Molecular and cellular pediatrics最新文献

{"title":"Chemotherapy and the pediatric brain.","authors":"Chrysanthy Ikonomidou","doi":"10.1186/s40348-018-0087-0","DOIUrl":"https://doi.org/10.1186/s40348-018-0087-0","url":null,"abstract":"<p><p>Survival rates of children with cancer are steadily increasing. This urges our attention to neurocognitive and psychiatric outcomes, as these can markedly influence the quality of life of these children. Neurobehavioral morbidity in childhood cancer survivors affects diverse aspects of cognitive function, which can include attention, memory, processing speed, intellect, academic achievement, and emotional health. Reasons for neurobehavioral morbidity are multiple with one major contributor being chemotherapy-induced central nervous system (CNS) toxicity. Clinical studies investigating the effects of chemotherapy on the CNS in children with cancer have reported causative associations with the development of leukoencephalopathies as well as smaller regional grey and white matter volumes, which have been found to correlate with neurocognitive deficits.Preclinical work has provided compelling evidence that chemotherapy drugs are potent neuro- and gliotoxins in vitro and in vivo and can cause brain injury via excitotoxic and apoptotic mechanisms. Furthermore, chemotherapy triggers DNA (deoxyribonucleic acid) damage directly or through increased oxidative stress. It can shorten telomeres and accelerate cell aging, cause cytokine deregulation, inhibit hippocampal neurogenesis, and reduce brain vascularization and blood flow. These mechanisms, when allowed to operate on the developing brain of a child, have high potential to not only cause brain injury, but also alter crucial developmental events, such as myelination, synaptogenesis, neurogenesis, cortical thinning, and formation of neuronal networks.This short review summarizes key publications describing neurotoxicity of chemotherapy in pediatric cancers and potential underlying pathomechanisms.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"5 1","pages":"8"},"PeriodicalIF":0.0,"publicationDate":"2018-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-018-0087-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36654375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of S100 proteins in the pathogenesis and monitoring of autoinflammatory diseases.","authors":"Dirk Holzinger,&nbsp;Dirk Foell,&nbsp;Christoph Kessel","doi":"10.1186/s40348-018-0085-2","DOIUrl":"https://doi.org/10.1186/s40348-018-0085-2","url":null,"abstract":"<p><p>S100A8/A9 and S100A12 are released from activated monocytes and granulocytes and act as proinflammatory endogenous toll-like receptor (TLR)4-ligands. S100 serum concentrations correlate with disease activity, both during local and systemic inflammatory processes. In some autoinflammatory diseases such as familial Mediterranean fever (FMF) or systemic juvenile idiopathic arthritis (SJIA), dysregulation of S100 release may be involved in the pathogenesis. Moreover, S100 serum levels are a valuable supportive tool in the diagnosis of SJIA in fever of unknown origin. Furthermore, S100 levels can be used to monitor disease activity to subclinical level, as their serum concentrations decrease with successful treatment.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"5 1","pages":"7"},"PeriodicalIF":0.0,"publicationDate":"2018-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-018-0085-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36523453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision medicine in pediatric oncology.","authors":"Stefan E G Burdach,&nbsp;Mike-Andrew Westhoff,&nbsp;Maximilian Felix Steinhauser,&nbsp;Klaus-Michael Debatin","doi":"10.1186/s40348-018-0084-3","DOIUrl":"https://doi.org/10.1186/s40348-018-0084-3","url":null,"abstract":"<p><p>Outcome in treatment of childhood cancers has improved dramatically since the 1970s. This success was largely achieved by the implementation of cooperative clinical research trial groups that standardized and developed treatment of childhood cancer. Nevertheless, outcome in certain types of malignancies is still unfavorable. Intensification of conventional chemotherapy and radiotherapy improved outcome only marginally at the cost of acute and long-term side effects. Hence, it is necessary to develop targeted therapy strategies.Here, we review the developments and perspectives in precision medicine in pediatric oncology with a special focus on targeted drug therapies like kinase inhibitors and inducers of apoptosis, the impact of cancer genome sequencing and immunotherapy.