Background: Array‐based genomic analysis is a gold standard for the detection of copy number variations (CNVs) as an important source of benign as well as pathogenic variations in humans. The introduction of chromosomal microarray (CMA) has led to a significant leap in diagnostics of genetically caused congenital malformations and neurodevelopmental disorders, with an average diagnostic yield of 15%. Here, we present our experience from a single laboratory perspective in four years’ postnatal clinical CMA application.Methods: DNA samples of 430 patients with congenital anomalies and/or neurodevelopmental disorders were analyzed by comparative genome hybridization using oligonucleotide‐based microarray platforms. Interpretation of detected CNVs was performed according to current guidelines. The detection rate (DR) of clinically significant findings (pathogenic/likely pathogenic CNVs) was calculated for the whole cohort and isolated or combined phenotypic categories.Results: A total of 140 non‐benign CNVs were detected in 113/430 patients (26.5%). In 70 patients at least one CNV was considered clinically significant thus reaching a diagnostic yield of 16.3%. The more complex the phenotype, including developmental delay/intellectual disability (DD/ID) as a prevailing feature, the higher the DR of clinically significant CNVs is obtained. Isolated congenital anomalies had the lowest, while the “dysmorphism plus” category had the highest diagnostic yield.Conclusion: In our study, CMA proved to be a very useful method in the diagnosis of genetically caused congenital anomalies and neurodevelopmental disorders. DD/ID and dysmorphism stand out as important phenotypic features that significantly increase the diagnostic yield of the analysis.

Recent scientific data recognize the B7-H3 checkpoint molecule as a potential target for immunotherapy of pediatric solid tumors (PSTs). B7-H3 is highly expressed in extracranial PSTs such as neuroblastoma, rhabdomyosarcoma, nephroblastoma, osteosarcoma, and Ewing sarcoma, whereas its expression is absent or very low in normal tissues and organs. The influence of B7-H3 on the biological behavior of malignant solid neoplasms of childhood is expressed through different molecular mechanisms, including stimulation of immune evasion and tumor invasion, and cell-cycle disruption. It has been shown that B7-H3 knockdown decreased tumor cell proliferation and migration, suppressed tumor growth, and enhanced anti-tumor immune response in some pediatric solid cancers. Antibody-drug conjugates targeting B7-H3 exhibited profound anti-tumor effects against preclinical models of pediatric solid malignancies. Moreover, B7-H3-targeting chimeric antigen receptor (CAR)-T cells demonstrated significant in vivo activity against different xenograft models of neuroblastoma, Ewing sarcoma, and osteosarcoma. Finally, clinical studies demonstrated the potent anti-tumor activity of B7-H3-targeting antibody-radioimmunoconjugates in metastatic neuroblastoma. This review summarizes the established data from various PST-related studies, including in vitro, in vivo, and clinical research, and explains all the benefits and potential obstacles of targeting B7-H3 by novel immunotherapeutic agents designed to treat malignant extracranial solid tumors of childhood.

Objectives: Inflammatory cytokines like tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, and IL-6 can cause brain injury, slow recovery, and adverse effects (ADEs) in ischemic stroke (IS) patients treated with recombinant tissue plasminogen activator (rtPA). We explored the relationship between selected polymorphisms within TNF-alpha, IL-1 beta and IL-6 genes, and post-IS outcome and ADEs in patients treated with rtPA.Methods: One hundred and sixty-six patients with IS treated with rtPA were included in this study. The modified Rankin Scale (mRS) was used to assess functional recovery 3 months after IS likewise thrombolytic therapy efficacy. Patients were classified into groups with favorable (0-1) or poor recovery based on their mRS score at the ninetieth day post-IS. During hospitalization, ADEs following rtPA were monitored. TNF-alpha-308 G/A (rs1800629), IL-1 beta-511 G/A (rs16944), and IL-6-174 G/C (rs1800795) polymorphisms were genotyped using Real-Time PCR. SPSS software version 22.0 was used for statistical analyses.Results: Patients with the TNF-alpha-308 G/A GG genotype had a higher mean NIHSS value at admission (12.75 +/- 5.176) than those carrying A-allele (10.56 +/- 3.979;p = 0.016). Individuals with the CC genotype of the IL-6-174 G/C polymorphism had significantly lower NIHSS scores (8.79 +/- 5.053) than those with G-allele (12.06 +/- 6.562) 24 hours after rtPA (p = 0.050). Patients with the GG genotype of the IL-6-174 G/C polymorphism had a significantly poorer outcome (p = 0.024; OR = 2.339; 95%CI 1.121-4.880), while patients who were G-allele carriers of the Il-6-174 G/C polymorphism and had the AA genotype of the IL-1 beta-511 G/A polymorphism were statistically significantly more likely to experience hemorrhagic transformation (p = 0.046; OR = 2.7273; 95%CI 1.0414-7.1426).Conclusion: GG genotype of the IL-6-174 G/C polymorphism is associated with poor recovery after IS treated with rtPA therapy.

