bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards a better understanding of ice mantle desorption by cosmic rays
Authors: Rawlings Jonathan M C 
Published: August 2022

ABSTRACT
The standard model of cosmic ray heating-induced desorption of interstellar ices is based on a continuous representation of the sporadic desorption of ice mantle components from classical ($0.1\, \mu$m) dust grains. This has been re-evaluated and developed to include tracking the desorption through (extended) grain cooling profiles, consideration of grain size-dependencies and constraints to the efficiencies. A model was then constructed to study the true, sporadic, nature of the process with possible allowances from species co-desorption and whole mantle desorption from very small grains. The key results from the study are that the desorption rates are highly uncertain, but almost certainly significantly larger than have been previously determined. For typical interstellar grain size distributions it is found that the desorption is dominated by the contributions from the smallest grains. The sporadic desorption model shows that, if the interval between cosmic ray impacts is comparable to, or less than, the freeze-out time-scale, the continuous representation is inapplicable; chemical changes may occur on very long time-scales, resulting in strong gas phase chemical enrichments that have very non-linear dependences on the cosmic ray flux. The inclusion of even limited levels of species co-desorption and/or the contribution from very small grains further enhances the rates, especially for species such as H2O. In general, we find that cosmic ray heating is the dominant desorption mechanism in dark environments. These results may have important chemical implications for protostellar and protoplanetary environments.
Multiply lensed star forming clumps in the A521-sys1 galaxy at redshift 1
Authors: Messa Matteo , Dessauges-Zavadsky Miroslava , Richard Johan , Adamo Angela , Nagy David , Combes Françoise , Mayer Lucio , Ebeling Harald 
Published: August 2022

ABSTRACT
We study the population of star-forming clumps in A521-sys1, a $z=1.04$ system gravitationally lensed by the foreground ($z=0.25$) cluster Abell 0521. The galaxy presents one complete counter-image with a mean magnification of $\rm \mu \sim 4$ and a wide arc containing two partial images of A521-sys1 with magnifications reaching $\mu &gt; 20$, allowing the investigations of clumps down to scales of ${\rm R}_{\rm eff} &lt; 50$ pc. We identify 18 unique clumps with a total of 45 multiple images. Intrinsic sizes and UV magnitudes reveal clumps with elevated surface brightnesses comparable to similar systems at redshifts $z\gtrsim 1.0$. Such clumps account for ${\sim}40\,\rm{per\ cent}$ of the galaxy UV luminosity implying a significant fraction of the recent star-formation activity is taking place there. Clump masses range from 106 to $10^9\,{\rm M}_\odot$ and sizes from tens to hundreds of parsec resulting in mass surface densities from 10 to $10^3\,{\rm M}_\odot\,{\rm pc}^{-2}$ with a median of ${\sim}10^2\,{\rm M}_\odot\,{\rm pc}^{-2}$. These properties suggest that we detect star formation taking place across a wide range of scale from cluster aggregates to giant star-forming complexes. We find ages of less than 100 Myr consistent with clumps being observed close to their natal region. The lack of galactocentric trends with mass, mass density, or age and the lack of old migrated clumps can be explained either by dissolution of clumps after few ∼100 Myr or by stellar evolution making them fall below the detectability limits of our data.
Sperm degradation after vasectomy follows a sperm chromatin fragmentation-dependent mechanism causing DNA breaks in the toroid linker regions
Authors: Ribas-Maynou Jordi , Nguyen Hieu , Valle Raquel , Wu Hongwen , Yeste Marc , Ward W Steven 
Published: August 2022

