Direct Observation of Cell-Cycle-Dependent Interactions between CTCF and Chromatin

The three-dimensional arrangement of chromatin encodes regulatory traits important for nuclear processes such as transcription and replication. Chromatin topology is in part mediated by the architectural protein CCCTC-binding factor (CTCF) that binds to the boundaries of topologically associating domains. Whereas sites of CTCF interactions are well characterized, little is known on how long CTCF binds to chromatin and how binding evolves during the cell cycle. We monitored CTCF-chromatin interactions by live cell single molecule tracking in different phases of the cell cycle.

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Optimal Affinity Enhancement by a Conserved Flexible Linker Controls p53 Mimicry in MdmX

MdmX contains an intramolecular binding motif that mimics the binding of the p53 tumor suppressor. This intramolecular binding motif is connected to the p53 binding domain of MdmX by a conserved flexible linker that is 85 residues long. The sequence of this flexible linker has an identity of 51% based on multiple protein sequence alignments of 52 MdmX homologs. We used polymer statistics to estimate a global KD value for p53 binding to MdmX in the presence of the flexible linker and the intramolecular binding motif by assuming the flexible linker behaves as a wormlike chain.

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A de novo missense mutation in SLC12A5 found in a compound heterozygote patient with epilepsy of infancy with migrating focal seizures

Abstract

Epilepsy of infancy with migrating focal seizures (EIMFS) is an infantile epileptic encephalopathy characterized by refractory seizures, severe psychomotor delay, and multiple moving epileptic discharges. The genetic etiology of EIMFS is relatively homogeneous with the majority of causative mutations found in KCNT1. Currently, gene panel or whole-exome sequencing is used for testing. To verify the pathogenicity of a variant, co-segregation of the variant and the disorder in a pedigree is important; hence, de novo mutations that are judged to be deleterious may be considered pathogenic because the patients are isolated. In contrast, in cases from non-consanguineous families, genes that cause disorders in a recessive manner should remain as potential candidates. Herein, we performed gene panel sequencing of a patient with EIMFS from a non-consanguineous family, and found a compound heterozygous constellation consisting of a maternally inherited p.Ser399Leu and a de novo p.Arg880Leu in SLC12A5, which encodes the neuronal KCC2 co-transporter. These unique mutations demonstrate gene variants that act in a recessive manner may be pathogenic for patients from non-consanguineous families.

Graphical Abstract

Identification of a novel compound heterozygous constellation (c.[1196C > T(;) 2639G > T]:p.[p.Ser399Leu(;) p.Arg880Leu]) in SLC12A5, which consisted of a maternally inherited mutation (p.Ser399Leu) and a de novo mutation (p.Arg880Leu), in a patient with epilepsy of infancy with migrating focal seizures from a non-consanguineous family.

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Case of disseminated histoplasmosis in a HIV-infected patient revealed by nasal involvement with maxillary osteolysis

Disseminated Histoplasmosis (DH) is a rare manifestation of Acquired Immune Deficiency Syndrome (AIDS) in European countries. Naso-maxillar osteolysis due to Histoplasma capsulatum var. capsulatum (Hcc) is unusua...

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Cataplexy and Its Mimics: Clinical Recognition and Management

Opinion statement

This review describes the diagnosis and management of cataplexy: attacks of bilateral loss of muscle tone, triggered by emotions and with preserved consciousness. Although cataplexy is rare, its recognition is important as in most cases, it leads to a diagnosis of narcolepsy, a disorder that still takes a median of 9 years to be diagnosed. The expression of cataplexy varies widely, from partial episodes affecting only the neck muscles to generalized attacks leading to falls. Moreover, childhood cataplexy differs from the presentation in adults, with a prominent facial involvement, already evident without clear emotional triggers ('cataplectic facies') and 'active' motor phenomena especially of the tongue and perioral muscles. Next to narcolepsy, cataplexy can sometimes be caused by other diseases, such as Niemann-Pick type C, Prader Willi Syndrome, or lesions in the hypothalamic or pontomedullary region. Cataplexy mimics include syncope, epilepsy, hyperekplexia, drop attacks and pseudocataplexy. They can be differentiated from cataplexy using thorough history taking, supplemented with (home)video recordings whenever possible. Childhood narcolepsy, with its profound facial hypotonia, can be confused with neuromuscular disorders, and the active motor phenomenona resemble those found in childhood movement disorders such as Sydenham's chorea. Currently, the diagnosis of cataplexy is made almost solely on clinical grounds, based on history taking and (home) videos. Cataplexy shows remarkable differences in childhood compared to adults, with profound facial hypotonia and complex active motor phenomena. Over time, these severe symptoms evolve to the milder adult phenotype, and this pattern is crucial to recognize when assessing the outcome of uncontrolled case series with potential treatments such as immunomodulation. Symptomatic treatment is possible with antidepressants and sodium oxybate. Importantly, management also needs to involve sleep hygiene advice, safety measures whenever applicable and guidance with regard to the social sequelae of cataplexy.

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Phenotypic and molecular differences between giant cell tumor of soft tissue and its bone counterpart

Abstract

Aims

Giant cell tumor of soft tissue (GCT-ST) is a primary soft tissue neoplasm histologically similar to GCT of bone (GCT-B). Recently, it has been reported that >90% of GCT-B have a driver mutation in H3F3A gene. Since the relationship between GCT-ST and GCT-B is unclear, we compared a series of GCT-ST and GCT-B for the presence of H3F3A mutations and for several immunophenotypic markers.

Methods and Results

Eight cases of GCT-ST were retrieved from our institutional archives. Fifteen GCT-B served as controls. Direct sequencing for H3F3A mutations in coding regions between codons 1 and 42, including the hot spot codons (28, 35 and 37) was performed on DNA extracted from formalin-fixed paraffin-embedded tissue. Tumors were studied immunohistochemically for the expression of CD14, CD33, RANKL, RANK, P63 and for the osteoblastic markers SATB2 and RUNX2. None of the 7 cases of GCT-ST that could be analyzed presented H3F3A mutations, whereas 14 GCT-Bs (93.3%) were mutated. All 8 cases of GCT-ST were positive for RANK and RUNX2, while RANKL and SATB2 were detected only in 2 cases (25%). CD14 was detected only in mononuclear elements, while multinucleated giant cells and part of the mononuclear population expressed CD33. Few mononuclear cells of GCT-ST expressed P63. In comparison, GCT-B showed higher expression of p63 (14/15 cases with >50% of positive mononuclear cells), RANKL and SATB2, while CD14, CD33, RANK and RUNX2 were similarly expressed.

Conclusions

Although similar in the histologic appearance, our results indicate that GCT-ST is immunophenotypically and genetically distinct from GCT-B.

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High grade serous carcinoma (HGSC) of tubo-ovarian origin: recent developments

Abstract

Extra-uterine high-grade serous carcinoma (HGSC) accounts for most of the morbidity and mortality associated with ovarian carcinoma, and is one of the leading causes of cancer death in women. Until recently our understanding of HGSC was very limited, compared to other common cancers, and it has only been in the last 15 years that we have learned how to accurately diagnose this ovarian carcinoma histotype. Since then, however, there has been rapid progress, with identification of a precursor lesion in the fallopian tube, development of prevention strategies for both those with inherited susceptibility (Hereditary Breast and Ovarian Cancer Syndrome) and without the syndrome, and elucidation of the molecular events important in oncogenesis. This molecular understanding has led to new treatment strategies for HGSC, with the promise of more to come in the near future. In this review we focus on these recent changes, including diagnostic criteria/differential diagnosis, primary site assignment, precursor lesions, and the molecular pathology of HGSC.

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