Kyoko Imoto

Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair

Background The frequency of cancer, neurologic degeneration and mortality in xeroderma pigmentosum (XP) patients with defective DNA repair was determined in a four decade natural history study. Methods All 106 XP patients admitted to the National Institutes of Health from 1971 to 2009 were evaluated from clinical records and follow-up. Results In the 65 per cent (n=69) of patients with skin cancer, non-melanoma skin cancer (NMSC) was increased 10 000-fold and melanoma was increased 2000-fold in patients under age 20. The 9 year median age at diagnosis of first non-melanoma skin cancer (NMSC) (n=64) was significantly younger than the 22 year median age at diagnosis of first melanoma (n=38)—a relative age reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. XP patients with pronounced burning on minimal sun exposure (n=65) were less likely to develop skin cancer than those who did not. This may be related to the extreme sun protection they receive from an earlier age, decreasing their total ultraviolet exposure. Progressive neurologic degeneration was present in 24% (n=25) with 16/25 in complementation group XP-D. The most common causes of death were skin cancer (34%, n=10), neurologic degeneration (31%, n=9), and internal cancer (17%, n=5). The median age at death (29 years) in XP patients with neurodegeneration was significantly younger than those XP patients without neurodegeneration (37 years) (p=0.02). Conclusion This 39 year follow-up study of XP patients indicates a major role of DNA repair genes in the aetiology of skin cancer and neurologic degeneration.

DNA single-strand break repair is impaired in aprataxin-related ataxia

Early‐onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive form of cerebellar ataxia. The causative protein for EAOH/AOA1, aprataxin (APTX), interacts with X‐ray repair cross‐complementing 1 (XRCC1), a scaffold DNA repair protein for single‐strand breaks (SSBs). The goal of this study was to prove the functional involvement of APTX in SSB repair (SSBR).

Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy†‡

Patients with xeroderma pigmentosum (XP) have a 1,000‐fold increase in ultraviolet (UV)‐induced skin cancers while trichothiodystrophy (TTD) patients, despite mutations in the same genes, ERCC2 (XPD) or ERCC3 (XPB), are cancer‐free. Unlike XP cells, TTD cells have a nearly normal rate of removal of UV‐induced 6‐4 photoproducts (6‐4PP) in their DNA and low levels of the basal transcription factor, TFIIH. We examined seven XP, TTD, and XP/TTD complex patients and identified mutations in the XPD gene. We discovered large differences in nucleotide excision repair (NER) protein recruitment to sites of localized UV damage in TTD cells compared to XP or normal cells. XPC protein was rapidly localized in all cells. XPC was redistributed in TTD, and normal cells by 3 hr postirradiation, but remained localized in XP cells at 24‐hr postirradiation. In XP cells recruitment of other NER proteins (XPB, XPD, XPG, XPA, and XPF) was also delayed and persisted at 24 hr (p<0.001). In TTD cells with defects in the XPD, XPB, or GTF2H5 (TTDA) genes, in contrast, recruitment of these NER proteins was reduced compared to normals at early time points (p<0.001) and remained low at 24 hr postirradiation. These data indicate that in XP persistence of NER proteins at sites of unrepaired DNA damage is associated with greatly increased skin cancer risk possibly by blockage of translesion DNA synthesis. In contrast, in TTD, low levels of unstable TFIIH proteins do not accumulate at sites of unrepaired photoproducts and may permit normal translesion DNA synthesis without increased skin cancer. Hum Mutat 0, 1–15, 2008. Published 2008 Wiley‐Liss, Inc.

