prednisone use at the time of the fracture as indicated in the FOP Treatment Guidelines for flare prevention (2 mg/kg once daily for 4 days), patient-reported flareups (episodic inflammatory lesions of muscle and deep soft connective tissue characterized variably by swelling, escalating pain, stiffness, and immobility) after the fracture, follow-up radiographs of the fracture if available, HO formation (yes or no) as a result of the fracture determined at a minimum of 6 weeks after the fracture, and patient-reported loss of motion at least 6 months after and as long as 20 years after the fracture. Postfracture radiographs were available in 76% (31 of 41) of fractures in 25 patients and were independently reviewed by the referring physician-author and senior author for radiographic criteria of fracture healing and HO. RESULTS: Radiographic healing was noted in 97% (30 of 31) of fractures at 6 weeks after the incident fracture. Painless nonunion was noted in one patient who sustained a displaced patellar fracture and HO. In seven percent (three of 41) of fractures, patients reported increased pain or swelling at or near the fracture site within several days after fracture immobilization that likely indicated a site-specific FOP flareup. The same three patients reported a residual loss of motion 1 year after the fracture compared with their prefracture status. HO developed in 10% (three of 31) of the fractures for which follow-up radiographs were available. Patient-reported loss of motion occurred in 10% (four of 41) of fractures. Two of the four patients reported noticeable loss of motion and the other two patients reported that the joint was completely immobile (ankylosis). CONCLUSION: Most fractures treated nonoperatively in individuals with FOP healed with few flareups, little or no HO, and preservation of mobility, suggesting an uncoupling of fracture repair and HO, which are two inflammation-induced processes of endochondral ossification. These findings underscore the importance of considering nonoperative treatment for fractures in individuals with FOP. Physicians who treat fractures in patients with FOP should consult with a member of the International Clinical Council listed in the FOP Treatment Guidelines ( https://www.iccfop.org ). LEVEL OF EVIDENCE: Level IV, therapeutic study.

Health-Promoting Properties: Anti-Inflammatory and Anticancer Properties of Sambucus nigra L. Flowers and Fruits.

Sambucus nigra L. has been used for centuries in traditional medicine thanks to its valuable healing properties. The healing properties result from its high content of biologically active compounds, mainly antioxidants, which contribute to its anti-inflammatory and anticancer properties. In our review, we have presented scientific studies evaluating the anti-inflammatory and anticancer effects of extracts and their components from S. nigra L. flowers and fruits. The results of the research show that the effect of antioxidant phytochemicals contained in their composition reduces the level of free radicals and pro-inflammatory cytokines, prevents mutations that increase the risk of cancer development, and inhibits cell proliferation, induction of apoptosis, and changes in intracellular signaling, consequently inhibiting the growth of malignant tumors and the formation of metastases. Flowers and fruits of S. nigra L. are a valuable source of nutraceutical and pharmacological substances that can support prevention and anti-inflammatory and oncological therapy without negative side effects for the patient.

Coincidence of selective immunoglobulin A deficiency in juvenile idiopathic arthritis - a series of three cases.

Immunoglobulin A (IgA) deficiency is the most common primary immunodeficiency in humans, with incidence depending on ethnic background and the highest frequency in Caucasians. Selective IgA deficiency may have an asymptomatic course and constitute a random laboratory finding with no clinical manifestation. There is, however, a group of patients with increased incidence of recurrent upper respiratory tract infections, allergies, asthma, atopic dermatitis and other pathologies connected with IgA deficiency. This group of patients often needs broad-spectrum antibiotic therapy with maximum doses and extended time of treatment as there is no causal treatment for IgA deficiency. An association between IgA deficiency and autoimmune diseases, such as juvenile idiopathic arthritis, has been proved before. Nonetheless, the frequency of co-occurrence of these disorders in an individual as well as the way immunodeficiency may influence the course of juvenile idiopathic arthritis is still undefined, with limited literature on this topic. This article presents case reports of three pediatric patients with confirmed co-occurrence of IgA deficiency and oligoarticular juvenile idiopathic arthritis.

An association of circulating Tregs and Th17 cells producing IL-21 and IL-22 with the ROMA in ovarian cancer patients.

