bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectral techniques for measuring bipartivity and producing partitions
Authors: Aleidan Azhar , Knight Philip A
Published: July 2023

Complex networks can often exhibit a high degree of bipartivity. There are many well-known ways for testing this, and in this article, we give a systematic analysis of characterizations based on the spectra of the adjacency matrix and various graph Laplacians. We show that measures based on these characterizations can be drastically different results and leads us to distinguish between local and global loss of bipartivity. We test several methods for finding approximate bipartitions based on analysing eigenvectors and show that several alternatives seem to work well (and can work better than more complex methods) when augmented with local improvement.
Life expectancy and end-of-life communication in adult patients with congenital heart disease, 40–53 years after surgery
Authors: Pelosi Chiara , Kauling Robert M , Cuypers Judith A A E , Utens Elisabeth M W J , van den Bosch Annemien E , van der Heide Agnes , Legerstee Jeroen S , Roos-Hesselink Jolien W
Published: July 2023

Aims

Although survival of patients with congenital heart disease (CHD) improved significantly over time, life expectancy is still not normal. We aimed to investigate how adult patients, their partners, and treating cardiologists estimated the individual life expectancy of CHD patients. Furthermore, preferences regarding end-of-life (EOL) communication were investigated.

Methods and results

In this study, we included 202 patients (age: 50 ± 5) who were operated in childhood (<15 years old) between 1968 and 1980 for one of the following diagnoses: atrial septal defect, ventricular septal defect, pulmonary stenosis, tetralogy of Fallot, or transposition of the great arteries. A specific questionnaire was administered to both the patients and their partners, exploring their perceived life expectancy and EOL wishes. Two cardiologists independently assessed the life expectancy of each patient. Most adults with CHD believed their life expectancy to be normal. However, significant differences were found between estimated life expectancy by the cardiologist and patients (female: P = 0.001, male: P = 0.002) with moderate/severe defects, as well as for males with mild defects (P = 0.011). Regarding EOL communication, 85.1% of the patients reported that they never discussed EOL with a healthcare professional. Compared with patients with mild CHD, significantly more patients with moderate/severe defect discussed EOL with a physician (P = 0.011). The wish to discuss EOL with the cardiologist was reported by 49.3% of the patients and 41.7% of their partners.

Conclusion

Adult patients, especially with moderate/severe CHD, perceived their life expectancy as normal, whereas cardiologists had a more pessimistic view than their patients. Increased attention is warranted for discussions on life expectancy and EOL to improve patient-tailored care.
Towards understanding paleoclimate impacts on primate de novo genes
Authors: Liang Xiao , Heath Lenwood S
Published: July 2023

De novo genes are genes that emerge as new genes in some species, such as primate de novo genes that emerge in certain primate species. Over the past decade, a great deal of research has been conducted regarding their emergence, origins, functions, and various attributes in different species, some of which have involved estimating the ages of de novo genes. However, limited by the number of species available for whole-genome sequencing, relatively few studies have focused specifically on the emergence time of primate de novo genes. Among those, even fewer investigate the association between primate gene emergence with environmental factors, such as paleoclimate (ancient climate) conditions. This study investigates the relationship between paleoclimate and human gene emergence at primate species divergence. Based on 32 available primate genome sequences, this study has revealed possible associations between temperature changes and the emergence of de novo primate genes. Overall, findings in this study are that de novo genes tended to emerge in the recent 13 MY when the temperature continues cooling, which is consistent with past findings. Furthermore, in the context of an overall trend of cooling temperature, new primate genes were more likely to emerge during local warming periods, where the warm temperature more closely resembled the environmental condition that preceded the cooling trend. Results also indicate that both primate de novo genes and human cancer-associated genes have later origins in comparison to random human genes. Future studies can be in-depth on understanding human de novo gene emergence from an environmental perspective as well as understanding species divergence from a gene emergence perspective.
Polygenic Propensity for Longevity,APOE-ε4 Status, Dementia Diagnosis, and Risk for Cause-Specific Mortality: A Large Population-Based Longitudinal Study of Older Adults
Authors: Ajnakina Olesya , Shamsutdinova Diana , Stahl Daniel , Steptoe Andrew
Published: July 2023