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"5 1","pages":"6"},"PeriodicalIF":0.0,"publicationDate":"2018-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-018-0084-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36452918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-inflammatory monocytes-interplay of innate and adaptive immunity.","authors":"Georg Varga, Dirk Foell","doi":"10.1186/s40348-018-0083-4","DOIUrl":"10.1186/s40348-018-0083-4","url":null,"abstract":"<p><p>Monocytes are central to our health as they contribute to both hemispheres of our immune system, the innate and the adaptive arm. Sensing signals from the outside world, monocytes govern the innate immunity by initiating inflammation, e.g., through production of IL-1β. Uncontrolled and sustained inflammation, however, leads to auto-inflammatory syndromes and sometimes to autoimmune diseases. Monocytes can be a driving force for the establishment of such diseases when their ability to also contribute to the resolution of inflammation is impaired. It is therefore of vast importance to gain knowledge about the anti-inflammatory mechanisms monocytes can use to participate in downregulation and resolution of inflammation. Here, we summarize some of the known anti-inflammatory mechanisms and features of regulatory monocytes and shed light on their importance in governing innate and adaptive immune responses. Considering anti-inflammatory mechanisms of monocytes will also help to develop new strategies to use monocytes as therapeutic targets in the future.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"5 1","pages":"5"},"PeriodicalIF":0.0,"publicationDate":"2018-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35976288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intrauterine growth restriction - impact on cardiovascular diseases later in life.","authors":"Carlos Menendez-Castro,&nbsp;Wolfgang Rascher,&nbsp;Andrea Hartner","doi":"10.1186/s40348-018-0082-5","DOIUrl":"https://doi.org/10.1186/s40348-018-0082-5","url":null,"abstract":"<p><p>Intrauterine growth restriction (IUGR) is a fetal pathology which leads to increased risk for certain neonatal complications. Furthermore, clinical and experimental studies revealed that IUGR is associated with a significantly higher incidence of metabolic, renal and cardiovascular diseases (CVD) later in life. One hypothesis for the higher risk of CVD after IUGR postulates that IUGR induces metabolic alterations that then lead to CVD.This minireview focuses on recent studies which demonstrate that IUGR is followed by early primary cardiovascular alterations which may directly progress to CVD later in life.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"5 1","pages":"4"},"PeriodicalIF":0.0,"publicationDate":"2018-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-018-0082-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35932597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The potential of antisense oligonucleotide therapies for inherited childhood lung diseases.","authors":"Kelly M Martinovich, Nicole C Shaw, Anthony Kicic, André Schultz, Sue Fletcher, Steve D Wilton, Stephen M Stick","doi":"10.1186/s40348-018-0081-6","DOIUrl":"10.1186/s40348-018-0081-6","url":null,"abstract":"<p><p>Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"5 1","pages":"3"},"PeriodicalIF":2.4,"publicationDate":"2018-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35803345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CISH promoter polymorphism effects on T cell cytokine receptor signaling and type 1 diabetes susceptibility.","authors":"Julia Seyfarth,&nbsp;Heinz Ahlert,&nbsp;Joachim Rosenbauer,&nbsp;Christina Baechle,&nbsp;Michael Roden,&nbsp;Reinhard W Holl,&nbsp;Ertan Mayatepek,&nbsp;Thomas Meissner,&nbsp;Marc Jacobsen","doi":"10.1186/s40348-018-0080-7","DOIUrl":"https://doi.org/10.1186/s40348-018-0080-7","url":null,"abstract":"<p><strong>Background: </strong>Impaired regulatory T cell immunity plays a central role in the development of type 1 diabetes (T1D). Interleukin-2 receptor (IL-2R) signaling is essential for regulatory T cells (T_REG), and cytokine-inducible SH2-containing protein (CIS) regulates IL-2R signaling as a feedback inhibitor. Previous studies identified association of CISH promoter region single nucleotide polymorphisms (SNPs) with susceptibility to infectious diseases.