The heterogeneous immune microenvironment in breast cancer is affected by hypoxia-related genes

The immune system constitutes an important first-line defence against malignant transformation. However, cancer mediated immunosuppression inactivates the mechanisms of host immune surveillance. Cancer cells shut down anti-cancer immunity through direct cell–cell interactions with leukocytes and through soluble factors, establishing an immunosuppressive environment for unimpeded cancer growth. The composition of the immunosuppressive microenvironment in breast tumours is not well documented. To address this question, selected immunosuppressive factors were analyzed in tumour specimens from 33 breast cancer patients after surgery. The mRNA expression of selected genes was quantified in fresh tumour samples. Tumour infiltrating leukocytes were characterized by flow cytometry to identify regulatory T cells, myeloid derived suppressor cells, and type 2 macrophages. Statistical analysis revealed several interesting correlations between the studied parameters and clinical features. Overall, a surprisingly high degree of heterogeneity in the composition of the immunosuppressive environment was found across all breast cancer samples which adds to the complexity of this disease. The influence of the hypoxia inducible factors (HIFs) on the immune microenvironment was also addressed. The level of HIFs correlated with hormone receptor status and the expression of several immunosuppressive molecules. Targeting HIFs might not only sensitize breast tumours for radiation and chemotherapies but also interfere with cancer immunosuppression.     

Thermophilic potentially pathogenic amoebae isolated from natural water bodies in Poland and their molecular characterization

The free-living amoebae (FLA) may live in the environment and also within other organisms as parasites and then they are called amphizoic. They are potentially pathogenic for humans and animals and are found in water that is a source of infection. The aim of this study was molecular detection and identification of these FLA in natural water bodies in North-Western Poland to evaluate the risk of the pathogenic amoebae infections. We examined surface water samples collected from 50 sites and first, the tolerance thermic test was performed in order to select thermophilic, potentially pathogenic strains. For molecular identification of FLA, regions of 18S rDNA, 16S rDNA and intergenic spacers were amplified. Acanthamoeba T4 and T16 genotypes of 18S rDNA gene and 18S rDNA of H. vermiformis were detected. We identified two variants of Acanthamoeba T4 genotype, two variants of Acanthamoeba T16 genotype and one variant of H. vermiformis. Identification of the T16 genotype and H. vermiformis in water was for the first time in Poland. Additionally, we made attempts to adapt the RLB method for detection and differentiation of FLA species and strains. PCR seems to be more sensitive than RLB hybridization, though.     

Elevated hemoglobin concentration in 3 children with HFE mutation

Aim

The aim of the study was to analyse the reason of elevated hemoglobin concentration in childhood.

Background

Elevated hemoglobin concentration is a rare abnormality during childhood. There are disorders of hereditary or acquired hyperproliferations of red cells or pseudo high hemoglobin conditions.

Materials and methods

We present 3 asymptomatic children in whom high hemoglobin concentration was diagnosed by a family doctor.

Results

Given that the iron concentration was elevated, genetic testing for HFE mutation was carried out.

Conclusion

Patients presented with HFE mutation might have an increased hemoglobin production.     

Six-month results following treatment of aggressive periodontitis with antimicrobial photodynamic therapy or amoxicillin and metronidazole

Objective

The use of antibacterial photodynamic therapy (aPDT) additionally to scaling and root planing (SRP) has been shown to positively influence the clinical outcomes. However, at present, it is unknown to what extent aPDT may represent a potential alternative to the use of systemic antibiotics in nonsurgical periodontal therapy in patients with aggressive periodontitis (AP). The aim of this study was to evaluate the outcomes following nonsurgical periodontal therapy and additional use of either aPDT or amoxicillin and metronidazole (AB) in patients with AP.

