No Association of Polymorphisms in the Genes Encoding Interleukin-6 and Interleukin-6 Receptor Subunit Alpha with the Risk of Keloids in Polish Patients.

A keloid is a benign fibroproliferative hypertrophy of scar tissue that extends outside the original wound and invades adjacent healthy skin. Keloid formation is thought to be a complex process including overactivity of the interleukin-6 signaling pathway and genetic susceptibility. The aim of the study was to investigate possible associations between rs1800797, rs1800796, and rs1800795 polymorphisms in the promoter of the IL6 gene encoding interleukin-6 and the rs2228145 polymorphism in the IL6R gene encoding the interleukin-6 receptor subunit alpha with the predisposition to keloids in Polish patients. The genetic polymorphisms were identified either using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) or sequencing of samples of genomic DNA extracted from blood leukocytes of 86 adult patients with keloids and 100 newborns comprising a control group. No significant differences in the distributions of IL6 or IL6R alleles or genotypes were found between keloid patients and newborn controls. There were also no significant differences between both groups in the distribution of IL6 haplotypes. The IL6 rs1800797, rs1800796 and rs1800795 and IL6R rs2228145 polymorphisms were not found to predispose individuals in the study group to keloids. IL6 promoter haplotypes were not found to be associated with a higher risk of keloids in the studied group.

Association of the IL1A and IL6 polymorphisms with posttraining changes in body mass, composition, and biochemical parameters in Caucasian women.

Polymorphisms located in IL1A and IL6 are promising markers of obesity-related traits; however, studies concerning their potential impact on the effectiveness of lifestyle interventions are lacking. Therefore, the aim was to examine the association between the polymorphic sites located in IL1A (rs1800587) and IL6 (rs1800795, rs1800796, and rs1800797) and the body's response to a 12-week training program. We studied the genotype distribution in a group of 168 Caucasian females in whom body mass and composition parameters, the lipid profile, and glucose levels were measured before and after the exercise period. Our results showed that carriers of the IL1A rs1800597 CC genotype exhibited a significant decrease in total body water (TBW) in response to training (p = 0.045). Additionally, carriers of the IL6 rs1800797 GG and GA genotypes demonstrated a posttraining decrease in body mass index (BMI) (p = 0.039). Haplotype analysis revealed that only rare haplotypes, namely, GGA, CGG and CCG (rs1800795, rs1800796, and rs1800797, respectively), were linked to changes in phenotype, yet assessing individual haplotype effects was not possible. Studies of the interactions between these genes showed that carrying the TC-GG genotype (rs1800587-rs1800795 and rs1800587-rs1800796) may be associated with greater posttraining decreases in fat mass percentage (%FM) and fat-free mass (FM). Carriers of the CC-CG genotype (rs1800587-rs1800795) had significantly greater changes in triglycerides (TGL) over the training period. Our study showed that the IL1A and IL6 genotypes, either individually, in haplotype, or in gene-gene combination, may modify training-induced changes in body mass, composition, glucose levels, and the lipid profile in healthy women.

Clinical impact of primary tumour 123ImIBG response to induction chemotherapy in children with high-risk neuroblastoma.

BACKGROUND: More than 50% children with high-risk neuroblastoma (HR-NBL) experience disease progression, which we hypothesise is due to non-response of primary tumour to treatment. Current imaging techniques are unable to characterise response in primary tumour (necrotic versus viable tissue) at diagnosis or follow-up. OBJECTIVES: Compare clinico-histological characteristics between primary 123ImIBG-avid tumours that became entirely 123ImIBG-non-avid (responders) after induction chemotherapy (IC) versus primary 123ImIBG-avid tumour that remained 123ImIBG-avid (non-responders). METHODS: Retrospective review of clinico-radiological data of children diagnosed with 123ImIBG-avid HR-NBL at our centre (2005-2016). Patients received Rapid COJEC IC and two additional courses of TVD if metastatic response was inadequate. Primary tumour 123ImIBG response was assessed qualitatively as positive, negative or intermediate at diagnosis and after IC. Post-surgical histopathology slices were marked considering percentage of viable tissue. RESULTS: Sixteen of 61 patients showed complete primary tumour 123ImIBG response, 20 partial response, while 25 no response. There was no statistically significant difference between clinical demographics of complete responders and group of non- or partial responders. Mean percentage of viable tumour cells was higher in non-responders than in complete responders (44.6% vs 20.6%; p = 0.05). Five-year EFS was significantly higher in complete responders than non-responders (43 ± 15% vs 7 ± 6%; p < 0.005). CONCLUSIONS: 123ImIBG response in primary HR-NBL correlates with amount of necrotic tissue, skeletal metastatic 123ImIBG response and outcome. An entirely 123ImIBG non-avid tumour can still harbour viable tumour cells. Therefore, our findings do not support utility of primary tumour 123ImIBG response in decision making regarding residual tumour surgery. Combining both, primary and metastatic 123ImIBG response will improve interpretability of clinical trial results.

