bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictions and analyses of RNA nearest neighbor parameters for modified nucleotides
Authors: Hopfinger Melissa C , Kirkpatrick Charles C , Znosko Brent M 
Published: August 2020

AbstractThe most popular RNA secondary structure prediction programs utilize free energy (ΔG°37) minimization and rely upon thermodynamic parameters from the nearest neighbor (NN) model. Experimental parameters are derived from a series of optical melting experiments; however, acquiring enough melt data to derive accurate NN parameters with modified base pairs is expensive and time consuming. Given the multitude of known natural modifications and the continuing use and development of unnatural nucleotides, experimentally characterizing all modified NNs is impractical. This dilemma necessitates a computational model that can predict NN thermodynamics where experimental data is scarce or absent. Here, we present a combined molecular dynamics/quantum mechanics protocol that accurately predicts experimental NN ΔG°37 parameters for modified nucleotides with neighboring Watson–Crick base pairs. NN predictions for Watson-Crick and modified base pairs yielded an overall RMSD of 0.32 kcal/mol when compared with experimentally derived parameters. NN predictions involving modified bases without experimental parameters (N6-methyladenosine, 2-aminopurineriboside, and 5-methylcytidine) demonstrated promising agreement with available experimental melt data. This procedure not only yields accurate NN ΔG°37 predictions but also quantifies stacking and hydrogen bonding differences between modified NNs and their canonical counterparts, allowing investigators to identify energetic differences and providing insight into sources of (de)stabilization from nucleotide modifications.
FANCJ compensates for RAP80 deficiency and suppresses genomic instability induced by interstrand cross-links
Authors: Awate Sanket , Sommers Joshua A , Datta Arindam , Nayak Sumeet , Bellani Marina A , Yang Olivia , Dunn Christopher A , Nicolae Claudia M , Moldovan George-Lucian , Seidman Michael M , Cantor Sharon B , Brosh Robert M 
Published: August 2020

AbstractFANCJ, a DNA helicase and interacting partner of the tumor suppressor BRCA1, is crucial for the repair of DNA interstrand crosslinks (ICL), a highly toxic lesion that leads to chromosomal instability and perturbs normal transcription. In diploid cells, FANCJ is believed to operate in homologous recombination (HR) repair of DNA double-strand breaks (DSB); however, its precise role and molecular mechanism is poorly understood. Moreover, compensatory mechanisms of ICL resistance when FANCJ is deficient have not been explored. In this work, we conducted a siRNA screen to identify genes of the DNA damage response/DNA repair regime that when acutely depleted sensitize FANCJ CRISPR knockout cells to a low concentration of the DNA cross-linking agent mitomycin C (MMC). One of the top hits from the screen was RAP80, a protein that recruits repair machinery to broken DNA ends and regulates DNA end-processing. Concomitant loss of FANCJ and RAP80 not only accentuates DNA damage levels in human cells but also adversely affects the cell cycle checkpoint, resulting in profound chromosomal instability. Genetic complementation experiments demonstrated that both FANCJ’s catalytic activity and interaction with BRCA1 are important for ICL resistance when RAP80 is deficient. The elevated RPA and RAD51 foci in cells co-deficient of FANCJ and RAP80 exposed to MMC are attributed to single-stranded DNA created by Mre11 and CtIP nucleases. Altogether, our cell-based findings together with biochemical studies suggest a critical function of FANCJ to suppress incompletely processed and toxic joint DNA molecules during repair of ICL-induced DNA damage.
The deacetylase SIRT6 promotes the repair of UV-induced DNA damage by targeting DDB2
Authors: Geng Anke , Tang Huanyin , Huang Jin , Qian Zhen , Qin Nan , Yao Yunxia , Xu Zhu , Chen Hao , Lan Li , Xie Hongjuan , Zhang Jian , Jiang Ying , Mao Zhiyong 
Published: August 2020

