bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ground-based transmission spectroscopy with FORS2: A featureless optical transmission spectrum and detection of H2O for the ultra-hot Jupiter WASP-103b
Authors: Wilson Jamie , Gibson Neale P , Nikolov Nikolay , Constantinou Savvas , Madhusudhan Nikku , Goyal Jayesh , Barstow Joanna K , Carter Aarynn L , de Mooij Ernst J W , Drummond Benjamin , Mikal-Evans Thomas , Helling Christiane , Mayne Nathan J , Sing David K 
Published: August 2020

ABSTRACT
We report ground-based transmission spectroscopy of the highly irradiated and ultra-short period hot-Jupiter WASP-103b covering the wavelength range ≈400–600 nm using the FORS2 instrument on the Very Large Telescope. The light curves show significant time-correlated noise which is mainly invariant in wavelength and which we model using a Gaussian process. The precision of our transmission spectrum is improved by applying a common-mode correction derived from the white light curve, reaching typical uncertainties in transit depth of ≈2 × 10−4 in wavelength bins of 15 nm. After correction for flux contamination from a blended companion star, our observations reveal a featureless spectrum across the full range of the FORS2 observations and we are unable to confirm the Na absorption previously inferred using Gemini/GMOS or the strong Rayleigh scattering observed using broad-band light curves. We performed a Bayesian atmospheric retrieval on the full optical-infrared transmission spectrum using the additional data from Gemini/GMOS, HST/WFC3, and Spitzer observations and recover evidence for H2O absorption at the 4.0 σ level. However, our observations are not able to completely rule out the presence of Na, which is found at 2.0 σ in our retrievals. This may in part be explained by patchy/inhomogeneous clouds or hazes damping any absorption features in our FORS2 spectrum, but an inherently small scale height also makes this feature challenging to probe from the ground. Our results none the less demonstrate the continuing potential of ground-based observations for investigating exoplanet atmospheres and emphasize the need for the application of consistent and robust statistical techniques to low-resolution spectra in the presence of instrumental systematics.
Mismatch repair and DNA polymerase δ proofreading prevent catastrophic accumulation of leading strand errors in cells expressing a cancer-associated DNA polymerase ϵ variant
Authors: Bulock Chelsea R , Xing Xuanxuan , Shcherbakova Polina V 
Published: August 2020

AbstractSubstitutions in the exonuclease domain of DNA polymerase ϵ cause ultramutated human tumors. Yeast and mouse mimics of the most common variant, P286R, produce mutator effects far exceeding the effect of Polϵ exonuclease deficiency. Yeast Polϵ-P301R has increased DNA polymerase activity, which could underlie its high mutagenicity. We aimed to understand the impact of this increased activity on the strand-specific role of Polϵ in DNA replication and the action of extrinsic correction systems that remove Polϵ errors. Using mutagenesis reporters spanning a well-defined replicon, we show that both exonuclease-deficient Polϵ (Polϵ-exo−) and Polϵ-P301R generate mutations in a strictly strand-specific manner, yet Polϵ-P301R is at least ten times more mutagenic than Polϵ-exo− at each location analyzed. Thus, the cancer variant remains a dedicated leading-strand polymerase with markedly low accuracy. We further show that P301R substitution is lethal in strains lacking Polδ proofreading or mismatch repair (MMR). Heterozygosity for pol2-P301R is compatible with either defect but causes strong synergistic increases in the mutation rate, indicating that Polϵ-P301R errors are corrected by Polδ proofreading and MMR. These data reveal the unexpected ease with which polymerase exchange occurs in vivo, allowing Polδ exonuclease to prevent catastrophic accumulation of Polϵ-P301R-generated errors on the leading strand.
Identification and characterization of hippuristanol-resistant mutants reveals eIF4A1 dependencies within mRNA 5′ leader regions
Authors: Steinberger Jutta , Shen Leo , J. Kiniry Stephen , Naineni Sai Kiran , Cencic Regina , Amiri Mehdi , Aboushawareb Sarah A E , Chu Jennifer , Maïga Rayelle Itoua , Yachnin Brahm J , Robert Francis , Sonenberg Nahum , Baranov Pavel V , Pelletier Jerry 
Published: August 2020

