bluuebunny/crossref_metadata_2025 huggingface dataset:
IL-33 prevents age-related bone loss and memory impairment by suppression of Th17 response: evidence in a d-galactose–induced aging mouse model
Authors: Kaushal Saurabh Kumar , Parul  , Tripathi Alok , Singh Devendra Pratap , Paul Ankita , Alka Kumari , Shukla Shubha , Singh Divya
Published: August 2024

Cytokines are the primary mediators of age-related disorders. The IL-17/IL-10 axis plays a crucial role in bone destruction and neuro-inflammation. Additionally, a new Th2 cytokine—IL-33—has gained attention for its potential implications in aging-associated conditions. However, the involvement of IL-33 in aging-mediated bone loss and memory impairment remains unclear and needs further investigation. This study reveals the impact of IL-33 on various aspects of the immune system, bone health, and neural functions. To induce senescence, we used d-galactose for its convenience and fewer side effects. The experimental design involved treating 20-week-old C57BL/6J mice with d-galactose subcutaneously for 10 weeks to induce aging-like effects. Thereafter, IL-33 recombinant protein was administered intraperitoneally for 15 days to evaluate its impact on various immune, skeletal, and neural parameters. The results demonstrated that d-galactose–induced aging led to bone loss and compromised osteogenic parameters, accompanied by increased oxidative stress and neurodegeneration in specific brain regions. Behavioral activities were also affected. However, supplementation with IL-33 mitigated these effects, elevating osteogenic parameters and reducing senescence markers in osteoblast cells in an aging mouse model and exerted neuroprotective potential. Notably d-galactose–induced aging was characterized by high bone turnover, reflected by altered serum levels of CTX, PTH, beta-galactosidase, and P1NP. IL-33 treatment attenuated these effects, suggesting its role in regulating bone metabolism. Furthermore, d-galactose–induced aging was associated with increased differentiation of Th17 cells and upregulation of associated markers, such as STAT-3 and ROR-γt, while downregulating Foxp3, which antagonizes Th17 cell differentiation. IL-33 treatment countered these effects by suppressing Th17 cell differentiation and promoting IL-10–producing T-regulatory cells. Overall, these findings provide insights into the potential therapeutic implications of IL-33 in addressing aging-induced bone loss and memory impairment.
Multi-site phantomless bone mineral density from clinical quantitative computed tomography in males
Authors: Haverfield Zachary A , Agnew Amanda M , Loftis Kathryn , Zhang Jun , Hayden Lauren E , Hunter Randee L
Published: August 2024

Volumetric bone mineral density (vBMD) is commonly assessed using QCT. Although standard vBMD calculation methods require phantom rods that may not be available, internal-reference phantomless (IPL) and direct measurements of Hounsfield units (HU) can be used to calculate vBMD in their absence. Yet, neither approach has been systemically assessed across skeletal sites, and HU need further validation as a vBMD proxy. This study evaluated the accuracy of phantomless methods, including IPL and regression-based phantomless (RPL) calibration using HU to calculate vBMD, compared to phantom-based (PB) methods. vBMD from QCT scans of 100 male post-mortem human subjects (PMHS) was calculated using site-specific PB calibration at multiple skeletal sites throughout the body. A development sample of 50/100 PMHS was used to determine site-specific reference material density for IPL calibration and RPL equations. Reference densities and equations from the development sample were used to calculate IPL and RPL vBMD on the remaining 50/100 PMHS for method validation. PB and IPL/RPL vBMD were not significantly different (p > .05). Univariate regressions between PB and IPL/RPL vBMD were universally significant (p < 0.05), except for IPL Rad-30 (p = 0.078), with a percent difference across all sites of 6.97% ± 5.95% and 5.22% ± 4.59% between PB and IPL/RPL vBMD, respectively. As vBMD increased, there were weaker relationships and larger differences between PB vBMD and IPL/RPL vBMD. IPL and RPL vBMD had strong relationships with PB vBMD across sites (R2 = 97.99, R2 = 99.17%, respectively), but larger residual differences were found for IPL vBMD. As the accuracy of IPL/RPL vBMD varied between sites, phantomless methods should be site-specific to provide values more comparable to PB vBMD. Overall, this study suggests that RPL calibration may better represent PB vBMD compared to IPL calibration, increases the utility of opportunistic QCT, and provides insight into bone quality and fracture risk.
Enhancing non-Bt corn refuge based on corn grower and seed dealer surveys
Authors: Alsdorf Alexis , Reisig Dominic , Brown Zach , Ferraro Greg , Rejesus Roderick
Published: August 2024

