bluuebunny/crossref_metadata_2025 huggingface dataset:
An enhancer variant associated with breast cancer susceptibility in Black women regulates TNFSF10 expression and antitumor immunity in triple-negative breast cancer
Authors: Han Yoo Jane , Zhang Jing , Hardeman Ashley , Liu Margaret , Karginova Olga , Romero Roger , Khramtsova Galina F , Zheng Yonglan , Huo Dezheng , Olopade Olufunmilayo I
Published: August 2022

Women of African ancestry have the highest mortality from triple-negative breast cancer (TNBC) of all racial groups. To understand the genomic basis of breast cancer in the populations, we previously conducted genome-wide association studies and identified single nucleotide polymorphisms (SNPs) associated with breast cancer in Black women. In this study, we investigated the functional significance of the top associated SNP rs13074711. We found the SNP served as an enhancer variant and regulated TNFSF10 (TRAIL) expression in TNBC cells, with a significant association between the SNP genotype and TNFSF10 expression in breast tumors. Mechanistically, rs13074711 modulated the binding activity of c-MYB at the motif and thereby controlled TNFSF10 expression. Interestingly, TNFSF10 expression in many cancers was consistently lower in African Americans compared with European Americans. Furthermore, TNFSF10 expression in TNBC was significantly correlated with the expression of antiviral immune genes and was regulated by type I interferons (IFNs). Accordingly, loss of TNFSF10 resulted in a profound decrease in apoptosis of TNBC cells in response to type I IFNs and poly(I:C), a synthetic analogue of double stranded virus. Lastly, in a syngeneic mouse model of breast cancer, TNFSF10-deficiency in breast tumors decreased tumor-infiltrated CD4+ and CD8+ T cell quantities. Collectively, our results suggested that TNFSF10 plays an important role in the regulation of antiviral immune responses in TNBC, and the expression is in part regulated by a genetic variant associated with breast cancer in Black women. Our results underscore the important contributions of genetic variants to immune defense mechanisms.
Smooth and Polyhedral Norms via Fundamental Biorthogonal Systems
Authors: Dantas Sheldon , Hájek Petr , Russo Tommaso
Published: August 2022

Let $\mathcal {X}$ be a Banach space with a fundamental biorthogonal system, and let $\mathcal {Y}$ be the dense subspace spanned by the vectors of the system. We prove that $\mathcal {Y}$ admits a $C^\infty $-smooth norm that locally depends on finitely many coordinates (LFC, for short), as well as a polyhedral norm that locally depends on finitely many coordinates. As a consequence, we also prove that $\mathcal {Y}$ admits locally finite, $\sigma $-uniformly discrete $C^\infty $-smooth and LFC partitions of unity and a $C^1$-smooth locally uniformly rotund norm. This theorem substantially generalises several results present in the literature and gives a complete picture concerning smoothness in such dense subspaces. Our result covers, for instance, every weakly Lindelöf determined Banach space (hence, all reflexive ones), $L_1(\mu )$ for every measure $\mu $, $\ell _\infty (\Gamma )$ spaces for every set $\Gamma $, $C(K)$ spaces where $K$ is a Valdivia compactum or a compact Abelian group, duals of Asplund spaces, or preduals of Von Neumann algebras. Additionally, under Martin Maximum MM, all Banach spaces of density $\omega _1$ are covered by our result.
A scoping review of publicly available language tasks in clinical natural language processing
Authors: Gao Yanjun , Dligach Dmitriy , Christensen Leslie , Tesch Samuel , Laffin Ryan , Xu Dongfang , Miller Timothy , Uzuner Ozlem , Churpek Matthew M , Afshar Majid
Published: August 2022

Objective

To provide a scoping review of papers on clinical natural language processing (NLP) shared tasks that use publicly available electronic health record data from a cohort of patients.

Materials and Methods

We searched 6 databases, including biomedical research and computer science literature databases. A round of title/abstract screening and full-text screening were conducted by 2 reviewers. Our method followed the PRISMA-ScR guidelines.

Results

A total of 35 papers with 48 clinical NLP tasks met inclusion criteria between 2007 and 2021. We categorized the tasks by the type of NLP problems, including named entity recognition, summarization, and other NLP tasks. Some tasks were introduced as potential clinical decision support applications, such as substance abuse detection, and phenotyping. We summarized the tasks by publication venue and dataset type.

