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Some secreted proteins that assemble into large complexes, such as extracellular matrices or hormones and enzymes in storage granules, must be kept at subaggregation concentrations during intracellular trafficking. We show surfeit locus protein 4 (Surf4) is the cargo receptor that establishes different steady-state concentrations for a variety of soluble cargo proteins within the endoplasmic reticulum (ER) through interaction with the amino-terminal tripeptides exposed after removal of leader sequences. We call this motif the ER-Exit by Soluble Cargo using Amino-terminal Peptide-Encoding motif (ER-ESCAPE motif). Proteins that most readily aggregate in the ER lumen (e.g., dentin sialophosphoprotein [DSPP] and amelogenin, X-linked [AMELX]) have strong ER-ESCAPE motifs to inhibit aggregate formation, while less susceptible cargo exhibits weaker motifs. Specific changes in a single amino acid of the tripeptide result in aggregate formation and failure to efficiently traffic cargo out of the ER. A logical subset of 8,000 possible tripeptides starting a model soluble cargo protein (growth hormone) established a continuum of steady-state ER concentrations ranging from low (i.e., high affinity for receptor) to the highest concentrations associated with bulk flow-limited trafficking observed for nonbinding motifs. Human cells lacking Surf4 no longer preferentially trafficked cargo expressing strong ER-ESCAPE motifs. Reexpression of Surf4 or expression of yeast's ortholog, ER-derived vesicles protein 29 (Erv29p), rescued enhanced ER trafficking in Surf4-null cells. Hence our work describes a new way of preferentially exporting soluble cargo out of the ER that maintains proteins below the concentrations at which they form damaging aggregates.
Asunto(s)
Retículo Endoplásmico/metabolismo , Proteínas de la Membrana/genética , Oligopéptidos/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Transporte Vesicular/genética , Secuencias de Aminoácidos , Sitios de Unión , Vesículas Cubiertas por Proteínas de Revestimiento/metabolismo , Vesículas Cubiertas por Proteínas de Revestimiento/ultraestructura , Retículo Endoplásmico/ultraestructura , Regulación de la Expresión Génica , Prueba de Complementación Genética , Células HEK293 , Humanos , Proteínas de la Membrana/metabolismo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Transporte de Proteínas , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Transducción de Señal , Proteínas de Transporte Vesicular/metabolismoRESUMEN
Cobb syndrome is a rare neurocutaneous disease characterized by multiple spinal vascular anomalies and vascular skin lesions affecting the corresponding dermatome. We present a case of a 12-year-old boy with history of spinal arteriovenous malformation (AVM) extending from T4-T5 status post partial embolization 3 years ago and hyperpigmented patch overlying his thoracic back region presenting with 2 days of back pain and lower extremity numbness and weakness. He had multiple Type III AVMs within the spinal and paraspinal tissues involving the T4-T7 vertebral elements, most extensively T4 and T5. The largest aneurysm located at the confluence of the main AVM nidus was a 4â mm anterior spinal artery aneurysm, which was embolized with partial embolization of the main AVM nidus, resulting in complete aneurysm occlusion. This report provides valuable insight on the natural history, recurrence risk, and treatment options of Cobb syndrome to aid in early diagnosis and improve outcomes.
RESUMEN
BACKGROUND: Neurofibromatosis type 1 (NF1) is a multisystemic autosomal dominant disorder that includes intracranial lesions such as unidentified bright objects (UBOs)-areas of increased T2 signal on magnetic resonance imaging (MRI)-and tumors known as gliomas. The presence of these lesions in the corpus callosum (CC) has not been previously studied in a large cohort. METHODS: We reviewed medical records of 681 patients (aged three months to 86 years) followed at our institution from 2000 to 2023 with NF1 and one or more brain MRI. Patients with lesions in the CC were identified, and RAPNO/RANO criteria were used to determine changes in size over time, where a change of 25% in the product of perpendicular measurements indicates growth or shrinkage. RESULTS: Forty-seven patients had CC UBOs, most of which were in the splenium (66.0%). Seventeen patients had CC gliomas (10% of those with any glioma), two of whom had two gliomas. Seventeen of 19 gliomas were in the splenium. Over follow-up, eight of 19 remained stable, three shrunk, and eight grew. The mean percentage change in the product of the dimensions was 311.5% (ranging from -46.7% to 2566.6%). Of the eight lesions that grew, one required treatment. CONCLUSIONS: There is a 6.9% and 2.5% prevalence of CC UBOs and gliomas, respectively, in our cohort of patients with NF1. Most lesions are present in the splenium, and although some gliomas demonstrate significant growth, they rarely require treatment. This work is the largest series of CC lesions in NF1 and adds to the growing data to inform appropriate follow-up.
Asunto(s)
Neoplasias Encefálicas , Cuerpo Calloso , Glioma , Imagen por Resonancia Magnética , Neurofibromatosis 1 , Humanos , Neurofibromatosis 1/diagnóstico por imagen , Neurofibromatosis 1/complicaciones , Neurofibromatosis 1/patología , Niño , Preescolar , Adolescente , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Masculino , Femenino , Lactante , Adulto , Adulto Joven , Glioma/diagnóstico por imagen , Glioma/patología , Persona de Mediana Edad , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/complicaciones , Anciano , Anciano de 80 o más Años , Estudios RetrospectivosRESUMEN
Streptococcus pneumoniae (S. Pneumoniae) is a common cause of bacterial meningitis in the pediatric population, but rarely causes complications such as encephalitis, abscess, and seizures with the prompt initiation of proper antimicrobial therapy. In this report, we present a rare and severe case of S. Pneumoniae meningoencephalitis in a full term 6-month-old which progressed to multiple cerebral and cerebellar infarcts with concomitant cerebellar tonsillar herniation and hypercarbic respiratory failure requiring intubation and mechanical ventilation despite early initiation of antibiotics. Given the patient's clinical status and poor neurological prognosis, the family eventually opted for palliative extubation.