To deepen the understanding of genetic mechanisms influencing mortality risk, we investigated the impact of genetic predisposition to longevity and APOE-ε4, on all-cause mortality and specific causes of mortality. We further investigated the mediating effects of dementia on these relationships. Using data on 7 131 adults aged ≥50 years (mean = 64.7 years, standard deviation [SD] = 9.5) from the English Longitudinal Study of Aging, genetic predisposition to longevity was calculated using the polygenic score approach (PGSlongevity). APOE-ε4 status was defined according to the absence or presence of ε4 alleles. The causes of death were ascertained from the National Health Service central register, which was classified into cardiovascular diseases, cancers, respiratory illness, and all other causes of mortality. Of the entire sample, 1 234 (17.3%) died during an average 10-year follow-up. One-SD increase in PGSlongevity was associated with a reduced risk for all-cause mortality (hazard ratio [HR] = 0.93, 95% confidence interval [CI]: 0.88–0.98, p = .010) and mortalities due to other causes (HR = 0.81, 95% CI: 0.71–0.93, p = .002) in the following 10 years. In gender-stratified analyses, APOE-ε4 status was associated with a reduced risk for all-cause mortality and mortalities related to cancers in women. Mediation analyses estimated that the percent excess risk of APOE-ε4 on other causes of mortality risk explained by the dementia diagnosis was 24%, which increased to 34% when the sample was restricted to adults who were aged ≤75 years old. To reduce the mortality rate in adults who are aged ≥50 years old, it is essential to prevent dementia onset in the general population.
Tripterine Inhibits Proliferation and Promotes Apoptosis of Keloid Fibroblasts by Targeting ROS/JNK Signaling
Authors: Huang Fang , Zhang Enjing , Lei Yan , Yan Qiong , Xue Chengbin
Published: July 2023

Keloids are benign skin tumors characterized by excessive fibroblast proliferation and collagen deposition. The current treatment of keloids with hormone drug injection, surgical excision, radiotherapy, physical compression, laser therapy, cryotherapy often have unsatisfactory outcomes. The phytochemical compounds have shown great potential in treating keloids. Tripterine, a natural triterpene derived from the traditional Chinese medicine Thunder God Vine (Tripterygium wilfordii), was previously reported to exhibit an anti-scarring bioactivity in mouse embryonic fibroblast NIH/3T3 cells. Accordingly, our study was dedicated to explore its role in regulating the pathological phenotypes of keloid fibroblasts. Human keloid fibroblasts were treated with tripterine (0–10 μM) for 24 hours. Cell viability, proliferation, migration, apoptosis, and extracellular matrix (ECM) deposition were determined by CCK-8, EdU, wound healing, Transwell, flow cytometry, western blotting, and RT-qPCR assays. The effects of tripterine treatment on reactive oxygen species (ROS) generation and JNK activation in keloid fibroblasts were assessed by DCFH-DA staining and western blotting analysis. Tripterine at the concentrations higher than 4 μM attenuated the viability of human keloid fibroblasts in a dose-dependent manner. Treatment with tripterine (4, 6, and 8 μM) dose-dependently inhibited cell proliferation and migration, promoted cell apoptosis, reduced α-SMA, Col1, and Fn expression, induced ROS production, and enhanced JNK phosphorylation in keloid fibroblasts. Collectively, tripterine ameliorates the pathological characteristics of keloid fibroblasts that are associated with keloidformation and growth by inducing ROS generation and activating JNK signalingpathway.
Cost-effectiveness analysis of 7 treatments in metastatic hormone-sensitive prostate cancer: a public-payer perspective
Authors: Yoo Minkyoung , Nelson Richard E , Haaland Benjamin , Dougherty Maura , Cutshall Zachary A , Kohli Rhea , Beckstead Rylee , Kohli Manish
Published: July 2023