Abstract
The NAD+-dependent deacetylase and mono-ADP-ribosyl transferase SIRT6 stabilizes the genome by promoting DNA double strand break repair, thereby acting as a tumor suppressor. However, whether SIRT6 regulates nucleotide excision repair (NER) remains unknown. Here, we showed that SIRT6 was recruited to sites of UV-induced DNA damage and stimulated the repair of UV-induced DNA damage. Mechanistic studies further indicated that SIRT6 interacted with DDB2, the major sensor initiating global genome NER (GG-NER), and that the interaction was enhanced upon UV irradiation. SIRT6 deacetylated DDB2 at two lysine residues, K35 and K77, upon UV stress and then promoted DDB2 ubiquitination and segregation from chromatin, thereby facilitating downstream signaling. In addition, we characterized several SIRT6 mutations derived from melanoma patients. These SIRT6 mutants ablated the stimulatory effect of SIRT6 on NER and destabilized the genome due to (i) partial loss of enzymatic activity (P27S or H50Y), (ii) a nonsense mutation (R150*) or (iii) high turnover rates (G134W). Overall, we demonstrate that SIRT6 promotes NER by deacetylating DDB2, thereby preventing the onset of melanomagenesis.
METTL4 catalyzes m6Am methylation in U2 snRNA to regulate pre-mRNA splicing
Authors: Goh Yeek Teck , Koh Casslynn W Q , Sim Donald Yuhui , Roca Xavier , Goh W S Sho 
Published: August 2020

AbstractN 6-methylation of 2′-O-methyladenosine (Am) in RNA occurs in eukaryotic cells to generate N6,2′-O-dimethyladenosine (m6Am). Identification of the methyltransferase responsible for m6Am catalysis has accelerated studies on the function of m6Am in RNA processing. While m6Am is generally found in the first transcribed nucleotide of mRNAs, the modification is also found internally within U2 snRNA. However, the writer required for catalyzing internal m6Am formation had remained elusive. By sequencing transcriptome-wide RNA methylation at single-base-resolution, we identified human METTL4 as the writer that directly methylates Am at U2 snRNA position 30 into m6Am. We found that METTL4 localizes to the nucleus and its conserved methyltransferase catalytic site is required for U2 snRNA methylation. By sequencing human cells with overexpressed Mettl4, we determined METTL4’s in vivo target RNA motif specificity. In the absence of Mettl4 in human cells, U2 snRNA lacks m6Am thereby affecting a subset of splicing events that exhibit specific features such as 3′ splice-site weakness and an increase in exon inclusion. These findings suggest that METTL4 methylation of U2 snRNA regulates splicing of specific pre-mRNA transcripts.
06. MALIGNANT SUBDURAL EFFUSION FROM DURAL METASTASES: A CASE REPORT AND REVIEW OF AVAILABLE LITERATURE
Authors: Pascual Juan Silvestre , Torio John Emmanuel , Legaspi Gerardo 
Published: August 2020

Abstract
Dural metastases from a distant primary site is a relatively uncommon entity. Two complications from this that have similar imaging findings and clinical presentation are subdural hematoma and subdural effusion. Multiple cases of subdural hematoma have been reported, but only eight other cases of subdural effusion have been reported in the literature. Here we present a case of subdural effusion as a complication from dural metastasis from a sigmoid adenocarcinoma in a 43 year old female. We also review the available literature, discussing the possible patho-etiologies, clinical presentations and imaging findings, as well as outcomes. We note the high recurrence rate (seen in 66% of all reported cases, including ours) and poor prognosis (days to months) of these cases.
34. TARGETED THERAPY FOR HER2-POSITIVE BREAST CANCER BRAIN METASTASES: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Erickson Anders , Ghodrati Farinaz , Das Sunit 
Published: August 2020

Abstract

INTRO
One in three women with HER2-positive breast cancer will develop brain metastases, or intracranial metastatic disease (IMD). Historically, treatment of IMD has been confined to surgery and radiotherapy, with a limited role for chemotherapy. However, recent interest has burgeoned in a role for targeted therapy for treatment of IMD. The lack of high-level evidence, such as meta-analyses, regarding the role of targeted therapy in the management of IMD has prevented its inclusion in guidelines directing treatment. We performed a systematic review and meta-analysis to clarify the role of targeted therapy for IMD in women with HER2-positive breast cancer.

METHODS
Following PRISMA guidelines, a search of MEDLINE, CENTRAL, EMBASE, Google Scholar, and grey literature sources was conducted by two independent reviewers. Controlled trials and cohort studies that reported survival, safety, or response outcomes for patients receiving HER2-targeted therapy following IMD diagnosis were included. Meta-analyses using a random-effects model were conducted for OS and PFS.

RESULTS
111 studies reporting on 8226 patients were included. Primary analysis of only RCTs found that HER2-targeted therapy was associated with improved OS (HR 0.63; 95% CI, 0.46–0.86; n = 392) but not PFS (HR 0.75; 95% CI, 0.30–1.85; n = 392) following IMD diagnosis. Secondary analysis combining RCTs and comparative observational studies found that HER2-targeted therapy was associated with improved OS (HR 0.42; 95% CI, 0.35–0.51; n = 2756) but not PFS (HR 0.58; 95% CI, 0.27–1.21; n = 460) following IMD diagnosis. Full analysis will be conducted for all 111 studies for pre-specified outcomes including intracranial PFS.