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux.

BACKGROUND: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood. METHODS: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry. RESULTS: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P=6.35×10-8) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1, and WNT5A). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P=1.86×10-9). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis. CONCLUSIONS: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.

Transcriptome Profile of Human Fibroblasts in an Ex Vivo Culture.

Implantation of autologous fibroblasts is a method used to correct age-related changes in facial skin. The aim of this study was to establish the optimal population of cultured human fibroblasts according to the organization of the extracellular matrix in the dermis. Transcriptome profile analysis of cells derived from three consecutive passages indicated that fibroblasts after the second passage were the population with the greatest number of upregulated genes encoding the critical biological processes responsible for skin regeneration, such as extracellular matrix organization, collagen fibril organization, and cell adhesion. Furthermore, genes encoding proteinases responsible for the degradation of dermal extracellular matrix proteins were noticeably downregulated at this stage of culture. Autologous fibroblasts seem to be an optimal and safe biological filler for the renewal of all skin structures.

Polymorphism of Interleukin 1B May Modulate the Risk of Ischemic Stroke in Polish Patients.

Background and Objectives: Inflammation plays a crucial role in the pathophysiology of ischemic stroke (IS). Interleukin-1B and interleukin-1 receptor antagonists are key factors in inflammatory processes. Aims: The aims of our study were to evaluate the relationship between genetic variation in interleukin-1B (IL1B) rs1143627 and interleukin-1 receptor antagonist (IL1RN) variable-number-tandem-repeats (VNTR), and overall IS and subtype prevalence rates. Materials and Methods: The analysis included 147 hospitalized Polish patients with IS diagnosed using conventional criteria. The control group consisted of 119 healthy subjects. Genotypes were determined by polymerase chain reaction. Results: A significant association between rs1143627 and stroke was found. The -31C IL1B polymorphism showed an association with overall IS, OR = 2.30 (1.36-3.87) p = 0.020. An association was also detected for LVI (large vessel infarction) subtypes of stroke. After risk factor adjustment (age, diabetes mellitus, dyslipidemia), the C allele was found to be an independent risk factor for LVI, OR = 1.99 (1.05-3.79) p = 0.036. Significant association was not observed between IL1RN alleles and IS. Conclusions: Our results suggest that the C allele of IL1B rs1143627 may be associated with susceptibility to overall IS and LVI subtypes of stroke in the Polish population.

Evidence for the efficacy of immunotherapy in children with high-risk neuroblastoma.

Neuroblastoma is the most common extra-cranial malignancy of childhood, with the highest incidence in children younger than 4 years. The prognosis depends on many factors, such as age at diagnosis, stage of disease and molecular genetic subtype. More than 50% of children who present with the disease are deemed to have high-risk neuroblastoma. The standard therapy for children with high-risk neuroblastoma consists of intensive chemotherapy, surgery, radiotherapy, myeloablative consolidation with autologous haematopoietic stem cell rescue followed by the treatment of minimal residual disease with 13-cis-retinoic acid. Unfortunately, more than half of the patients relapse regardless of the treatment intensity. Combined therapy with monoclonal antibodies (anti-GD2), intravenous interleukin-2 (Il-2), intravenous granulocyte-macrophage colony-stimulating factor (GM-CSF) and oral 13-cis-retinoic acid have been proved to be effective in some randomised trials. A better understanding of the underlying immunological processes in therapy with anti-GD2 antibodies will allow its success to be evaluated more accurately and direct future endeavours. Nevertheless, the long-term benefit of this treatment approach needs to be established.

The Impact of Different Types of Physical Effort on the Expression of Selected Chemokine and Interleukin Receptor Genes in Peripheral Blood Cells.

