bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing Clinical Utility of Pharmacogenetic Testing in the Military Health System
Authors: Hellwig Lydia D , Turner Clesson , Olsen Cara , Libbus Joya , Markos Bethelhem , Koehlmoos Tracey , Haigney Mark , De Castro Mauricio , Saunders David 
Published: July 2023

ABSTRACT

Introduction
Response to medications can differ widely among individual patients. Adverse drug reactions can lead to serious morbidity and mortality. Pharmacogenetic (PGx) testing can predict responses to medications and increased risks of adverse events where the genetic basis is understood. Several published manuscripts suggest positive impacts of systematic preemptive PGx testing. However, few studies have been conducted on PGx implementation in the Military Health System (MHS).

Material and Methods
A cross-sectional study of adult beneficiaries in a primary care clinic at a large military treatment facility was conducted in 2022. Participants underwent PGx genotyping of CYP2C19 and CYP2D6 genes at the Defense Health Agency Genetics Reference Laboratory. Participant medication lists were compared to the current Clinical Pharmacogenetic Implementation Consortium (CPIC) PGx gene–drug guidelines to assess potential actionability of these results.

Results
Genotyping of CYP2C19 and CYP2D6 in 165 MHS beneficiaries (mean age: 65 years) revealed that 81.2% of participants had at least one abnormal PGx finding. Among those with an abnormal PGx result, 65% were taking a medication listed on the CPIC website with an association with the particular gene in which the finding was identified. In addition, 78% of all of the participants in the study were taking at least one medication that is metabolized by CYP2C19 or CYP2D6 with associated CPIC guidelines.

Conclusions
Pharmacogenetic testing for CYP2C19 and CYP2D6 identified a substantial proportion of MHS patients at a single center who could benefit from evaluation of current medication regimens based on the CPIC guidelines. Individualized medical management may be warranted to a greater degree than previously recognized based on the findings given possible differences in medication metabolism. Many MHS beneficiaries already take medications metabolized by CYP2C19 and CYP2D6, and a substantial proportion may be at risk for preventable adverse events for medications metabolized by these enzymes. While preliminary, a large number of actionable polymorphisms among a relatively small set of individuals taking at-risk medications suggest that implementing PGx testing in clinical practice may be beneficial in the MHS with appropriate clinical infrastructure.
ALMA and Keck analysis of Fomalhaut field sources: JWST’s Great Dust Cloud is a background object
Authors: Kennedy Grant M , Lovell Joshua B , Kalas Paul , Fitzgerald Michael P 
Published: July 2023

ABSTRACT
At 7.7 pc, the A-type star Fomalhaut hosts a bright debris disc with multiple radial components. The disc is eccentric and misaligned, strongly suggesting that it is sculpted by interaction with one or more planets. Compact sources are now being detected with JWST, suggesting that new planet detections may be imminent. However, to confirm such sources as companions, common proper motion with the star must be established, as with unprecedented sensitivity comes a high probability that planet candidates are actually background objects. Here, Atacama Large Millimetre/Submillimetre Array and Keck observations of Fomalhaut are found to show significant emission at the same sky location as multiple compact sources in JWST Mid-Infrared Instrument coronagraphic observations, one of which has been dubbed the ‘Great Dust Cloud’ because it lies within the outer belt. Since the ground-based data were obtained between 6 and 18 yr prior to the JWST observations, these compact sources are unlikely to be common proper motion companions to Fomalhaut. More generally, this work illustrates that images collected at a range of wavelengths can be valuable for rejecting planet candidates uncovered via direct imaging with JWST.
Accreting luminous low-mass planets escape from migration traps at pressure bumps
Authors: Chrenko Ondřej , Chametla Raúl O 
Published: July 2023

