Intracranial hematolymphoid malignancies: A case series with molecular characterization.

OBJECTIVE: Central nervous system (CNS) manifestations of hematologic malignancies are uncommon and often have a poor prognosis. As hematologic neoplasms are typically chemotherapy- and radiotherapy-sensitive, surgical resection is usually not indicated; thus, opportunities for in-depth characterization of CNS hematologic tumors are limited. Here, we report four cases of rare intracranial hematologic tumors requiring surgical intervention, allowing for histopathologic and genomic characterization. METHODS: The clinical course, genetic perturbations, and histopathological features are described for a case of 1) primary marginal zone B-cell lymphoma of the dura as well as cases of brain metastases of 2) cutaneous T-cell lymphoma, 3) acute myeloid leukemia/myeloid sarcoma, and 4) multiple myeloma. Targeted DNA sequencing, fluorescence in situ hybridization, cytogenetic analysis, flow cytometry and immunohistochemical staining were used to assess the lesions. RESULT: Molecular and histopathological characterizations of four unusual presentations of hematolymphoid diseases involving the CNS are presented. Genetic abnormalities were identified in each lesion, including chromosomal aberrations and single nucleotide variants resulting in missense or nonsense mutations in oncogenes. CONCLUSIONS: Our case series provides insight into unique pathological phenotypes of hematologic neoplasms with atypical CNS involvement. We offer targets for future studies by identifying potentially pathogenic genetic variants in these lesions, as the full implications of the novel molecular abnormalities described remain unclear.

Correction: Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia.

[This corrects the article DOI: 10.1371/journal.pbio.3001480.].

Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia.

Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal dominant Parkinson disease (PD), while polymorphic LRRK2 variants are associated with sporadic PD. PD-linked mutations increase LRRK2 kinase activity and induce neurotoxicity in vitro and in vivo. The small GTPase Rab8a is a LRRK2 kinase substrate and is involved in receptor-mediated recycling and endocytic trafficking of transferrin, but the effect of PD-linked LRRK2 mutations on the function of Rab8a is poorly understood. Here, we show that gain-of-function mutations in LRRK2 induce sequestration of endogenous Rab8a to lysosomes in overexpression cell models, while pharmacological inhibition of LRRK2 kinase activity reverses this phenotype. Furthermore, we show that LRRK2 mutations drive association of endocytosed transferrin with Rab8a-positive lysosomes. LRRK2 has been nominated as an integral part of cellular responses downstream of proinflammatory signals and is activated in microglia in postmortem PD tissue. Here, we show that iPSC-derived microglia from patients carrying the most common LRRK2 mutation, G2019S, mistraffic transferrin to lysosomes proximal to the nucleus in proinflammatory conditions. Furthermore, G2019S knock-in mice show a significant increase in iron deposition in microglia following intrastriatal LPS injection compared to wild-type mice, accompanied by striatal accumulation of ferritin. Our data support a role of LRRK2 in modulating iron uptake and storage in response to proinflammatory stimuli in microglia.

Characteristics and career outcomes of Neurosurgery Research and Education Foundation research fellowship recipients.

OBJECTIVE: The American Association of Neurological Surgeons (AANS) Neurosurgery Research and Education Foundation (NREF) provides ongoing competitive research fellowships for residents and young investigators. The authors sought to determine the characteristics and career tracks of award recipients. METHODS: The authors analyzed characteristics and academic productivity parameters of NREF resident and young investigator awardees in the United States and Canada from 1983 to 2017. Data were extracted from the NREF database and online resources (Web of Science, NIH reporter). RESULTS: In total, 224 research grants were awarded to 31 women (14%) and 193 men (86%) from 1983 to 2017. Neuro-oncology (36%) was the most common research category. Sixty percent of awardees were in training and most resident award winners were in postgraduate year 5 (37%). Forty-nine percent of all awardees had an additional postgraduate degree (PhD 39%, Master's 10%) with a significantly higher number of PhD recipients being from Canada in comparison to any US region (p = 0.024). The Northeastern and Southeastern United States were the regions with the highest and lowest numbers of award recipients, respectively. More than one-third (40%) of awardees came from institutions that have a National Institute of Neurological Disorders and Stroke Research Education Grant (NINDS R25) for neurosurgical training. Awardees from NINDS R25-funded programs were significantly more likely to go on to receive funding from the National Institutes of Health (NIH) (40.4% vs 26.1%; p = 0.024). The majority of recipients (72%) who were no longer in training pursued fellowships, with a significant likelihood that fellowship subspecialty correlated with NREF research category (p < 0.001). Seventy-nine percent of winners entered academic neurosurgery practice, with 18% obtaining the position of chair. The median h-index among NREF winners was 11. NIH funding was obtained by 71 awardees (32%) with 36 (18%) being a principal investigator on an R01 grant from the NIH Research Project Grant Program. CONCLUSIONS: The majority of AANS/NREF research award recipients enter academics as fellowship-trained neurosurgeons, with approximately one-third obtaining NIH funding. Analysis of this unique cohort allows for identification of characteristics of academic success.