The purpose of the present study was to assess the association of regulatory T cells (Tregs; CD4+ FOXP3+) and helper T lymphocytes (Th17) releasing interleukin (IL)-21 and IL-22, with the Risk of Ovarian Malignancy Algorithm (ROMA). Similar association was made with two additional tumour markers, human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125) from patients serum. The presence of Tregs and Th17 was determined both in the peripheral blood and in the tissue of epithelial ovarian tumors. Mononuclear cells obtained from patient's peripheral blood (PBMCs) and from ovarian tissue were isolated by density gradient centrifugation. As a control group patients who had undergone surgery for infertility without ovarian pathology were selected. The percentage of Tregs and Th17 releasing IL-21 or IL-22 cells from both peripheral blood and tumor tissue was measured by flow cytometry. No differences in demographic parameters like body mass index, age, or gravidity were observed among the studied groups. However, an increased concentration of marker HE4 and value of ROMA was identified in individuals with ovarian cancer when compared with women with cystadenomas. Furthermore, a negative correlation between the ROMA value in the serum and Tregs from the peripheral blood of patients with cystadenoma ovarian tumors was detected. The presented work documents, for the first time, the negative association between peripheral blood Tregs and ROMA evaluation based on the tumour markers present in the serum of women with ovarian cystadenoma. Such an effect might result from the negative impact of Tregs on the inflammation process and on tumorigenesis caused by the persistent inflammation.

Scientific reports concerning the impact of interleukin 4, interleukin 10 and transforming growth factor ß on cancer cells.

Cytokines are signalling proteins generated in most part by immune cells that have critical functions in cellular lifespan. Here we present recent data on three selected anti-inflammatory cytokines: interleukin (IL)-10, IL-4 and transforming growth factor ß (TGF-ß). IL-10 inhibits the synthesis of major pro-inflammatory cytokines, chemokines, and mediates anti-inflammatory reactions. IL-4 is a multifunctional cytokine which plays a crucial role in the regulation of immune responses and is involved in processes associated with development and differentiation of lymphocytes and regulation of T cell survival. Transforming TGF-ß, which in normal cells or pre-cancerous cells, promotes proliferation arrest which represses tumour growth. In this review, we focus on the influence of IL-10, IL-4 and TGF-ß on various types of cancer as well as potential of these selected cytokines to serve as new biomarkers which can support effective therapies for cancer patients. This article is presented based on a review of the newest research results.

Influence of antiphospholipid antibody positivity on glomerular filtration rate markers in a group of systemic sclerosis patients - a 24-month observation.

AIM OF THE STUDY: The aim of the study was the assessment of changes in the glomerular filtration rate (GFR) during long-term observation in a group of systemic sclerosis (SSc) patients with and without chronic antiphospholipid (aPL) antibody positivity. MATERIAL AND METHODS: The observation comprised 50 patients - 23 with diffuse cutaneous SSc - dcSSc and 27 limited cutaneous SSc - lcSSc. After 24 months we assessed 27 patients (9 died, 14 lost follow up); 24 patients (88%) were treated chronically with angiotensin-converting-enzyme inhibitors (ACEIs). Patients were investigated for the presence of aPL: to cardiolipin and to ß2 glycoprotein I in IgM and IgG classes. Serum levels of creatinine (S-Cr), cystatin C and creatinine clearance values were determined in all patients. According to the presence of a significant level of at least one of aPL antibodies, pts were divided into groups: group I aPL positive: 14 patients, group II aPL negative - 13 patients. RESULTS: We did not find significant differences in S-Cr, cystatin C levels and creatinine clearance before and after 24 months of observation between both groups. In follow up observations, the presence of anti-centromere antibodies was significantly more frequent in the aPL positive, as compared to the aPL negative group (p = 0.01). In follow up observations, the level of anticardiolipin antibodies in IgG class was significantly higher in dcSSc compared to lcSSc patients (p = 0.02). CONCLUSIONS: In long-term observation chronic positivity for aPL antibodies does not significantly decrease the GFR in patients with SSc treated with ACEIs.

Indoleamine 2,3-dioxygenase mediates inhibition of virus-specific CD8(+) T cell proliferation by human mesenchymal stromal cells.