CONCLUSION
These findings support a potential role for HER2-targeted therapy in the management of IMD from HER2-positive breast cancer. Final analysis will synthesize current evidence for outcomes of intracranial response, survival, and safety.
43. DELAYS IN ADJUVANT STEREOTACTIC RADIOSURGERY REDUCE LOCAL CONTROL FOR RESECTED BRAIN METASTASES
Authors: Roth O’Brien Diana , Poppas Phillip , Kaye Sydney , Mahase Sean , An Anjile , Christos Paul , Liechty Benjamin , Pisapia David , Ramakrishna Rohan , Wernicke A Gabriella , Knisely Jonathan , Pannullo Susan , Schwartz Theodore 
Published: August 2020

Abstract

OBJECTIVE
For resected brain metastases (BM), stereotactic radiosurgery (SRS) is often offered to minimize local recurrence (LR). Although the aim is to deliver SRS within a few weeks of surgery, a variety of socioeconomic, medical, and procedural issues can cause delays. We evaluated the relationship between timing of postoperative SRS and LR.

METHODS
We retrospectively identified a consecutive series of BM patients managed with resection and adjuvant SRS, recommended within two weeks of surgery, at our institution from 2012–2018. We assessed the correlation between time to SRS, as well as other demographic, disease, and treatment variables, and LR, distant recurrence (DR), and overall survival (OS).

RESULTS
133 patients met inclusion criteria. Median age was 64.5 years. Approximately half of patients had a single BM, and median BM size was 2.9 cm. Gross total resection was achieved in 111 (83.6%) patients, and &gt;90% received fractionated SRS. Median time to adjuvant SRS was 37.0 days and LR rate was 16.4%. The factor most predictive of LR was time from surgery to SRS. Median time from surgery to SRS was 34.0 days for patients without LR, versus 61.0 days for those with LR (p&lt;0.01). LR was 2.3% with SRS administered ≤4 weeks postoperatively, compared to 23.6% if delayed &gt;4 weeks (p&lt;0.01). Local recurrence-free survival (LRFS) was also improved for patients who had SRS at ≤4 weeks (p=0.02). Delayed SRS was also predictive of DR (p=0.02), but not OS.

CONCLUSIONS
We demonstrate that the strongest predictor of failure of postoperative SRS for BM is the delay to SRS. A cut-off of 4 weeks is a reliable predictor of increased LR. Every effort should be made to perform SRS within 4 weeks of surgery, and if this cannot be achieved, other RT modalities, such as brachytherapy or preoperative SRS, should be strongly considered.
48. DEVELOPING TUMOR-HOMING CYTOTOXIC HUMAN INDUCED NEURAL STEM CELLS AS AN ADJUVANT TREATMENT FOR RADIATION THERAPY OF BRAIN METASTASES
Authors: Mercer-Smith Alison , Jiang Wulin , Valdivia Alain , Bago Juli , Floyd Scott , Hingtgen Shawn 
Published: August 2020

Abstract

INTRODUCTION
Non-small cell lung cancer (NSCLC) is the most common primary cancer to metastasize to the brain. Radiation is first-line for multifocal brain metastases, but recurrence is observed in 40% of patients. An adjuvant treatment to radiation is needed to effectively treat post-radiation tumor. Genetically engineered neural stem cells (NSCs) have the unique ability to seek out tumors and deliver therapeutic payloads that significantly reduce tumor burden. Here we have transdifferentiated human fibroblasts into induced neural stem cells (hiNSC) and explored the efficacy of hiNSCs therapy for NSCLC brain metastases.

METHODS
hiNSCs were infused intracerebroventricularly (ICV) into mice with bilateral intracranial H460 NSCLC tumors. Bioluminescent imaging (BLI) was used to determine hiNSCs persistence while fluorescent analysis of brain sections characterized tumor-homing migration. In vitro co-culture assays and isobologram analysis were used to determine the synergistic effect of the cytotoxic protein TRAIL and radiation therapy on NSCLC tumor cells. To determine efficacy in vivo, H460 cells were implanted in the brains of mice and treated with either hiNSC-TRAIL alone or in combination with 2 Gy radiation. Tumor volumes were then tracked via BLI.