To delay Bacillus thuringiensis (Bt) resistance, southern US corn growers are required to plant 20% of their total corn acres to non-Bt hybrids. However, most do not, possibly due to negative perceptions or the lack of availability of non-Bt hybrids. We surveyed 174 corn growers and 32 corn seed dealers in eastern North Carolina, an area that historically has planted little non-Bt corn. Our questions focused on planting behavior and hybrid choice, barriers to planting non-Bt corn, and preferences and challenges for non-Bt corn sales. Only 32% of growers surveyed planted the mandated non-Bt refuge acres. Growers from counties with smaller crop operations and in counties where growers had less graduate education planted less non-Bt seed. Grower perceptions of yield differences between Bt and non-Bt hybrids were ambiguous, but only a few had limited availability or knowledge of non-Bt seed options. Seed dealers were familiar with non-Bt corn hybrids in their portfolio, but not as familiar with non-Bt refuge requirements. Furthermore, dealers indicated obstacles in providing diverse herbicide packages and seed treatments for non-Bt hybrids. We highlight the need for enhanced communication and education initiatives. Strengthening educational outreach to clarify refuge requirements and addressing perceived yield disparities between Bt and non-Bt hybrids could also increase planting of non-Bt refuge. Finally, incentivizing seed dealers to offer and promote non-Bt seed options, coupled with diverse herbicide packages, might increase refuge planting. Our surveys underscore the complexity surrounding grower behaviors, seed dealer dynamics, and the importance of educational efforts and incentives to non-Bt refuge.
Night sky polarization model for a cloud-free atmosphere illuminated by ground-based light sources
Authors: Kocifaj M , Markoš P , Kundracik F , Barentine J C , Wallner S
Published: August 2024

Skyglow from sources of artificial light at night poses a significant challenge to ground-based astronomical research and discovery. Although astronomers, conservationists, and light-pollution researchers have measured skyglow for decades, their data on diffuse night-time light fields are incomplete as they lacks information about the polarization state of the light. Here, we present the first successful theoretical model that predicts the degree and angle of linear polarization of scattered night sky light and accounts for complex, real-world distributions of ground light sources. The model proceeds from an analytical solution to the polarized radiative transfer equation that is validated by field experiments. We discuss several use cases of the model and demonstrate its practical consequences, such as the ability to more reliably determine which ground sources in the area around an observer contribute the most scattered light in a given sky element.
Primeval very low-mass stars and brown dwarfs – VIII. The first age benchmark L subdwarf, a wide companion to a halo white dwarf
Authors: Zhang Z H , Raddi R , Burgasser A J , Casewell S L , Smart R L , Gálvez-Ortiz M C , Jones H R A , Baig S , Lodieu N , Gauza B , Pavlenko Ya V , Jiao Y F , Zhao Z K , Zhou S Y , Pinfield D J
Published: August 2024

We report the discovery of five white dwarf + ultracool dwarf systems identified as common proper motion wide binaries in the Gaia Catalogue of Nearby Stars. The discoveries include a white dwarf + L subdwarf binary, VVV 1256−62AB, a gravitationally bound system located 75.6$^{+1.9}_{-1.8}$ pc away with a projected separation of 1375$^{+35}_{-33}$ au. The primary is a cool DC white dwarf with a hydrogen dominated atmosphere, and has a total age of $10.5^{+3.3}_{-2.1}$ Gyr, based on white dwarf model fitting. The secondary is an L subdwarf with a metallicity of [M/H] = $-0.72^{+0.08}_{-0.10}$ (i.e. [Fe/H] = $-0.81\pm 0.10$) and $T_{\rm eff}$ = 2298$^{+45}_{-43}$ K based on atmospheric model fitting of its optical to near infrared spectrum, and likely has a mass just above the stellar/substellar boundary. The subsolar metallicity of the L subdwarf and the system’s total space velocity of 406 km s−1 indicates membership in the Galactic halo, and it has a flat eccentric Galactic orbit passing within 1 kpc of the centre of the Milky Way every $\sim$0.4 Gyr and extending to 15–31 kpc at apogal. VVV 1256−62B is the first L subdwarf to have a well-constrained age, making it an ideal benchmark of metal-poor ultracool dwarf atmospheres and evolution.
Characterization of the δ Scuti eclipsing binary KIC 4851217 and its tertiary companion as well as detection of tidally tilted pulsations
Authors: Jennings Z , Southworth J , Rappaport S A , Borkovits T , Handler G , Kurtz D W
Published: August 2024

