Histone lysine methyltransferase-related neurodevelopmental disorders: current knowledge and saRNA future therapies

Neurodevelopmental disorders encompass a group of debilitating diseases presenting with motor and cognitive dysfunction, with variable age of onset and disease severity. Advances in genetic diagnostic tools have facilitated the identification of several monogenic chromatin remodeling diseases that cause Neurodevelopmental disorders. Chromatin remodelers play a key role in the neuro-epigenetic landscape and regulation of brain development; it is therefore not surprising that mutations, leading to loss of protein function, result in aberrant neurodevelopment. Heterozygous, usually de novo mutations in histone lysine methyltransferases have been described in patients leading to haploinsufficiency, dysregulated protein levels and impaired protein function. Studies in animal models and patient-derived cell lines, have highlighted the role of histone lysine methyltransferases in the regulation of cell self-renewal, cell fate specification and apoptosis. To date, in depth studies of histone lysine methyltransferases in oncology have provided strong evidence of histone lysine methyltransferase dysregulation as a determinant of cancer progression and drug resistance. As a result, histone lysine methyltransferases have become an important therapeutic target for the treatment of different cancer forms. Despite recent advances, we still lack knowledge about the role of histone lysine methyltransferases in neuronal development. This has hampered both the study and development of precision therapies for histone lysine methyltransferases-related Neurodevelopmental disorders. In this review, we will discuss the current knowledge of the role of histone lysine methyltransferases in neuronal development and disease progression. We will also discuss how RNA-based technologies using small-activating RNAs could potentially provide a novel therapeutic approach for the future treatment of histone lysine methyltransferase haploinsufficiency in these Neurodevelopmental disorders, and how they could be first tested in state-of-the-art patient-derived neuronal models

Classification of unknown primary tumors with a data-driven method based on a large microarray reference database

We present a new method to analyze cancer of unknown primary origin (CUP) samples. Our method achieves good results with classification accuracy (88% leave-one-out cross validation for primary tumors from 56 categories, 78% for CUP samples), and can also be used to study CUP samples on a gene-by-gene basis. It is not tied to any a priori defined gene set as many previous methods, and is adaptable to emerging new information

Histone lysine methyltransferase-related neurodevelopmental disorders: current knowledge and saRNA future therapies

Neurodevelopmental disorders encompass a group of debilitating diseases presenting with motor and cognitive dysfunction, with variable age of onset and disease severity. Advances in genetic diagnostic tools have facilitated the identification of several monogenic chromatin remodeling diseases that cause Neurodevelopmental disorders. Chromatin remodelers play a key role in the neuro-epigenetic landscape and regulation of brain development; it is therefore not surprising that mutations, leading to loss of protein function, result in aberrant neurodevelopment. Heterozygous, usually de novo mutations in histone lysine methyltransferases have been described in patients leading to haploinsufficiency, dysregulated protein levels and impaired protein function. Studies in animal models and patient-derived cell lines, have highlighted the role of histone lysine methyltransferases in the regulation of cell self-renewal, cell fate specification and apoptosis. To date, in depth studies of histone lysine methyltransferases in oncology have provided strong evidence of histone lysine methyltransferase dysregulation as a determinant of cancer progression and drug resistance. As a result, histone lysine methyltransferases have become an important therapeutic target for the treatment of different cancer forms. Despite recent advances, we still lack knowledge about the role of histone lysine methyltransferases in neuronal development. This has hampered both the study and development of precision therapies for histone lysine methyltransferases-related Neurodevelopmental disorders. In this review, we will discuss the current knowledge of the role of histone lysine methyltransferases in neuronal development and disease progression. We will also discuss how RNA-based technologies using small-activating RNAs could potentially provide a novel therapeutic approach for the future treatment of histone lysine methyltransferase haploinsufficiency in these Neurodevelopmental disorders, and how they could be first tested in state-of-the-art patient-derived neuronal models

Primary hyperparathyroidism caused by bilateral parathyroid cystic carcinoma in a cat