Discussion

The breadth of clinical NLP tasks continues to grow as the field of NLP evolves with advancements in language systems. However, gaps exist with divergent interests between the general domain NLP community and the clinical informatics community for task motivation and design, and in generalizability of the data sources. We also identified issues in data preparation.

Conclusion

The existing clinical NLP tasks cover a wide range of topics and the field is expected to grow and attract more attention from both general domain NLP and clinical informatics community. We encourage future work to incorporate multidisciplinary collaboration, reporting transparency, and standardization in data preparation. We provide a listing of all the shared task papers and datasets from this review in a GitLab repository.
Give and take: Effects of genetic admixture on mutation load in endangered Florida panthers
Authors: Ochoa Alexander , Onorato David P , Roelke-Parker Melody E , Culver Melanie , Fitak Robert R
Published: August 2022

Genetic admixture is a biological event inherent to genetic rescue programs aimed at the long-term conservation of endangered wildlife. Although the success of such programs can be measured by the increase in genetic diversity and fitness of subsequent admixed individuals, predictions supporting admixture costs to fitness due to the introduction of novel deleterious alleles are necessary. Here, we analyzed nonsynonymous variation from conserved genes to quantify and compare levels of mutation load (i.e. proportion of deleterious alleles and genotypes carrying these alleles) among endangered Florida panthers and non-endangered Texas pumas. Specifically, we used canonical (i.e. non-admixed) Florida panthers, Texas pumas, and F1 (canonical Florida × Texas) panthers dating from a genetic rescue program and Everglades National Park panthers with Central American ancestry resulting from an earlier admixture event. We found neither genetic drift nor selection significantly reduced overall proportions of deleterious alleles in the severely bottlenecked canonical Florida panthers. Nevertheless, the deleterious alleles identified were distributed into a disproportionately high number of homozygous genotypes due to close inbreeding in this group. Conversely, admixed Florida panthers (either with Texas or Central American ancestry) presented reduced levels of homozygous genotypes carrying deleterious alleles but increased levels of heterozygous genotypes carrying these variants relative to canonical Florida panthers. Although admixture is likely to alleviate the load of standing deleterious variation present in homozygous genotypes, our results suggest that introduced novel deleterious alleles (temporarily present in heterozygous state) in genetically rescued populations could potentially be expressed in subsequent generations if their effective sizes remain small.
Multiplex Polymerase Chain Reaction Reveals Unique Trends in Pathogen and Parasitoid Infestations of Alfalfa Leafcutting Brood Cells
Authors: Clements Justin , Haylett Maggie , Nelson Brenda , Shumate Silas , Young Nicole , Bradford Benjamin , Walsh Doug , Lamour Kurt
Published: August 2022

The alfalfa leafcutting bee Megachile rotundata Fabricius (HYMENOPTERA: Megachilidae) is an important pollinator for multiple agricultural seed commodities in the United States. M. rotundata is a solitary cavity nesting bee that forms brood nests where its larvae can develop. During the developmental stages of growth, brood can be preyed upon by multiple different fungal pathogens and insect predators and parasitoids, resulting in the loss of the developing larvae. Larval loss is a major concern for alfalfa (Medicago sativa L.) seed producers because they rely on pollination services provided by M. rotundata. Reduced pollination rates result in lower yields and increased production costs. In the present study, we examined the taxonomic composition of organisms found within M. rotundata brood cells using a multiplex PCR assay which was developed for the detection of bacterial, fungal, and invertebrate pests and pathogens of M. rotundata larvae. Known pests of M. rotundata were detected, including members of the fungal genus Ascosphaera, the causative agent of chalkbrood. The presence of multiple Ascosphaera species in a single brood cell was observed, with potential implications for chalkbrood disease management. The multiplex assay also identified DNA from more than 2,400 total species, including multiple predators and pathogenetic species not previously documented in association with M. rotundata brood cells.
Law Matters—Less Than We Thought
Authors: Klerman Daniel , Spamann Holger
Published: August 2022

In a pre-registered 2 × 2 × 2 factorial between-subject randomized lab experiment with 61 federal judges, we test if the law influences judicial decisions, if it does so more under a rule than under a standard, and how its influence compares to that of legally irrelevant sympathies. Participating judges received realistic materials and a relatively long period of time (50 min) to decide an auto accident case. We find at best weak evidence that the law matters or that rules constrain more than standards, and no evidence of a sympathy effect. (JEL K00, K13, K40, K41)
Quantitative Analysis of Vertical Transmission of Maternal SARS-CoV-2 Antibodies to Neonates and Young Infants Following Immunization During Pregnancy
Authors: Golan Naama , Ashkenazi Shai , Davidovich Rotem , Levinsky Alina , Bar Chaim Adina , Abu Hamad Ramzia , Raveh Omer , Yitzhaki Shai , Livni Gilat
Published: August 2022