Stellar theory enables us to understand the properties of stars at different stages of their evolution, and contributes to other fields of astrophysics such as galactic and exoplanet studies. Assessing the accuracy of stellar theories necessitates high precision, model-independent measurements of the properties of real stars, such as those obtainable for the components of double-lined eclipsing binaries (DLEBs), while asteroseismology offers probing power of the stellar interior if one or both components pulsate. KIC 4851217 is a DLEB containing two late A-type stars and exhibits pulsations of the $\delta$ Scuti type. By analysing high resolution HERMES and moderate resolution ISIS spectra, jointly with Kepler and Transiting Exoplanet Survey Satellite light curves, we measured the masses, radii, and effective temperatures of the components to precisions of $\sim$0.5, $\sim$1.1, and $\sim$1 per cent, respectively. We additionally report the discovery and characterization of a tertiary M-dwarf companion. Models of the system’s spectral energy distribution agree with an age of 0.82 Gyr, with the more massive and larger secondary component near the end of the main-sequence lifetime. An examination of the pulsating component’s pulsation frequencies reveals 39 pulsation multiplets that are split by the orbital frequency. For most of these, it is evident that the pulsation axes have been tilted into the orbital plane. This makes KIC 4851217 a tidally tilted pulsator (TTP). This precisely characterized $\delta$ Scuti DLEB is an ideal candidate for advancing intermediate-mass stellar theory, contributing to our understanding of hierarchical systems as well as to the topic of TTPs.
Effect of area divergence and frequency on damping of slow magnetoacoustic waves propagating along umbral fan loops
Authors: Rawat Ananya , Gupta Girjesh R
Published: August 2024

Waves play an important role in the heating of solar atmosphere; however, observations of wave propagation and damping from the solar photosphere to corona through chromosphere and transition region are very rare. Recent observations have shown propagation of 3-min slow magnetoacoustic waves (SMAWs) along fan loops from the solar photosphere to corona. In this work, we investigate the role of area divergence and frequencies on the damping of SMAWs propagating from the photosphere to the corona along several fan loops rooted in the sunspot umbra. We study the Fourier power spectra of oscillations along fan loops at each atmospheric height which showed significant enhancements in 1–2, 2.3–3.6, and 4.2–6 min period bands. Amplitude of intensity oscillations in different period bands and heights are extracted after normalizing the filtered light curves with low-frequency background. We find damping of SMAW energy flux propagating along the fan loop 6 with damping lengths $\approx 170$ and $\approx 208$ km for 1.5- and 3-min period bands. We also show the decay of total wave energy content with height after incorporating area divergence effect, and present actual damping of SMAWs from photosphere to corona. Actual damping lengths in this case increases to $\approx 172$ and $\approx 303$ km for 1.5- and 3-min period bands. All the fan loops show such increase in actual damping lengths, and thus highlight the importance of area divergence effect. Results also show some frequency-dependent damping of SMAW energy fluxes with height where high-frequency waves are damped faster than low-frequency waves.
Costless correction of chain based nested sampling parameter estimation in gravitational wave data and beyond
Authors: Prathaban Metha , Handley Will
Published: August 2024

Nested sampling parameter estimation differs from evidence estimation, in that it incurs an additional source of uncertainty. This uncertainty affects estimates of parameter means and credible intervals in gravitational wave analyses and beyond, and yet, it is typically not accounted for in standard uncertainty estimation methods. In this paper, we present two novel methods to quantify this uncertainty more accurately for any chain based nested sampler, using the additional likelihood calls made at run time in producing independent samples. Using injected signals of black hole binary coalescences as an example, we first show concretely that the usual uncertainty estimation method is insufficient to capture the true error bar on parameter estimates. We then demonstrate how the extra points in the chains of chain based samplers may be carefully utilized to estimate this uncertainty correctly, and provide a way to check the accuracy of the resulting error bars. Finally, we discuss how this uncertainty affects p–p plots and coverage assessments.
Simultaneous onset of chronic nonbacterial osteomyelitis in siblings
Authors: Patel Jenny A , Thomas Kristen B , Ristagno Elizabeth H , Basiaga Matthew L
Published: August 2024