Abstract Case summary A 16-year-old neutered female Korat cat presented with chronic vomiting, mild azotaemia and mild hypercalcaemia. Physical examination revealed bilateral palpable masses on each side of the trachea. Laboratory results were consistent with primary hyperparathyroidism, diagnostic imaging findings with cystic thyroid or parathyroid masses, and fine-needle aspiration cytology with thyroid hyperplasia or adenoma. In order to confirm whether one or two of the masses were the cause of the hyperparathyroidism, cystic fluid was aspirated from both for parathyroid hormone concentration measurement. The concentration was shown to exceed that of the serum manyfold in both samples, confirming both masses to be functional and of parathyroid origin. A total parathyroidectomy and thyroidectomy were performed on the right side, and a subtotal thyroidectomy and a subtotal to total parathyroidectomy on the left, without any major postoperative complications. Histopathology was consistent with bilateral parathyroid carcinoma. Relevance and novel information To our knowledge, this report is the first to describe a rare case of bilateral parathyroid cystic carcinoma in a cat. It highlights the usefulness of determining parathyroid hormone concentration in the cystic fluid of a suspected neoplastic parathyroid mass preoperatively. It also demonstrates that it may be possible to remove most of the cervical parathyroid and thyroid tissue of a cat without causing any clinically relevant hypocalcaemia or iatrogenic hypothyroidism. However, serum concentrations of ionised calcium, thyroxine and creatinine should be closely monitored in the postoperative period in order to detect and control possible complications.Peer reviewe

Control methods for Dermanyssus gallinae in systems for laying hens: results of an international seminar

This paper reports the results of a seminar on poultry red mite (PRM), Dermanyssus gallinae. Eighteen researchers from eight European countries discussed life cycle issues of the mite, effects of mites on hens and egg production, and monitoring and control methods for PRM in poultry facilities. It was determined that PRM probably causes more damage than envisaged, with the cost in The Netherlands alone reaching 11 million euro per annum. However a great deal is still unknown about PRM (e.g. reproduction, survival methods, etc.) and that PRM monitoring is an important instrument in recognising and admitting the problem and in taking timely measures. Currently, the most promising control method combines heating the hen house in combination with chemical treatments. Future areas of development which show promise include the use of entomopathogenic fungi, vaccination and predatory mites. The final aim is to solve the problem of D. gallinae in housing systems for laying hens

Alignment of gene expression profiles from test samples against a reference database: New method for context-specific interpretation of microarray data

Alignment of gene expression profiles from test samples against a reference database: New method for context-specific interpretation of microarray data Kilpinen, Sami K Ojala, Kalle A Kallioniemi, Olli P England BioData mining BioData Min. 2011 Mar 31;4:5. engBACKGROUND: Gene expression microarray data have been organized and made available as public databases, but the utilization of such highly heterogeneous reference datasets in the interpretation of data from individual test samples is not as developed as e.g. in the field of nucleotide sequence comparisons. We have created a rapid and powerful approach for the alignment of microarray gene expression profiles (AGEP) from test samples with those contained in a large annotated public reference database and demonstrate here how this can facilitate interpretation of microarray data from individual samples. METHODS: AGEP is based on the calculation of kernel density distributions for the levels of expression of each gene in each reference tissue type and provides a quantitation of the similarity between the test sample and the reference tissue types as well as the identity of the typical and atypical genes in each comparison. As a reference database, we used 1654 samples from 44 normal tissues (extracted from the Genesapiens database). RESULTS: Using leave-one-out validation, AGEP correctly defined the tissue of origin for 1521 (93.6%) of all the 1654 samples in the original database. Independent validation of 195 external normal tissue samples resulted in 87% accuracy for the exact tissue type and 97% accuracy with related tissue types. AGEP analysis of 10 Duchenne muscular dystrophy (DMD) samples provided quantitative description of the key pathogenetic events, such as the extent of inflammation, in individual samples and pinpointed tissue-specific genes whose expression changed (SAMD4A) in DMD. AGEP analysis of microarray data from adipocytic differentiation of mesenchymal stem cells and from normal myeloid cell types and leukemias provided quantitative characterization of the transcriptomic changes during normal and abnormal cell differentiation. CONCLUSIONS: The AGEP method is a widely applicable method for the rapid comprehensive interpretation of microarray data, as proven here by the definition of tissue- and disease-specific changes in gene expression as well as during cellular differentiation. The capability to quantitatively compare data from individual samples against a large-scale annotated reference database represents a widely applicable paradigm for the analysis of all types of high-throughput data. AGEP enables systematic and quantitative comparison of gene expression data from test samples against a comprehensive collection of different cell/tissue types previously studied by the entire research community.Peer reviewe

