Mosaic IL6ST variant inducing constitutive GP130 cytokine receptor signaling as a cause of neonatal onset immunodeficiency with autoinflammation and dysmorphy.

Interleukin-6 signal transducer (IL6ST) encodes the GP130 protein which transduces the proinflammatory signaling of the IL6 cytokine family through Janus kinase signal transducers and activators of transcription pathway (JAK/STAT) activation. Biallelic loss-of-function IL6ST variants cause autosomal recessive hyper-IgE syndrome or a variant of the Stuve-Wiedemann syndrome. Somatic gain-of-function IL6ST mutations, in particular, small monoallelic in-frame deletions of which the most prevalent is the IL6ST Ser187_Tyr190del, are an established cause of inflammatory hepatocellular tumors, but so far, no disease caused by such mutations present constitutively has been described.

Variable degree of mosaicism for tetrasomy 18p in phenotypically discordant monozygotic twins-Diagnostic implications.

Background: Phenotypically discordant monozygotic twins (PDMZTs) offer a unique opportunity to study post-zygotic genetic variation and provide insights into the linkage between genotype and phenotype. We report a comprehensive analysis of a pair of PDMZTs.

Methods: Dysmorphic features and delayed neuro-motor development were observed in the proband, whereas her twin sister was phenotypically normal.

New Treatment of Wound Healing With Allogenic Acellular Human Skin Graft: Preclinical Assessment and In Vitro Study.

Background: Nonhealing wounds can be a major clinical problem. Impaired wound healing is often related to massive tissue injury, concomitant wound healing deficiencies (chronic wounds), burn injury, or congenital conditions. We propose a novel biological dressing as an alternative surgical approach.

Transplantation of a New Biological Product in Rare Diseases, Such as Epidermolysis Bullosa: Response and Clinical Outcome.

Background: Epidermolysis bullosa (EB) is a phenotypically diverse group of hereditary blistering disorders involving mutations in 20 different genes. Those debilitating disorders are currently incurable; however, there are a number of promising preclinical trials, where some treatments already approach the stage of early clinical trial. In this paper we introduce a novel surgical approach to the treatment of EB-induced ulcerations.

Cell and Gene Therapies: European View on Challenges in Translation and How to Address Them.

Advanced therapy medicinal products (ATMPs), ., cell and gene therapy products, is a rapidly evolving field of therapeutic development. A significant proportion of the products are being developed by academia or small/medium-sized enterprises (SMEs).

Dominant mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features.

Background: Ichthyosis and neurological involvement occur in relatively few known Mendelian disorders caused by mutations in genes relevant both for epidermis and neural function.

Objectives: To identify the cause of a similar phenotype of ichthyotic keratoderma, spasticity, mild hypomyelination (on MRI) and dysmorphic features (IKSHD) observed in two unrelated paediatric probands without family history of disease.

Methods: Whole exome sequencing was performed in both patients.

Reconstruction method for extended depth-of-field optical diffraction tomography.

In the paper we present a novel method of extended depth-of-field limited-angle optical diffraction tomography, in which the change of a focal plane position is performed with a liquid focus-tunable lens. One sinogram is acquired for each state of a focus-tunable lens. After acquisition process is complete, all sinograms are independently reconstructed and stitched to form the final tomographic reconstruction.

Clinical Development and Commercialization of Advanced Therapy Medicinal Products in the European Union: How Are the Product Pipeline and Regulatory Framework Evolving?

The research and development of advanced therapy medicinal products (ATMPs) has been active in Europe and worldwide during recent years. Yet, the number of licensed products remains low. The main expected legal change in the near future in the European Union (EU) concerns the regulation on clinical trials (536/2014), which will come into force in 2018.

Synthesis and anticancer activity of 7-hydroxycoumarinyl gallates.

Background: The search for anti-cancer agents includes naturally occurring substances and theirs modifications. Therefore we invented and designed compounds that represent fused derivatives of gallic acid with coumarins.

Methods: As a result, a series of 8 novel esters of gallic acid and 7-hydroxycoumarins were synthesized and evaluated for anticancer activity.

Manufacturing, characterization and control of cell-based medicinal products: challenging paradigms toward commercial use.

During the past decade, a large number of cell-based medicinal products have been tested in clinical trials for the treatment of various diseases and tissue defects. However, licensed products and those approaching marketing authorization are still few. One major area of challenge is the manufacturing and quality development of these complex products, for which significant manipulation of cells might be required.

Xenotransplantation of human cultured parathyroid progenitor cells into mouse peritoneum does not induce rejection reaction.

Introduction: Parathyroid progenitor cells devoid of immunogenic antigens were used for human allotransplantation. Although there were many potential reasons for the expiry of transplant activity in humans, we decided to exclude a subclinical form of rejection reaction, and test the rejection reaction in an animal model.

Material And Methods: Experiments were carried out on 40 conventional male mice in their third month of life.

[Collagen based dressings in the treatment of wound healing].

Collagen is the fundamental protein forming the connective tissues matrix, improves the ability of keratinocytes to migrate to sites that require rebuilding of the damaged epidermis, is one of the component of dressings used to accelerate wound healing. Because of the potential risk of the presence of pathogenic prions in bovine collagen, part of collagen dressings is formed on the basis of porcine collagen. Currently, a least of an immunogenic form of collagen is atelocollagen, which is subjected to enzyme-treated collagen, in which the terminal amino acids are removed from the collagen.

