Cerebrospinal fluid and blood profiles of transfer RNA fragments show age, sex, and Parkinson's disease-related changes.

Transfer RNA fragments (tRFs) have recently been shown to be an important family of small regulatory RNAs with diverse functions. Recent reports have revealed modified tRF blood levels in a number of nervous system conditions including epilepsy, ischemic stroke, and neurodegenerative diseases, but little is known about tRF levels in the cerebrospinal fluid (CSF). To address this issue, we studied age, sex, and Parkinson's disease (PD) effects on the distributions of tRFs in the CSF and blood data of healthy controls and PD patients from the NIH and the Parkinson's Progression Markers Initiative (PPMI) small RNA-seq datasets. We discovered that long tRFs are expressed in higher levels in the CSF than in the blood. Furthermore, the CSF showed a pronounced age-associated decline in the level of tRFs cleaved from the 3'-end and anti-codon loop of the parental tRNA (3'-tRFs, i-tRFs), and more pronounced profile differences than the blood profiles between the sexes. In comparison, we observed moderate age-related elevation of blood 3'-tRF levels. In addition, distinct sets of tRFs in the CSF and in the blood segregated PD patients from controls. Finally, we found enrichment of tRFs predicted to target cholinergic mRNAs (Cholino-tRFs) among mitochondrial-originated tRFs, raising the possibility that the neurodegeneration-related mitochondrial impairment in PD patients may lead to deregulation of their cholinergic tone. Our findings demonstrate that the CSF and blood tRF profiles are distinct and that the CSF tRF profiles are modified in a sex-, age-, and disease-related manner, suggesting that they reflect the inter-individual cerebral differences and calling for incorporating this important subset of small RNA regulators into future studies.

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.

INTRODUCTION: Females with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in transfer RNS (tRNA) fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). METHODS: We analyzed small RNA-sequencing (RNA-Seq) data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation. RESULTS: NAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single-cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations. DISCUSSION: Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.

[FALSE POSITIVE 5-ALA INDUCED FLUORESCENCE OF HEMATOLOGICAL MALIGNANCIES, BENIGN TUMORS, INFECTIOUS AND INFLAMMATORY PATHOLOGIES PRESENTED AS BRAIN LESIONS - A CASE SERIES].

INTRODUCTION: The 5-aminolevulinic acid (5-ALA) fluorescence-guided resection is an essential part of the current state-of-the-art treatment of primary malignant brain tumors. Metabolized by tumor cells, creating Protoporphyrin-IX, which is fluorescent under UV light emitted from the microscope, 5-ALA facilitates visual distinction between the tumor and the normal brain tissue surrounding it, coloring it pink. This real-time diagnostic feature was shown to lead to more complete removal of the tumor and confers a survival benefit. Nevertheless, despite the high sensitivity and specificity that was described using this method, there are other pathological processes in which 5-ALA is being metabolized that fluoresce similarly to a malignant glial tumor.

Identification of vascular cues contributing to cancer cell stemness and function.

Glioblastoma stem cells (GSCs) reside close to blood vessels (BVs) but vascular cues contributing to GSC stemness and the nature of GSC-BVs cross talk are not fully understood. Here, we dissected vascular cues influencing GSC gene expression and function to perfusion-based vascular cues, as well as to those requiring direct GSC-endothelial cell (EC) contacts. In light of our previous finding that perivascular tumor cells are metabolically different from tumor cells residing further downstream, cancer cells residing within a narrow, < 60 µm wide perivascular niche were isolated and confirmed to possess a superior tumor-initiation potential compared with those residing further downstream. To circumvent reliance on marker expression, perivascular GSCs were isolated from the respective locales based on their relative state of quiescence. Combined use of these procedures uncovered a large number of previously unrecognized differentially expressed GSC genes. We show that the unique metabolic milieu of the perivascular niche dominated by the highly restricted zone of mTOR activity is conducive for acquisition of GSC properties, primarily in the regulation of genes implicated in cell cycle control. A complementary role of vascular cues including those requiring direct glioma/EC contacts was revealed using glioma/EC co-cultures. Outstanding in the group of glioma cells impacted by nearby ECs were multiple genes responsible for maintaining GSCs in an undifferentiated state, a large fraction of which also relied on Notch-mediated signaling. Glioma-EC communication was found to be bidirectional, evidenced by extensive Notch-mediated EC reprogramming by contacting tumor cells, primarily metabolic EC reprogramming.

Intraoperative neuromonitoring during resection of cranial meningiomas and its effect on the surgical workflow.