RESULTS/CONCLUSION
hiNSCs persisted in the brain &gt;1 week after ICV injection, and hiNSCs were found to co-localize with both bilateral tumor foci. Isobologram analysis showed a combination index of 0.64, suggesting radiation and TRAIL have a synergistic cytotoxic effect on NSCLC tumors. In vivo, radiation and hiNSC-TRAIL therapy reduced tumor volumes 90% compared to control-treated animals, while each therapy alone only reduced tumors 21% and 52%, respectively. While neither monotherapy significantly impacted survival, combination therapy demonstrated a 40% extension in survival, with treated mice surviving a median of 28 days while controls animals only survived 20 days. Together, these results demonstrate the therapeutic potential of hiNSC-TRAIL as an adjuvant to radiation for treatment of NSCLC brain metastases.
49. CORRELATES AND PREDICTORS OF HEALTH-RELATED QUALITY OF LIFE IN METASTATIC BRAIN CANCER
Authors: Marotta Dario , Hayward Emily , Tucker Zachary , Gerstenecker Adam , Gammon Meredith , Mason Matthew , Willhelm Gabrielle , Bae Helen , Triebel Kristen 
Published: August 2020

Abstract

PURPOSE
Neurocognitive functioning (NCF), mood disturbances, physical functioning, and social support all share a relationship with health-related quality of life (HRQOL). However, a characterization of these relationships in persons with brain metastases (BM) has yet to be identified.

METHODS
Ninety-three newly diagnosed persons with BM were administered a cognitive battery to assess neurocognitive functioning, mood disturbances, physical functioning, and social support. The Functional Assessment of Cancer Treatment (FACT) scale was used to measure HRQOL.

RESULTS
Mood and physical function correlated with lower HRQOL in every measured domain. Verbal learning and memory correlated with every FACT subscale except emotional quality of life. Social support also correlated with several HRQOL domains. Stepwise linear regressions revealed that mood was the predominate predictor of HRQOL. Social support, physical functioning, verbal learning, and memory also contribute to HRQOL, but to a lesser extent.

CONCLUSION
HRQOL is a complex construct affected by mood, physical functioning, and learning and memory. Mood is a domain-independent predictor of HRQOL, while non-mood variables predict HRQOL in domain-specific ways. Thus, multifactorial baseline assessments of persons with BM are encouraged to help mitigate the impact that BM has on HRQOL.
50. RISK OF TRACT RECURRENCE WITH STEREOTACTIC BIOPSY OF BRAIN METASTASES: AN 18-YEAR CANCER CENTER EXPERIENCE
Authors: Carnevale Joseph , Winston Graham , Goldberg Jacob , Brennan Cameron , Tabar Viviane , Moss Nelson 
Published: August 2020

Abstract

BACKGROUND
Stereotactic biopsy is increasingly performed on brain metastases (BrM) as improving cancer outcomes drive aggressive multimodality treatment, however the risk of tract recurrence for such biopsies, in both the upfront and recurrent settings, are poorly defined in an era defined by focused-irradiation paradigms. As such, the rate of tract recurrence was evaluated.

METHODS
A retrospective review was performed to identify stereotactic biopsies performed for BrM at Memorial Sloan Kettering Cancer Center from 2002–2020. Data including surgical indications, tumor type, radiographic characteristics, stereotactic planning, pre- and post-operative CNS-directed and systemic treatments, and clinical courses were collected. Recurrence was evaluated using RANO-BM criteria.

RESULTS
Four-hundred-and-seventy-nine patients underwent stereotactic intracranial biopsy for any diagnosis (&gt;80% were gliomas or CNS lymphoma). Twenty-two (4.5%) were for pathologically-confirmed viable BrM and 91% (20/22) of these underwent postoperative irradiation with either stereotactic radiotherapy (14/20, 70%; SBRT) in plans that did not specifically target the biopsy tract, or whole-brain irradiation (6/20, 30%; WBRT). Eleven patients (50%) had &gt;/=3 months radiographic follow-up (median 11.9; 4.5–30.6), of which 6 (55%) developed discontinuous enhancement along the tract at a median 6.4 months (2.3–17.1) post-biopsy. Of these, 2 had previously been treated with SBRT and were sampled in the setting of diagnostic ambiguity (one additionally with WBRT for small cell carcinoma) and underwent intraoperative laser interstitial thermal therapy (LITT) immediately following biopsy. The remainder were treated with SBRT +/- LITT (n=3 and 4, respectively) following biopsy. Tract recurrences were treated with resection (n=2, both with pathologic confirmation), re-irradiation (n=1) or observation/systemic therapy.

