bluuebunny/crossref_metadata_2025 huggingface dataset:
Time-domain variability properties of XTE J1650−500 during its 2001 outburst: evidence of disc–jet connection
Authors: Chatterjee Arka , Dutta Broja G , Nandi Prantik , Chakrabarti Sandip K
Published: August 2020

The evolution of variability properties of Galactic transient sources is a diagnostic tool to understand various regimes of the accretion flow and its dynamics close to the central black hole. In this paper, we concentrate on the variability properties of the X-ray transient XTE J1650−500 and investigate the evolution of viscous delay, time lag, quasi-periodic oscillation (QPO) frequency, and their energy dependence throughout the rising phase as observed by Rossi X-ray Timing Explorer(RXTE) during its outburst in 2001. Our analysis reveals (1) a delay of 12 ± 1 d between 1 d-averaged hard (5–12 keV) and soft (1.5–3 keV) photon light curves as observed by RXTE/ASM; (2) QPOs with high rms values are observed in lower energy (4–8 keV) range; (3) the QPO frequencies and associated time lags were anticorrelated during the initial days of the rising phase, and later on, they were found to be correlated; (4) the time lags of Fe-line photons with respect to hard and soft photons remained almost constant during the initial days of hard state and the lag magnitude increased during the state transition. We perform comparative studies with outbursts of GX 339−4 and XTE J1550−564. We find the evolution of time lags associated with the QPO characteristics during the outburst – stronger QPOs at low energy and constant lags of broad Fe-line photons present a unique nature of outburst profile in XTE J1650−500. The possible cause of such variabilities is explained by considering disc–jet geometry closer to the central black hole.
The fates of massive stars: exploring uncertainties in stellar evolution with metisse
Authors: Agrawal Poojan , Hurley Jarrod , Stevenson Simon , Szécsi Dorottya , Flynn Chris
Published: August 2020

In the era of advanced electromagnetic and gravitational wave detectors, it has become increasingly important to effectively combine and study the impact of stellar evolution on binaries and dynamical systems of stars. Systematic studies dedicated to exploring uncertain parameters in stellar evolution are required to account for the recent observations of the stellar populations. We present a new approach to the commonly used single-star evolution (sse) fitting formulae, one that is more adaptable: method of interpolation for single star evolution (metisse). It makes use of interpolation between sets of pre-computed stellar tracks to approximate evolution parameters for a population of stars. We have used metisse with detailed stellar tracks computed by the modules for experiments in stellar astrophysics (mesa), the bonn evolutionary code (bec), and the Cambridge stars code. metisse better reproduces stellar tracks computed using the stars code compared to sse, and is on average three times faster. Using stellar tracks computed with mesa and bec, we apply metisse to explore the differences in the remnant masses, the maximum radial expansion, and the main-sequence lifetime of massive stars. We find that different physical ingredients used in the evolution of stars, such as the treatment of radiation-dominated envelopes, can impact their evolutionary outcome. For stars in the mass range 9–100 M⊙, the predictions of remnant masses can vary by up to 20 M⊙, while the maximum radial expansion achieved by a star can differ by an order of magnitude between different stellar models.
The PAU Survey: Photometric redshifts using transfer learning from simulations
Authors: Eriksen M , Alarcon A , Cabayol L , Carretero J , Casas R , Castander F J , De Vicente J , Fernandez E , Garcia-Bellido J , Gaztanaga E , Hildebrandt H , Hoekstra H , Joachimi B , Miquel R , Padilla C , Sanchez E , Sevilla-Noarbe I , Tallada P
Published: August 2020

In this paper, we introduce the deepz deep learning photometric redshift (photo-z) code. As a test case, we apply the code to the PAU survey (PAUS) data in the COSMOS field. deepz reduces the σ68 scatter statistic by 50 per cent at iAB = 22.5 compared to existing algorithms. This improvement is achieved through various methods, including transfer learning from simulations where the training set consists of simulations as well as observations, which reduces the need for training data. The redshift probability distribution is estimated with a mixture density network (MDN), which produces accurate redshift distributions. Our code includes an autoencoder to reduce noise and extract features from the galaxy SEDs. It also benefits from combining multiple networks, which lowers the photo-z scatter by 10 per cent. Furthermore, training with randomly constructed coadded fluxes adds information about individual exposures, reducing the impact of photometric outliers. In addition to opening up the route for higher redshift precision with narrow bands, these machine learning techniques can also be valuable for broad-band surveys.
The effect of tides on near-core rotation: analysis of 35 Kepler γ Doradus stars in eclipsing and spectroscopic binaries
Authors: Li Gang , Guo Zhao , Fuller Jim , Bedding Timothy R , Murphy Simon J , Colman Isabel L , Hey Daniel R
Published: August 2020