Secondary peritonitis (SP) remains a major clinical challenge due to its high complication rates and it often results in sepsis and multi-organ dysfunction. This study investigated the association between four nitric oxide synthase (NOS) single-nucleotide polymorphisms (SNPs)—NOS3 c.-786T>C (rs2070744), NOS3 c.894G>T (rs1799983), NOS3 27 bp variable number tandem repeat (VNTR) (rs61722009), and NOS2 (rs2297518)—and sepsis-related complications in 202 patients with SP. Demographic and baseline clinical characteristics, Acute Physiology and Chronic Health Evaluation (APACHE) II scores, Mannheim Peritonitis Index, and complications (multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF), acute respiratory distress syndrome (ARDS), and sepsis) were analyzed for associations with the NOS gene variants. Haplotype analysis was also performed. No SNP showed an association with in-hospital mortality. However, the NOS3 c.-786T>C TT genotype was significantly associated with an increased risk of MOF (p = 0.008), and remained independently associated after multivariate adjustment (p_MOF = 0.006). The T4bG haplotype was significantly more frequent among patients with MODS (p = 0.026), MOF (p = 0.048), and sepsis (p = 0.018). These findings suggest that NOS gene variants, particularly NOS3 c.-786T>C and the T4bG haplotype, may potentially serve as biomarkers for risk stratification in critically ill patients.

Objectives: Thrombolytic therapy with Alteplase is the standard treatment for eligible patients with acute ischemic stroke, but clinical response and hemorrhagic complications vary considerably among patients. This study aimed to investigate whether selected polymorphisms within the MMP-8 and MMP-9 genes are associated with baseline stroke severity, functional recovery, and hemorrhagic complications after thrombolytic therapy. Materials and Methods: Over a 24-month period, 166 Caucasian patients with acute ischemic stroke treated with intravenous Alteplase were prospectively enrolled. Genotyping was performed for MMP-9 rs3918241 and rs3918249, and MMP-8 rs1940475 and rs11225395 polymorphisms. Associations with neurological severity, functional outcome, and postthrombolytic hemorrhagic complications were analyzed. Haplotype analysis was performed for the investigated MMP-8 and MMP-9 variants. Results: No significant associations were observed between the investigated MMP-9 polymorphisms and functional recovery or hemorrhagic complications after Alteplase treatment. However, carriers of the MMP-9 rs3918249 T allele had lower National Institutes of Health Stroke Scale scores at admission, suggesting a less severe initial clinical presentation. For MMP-8 , patients who developed symptomatic intracerebral hemorrhage were significantly more likely to carry the rs1940475 TT genotype ( P = 0.032; odds ratio = 5.10; 95% CI: 1.27-20.56). Haplotype analysis showed strong linkage disequilibrium between rs1940475 and rs11225395, and the TG haplotype was significantly more frequent in patients without hemorrhagic transformation than in those with hemorrhagic transformation. Conclusions: The investigated MMP-9 polymorphisms were not associated with postthrombolytic recovery or hemorrhagic complications. In contrast, MMP-8 rs1940475 and MMP-8 haplotypes may be related to hemorrhagic risk after Alteplase therapy.