IGF-1R is a molecular determinant for response to p53 reactivation therapy in conjunctival melanoma

AbstractMissense mutations in Valosin-Containing Protein (VCP) are linked to diverse degenerative diseases including IBMPFD, amyotrophic lateral sclerosis (ALS), muscular dystrophy and Parkinson’s disease. Here, we characterize a VCP-binding co-factor (SVIP) that specifically recruits VCP to lysosomes. SVIP is essential for lysosomal dynamic stability and autophagosomal–lysosomal fusion. SVIP mutations cause muscle wasting and neuromuscular degeneration while muscle-specific SVIP over-expression increases lysosomal abundance and is sufficient to extend lifespan in a context, stress-dependent manner. We also establish multiple links between SVIP and VCP-dependent disease in our Drosophila model system. A biochemical screen identifies a disease-causing VCP mutation that prevents SVIP binding. Conversely, over-expression of an SVIP mutation that prevents VCP binding is deleterious. Finally, we identify a human SVIP mutation and confirm the pathogenicity of this mutation in our Drosophila model. We propose a model for VCP disease based on the differential, co-factor-dependent recruitment of VCP to intracellular organelles.

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Fluorescent in situ hybridization (FISH): A useful diagnostic tool for childhood conjunctival melanoma

European Journal of Ophthalmology ◽

10.1177/11206721211030775 ◽

2021 ◽

pp. 112067212110307

Author(s):

Raquel María Moral ◽

Carlos Monteagudo ◽

Javier Muriel ◽

Lucía Moreno ◽

Ana María Peiró

Keyword(s):

In Situ Hybridization ◽

Fluorescent In Situ Hybridization ◽

Pediatric Population ◽

Diagnostic Technique ◽

Histopathological Diagnosis ◽

Fish Analysis ◽

Conjunctival Melanoma ◽

Adequate Treatment ◽

First Case

Introduction: Conjunctival melanoma is extremely rare in children and has low rates of resolution. Definitive histopathological diagnosis based exclusively on microscopic findings is sometimes difficult. Thus, early diagnosis and adequate treatment are essential to improve clinical outcomes. Clinical case: We present the first case in which the fluorescent in situ hybridization (FISH) diagnostic technique was applied to a 10-year-old boy initially suspected of having amelanotic nevi in his right eye. Based on the 65% of tumor cells with 11q13 (CCND1) copy number gain and 33% with 6p25 (RREB1) gain as measured by the FISH analysis, and on supporting histopathological findings, the diagnosis of conjunctival melanoma could be made. Following a larger re-excision, adjuvant therapy with Mitomycin C (MMC), cryotherapy and an amniotic membrane graft, the patient has remained disease-free during 9 years of long-term follow-up. Case discussion: Every ophthalmologist should remember to consider and not forget the possibility of using FISH analyses during the differential diagnosis of any suspicious conjunctival lesions. Genetic techniques, such as FISH, have led to great advances in the classification of ambiguous lesions. Evidence-based guidelines for diagnosing conjunctival melanoma in the pediatric population are needed to determine the most appropriate strategy for this age group.

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Conjunctival melanoma treatment outcomes in 288 patients: a multicentre international data-sharing study

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2020-316293 ◽

2020 ◽

pp. bjophthalmol-2020-316293

Author(s):

Puneet Jain ◽

Paul T Finger ◽

Maria Fili ◽

Bertil Damato ◽

Sarah E Coupland ◽

...