Abstract
Vasectomy is a widely used surgical technique creating an obstructive azoospermia. Although sperm cannot be ejaculated, the testis maintains sperm production in vasectomized males. The continuous accumulation of sperm deposited in the epididymis and the vas deferens fraction necessarily need to be degraded and eliminated. While the elimination process is carried out by granulomas that form after vasectomy, the detailed mechanisms of sperm degradation are still not known. The aim was to assess whether sperm chromatin fragmentation (SCF), a mechanism that degrades the entire sperm genome at the toroid linker regions (TLRs), is activated after vasectomy in sperm cells. We vasectomized mice and evaluated the presence of TLR-specific double-strand breaks through pulsed-field gel electrophoresis and the Comet assay at 1, 2 and 3 weeks after surgery. Results for DNA damage (Olive tail moment) at single-cell level showed an increase of double-strand breaks after vasectomy for vas deferens sperm after 1, 2 and 3 weeks postvasectomy (21.78 ± 2.29; 19.71 ± 1.79 and 32.59 ± 1.81, respectively), compared to mock surgery (7.04 ± 1.03; 10.10 ± 1.29 and 8.64 ± 0.85, respectively; P &lt; 0.001). Similar findings were obtained for cauda epididymis sperm (P &lt; 0.001), but not for caput epididymis (P &gt; 0.05). Pulsed-field gel electrophoresis showed the presence of double-stranded breaks between 15 and 145 kb, indicating that DNA breaks were produced mainly in the sperm TLRs. Results presented here suggest that SCF is a mechanism activated in vas deferens after vasectomy to degrade sperm DNA when they cannot be ejaculated, preventing their function.
SRRM2 organizes splicing condensates to regulate alternative splicing
Authors: Xu Shaohai , Lai Soak-Kuan , Sim Donald Yuhui , Ang Warren Shou Leong , Li Hoi Yeung , Roca Xavier 
Published: August 2022

AbstractSRRM2 is a nuclear-speckle marker containing multiple disordered domains, whose dysfunction is associated with several human diseases. Using mainly EGFP-SRRM2 knock-in HEK293T cells, we show that SRRM2 forms biomolecular condensates satisfying most hallmarks of liquid-liquid phase separation, including spherical shape, dynamic rearrangement, coalescence and concentration dependence supported by in vitro experiments. Live-cell imaging shows that SRRM2 organizes nuclear speckles along the cell cycle. As bona-fide splicing factor present in spliceosome structures, SRRM2 deficiency induces skipping of cassette exons with short introns and weak splice sites, tending to change large protein domains. In THP-1 myeloid-like cells, SRRM2 depletion compromises cell viability, upregulates differentiation markers, and sensitizes cells to anti-leukemia drugs. SRRM2 induces a FES splice isoform that attenuates innate inflammatory responses, and MUC1 isoforms that undergo shedding with oncogenic properties. We conclude that SRRM2 acts as a scaffold to organize nuclear speckles, regulating alternative splicing in innate immunity and cell homeostasis.
BSCI-04 TARGETING THE PI3K-MTOR PATHWAY TO TREAT UBE2C-DRIVEN BRAIN METASTASES
Authors: Paisana Eunice , Cascão Rita , Custódia Carlos , Qin Nan , Picard Daniel , Pauck David , Carvalho Tânia , Ruivo Pedro , Roque Rafael , Pimentel José , Remke Marc , Barata João T , Faria Cláudia C 
Published: August 2022

Abstract
Brain metastases (BMs) are a devastating complication of advanced cancers associated with poor prognosis. Contrarily to the current improvement in systemic therapies, BMs are still incurable and one of the main causes of death in cancer patients. We analyzed BMs from thirty patients with various primary tumor origins by RNA sequencing and identified the upregulation of UBE2C, a gene involved in the correct transition from metaphase to anaphase. Using an independent cohort of patients with BMs, we demonstrated that high protein expression of UBE2C was associated with worse survival. UBE2C-driven cancer cells promoted migration and invasion in vitro and induced an aggressive phenotype and decreased survival in mouse orthotopic xenografts. PI3K/mTOR inhibition effectively blocked cancer cell signaling and prevented the development of leptomeningeal metastases. Therefore, we have identified UBE2C as a molecular marker of worse outcome in BMs patients and pre-clinically validated an effective therapy against UBE2C-driven brain metastatic disease.
BSCI-08 NEURONAL MIMICRY PROMOTES BREAST CANCER LEPTOMENINGEAL METASTASIS FROM BONE MARROW
Authors: Whiteley Andrew , Price Trevor , Simon Brennan , Xu Katie , Sipkins Dorothy 
Published: August 2022