Material and methods

Thirty-six patients with AP displaying at least three sites with pocket depth (PD) ≥6 mm were treated with SRP and either systemic administration of AB for 7 days or with two episodes of aPDT. The following clinical parameters were evaluated at baseline and at 6 months: plaque index (PI), bleeding on probing (BOP), PD, gingival recession (GR) and clinical attachment level (CAL).

Results

Thirty-five patients have completed the 6-month evaluation. At 6 months, mean PD was statistically significantly reduced in both groups (from 5.0?±?0.8 to 3.0?±?0.6 mm with AB and from 5.1?±?0.5 to 3.9?±?0.8 mm with aPDT (p?p?p?p?=?0.03). Both therapies resulted in statistically significant reductions in all parameters compared to baseline.

Conclusion

While both treatments resulted in statistically significant clinical improvements, AB showed statistically significantly higher PD reduction and lower number of pockets ≥7 mm compared to aPDT.

Clinical relevance

In patients with AP, the two times application of aPDT in conjunction with nonsurgical periodontal therapy cannot be considered an alternative to the systemic use of amoxicillin and metronidazole.     

OSU-6162, a Sigma1R Ligand in Low Doses,Can Further Increase the Effects of Cocaine Self-Administration on Accumbal D2R Heteroreceptor Complexes

Neurotoxicity Research - Cocaine was previously shown to act at the Sigma1R which is a target for counteracting cocaine actions. It therefore becomes of interest to test if the monoamine stabilizer...     

Novel engineered TRAIL-based chimeric protein strongly inhibits tumor growth and bypasses TRAIL resistance

Targeting of the TRAIL-DR4/5 pathway was proposed as a promising approach for specific induction of apoptosis in cancer cells. Clinical trials, however, showed inadequate efficiency of TRAIL as a monotherapy. It is a widely held view that the application of multifunctional molecules or combination therapy may lead to substantial improvement. Here, we demonstrate the effectiveness and safety of a novel chimeric protein, AD-O51.4, which is a TRAIL equipped with positively charged VEGFA-derived effector peptides. The study was performed in multiple cancer cell line- and patient-derived xenografts. A pharmacokinetic profile was established in monkeys. AD-O51.4 strongly inhibits tumor growth, even leading to complete long-term tumor remission. Neither mice nor monkeys treated with AD-O51.4 demonstrate symptoms of drug toxicity. AD-O51.4 exhibits a satisfactory half-life in plasma and accumulates preferentially in tumors. The cellular mechanism of AD-O51.4 activity involves both cytotoxic effects in tumor cells and antiangiogenic effects on the endothelium. The presence of DRs in cancer cells is crucial for AD-O51.4-driven apoptosis execution. The TRAIL component of the fusion molecule serves as an apoptosis inducer and a cellular anchor for the effector peptides in TRAIL-sensitive and TRAIL-resistant cancer cells, respectively. The FADD-dependent pathway, however, seems to be not indispensable in death signal transduction; thus, AD-O51.4 is capable of bypassing the refractoriness of TRAIL. AD-O51.4-driven cell death, which exceeds TRAIL activity, is achieved due to the N-terminally fused polypeptide, containing VEGFA-derived effector peptides. The high anticancer efficiency of AD-O51.4 combined with its safety has led to the entry of AD-O51.4 into toxicological studies.     

Management of adenovirus infection in patients after haematopoietic stem cell transplantation: State‐of‐the‐art and real‐life current approach

The important insights gained over the past years in diagnosis and treatment of invasive adenoviral infections provide new paradigms for the monitoring and clinical management of these life‐threatening complications. A meeting was held to discuss and subsequently disseminate the current advances in our understanding of the aetiology/pathogenesis and future treatment options facilitating effective control or prevention of adenovirus‐related diseases in the allogeneic haematopoietic stem cell transplant setting. Invited experts in the field discussed recent progress with leading members of the Infectious Diseases Working Party of the European Society of Blood and Marrow Transplantation at the “State‐of‐the‐art” Meeting in Poznan, Poland, in October 2017. In this review article, the panel of experts presents a concise summary of the current evidence based on published data from the last 15 years and on recent achievements resulting from real‐life practice. The present position statement reflects an expert opinion on current approaches to clinical management of adenovirus infections in patients undergoing allogeneic haematopoietic stem cell transplant and provides graded recommendations of the panel for diagnostic approaches and preemptive therapy reflecting the present state of knowledge.     

Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive organ-specific autoimmune disorder that is characterized by a variable combination of (i) chronic mucocutaneous candidiasis, (ii) polyendocrinopathy and/or hepatitis and (iii) dystrophy of the dental enamel and nails. We analyzed the AIRE (autoimmune regulator) gene in subjects who presented any symptom that has been associated with APECED, including candidiasis and autoimmune endocrinopathy. We observed that 83.3% of patients presented at least two of the three typical manifestations of APECED, while the remaining 16.7% of patients showed other signs of the disease. Analysis of the genetic diagnosis of these subjects revealed that a considerable delay occurs in the majority of patients between the appearance of symptoms and the diagnosis. Overall, the mean diagnostic delay in our patients was 10.2 years. These results suggest that molecular analysis of AIRE should be performed in patients with relapsing mucocutaneous candidiasis for early identification of APECED.     

Association between vascular endothelial growth factor gene polymorphisms and age-related macular degeneration in a Polish population

The pathogenesis of age-related macular degeneration (AMD) is thought to be determined by an array of environmental and genetic factors. The association of increased expression of vascular endothelial growth factor (VEGF) with AMD, especially the wet form of AMD, was reported in several studies. The VEGF gene is highly polymorphic and some of its polymorphisms may affect its expression. In our work, we searched for an association between the −460C> (rs833061) and −634G>C (rs2010963) polymorphisms of the VEGF gene and the occurrence of AMD and its dry and wet forms. We have chosen these polymorphisms because they were shown to be significant in other studies and we previously showed their association with diabetic retinopathy. A total of 401 individuals were enrolled in this study: 136 controls, and 88 patients with dry and 177 with wet AMD. The polymorphisms were determined with DNA from peripheral blood lymphocytes by allele-specific and restriction fragment length polymorphism polymerase chain reaction. The significance of the polymorphisms was assessed by multiple logistic regression, producing odds ratios (ORs) and 95% confidence intervals (CIs). We observed a weak association (OR 2.90) between AMD occurrence and the C/T genotype of the −460C>T polymorphism. An association (OR 3.77) between the C/T genotype of the −460C>T polymorphism and the occurrence of dry AMD was observed. The T/T genotype considerably lowered the risk of dry AMD (OR 0.19). Dry AMD was associated with the C/C genotype of the −634G>C polymorphism (OR 3.68). Another weak association (OR 2.63) was found between the C/T genotype of the −460C>T polymorphism and the occurrence of wet AMD. The occurrence of AMD was correlated with the presence of the combined C/T–G/G genotype of both polymorphisms (OR 2.41), whereas the T/T–G/G and T/T–G/C genotypes exerted a protective effect against the disease (OR 0.22 and 0.48, respectively). The presence of the C/T–G/G and C/T–C/C combined genotypes increased the risk of dry AMD (OR 2.08 and 3.77, respectively), whereas the presence of the T/T–G/G and T/T–G/C genotypes decreased the risk (OR 0.15 and 0.28, respectively). In the wet form of AMD, the combined genotype C/T–G/G slightly favored the disease (OR 2.61) and the T/T–G/G genotype had a protective effect (OR 0.25). Analysis of haplotypes of both polymorphisms yielded similar results for AMD in general as well as for the dry and wet forms of the disease: the CG haplotype favored both forms of AMD, whereas the TG haplotype protected against both forms of AMD. The results obtained indicate that the −460C>T and −634G>C polymorphisms of the VEGF gene may be associated with the dry and wet forms of AMD in a Polish population.