</p><p><strong>Methods: </strong>Here we analyzed allele frequencies of three CISH SNPs (i.e., rs809451, rs414171, rs2239751) in a study of T1D patients (n = 260, onset age < 5 years, duration > 10 years). Minor allele frequencies were compared to a control cohort of the 1000 Genomes Project. Assigned haplotypes were determined for effects on T1D manifestation and severity. Finally, the CISH haplotype influence on cytokine signaling and function was explored in T cells from healthy donors.</p><p><strong>Results: </strong>We detected similar minor allele frequencies between T1D patients and the control cohort. T1D onset age, residual serum C-peptide level, and insulin requirement were comparable between different haplotypes. Only minor differences between the haplotypes were found for in vitro cytokine (i.e., IL-2, IL-7)-induced CIS mRNA expression. STAT5 phosphorylation was induced by IL-2 or IL-7, but no differences were found between the haplotypes. T_REG purified from healthy donors with the two most common haplotypes showed similar capacity to inhibit heterologous effector T cells.</p><p><strong>Conclusions: </strong>This study provides no evidence for an association of CISH promoter SNPs with susceptibility to T1D or severity of disease. In contrast to previous studies, no influence of different haplotypes on CIS mRNA expression or T cell-mediated functions was found.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"5 1","pages":"2"},"PeriodicalIF":0.0,"publicationDate":"2018-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-018-0080-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35803273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preserved in vitro immunoreactivity in children receiving long-term immunosuppressive therapy due to inflammatory bowel disease or autoimmune hepatitis.","authors":"Teresa Schleker,&nbsp;Eva-Maria Jacobsen,&nbsp;Benjamin Mayer,&nbsp;Gudrun Strauss,&nbsp;Klaus-Michael Debatin,&nbsp;Carsten Posovszky","doi":"10.1186/s40348-018-0079-0","DOIUrl":"https://doi.org/10.1186/s40348-018-0079-0","url":null,"abstract":"<p><strong>Background: </strong>Children with inflammatory bowel disease (IBD) or autoimmune hepatitis (AIH) are at risk for severe infections. This is partially a result of their chronic disease condition but, moreover, a side effect of their immunosuppressive therapy. Currently, vaccinations with live vaccines are regarded as contraindicated under immunosuppressive therapy, mainly because of concerns about side effects and a lack of data showing an adequate immune reaction. As there is no systematic study on the individual immunoreactivity under immunosuppressive therapy in this patient group, we analyzed the lymphocyte subgroups and immunoreactivity of lymphocytes in children with IBD or AIH with and without immunosuppressive therapy in vitro.</p><p><strong>Methods: </strong>We collected whole blood samples from 17 children with IBD or AIH on high-level immunosuppression (IS) (group 1) and 8 on low-level IS (group 2) in comparison with 6 patients without systemic IS (group 3). After Ficoll separation of peripheral mononuclear cells, the samples were analyzed by flow cytometry to determine the lymphocyte subgroups. Furthermore, we stimulated the isolated lymphocytes with phytohemagglutinin (PHA), tetanus antigen, and adenovirus antigen and measured their proliferation by incorporation of H₃-thymidine detected in a beta counter. The statistical evaluation was performed by Kruskal-Wallis test and Mann-Whitney U test using a bilateral level of significance of α = 5%.</p><p><strong>Results: </strong>Patients with low- or high-level IS showed no significant difference in the number of lymphocytes or T cells. Interestingly, IS did not influence the lymphocyte proliferation assay significantly regarding median reaction to PHA, tetanus antigen, or adenovirus antigen between the three groups. However, comparing all immunosuppressed patients to the patients without IS, there was a significant difference towards stimulation with tetanus antigen.</p><p><strong>Conclusions: </strong>Contrary to expectations of a strong influence of IS therapy on the immunoreactivity, this study showed only minor differences between the groups with high-level, low-level, and no IS. Particularly, the in vitro reactivity to adenovirus antigen was nearly the same in all three groups. We assume that-provided a normal distribution and count of lymphocyte subgroups-patients with moderate immunosuppression might be capable of raising an effective immune response to inactivated and live vaccines.