Signaling Pathways, Chemical and Biological Modulators of Nucleotide Excision Repair: The Faithful Shield against UV Genotoxicity.

The continuous exposure of the human body's cells to radiation and genotoxic stresses leads to the accumulation of DNA lesions. Fortunately, our body has several effective repair mechanisms, among which is nucleotide excision repair (NER), to counteract these lesions. NER includes both global genome repair (GG-NER) and transcription-coupled repair (TC-NER). Deficiencies in the NER pathway underlie the development of several DNA repair diseases, such as xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). Deficiencies in GG-NER and TC-NER render individuals to become prone to cancer and neurological disorders, respectively. Therefore, NER regulation is of interest in fine-tuning these risks. Distinct signaling cascades including the NFE2L2 (NRF2), AHR, PI3K/AKT1, MAPK, and CSNK2A1 pathways can modulate NER function. In addition, several chemical and biological compounds have proven success in regulating NER's activity. These modulators, particularly the positive ones, could therefore provide potential treatments for genetic DNA repair-based diseases. Negative modulators, nonetheless, can help sensitize cells to killing by genotoxic chemicals. In this review, we will summarize and discuss the major upstream signaling pathways and molecules that could modulate the NER's activity.

Xeroderma pigmentosum complementation group F: A rare cause of cerebellar ataxia with chorea.

The complementation group F of Xeroderma pigmentosum (XP-F) is rare in the Caucasian population, and usually devoid of neurological symptoms. We report two cases, both Caucasian, who exhibited progressive cerebellar ataxia, chorea, a mild subcortical frontal cognitive impairment, and in one case severe polyneuropathy. Brain MRI demonstrated cerebellar (2/2) and cortical (1/2) atrophy. Both patients had only mild sunburn sensitivity and no skin cancer. Mini-exome sequencing approach revealed in ERCC4, two heterozygous mutations, one of which was never described (c.580-584+1delCCAAGG, exon 3), in the first case, and an already reported homozygous mutation, in the second case. These cases emphasize that XP-F is a rare cause of recessive cerebellar ataxia and can in some cases clinically mimic Huntington's disease due to chorea and executive impairment. The association of ataxia, chorea, and sun hypersensitivity are major guidance for the diagnosis, which should not be missed, in order to prevent skin neoplastic complications.

Skin equivalents: skin from reconstructions as models to study skin development and diseases.

While skin is readily available for sampling and direct studies of its constituents, an important intermediate step is to design in vitro and/or in vivo models to address scientific or medical questions in dermatology and skin biology. Pioneered more than 30 years ago, human skin equivalents (HSEs) have been refined with better cell culture techniques and media, together with sophisticated cell biology tools including genetic engineering and cell reprogramming. HSEs mimic key elements of human skin biology and have been instrumental in demonstrating the importance of cell-cell interactions in skin homeostasis and the role of a complex cellular microenvironment to coordinate epidermal proliferation, differentiation and pigmentation. HSEs have a wide field of applications from cell biology to dermocosmetics, modelling diseases, drug development, skin ageing, pathophysiology and regenerative medicine. In this article we critically review the major current approaches used to reconstruct organotypic skin models and their application with a particular emphasis on skin biology and pathophysiology of skin disorders.

Pedicle length in the inferiorly based buccinator myomucosal island flap: a cadaveric study.

The inferiorly based buccinator myomucosal island flap is a useful reconstructive option for medium-sized intraoral mucosal defects. The pedicle length of this flap has not yet been determined. Thirteen fresh cadavers (26 sides) with intact faces were studied. An inferiorly based buccinator myomucosal island flap was elevated. Various measurements were taken, including pedicle length, paddle area, and pedicle length after dissection of the facial artery through the submandibular salivary gland; the presence of the facial artery or vein in the pedicle and the number of perforators were also evaluated. The mean pedicle lengths in the right and left sides were 4.8±0.6cm and 4.9±0.6cm, respectively. The mean pedicle lengths after dissection of the facial artery through the submandibular salivary gland were 7.8±0.7cm (right side) and 7.7±0.6cm (left side). The pedicle contained only the facial artery in six sides. There were two to three perforator branches from the facial artery to the mucosal paddle. Paddle sizes of the flap were in the range of 2.2×2.1cm to 3.5×3cm. This flap is suitable for the reconstruction of the floor of the mouth and tongue. Pedicle length can be increased significantly by dissecting the facial artery through the submandibular salivary gland.