Correlation of intestinal histopathologic findings with mucosa-attached bacteria, clinical disease activity, and clinical outcome in dogs with chronic enteropathies

Peer reviewe

Non-tuberculous Mycobacteria can Cause Disseminated Mycobacteriosis in Cats

Mycobacteriosis caused by non-tuberculous mycobacteria (NTM) is a rising concern in human medicine both in immunocompromised and immunocompetent patients. In cats, mycobacteriosis caused by NTM is considered mostly to be a focal or dermal infection, with disseminated disease mostly caused by Mycobacterium avium. We describe three cases of disseminated mycobacteriosis in cats, caused by Mycobacterium malmoense, Mycobacterium branderi/shimoidei and M. avium, with no identified underlying immunosuppression. In all cases, extracellular mycobacteria were seen in the pulmonary epithelium, intestinal lumen and glomerular tufts, which could affect the shedding of the organism. The present study highlights the importance of mycobacteriosis as a differential even in immunocompetent animals. Considering the close relationship of owners and pets and the potential presence of free mycobacteria in secretions, cats should be considered as a possible environmental reservoir for mycobacteria. (C) 2018 Elsevier Ltd. All rights reserved.Peer reviewe

Control methods for Dermanyssus gallinae in systems for laying hens: results of an international seminar

This paper reports the results of a seminar on poultry red mite (PRM), Dermanyssus gallinae. Eighteen researchers from eight European countries discussed life cycle issues of the mite, effects of mites on hens and egg production, and monitoring and control methods for PRM in poultry facilities. It was determined that PRM probably causes more damage than envisaged, with the cost in The Netherlands alone reaching 11 million euro per annum. However a great deal is still unknown about PRM (e.g. reproduction, survival methods, etc.) and that PRM monitoring is an important instrument in recognising and admitting the problem and in taking timely measures. Currently, the most promising control method combines heating the hen house in combination with chemical treatments. Future areas of development which show promise include the use of entomopathogenic fungi, vaccination and predatory mites. The final aim is to solve the problem of D. gallinae in housing systems for laying hen

Bacterial Biogeography of the Colon in Dogs With Chronic Inflammatory Enteropathy

The intestinal microbiota is believed to play a role in the pathogenesis of inflammatory bowel disease in humans and chronic inflammatory enteropathy (CIE) in dogs. While most previous studies have described the gut microbiota using sequencing methods, it is fundamental to assess the spatial distribution of the bacteria for a better understanding of their relationship with the host. The microbiota in the colonic mucosa of 22 dogs with CIE and 11 control dogs was investigated using fluorescence in situ hybridization (FISH) with a universal eubacterial probe (EUB338) and specific probes for select bacterial groups. The number of total bacteria labeled with EUB338 probe was lower within the colonic crypts of dogs with CIE compared to controls. Helicobacter spp. and Akkermansia spp. were decreased on the colonic surface and in the crypts of dogs with CIE. Dogs with CIE had increased number of Escherichia coli/Shigella spp. on the colonic surface and within the crypts compared to control dogs. In conclusion, the bacterial microbiota in the colonic mucosa differed between dogs with and without CIE, with depletion of the crypt bacteria in dogs with CIE. The crypt bacterial species that was intimately associated with the host mucosa in control dogs was composed mainly of Helicobacter spp.Peer reviewe