Background

Recently, several new treatment regimens have been approved for treating metastatic hormone-sensitive prostate cancer, building on androgen deprivation therapy alone. These include docetaxel androgen deprivation therapy, abiraterone acetate-prednisone androgen deprivation therapy, apalutamide androgen deprivation therapy, enzalutamide androgen deprivation therapy, darolutamide-docetaxel androgen deprivation therapy, and abiraterone-prednisone androgen deprivation therapy with docetaxel. There are no validated predictive biomarkers for choosing a specific regimen. The goal of this study was to conduct a health economic outcome evaluation to determine the optimal treatment from the US public sector (Veterans Affairs).

Methods

We developed a partitioned survival model in which metastatic hormone-sensitive prostate cancer patients transitioned between 3 health states (progression free, progressive disease to castrate resistance state, and death) at monthly intervals based on Weibull survival model estimated from published Kaplan–Meier curves using a Bayesian network meta-analysis of 7 clinical trials (7208 patients). The effectiveness outcome in our model was quality-adjusted life-years (QALYs). Cost input parameters included initial and subsequent treatment costs and costs for terminal care and for managing grade 3 or higher drug-related adverse events and were obtained from the Federal Supply Schedule and published literature.

Results

Average 10-year costs ranged from $34 349 (androgen deprivation therapy) to $658 928 (darolutamide-docetaxel androgen deprivation therapy) and mean QALYs ranged from 3.25 (androgen deprivation therapy) to 4.57 (enzalutamide androgen deprivation therapy). Treatment strategies docetaxel androgen deprivation therapy, enzalutamide androgen deprivation therapy docetaxel, apalutamide androgen deprivation therapy, and darolutamide-docetaxel androgen deprivation therapy were eliminated because of dominance (ie, they were more costly and less effective than other strategies). Of the remaining strategies, abiraterone acetate-prednisone androgen deprivation therapy was the most cost-effective strategy at a willingness-to-pay threshold of $100 000/QALY (incremental cost-effectiveness ratios = $21 247/QALY).

Conclusions

Our simulation model found abiraterone acetate-prednisone androgen deprivation therapy to be an optimal first-line treatment for metastatic hormone-sensitive prostate cancer from a public (Veterans Affairs) payer perspective.
A framework for assessing interactions for risk stratification models: the example of ovarian cancer
Authors: Phung Minh Tung , Lee Alice W , McLean Karen , Anton-Culver Hoda , Bandera Elisa V , Carney Michael E , Chang-Claude Jenny , Cramer Daniel W , Doherty Jennifer Anne , Fortner Renee T , Goodman Marc T , Harris Holly R , Jensen Allan , Modugno Francesmary , Moysich Kirsten B , Pharoah Paul D P , Qin Bo , Terry Kathryn L , Titus Linda J , Webb Penelope M , Wu Anna H , Zeinomar Nur , Ziogas Argyrios , Berchuck Andrew , Cho Kathleen R , Hanley Gillian E , Meza Rafael , Mukherjee Bhramar , Pike Malcolm C , Pearce Celeste Leigh , Trabert Britton
Published: July 2023

Generally, risk stratification models for cancer use effect estimates from risk/protective factor analyses that have not assessed potential interactions between these exposures. We have developed a 4-criterion framework for assessing interactions that includes statistical, qualitative, biological, and practical approaches. We present the application of this framework in an ovarian cancer setting because this is an important step in developing more accurate risk stratification models. Using data from 9 case-control studies in the Ovarian Cancer Association Consortium, we conducted a comprehensive analysis of interactions among 15 unequivocal risk and protective factors for ovarian cancer (including 14 non-genetic factors and a 36-variant polygenic score) with age and menopausal status. Pairwise interactions between the risk/protective factors were also assessed. We found that menopausal status modifies the association among endometriosis, first-degree family history of ovarian cancer, breastfeeding, and depot-medroxyprogesterone acetate use and disease risk, highlighting the importance of understanding multiplicative interactions when developing risk prediction models.
Constraints on communicating the order of events in stories through pantomime
Authors: Sibierska Marta , Żywiczyński Przemysław , Zlatev Jordan , van de Weijer Joost , Boruta-Żywiczyńska Monika
Published: July 2023