The cytoprotective drug amifostine modifies both expression and activity of the pro-angiogenic factor VEGF-A.

BACKGROUND: Amifostine (WR-2721, delivered as Ethyol) is a phosphorylated aminothiol compound clinically used in addition to cis-platinum to reduce the toxic side effects of therapeutic treatment on normal cells without reducing their efficacy on tumour cells. Its mechanism of action is attributed to the free radical scavenging properties of its active dephosphorylated metabolite WR-1065. However, amifostine has also been described as a potent hypoxia-mimetic compound and as a strong p53 inducer; both effects are known to potently modulate vascular endothelial growth factor (VEGF-A) expression. The angiogenic properties of this drug have not been clearly defined. METHODS: Cancer cell lines and endothelial cells were used in culture and treated with Amifostine in order to study (i) the expression of angiogenesis related genes and proteins and (ii) the effects of the drug on VEGF-A induced in vitro angiogenesis. RESULTS: We demonstrated that the treatment of several human cancer cell lines with therapeutical doses of WR-1065 led to a strong induction of different VEGF-A mRNA isoforms independently of HIF-1alpha. VEGF-A induction by WR-1065 depends on the activation of the eIF2alpha/ATF4 pathway. This up-regulation of VEGF-A mRNA was accompanied by an increased secretion of VEGF-A proteins fully active in stimulating vascular endothelial cells (EC). Nevertheless, direct treatment of EC with amifostine impaired their ability to respond to exogenous VEGF-A, an effect that correlated to the down-regulation of VEGFR-2 expression, to the reduction in cell surface binding of VEGF-A and to the decreased phosphorylation of the downstream p42/44 kinases. CONCLUSIONS: Taken together, our results indicate that amifostine treatment modulates tumour angiogenesis by two apparently opposite mechanisms - the increased VEGF-A expression by tumour cells and the inhibition of EC capacity to respond to VEGF-A stimulation.

The effect of imatinib (Glivec) on scleroderma and normal dermal fibroblasts: a preclinical study.

BACKGROUND: Scleroderma skin overexpresses the platelet-derived growth factor receptor beta-subunit (PDGFR-beta) in dermal vessels and PDGFR-beta messenger RNA in cultured fibroblasts. Moreover, increased levels of PDGF and stimulatory autoantibodies to PDGFR have been identified in the serum of scleroderma patients. OBJECTIVE: Imatinib being an inhibitor of tyrosine kinase receptors such as PDGFR, its effect on scleroderma fibroblasts was evaluated in vitro as a preclinical therapeutic step. METHODS: The effect of imatinib on fibroblasts grown from normal or involved/uninvolved scleroderma skin was studied by Western blot and the methyltetrazolium test. The pattern of distribution of PDGFR-beta in scleroderma versus normal skin was studied by immunohistochemistry. RESULTS: In vitro, imatinib inhibited the proliferation of normal dermal and scleroderma fibroblasts at least partly via the inhibition of the phosphorylation of PDGFR. PDGFR-beta was expressed in the epidermis and adnexae in 5 lesional scleroderma biopsies and not in controls. CONCLUSION: This study suggests that imatinib can serve as therapy to limit dermal fibroblast proliferation in scleroderma.

Catalase overexpression reduces UVB-induced apoptosis in a human xeroderma pigmentosum reconstructed epidermis.