We systematically searched for gravity- and Rossby-mode period spacing patterns in Kepler eclipsing binaries with γ Doradus pulsators. These stars provide an excellent opportunity to test the theory of tidal synchronization and angular momentum transport in F- and A-type stars. We discovered 35 systems that show clear patterns, including the spectroscopic binary KIC 10080943. Combined with 45 non-eclipsing binaries with γ Dor components that have been found using pulsation timing, we measured their near-core rotation rates and asymptotic period spacings. We find that many stars are tidally locked if the orbital periods are shorter than 10 d, in which the near-core rotation periods given by the traditional approximation of rotation are consistent with the orbital period. Compared to the single stars, γ Dor stars in binaries tend to have slower near-core rotation rates, likely a consequence of tidal spin-down. We also find three stars that have extremely slow near-core rotation rates. To explain these, we hypothesize that unstable tidally excited oscillations can transfer angular momentum from the star to the orbit, and slow the star below synchronism, a process we refer to as ‘inverse tides’.
Short-term stability of particles in the WD J0914+1914 white dwarf planetary system
Authors: Zotos Euaggelos E , Veras Dimitri , Saeed Tareq , Darriba Luciano A
Published: August 2020

Nearly all known white dwarf planetary systems contain detectable rocky debris in the stellar photosphere. A glaring exception is the young and still evolving white dwarf WD J0914+1914, which instead harbours a giant planet and a disc of pure gas. The stability boundaries of this disc and the future prospects for this white dwarf to be polluted with rocks depend upon the mass and orbit of the planet, which are only weakly constrained. Here, we combine an ensemble of plausible planet orbits and masses to determine where observers should currently expect to find the outer boundary of the gas disc. We do so by performing a sweep of the entire plausible phase space with short-term numerical integrations. We also demonstrate that particle-star collisional trajectories, which would lead to the (unseen) signature of rocky metal pollution, occupy only a small fraction of the phase space, mostly limited to particle eccentricities above 0.75. Our analysis reveals that a highly inflated planet on a near-circular orbit is the type of planet which is most consistent with the current observations.
Comprehensive multi-omics analysis uncovers a group of TGF-β-regulated genes among lncRNA EPR direct transcriptional targets
Authors: Zapparoli Ettore , Briata Paola , Rossi Martina , Brondolo Lorenzo , Bucci Gabriele , Gherzi Roberto
Published: August 2020

Long non-coding RNAs (lncRNAs) can affect multiple layers of gene expression to control crucial cellular functions. We have previously demonstrated that the lncRNA EPR, by controlling gene expression at different levels, affects cell proliferation and migration in cultured mammary gland cells and impairs breast tumor formation in an orthotopic transplant model in mice. Here, we used ChIRP-Seq to identify EPR binding sites on chromatin of NMuMG mammary gland cells overexpressing EPR and identified its trans binding sites in the genome. Then, with the purpose of relating EPR/chromatin interactions to the reshaping of the epitranscriptome landscape, we profiled histone activation marks at promoter/enhancer regions by ChIP-Seq. Finally, we integrated data derived from ChIRP-Seq, ChIP-Seq as well as RNA-Seq in a comprehensive analysis and we selected a group of bona fide direct transcriptional targets of EPR. Among them, we identified a subset of EPR targets whose expression is controlled by TGF-β with one of them—Arrdc3—being able to modulate Epithelial to Mesenchymal Transition. This experimental framework allowed us to correlate lncRNA/chromatin interactions with the real outcome of gene expression and to start defining the gene network regulated by EPR as a component of the TGF-β pathway.
Predictions and analyses of RNA nearest neighbor parameters for modified nucleotides
Authors: Hopfinger Melissa C , Kirkpatrick Charles C , Znosko Brent M
Published: August 2020

The 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

FANCJ, 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

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

N 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

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

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

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 >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<0.01). LR was 2.3% with SRS administered ≤4 weeks postoperatively, compared to 23.6% if delayed >4 weeks (p<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

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 >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

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

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 (>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 >/=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

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

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.
60. IDEAL TREATMENT REGIMEN FOR PATIENTS WITH ≥1 BRAIN METASTASIS FROM PRIMARY NON-SMALL-CELL LUNG CANCER – A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS
Authors: Brar Karanbir , Ellenbogen Yosef , Sadeghirad Behnam , Deng Jiawen , Hou Winston , Wang Xiaoqin , Taslimi Shervin , Mansouri Alireza
Published: August 2020

BACKGROUND

Brain metastases (BM) are common in non-small cell lung cancer (NSCLC). The aim of this study was to assess the comparative effectiveness of treatments for BM from NSCLC.