Fluvastatin increases tyrosinase synthesis induced by alpha-melanocyte-stimulating hormone in B16F10 melanoma cells.

The aim of this study was to evaluate the effect of fluvastatin on the alpha-melanocyte-stimulating hormone-mediated increase in tyrosinase activity in the melanoma B16F10 cell line and to establish whether Akt and extracellular signal-regulated kinase (Erk) inhibition is involved in tyrosinase synthesis after fluvastatin administration. Fluvastatin modulates alpha-melanocyte-stimulating hormone induced melanogenesis by increasing tyrosinase mRNA production, as shown by real time PCR, or tyrosinase protein synthesis, as presented by western blot technique. The stimulatory effect of fluvastatin on melanogenesis was, in part, induced by modulation of cell proliferation (decreased melanoma cell proliferation in G2/M phase) and possibly decrease of Akt.

An evaluation of sterilisation processes.

A sterile environment is one of the basic elements of in vitro cell culture. When choosing an appropriate sterilisation method, the possibility that the physical and chemical properties of the sterilised material could be altered by the sterilisation process itself, should be considered. Avoiding any potential problems of toxicity arising as a consequence of the sterilisation process is essential, not only in in vitro cell culture procedures, but especially in the case of the sterilisation of medical devices which come into contact with human tissue (e.

The possible role of factor H in colon cancer resistance to complement attack.

A soluble complement inhibitor factor H (FH) and its splice variant factor H-like protein (FHL) have been recently discovered to play a major role in malignant cell escape from complement-mediated cytotoxicity in lung-, ovarian- and glia-derived neoplasms. The role of FH in colon cancer has not yet been examined. Here, we studied immunocytochemically FH/FHL expression in tumor samples derived from 40 patients, with both primary colon adenocarcinoma and metastatic foci in the liver.

Mechanical properties of bone fixation devices prepared from a human allogenic bone.

Background: The major goal of the study was to create a novel, internal fixation devices based on human cortical bone for use in the orthopedic surgery. Because the biological properties of processed tissue have already been intensively studied, it was mandatory to evaluate the mechanical properties of our new products before introduction into clinical use.

Materials And Methods: Pins and screws of different diameters were formed from processed human lower limb bones prepared according to standard tissue banking procedures: freezing, de-fatting and radiation sterilization (35 kGy).

Allotransplantation of cultured parathyroid progenitor cells without immunosuppression: clinical results.

Background: Hypoparathyroidism is a well-known consequence of extensive thyroid and parathyroid surgery. Allotransplantation of cultured parathyroid cells can be considered as an alternative to vitamin D3 and calcium supplementation in treatment of hypoparathyroidism. We present the long-term allotransplant activity in 85 patients who had undergone cellular allotransplantation for surgical hypoparathyroidism.

Expression of the membrane complement regulatory proteins (CD55 and CD59) in human thymus.

CD59 is one of the key molecules involved in cell protection against autologus complement. The fact that complement regulatory proteins are able to prevent hyperacute rejection of organs in pig to primate model, raises the question of possible complement regulatory protein (CRP) involvement in the maturation of immunological system. We report here that in foetal and postnatal human thymus, CD59 and CD55 are primarily located on Hassall's corpuscles and medullary epithelial cells.

[The effect of retinoic acid on primary cultures of human pheochromocytoma cells].

Introduction: Retinoic acid is a regulator of gene expression which, by binding to its nuclear receptor, determines the degree of differentiation in multiple cancer cell types. On the basis of this capability it was introduced, e.g.

ESTIV questionnaire on the acquisition and use of primary human cells and tissue in toxicology.

The ability to use human cells and tissues in toxicology research and testing has the benefit that it obviates the need to undertake species extrapolation when assessing human hazard. However, obtaining and using human cells and tissues is logistically difficult, ethically complex and is a potential source of infections to those coming into contact with human cell material. The issue is also controversial, with the recent EU legislation draft on tissue engineering, and also due to some instances of human material being obtained and used without informed consent.

Culture of the primary corneal epithelium as a potential component of test batteries for eye irritancy testing.

One of the main goals for toxicologists working on the development of in vitro tests is to replace the animal-based eye irritation test. Inflammation is one of the mechanisms which have not been covered sufficiently by the existing in vitro ocular irritancy test systems. As there are major species differences between the human and rabbit eye inflammation mechanisms, the most relevant test system is the human eye itself.

Preserved tissue allografts in reconstructive surgery.

Results of treatment with three various kinds of allografts: lyophilized bone, deep frozen bone and cartilage preserved in physiological solution, all of them radiation-sterilized are presented. We believe that this presentation may be helpful in estimating the tissue bank's allografts and in establishing indications and contraindications in the application of allografts in surgery.The 'indices of coincidence' were compared in a group of 1014 patients after bone (lyophilized and radiation-sterilized) transplantation.

In vitro reconstruction of full thickness human skin on a composite collagen material.

Rapid progress of in vitro techniques in the last years enabled the creation of organotypic skin cultures offering new possibilities in wound treatment. Rebuilding of graft is one of the key elements of successful outcome of the procedure. In search for the best scaffold for organotypic skin culture, the novel composite xenogenic collagen based material with unique properties has been created and used to reconstitute full thickness human skin in vitro.