ABSTRACT
We investigate the migration of Mars- to super-Earth-sized planets in the vicinity of a pressure bump in a 3D radiative protoplanetary disc while accounting for the effect of accretion heat release. Pressure bumps have often been assumed to act as efficient migration traps, but we show that the situation changes when thermal forces are taken into account. Our simulations reveal that for planetary masses ≲$2\, M_{{\oplus}}$, once their luminosity exceeds the critical value predicted by linear theory, thermal driving causes their orbits to become eccentric, quenching the positive corotation torque responsible for the migration trap. As a result, planets continue migrating inward past the pressure bump. Additionally, we find that planets that remain circular and evolve in the super-Keplerian region of the bump exhibit a reversed asymmetry of their thermal lobes, with the heating torque having an opposite (negative) sign compared to the standard circular case, thus leading to inward migration as well. We also demonstrate that the supercritical luminosities of the planets in question can be reached through the accretion of pebbles accumulating in the bump. Our findings have implications for planet formation scenarios that rely on the existence of migration traps at pressure bumps, as the bumps may repeatedly spawn inward-migrating low-mass embryos rather than harbouring newborn planets until they become massive.
Long-term X-ray/UV variability in ULXs
Authors: Khan Norman , Middleton Matthew J 
Published: July 2023

ABSTRACT
The focus of NASA’s Swift telescope has been transients and target-of-opportunity observing, resulting in many observations of ultraluminous X-ray sources (ULXs) over the last ∼20 yr. For the vast majority of these observations, simultaneous data have been obtained using both the X-ray telescope (XRT) and the ultraviolet and optical telescope (UVOT), providing a unique opportunity to study coupled variability between these bands. Using a sample of ∼40 ULXs with numerous repeat observations, we extract stacked images to characterize the spatial extent of the UV/optical emission and extract long-term light curves to search for first-order linear correlations between the UV and X-ray emission. We find that a small subset may show weakly correlated joint variability, while other sources appear to display non-linear relationships between the bands. We discuss these observations in the context of several theoretical models: precession, irradiation of the outer accretion disc, and irradiation of the companion star. We conclude that more complicated analysis or higher quality data may be required to accurately constrain the nature of the joint X-ray and UV/optical emission in these sources.
SONIC HEDGEHOG (SHH) PROMOTES BLOOD-BRAIN BARRIER (BBB) INTEGRITY IN DIFFUSE MIDLINE GLIOMA OF THE PONS
Authors: Line Stacey , Sajesh Babu V , Yathindranath Vinith , On Nog H , Miller Donald W , Vanan Magimairajan Issai 
Published: July 2023

Abstract
Diffuse Midline Glioma of the Pons (DMG-P) is the most common brainstem tumor in children and is universally lethal in this age group. The intact Blood-Brain Barrier (BBB) in these tumors are believed to play a major role in preventing systemically administered therapeutic agents from reaching therapeutic concentrations in the tumor. The factors that contribute to the integrity of BBB in DMG-P is not well understood. Sonic Hedgehog (SHH) signaling promotes BBB integrity in the developing and adult brain and plays an important role in the formation and maintenance of DMG-P tumors. In the present study, we show that DMG-P tumor cells secrete SHH ligand. Secreted SHH present in the tumor conditioned media (TCM) tightens the BBB by increasing electrical impedance and decreased paracellular and transcellular permeability in BBB Endothelial cells (ECs). Mechanistically, SHH in TCM causes tightening of the BBB by increasing the expression of junctional proteins in BBB-ECs, likely by signaling through non- canonical pathways. SHH in the TCM also increased the expression of ATP-binding cassette (ABC) transporter proteins ABCB1(P- glycoprotein) and ABCG2 (BCRP- Breast cancer resistance protein) in the Endothelial cells. These pro-barrier functions of SHH in TCM can be reversed by pharmacological inhibition of the S-acylation of the SHH ligand using Hedgehog acyltransferase (HHAT) inhibitor RUSKI-201. Our study demonstrates a potential therapeutic strategy of altering the BBB permeability to increase the efficacy of systemic therapies in DMG-P tumors. Ongoing studies will validate these findings in orthotopic murine models of DMG-P.
EXPLORING THE INTERPLAY BETWEEN BRAIN TUMOUR INITIATING CELLS AND THE TUMOUR MICROENVIRONMENT: POTENTIAL TARGETING STRATEGIES FOR GLIOBLASTOMA
Authors: Lubanska Dorota , Alrashed Sami , Sorge Alexandra , Cieslukowski Alan , Mahendran Hema Priya , Nadeem Fatima , Shamisa Abdalla , deCarvalho Ana , Kulkarni Swati , Soliman Mohamed A R , Rondeau-Gagne Simon , Porter Lisa A 
Published: July 2023

