L. Verneuil

The human cytomegalovirus-encoded chemokine receptor US28 induces caspase-dependent apoptosis

Viral subversion of apoptosis regulation plays an important role in the outcome of host/virus interactions. Although human cytomegalovirus (HCMV) encodes several immediate early (IE) antiapoptotic proteins (IE1, IE2, vMIA and vICA), no proapoptotic HCMV protein has yet been identified. Here we show that US28, a functional IE HCMV‐encoded chemokine receptor, which may be involved in both viral dissemination and immune evasion, constitutively induces apoptosis in several cell types. In contrast, none of nine human cellular chemokine receptors, belonging to three different subfamilies, induced any significant level of apoptosis. US28‐induced cell death involves caspase 10 and caspase 8 activation, but does not depend on the engagement of cell‐surface death receptors of the tumour necrosis factor receptor/CD95 family. US28 cell‐death induction is prevented by coexpression of C‐FLIP, a protein that inhibits Fas‐associated death domain protein (FADD)‐mediated activation of caspase 10 and caspase 8, and by coexpression of the HCMV antiapoptotic protein IE1. The use of US28 mutants indicated that the DRY sequence of its third transmenbrane domain, required for constitutive G‐protein signalling, and the US28 intracellular terminal domain required for constitutive US28 endocytosis, are each partially required for cell‐death induction. Thus, in HCMV‐infected cells, US28 may function either as a chemokine receptor, a phospholipase C activator, or a proapoptotic factor, depending on expression levels of HCMV and/or cellular antiapoptotic proteins.

Cutaneous amyloidosis and possible association with systemic amyloidosis.

Cutaneous amyloidoses is a group of disabling disorders characterized by uncontrolled deposition of amyloid in the epidermis and the dermis which may be located in vital organs such as kidneys, heart, liver or lungs. Mucocutaneous signs of localized cutaneous amyloidosis such as lichen amyloidosis and macular and pigmented amyloidosis are completely different from those of amyloid light chain (AL) systemic amyloidosis. Nodular amyloidosis is usually considered as a localized cutaneous amyloidosis but it may occur as a manifestation of systemic amyloidosis after-long-term follow-up.

Prevalence and risk factors of the whole spectrum of sexually transmitted diseases in male incoming prisoners in France

Sexually transmitted diseases (STD) are a public health issue in prison. As inmates are eventually released, it is also a community concern. There are very few data on the entire spectrum of STDs, particularly condyloma among prisoners. To determine the prevalence of all STDs: infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), Chlamydia trachomatis, Neisseria gonorrhoea, syphilis, and condyloma among entering inmates. A cross-sectional study was conducted in France from November 2000 to June 2003. Male adults entering a prison remand center in Caen had a medical consultation and physical examination including external genital organs and perianal area for condyloma and herpes infection, a urethral swab for Chlamydia trachomatis and Neisseria gonorrhoea detection, and a blood sample for HBV, HCV, HIV, and syphilis serology. Five hundred and ninety-seven inmates agreed to participate in the study. Sixteen percent had at least one STD: 4.0% had condyloma, 4.0% chlamydia infection, and 4.9% were positive for HCV antibodies. Two had early syphilis and 1 had acute HBV, but no HIV infection, neither genital herpes nor gonorrhea. The analysis of the STD risk behaviors did not show any difference between the infected and uninfected participants, except that HCV-positive participants were more likely to be intravenous drug users. Results suggest that a systematic screening of all STDs should be at least proposed to every entering inmate since no demographic or sexual characteristics are consistently associated with STDs.

CD95 ligand-dependant endothelial cell death initiates oral mucosa damage in a murine model of acute graft versus host disease

Oral mucosa lesions are one of the common pathological consequences of acute graft versus host disease (aGVHD), the major complication of allogeneic bone marrow transplantation caused by mature T lymphocytes of donor origin. Oral mucosa damage in aGVHD is characterized by apoptosis induction in the basal keratinocytes, associated with immune effector T-cell infiltration, but its pathogenesis remains unclear because these lesions might result from the patient conditioning therapy that includes radiation and/or chemotherapy. Here, using a murine model of aGVHD that does not involve any conditioning treatment, we show that the earliest detectable oral mucosa lesion is apoptosis of the endothelial cells from chorion capillaries, which precedes basal keratinocyte apoptosis induction. Neither vascular damage nor epithelial-cell death occurred in recipients of allogeneic lymphocytes from CD95 ligand (CD95L)-defective mice. Our findings indicate that oral mucosa lesions in aGVHD are initiated by endothelial-cell death and require CD95L expression by the allogeneic lymphocytes. This early vascular damage may contribute to the induction of further tissue damage in the oral mucosa, through the induction of hypoxia and vascular leakage of immune cells or soluble proapoptotic mediators.