Abstract
Hippuristanol (Hipp) is a natural product that selectively inhibits protein synthesis by targeting eukaryotic initiation factor (eIF) 4A, a DEAD-box RNA helicase required for ribosome recruitment to mRNA templates. Hipp binds to the carboxyl-terminal domain of eIF4A, locks it in a closed conformation, and inhibits its RNA binding. The dependencies of mRNAs for eIF4A during initiation is contingent on the degree of secondary structure within their 5′ leader region. Interest in targeting eIF4A therapeutically in cancer and viral-infected settings stems from the dependencies that certain cellular (e.g. pro-oncogenic, pro-survival) and viral mRNAs show towards eIF4A. Using a CRISPR/Cas9-based variomics screen, we identify functional EIF4A1 Hipp-resistant alleles, which in turn allowed us to link the translation-inhibitory and cytotoxic properties of Hipp to eIF4A1 target engagement. Genome-wide translational profiling in the absence or presence of Hipp were undertaken and our validation studies provided insight into the structure-activity relationships of eIF4A-dependent mRNAs. We find that mRNA 5′ leader length, overall secondary structure and cytosine content are defining features of Hipp-dependent mRNAs.
Rational design of minimal synthetic promoters for plants
Authors: Cai Yao-Min , Kallam Kalyani , Tidd Henry , Gendarini Giovanni , Salzman Amanda , Patron Nicola J 
Published: August 2020

AbstractPromoters serve a critical role in establishing baseline transcriptional capacity through the recruitment of proteins, including transcription factors. Previously, a paucity of data for cis-regulatory elements in plants meant that it was challenging to determine which sequence elements in plant promoter sequences contributed to transcriptional function. In this study, we have identified functional elements in the promoters of plant genes and plant pathogens that utilize plant transcriptional machinery for gene expression. We have established a quantitative experimental system to investigate transcriptional function, investigating how identity, density and position contribute to regulatory function. We then identified permissive architectures for minimal synthetic plant promoters enabling the computational design of a suite of synthetic promoters of different strengths. These have been used to regulate the relative expression of output genes in simple genetic devices.
Altered Motor Excitability in Patients With Diffuse Gliomas Involving Motor Eloquent Areas: The Impact of Tumor Grading
Authors: Lavrador José Pedro , Gioti Ifigeneia , Hoppe Szymon , Jung Josephine , Patel Sabina , Gullan Richard , Ashkan Keyoumars , Bhangoo Ranjeev , Vergani Francesco 
Published: August 2020

Abstract

BACKGROUND
Diffuse gliomas have an increased biological aggressiveness across the World Health Organization (WHO) grading system. The implications of glioma grading on the primary motor cortex (M1)-corticospinal tract (CST) excitability is unknown.

OBJECTIVE
To assess the excitability of the motor pathway with navigated transcranial magnetic stimulation (nTMS).

METHODS
Retrospective cohort study of patients admitted for surgery with diffuse gliomas within motor eloquent areas. Demographic, clinical, and nTMS-related variables were collected. The Cortical Excitability Score (CES 0 to 2 according to the number of abnormal interhemispheric resting motor threshold (RMT) ratios) was calculated for patients where bilateral upper and lower limb mapping was performed.

RESULTS
A total of 45 patients were included: 9 patients had a low-grade glioma and 36 patients had a high-grade glioma. The unadjusted analysis revealed an increase in the latency of the motor evoked potential of the lower limb with an increase of the WHO grade (P = .038). The adjusted analysis confirmed this finding (P = .013) and showed a relation between the increase in the WHO and a decreased RMT (P = .037) of the motor evoked responses in the lower limb. When CES was calculated, an increase in the score was related with an increase in the WHO grade (unadjusted analysis—P = .0001; adjusted analysis—P = .001) and in isocitrate dehydrogenase (IDH) wild-type tumors (unadjusted analysis—P = .020).

CONCLUSION
An increase in the WHO grading system and IDH wild-type tumors are associated with an abnormal excitability of the motor eloquent areas in patients with diffuse gliomas.
12. OUTCOMES AFTER SURGICAL RESECTION OF MELANOMA BRAIN METASTASES IN THE AGE OF CHECKPOINT INHIBITOR TREATMENT
Authors: Morshed Ramin , Chung Jason , Sudhakar Vivek , Cummins Daniel , Young Jacob , Daras Mariza , Aghi Manish 
Published: August 2020

Abstract

BACKGROUND
Metastasis of melanoma to the brain is associated with poor outcomes. Recent trials demonstrate improved survival after treatment with immune checkpoint inhibitors.