BACKGROUND AIMS: Mesenchymal stromal cells (MSCs) exert broad immunomodulatory functions. We recently demonstrated a strong suppressive effect of MSCs on virus-specific CD8(+) T-cell proliferation. Here, we further explored the underlying mechanism. METHODS: The role of indoleamine 2,3-dioxygenase (IDO) in inhibition of virus-specific CD8(+) T-cell proliferation by human MSCs was investigated using a mixed lymphocyte peptide culture assay, IDO intracellular staining and IDO inhibition through 1-methyl-DL-tryptophan (1-MT). Moreover, the influence of the number of passages and the seeding density of MSCs on their IDO expression and immunosuppressive ability were investigated. RESULTS: MSCs with low IDO expression exhibited a reduced suppressive effect on both allo-antigen- and cytomegalovirus (CMV)-specific CD8(+) T-cell proliferation. 1-MT could partially abrogate the suppressive effect. MSCs inhibited CMV-specific CD8(+) T-cell proliferation regardless of the number of passages and the seeding density. IDO expression of MSCs was not significantly affected by the number of passages or the seeding density. In addition, the interferon (IFN)-γ level in the culture system was crucial for MSCs to inhibit the proliferation of CMV-specific CD8(+) T cells. SUMMARY: MSCs inhibit virus-specific CD8(+) T-cell proliferation through IFN-γ-induced IDO activity, resolving current conflicting reports on this issue and indicating the potential need for prophylaxis and surveillance of virus infection in patients treated with MSCs. In addition, our study makes a contribution to the development of MSC potency assay for clinical use.

[Umbilical cord blood as a source of nerve and stem cells]. / Krew pepowinowa jako zródlo komórek nerwowych i macierzystych.

OBJECTIVES: The aim of the study was to assess proliferative ability of the stem cells in the umbilical cord blood and their potential to differentiate in in vitro culture. MATERIAL AND METHODS: The material consisted of 14 samples of umbilical cord blood collected from the umbilical cord vein. Mononuclear cells were isolated using the method of density gradient medium. Next, CD34 cells were isolated from the interphase with the use of the VarioMACS sorter and anti-CD34 antibodies. Long-term cultures were conducted on Iscove's modified Dulbecco medium (IMDM) with addition of granulocyte-macrophage colony stimulating factor (GM-CSF) and nerve growth factor (NGF). Qualitative identification was performed using the May-Grunwald-Giemsy staining method, taking photographs with a confocal microscope, and with the immunoenzymatic method. RESULTS: In our research, CD34+ stem cells constituted 1.16% of the mononuclear cells, and after centrifugation in medium 0.37% of leukocytes in whole umbilical cord blood. Even after 60 days of culture without addition of the growth factors, CD34+ cells were present in the fraction of adherent cells. After stimulation with GM-CSF and NGF a part of the umbilical cord blood cells were transformed into nerve cells (presence of neuron-specific enolase was shown) and into cells morphologically similar to fibroblast and dendritic cells. CONCLUSIONS: After stimulation with GM-CSF and NGF cytokines, the umbilical cord blood cells proliferate in long-term medium, transform into nerve cells and into cells similar to fibroblast and dendritic cells.

Autoantibodies against gliadin in rheumatoid arthritis and primary Sjögren's syndrome patients.

INTRODUCTION: Patients with rheumatoid arthritis (RA) and those with primary Sjögren's syndrome (pSS), beside non-specific antibodies, present with organ-specific autoantibodies, including those typical of celiac disease (CD). In the pathogenesis of CD, a role is played by anti-tissue transglutaminase, anti-endomysium, and anti-gliadin (AGA) antibodies. CD can be comorbid with RA and pSS. The aim of the study was to evaluate the prevalence of AGA in RA and pSS patients and discussion of their clinical significance. MATERIAL AND METHODS: The study included 121 patients with RA and 30 patients with pSS. IgG AGA were determined by ELISA method. Additionally, the presence of IgG antimitochondrial antibodies (AMA) was determined in all patients. A further observation included patients with AGA. RESULTS: In the RA group, AGA were detected in five patients (4.1%), and in the pSS group - in two patients (6.7%). All patients in the pSS AGA (+) had AMA and autoimmune thyroid disease (AITD). These differences were statistically significant compared to the pSS AGA (-) and AMA (+) group (p=0.002) and the AGA (-) and AITD (+) group (p=0.003). At the time of the study, none of the patients had been diagnosed with CD. CONCLUSIONS: AGA, typical of CD, are significantly more frequently detected in patients with RA and pSS than in the general population. The presence of autoantibodies may have an impact on the clinical picture of the disease and further medical procedures. CD testing is warranted in selected patients.