Chronic nonbacterial osteomyelitis (CNO) is an uncommon autoinflammatory disorder. Significant effort has recently been spent to better define and treat this disorder including development of consensus treatment protocols, validate disease activity tools, and refining classification criteria. However, the underlying immunopathogenesis of the disease remains elusive. In this report, we describe the simultaneous onset of CNO in siblings. A pathogenic gene mutation was not identified, and these sisters lacked a similar biomarker profile. This report highlights that if a genetic predisposition for CNO exists, it may be related to complex polygenic or multifactorial mechanisms of disease evolution.
Glioma resource outreach with support: A program to identify and initiate supportive care interventions for unmet needs among adult lower-grade glioma patients
Authors: Garcia Fox Rachel , Chukwueke Ugonma N , Sannes Timothy , Miran Damien , Chiu Daniel , Bagley Christina , Holmes Emerson Grace , Peirce Benjamin , Beroukhim Rameen , Youssef Gilbert , McFaline-Figueroa J Ricardo , Aquilanti Elisa , Quant Lee Eudocia , Nayak Lakshmi , Wen Patrick Y , Gonzalez Castro L Nicolas , Reardon David A
Published: August 2024

Background

Lower-grade (WHO grades 2–3) gliomas typically affect young and middle-aged adults and exhibit isocitrate dehydrogenase (IDH) mutations. For such patients, symptoms related to the tumor and associated treatment contribute to morbidity and erode quality of life. With improved treatment, a better understanding of these effects over time is critically needed. Existing data characterizing unmet needs of lower-grade glioma patients is limited and little consensus exists on addressing these needs in clinical practice.

Methods

In order to better identify and address the unmet needs of lower-grade glioma patients, focus groups among patients and caregivers were initially conducted among patients treated at a single academic center. A semi-structured interview guide to comprehensively understand unmet needs was then developed. Each patient-defined unmet need was categorized into domains through qualitative content analysis. In parallel, a database of established local and regional community-based resources was established, and a dedicated resource specialist provided patient-specific referrals and follow-up.

Results

Eighty-five patients were interviewed. Median age was 41 years and the median time from tumor diagnosis was 63 months. Approximately 68% had a WHO grade 2 tumor and 60% were off therapy. Qualitative analysis of interview content identified 5 overarching domains of unmet need: Psychosocial; Neurologic/Cognitive; Lifestyle; Financial; and Other Medical. At least one unmet need was identified by 71% of participants and the most common domains were Psychosocial (40.7%) and Lifestyle (34.9%).

Conclusions

Our program begins to address frequently unmet survivorship needs of lower-grade glioma patients that spanned 5 major domains. Further research aimed to better define and address unmet needs among these patients is warranted.
Illness understanding and religiousness in patients with recurrent glioblastoma
Authors: Fortunato John T , Walsh Leah E , Polacek Laura C , Reiner Anne S , Walbert Tobias , Thomas Alissa A , Buthorn Justin , Sigler Allison , Prigerson Holly G , Applebaum Allison J , Diamond Eli L
Published: August 2024

Background

Patients with glioblastoma (GBM) often have inaccurate perceptions of prognosis. Strong religious beliefs have been associated with limited illness understanding (IU) in patients with advanced cancer, but IU and religiousness have not been investigated in patients with GBM. The aim of this study was to evaluate the association between religiousness and spirituality and IU in patients with GBM.

Methods

Patients enrolled in a prospective multicenter study of recurrent GBM (Coping with Glioblastoma, NCT02375841). Within one month of medical visits discussing MRI scans showing GBM progression, patients completed study surveys containing published measures of IU and religiousness. IU was compared between participants with moderate or high versus slight or no religiousness based on several patient-reported prompts using Fisher’s exact tests.

Results

Twenty-four patients completed surveys of religiousness and IU. IU was partial within our cohort. Fifteen participants (62.5%) acknowledged that their illness was terminal. Only 6 (25%) correctly acknowledged their prognosis (months). Eleven patients (46%) were moderately or very religious, while 9 (38%) were either slightly religious or not at all religious. High religiousness and spirituality were each associated with partial IU (P = .06 and P = .01, respectively). A belief that God could perform a miracle to cure them of cancer and a belief in sanctity through suffering were also each associated with partial IU.