This study aimed to assess the post-effort transcriptional changes of selected genes encoding receptors for chemokines and interleukins in young, physically active men to better understand the immunomodulatory effect of physical activity. The participants, aged 16-21 years, performed physical exercise tasks of either a maximal multistage 20 m shuttle-run test (beep test) or a repeated speed ability test. The expression of selected genes encoding receptors for chemokines and interleukins in nucleated peripheral blood cells was determined using RT-qPCR. Aerobic endurance activity was a positive stimulant that induced increased expression of CCR1 and CCR2 genes following lactate recovery, while the maximum expression of CCR5 was found immediately post-effort. The increase in the expression of inflammation-related genes encoding chemokine receptors triggered by aerobic effort strengthens the theory that physical effort induces sterile inflammation. Different profiles of studied chemokine receptor gene expression induced by short-term anaerobic effort suggest that not all types of physical effort activate the same immunological pathways. A significant increase in IL17RA gene expression after the beep test confirmed the hypothesis that cells expressing this receptor, including Th17 lymphocyte subsets, can be involved in the creation of an immune response after endurance efforts.

TTN Variants Are Associated with Physical Performance and Provide Potential Markers for Sport-Related Phenotypes.

TTN encodes the third myofilament, titin, which plays structural, mechanical, regulatory, and developmental roles in sarcomeres. The aim of this research was to determine the interaction between novel and previously described TTN variants and athletic performance, as well as competition level, in Caucasians. Firstly, 100 athletes and 47 controls were recruited, and whole-genome sequencing was performed. Secondly, 348 athletes (108 endurance, 100 sprint/power, 140 mixed-sport athletes) and 403 volunteers were included, and real-time PCR was performed. We found a significant overrepresentation of the rs10497520 CT and TT genotypes in the sprint/power athlete group (95% CI, 1.41-3.66, p = 0.0013). The rs10497520 T carriers were 2.17 times more likely to become sprint/power athletes (95% CI 1.35-3.49, p = 0.0021). We also found that the likelihood of having the TT genotype was higher for the highly elite and sub-elite sprint/power athletes. Possessing at least one TAA (rs10497520, rs55837610, rs72648256) haplotype resulted in an increase in the log-odds ratio by 0.80 (p = 0.0015), 1.42 (p = 0.003), and 0.77 (p = 0.044) for all, highly elite, and sub-elite sprint/power athletes, respectively. We demonstrated that harbouring the rs10497520 T allele, individually and in a haplotype combination, increased the chance of being an elite sprint/power athlete, indicating that this allele may be favourable for sprint/power performance.

Thiopurine S-methyltransferase (TPMT) polymorphisms in children with acute lymphoblastic leukemia, and the need for reduction or cessation of 6-mercaptopurine doses during maintenance therapy: the Polish multicenter analysis.

BACKGROUND: 6-Mercaptopurine (6-MP) is used for the treatment of pediatric acute lymphoblastic leukemia (ALL). Mutations in the TPMT gene may influence the efficacy and safety of 6-MP treatment. This multicenter study investigated the association between TPMT genotype, 6-MP dose adjustments, and the incidence of adverse effects in patients. PROCEDURE: A total of 203 ALL children were genotyped using PCR/allele-specific amplification and PCR/RFLP. The control group consisted of 394 healthy volunteers. RESULTS: The TPMT*3A variant allele was found in 16 patients (15 TPMT*1/*3A, 1 TPMT*3A/*3A) and the TPMT*3C (A719G) allele in 1 patient. No TPMT*2 (G238C) or TPMT*3B (G460A) alleles were detected in the study group. TPMT*3A, TPMT*1 (wild-type), and TPMT*3C alleles were detected at frequencies of 3.94%, 95.81%, and 0.25%, respectively. The genotype and allele distributions were similar in the ALL and control groups. The 6-MP dose was reduced more frequently in patients with TPMT*3A and TPMT*3C alleles, compared with wild-type alleles (P = 0.042). Reductions because of leucopenia with respiratory tract infection, or because of leucopenia, anemia and/or thrombocytopenia were four (P = 0.007) and five (P = 0.03) times more common, respectively. The groups differed with regard to the rates of 6-MP dose reduction (P = 0.028). 6-MP was discontinued more often in patients with TPMT*3A and TPMT*3C alleles (14-fold) as a result of leucopenia, anemia, and/or thrombocytopenia (P = 0.004). CONCLUSIONS: The results indicate that TPMT genotype influences the safety and efficacy of ALL treatment and genotype information may therefore be useful for optimizing 6-MP therapy.

Congenital nasolacrimal duct mucocele--a case report.