Xeroderma pigmentosum type C (XPC) is a rare autosomal recessive disorder that occurs due to inactivation of the XPC protein, an important DNA damage recognition protein involved in DNA nucleotide excision repair (NER). This defect, which prevents removal of a wide array of direct and indirect DNA lesions, is associated with a decrease in catalase activity. To test the hypothesis of a novel photoprotective approach, we irradiated epidermis reconstructed with XPC human keratinocytes sustainably overexpressing lentivirus-mediated catalase enzyme. Following UVB irradiation, there was a marked decrease in sunburn cell formation, caspase-3 activation and p53 accumulation in human XPC-reconstructed epidermis overexpressing catalase. Moreover, XPC-reconstructed epidermis was more resistant to UVB-induced apoptosis than normal reconstructed epidermis. While not correcting the gene defect, indirect gene therapy using antioxidant enzymes may be of help in limiting photosensitivity in XPC and probably in other monogenic/polygenic photosensitive disorders characterized by ROS accumulation.

Protection of normal human reconstructed epidermis from UV by catalase overexpression.

Reactive oxygen species (ROS) generated by ultraviolet (UV) irradiation are counterbalanced by endogenous antioxidant systems. To test the hypothesis of a novel photoprotective approach, we irradiated epidermis reconstructed with normal human keratinocytes overexpressing sustainably lentivirus-mediated catalase (CAT), copper/zinc superoxide dismutase (CuZnSOD) or manganese superoxide dismutase (MnSOD) enzymes. We found that following UVB irradiation there was a marked decrease in sunburn cell formation, caspase-3 activation and p53 accumulation in human reconstructed epidermis overexpressing CAT. Moreover, UVA-induced hypertrophy and DNA oxidation (8-oxodeoxyguanosine) were decreased by CAT overexpression. These effects were not achieved by overexpression of CuZnSOD or MnSOD. In conclusion, vector-mediated CAT overexpression could be a promising photoprotective tool against deleterious effects of UV irradiation such skin cancer especially in monogenic/polygenic photosensitive disorders characterized by ROS accumulation.

Psychogenic parasitosis. A case series and literature review.

About 100 years ago, psychogenic parasitosis was first described in the literature. This peculiar symptom may complicate medical and psychiatric conditions or indicate the presence of a delusional disorder (somatic type). By using the authors' case series of 12 patients, which are reported in the article, and a review of the literature, an historical perspective and the authors' clinical orientation to evaluation and treatment of psychogenic parasitosis are presented.

[Pediculated anterior graft for reducing necrosis of the femur head in femoral neck fractures]. / La greffe pédiculée antérieure pour réduire la nécrose de la tête fémorale dans les fractures cervicales.

This article in addition of reviewing the current techniques of surgical treatment of femoral neck fractures, also presents a newly devised technique, in which by anterior approach the pediculated muscle bone graft from the anterior part of the greater trochanter with attached gluteus medius insertion is placed at anterosuperior part of the fractured femoral neck (type 3 & 4 Garden and old neglected fractures). This paper reviews the older techniques of Judet and Meyer in which the pediculated bone graft is taken from quadratus femoris insersion and placed posteriorly to the femoral neck which may compromise the important vascular supply (posterior subsynovial retinacular artery) posteriorly to the neck. The new anterior technique has been used for 20 patients successfully for the first time in department of orthopaedic surgery in Imam Reza Medical Center. In Mashhad-Iran from 21/3/93. The ultimate analysis of results will be possible 3 years after operation.

A survey of intestinal parasitic infestation in Khorasan Province, Iran.

The prevalance of various intestinal parasites has been determined from a study of 40, 267 people from both urban and rural areas of Khorasan province, Iran. Except for G. lamblia, T. hominis, and H. nana, the prevalence of intestinal parasites seems to be lower in this province than in other areas of Iran. The incidence of infestation in village females was higher than in village males, but was similar in the two sexes in the towns and cities. Of those infested, more than 20% from urban areas and 35% from rural areas had multiple infestations.