Despite similarities between tumor-initiating cells with stem-like properties (TICs) and normal neural stem cells, we hypothesized that there may be differences in their differentiation potentials. We now demonstrate that both bone morphogenetic protein (BMP)-mediated and ciliary neurotrophic factor (CNTF)-mediated Jak/STAT-dependent astroglial differentiation is impaired due to EZH2-dependent epigenetic silencing of BMP receptor 1B (BMPR1B) in a subset of glioblastoma TICs. Forced expression of BMPR1B either by transgene expression or demethylation of the promoter restores their differentiation capabilities and induces loss of their tumorigenicity. We propose that deregulation of the BMP developmental pathway in a subset of glioblastoma TICs contributes to their tumorigenicity both by desensitizing TICs to normal differentiation cues and by converting otherwise cytostatic signals to proproliferative signals.

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To assess the role of DNA repair in maintenance of hearing function and neurological integrity, we examined hearing status, neurological function, DNA repair complementation group and history of acute burning on minimal sun exposure in all patients with xeroderma pigmentosum, who had at least one complete audiogram, examined at the National Institutes of Health from 1971 to 2012. Seventy-nine patients, aged 1-61 years, were diagnosed with xeroderma pigmentosum (n = 77) or xeroderma pigmentosum/Cockayne syndrome (n = 2). A total of 178 audiograms were included. Clinically significant hearing loss (>20 dB) was present in 23 (29%) of 79 patients. Of the 17 patients with xeroderma pigmentosum-type neurological degeneration, 13 (76%) developed hearing loss, and all 17 were in complementation groups xeroderma pigmentosum type A or type D and reported acute burning on minimal sun exposure. Acute burning on minimal sun exposure without xeroderma pigmentosum-type neurological degeneration was present in 18% of the patients (10/55). Temporal bone histology in a patient with severe xeroderma pigmentosum-type neurological degeneration revealed marked atrophy of the cochlear sensory epithelium and neurons. The 19-year mean age of detection of clinically significant hearing loss in the patients with xeroderma pigmentosum with xeroderma pigmentosum-type neurological degeneration was 54 years younger than that predicted by international norms. The four frequency (0.5/1/2/4 kHz) pure-tone average correlated with degree of neurodegeneration (P < 0.001). In patients with xeroderma pigmentosum, aged 4-30 years, a four-frequency pure-tone average ≥10 dB hearing loss was associated with a 39-fold increased risk (P = 0.002) of having xeroderma pigmentosum-type neurological degeneration. Severity of hearing loss parallels neurological decline in patients with xeroderma pigmentosum-type neurological degeneration. Audiometric findings, complementation group, acute burning on minimal sun exposure and age were important predictors of xeroderma pigmentosum-type neurological degeneration. These results provide evidence that DNA repair is critical in maintaining neurological integrity of the auditory system.

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Introduction Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by mutations resulting in defective repair of DNA damage. XP patients have a markedly increased risk of ultraviolet induced neoplasms and premature aging of sun-exposed tissue. About 25% of XP patients in the US have neurologic abnormalities including progressive sensorineural hearing loss (SNHL). Objective To describe the temporal bone histopathology in two individuals with Xeroderma Pigmentosum (XPA and XPD) with neurological degeneration and to discuss the possible causes of deafness in these patients. Methods Temporal bones were removed at autopsy and studied using light microscopy. Results In the case with XPD, the organ of Corti was missing throughout the cochlea, whereas the case with XPA demonstrated scattered presence of sensory cells in the middle and apical turns. In both cases, there was moderate-to-severe patchy atrophy of the stria vascularis in all turns, and cochlear neurons were severely atrophied compared to age-matched controls, with loss of both peripheral dendrites and central axons. There was severe degeneration of Scarpa’s ganglion in the case with XPA. Conclusion Two cases of XP with neurological degeneration are reported. The case with XPD demonstrated a more severe audiologic phenotype than XPA, although both had similar findings such as atrophy of the organ of Corti, stria vascularis and spiral ganglia leading to severe or profound SNHL by the third decade of life. It is not clear if the neuronal degeneration in the inner ear was primary or secondary to loss of neuroepithelial cells.

Extracellular GRP94 (gp96) can initiate both innate and adaptive immune responses through interactions with antigen presenting cell surface receptors. Following the identification of CD91 as a receptor functioning in the cross-presentation of GRP94-associated peptides, scavenger receptors SR-A and SREC-I were demonstrated to function in GRP94 cell surface binding and endocytosis, lending controversy to the assignment of CD91 as the unique GRP94 endocytic receptor. To assess CD91 function in GRP94 surface binding and endocytosis, these parameters were examined in murine embyronic fibroblast (MEF) cell lines whose expression of CD91 was either reduced via RNAi or eliminated by genetic disruption of the CD91 locus. Reduction or loss of CD91 expression abrogated the binding and uptake of the CD91 ligand receptor-associated protein (RAP); surface binding and uptake of an N-terminal domain of GRP94 (GRP94.NTD) was unaffected. GRP94.NTD surface binding was markedly suppressed following treatment of MEF cell lines with heparin, the sulfation inhibitor sodium chlorate, or heparinase II, demonstrating that heparin sulfate proteoglycans can function in GRP94.NTD surface binding. The role of CD91 in the cross-presentaton of GRP94-associated peptides was examined in the DC2.4 dendritic cell line. In DC2.4 cells, which express CD91, GRP94.NTD-peptide cross-presentation was insensitive to RAP or activated α2-macroglobulin and occurred primarily via a fluid phase uptake pathway. In summary, these data clarify conflicting data on CD91 function in GRP94 surface binding, endocytosis and peptide cross-presentation and identify HSPGs as novel GRP94 cell surface binding sites.

At a 12-week follow-up appointment, a dramatic improvement in the appearance of the cutaneous lesions was noted, with near complete resolution of the patches and plaques and small residual foci at the prior larger nodular areas. The patient continued topical nitrogen mustard with continued improvement over 12 additional weeks (Figure 1B). However, the patient subsequently developed ophthalmic symptoms, including vertical and abduction defects, blurred vision, and peripheral vision loss, attributed to ocular involvement of the NXG. The patient then began dexamethasone 20-mg doses twice a week and cyclophosphamide 300-mg/m 2 doses on days 1, 8, and 15 of a 28-day cycle. He has shown clinical and laboratory improvement after 6 months.

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