Congenital nasolacrimal duct mucocele (CNDM) is a very rare condition in newborns. Prolapse or expansion of the mucocele into the nose may lead to respiratory distress and difficulty in feeding. The triad of cystic medial canthal mass, dilatation of the nasolacrimal duct and a contiguous sub-mucosal nasal mass on computed tomography (CT) is indicative in the diagnosis of CNDM. The case of a five-week-old girl with infected CNDM is described. The authors aim to emphasize the very rare incidence of CNDM in Polish newborns, delayed diagnosis in the case described and the paramount importance of CT of the head for the correct diagnosis and treatment.

"Treasure your exceptions": recent advances in molecular genetics of glomerular disease.

The glomerular filtration barrier consists of endothelial cells, the glomerular basement membrane, and podocytes. The membrane is a highly crosslinked macromolecular meshwork composed of specific extracellular matrix proteins. The adjacent foot processes of podocytes are bridged along their basolateral surfaces by a slit diaphragm (a porous filter structure of nephrin molecules). Recent discoveries of mutations in the range of genes encoding proteins involved in the structure or function of the glomerular filtration barrier have provided new insights into mechanisms of glomerular diseases. In this review, we summarize recent progress in the elucidation of the genetic basis of some glomerulopathies in humans.

[Evaluation of the immune system following splenectomy in childhood: preliminary study]. / Ocena stanu immunologicznego dzieci po splenektomii--doniesienie wstepne.

The authors would like to point out a possibility of immune system disturbances (especially lymphocyte T), severe infection occurring in patients following splenectomy. Five children following splenectomy due to severe spherocytosis were studied. In all children serum level of IgA, IgG, IgM immunoglobulins, phagocytic index, Hamburger count and lymphocyte antigen surface expression CD3, CD4 CD10, CD19, CD20, CD29, CD45RA, CD56 were evaluated. In comparison to control group, median numbers of lymphocyte T CD3 (p < 0.05), lymphocyte CD4 (p < 0.05), lymphocyte T CD4CD29 (p < 0.001) and percentage of cells reacting with z CD4CD45RA (p < 0.001) were significantly lower in splenectomized children, whereas number of NK cells occurred to be noticeable higher (p < 0.001). Immunoglobulins' levels, Hamburger count, phagocytic index and percentage of lymphocyte CD8, CD19 and CD20 did not differ between groups. On the basis of the results, the authors recommend the necessity of routine vaccination in this group of patients against most common pathogens.

[Embryonal rhabdomyosarcoma of the nasopharynx in a 3-year old girl]. / Rhabdomyosarcoma embryonale nosogardla u 3-letniej dziewczynki.

A case of rhabdomyosarcoma embryonal of the nasopharynx in a 3-year-old girl has been described. Clinical manifestations and initial diagnostic difficulties resulting in delay of proper diagnosis were discussed. Division of RMS, etiology, differentiation of the most often applied clinical sign and modern therapeutic opportunities depending on the location, histopathological type, the disease advancement level and the patient's age were described. Late outcome and the initially positive results of the employed treatment were emphasized in the presented case. The authors would like to underline the necessity to apply all imaging methods available (CT scan and MRI), in order to determine the exact site and extensiveness of malignancy which is crucial for evaluation of appropriate treatment and therapy.

How have advances in our understanding of the molecular genetics of paediatric leukaemia led to improved targeted therapies for these diseases?

The term "leukaemia" refers to a large and heterogenous group of diseases, with treatment response and outcome dependent on the specific type of malignancy. New molecular methods allow us to specifically evaluate the type of disorder, and provide treatment of necessary intensity. The aim of this review is to provide insight into the progress in leukaemia treatment that had been possible due to advances in molecular genetics over the last few decades. Those new sophisticated diagnostic methods have allowed us not only to predict patients' prognosis but also to provide a specific therapy depending on the molecular and genetic characteristics of patients. Our review is based on 25 articles regarding novel diagnostic and therapeutic methods as well as prognostic factors, released between 1992 and 2011. Those articles focus mostly on molecular and cytogenetic testing allowing revolutionary methods of patient classification and individual therapy for this highly heterogeneous group of disorders. Implementation of molecular genetic testing to evaluate the type of leukaemia allowed paediatric oncologists and haematologists to adjust the intensity of treatment, improve outcome, minimize toxicity of therapies and considerably lower the risk of side effects. In the last few decades there has been a great improvement in survival among children suffering from haematopoietic malignancies. Progress made in molecular genetics allowed the creation of new treatment protocols that are designed to maintain a high cure rate for children with leukaemia while reducing toxicity.