Abstract
Breast cancer (BC) patients diagnosed with leptomeningeal disease (LMD) have a median survival of less than six months. There has been limited therapeutic innovation in treating LMD due to our poor understanding of the molecular mechanisms governing breast cancer cell (BCC) invasion and survival within the leptomeninges (LM). Here we show that BCCs can invade the LM by migrating along the outer surface of emissary vessels that passage from the skull and vertebral bone marrow through cortical bone fenestrations, emerging as LM vasculature in the sub-arachnoid space. This process requires BCC integrin α6 engaging laminin on the vascular basement membrane of emissary vessels, mimicking an α6 integrin-dependent mechanism used by neural progenitors to migrate to the olfactory bulb. Once in the LM, BCCs co-localize with perivascular CSF1R+ meningeal macrophages which support BCC survival through the secretion of the protective neurotrophin, GDNF. Pharmacologic depletion of these meningeal macrophages causes a marked reduction of GDNF concurrent with a decrease in LMD progression, which is rescued by intraventricular delivery of recombinant GDNF. Together these data suggest that BCCs hijack neural migratory pathways and leptomeningeal macrophages to invade and survive in the LM niche. Finally, analysis of craniotomy samples from patients with breast cancer revealed a correlation between BCC integrin α6 expression and meningeal metastasis suggesting the potential of integrin α6 as a novel target to predict or treat LMD.
CLRM-05 FEASIBILITY OF EVALUATING ABEMACICLIB NEUROPHARMACOKINETICS OF DIFFUSE MIDLINE GLIOMA USING INTRATUMORAL MICRODIALYSIS
Authors: Dalmage Mahalia , Brown Desmond , Nduom Edjah , Jackson Sadhana 
Published: August 2022

Abstract

INTRODUCTION
Diffuse midline gliomas are the most aggressive brain tumors of childhood and young adults, with documented 2 year survival rates of &lt;10%. Treatment failure is due in part to the presence of the blood-brain barrier (BBB), which limits permeability of varied agents. Efforts to evaluate drug delivery across the BBB in midline gliomas have been restricted to post biopsy specimens. Intracerebral microdialysis sampling of cortical tissue has been shown to be a highly effective tool in determining neuropharmacokinetics in adult brain tumors.

METHODS
All participants will take abemaciclib pre-operatively for 4.5 days at twice daily dosing. A maximally safe surgical resection for cortical high grade glioma or stereotactic needle biopsy for midline glioma will be performed in the OR and verified by brain CT. Continuous microdialysis sampling will be obtained over the course of the next 48 hours. We propose to evaluate 5 participants.

RESULTS
This is a safety and feasibility study to evaluate tumor pharmacokinetics (PK) and pharmacodynamics (PD) of abemaciclib in recurrent high grade glioma and midline glioma participants in need of surgical resection or biopsy respectively. If intratumoral or PK brain dialysate sampling concentrations are &gt;10nmol/L, or PD findings suggest CDK inhibition (decreased expression of Rb and/or topoIIα), then restart of abemaciclib therapy along with temozolomide will be administered for maintenance therapy post resection or biopsy. After every 3 cycles, repeat brain MRI’s will be obtained to evaluate treatment response and disease progression. Exploratory aims include catheter stability testing, tissue genomic sequencing and PDX modeling.