Prevalence of selected organ-specific autoantibodies in rheumatoid arthritis and primary Sjögren's syndrome patients.

OBJECTIVES: The aim of the study was to investigate the prevalence of selected organ-specific autoantibodies in rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS) patients, and discuss their clinical significance. MATERIAL AND METHODS: The study included 121 RA and 30 pSS patients. Sera were tested for the presence of autoantibodies to thyroid peroxidase (anti-TPO), thyroglobulin (anti-TG), TSH receptor (TRAbs), mitochondrial antigen M2 (AMA-M2-3E) and gliadin-analogous fusion peptides (anti-GAF(3X)) using the ELISA method. Non-organ-specific antibodies were determined: rheumatoid factor in IgM class, anti-citrullinated peptide antibodies and antinuclear antibodies. The occurrence of antibodies was also examined with regards to RA activity. RESULTS: The following autoantibodies were detected in RA patients: anti-TPO - 13 (10.7%), anti-TG - 6 (5%), AMA-M2-3E - 3 (2.5%), anti-GAF(3X) - 5 (4.1%). The respective levels of these autoantibodies in pSS patients were 3 (10%), 2 (6.7%), 4 (13.3%) and 2 (6.7%). Polyautoimmunity was confirmed in 34 RA patients (including 20 cases of autoimmune thyroid disease [AITD]) and in 6 pSS patients (6 cases of AITD). When RA patients were divided into anti-TPO positive and anti-TPO negative groups, we found a statistically significant relationship between groups regarding age and hemoglobin concentration. In pSS patients the anti-TPO positive group was less likely to use immunosuppressive drugs as compared with the anti-TPO negative group. Anti-TPO was significantly more frequently detected in RA + AITD vs. RA, RA + SS + AITD vs. RA and in pSS + AITD vs. pSS patients. CONCLUSIONS: Organ-specific autoantibodies are relatively frequently observed in patients with RA and pSS. Their presence is connected with the clinical picture of the diseases.

Placental Cannabinoid Receptor Expression in Preterm Birth.

Background: The cannabinoid receptor (CBR) plays a significant role in oogenesis, pregnancy, and childbirth. It might also play a significant role in preterm birth (PTB). The aim of the study was to investigate the association between the expression of the CBR in the placenta and the incidence of PTB. Methods: This prospective, observational, multicentre preliminary study was conducted on placental samples obtained from 109 women. The study included 95 patients hospitalized due to the high risk of PTB. They were divided into two groups: Group 1, where the expression of the CBR1 and CBR1a was analyzed, and Group 2, in which we examined CBR2 expression. The control group, that is, Group 3, consisted of 14 women who delivered at term, and their placentas were tested for the presence of all three receptor types (CBR1, CBR1a, and CBR2). Results: The study used reverse transcription and real-time PCR methods to assess the expression of CBRs in the placental tissues. The expression of the CBR2, CBR1, and CBR1a receptors was significantly lower in the placentas of women after PTB compared to those after term births, p = 0.038, 0.033, and 0.034, respectively. Conclusions: The presence of CBR mRNA in the human placental tissue was confirmed. The decreased expression of CBRs could serve as an indicator in predicting PTB.

Expression of lncRNAs NEAT1, PACERR, and GAS5 can be associated with disease activity in rheumatoid arthritis patients.