CONCLUSIONS
In this largest reported series of biopsied BrM, we identify a nontrivial rate, higher than previously described, of recurrence along stereotactic biopsy tracts. As BrM are most commonly treated with focused radiotherapy centered on enhancing tumor margins, consideration should be made to include biopsy tracts where feasible.
52. BrMPANEL: A PUBLIC RESOURCE OF ORGANOTROPIC CELL LINES
Authors: Valiente Manuel , Van Swearingen Amanda , Anders Carey , Bairoch Amos , Boire Adrienne , Bos Paula , Cittelly Diana , Erez Neta , Ferrarro Gino , Fukumura Dai , Gril Brunilde , Herlyn Meenhard , Holmen Sheri , Jain Rakesh , Joyce Johanna , Lorger Mihaela , Massague Joan , Neman Josh , Sibson Nicola , Steeg Patricia , Thorsen Frits , Young Leonie , Vareslija Damir , Vultur Adina , Weis-Garcia Frances , Winkler Frank 
Published: August 2020

Abstract
Central nervous system (CNS), notably brain, metastases are most prevalent in lung cancer (20–56% of patients), breast cancer (5–20%) and melanoma (7–16%). Lesions occur in both the brain parenchyma and the meninges. To mechanistically understand CNS metastasis formation and develop preventive and therapeutic strategies, it is essential to use model systems that, as much as possible, faithfully recapitulate the clinical disease process. Furthermore, the complexities of brain metastases dictate that studies should utilize multiple model systems in various stages of brain metastases progression. To facilitate brain metastasis research, 19 laboratories around the world have compiled comprehensive information on their brain metastasis mouse models. Each lab has provided details on the cell lines that they have generated or characterized as being capable of forming metastatic colonies in the brain, as well as principle methodologies of brain metastasis research. This Brain Metastasis Cell Lines Panel (BrMPanel, https://apps.cnio.es/app/BrainMetastasis/CellLines) represents the first of its class and includes information about each cell line, how tropism to the brain was established, and the behavior of each model in vivo. The BrMPanel is composed of 60 cell lines, derived from patients (32 cell lines, 53%), mouse (27, 45%) or rat (1, 2%), and represent the three main cancer types that result in brain metastasis: breast cancer (38 cell lines, 63%), lung cancer (8, 13%) and melanoma (14, 23%). This resource is intended to assist investigators in choosing the most suitable model for research on brain metastasis, and is available to the entire scientific community. The ultimate goal of this effort is to facilitate research on this unmet clinical need, to improve models through a collaborative environment, and to promote the exchange of information on these valuable resources. We invite other collaborators to contribute their models to the BrMPanel to grow this resource.
58. CLINICAL PRESENTATION AND IMAGING CHARACTERISTICS OF LEPTOMENINGEAL CARCINOMATOSIS (LC) IN PATIENTS WITH EGFR MUTATED NON-SMALL CELL LUNG CANCER (NSCLC)
Authors: Eastman Boryana , Merkhofer Cristina , Densmore Isabella , Baik Christina , Halasz Lia , McGranahan Tresa 
Published: August 2020

Abstract

BACKGROUND
LC is a late and often fatal manifestation of advanced EGFR mutated NSCLC with up to 9% of patients developing LC. Given the higher incidence of LC in EGFR mutated tumors, we hypothesized it may have unique imaging and clinical characteristics.

METHODS
We identified 23 patients with EGFR mutated NSCLC and LC treated at a large academic institution between 2016 and 2019. Clinical and treatment characteristics were obtained from the electronic medical record. Radiographic subtype of LC and presence of ventriculomegaly were determined by independent review of available brain and spine MRI imaging.

RESULTS
Among 23 eligible patients, mean age was 57 years, 96% had advanced NSCLC at diagnosis and 61% had EGFR exon 19 deletion. Median time from NSCLC diagnosis to LC development was 23 months (95% CI:13–33), with only 17% of patients presenting with LC in the absence of parenchymal brain metastases. Of the 91% of patients with radiographic evidence of LC, equal numbers had nodular or linear LC (22% each) and 39% had a mixed presentation. Additionally, 30% of patients had evidence of spinal LC. Ventriculomegaly was present in 52% of patients, with 48% developing clinical symptoms of hydrocephalus and 13% receiving shunt placement. Median overall survival (OS) from time of LC diagnosis was 3.9 months (95% CI:2.7–10.0), which is lower than in prior published studies. Patients with nodular LC and absence of ventriculomegaly fared better with a median OS of 6.5 months and 5.7 months respectively.

CONCLUSIONS
OS is poor in patients with LC associated with EGFR mutated NSCLC, although appears better in patients with nodular LC. The high incidence of hydrocephalus emphasizes the need for its early recognition and treatment. Further studies are needed to identify promising treatment strategies and to determine factors associated with improved OS in this population.