VZV skin-test reaction, but not antibody, is an important predictive factor for postherpetic neuralgia

BACKGROUND The decline of cell-mediated immunity (CMI) is thought to be related to the risk of postherpetic neuralgia (PHN) as well as herpes zoster (HZ). However, the relationship between immunological condition and the incidence of PHN is still unclear. OBJECTIVE We conducted a large-scale prospective cohort study to clarify the relationship between immunological factors for varicella-zoster virus (VZV) and the incidence of PHN. METHODS We carried out a cohort study on VZV immunity in a population living on an island cluster, Shozu County in Japan, and examined the people who developed HZ during a follow-up period of 3 years, with a focus on the relationship between cell-mediated and humoral immunity and the incidence of PHN. A total of 12,522 people over the age of 50 were enrolled in this study, and 401 registrants were diagnosed with HZ, including 79 PHN cases. We evaluated anatomical location and severity of skin lesion, acute pain severity, presence or absence of abnormal sensations, CMI assessed by VZV skin test, and VZV-specific antibody titer measured by serological tests. RESULTS The incidence of PHN was significantly associated with a weak response to the VZV skin test, as well as facial or lumbosacral localization of skin rash, severe skin lesion, severe acute pain, and presence of abnormal sensations, but not related to VZV-specific antibody titer. CONCLUSION The incidence of PHN is significantly associated with the decline of VZV-specific CMI, but not related to VZV-specific humoral immunity.

Epidermal growth factor receptor inhibitors selectively inhibit the expressions of human β-defensins induced by Staphylococcus epidermidis

BACKGROUND Epidermal growth factor receptor inhibitors (EGFRIs) have developed as one of the potential treatment options for various kinds of cancers. Although a variety of dermatological adverse reactions such as follicular acneiform eruptions is commonly encountered, the mechanism of the reactions remains unclear. OBJECTIVES We investigated the effects of EGFRIs on the expression of human β-defensins against staphylococci to study the pathomechanism of cutaneous adverse reactions caused by EGFRIs. METHODS We investigated the expressions of human β-defensins 1, 2, and 3 (hBD1, 2, and 3) from staphylococci-stimulated normal human epidermal keratinocytes (NHEKs) cultured with or without the effects of two EGFRIs, gefitinib and erlotinib. We stimulated NHEKs with the supernatant of Staphylococcus aureus (S. aureus) and S. epidermidis and the live staphylococci. We measured hBDs in the culture supernatants of NHEKs by enzyme-linked immunosorbent assay (ELISA). RESULTS EGFRIs did not suppress the expressions of hBD1 and 3 induced by S. aureus. In contrast, EGFRIs suppressed the expressions of hBD2 and 3 induced by S. epidermidis. CONCLUSION EGFRIs may cause cutaneous adverse effects through selectively perturbing innate immune responses induced by commensal and pathogenic bacteria.

Nucleotide Excision Repair Proteins Rapidly Accumulate but Fail to Persist in Human XP‐E (DDB2 Mutant) Cells

The xeroderma pigmentosum (XP‐E) DNA damage binding protein (DDB2) is involved in early recognition of global genome DNA damage during DNA nucleotide excision repair (NER). We found that skin fibroblasts from four newly reported XP‐E patients with numerous skin cancers and DDB2 mutations had slow repair of 6‐4 photoproducts (6‐4PP) and markedly reduced repair of cyclobutane pyrimidine dimers (CPD). NER proteins (XPC, XPB, XPG, XPA and XPF) colocalized to CPD and 6‐4PP positive regions immediately (<0.1 h) after localized UV irradiation in cells from the XP‐E patients and normal controls. While these proteins persist in normal cells, surprisingly, within 0.5 h these repair proteins were no longer detectable at the sites of DNA damage in XP‐E cells. Our results indicate that DDB2 is not required for the rapid recruitment of NER proteins to sites of UV photoproducts or for partial repair of 6‐4PP but is essential for normal persistence of these proteins for CPD photoproduct removal.

Differential expression profile of Th1/Th2-associated chemokines characterizes Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) as distinct entities

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are two of a triad of severe cutaneous adverse reactions (SCAR) to drugs [1, 2]. The rapid recognition of DIHS/DRESS and SJS/TEN is essential because they are potentially life-threatening syndromes. Thus, diagnostic markers or predictive factors need to be defined.We previously reported that thymus and activation-regulated chemokine [...]