Epstein–Barr virus involvement in the pathogenesis of hydroa vacciniforme: an assessment of seven adult patients with long-term follow-up

Background  Hydroa vacciniforme (HV) is a chronic papulovesicular photodermatosis of childhood, with some cases persisting through adulthood. In children, the Epstein–Barr virus (EBV) has been detected in typical HV and in HV evolving into natural killer/T‐cell lymphoma. No exploration of EBV infection has been performed in adult patients with HV with long‐term follow‐up.

Endothelial cell apoptosis in severe drug-induced bullous eruptions

Background  Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are characterized by extensive keratinocyte apoptosis mediated by cytotoxic proteins. Similar features have been found in another severe dysimmune syndrome, allogeneic acute graft‐versus‐host disease, where endothelial cell apoptosis has been recently characterized.

Targeting autophagic cancer stem-cells to reverse chemoresistance in human triple negative breast cancer

There is growing evidence for the role of cancer stem-cells in drug resistance, but with few in situ studies on human tumor samples to decipher the mechanisms by which they resist anticancer agents. Triple negative breast cancer (TNBC) is the most severe sub-type of breast cancer, occurring in younger women and associated with poor prognosis even when treated at a localized stage. We investigated here the relationship between complete pathological response after chemotherapy and breast cancer stem-cell characteristics in pre-treatment biopsies of 78 women with triple negative breast carcinoma (TNBC). We found that chemoresistance was associated with large numbers of breast cancer stem-cells, and that these cancer stem-cells were neither proliferative nor apoptotic, but in an autophagic state related to hypoxia. Using relevant pharmacological models of patient-derived TNBC xenografts, we further investigated the role of autophagy in chemoresistance of breast cancer stem-cells. We demonstrated that hypoxia increased drug resistance of autophagic TNBC stem-cells, and showed that molecular or chemical inhibition of autophagic pathway was able to reverse chemoresistance. Our results support breast cancer stem-cell evaluation in pre-treatment biopsies of TNBC patients, and the need for further research on autophagy inhibition to reverse resistance to chemotherapy.

Vemurafenib skin phototoxicity is indirectly linked to ultraviolet A minimal erythema dose decrease

Vemurafenib, an anti‐rapidly accelerated fibrosarcoma kinase B (BRAF) molecule, improves survival among patients with metastatic BRAF‐mutated melanoma. Photosensitivity, a frequent cutaneous adverse effect induced by vemurafenib, can lead to cessation of treatment.

Human skin carcinoma arising from kidney transplant-derived tumor cells.

Tumor cells with donor genotype have been identified in human skin cancer after allogeneic transplantation; however, the donor contribution to the malignant epithelium has not been established. Kidney transplant recipients have an increased risk of invasive skin squamous cell carcinoma (SCC), which is associated with accumulation of the tumor suppressor p53 and TP53 mutations. In 21 skin SCCs from kidney transplant recipients, we systematically assessed p53 expression and donor/recipient origin in laser-microdissected p53+ tumor cells. In one patient, molecular analyses demonstrated that skin tumor cells had the donor genotype and harbored a TP53 mutation in codon 175. In a kidney graft biopsy performed 7 years before the skin SCC diagnosis, we found p53+ cells in the renal tubules. We identified the same TP53 mutation in these p53+ epithelial cells from the kidney transplant. These findings provide evidence for a donor epithelial cell contribution to the malignant skin epithelium in the recipient in the setting of allogeneic kidney transplantation. This finding has theoretical implications for cancer initiation and progression and clinical implications in the context of prolonged immunosuppression and longer survival of kidney transplant patients.

Intralesional Cryosurgery to Treat Keloid Scars: Results from a Retrospective Study

Background: A variety of treatment modalities have been proposed to treat keloid scars, but outcomes are often disappointing. Intralesional cryosurgery may significantly reduce these scars. Objective: To evaluate the clinical safety and efficacy of intralesional cryosurgery to treat keloid scars. Feedback from patients on pain, pruritus and aesthetic discomfort was recorded before and after treatment. Methods: A total of 10 patients with 14 keloid scars resistant to conventional treatments were enrolled in a retrospective study between October 2007 and October 2013. The efficacy of this treatment was evaluated by measuring the reduction in scar surface. Results: Scar surface was reduced by an average of 58.5% after intralesional cryosurgery treatment for all scars (average pre-operative keloid scar surface: 874.6 ± 954.1 mm2; average post-operative keloid scar surface: 505.8 ± 1,024.7 mm2; p = 0.002). Pain and aesthetic discomfort were significantly decreased after treatment in all patients (p = 0.008 and p = 0.012, respectively). Conclusion: Our data suggest that intralesional cryosurgery is an effective treatment for keloids.