The significance of molecular studies in the long-term follow-up of children with beckwith- wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is a congenital disorder of imprinting caused by epimutations and mutations affecting two imprinted loci on chromosome 11p15. Its clinical features are heterogeneous, including macrosomia, macroglossia, hemihyperplasia, abdominal wall defects, neonatal hypoglycemia, and increased risk of embryonal tumors such as Wilms tumor, adrenocortical carcinoma, hepatoblastoma, and neuroblastoma. The molecular and clinical heterogeneity of BWS makes the diagnosis challenging, but essential, since different etiologies of BWS have different clinical prognoses - most crucially, patients with gain of maternal methylation at imprinting control region type 1 (ICR1) are at significant risk of Wilms tumor or hepatoblastoma. We present three cases of BWS with different symptomatology and two different molecular diagnoses. The authors emphasize the importance of molecular studies in the long-term follow-up of children with BWS, including refinement of phenotype-genotype correlation and its connection with optimal management and tumor surveillance.

Will therapies that target tumour suppressor genes be useful in cancer treatment?

Human cancers represent one of the biggest challenges for modern societies. By 2020, cancer deaths worldwide could reach 10 million. Therefore, one of the important aims of science research is the improvement of anti-malignant treatment options to mitigate cancer-related morbidity and mortality. This essay summarises current trends and future directions of target tumour suppressor genes therapies based on an example of one of the most promising targets, p53.

Highly effective unconventional management of aspergillosis of the left maxillary sinus in an 11-year-old girl with rhabdomyosarcoma embryonale of the frontal sinus.

Invasive fungal infections are common causes of death in children treated for malignancies, and therefore present an important and growing clinical problem. Fungal invasion usually affects immunocompromised patients, but increased incidences are also associated with intensification of antineoplastic therapy and increased numbers of organ and bone marrow transplantations. Fungal infections in parameningeal and cerebral locations carry high risks of treatment failure. We describe the case of an 11-year-old female patient with rhabdomyosarcoma embryonale of the frontal sinuses with metastases to the neck lymph nodes, treated according to the CWS 2002 protocol for high-risk patients. Left maxillary sinus aspergillosis was diagnosed during chemotherapy following radiotherapy, and 56 days after surgical excision of the tumour. No effect was achieved by use of amphotericin B. Further treatment included intravenous voriconazole at 6 mg per kg body weight every 12 h for 2 weeks, followed by oral voriconazole at 4 mg per kg body weight twice daily for 6 months. Simultaneous excision of necrotic tissues from the nasal cavity, ethmoid bone, maxillary sinus and frontal recess was performed. The sinus was kept open for 3 weeks to allow voriconazole lavage every 12 h for 3 weeks. This unconventional treatment resulted in eradication of sinus aspergillosis and allowed intensive chemotherapy to be continued with no recurrence of aspergillosis.

An insertion/deletion ACE polymorphism and kidney size in Polish full-term newborns.

The number of nephrons is a multifactorial trait controlled by the interaction of environmental factors and genetic variants that influence the extent of branching nephrogenesis during foetal life. A correlation between renal mass and nephron number in newborns allows the use of the total kidney volume at birth as a surrogate for congenital nephron number. Since the renin-angiotensin system plays an important role in renal development we hypothesized that the common, functional insertion/deletion (I/D) polymorphism in the ACE gene might be responsible for the variation in kidney size amongst healthy individuals. We recruited 210 healthy Polish full-term newborns born to healthy women with uncomplicated pregnancies. The kidney volume was measured sonographically. Total kidney volume (TKV) was calculated as the sum of left kidney volume and right kidney volume. TKV was normalized to body surface area (TKV/BSA). The I and D alleles were identified using polymerase chain reaction. TKV/BSA in newborns carrying at least one insertion ACE allele was significantly reduced by approximately 8% as compared with homozygous newborns for the D allele (DD genotype) (105.1±23.6 vs. 114.2±28.2 cm(3)/m(2), p<0.05). The results of this study suggest that I/D ACE polymorphism may account for subtle variation in kidney size at birth, which reflects congenital nephron endowment.

The rationale behind hypofractionated high-dose intensity-modulated radiotherapy in patients with localized prostate cancer: short review.

The use of improved technology has fostered increasing interest in hypofractionated radiation therapy for prostate cancer. There also is convincing evidence that an unusual aspect of prostate cancer radiobiology allow a different approach to dose escalation that is radiobiological in nature. The aim of this paper is to explain the rationale behind hypofractionated high-dose intensity-modulated radiotherapy in patients with localized prostate cancer.