CONCLUSION
We propose a trial using clinical microdialysis, placed in diffuse midline glioma tissue post biopsy, as an experimental research tool, to assess CNS drug entry and targeted inhibition with abemaciclib. These studies will be the first of their kind focused on the dynamic nature of CNS drug delivery with the overall intent to inform future clinical therapies.
CLRM-19 USING FUNCTIONAL PRECISION MEDICINE TO GUIDE CLINICAL TRIAL ENROLLMENT IN GBM
Authors: Ledford Aubrey , Smith Ashley , DesRochers Tessa , Vibat Cecile Rose 
Published: August 2022

Abstract
Interventional clinical trials in glioblastoma (GBM) have been consistently disappointing, attributable to various factors such as ineffective therapies, inadequate trial designs including lack of control arms, or enrollment criteria that do not represent real-world practice. Novel paradigms for clinical trial design(s) in GBM are desperately needed to produce clinically useful patient outcomes. KIYATEC has developed a patient- and tumor-specific technology platform to evaluate cellular response(s) to therapeutics using 3D cell culture methods that provide functional, patient-specific response predictions. Employing KIYATEC’s technology to screen compounds against both primary patient-, and PDX-derived specimens, enables clinical prioritization of early-stage assets most likely to have therapeutic response in vivo. In addition, KIYATEC’s 3D Predict™ Glioma test has shown clinical correlation of test-predicted response(s) and clinical outcomes in GBM patients. Incorporating KIYATEC’s 3D ex vivo technology into GBM therapeutic development is positioned to accelerate more successful trial results by 1) identifying early-stage compounds likely to possess clinical effects in vivo, and 2) prospectively identifying patients expected to have a clinical response to therapeutics in development. 3D Predict Glioma provides patient-specific responses within 7-10 days of tissue acquisition, providing an avenue for test integration into adaptive clinical trials, whereby functional characterization could provide gating information relating to trial execution. Specifically, functional response prediction may play a pivotal role in identifying newly diagnosed patients who might derive greater benefit from clinical trials compared to standard of care and by optimizing effective therapeutic selection in the recurrent setting. Therefore, a priori knowledge of an early-stage assets’ potential, combined with therapeutic sensitivity of individual patient tissue, may facilitate a new era for adaptive clinical trial design by assimilating KIYATEC’s analytically and clinically validated test into various steps of clinical trial execution such as randomization, stratification, therapy-switching, or compound addition/discontinuation.
LOCL-03 INTRATUMORAL DELIVERY OF CONDITIONALLY REPLICATIVE HUMAN ADENOVIRUS 657 EXPRESSING THE IMMUNE CO-STIMULATOR CD40L (CRAD657-CD40L) AS A POTENTIALLY PROMISING TREATMENT FOR RECURRENT PEDIATRIC HIGH GRADE GLIOMA
Authors: Webb Mason , Khatua Soumen , Thompson Jill , Yerovi Maria Chiriboga , Daniels David , Schartz Jonathan , Wongthida Phonphimon , Hopps Sidney , Barry Mary , Barry Michael , Vile Richard , Diaz Rosa 
Published: August 2022

Abstract

INTRODUCTION
Malignancies of the central nervous system (CNS) have had largely unchanged survival outcomes despite decades of research. Recently, viral-based therapeutics have shown some benefit for patients with CNS malignancies in early clinical trials. Adenovirus has been demonstrated as safe and is currently being examined in several phase I and II clinical trials. We recently demonstrated that adenovirus expressing CD40L is effective in enhancing survival in murine models of diffuse midline glioma. Therefore, to enhance the tumor specificity of this virotherapy, we hypothesized that by using a novel conditionally replicative adenovirus expressing CD40L, CRAd657-CD40L, we would maintain this survival benefit in multiple murine models for high grade glioma while decreasing off-target toxicity.

METHODS
We examined the utility of conditionally replicative adenovirus expressing CD40L in both in vitro and in vivo studies. Human cell lines from diffuse intrinsic pontine glioma (DIPG) and glioblastoma were used to confirm infectivity and CD40L expression, and syngeneic murine models of glioma were evaluated for toxicity and survival following intratumoral injection of a conditionally replicative adenoviral vector.