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Background Brachial plexus birth injury results in deficits in strength and motion, occasionally requiring surgery to restore power to the deficient external rotators of the shoulder in these patients. This is a retrospective analysis of the long-term results of an isolated latissimus dorsi transfer to the rotator cuff in patients with brachial plexus birth injury. Methods This is a retrospective review of prospectively collected data for patients undergoing isolated latissimus dorsi transfer into the infraspinatus in addition to release of the internal rotation contracture of the shoulder with greater than 5 years' follow-up. Preoperative and postoperative shoulder elevation and external rotation were documented. Failure of surgery was defined as a return of the internal rotation contracture and a clinically apparent clarion sign. Results A total of 22 patients satisfied the inclusion criteria: 9 global palsies and 13 upper trunk palsies. The average follow-up was 11 years, ranging from 7.5 to 15.9 years. There was a trend for improved external rotation in the global palsy cohort at final follow-up ( p = 0.084). All nine global palsies maintained adequate external rotation without a clarion sign. Five of the 13 upper trunk palsies failed the latissimus dorsi transfer and subsequently required either teres major transfer and/or rotational osteotomy. In these five failures, the period from initial transfer to failure averaged 6.6 years, ranging from 3.4 to 9.5 years. Conclusion The results of this study indicate that patients with global palsy have sustained long-term improved outcomes with isolated latissimus dorsi transfer while patients with upper trunk palsy have a high rate of failure. Based on these results, we recommend isolated latissimus dorsi transfer for global palsy patients who have isolated infraspinatus weakness. Level of Evidence: Case series - Level IV.
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BACKGROUND: Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma. METHODS: We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts. RESULTS: There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P valueâ =â .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P valueâ =â .0534). CONCLUSIONS: The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.
Asunto(s)
Astrocitoma , Biomarcadores de Tumor , Neoplasias Encefálicas , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Metilación de ADN , Isocitrato Deshidrogenasa , Mutación , Humanos , Astrocitoma/genética , Astrocitoma/patología , Astrocitoma/mortalidad , Isocitrato Deshidrogenasa/genética , Masculino , Pronóstico , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Femenino , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/mortalidad , Adulto , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Anciano , Tasa de Supervivencia , Estudios de Seguimiento , Adulto Joven , Homocigoto , Eliminación de GenRESUMEN
The incidence of childhood central nervous system tumors in infants is about 6 per 100â 000 children. Recent studies have showed recurrent fusion of the neurotrophic tyrosine receptor kinase (NTRK) gene in 10% of non-brainstem high grade glioma in very young children suggesting an oncogenic effect of the NTRK fusion genes. In this report, we present a rare, severe case of a full-term neonate who was noted to have widely splayed sutures and a bulging fontanelle at birth who was found to have infant-type hemispheric glioma with NTRK1 fusion with course complicated by seizures refractory to medical treatment. Patient was deemed a poor surgical candidate due to the size of the mass and thus parents opted for comfort care.
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Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64 years (range 1-82) and the overall median survival was 397 days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (p = 0.366) or radiation (p = 0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.
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Neoplasias Encefálicas , Glioma , Neoplasias de la Médula Espinal , Adulto , Masculino , Femenino , Humanos , Niño , Recién Nacido , Lactante , Neoplasias Encefálicas/patología , Estudios Retrospectivos , Histonas/genética , Glioma/genética , Glioma/patología , Neoplasias de la Médula Espinal/genética , Mutación/genéticaRESUMEN
Mucopolysaccharidosis type I (MPS I), is an autosomal recessive lysosomal storage disorder caused by a deficiency in the α-L-iduronidase enzyme, resulting in decreased enzymatic activity and accumulation of glycosaminoglycans. The disorder phenotypically manifests with increased urine glycosaminoglycan excretion, facial dysmorphology, neuropathology, cardiac manifestations, and bone deformities. While the development of new treatment strategies have shown promise in attenuating many symptoms associated with the disorder, the bone phenotype remains unresponsive. The aim of this study was to investigate and further characterize the skeletal manifestations of the Idua-W392X knock-in mouse model, which carries a nonsense mutation corresponding to the IDUA-W402X mutation found in Hurler syndrome (MPS I-H) patients. µCT analysis of the microarchitecture demonstrated increased cortical thickness, trabecular number, and trabecular connectivity along with decreased trabecular separation in the tibiae of female homozygous Idua-W392X knock-in (IDUA-/-) mice, and increased cortical thickness in male IDUA-/- tibiae. Cortical density, as determined by µCT, and bone mineral density distribution, as determined by quantitative backscattered microscopy, were equivalent in IDUA-/- and wildtype (Wt) bone. However, tibial porosity was increased in IDUA-/- cortical bone. Raman spectroscopy results indicated that tibiae from female IDUA-/- had decreased phosphate to matrix ratios and increased carbonate to phosphate ratios compared to Wt female tibiae, whereas these ratios remained equivalent in male IDUA-/- and Wt tibiae. Femora demonstrated altered geometry and upon torsional loading to failure analysis, female IDUA-/- mouse femora exhibited increased torsional ultimate strength, with a decrease in material strength relative to Wt littermates. Taken together, these findings suggest that the IDUA-/- mutation results in increased bone torsional strength by altering the overall bone geometry and the microarchitecture which may be a compensatory response to increased porosity, reduced bone tensile strength and altered physiochemical composition.