Pantomime is a means of bodily visual communication that is based on iconic gestures that are not fully conventional. It has become a key element in many models of language evolution and a strong candidate for the original human-specific communicative system (Zlatev et al. 2020). Although pantomime affords successful communication in many contexts, it has some semiotic limitations. In this study, we looked at one of them, connected with communicating the order of events in stories. We assumed that pantomime is well-suited for communicating simple stories, where events are arranged in chronological order, and less so for communicating complex stories, where events are arranged in a non-chronological order. To test this assumption, we designed a semiotic game in which participants took turns as directors and matchers. The task of the directors was to mime a story in one of two conditions: chronological or non-chronological; the task of the matchers was to interpret what was mimed. The results showed that the chronological condition was easier for the participants. In the non-chronological condition, we observed that initially, poor communicative success improved as the participants started to use various markers of event order. The results of our study provide insight into the early stages of conventionalisation in bodily visual communication, a potential first step towards protolanguage.
Incarcerated native orthotopic kidney through an inguinal hernia: a case report and literature review
Authors: Kim Jisoo , Harper Brittany , Turner Alisan , Gonzalez Irving Alvarado , Andrade Alonso
Published: July 2023

This is a case report of a 66-year-old male with an incarcerated inguinal hernia that contained native orthotopic kidney causing obstructive uropathy. The patient presented to the hospital due to intractable right groin pain, and CT imaging showed herniation of the right kidney in the right inguinal hernia with the upper pole squeezed in the inguinal canal. The patient underwent surgery to reduce the hernia contents and hernia repair with mesh. He was discharged on postoperative day 3 without complication. To the best of our knowledge, this is the first reported case of an incarcerated native orthotopic kidney without anatomic abnormality that had to undergo surgical intervention.
TLR4, MyD88, and TNF-α Expression in the Lungs of Akkaraman and Romanov Lambs in Response to LPS and LTA
Authors: Alan Emel , Daldaban Fadime , Alan Aydın , Aksel Esma Gamze , Orhan İmdat , Ulaş Çinar Mehmet , Akyüz Bilal , Arslan Korhan
Published: July 2023

Toll-like receptors are involved in the recognition of bacterial toxins, which cause infection in the respiratory system. This study aimed to evaluate microanatomical and histological alterations in the lungs of 24 healthy Akkaraman and Romanov lambs after the administration of lipoteichoic acid (LTA), lipopolysaccharide (LPS), and LTA + LPS and investigate the gene, protein, and immune expression levels of TLR4, MyD88, and TNF-α molecules, known to have immune functions. Microanatomical examinations showed thickened peribronchial and alveolar walls in the lungs of groups LTA, LPS, and LTA + LPS of both breeds due to immune cell infiltration. TLR4, MyD88, and TNF-α immunoexpressions were positive to varying degrees in the cytoplasm and nucleus of the bronchial and bronchiolar luminal epithelial cells, alveolar epithelial cells, and alveolar macrophages. TLR4 and TNF-α protein expressions were statistically different in the LPS-treated Romanov lambs, compared to the other groups. Among the Akkaraman lambs, TLR4 gene expression was significantly higher in group LPS, and among the Romanov lambs, TLR4, MyD88, and TNF-α gene expressions were significantly higher in group LTA + LPS. Therefore, TLR4, MyD88, and TNF-α molecules, involved in the immune response, were found to be expressed at different levels against LTA and LPS in the lungs of two different sheep breeds.
Understanding Ion-Beam Damage to Air-Sensitive Lithium Metal With Cryogenic Electron and Ion Microscopy
Authors: Koh Hyeongjun , Detsi Eric , Stach Eric A
Published: July 2023