METHODS

We searched MEDLINE, EMBASE, Web of Science, ClinicalTrials.gov, CENTRAL and references of key studies for randomized controlled trials (RCTs) published until October 2018. We also searched the Chinese databases Wanfang Data, Wanfang Med Online, China National Knowledge Infrastructure, and Chongqing VIP Information for RCTs published until September 2019. Trials including > 10 patients were selected. The primary outcomes were overall survival (OS) and intracranial progression-free survival (PFS). We used a frequentist random-effects model for network meta-analysis and assessed the certainty of evidence using the GRADE approach.

RESULTS

Among 8798 abstracts, 106 RCTs (9452 patients) met inclusion criteria. Median sample size was 67 (range 25–554). All trials included adult patients with histologically proven NSCLC and >1 BM proven on CT/MRI. Of trials that reported performance status (e.g. ECOG or KPS, n=67), 63/67 excluded patients with non-favorable performance status. Interventions assessed included surgery, WBRT, SRS, targeted therapies (i.e. EGFR/ALK inhibitors), and chemotherapy. Compared to WBRT alone, several interventions demonstrated a statistically significant increase in median OS, including non-targeted chemotherapy + surgery (MD: 415.3 days, 95% CI: 31.3–799.4), WBRT + EGFRi (MD: 200.2 days, 95% CI:146.3–254.1), and EGFRi alone (MD: 169.7 days, 95% CI: 49.7–289.7). Among all interventions, only WBRT + EGFRi showed a significant improvement in median PFS (MD: 108.0 days, 95%CI: 48.5–167.5).

CONCLUSIONS

Our preliminary analyses indicate an OS and PFS benefit on the addition of EGFR inhibitors to WBRT for the treatment of BMs from NSCLC. Further analyses of hazard ratios for OS/PFS are underway, and subgroup analyses are planned. These data support the growing role of targeted therapies in the treatment of BMs, particularly in susceptible mutant tumours.
71. MGMT PROMOTER METHYLATION IS A PROGNOSTIC BIOMARKER IN EGFR MUTANT LUNG ADENOCARCINOMA WITH BRAIN METASTASES
Authors: Mamatjan Yasin , Zuccato Jeffrey , Moraes Fabio , Cabanero Michael , Shali Wumairehan , Weiss Jessica , Tsao Ming , Aldape Kenneth , Shepherd Frances , Zadeh Gelareh
Published: August 2020

EGFR-mutant lung adenocarcinomas (EGFRm-LUAD) have a higher risk of brain metastasis (BM) development than non-mutant lesions regardless of cancer stage. BM development is a marker of tumor aggressiveness and has significant prognostic impact that leads to treatment failure. MGMT promoter methylation is known to determine response to therapy in other cancer types but it has not been investigated in EGFRm-LUAD brain metastases. This work aims to assess whether MGMT promoter methylation predicts patient survival or BM development in EGFRm-LUAD patients. A large cohort of 90 primary EGFRm-LUAD, 33(37%) of which developed BM, were profiled using Illumina Infinium MethylationEPIC Beadchip. We utilized genome-wide methylation signatures to determine MGMT methylation status using the previously reported MGMT-STP27 approach that uses two CpG sites to predict MGMT methylation status. Cox modeling was performed to assess whether MGMT methylation status correlates with overall survival independent of other clinical factors. MGMT methylation significantly predicted poorer survival in EGFRm-LUAD patients developed BM (p=0.0003) and those who did not (p=0.003). A multivariate Cox analysis, adjusting for stage and smoking status as potential confounders, showed that MGMT methylation (HR=6.2, 95%CI:2.2–17.4, p=0.0005) and BM (HR=2.6, 95%CI:1.3–5.3, p=0.007) were both independently predictive of worsened survival. Total Mutation Burden calculated by the number of mutations per megabase of DNA was higher in MGMT methylated tumours with an interquartile range (IQR) of 58(30–71) compared to MGMT unmethylated tumours with IQR of 5.5(4.3–6.1). This work shows that MGMT promoter methylation status is an important prognostic biomarker in EGFRm-LUAD patients. Further work will validate these findings obtained using whole-genome DNA methylation by comparing to results using methylation specific PCR assays. MGMT promoter methylation status in EGFRm–LUAD patients with BM may be used to guide patient treatment with potentially a greater extent of treatment for those higher risk patients.
73. PREDICTION OF A SECOND LOCAL RECURRENCE IN SURGICALLY TREATED RECURRENT BRAIN METASTASES PATIENTS
Authors: Tewarie Ishaan , Hulsbergen Alexander , Paranjpe Manish , Jhun Ray , Job Arun , Broekman Marike , Smith Timothy
Published: August 2020