Serum antibody levels to SARS-CoV-2 in infants born to mothers who had received 2 doses of the BNT2b2 vaccine during pregnancy correlated positively with increasing gestational age at vaccination (P < .01) and negatively with increasing time from vaccination (P < .01), with a significant drop in infants aged >60 days (P = .045).
Predictors of Septic Shock or Bacteremia in Children Experiencing Febrile Neutropenia Post-Chemotherapy
Authors: Avilés-Robles Martha , Schnur Jennifer J , Dorantes-Acosta Elisa , Márquez-González Horacio , Ocampo-Ramírez Luis A , Chawla Nitesh V
Published: August 2022

Background

Febrile neutropenia (FN) is an early indicator of infection in oncology patients post-chemotherapy. We aimed to determine clinical predictors of septic shock and/or bacteremia in pediatric cancer patients experiencing FN and to create a model that classifies patients as low-risk for these outcomes.

Methods

This is a retrospective analysis with clinical data of a cohort of pediatric oncology patients admitted during July 2015 to September 2017 with FN. One FN episode per patient was randomly selected. Statistical analyses include distribution analysis, hypothesis testing, and multivariate logistic regression to determine clinical feature association with outcomes.

Results

A total of 865 episodes of FN occurred in 429 subjects. In the 404 sampled episodes that were analyzed, 20.8% experienced outcomes of septic shock and/or bacteremia. Gram-negative bacteria count for 70% of bacteremias. Features with statistically significant influence in predicting these outcomes were hematological malignancy (P < .001), cancer relapse (P = .011), platelet count (P = .004), and age (P = .023). The multivariate logistic regression model achieves AUROC = 0.66 (95% CI 0.56–0.76). The optimal classification threshold achieves sensitivity = 0.96, specificity = 0.33, PPV = 0.40, and NPV = 0.95.

Conclusions

This model, based on simple clinical variables, can be used to identify patients at low-risk of septic shock and/or bacteremia. The model’s NPV of 95% satisfies the priority to avoid discharging patients at high-risk for adverse infection outcomes. The model will require further validation on a prospective population.
Maize sterility gene DRP1 encodes a desiccation-related protein that is critical for Ubisch bodies and pollen exine development
Authors: Hu Mingjian , Li Yunfei , Zhang Xiangbo , Song Weibin , Jin Weiwei , Huang Wei , Zhao Haiming
Published: August 2022

Desiccation tolerance is a remarkable feature of pollen, seeds, and resurrection-type plants. Exposure to desiccation stress can cause sporophytic defects, resulting in male sterility. Here, we report the novel maize sterility gene DRP1 (Desiccation-Related Protein 1), which was identified by bulked-segregant analysis sequencing and encodes a desiccation-related protein. Loss of function of DRP1 results in abnormal Ubisch bodies, defective tectum of the pollen exine, and complete male sterility. Our results suggest that DRP1 may facilitate anther dehydration to maintain appropriate water status. DRP1 is a secretory protein that is specifically expressed in the tapetum and microspore from the tetrad to the uninucleate microspore stage. Differentially expressed genes in drp1 are enriched in Gene Ontology terms for pollen exine formation, polysaccharide catabolic process, extracellular region, and response to heat. In addition, DRP1 is a target of selection that appears to have played an important role in the spread of maize from tropical/subtropical to temperate regions. Taken together, our results suggest that DRP1 encodes a desiccation-related protein whose loss of function causes male sterility. Our findings provide a potential genetic resource that may be used to design crops for heterosis utilization.
Clinician Perceptions of Transition From Legacy Electronic Health Record to MHS GENESIS: A Pilot Study
Authors: Knobloch Glynnis , Milliren Anna , Winnie Kirsten
Published: August 2022

Introduction

The implementation of a new electronic health record (EHR) presents significant challenges as users navigate a new interface. Our institution was an early adopter of MHS GENESIS (MHSG), the MHS’s new EHR. This study investigated provider perceptions of usability and the prevalence of burnout during an EHR transition from the Legacy system (LEHR) utilizing online, anonymous surveys before implementation and at several points post-implementation.