It is essential to understand the nanoscale structure and chemistry of energy storage materials due to their profound impact on battery performance. However, it is often challenging to characterize them at high resolution, as they are often fundamentally altered by sample preparation methods. Here, we use the cryogenic lift-out technique in a plasma-focused ion beam (PFIB)/scanning electron microscope (SEM) to prepare air-sensitive lithium metal to understand ion-beam damage during sample preparation. Through the use of cryogenic transmission electron microscopy, we find that lithium was not damaged by ion-beam milling although lithium oxide shells form in the PFIB/SEM chamber, as evidenced by diffraction information from cryogenic lift-out lithium lamellae prepared at two different thicknesses (130 and 225 nm). Cryogenic energy loss spectroscopy further confirms that lithium was oxidized during the process of sample preparation. The Ellingham diagram suggests that lithium can react with trace oxygen gas in the FIB/SEM chamber at cryogenic temperatures, and we show that liquid oxygen does not contribute to the oxidation of lithium process. Our results suggest the importance of understanding how cryogenic lift-out sample preparation has an impact on the high-resolution characterization of reactive battery materials.
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

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

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

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

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

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

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

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

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

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

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 (>300 days) compared to short-term survivors (<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

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

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.
Nicotine Delivery of a Menthol-Flavored Heat-not-Burn Tobacco Product During Directed Use
Authors: Yingst Jessica M , Bordner Candace , Hrabovsky Shari , Hobkirk Andrea L , Trushin Neil , Richie John P , Foulds Jonathan
Published: July 2023

Introduction

IQOS was authorized by the U.S. Food and Drug Administration (FDA) as a modified-risk tobacco product. We conducted a pharmacokinetic study evaluating the nicotine delivery and subjective effects of IQOS use among current menthol cigarette smokers to better understand if IQOS is an acceptable cigarette alternative in light of the proposed menthol cigarette ban.

Aims and Methods

Participants were adult smokers of >4 menthol cigarettes per day. After 14-hour nicotine abstinence, participants were provided an IQOS device and menthol heatstick to puff every 20 seconds for a total of 14 puffs. Blood samples were collected at baseline and during active use to calculate nicotine boost from baseline to peak concentration. Nicotine withdrawal symptoms were collected before and after IQOS use. In addition, a modified Product Evaluation Scale for IQOS was collected after use.

Results

Participants (n = 8) were a mean age of 43.9 years, 63% were female, 88% identified as White, and they smoked a mean of 17.1 menthol cigarettes per day. After IQOS use, the mean nicotine boost obtained was 15.96 ng/mL (SD = 6.91) (range 9.31 to 30.55 ng/mL). Most (75%) participants reported enjoying use of the product “a lot” or greater and more than half (62.5%) reported reduced cigarette cravings. Most participants reported no side effects after use; however, two experienced dry mouth, three experienced dizziness, one experienced throat irritation, and one experienced headache.

Conclusion

We found that directed use (14 puffs) of menthol IQOS delivered a mean nicotine boost of 15.96 ng/mL which reduced craving for a cigarette. The majority of participants enjoyed use of IQOS and reported mild side effects.