OBJECTIVE
To examine the impact that checkpoint inhibitor treatment has on overall survival (OS) and central nervous system (CNS) progression in a cohort of patients undergoing surgical resection of melanoma brain metastases.

METHODS
This retrospective, single-center study included patients undergoing first-time surgical resection of melanoma brain metastases. A multivariate Cox proportional model was used to estimate the association of patient and treatment factors with OS and CNS progression.

RESULTS
85 patients underwent first-time resection of 97 melanoma brain metastases with a median follow-up of 9.5 months. Checkpoint inhibitors (Pembrolizumab, Ipilimumab, and/or Nivolumab) were used in 55.1% of cases (19 pre-op; 47 post-op; median 9 cycles). Patients treated with checkpoint inhibitors had similar peri-op systemic disease status and KPS but had been treated with more systemic agents and had more instances of CNS progression prior to surgery. Median OS and time to CNS progression for the cohort were 1 year and 237 days, respectively. In a multivariate Cox regression model, age (HR 1.03 by decade; p=0.02), treatment with a checkpoint inhibitor (HR 0.27; p&lt;0.0001), prior radiotherapy (HR 2.44; p=0.007), and number of brain metastases at the time of surgery (HR 1.05 per metastasis; p=0.04) were significant predictors of OS. Checkpoint inhibitor treatment was associated with longer OS from surgery (median 3 vs 0.5 yrs, log-rank p=0.004). However, patients who underwent craniotomy after prior checkpoint inhibitor treatment had poor OS (median 0.56 yrs). Prior radiotherapy was also associated with poor OS (median 0.53 yrs).

CONCLUSIONS
While checkpoint inhibitor treatment was associated with improved survival in this surgical cohort of melanoma brain metastases, patients who require surgical resection after checkpoint inhibitor treatment or radiotherapy are poor surgical candidates.
23. RETROSPECTIVE REVIEW OF ADULT PATIENTS WITH LEPTOMENINGEAL DISEASE SECONDARY TO MELANOMA AT MOFFITT CANCER CENTER: DIAGNOSIS, TREATMENT AND OUTCOMES
Authors: Pina Yolanda , Evernden Brittany , Smalley Keiran , Forsyth Peter 
Published: August 2020

Abstract

BACKGROUND
Nearly 5–8% of solid cancers present with leptomeningeal disease (LMD). Patients with LMD have a dismal prognosis with survival measured in weeks-to-months. The pathophysiology of this devastating disease remains unknown.

METHODS
A retrospective chart review was performed of twenty-five adult patients with LMD due to melanoma who were enrolled in the MCC 50172 clinical trial between 05/26/2015 and 07/17/2018.

RESULTS
Patients had a median age 63 years (31–80) at diagnosis with LMD. Sixteen had confirmed LMD and five did not meet criteria for LMD, but had positive cerebrospinal fluid (CSF)-circulating tumor cells (CTC’s). Those with LMD had a median KPS of 70 (30–90) at presentation, and symptoms most commonly included altered mentation n=6 (37%), headaches n=4 (25%), focal weakness n=3 (19%), and paresthesia n=2 (12%). Eleven patients were diagnosed by MRI. Ten patients (62%) had positive CSF cytology on first attempt and fourteen (87%) on first-two attempts. Lumbar puncture mean OP was 29.4 cmH2O (18–65), with CSF WBC 21.8/cumm (SD 25.6), RBC 2942.5/cumm (SD 9056.1), and protein 187.6 mg/dL (SD 166.1). CSF-CTC’s CellSearch analysis had a sensitivity of 0.75 (12[12 + 4]) and specificity of 0.44 (4[4 + 5]); PPV 0.71 and NPV 0.50. Twelve patients with LMD had positive CSF-CTC’s. Prior to LMD diagnosis, patients were treated with immune checkpoint inhibitors (ICI’s) n=9 (56%), BRAF+/-MEK inhibitors n=5 (31%), and/or RT n=5 (31%). Patients with LMD were treated with Ommaya n=13 +VPS n=3, WBRT n=7, ICI’s n=5, BRAF+MEK inhibitors n=4, and IT topotecan. LMD patients had a median survival 3.27 months after diagnosis (0.30–39). Two patients outlived their counterparts by 21.1 and 39.0 months. The 2 long-term survivors were treated with WBRT and either ICI, pembrolizumab or ipilimumab+nivolumab.