Materials and Methods

Clinician satisfaction, perceptions of EHR impact on safety, communication, reliability, and chart completion were assessed on five-point Likert scales. Usability was assessed using the validated System Usability Scale (SUS). Burnout prevalence was assessed using a validated single-item measure. Data were gathered via online, anonymous surveys before implementation and at 1, 3-6, and 9-12 months post “Go-Live.”

Results

Of 367 clinicians, 56 responded to the baseline survey; on average, 29% of responses were positive (i.e., satisfied or very satisfied) with LEHR. Following implementation, an average of 47%, 37%, and 47% of responses were positive for MHSG at 1 months (n = 42), 6 months (n = 55), and 12 months (n = 30), respectively. The mean SUS for LEHR was 48 (on a scale of 1-100); for MHSG, the mean SUS was 48 (1 month), 41 (6 months), and 44 (12 months). The burnout rate was reported as 39% (baseline), 26% (1 month), 33% (6 months), and 37% (12 months).

Conclusions

Perceptions of system usability, physician satisfaction, and burnout were not remarkably different between the two systems. Study results imply a need for further investigation as to why most clinicians continue to be unsatisfied with MHSG and wish to return to LEHR and whether or how this EHR transition contributed to burnout or if other factors are more contributory in this population. Future studies could also explore whether changes in the clinician interface, training, or implementation process impact clinician satisfaction, burnout, and desire to return to LEHR, or if these measures change with longer follow-up or in more varied populations.
Towards a better understanding of ice mantle desorption by cosmic rays
Authors: Rawlings Jonathan M C
Published: August 2022

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

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 $\mu > 20$, allowing the investigations of clumps down to scales of ${\rm R}_{\rm eff} < 50$ 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

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 < 0.001). Similar findings were obtained for cauda epididymis sperm (P < 0.001), but not for caput epididymis (P > 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

SRRM2 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

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

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

INTRODUCTION

Diffuse midline gliomas are the most aggressive brain tumors of childhood and young adults, with documented 2 year survival rates of <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 >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

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

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

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 (<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

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

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 <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.
NEIM-04 LEVERAGING NOVEL NEUROIMAGING TECHNIQUES TO LINK BRAIN METASTASES AND LOCAL GENE EXPRESSION
Authors: Germann Jurgen , Loh Aaron , Dudek Cain , Chow Clement , Boutet Alexandre , Lozano Andres , Mansouri Alireza
Published: August 2022

Metastases are the most prevalent adult brain tumour, most commonly arising from lung, breast, or melanoma primaries. Studies have suggested that different primary tumor types may have predilection for seeding to specific brain regions. One hypothesis is that the interaction of the genomic environment within specific brain region(s) and seeding tumor cells is ideal for supporting this process. The recent availability of neuroimaging based transcriptomic atlases make it feasible to test this hypothesis. In this proof-of-concept study, we leverage the Allen atlas to evaluate whether variance in location among different tumour subtypes can be explained by normative gene expression. Manual segmentation was done on contrast-enhanced T1-weighted MRIs in 31 patients with brain metastases and known primary tumour [breast (n=7), lung (n=14), genitourinary (n=5) and melanoma (n=5)]. Segmented lesions were transformed to template brain space. First, odds-ratio maps were created for each primary tumour subtype. These maps delineate brain regions that were preferentially engaged by each subtype. Consistent with prior literature, odds-ratio maps demonstrated a preference for metastases to seed to different brain regions according to primary tumour subtype, e.g. lung - cerebellum, melanoma - frontal and temporal lobes. Next, mapping our lesions on the Allen atlas of normative gene expression, we identified significant (p<0.01) differences in the local expression of certain genes– such as LEPROT and ITPKA – related to the spatial pattern of breast, lung, genitourinary, and melanoma. This novel approach integrates imaging and transcriptomic techniques that could be used towards an improved understanding of neuro-oncologic processes. Crucially, this approach would allow investigators to leverage conventional anatomical images – acquired as part of a patient’s normal clinical course and in the absence of tissue samples – to better understand cancer mechanics. This has potential ramifications for therapeutic decision-making. Large-scale prospective studies are underway.
NEIM-06 COMBINING CLINICAL VARIABLES AND RADIOMIC FEATURES TO HELP DISTINGUISH RADIATION NECROSIS FROM TUMOR IN PATIENTS WITH MELANOMA BRAIN METASTASES TREATED WITH RADIOSURGERY
Authors: Tran Benjamin , Buszek Samantha , Mitchell Drew , Long James , Elliott Andrew , Langshaw Holly , Erickson Lily , Farhat Maguy , Bronk Julianna , Ferguson Sherise , Chung Caroline
Published: August 2022

BACKGROUND

Following Gamma Knife SRS (GK-SRS), the conventional imaging characteristics of radiation necrosis (RN) mimic those of tumor progression, introducing considerable uncertainty in diagnosis. Previous studies have identified clinical variables associated with RN; however, diagnosis primarily relied on interpretation of imaging with only a minority confirmed using the gold standard of pathological examination. Furthermore, the cohorts of these studies included a mix of primary histologies.