INTRODUCTION: Long non-coding RNAs (lncRNAs) have long been considered molecular noise within the transcriptome, but over time it has been shown that they perform many important biological functions and are associated with various inflammatory and autoimmune diseases, including rheumatoid arthritis (RA). OBJECTIVES: The aim of this study was to evaluate the association between circulating lncRNAs and RA activity. PATIENTS AND METHODS: The study included 63 patients with well-established RA (median disease duration 12 years), 51.7 (13); mean (SD) aged, 88.9% women and 25 healthy controls (HCs) 51.8 (8.2) aged, 80% women. Quantitative real-time polymerase chain reaction was used to evaluate the plasma concentration levels of 6 lncRNAs: PACERR, NEAT1, HOTTIP, GAS5, MALAT1 and HIX003209. RESULTS: Among the tested molecules, 5 targets (PACERR, NEAT1, HOTTIP, GAS5 and HIX003209) had decreased concentration in RA patients compared to HCs. LncRNAs NEAT1, PACERR, and GAS5 showed differences between the severe disease activity group (the 28 joint disease activity score, DAS28>5.1) and HCs; (P = 0.02, P = 0.003 and P = 0.04, respectively). The multiple linear regression analysis indicated that GAS5 (P = 0.01) had the greatest impact on disease activity based on DAS28. CONCLUSIONS: Circulating plasma lncRNAs may be considered as supporting molecular markers associated with RA activity and may be useful in identifying disease exacerbation.

Characterization of flare-ups and impact of garetosmab in adults with fibrodysplasia ossificans progressiva: a post hoc analysis of the randomized, double-blind, placebo-controlled LUMINA-1 trial.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder, characterized by progressive heterotopic ossification (HO) and painful soft-tissue inflammatory flare-ups. This was a post hoc analysis from a phase 2 (NCT03188666) trial in which adults with FOP received intravenous anti-activin A antibody garetosmab 10 mg/kg or placebo every 4 wk over 28 wk (Period 1), followed by a 28-wk open-label treatment and extension (Periods 2 and 3). Here we describe flare-ups, their relationship to new HO lesions, and the impact of garetosmab on flare-ups. Volume of new HO lesions was measured by CT. Patient-reported flare-ups were defined by any 2 of the following: new onset of pain, swelling, joint stiffness, decrease in movement, or perceived presence of HO. Flare-ups were experienced by 71% (17/24) of placebo-treated patients, 59% (10/17) of whom developed a new HO lesion irrespective of flare-up location; 24% of flare-ups location-matched new HO lesions. Twenty-nine new HO lesions occurred in the placebo cohort by week 28, of which 12 (41%) occurred in the same location as new or ongoing flare-ups. A higher volume of newly formed heterotopic bone (week 28) occurred in placebo-treated patients who had experienced a prior flare-up vs those without (median [Q1:Q3] of 16.6 [12.0:31.1] vs 3.2 cm3). Garetosmab was previously shown to decrease patient-reported flare-up frequency in Period 1; here, garetosmab reduced the median (Q1:Q3) duration of patient-reported flares (15.0 [6.0:82.0] vs 48.0 [15.0:1.00] d) and the severity of flare-ups vs placebo. Frequency of corticosteroid use was numerically reduced in those treated with garetosmab (40.0%) vs placebo (58.3%). In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28 wk, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups, with effects sustained during the entire trial.

Fibrodysplasia ossificans progressiva (FOP) is a very rare genetic disorder caused by mutations in the ACVR1 gene. People with FOP experience growth of new bone in places where bone does not usually develop. Soft tissues (like skeletal muscles) and connective tissues (like tendons and ligaments) are gradually replaced by bone beyond the normal skeleton­a process called heterotopic ossification (HO). People with FOP experience flare-ups, which are painful swellings of the soft tissues. In this clinical study in people with FOP, we looked at the number of flareups, whether flareups were linked to new HO lesions, and the impact of garetosmab (a monoclonal antibody) on flareups. At random, about half the patients received placebo, or inactive drug, with the other half receiving garetosmab, the study drug. Of the patients who received placebo, 71% had flare-ups and 59% percent of those who had flare-ups also had a new HO lesion, which was not always related to the location of the flare-up. We have previously shown that garetosmab reduces the number of flareups patients report. In this study, we show that garetosmab reduces the length and pain severity of flare-ups too. The treatment effects were maintained for the whole study.

[NKT cells: their development, mechanisms and effects of action]. / Komórki NKT: powstawanie, mechanizmy i efekty dzialania.