BACKGROUND

Local recurrence is a common occurrence after resection or radiotherapy for brain metastasis (BM). Very little is known about the benefit of (re-)craniotomy in this scenario: does resecting the initial local recurrence (LR1) invariably lead to a second local recurrence (LR2)? This study aimed to analyze occurrence and predictors of LR2 in BM patients undergoing craniotomy for LR1.

METHODS

Patients were identified from a departmental database at the Brigham and Women’s Hospital, Boston, MA. Multivariable logistic regression and cox regression analysis was performed to identify predictors of binary occurrence of LR2 (yes/no) and time-to-LR2, respectively. Based on predictors, subgroup-specific prevalence of LR2 was explored.

RESULTS

A total of 188 patients were identified. The median age was 59.5 years and 117 patients (62.2%) were female. Treatment-wise, 64 patients (34.0%) underwent subtotal resection (STR) and 66 (35.1%) received adjuvant radiation. Eighty-one (43.1%) patients experienced LR2 at a median of 7 months after craniotomy. Occurrence of LR2 was significantly associated with STR (OR 6.88, p = 0.0008), surgery as treatment for LR1 (OR = 0.26, p = 0.03), larger tumor volume (OR = 1.14 per 1000 mm3, p = 0.01), and frontal location (OR = 5.23, p = 0.02). Shorter time-to-LR2 was associated with STR (HR = 5.31, p = 0.01) and adjuvant radiation (HR = 2.22, p = 0.03), while temporal (HR = 0.16, p = 0.03) and parietal (0.13, p = 0.03) location were associated with longer time-to-LR2. When stratifying by extent of resection, prevalence of LR2 was 32.8% after gross total resection and 57.1% after STR.

CONCLUSION

In this population, LR2 occurred in 43.1% of patients. STR was the strongest risk factor for LR2, while tumor size, location, surgical treatment of LR1, and receipt of adjuvant radiation may also influence subsequent recurrence.
76. THE ROLE OF FRAILTY IN PREDICTING POSTOPERATIVE SOCIOECONOMIC OUTCOMES AMONG PATIENTS WITH METASTATIC BRAIN CANCER
Authors: Khalafallah Adham M , Jimenez Adrian E , Huq Sakibul , Patel Palak , Mukherjee Debraj
Published: August 2020

BACKGROUND

Patient frailty is an important consideration in the context of providing high-value, cost-effective care, as it has shown to effectively predict postoperative morbidity and mortality in many surgical subspecialties. However, for metastatic cancer patients, there is a lack of consensus as to whether frailty effectively predicts postoperative outcomes such as survival and length of stay (LOS), specifically among patients with metastatic brain tumors.

OBJECTIVE

The present study sought to determine if the 5-factor modified frailty index (mFI-5) independently predicts LOS, discharge disposition, and total hospital charges among patients with metastatic brain cancer.

METHODS

Patients diagnosed with metastatic brain cancer who underwent surgery between 2017–2019 at a single academic institution were analyzed. Bivariate analysis identified patient characteristics significantly associated of LOS, discharge disposition, and total hospital charges. Multivariate linear regression was used to identify independent predictors of LOS and total hospital charges, while multivariate logistic regression was used to identify independent predictors of non-routine discharge disposition. P <0.05 was considered statistically significant.