Keyword(s):

Local Recurrence ◽

Local Excision ◽

External Beam Radiotherapy ◽

Staging System ◽

Primary Treatment ◽

Excision Biopsy ◽

Conjunctival Melanoma ◽

Recurrence Rates ◽

Increased Risk ◽

Eighth Edition

BackgroundTo relate conjunctival melanoma characteristics to local control.MethodsRetrospective, registry-based interventional study with data gathered from 10 ophthalmic oncology centres from 9 countries on 4 continents. Conjunctival melanoma patients diagnosed between January 2001 and December 2013 were enrolled in the study. Primary treatments included local excision, excision with cryotherapy and exenteration. Adjuvant treatments included topical chemotherapy, brachytherapy, proton and external beam radiotherapy (EBRT). Cumulative 5-year and 10-year Kaplan-Meier local recurrence rates were related to clinical and pathological T-categories of the eighth edition of the American Joint Committee on Cancer (AJCC) staging system.Results288 patients had a mean initial age of 59.7±16.8 years. Clinical T-categories (cT) were cT1 (n=218,75.7%), cT2 (n=34, 11.8%), cT3 (n=15, 5.2%), cTx (n=21,7.3%) with no cT4. Primary treatment included local excision (n=161/288, 55.9%) followed by excision biopsy with cryotherapy (n=108/288, 37.5%) and exenteration (n=5/288, 1.7%). Adjuvant therapies included topical mitomycin (n=107/288, 37.1%), plaque-brachytherapy (n=55/288, 19.1%), proton-beam (n=36/288, 13.5%), topical interferon (n=20/288, 6.9%) and EBRT (n=15/288, 5.2%). Secondary exenteration was performed (n=11/283, 3.9%). Local recurrence was noted in 19.1% (median=3.6 years). Cumulative local recurrence was 5.4% (3.2–8.9%), 19.3% (14.4–25.5%) and 36.9% (26.5–49.9%) at 1, 5 and 10 years, respectively. cT3 and cT2 tumors were twice as likely to recur than cT1 tumours, but only cT3 had statistically significantly greater risk of local recurrence than T1 (p=0.013). Factors such as tumour ulceration, plica or caruncle involvement and tumour thickness were not significantly associated with an increased risk of local recurrence.ConclusionThis multicentre international study showed that eighth edition of AJCC tumour staging was related to the risk of local recurrence of conjunctival melanoma after treatment. The 10-year cumulative local recurrence remains high despite current management.

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Ptf1a Is a Molecular Determinant for Both Glutamatergic and GABAergic Neurons in the Hindbrain

Journal of Neuroscience ◽

10.1523/jneurosci.5139-07.2008 ◽

2008 ◽

Vol 28 (2) ◽

pp. 338-339 ◽

Cited By ~ 6

Author(s):

K. A. Aldinger ◽

G. E. Elsen

Keyword(s):

Gabaergic Neurons ◽

Molecular Determinant

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Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers

Nature Communications ◽

10.1038/s41467-021-23507-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ladan Amin ◽

David A. Harris

Keyword(s):

Amyloid Β ◽

Super Resolution ◽

Structural Motif ◽

Aβ Oligomers ◽

Surface Receptors ◽

Molecular Features ◽

Molecular Determinant ◽

Receptor Interactions ◽

Aβ Fibrils ◽

Super Resolution Microscopy

AbstractSeveral cell-surface receptors for neurotoxic forms of amyloid-β (Aβ) have been described, but their molecular interactions with Aβ assemblies and their relative contributions to mediating Alzheimer’s disease pathology have remained uncertain. Here, we used super-resolution microscopy to directly visualize Aβ-receptor interactions at the nanometer scale. We report that one documented Aβ receptor, PrPC, specifically inhibits the polymerization of Aβ fibrils by binding to the rapidly growing end of each fibril, thereby blocking polarized elongation at that end. PrPC binds neurotoxic oligomers and protofibrils in a similar fashion, suggesting that it may recognize a common, end-specific, structural motif on all of these assemblies. Finally, two other Aβ receptors, FcγRIIb and LilrB2, affect Aβ fibril growth in a manner similar to PrPC. Our results suggest that receptors may trap Aβ oligomers and protofibrils on the neuronal surface by binding to a common molecular determinant on these assemblies, thereby initiating a neurotoxic signal.

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