CONCLUSION
Clinical studies in LMD can provide critical insights and help to develop improved guidelines and current therapies.
30. RADIOSURGERY FOLLOWED BY TUMOR TREATING FIELDS FOR BRAIN METASTASES (1–10) FROM NSCLC IN THE PHASE 3 METIS TRIAL
Authors: Mehta Minesh P , Gondi Vinai , Brown Paul , Ahluwalia Manmeet 
Published: August 2020

Abstract

BACKGROUND
Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising alternating electric fields. TTFields have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The objective of the METIS study [NCT02831959] is evaluation of the efficacy and safety of TTFields in NSCLC patients with brain metastases.

METHODS
NSCLC patients (N=270) with 1–10 brain metastases were randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, &gt; 18 hours/day) within 7 days of SRS or supportive care. The portable device delivered TTFields to the brain using 4 transducer arrays, while patients received the best standard-of-care for systemic disease. Patients were followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; and optimal therapy for extracranial disease. Prior WBRT, surgical resection of metastases, or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at two sided alpha of 0.05 to detect a hazard ratio of 0.57. On September, 2019, an independent Data Monitoring Committee (DMC) reviewed METIS trial data collected to that point. The DMC concluded that no unexpected safety issues had emerged and recommended continuation of the METIS study as planned.
41. PROGNOSTIC VALIDATION OF THE EANO ESMO CLASSIFICATION OF LEPTOMENINGEAL METASTASIS
Authors: Le Rhun Emilie , Devos Patrick , Weller Johannes , Seystahl Katharina , Mo Francesca , Compter Annette , Sophie Berghoff Anna , Jongen Joost , Wolpert Fabian , Rudà Roberta , Brandsma Dieta , van den Bent Martin , Preusse Matthias , Herrlinger Ulrich , Weller Michael 
Published: August 2020

Abstract

BACKGROUND
The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) based on clinical (typical/atypical), cytological (positive/negative/equivocal) and MRI (A linear, B nodular, C linear and nodular, D normal or hydrocephalus only) presentation. Type I LM is defined by the presence of tumor cells in the cerebrospinal fluid (CSF) (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the clinical utility of these EANO ESMO LM subtypes.

PATIENTS AND METHODS
We retrospectively assembled data from 254 patients with newly diagnosed LM from different solid tumors, including as main primary tumors breast cancer (n=98, 45%), lung cancer (n=65, 25.5%) and melanoma (n=51, 13.5%). Survival curves were estimated using the Kaplan-Meier method and compared by Log-rank test.

RESULTS
Median age at LM diagnosis was 56.5 years (range 20–82 years). Typical clinical LM symptoms or signs were noted in 225 patients (88.5%); only 13 patients (5%) were clinically asymptomatic. The most common MRI subtype was A seen in 117 patients (46%). Types B (n=33, 13%), C (n=54, 21%) and D (n=50, 19.5%) were less common. Tumor cells were observed in the CSF in 186 patients (73%) whereas the CSF was equivocal in 24 (9.5%) and negative in 44 (17.5%) patients. Patients with confirmed LM had inferior outcome than patients with probable or possible LM (p=0.0063). Type I patients had inferior outcome than type II patients (p=0.0019). Nodular disease was a negative prognostic factor in type II LM, but not in type I LM (p=0.0138).

CONCLUSION
The presence of tumor cells in the CSF appears to have a greater prognostic role than the neuroimaging presentation. EANO ESMO LM subtypes are highly prognostic and should be considered in the design of clinical trials.
45. DELAY OR FAILURE TO ADMINISTER STEREOTACTIC RADIOSURGERY TO THE CAVITY AFTER SURGERY FOR BRAIN METASTASES. AN INTENTION-TO-TREAT ANALYSIS
Authors: O’Brien Diana Roth , Kaye Sydney , Poppas Phillip , 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

BACKGROUND
Data regarding the efficacy of adjuvant stereotactic radiosurgery (SRS) for resected brain metastases (BM) is often limited to patients completing SRS within a specified timeframe. We performed an intention-to-treat analysis to determine local recurrence (LR) for all BM patients referred for SRS.