RESULTS

A total of 302 patients were included in our analysis. Our patient cohort had a mean age (standard deviation) of 62.27 11.86 years, and was majority female (52.0%) and Caucasian (74.2%). The majority of patients had a primary lung cancer (24.8%), followed by breast cancer (13.6%). There was no significant difference in mFI-5 score between patients with metastatic tumors of known origin compared to patients with metastatic tumors of unknown origin (p=0.61). In multivariate analysis, a higher mFI-5 score independently predicted longer LOS (regression coefficient [Coef]=1.36 days, p<0.001), non-routine discharge disposition (odds ratio [OR]=1.60, p=0.0079), and higher total hospital charges (Coef=$4325.54, p=0.0010).

CONCLUSION

The mFI-5 independently predicts LOS, discharge disposition, and total hospital charges among our cohort of metastatic brain cancer patients. Our findings may be used to aid physicians in providing high-value neurosurgical care.
Natural selection contributes to the myopia epidemic
Authors: Long Erping , Zhang Jianzhi
Published: August 2020

The prevalence of myopia, or nearsightedness, has skyrocketed in the past few decades, creating a public health crisis that is commonly attributed to lifestyle changes. Here we report an overall increase in the frequencies of myopia-associated mutant alleles over 25 years among participants of the UK Biobank. Although myopia itself appears to be selected against, many of the mutant alleles are associated with reproductive benefits, suggesting that reproduction-related selection inadvertently contributes to the myopia epidemic. We estimate that, in the UK alone, natural selection adds more than 100 000 myopia cases per generation, and argue that antagonistic pleiotropy be broadly considered in explaining the spreads of apparently disadvantageous phenotypes in humans and beyond.
Two-dimensional optical spatial differentiation and high-contrast imaging
Authors: Zhou Junxiao , Qian Haoliang , Zhao Junxiang , Tang Min , Wu Qianyi , Lei Ming , Luo Hailu , Wen Shuangchun , Chen Shaochen , Liu Zhaowei
Published: August 2020

Optical analog signal processing technology has been widely studied and applied in a variety of science and engineering fields, with the advantages of overcoming the low-speed and high-power consumption associated with its digital counterparts. Much attention has been given to emerging metasurface technology in the field of optical imaging and processing systems. Here, we demonstrate, for the first time, broadband two-dimensional spatial differentiation and high-contrast edge imaging based on a dielectric metasurface across the whole visible spectrum. This edge detection method works for both intensity and phase objects simply by inserting the metasurface into a commercial optical microscope. This highly efficient metasurface performing a basic optical differentiation operation opens up new opportunities in applications of fast, compactible and power-efficient ultrathin devices for data processing and biological imaging.
Should Graphic Warning Labels Proposed for Cigarette Packages Sold in the United States Mention the Food and Drug Administration?
Authors: Jovanova Mia , Skurka Chris , Byrne Sahara , Kalaji Motasem , Greiner Safi Amelia , Porticella Norman , Mathios Alan D , Avery Rosemary J , Dorf Michael C , Niederdeppe Jeff
Published: August 2020

Introduction

Under the US Family Smoking Prevention and Tobacco Control Act, the US Food and Drug Administration (FDA) has the authority to implement graphic warning labels (GWLs) on cigarette packages. Neither the original labels proposed by the FDA nor the revised labels include a source to indicate sponsorship of the warnings. This study tests the potential impact of adding a sponsor to the content of GWLs.

Methods

We recruited adult smokers (N = 245) and middle-school youth (N = 242) from low-income areas in the Northeastern US. We randomly assigned participants to view one of three versions of the original FDA–proposed warning labels in a between-subjects experiment: no sponsor, “US Food and Drug Administration,” or “American Cancer Society” sponsor. We tested the effect of varying sponsorship on source attribution and source credibility.

Results

Compared to unsponsored labels, FDA sponsorship increased source attributions that the FDA sponsored the labels among both middle-school, largely nonsmoking youth and adult smokers. However, sponsorship had no effect on source credibility among either population.

Conclusions

We found no evidence that adding FDA as the source is likely to boost source credibility judgments, at least in the short term; though doing so would not appear to have adverse effects on credibility judgments. As such, our data are largely consistent with the Tobacco Control Act’s provisions that allow, but do not require, FDA sponsorship on the labels.

Implications

This study addresses the FDA’s regulatory efforts by informing the possible design and content of future cigarette warning labels. Our results do not offer compelling evidence that adding the FDA name on GWLs will directly increase source credibility. Future work may test more explicit FDA source labeling and continue to examine the credibility of tobacco message content among high–priority populations.