Enhancement of Radiation Effect on Cancer Cells by Gold-pHLIP

Previous research has shown that gold nanoparticles can increase the effectiveness of radiation on cancer cells. Improved radiation effectiveness would allow lower radiation doses given to patients, reducing adverse effects; alternatively, it would provide more cancer killing at current radiation doses. Damage from radiation and gold nanoparticles depends in part on the Auger effect, which is very localized; thus, it is important to place the gold nanoparticles on or in the cancer cells. In this work, we use the pH-sensitive, tumor-targeting agent, pH Low-Insertion Peptide (pHLIP), to tether 1.4-nm gold nanoparticles to cancer cells. We find that the conjugation of pHLIP to gold nanoparticles increases gold uptake in cells compared with gold nanoparticles without pHLIP, with the nanoparticles distributed mostly on the cellular membranes. We further find that gold nanoparticles conjugated to pHLIP produce a statistically significant decrease in cell survival with radiation compared with cells without gold nanoparticles and cells with gold alone. In the context of our previous findings demonstrating efficient pHLIP-mediated delivery of gold nanoparticles to tumors, the obtained results serve as a foundation for further preclinical evaluation of dose enhancement

Congenital nephrotic syndrome

Congenital nephrotic syndrome (CNS) is a rare kidney disorder characterized by heavy proteinuria, hypoproteinemia, and edema starting soon after birth. The majority of cases are caused by genetic defects in the components of the glomerular filtration barrier, especially nephrin and podocin. CNS may also be a part of a more generalized syndrome or caused by a perinatal infection. Immunosuppressive medication is not helpful in the genetic forms of CNS, and kidney transplantation is the only curative therapy. Before the operation, management of these infants largely depends on the magnitude of proteinuria. In severe cases, daily albumin infusions are required to prevent life-threatening edema. The therapy also includes hypercaloric diet, thyroxin and mineral substitution, prevention of thrombotic episodes, and prompt management of infectious complications. The outcome of CNS patients without major extrarenal manifestations is comparable with other patient groups after kidney transplantation

Court Cases, Cultural Expertise and ´Female Genital Mutilation' in Europe

This chapter discusses adjudication, expertise, and cultural difference as it appears in criminal court cases concerning female genital cutting (FGM) in the EU, as reported in a 2015 comparative overview. It begins with the distinction between typical and atypical FGM cases; a distinction that connects court cases to the cultural realities of the practicing communities, suggesting that the lack of cultural knowledge can cause unnecessary suffering to families and/or individuals who wrongly undergo prosecution in alleged FGM cases. A contrario, the intervention of experts in FGM court cases could be a positive approach to assessing the legitimacy of public intervention in certain cases

Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review

This review deals with podocyte proteins that play a significant role in the structure and function of the glomerular filter. Genetic linkage studies has identified several genes involved in the development of nephrotic syndrome and contributed to the understanding of the pathophysiology of glomerular proteinuria and/or focal segmental glomerulosclerosis. Here, we describe already well-characterized genetic diseases due to mutations in nephrin, podocin, CD2AP, alpha-actinin-4, WT1, and laminin β2 chain, as well as more recently identified genetic abnormalities in TRPC6, phospholipase C epsilon, and the proteins encoded by the mitochondrial genome. In addition, the role of the proteins which have shown to be important for the structure and functions by gene knockout studies in mice, are also discussed. Furthermore, some rare syndromes with glomerular involvement, in which molecular defects have been recently identified, are briefly described. In summary, this review updates the current knowledge of genetic causes of congenital and childhood nephrotic syndrome and provides new insights into mechanisms of glomerular dysfunction

FAT1 mutations cause a glomerulotubular nephropathy

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function

Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders.

Congenital nephrotic syndrome is clinically and genetically heterogeneous. The majority of cases can be attributed to mutations in the genes NPHS1, NPHS2, and WT1. By homozygosity mapping in a consanguineous family with isolated congenital nephrotic syndrome, we identified a potential candidate region on chromosome 3p. The LAMB2 gene, which was recently reported as mutated in Pierson syndrome (microcoria-congenital nephrosis syndrome; OMIM #609049), was located in the linkage interval. Sequencing of all coding exons of LAMB2 revealed a novel homozygous missense mutation (R246Q) in both affected children. A different mutation at this codon (R246W), which is highly conserved through evolution, has recently been reported as causing Pierson syndrome. Subsequent LAMB2 mutational screening in six additional families with congenital nephrotic syndrome revealed compound heterozygosity for two novel missense mutations in one family with additional nonspecific ocular anomalies. These findings demonstrate that the spectrum of LAMB2-associated disorders is broader than previously anticipated and includes congenital nephrotic syndrome without eye anomalies or with minor ocular changes different from those observed in Pierson syndrome. This phenotypic variability likely reflects specific genotypes. We conclude that mutational analysis in LAMB2 should be considered in congenital nephrotic syndrome, if no mutations are found in NPHS1, NPHS2, or WT1

Cervikales Lymphangiom in einem männlichen Erwachsenen - ein Fallbericht

Lymphangiome im HNO-Bereich stellen eine seltene, gutartige Entität dar. Etwa 90% der Fälle manifestieren sich bei Geburt oder während der ersten zwei Lebensjahre und nur Einzelfälle im Jugend- oder Erwachsenenalter sind in der Literatur beschrieben. Ein 25-jähriger Mann stellte sich 6/2012 mit einer seit 8 Wochen spontan aufgetretenen, progredienten linksseitigen Halsschwellung vor. Spiegelbefundlich zeigte sich eine Tonsillenasymmetrie links und eine weiche, schmerzlose Schwellung der Parotisregion links. Im Hals-Ultraschall konnte eine polyzystische Raumforderung in und an der Gld. Parotis nachgewiesen werden. Im MR-Hals/Angiographie wurde der Verdacht auf einen bis nach parapharyngeal reichenden, verdrängend wachsenden Tumor geäußert; gut vereinbar mit einem Hämangiom oder Lymphangioms. Bei Größenprogredienz und dem klinischen Verdacht eines Lymphangioms erfolgte die chirurgische Tumorentfernung. In der Histologie bestätigte sich der Befund eines Lymphangioms. Postoperativ litt der Patient unter einer Facialisparese links (House-Brackmann III°). Ca. 2 Monate später stellte er sich mit einer neuen Schwellung nuchal links vor. Bei sonographischem und radiologischem Verdacht eines Lymphangiomrezidivs folgte die operative Resektion in toto. Im regelmäßigen klinischen follow-up ist der Patient bisher rezidivfrei und die Fazialisparese komplett regredient.Lymphangiome bei Erwachsenen stellen eine seltene Entität dar. Bei vorbestehender Fehlbildung des Lymphsystems werden als möglicher Auslöser für eine plötzliche Größenzunahme Traumata diskutiert; dies war hier nicht zu eruieren. Abhängig von Lokalisation und Ausdehnung muss individuell ein geeignetes Behandlungskonzept mit chirurgischem Ansatz, konservativ (z.B. Sklerotherapie) oder aber kombiniert gewählt werden.Der Erstautor gibt keinen Interessenkonflikt an