METHODS
We retrospectively identified resected BM patients referred for SRS between 2012 and 2018. Patients were divided based on delay to SRS into four categories: 1) ≤4 weeks, 2) &gt;4–8 weeks, 3) &gt;8 weeks, and 4) never received. We investigated the relationship between delay to SRS and LR, local recurrence-free survival (LRFS), and overall survival, as well as the predictors of and reason for delays.

RESULTS
In our cohort of 159 patients, median age was 64.0 years, 56.5% patients were female, median tumor diameter was 2.9 cm, and gross total resection was achieved in 83.0%. On intention-to-treat analysis, LR was 22.6%. Delays to SRS correlated with LR: 2.3% with SRS ≤4 weeks postoperatively, 14.5% with SRS at &gt;4–8 weeks (p=0.03), 48.5% with SRS at &gt;8 weeks (p&lt;0.001). No LR difference was observed with SRS delayed by &gt;8 weeks, vs. never completed, 48.5% vs. 50.0% (p=0.91). 53 (33.3%) patients comprised these latter two categories. A similar relationship emerged between delay to SRS and LRFS (p&lt;0.01). Non-small cell lung cancer pathology (p=0.04) and earlier year of treatment (p&lt;0.01) were predictive of delays. Common reasons for delays included logistics, management of systemic disease, complications, or comorbidities.

CONCLUSION
A significant number of patients referred for SRS never receive it, or are treated with a delay &gt;8 weeks, conferring equivalent LR risk. Accordingly, the actual efficacy of adjuvant SRS may need reassessment. Reasons for delays and mechanisms for reducing them are discussed. For patients likely to experience significant delays, other techniques, such as preoperative SRS or intraoperative brachytherapy, may be considered.
46. PAN-CANCER ANALYSIS OF ORTHOTOPIC PATIENT DERIVED XENOGRAFTS FROM BRAIN METASTASES
Authors: Zeng Yu , Pelton Kristine , Yerrum Smitha , Kao Pei-Lun , Sinai Claire , Tran Tony , Sinha Rileen , Shetty Aniket , Tolstorukov Michael Y , Jaber Aliya , Freitas Dylan E , Pisano William , Verselis Sigitas J , Herbert Zach T , Lin Nancy U , Zhao Jean J , Weinstock David M , Chukwueke Ugonma N , Aizer Ayal A , Chiocca E Antonio , Bi Wenya Linda , Wen Patrick Y , Lee Eudocia Q , Nayak Lakshmi , Meredith David M , Santagata Sandro , Chow Kin-Hoe , Ligon Keith L 
Published: August 2020

Abstract
Brain metastases (BM) are a leading cause of cancer death and prognosis remains poor despite treatment advances at other sites. Models are central to therapeutic development, but few orthotopic patient-derived xenograft (PDX) models of BM exist. To represent diversity across BM types, we established a program to create orthotopic PDX at scale from all BM patients. To date BM were received from 100 patients and PDX attempted by direct brain injection (PDX, n=89) or injection of low passage patient-derived cell lines (PDCLX, n=11). We created 65 successful BM PDX from 13 cancers: 17 lung (55% take), 15 breast (68%), 6 melanoma (75%), 5 CNS lymphoma (83%), 3 gastrointestinal (75%), 2 esophageal (40%), 2 ovarian (67%), 1 sarcoma (100%), 1 laryngeal (100%), 1 prostate (100%), 1 pancreatic (100%), 1 uterine adenosarcoma (100%), and 1 yolk sac tumor (100%). Take rate was similar for models derived from patients with prior chemotherapy-only versus immune/targeted therapy-only (63 vs 58%). Fifteen patients had live tumor and matching PBMCs archived for modeling in vitro immunotherapy responses. Mean time to moribund among different cancer types ranged from 27 days (yolk sac tumor) to 177.5 days (ovarian). BM PDX had a favorable timeline for preclinical study (90% moribund at 180 days). All PDX matched the patient driver SNVs and copy aberrations, even at &gt;P4. No significant differences noted by immunodeficient strain (SCID versus NSG) or injection site (orthotopic versus heterotopic). Explants from BM PDX were able to generate long-term cell lines (60%) or short-term cultures with qualitative concordance of model-to-patient responses to targeted therapy (Osimertinib, EGFRi) and immunotherapy (Pembrolizumab, PD1i). Genomic and clinical data were used to create the DFCI BM PDX cBioPortal for public release and models distribution will be available through the DFCI Center for Patient Derived Models.