Implications

Menthol IQOS delivered a sufficient dose of nicotine perceived as satisfying by menthol cigarette smokers and it reduced craving with mild side effects. Menthol IQOS has potential to serve as a less harmful alternative for menthol cigarette smokers. The availability of modified risk products like IQOS should be considered by FDA’s Comprehensive Plan for Tobacco and Nicotine Regulation.
Intramuscular vs Intravenous SARS-CoV-2 Neutralizing Antibody Sotrovimab for Treatment of COVID-19 (COMET-TAIL): A Randomized Noninferiority Clinical Trial
Authors: Shapiro Adrienne E , Sarkis Elias , Acloque Jude , Free Almena , Gonzalez-Rojas Yaneicy , Hussain Rubaba , Juarez Erick , Moya Jaynier , Parikh Naval , Inman David , Cebrik Deborah , Nader Ahmed , Noormohamed Nadia , Wang Qianwen , Skingsley Andrew , Austin Daren , Peppercorn Amanda , Agostini Maria L , Parra Sergio , Chow Sophia , Mogalian Erik , Pang Phillip S , Hong David K , Sager Jennifer E , Yeh Wendy W , Alexander Elizabeth L , Gaffney Leah A , Kohli Anita
Published: July 2023

Background

Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19.

Method

This multicenter phase 3 study based on a randomized open-label design tested the noninferiority of IM to IV administration according to an absolute noninferiority margin of 3.5%. From June to August 2021, patients aged ≥12 years with COVID-19, who were neither hospitalized nor receiving supplemental oxygen but were at high risk for progression, were randomized 1:1:1 to receive sotrovimab as a single 500-mg IV infusion or a 500- or 250-mg IM injection. The primary composite endpoint was progression to (1) all-cause hospitalization for >24 hours for acute management of illness or (2) all-cause death through day 29.

Results

Sotrovimab 500 mg IM was noninferior to 500 mg IV: 10 (2.7%) of 376 participants vs 5 (1.3%) of 378 met the primary endpoint, respectively (absolute adjusted risk difference, 1.06%; 95% CI, −1.15% to 3.26%). The 95% CI upper limit was lower than the prespecified noninferiority margin of 3.5%. The 250-mg IM group was discontinued early because of the greater proportion of hospitalizations vs the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease-related events and died (500 mg IM, 2/393, <1%; 250 mg IM, 2/195, 1%).

Conclusions

Sotrovimab 500-mg IM injection was well tolerated and noninferior to IV administration. IM administration could expand outpatient treatment access for COVID-19.

Clinical Trials Registration

ClinicalTrials.gov: NCT04913675.
A Graphical Overview of the Histopathology of Human Melioidosis: A Case Series
Authors: Savelkoel Jelmer , Tiemensma Marianne , Birnie Emma , Wiersinga W Joost , Currie Bart J , Roelofs Joris J T H
Published: July 2023

Background

Melioidosis, caused by the Gram-negative bacterium Burkholderia pseudomallei, has a major global health impact and a wide range of different disease manifestations. Histopathological descriptions of melioidosis remain limited. Granulomatous inflammation with multinucleated giant cells are considered classic features. We aim to present a graphical overview of histopathological manifestations of melioidosis, serving as an aid in diagnosing this disease.

Methods

We performed a retrospective international multicenter laboratory-based analysis of formalin-fixed paraffin-embedded (FFPE) tissue from culture-confirmed melioidosis autopsy and biopsy cases. Available FFPE tissue was stained with hematoxylin and eosin and immunostainings including a monoclonal antibody targeting the capsular polysaccharide (CPS) of B pseudomallei. Tissue with site-specific cultures and/or positive CPS staining were included in the graphical histopathological overview.

Results

We identified tissue of 8 autopsy and 5 biopsy cases. Pneumonia and soft tissue abscesses were the leading foci of disease displaying mainly necrosis and suppuration. Infrequent disease manifestations included involvement of bone marrow and adrenal glands in an autopsy case and biopsied mediastinal tissue, the latter being the only case in which we identified multinucleated giant cells. Using the CPS staining, we demonstrated granulomata as part of rare gastric tissue involvement.

Conclusions

We found fatal melioidosis to be a necrotizing and suppurative inflammation, usually without multinucleated giant cell formation. Gastric and mediastinal involvement points to ingestion and inhalation as possible routes of infection. The CPS staining proved beneficial as an aid to establish a histopathological diagnosis. Our graphical overview can be used by infectious diseases specialists, microbiologists, and pathologists.