Abstract
The aggressive biology and poor response to therapy resulting in relapse of patients with GBM is attributed to the existence of Brain Tumour Initiating Cells (BTICs) with stem cell properties. Targeting BTICs in isolation of their surrounding tumour microenvironment (TME) has proven ineffective. Determining the molecular effects of the TME on BTICs is an evolving area that requires more focus.
OUR APPROACH: Using innovative patient-derived organoid co-culture models paired with an in vivo zebrafish xenograft system our multidisciplinary team is exploring the biology of BTICs in the context of their microenvironment in search for novel therapeutic options that will benefit GBM patients. RESULTS: Our data supports an important role for activated cancer associated fibroblasts and endothelial cells in driving BTIC expansion and resistance to therapy. We further show that these effects, at least in part, are attributed to changes in the composition of the TME. Using semi-conducting conjugated polymer nanoparticles designed to selectively disrupt microenvironment interactions with BTICs, we show a reduction in anti-apoptotic and proliferation markers and a decreased self-renewal in functional assays. In vitro and in vivo drug response assays reveal this combined approach sensitizes to standard of care Temozolomide. CONCLUSIONS: Our data reveals novel aspects of the TME that play an essential role in the biology of GBM and in resistance to therapy. We propose that this offers unique opportunities for drug targeting that may improve patient outcomes for this aggressive disease.
THE SPATIAL TRANSCRIPTOMIC LANDSCAPE OF BREAST CANCER BRAIN METASTASIS
Authors: Abdo Rober , Li Shawn S , Zhang Qi 
Published: July 2023

Abstract
Brain metastases (BM) are responsible for the majority of cancer mortality. Breast cancer is one of the most common primary sites for brain metastasis. Metastatic cancer cells are known to diverge genetically and phenotypically from their primary counterpart. Together with the unique tumor brain microenvironment (TBME), this poses additional challenges in the treatment of BM.
METHODS: We identified 30 cases of patient-paired, surgically resected brain metastasis with breast origin. Six cases of non-tumoral brain control were also included. Two tissue microarray (TMA) blocks were constructed to include all cases. Spatial RNAseq was performed while PanCK, CD45, and GFAP were used as morphology markers to annotate the regions of interest (ROIs). For each patient, five ROIs were analyzed: primary breast cancer (BC), primary breast cancer microenvironment (BCME), metastatic tumor cells (MTC), immediate TBME (iTBME), and distant TBME (dTBME). RESULTS: 1) Triple-negative breast cancers (TNBC) demonstrated distinct gene signatures in both primary and metastatic sites. 2) There were 9 BC shifted their genetic profiles and were reclassified into different molecular subtypes at their matched brain metastatic site. Functional enrichment analysis revealed enriched EMT, ECM-receptor interaction, and the complement system in these profile shifting-BC cases. In contrast, the BC cases that preserved their original profiles (non-shifting BC) shared upregulated pathways of ribosome biogenesis and cell cycle. 3) TBME underwent cellular and molecular plasticity characterized by elevated neutrophils, reactive astrocytes, and activated microglia. In the TBME homing TNBC, cancer-associated fibroblasts (CAF) represented a hub in the cellular interaction between MTCs and TBME.
NOVEL ADJUVANT TARGETED APPROACH FOR PTEN MUTATED CHOROID PLEXUS CARCINOMA IN ADULTS: CASE REPORT AND LITERATURE REVIEW
Authors: Nahm Joshua K , Zhang Jackie J , Rodriguez Quintero Juan C , Bhattacharjee Meena B , Nunez- Rubiano Luis , Riascos-Castaneda Roy , Blanco Angel I , Day Arthur L , Zhu Jay-Jiguang 
Published: July 2023

