Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth.

Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo- and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumor-initiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs.

Retinoblastoma (Rb) tumor-suppressor pathway alterations in meningeal hemangiopericytomas: High E2F transcription factor 1 expression and loss of Rb expression: study by double immunofluorescence staining and laser-scanning confocal microscopy.

BACKGROUND: The authors analyzed the retinoblastoma (Rb) tumor-suppressor pathway in meningeal hemangiopericytomas (MHPCs). METHODS: : Immunohistochemical detection of the Rb pathway proteins (Rb; E2F transcription factor 1 [E2F1]; cyclins D1, D3, and E; cyclin-dependent kinase 4 [CDK4]; and the CDK4 inhibitor p16/INKa) was followed by double immunofluorescence (DIF) staining and laser-scanning confocal microscopy (LSCM) in 11 MHPC specimens and from 4 specimens of recurrent disease from 1, 2, and 4 recurrences (total, 18 specimens). RESULTS: : All specimens displayed Rb pathway alterations, including low or negative Rb protein expression (17 specimens), high Rb protein expression (1 specimen), and loss of p16/INK4a expression (17 specimens). High levels of positive cell-cycle regulators were observed for E2F1 (10 specimens), cyclin E (7 specimens), CDK4 (5 specimens), cyclin D3 (1 specimen), and cyclin D1 (1 specimen). DIF and LSCM revealed no or very weak Rb and E2F1 colocalization, indicating that Rb does not act as a growth suppressor. High levels of human mouse double-minute 2 (HDM2) expression were observed in a previous study of these tumors, and they displayed colocalization with E2F1 and Rb in the current study, which supports the argument that HDM2 activates E2F1 and inactivates Rb. CONCLUSIONS: : The current findings demonstrated that loss of Rb and p16/INKa expression and high E2F1 expression indicate impairment of the Rb suppressor pathway. HDM2 colocalization with E2F1 and Rb also indicates that Rb suppressor pathway inactivation and transactivation of DNA synthesis genes may play pathogenic roles in MHPCs. High expression levels of cyclin E, cyclin D1, cyclin D3, and CDK4 were associated with Rb suppressor pathway neutralization.

Schwannoma of the eyelid: report of two cases.

Schwannomas are rare benign neurogenic tumors that show differentiation of Schwann cells that form the neural sheath. Only five reports of eyelid schwannomas in adults have been found in the English literature. We report the unusual cases of two females, aged 41 and 70 years, who developed eyelid schwannomas. Neither tumor was diagnosed clinically; both were erroneously considered as epidermal inclusion cysts. The masses were surgically removed by excisional biopsy. The histopathological examination showed encapsulated tumors composed of interlacing bundles of spindle cells with slightly wavy nuclei. Immunocytochemistry for S-100 protein was strongly positive. The diagnosis of schwannoma was made. After 12 and 2 years of follow-up, no recurrences have been observed. This entity should be included in the differential diagnosis of eyelid tumors.

Nemaline myopathy caused by absence of alpha-skeletal muscle actin.

OBJECTIVE: To investigate seven congenital myopathy patients from six families: one French Gypsy, one Spanish Gypsy, four British Pakistanis, and one British Indian. Three patients required mechanical ventilation from birth, five died before 22 months, one is ventilator-dependent, but one, at 30 months, is sitting with minimal support. All parents were unaffected. METHODS: The alpha-skeletal muscle actin gene (ACTA1) was sequenced. Available muscle biopsies were investigated by standard histological and electron microscopic techniques. The expression of various proteins was determined by immunohistochemistry, western blotting, or both. RESULTS: Three homozygous ACTA1 null mutations were identified: p.Arg41X in the French patient, p.Tyr364fsX in the Spanish patient, and p.Asp181fsX10 in all five British patients. An absence of alpha-skeletal muscle actin protein but presence of alpha-cardiac actin was shown in all muscle biopsies examined, with more alpha-cardiac actin in the biopsy from the child with the greatest muscle function. Muscle biopsies from all patients exhibited nemaline bodies whereas three also contained zebra bodies. INTERPRETATION: The seven patients have recessive nemaline myopathy caused by absence of alpha-skeletal muscle actin. The level of retention of alpha-cardiac actin, the skeletal muscle fetal actin isoform, may determine alpha-skeletal muscle actin disease severity. This has implications for possible future therapy.

Macrophagic myofasciitis in childhood: a controversial entity.

Macrophagic myofasciitis is an unusual inflammatory myopathy, which has been almost exclusively reported in French adults with diffuse arthromyalgias and asthenia. It is characterized by an infiltrate of densely packed macrophages, with granular periodic-acid-Schiff positive content, on muscle biopsies at the site of vaccination. The presence of aluminum inclusions in these macrophages points to an inappropriate reaction to aluminum used as an adjuvant in some vaccines. Although in adults this entity is well defined, less than 15 cases have been reported in children. This study describes seven children, younger than 3 years of age, with typical lesions of macrophagic myofasciitis on quadriceps muscle biopsy. In five cases, biopsies were performed to exclude mitochondrial pathology. All the children developed hypotonia and motor or psychomotor delay, associated with others symptoms. Abnormal neuroimaging was evident in six cases. Spectrometry studies detected elevated levels of aluminum in muscle in three of four cases tested. Despite the wide use of vaccines in childhood, macrophagic myofasciitis was rarely observed in children and its characteristic histologic pattern could not be correlated with a distinctive clinical syndrome.

Cutaneous horns of the eyelid: a clinicopathological study of 48 cases.

BACKGROUND: Cutaneous horn (cornu cutaneum) is a morphological designation for a protuberant mass of keratin that resembles the horn of an animal. It results from unusual cohesiveness of keratinized material from the superficial layers of the skin or implanted deeply in the cutis. This lesion may be associated with a benign, premalignant, or malignant lesion at the base, masking numerous conditions. METHODS: A retrospective analysis of 48 cases of cutaneous horns of the eyelid treated between 1992 and 2002 has been performed. RESULTS: Twenty-four men and 19 women, with a mean age of 62 years (range 16-90), were treated by surgery. Histologically, 77.1% were associated with benign specimens at the base pathology, 14.6% were premalignant, and finally, 8.3% were caused by malignant skin tumors. The most common lesion was seborrheic keratosis among the benign lesions, actinic keratosis among the premalignant ones, and basal cell carcinoma and squamous cell carcinoma among the malignant ones. CONCLUSION: Cutaneous horns usually appear on exposed skin areas in elderly men. The important issue in this condition is not the horn itself, which is just dead keratin, but rather the nature of the underlying disease, although the horns are usually benign.

Eyelid pilomatricomas in young adults: a report of 8 cases.

Pilomatricomas are common benign childhood tumors, which usually occur in the head and neck region. We present 8 patients and review the clinical and histopathologic features of pilomatricoma of the eyelids and eyebrows in young adults. From 1992 to 2000, diagnosis of eyelid pilomatricoma was performed in 8 young adults (13-36 years). The female-male ratio was 3:1. The mean age at presentation was 22 years. Each of our 8 patients had a single tumor, 4 on the upper eyelid and 4 on the eyebrow. Ossification existed in 4 cases. No tumor recurrence has been noted at 3.9 years. Pilomatricomas are uncommon tumors on the eyelid and brow region of young adults. These lesions are frequently misdiagnosed when evaluation is based on clinical evidence alone: only 4 of our cases were correctly diagnosed prior to excisional biopsy.