PURPOSE

To identify the combination of clinical variables and radiomic features most predictive of RN in patients with melanoma brain metastasis (BM) with GK-SRS in order to train a machine learning classifier to distinguish RN from tumor progression.

METHODS

We retrospectively studied 86 patients with a melanoma BM that received initial GK-SRS followed by resection, thereby pathologically confirming tumor or RN. Clinical variables including lesion volume, age at surgery, GK-SRS dose, lesion hemorrhage, lesion location, gender, BM velocity, and drug therapy type were obtained from chart review. We extracted radiomic features from contrast-enhanced T1-weighted MR images using PyRadiomics. A consensus clustering algorithm identified representative radiomic features. Non-parametric hypothesis testing was performed on the clinical variables and representative radiomic features.

RESULTS

Of the 86 patients, 17 (19.8%) patients exhibited RN and 69 exhibited tumor progression. Lesion volume was associated with development of RN (p = 0.038<0.05) with a median volume of 1.5 cc (0.01-26.71 cc). Clustering analysis identified seven representative radiomic features; five were found to have statistically significant association with development of RN.

CONCLUSION

In this dataset with pathologically confirmed diagnoses in a histologically homogeneous patient cohort, we reproduced previously reported findings that the clinical variable of lesion volume is associated with RN and we identified several radiomic features associated with RN in patients with melanoma BM. We are using these variables and features to train a machine learning classifier to distinguish RN from tumor.
SYST-07 WINDOW-OF-OPPORTUNITY STUDY OF ONC201 IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND THALAMIC GLIOMA
Authors: Odia Yazmin , Koschmann Carl , Tarapore Rohinton , Allen Jeffrey , Hall Matthew , Daghistani Doured , Khatib Ziad , Aguilera Dolly , MacDonald Tobey , de Blank Peter , McGovern Susan Lynne , Mueller Sabine , Kline Cassie , Vitanza Nicholas , Allen Joshua E , Zaky Wafik , Gardner Sharon
Published: August 2022

BACKGROUND

H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults; no effective systemic therapy is available. ONC201, a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 and agonist of the mitochondrial protease ClpP. ONC201 monotherapy demonstrated durable objective responses in adults with recurrent H3 K27M-mutant glioma. This phase 1 trial will evaluate ONC201±radiotherapy (RT) in pediatric patients with H3 K27M-mutant midline glioma DIPG.

METHODS

This multicenter, open-label, dose escalation and expansion phase 1 study of ONC201 is comprised of eight arms that will evaluate the recommended phase 2 dose (RP2D) of ONC201, biomarkers, and pharmacokinetics (PK) of ONC201±RT in various treatment settings (NCT03416530). Arm G previously defined the RP2D for twice-weekly ONC201 on consecutive days. Arm H, for which enrollment is ongoing, will estimate the influence of tumor location and blood-brain barrier integrity on PK and intratumoral ONC201 exposure in biopsy-eligible pediatric tumors (DIPG or contrast-enhancing thalamic glioma). Patients eligible for Arm H will be aged 2-≤19 years, ≥2 weeks from last RT administration, and have a KPS/LPS ≥50; prior confirmation of H3 K27M mutation is not required. In Arm H, single-agent ONC201 administration will occur twice-weekly on consecutive days during each 21-day cycle at the RP2D defined in Arm G. Arm H has a planned enrollment of 27 patients (DIPG, n=15; thalamic glioma, n=12), with three patients undergoing a single biopsy at each of the following time points: 1-3 h post-first dose, 22-26 h post-second dose, 1-3 h post-first dose, 6-10 h post-second dose, and 22-26 h post-second dose. The 22-26 h post-first dose biopsy in thalamic glioma was previously collected and will not be assessed in this treatment arm. Plasma for PK analysis will be collected from all patients.