Conclusions

This prospective study that suggests religiousness, including the belief in miracles and a belief in sanctification through suffering, might influence patients’ IU. Further research is warranted to study this association.
Kilogram-scale production of strong and smart cellulosic fibers featuring unidirectional fibril alignment
Authors: Li Jianguo , Chen Chaoji , Chen Qiongyu , Li Zhihan , Xiao Shaoliang , Gao Jinlong , He Shuaiming , Lin Zhiwei , Tang Hu , Li Teng , Hu Liangbing
Published: August 2024

Multifunctional fibers with high mechanical strength enable advanced applications of smart textiles, robotics, and biomedicine. Herein, we reported a one-step degumming method to fabricate strong, stiff, and humidity-responsive smart cellulosic fibers from abundant natural grass. The facile process involves partially removing lignin and hemicellulose functioning as glue in grass, which leads to the separation of vessels, parenchymal cells, and cellulosic fibers, where cellulosic fibers are manufactured at kilogram scale. The resulting fibers show dense and unidirectional fibril structure at both micro- and nano-scales, which demonstrate high tensile strength of ∼0.9 GPa and Young's modulus of 72 GPa, being 13- and 14-times higher than original grass. Inspired by stretchable plant tendrils, we developed a humidity-responsive actuator by engineering cellulosic fibers into the spring-like structures, presenting superior response rate and lifting capability. These strong and smart cellulosic fibers can be manufactured at large scale with low cost, representing promising a fiber material derived from renewable and sustainable biomass.
Sulfur filling activates vacancy-induced C–C bond cleavage in polyol electrooxidation
Authors: Shi Jianqiao , Chen Wei , Wu Yandong , Zhu Yanwei , Xie Chao , Jiang Yimin , Huang Yu-Cheng , Dong Chung-Li , Zou Yuqin
Published: August 2024

Using the electrochemical polyol oxidation reaction (POR) to produce formic acid over nickel-based oxides/hydroxides (NiOxHy) is an attractive strategy for the electrochemical upgrading of biomass-derived polyols. The key step in the POR, i.e. the cleavage of the C–C bond, depends on an oxygen-vacancy-induced mechanism. However, a high-energy oxygen vacancy is usually ineffective for Schottky-type oxygen-vacancy-rich β-Ni(OH)2 (VSO-β-Ni(OH)2). As a result, both β-Ni(OH)2 and VSO-β-Ni(OH)2 cannot continuously catalyze oxygen-vacancy-induced C–C bond cleavage during PORs. Here, we report a strategy of oxygen-vacancy-filling with sulfur to synthesize a β-Ni(OH)2 (S-VO-β-Ni(OH)2) catalyst, whose oxygen vacancies are protected by filling with sulfur atoms. During PORs over S-VO-β-Ni(OH)2, the pre-electrooxidation-induced loss of sulfur and structural self-reconstruction cause the in-situ generation of stable Frenkel-type oxygen vacancies for activating vacancy-induced C–C bond cleavage, thus leading to excellent POR performances. This work provides an intelligent approach for guaranteeing the sustaining action of the oxygen-vacancy-induced catalytic mechanism in electrooxidation reactions.
Estimating the Causal Effect of Filter Ventilation Levels in Cigarettes on Past 30-Day Smoking
Authors: Eaton Anne A , Hatsukami Dorothy K , Stepanov Irina , Shields Peter G , Carroll Dana Mowls
Published: August 2024

Introduction

Cigarettes with higher levels of filter ventilation (FV) are misperceived as less harmful and may be more appealing to consumers. Setting limits on FV has been considered as a policy, but a better understanding of any potential unintended consequences is needed.

Methods

FV (0.2%–61.1%) measured for 114 subbrands was merged with Wave 1 (2012–2013) of the Population Assessment of Tobacco Use and Health (PATH) data, restricted to adults 25+ years of age who smoked daily, and examined by quartiles. Inverse probability of exposure weights were used to estimate the causal effect of FV on past 30-day smoking at subsequent waves while accounting for potential confounders including demographics, menthol, heaviness of smoking, and past quit attempts.