RESULTS
CRAd657-CD40L generated strong expression of CD40L in human in vitro DIPG XIII and U251 cell lines and induced MHCII expression on CD11c+ DC’s in U251/DC co-culture. Further, in syngeneic murine models of glioma, conditionally replicative adenoviral treatment significantly reduced toxicity while retaining survival efficacy.

CONCLUSIONS
Given these promising results as well as the critical need for novel therapeutics in CNS malignancies, we are now progressing to human trials targeting pediatric HGG, an unmet need in pediatric neuro-oncology. This would be the first-in-human study using CRAd-657-CD40L in pediatric HGG. In this Phase 1 clinical trial, we hypothesize that intratumoral injection of CRAd657-CD40L will cause selective expression of CD40L, increased infiltration of immune cells into the tumor, and safely enhance tumor clearance.
LOCL-14 FACTORS ASSOCIATED WITH TRACT SEEDING AFTER LASER INTERSTITIAL THERMAL THERAPY FOR INTRACRANIAL TUMORS
Authors: Haskell-Mendoza Aden , Srinivasan Ethan , Lerner Emily , Edwards Ryan , Jackson Joshua , Hardigan Andrew , Vaios Eugene , Fecci Peter 
Published: August 2022

Abstract
Laser interstitial thermal therapy (LITT) is a growing minimally-invasive approach for treatment of intracranial tumors. Stereotactic placement of the laser catheter within the target lesion carries a theoretical risk of tract seeding, which could lead to disease progression. A retrospective analysis of patients treated with LITT for biopsy-confirmed tumor from 2016-2020 was conducted to characterize the risk of post-LITT tract seeding. Forty-two patients met inclusion criteria, of whom 23 (54.7%) had primary brain tumors and 19 (45.3%) metastases. Thirty-three (78.6%) lesions were recurrent disease at the time of LITT. On follow-up MRI, 3 patients (7.1%) were identified to have had tumor seeding along the LITT tract resulting in progressing disease. There were no significant differences in tumor histology, pre-operative maximum lesion diameter, number of LITT trajectories, rounds of lasing, or post-LITT radiotherapy or surgery between patients with and without tract seeding. All patients with tract seeding were treated for periventricular lesions (&lt;1cm). Patients with tract seeding were also more likely to have received LITT ablations administered from the superficial to deepest elements of the lesion (p=0.05). The median time to progression post-LITT for patients with tract seeding was significantly shorter than those without (1.1 vs 5.9 months, p=0.02). Additional analyses revealed trends towards longer median tract length (4.0 vs. 2.2 cm, p=0.23) and shorter overall survival (5.4 vs. 14.2 months, p=0.17) in the tract seeding cohort. In summary, tract seeding is an infrequent complication associated with both LITT and traditional biopsy. In LITT, tract seeding progression occurs significantly faster than at the treated site, which may be associated with a worse overall prognosis. Prophylactic stereotactic radiosurgery to the LITT tract could be of benefit, however this may pose further risk to patients given the low overall frequency. More frequent monitoring may be necessary lesions in periventricular or difficult to ablate regions, or with longer LITT tracts.
MMAP-04 CYTOTOXIC, TUMOR-HOMING INDUCED NEURAL STEM CELLS AS AN ADJUVANT TO RADIATION IN THE TREATMENT OF NON-SMALL CELL LUNG CANCER LEPTOMENINGEAL METASTASES
Authors: Mercer-Smith Alison , Jiang Wulin , Valdivia Alain , Bell Noah , Woodell Alex , Floyd Scott , Hingtgen Shawn 
Published: August 2022

Abstract

INTRODUCTION
Non-small cell lung cancer (NSCLC) is the most common cancer to spread to the brain, and spread to the leptomeninges is particularly devastating, with a median survival of only months. While radiation may offer symptomatic relief, new adjuvant therapies are needed for more durable tumor kill. Spheroidal, human induced neural stem cells (hiNeuroS) transdifferentiated from fibroblasts are inherently tumoritropic. When engineered to secrete the cytotoxic protein TRAIL, they provide the potential for a personalized, targeted approach to NSCLC leptomeningeal metastases.