Abstract
Choroid plexus carcinoma (CPC) is a malignant primary brain tumor that is extremely rare in adults. Previous literature has reported a median overall survival of 2.7 years among pediatric and adult cases. However, data regarding adult CPC's genomic profile by next-generation sequencing (NGS), pathogenesis, and adjuvant treatments after maximum safe resection and radiotherapy remains limited.
CASE DESCRIPTION: A 53-year-old female was diagnosed with CPC and found with PTEN and PREX2 mutations by NGS. She underwent near total resection and craniospinal irradiation, followed by a novel mTOR-targeted chemotherapy with everolimus for 12 months. She has remained in remission with no evidence of tumor growth upon follow-up magnetic resonance imaging (MRI). There are notable MRI T2-fluid-attenuated inversion recovery (FLAIR) signal changes likely due to radiation effects. Currently, the patient is doing well with mild cognitive impairments and an overall survival of 5.2 years. DISCUSSION: Since PTEN and PREX2 are involved with the mTOR pathway, this case provides insight into the pathogenesis of adult CPC and evidence of a viable adjuvant treatment. Treatments such as stem cell transplants and ifosfamide, carboplatin, and etoposide chemotherapy have not shown to prevent recurrence. This is also the first study to calculate CPC's natural growth rate using MRI volumetric analysis with a 7.74% tumor growth in 51 days. Further studies are warranted in prospective clinical trials to assess everolimus' efficacy as an adjuvant therapy. NGS focusing on mTOR pathway abnormalities are also recommended to expand the present knowledge of this rare tumor.
REGIONAL DIFFERENCES IN THE SURVIVAL EXPERIENCE OF PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMOURS IN CANADA
Authors: Wu Yifan , Yuan Yan , Walker Emily V 
Published: July 2023

Abstract
Health care in Canada is delivered on a provincial or territorial level. The objective of our population-based study was to investigate regional differences in survival among Canadians diagnosed with central nervous system (CNS) tumours. We identified 50,670 patients diagnosed with a first-ever primary CNS tumour between 2008 and 2017 with follow-up until December 31, 2017 (excluding Quebec) from the Canadian Cancer Registry linked to vital statistics. We selected the four highest incidence histologies and used Cox proportional hazards regression to estimate hazard ratios (HRs) for regions in Canada (British Columbia, the Prairie provinces, Ontario, the Atlantic provinces, and the Territories) adjusting for sex and tumour behaviour (malignant vs. non-malignant), and stratified by patient age. Ontario was the reference region and had the best survival profile for all histologies investigated. The Atlantic provinces had the highest HR for glioblastomas (HR=1.26, 95% CI:1.18-1.35), gliomas not otherwise specified (NOS) (Overall: HR=1.87, 95% CI:1.43-2.43; Pediatric population: HR=2.86, 95% CI:1.28-6.39) and unclassified tumours (HR=1.95, 95% CI:1.63-2.34). For meningiomas, the Territories had the highest HR (HR=2.44, 95% CI:1.09-5.45) followed by the Prairie provinces (HR=1.52, 95% CI:1.38-1.67). Our findings suggest that regional differences in survival may exist for patients with specific histological subtypes of CNS tumours at the population level. Whether the differential capture of non-malignant tumours across regions, tumour misclassification, or both contributes to the observed regional survival differences warrants further investigation.
NUCLEAR DEFECTIVE IL-33 DRIVES AN ANTI-TUMORIGENIC MICROENVIRONMENT IN GLIOBLASTOMA
Authors: Menon Shyam V , Lun Xueqing , Zhang Jianbo , Ahn Bo Young , Yu Henry , Poole Alisha , Dang Ngoc Ha , Osz Katalin , Chan Jennifer , Robbins Stephen M , Senger Donna L 
Published: July 2023

Abstract
Despite a sophisticated treatment regimen, including surgery, chemotherapy, and radiotherapy, survival outcomes for glioblastoma remain at a dismal 14.6 months. Multi-omics profiling have established that myeloid phagocytes drive glioma progression and contribute to therapeutic resistance. However, effective targeting of this axis remains an unmet clinical opportunity. Previously, we found that the dual-function (secreted and nuclear) cytokine IL-33 is a key regulator of the inflammatory microenvironment that aids glioma tumorigenesis through phenotypic and functional changes in the innate immune cell repertoire. Strikingly, when IL-33 is prevented from entering the nucleus, by deletion of its nuclear localization signal (ΔNLS IL-33), but is still secreted, in vivo tumor growth is dramatically suppressed resulting in extended long-term survival. Using spatial transcriptomics and multiplex immunohistochemistry with temporal resolution at different stages of tumor progression, we identified a population of glioma-inhibitory macrophages (GIMs) unique to this suppressive environment. Assessment of xenografts generated from patient brain tumor initiating cells found an enrichment of GIMs in xenografts with long-term survival (&gt;300 days) compared to short-term survivors (&lt;100 days). The ability of GIMs to inhibit glioma progression was further highlighted when tumors established using a combination of ΔNLS IL-33 expressing cancer cells together with highly tumorigenic cells resulted in a growth inhibitory environment that significantly prolonged survival through the polarization and activation of GIMs. Additional characterization of this phenotype and development of clinical strategies to deliver ΔNLS IL-33 to brain tumors is warranted to determine if recruitment and activation of GIMs is a translatable therapeutic strategy for glioma patients.
OSMR INTERACTOME MAPPING REVEALS THE SIGNIFICANCE OF A CHLORIDE CHANNEL IN CYTOKINE REGULATION AND BRAIN TUMOUR STEM CELL SELF-RENEWAL
Authors: Randhawa Kamaldeep , Snider Jamie , Raco Laura , Stagljar Igor , Jahani-Asl Arezu 
Published: July 2023