Results

Compared to those in the first (lowest) quartile of FV, those in the second, third, and fourth quartiles had 1.02 (95% confidence interval = 0.57, 1.82), 0.86 (0.42, 1.73), and 1.52 (0.90, 2.56) times the odds of no past 30-day smoking at Wave 2 (approximately 1 year later, p = .163), and 1.28 (0.80, 2.07), 1.11 (0.67, 1.83), and 1.65 (1.01, 1.24) times the odds of no past 30-day smoking at Wave 4 (3 years later, p = .238).

Conclusions

This observational study found no strong evidence of a causal effect of FV on past 30-day smoking at approximately 1 and 3 years follow-up. However, our effect size estimates were not precise and thus an increase in the ability to quit smoking due to higher FV levels cannot be ruled out.

Implications

Setting a maximum limit on FV in cigarettes could address the misperception that highly ventilated cigarettes are less harmful and the link between FV and lung adenocarcinoma. It is important to understand whether such a policy would have unintended consequences on longer-term smoking behavior. We found no strong evidence that FV affects past 30-day smoking 1–3 years later, but could not rule out the possibility that higher FV increases cessation rates. If future studies confirm these epidemiologic findings, this could mean that setting a limit on FV would not lead to reductions in the ability to quit smoking.
11 Tumor evolution of brain-specific tropism in metastatic renal cell carcinoma
Authors: Elias Roy
Published: August 2024

Background

Brain metastases (BMets) pose a clinical challenge in the management of patients (pts) with metastatic renal cell carcinoma (RCC), leading to significant morbidity and mortality. Herein, we sought to comprehensively characterize the molecular landscape of BMets in RCC.

Methods

We performed panel-based DNA (DNAseq) and whole transcriptome (RNAseq) sequencing to analyze BMets, matched non-Brain metastases (nBMets), and matched primary renal tumors (PRT) from pts who underwent surgical resection of BMet(s) from RCC at our institution.

Results

Our cohort consisted of 95 samples from 53 patients (BMets = 54, nBMets = 14, PRT = 27) with clear cell histology in 45 pts (84.9%). DNAseq was available on 85 samples (50 pts). Patient-level mutations revealed recurring mutations in VHL (18 pts, 36%), TP53 (n = 12 pts, 24%), PBRM1 (12 pts, 24%), SETD2 (12 pts, 24%), and BAP1 (4 pts, 8%). Mutations within the MTOR signaling pathway were enriched, with 25 pts (50%) having at least one mutation in PTEN (12 pts, 24%), TSC1 (4 pts, 8%), TSC2 (5 pts, 10%), or MTOR (9 pts, 18%). Copy number analyses revealed frequent deletions in chr14q21 (34 pts, 68%) and chr9p21 (35 pts, 70%) and gains in chr20q13 (n = 31, 62%) and chr7p15 (n = 31, 62%).

At the sample-level, PTEN mutations were more common in BMets (11 pts, 22.9%) vs nBMets (0 pts) and PRTs (3 pts, 12%, p = 0.124), as were deletions in chr13q22 (BMets = 13pts [26.5%], nBMet = 1pts [8.3%], PRT = 1 [4%]; p = 0.036) and gains in chr20q13 (BMets = 30pts [61.2%], nBMet = 4pts [33.3%], PRT = 8 [32%]; p = 0.03). Deletions in chr9p21 were enriched in BMets (32, 65.3%) and nBMets (8, 66.7%) relative to PRTs (7, 28%, p = 0.006), whereas other copy number alterations and somatic mutations exhibited similar proportions across specimen sites.

Differential expression analysis performed on 86 samples (51 pts) identified 806 differentially expressed genes (DEGs) between BMets and PRT (adjusted [adj.] p < 0.05) and 399 DEGs between BMet and nBMets (adj. p < 0.05). Gene set enrichment analysis of MSigDB Hallmark gene sets revealed upregulation of MTORC1 signaling, glycolysis, and MYC targets in BMets comparted to PRT and nBMETs (adj. p <0.0001). In contrast, immune-related gene sets, such as interferon-alpha, interferon-gamma, and tumor necrosis factor-alpha, were enriched in PRT relative to BMets (adj. p <0.0001), but not nBMETs (adj. p > 0.05). CIBERSORT cellular deconvolution analysis comparing BMets with PRT revealed decreased proportions of M1 macrophages (p = 0.0003) and CD8+ T-cells (p = 0.0106), but an increased proportion of M2 macrophages (p = 0.0009).