NKT cells are a heterogeneous subset of T lymphocytes that share surface markers and functional characteristics with both conventional T lymphocytes and natural killer cells. Most NKT cells express a semi-invariant T cell receptor that reacts with glycolipid antigens presented by the CD1d molecule on the surface of antigen-presenting cells. NKT cells can modulate the immune response against infectious agents, autoantigens, tumors, tissue grafts and allergens. NKT cells mediate the activities through their ability to express pro- and anti-inflammatory cytokines that influence the type and magnitude of the immune response. The manuscript summarizes current views on development of NKT cells as well as mechanisms and effects of their action. 

Bioleptin as a useful marker of metabolic status in children with diabetes mellitus type 1.

Introduction: The purpose of our study was tomeasure the level of leptin and biologically active leptin (bioLEP) in children with type 1 diabetes, depending on the duration of diabetes and its degree of metabolic control. Methods: The study included 94 children (58 boys and 36 girls). In a group of children with diabetes, 40 patients were newly diagnosed with type 1 diabetes, 40 children who have diabetes for more than a year (20 with good metabolic control and 20 with poor metabolic control). The control group consisted of 14 healthy children. The serum level of leptin and bioLEP was measured using a sandwich enzyme-linked immunosorbent assay. To our knowledge, this is the first study to describe bioLEP levels among diabetic children with different forms of disease control. Results: Lower levels of leptin were found in children with diabetes compared to healthy children. Furthermore, we found a statistically higher concentration of leptin in the group of children with newly diagnosed diabetes compared to children from the diabetic group with poor metabolic control and lower than healthy children (11.19 vs. 7.84 and 20.94 ng/mL). Moreover, children in the metabolically well-controlled group had statistically lower levels of this hormone (5.11 ng/mL) than healthy children. Leptin concentrations differed significantly between underweight, overweight, and obese children. Discussion: In our study, the level of bioLEP differed significantly between children in the newly diagnosed diabetes group and children in the long-term, poorly controlled diabetes group and healthy controls. Despite many studies published in recent years, many aspects of leptin secretion, action, and mechanisms of its influence on carbohydrate and fat metabolism are still to be clarified. In our opinion, studies evaluating the status of bioLEP in diabetes can also contribute to a better understanding of the mechanisms regulating metabolism.

Garetosmab in fibrodysplasia ossificans progressiva: a randomized, double-blind, placebo-controlled phase 2 trial.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 .

Apoptosis signaling is altered in CD4⁺CD25⁺FoxP3⁺ T regulatory lymphocytes in pre-eclampsia.

The aim of our study was to estimate the surface expressions of CD95 (APO-1/Fas) antigen and the intracellular expressions of anti-apoptotic protein Bcl-2 and pro-apoptotic protein Bax in CD4(+)CD25(+)FoxP3(+) T regulatory lymphocytes (Tregs) as well as the percentage of CD8(+)CD28(+) T cytotoxic cells in peripheral blood of patients with pre-eclampsia in comparison with healthy pregnant women in the third trimester of physiological pregnancy. Twenty-four women with pre-eclampsia and 20 normal third trimester pregnant women were included in the study. The lymphocytes were isolated from peripheral blood samples and labeled with monoclonal antibodies. The expressions of surface antigens and intracellular proteins were estimated using flow cytometry. The population of CD4(+)CD25(+)FoxP3(+) Treg cells was significantly lower in peripheral blood of patients with pre-eclampsia when compared to normal third trimester pregnant women. The percentages of CD4(+)CD25(+)FoxP3(+) Treg cells that express Bcl-2 protein were significantly lower in peripheral blood of patients with pre-eclampsia when compared to healthy pregnant women, whereas the percentages of CD4(+)CD25(+)FoxP3(+) Treg cells with the expressions of Bax protein did not differ in both groups. Moreover, the mean fluorescence intensity (MFI) of Bcl-2 protein in CD4(+)CD25(+)FoxP3(+) Treg cells was significantly lower and MFI of Bax protein significantly higher in pre-eclampsia when compared to the control group. The percentage of CD8(+)CD28(+) T cells did not differ in both studied groups but MFI of CD28 antigen on T CD8(+) cells was significantly higher in pre-eclampsia when compared to the control group. The obtained results suggest that the deficit of CD4(+)CD25(+)FoxP3(+) Treg lymphocytes which is observed in pre-eclampsia may be associated with altered apoptosis signaling in Tregs.