Abstract
Oncostatin M Receptor (OSMR) is a key regulator of brain tumour stem cell (BTSC) self-renewal and glioblastoma (GB) tumourigenesis. This receptor is found in a complex with Epidermal Growth Factor Receptor variant III (EGFRvIII) and orchestrates a positive feedback loop with STAT3. OSMR also regulates oxidative phosphorylation and participates in promoting the transition of cells towards mesenchymal-like glioma states. How OSMR drives GB tumorigenesis via multiple mechanisms remains largely unclear. Here, we map OSMR interactome in different GB subtypes using the Mammalian Membrane Two Hybrid High Throughput Screen (MaMTH-HTS). Analysis of these data followed by functional validation has uncovered distinct OSMR interactome in a context dependent manner. Follow up investigations, however, have led to the discovery of the Chloride Intracellular Channel 1 (CLIC1), essential in the regulation of OSMR cytokine signaling and GB progression independently of the genetic profile of the GB tumour. CLIC1 forms a complex with OSMR to promote BTSC self-renewal and knockout of CLIC1 or pharmacological inhibitors to CLIC1 impairs OSM mediated STAT3 phosphorylation. Our work suggests that CLIC1 and OSMR forms a complex in BTSCs and functionally interact to activate STAT3.
EVALUATING PNEUMOCYSTIS JIROVECII PNEUMONIA (PCP) PROPHYLAXIS IN PATIENTS WITH GLIOMA RECEIVING CONCURRENT TEMOZOLOMIDE AND RADIATION – A PATIENT AND PHYSICIAN SURVEY
Authors: Beltran-Bless1 Ana-Alicia , Alshamsan Bader , Jia Jason , Lo Victor , Climans Seth , Nicholas Garth , Ng Terry L 
Published: July 2023

Abstract
Temozolomide (TMZ) given concurrently with radiation (TMZ-RT) is essential in glioma therapy. Pneumocystis jirovecii pneumonia (PCP) prophylaxis is required by provincial and national drug monographs based on two incidents of PCP in a pilot study. There is otherwise limited evidence to inform the need for PCP prophylaxis in this population.
METHODS: We conducted a single-centre survey of patients and national survey of physicians on the role of PCP prophylaxis in patients with glioma receiving concurrent TMZ-RT. RESULTS: Fifteen percent (31/212) of physicians and 60% (44/73) of patients completed a survey. The median age of patients was 42 (20-77); 85% (34/40) had completed adjuvant TMZ, and 59% (24/41) were not offered PCP prophylaxis. After reviewing the hypothetical risks of PCP, 13.2% (5/38) of patients were concerned about PCP infection, whereas 26% (10/38) were concerned about potential side effects from prophylactic antibiotics. Physician participants included medical (29%, 9/31) radiation (29%, 9/31), and neuro-oncologists (32%, 10/31). Most physicians (77%, 17/22) felt the evidence informing PCP prophylaxis in this population was weak; 58% (11/19) were not routinely prescribing prophylaxis, and 73% (16/22) felt that PCP prophylaxis should be limited to patients with additional risk factors. Sixty-three percent (22/35) of patients and 57% (12/21) of physicians were interested in a clinical trial to assess the risk of PCP infection in this setting. CONCLUSION: Clinical equipoise exists on the role of PCP prophylaxis during and after TMZ-RT amongst patients and physicians. Rigorous prospective studies need to be conducted to inform and standardize best practices.