METHODS
hiNeuroS-TRAIL in vivo efficacy was determined by tracking the progression and survival of mice with NSCLC leptomeningeal tumors treated with intracerebroventricular hiNeuroS, radiation, or both. To determine the impact of radiation on the tumor tropism of hiNeuroS, we performed 2-dimensional motion assays on hiNeuroS with and without the presence of NSCLC pre- and post-radiation. Migrational capacity in vivo was determined by infusing hiNeuroS into the lateral ventricles of mice with established NSCLC tumors and monitoring hiNeuroS accumulation using post-mortem fluorescent analysis.

RESULTS/CONCLUSION
Mice treated with the combination of hiNeuroS-TRAIL and 2 Gy showed a significantly reduced mean tumor signal (2.7%) compared to controls (100%) or 2 Gy-only (54.9%). Mice treated with 2 Gy alone showed no significant survival difference compared to controls. Both combination and hiNeuroS-TRAIL-only-treated mice showed a significant improvement in median survival compared to controls (36.6% and 46.3% improvement, respectively). hiNeuroS showed enhanced directionality and displacement in the presence of NSCLC in 2-dimensional motion assays, indicating directional migration, and they maintained this ability following exposure to radiation. Co-localization of hiNeuroS with NSCLC was also observed in vivo. These results suggest the potential of hiNeuroS-TRAIL as a powerful adjuvant to radiation in the treatment of leptomeningeal NSCLC.
NEIM-03 A MULTICENTER PHASE 3 TRIAL IN PROGRESS: DIAGNOSTIC PERFORMANCE OF18F-FLUCICLOVINE PET FOR THE DETECTION OF RECURRENT BRAIN METASTASES AFTER RADIATION THERAPY (REVELATE)
Authors: Chao Samuel , Chaglassian Alain , Tainer Nancy , Teoh Eugene 
Published: August 2022

Abstract

INTRODUCTION
Following treatment of brain metastases, which can affect up to 40% of patients with cancer, patients will typically be closely monitored with serial brain magnetic resonance imaging (MRI) owing to the high likelihood of recurrence. The recommended follow-up modalities (CE-T1-weighted and FLAIR/T2-weighted MRI) have poor specificity, meaning that differentiation of true disease from treatment-related changes such as radiation necrosis can be difficult. Recent pilot studies have reported amino acid PET radiopharmaceutical, 18F-fluciclovine, to be potentially useful in discriminating tumor recurrence from treatment-related changes. This may potentially aid physicians in making confident diagnoses and inform subsequent treatment plans.

METHODS
REVELATE (NCT04410133) will evaluate the diagnostic performance of 18F-fluciclovine PET (read with conventional MRI for anatomical reference) for the detection of recurrent brain metastases in patients for whom MRI is equivocal. This multicenter, phase 3, prospective, open-label trial aims to enroll approximately 150 subjects from across 19 US sites with solid tumor brain metastases who have undergone radiation therapy, if they have a lesion considered equivocal on MRI that requires further confirmatory diagnostic procedures (either biopsy/neurosurgical intervention or clinical follow-up). Patients will undergo 18F-fluciclovine PET &lt;42 days after the equivocal MRI and 1–21 days pre-biopsy/neurosurgical intervention. Clinical follow-up will occur for 6m post-18F-fluciclovine PET. Secondary objectives include evaluation of subject- and lesion-level 18F-fluciclovine negative and positive percent agreement (equivalent to specificity and sensitivity, respectively) for recurrent brain metastases, inter-reader and intra-reader agreement, and safety evaluations. Enrolment began in October 2020 and the trial is active but not recruiting at the time of submission.