Conclusions

RCC with brain metastases are characterized by distinct copy number alterations, enrichment of MTOR pathway mutations, MTOR pathway hyperactivation, and an immunosuppressive tumor milieu. These findings may hold therapeutic implications of MTOR pathway inhibition and immune modulators in treating RCC BMets.
Advanced Renal Cell Cancer Combination Immunotherapy Clinical Trial (ARCITECT; HCRN GU 22-587)
Authors: Serzan Michael
Published: August 2024

Background

First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy.

Methods

ARCITECT is a phase II, multicenter study evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has > 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR > 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806.

Results
24 Applying genomic analysis to refine unclassified renal cell carcinoma
Authors: Yekeduz Emre , Braun David A , Chehade Razane El Hajj , Eid Marc , Labaki Chris , Machaalani Marc , Nassar Amin , Nawfal Rashad , Saad Eddy , Saliby Renee Maria , Semaan Karl , Sun Maxine , Hirsch Michelle S , Ürün Yüksel , Zarif Talal El , Choueiri Toni K
Published: August 2024

Background

Despite the improvements in genomic and pathological techniques to identify renal cell carcinoma (RCC), 2-6% of all patients with RCC cannot be classified into a particular subgroup, thus called “unclassified” RCC (uRCC). Ascertaining the genomic profile of those patients may help select proper treatment and find novel targets.

Methods

The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database v15.0 was used to select patients with RCC by using the OncoTree codes. All included patients were divided into four groups based on the most frequent subtypes of RCC: clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chRCC), and uRCC. The Cancer Genome Atlas (TCGA) was additionally used to assess corresponding oncogenic signaling pathways. We employed the chi-squared test to compare categorical variables and applied the Benjamini-Hochberg correction to calculate Q-values, thereby controlling the false discovery rate.

Results

Overall, 1,990 tumor samples from 1,888 patients were evaluated. uRCC was observed in 184 patients (9.7%), whereas most had ccRCC (n=1339, 70.9%), followed by pRCC (n=224, 11.9%) and chRCC (n=141, 7.5%). Age distribution at sample sequencing was comparable between uRCC and other RCC subtypes (P>0.05). The proportion of female patients with uRCC was higher at 38.4%, compared to 26.5% in ccRCC (Q=0.002) and 16.3% in pRCC (Q<0.001), yet was comparable to chRCC at 48.6% (Q=0.210). The prevalence of uRCC was also greater among black patients, accounting for 8.6% vs. 2.1% in ccRCC (Q=0.001). Among patients with uRCC (n=224), the most common genomic alterations (GAs) were detected in NF2 (15.8%), SETD2 (15.8%), TP53 (13.9%), TERT (13.4%), and VHL (11.8%). NF2 alterations were also more prevalent in patients with uRCC than in patients with ccRCC (1.8%, Q<0.001), chRCC (0.7%, Q<0.001), and pRCC (5.8%, Q=0.058). Notably, median overall survival (OS) was poorer in uRCC patients with altered NF2 (n=29) than in those with unaltered NF2 (n=155, 30.7 vs. 87.1 months, p=0.058). Of patients with uRCC, 135 (72.5%) samples were from primary tumors and 39 (20.9%) from metastatic sites, with no difference in GA frequencies between the two. CDKN2A and CDKN2B were the most frequent co-mutated genes in uRCC (Q<0.001), followed by VHL and BAP1 (Q<0.001), and SETD2 and PBRM1 (Q=0.023). GAs in uRCC were primarily observed in pathways related to TP53 (42.8%), cell cycle (33.3%), PI3K (23.5%), and HIPPO (7.7%).

Conclusions

uRCC exhibited a unique genomic profile distinct from other common RCC subtypes. Notably, NF2 alterations were frequent and correlated with a poorer prognosis.
40 Preclinical evaluation of a novel dendritic cell vaccine for kidney cancer
Authors: Gau David , Taylor Jennifer , Storkus Walter , Roy Partha
Published: August 2024

Background

Dendritic cell (DC)-based vaccines have been previously shown to promote therapeutic T cell responses in both preclinical tumor models and in cancer patients, where extended patient overall survival has been noted in many cases. The goal of the present study is to develop a novel DC-based vaccine as an effective immuno-oncology (IO) agent for the prevention/treatment of kidney cancer. We previously demonstrated that actin-binding protein profilin1 (Pfn1) is overexpressed in tumor-associated vascular endothelial cells (ECs), where it may serve as a prognostic factor in human clear cell renal cancer (ccRCC). We further established a direct causal relationship between EC Pfn1 dysregulation, immune microenvironment alterations, and tumor progression in mouse models of RCC. The current work specifically explores whether Pfn1-targeted DC-based vaccines are effective in preventing orthotopic RCC in mice.