PURPOSE: Resection of meningiomas adjacent to the central sulcus entails a high rate of morbidity. Explored for intra-axial lesion resection, intraoperative neuromonitoring intraoperative neuromonitoring (IONM) has been shown to decrease neurological deficits. The use of IONM is relatively uncommon and is not considered routine practice in the removal of extra-axial lesions. We sought to characterize IONM's impact on the surgical workflow in supratentorial meningiomas. METHODS: We retrospectively analyzed a prospectively collected database, searching cases in which IONM was used for resection of meningioma between 2017 and 2020. We classified the IONM effect on surgical workflow into 5 distinct categories of workflow changes (WFC). RESULTS: Forty cases of meningiomas with IONM use were identified. In 1 case (class 1 WFC), the operation was stopped due to IONM input. In 5 cases (class 2 WFC), the tumor was incompletely resected due to input from the IONM. In 14 cases (35%), IONM leads to an alteration of the resection process (alteration of approach, class 3 WFC). In 4 cases (10%), anesthesia care was modified based on IONM input (class 4 WFC). In 16 cases, no changes were made (class 5 WFC). In all patients in whom a change was made (24 cases, WFC 1-4), only 8.3% suffered a temporary deficit, and there were no permanent deficits, whereas when no change was made, there were 18.75% temporary deficit and 6.25% permanent deficit. CONCLUSION: IONM has an impact during resection of meningiomas in eloquent areas and may guide the surgical technique, approach to tumor resection, and extent of resection.

Metastases to meningioma-review and meta-analysis.

PURPOSE: Meningiomas are a common tumor within the cranial cavity. They may be a target for metastatic spread of cancer elsewhere in the body. We analyzed all the data in the literature about tumor-to-meningioma metastasis (TTMM). METHODS: We performed a meta-analysis using the PRISMA checklist to locate all cases of TTMM in the PubMed and Medline databases. We collected patient and cancer parameters, meningioma parameters, and clinical factors. RESULTS: We located 124 articles, describing 152 cases of patients with TTMM. The mean (± SD) age of all patients was 62.21 ± 10.8 years, with even distribution above and below the mean. Of the cases, 65.9% were reported in women. The most common cancer origins of TTMM were breast and lung carcinoma, followed by kidney, prostate, and GI tract carcinoma. Cancer status is not a good marker of TTMM when managing a meningioma. In 36.69% of cases, TTMM was the presentation of an unknown cancer. In nearly 60% of the known cases, cancer was considered in remission for at least 1 year. Meningioma parameters are unhelpful when considering a TTMM. The distribution of meningioma location is similar to other series of meningioma reported in the literature. Meningioma grade is similar to meningiomas without TTMM. In 57.89%, the patient presented with a focal deficit. Presenting factors were seizures, elevated ICP, and others. Over 95% of cases were symptomatic at presentation. CONCLUSION: TTMM should be suspected in cases of meningioma in a patient with background cancer, regardless of meningioma parameters or cancer status.

Correction to: Serum microRNA is a biomarker for post-operative monitoring in glioma.

For the reference citation '[57]' in the second paragraph of the Results section of the original article there was no corresponding entry in the References section. It should have referred to the below mentioned article by Ebrahimkhani et al. (2018).

Serum microRNA is a biomarker for post-operative monitoring in glioma.

PURPOSE: A circulating biomarker has potential to provide more accurate information for glioma progression post treatment, however no such biomarker is currently available. We aimed to discover a microRNA serum biomarker for longitudinal monitoring of glioma patients. METHODS: A prospectively collected cohort of 91 glioma patients and 17 healthy controls underwent pre and post-operative serum miRNA profiling using Nanostring®. Differentially expressed miRNAs were discovered using a machine learning random forest analysis. Candidate miRNAs were then assessed by droplet digital PCR in 11 patients with multiple follow up samples and compared to tumor volume based on magnetic resonance imaging. RESULTS: A 9-gene miRNA signature was identified that could distinguish between glioma and healthy controls with 99.8% accuracy. Two miRNAs miR-223 and miR-320e, best demonstrated dynamic changes that correlated closely with tumor volume in LGG and GBM respectively. Importantly, miRNA levels did not increase in two cases of pseudo-progression, indicating the potential utility of this test in guiding treatment decisions. CONCLUSIONS: We identified a highly accurate 9-miRNA signature associated with glioma serum. Additionally, we observed dynamic changes in specific miRNAs correlating with tumor volume over long-term follow up. These results support a large prospective validation study of serum miRNA biomarkers in glioma.

The efficacy of lapatinib and nilotinib in combination with radiation therapy in a model of NF2 associated peripheral schwannoma.

Neurofibromatosis type 2 (NF2), a neurogenetic condition manifest by peripheral nerve sheath tumors (PNST) throughout the neuroaxis for which there are no approved therapies. In vitro and in vivo studies presented here examine agents targeting signaling pathways, angiogenesis, and DNA repair mechanisms. In vitro dose response assays demonstrated potent activity of lapatinib and nilotinib against the mouse schwannoma SC4 (Nf2 -/-) cell line. We then examined the efficacy of everolimus, nilotinib, lapatinib, bevacizumab and radiation (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 -/-) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748). Lapatinib, nilotinib and RT significantly reduced tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas bevacizumab and everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed nilotinib or lapatinib as single agents (nilotinib vs. nilotinib + RT, p = 0.0001; lapatinib versus lapatinib + RT, p < 0.0001) with no observed toxicity. There was no re-growth of tumors even 14 days after treatment was stopped. The combination of either lapatinib or nilotinib with RT resulted in greater delays in tumor growth rate than any modality alone. This data suggest that concurrent low dose RT and targeted therapy may have a role in addressing progressive PNST in patients with NF2.