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"5 1","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2018-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-018-0079-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35752286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Concepts for a therapeutic prolongation of nephrogenesis in preterm and low-birth-weight babies must correspond to structural-functional properties in the nephrogenic zone.","authors":"Will W Minuth","doi":"10.1186/s40348-017-0078-6","DOIUrl":"https://doi.org/10.1186/s40348-017-0078-6","url":null,"abstract":"<p><p>Numerous investigations are dealing with anlage of the mammalian kidney and primary development of nephrons. However, only few information is available about the last steps in kidney development leading at birth to a downregulation of morphogen activity in the nephrogenic zone and to a loss of stem cell niches aligned beyond the organ capsule. Surprisingly, these natural changes in the developmental program display similarities to processes occurring in the kidneys of preterm and low-birth-weight babies. Although those babies are born at a time with a principally intact nephrogenic zone and active niches, a high proportion of them suffers on impairment of nephrogenesis resulting in oligonephropathy, formation of atypical glomeruli, and immaturity of parenchyma. The setting points out that up to date not identified noxae in the nephrogenic zone hamper primary steps of parenchyma development. In this situation, a possible therapeutic aim is to prolong nephrogenesis by medications. However, actual data provide information that administration of drugs is problematic due to an unexpectedly complex microanatomy of the nephrogenic zone, in niches so far not considered textured extracellular matrix and peculiar contacts between mesenchymal cell projections and epithelial stem cells via tunneling nanotubes. Thus, it remains to be figured out whether disturbance of morphogen signaling altered synthesis of extracellular matrix, disturbed cell-to-cell contacts, or modified interstitial fluid impair nephrogenic activity. Due to most unanswered questions, search for eligible drugs prolonging nephrogenesis and their reliable administration is a special challenge for the future.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"4 1","pages":"12"},"PeriodicalIF":0.0,"publicationDate":"2017-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-017-0078-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35232154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human perinatal immunity in physiological conditions and during infection.","authors":"Gijs T J van Well, Leonie A Daalderop, Tim Wolfs, Boris W Kramer","doi":"10.1186/s40348-017-0070-1","DOIUrl":"10.1186/s40348-017-0070-1","url":null,"abstract":"<p><p>The intrauterine environment was long considered sterile. However, several infectious threats are already present during fetal life. This review focuses on the postnatal immunological consequences of prenatal exposure to microorganisms and related inflammatory stimuli. Both the innate and adaptive immune systems of the fetus and neonate are immature, which makes them highly susceptible to infections. There is good evidence that prenatal infections are a primary cause of preterm births. Additionally, the association between antenatal inflammation and adverse neonatal outcomes has been well established. The lung, gastrointestinal tract, and skin are exposed to amniotic fluid during pregnancy and are probable targets of infection and subsequent inflammation during pregnancy. We found a large number of studies focusing on prenatal infection and the host response. Intrauterine infection and fetal immune responses are well studied, and we describe clinical data on cellular, cytokine, and humoral responses to different microbial challenges. The link to postnatal immunological effects including immune paralysis and/or excessive immune activation, however, turned out to be much more complicated. We found studies relating prenatal infectious or inflammatory hits to well-known neonatal diseases such as respiratory distress syndrome, bronchopulmonary dysplasia, and necrotizing enterocolitis. Despite these data, a direct link between prenatal hits and postnatal immunological outcome could not be undisputedly established. We did however identify several unresolved topics and propose questions for further research.</p>","PeriodicalId":74215,"journal":{"name":"Molecular and cellular pediatrics","volume":"4 1","pages":"4"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s40348-017-0070-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34933272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}