Methods

To generate Pfn1-targeted DC vaccines, we harvested and matured DCs from Balb/C mouse bone marrow-derived precursor cells in cultures containing rmIL4 and rmGM-CSF. DCs loaded with individual Pfn1 synthetic peptides (these sequences were identified using three MHC class I/II peptide-binding algorithms) were injected into syngeneic mice on days 0, 7 and 14. Spleens were harvested from immunized mice on day 21 to isolate CD4+ and CD8+ T cells, with T cells then stimulated with unmanipulated DCs or DCs pulsed with individual immunizing peptides to detect specific T cell activation, as measured by IFN-gamma release quantitated by ELISA. Tissue histology was performed to assess immune-related adverse events (iRAE) in vaccinated mice as a safety index. For cancer studies, Balb/c mice were immunized with DCs loaded with pooled Pfn1 peptides a few days prior to establishing either subcutaneous or orthotopic RCC tumors. Tumor-bearing mice were subjected to an identical booster vaccine prior one week later in advance of euthanasia and study end-point analyses.

Results

Our studies show that vaccination of Balb/c mice with DCs pulsed with Pfn1 peptides elicit specific CD4+ and/or CD8+ T cell responses without promoting irAEs. When applied in the prophylactic setting, DC-Pfn1 peptide vaccines substantially slow the growth of subcutaneous RCC tumors. In support of these findings, we have also developed preliminary data supporting the therapeutic effects of DC/Pfn1-peptide vaccines in a murine orthotopic model of RCC.

Conclusions

In summary, our studies provide first evidence for Pfn1-targeted IO agent in the cancer setting. Given that the survival benefit for dual immune-check point inhibitors (ICI)/anti-angiogenic therapy remains modest and is limited to a small minority of ccRCC patients, Pfn1-targeted vaccines could represent a novel therapeutic agent for improved patient outcomes when applied alone or in combination with in-clinic ICI agents.

DOD CDMRP Funding: yes
47 Generation and Characterization of Ex Vivo Expanded Tumor-Infiltrating Lymphocytes from Renal Cell Carcinoma Tumors for Adoptive Cell Therapy
Authors: Einstein David
Published: August 2024

Background

Autologous therapeutic tumor-infiltrating lymphocyte (TIL) therapy is a promising strategy to enhance anti-tumor immunity. Optimization of ex vivo TIL expansion could expand current immunotherapy options. Previous attempts to generate TIL in renal cell carcinoma (RCC) have been technically challenging. We applied a second-generation manufacturing process, currently used to generate the melanoma TIL product lifileucel, in RCC.

Methods

Resected primary and metastatic RCC samples were processed using the Gen 2 manufacturing process comprising of pre-Rapid Expansion Protocol (pre-REP) and REP steps. We assessed REP TILs for viability and performed phenotypic and functional characterization. We correlated the tumor immune microenvironment (TIME) with successful TIL expansion.

Results

Eight of 11 RCC samples underwent successful REP. Three failed cases demonstrated low CD8/FoxP3 ratio and high expression of PD-1 within FoxP3 cells. Expression of exhaustion markers differed between the TIME and expanded TILs; the latter had a TIM3-high/PD-1-low phenotype but retained functional capacity comparable to lifileucel.

Figure: Assessment of tumor immune microenvironment (TIME) via multiplex immunofluorescence (IF). Cases that failed REP are indicated in red. (A) Representative image at 60x magnification, fluorophore colors as indicated. (B) Density of tumor-infiltrating CD8+ and FoxP3+ cells. (C) Expression of co-inhibitory exhaustion markers as a percentage of total CD8+ cells. (D) Expression of PD-1 in FoxP3+ cells. (E) Comparison of tissue TIME (dots) with TIL product post-REP (open circles) exhaustion profiles as a percentage of total CD8+ cells.

Conclusions

The Gen 2 manufacturing process used for lifileucel successfully expanded functional TILs from RCC samples, enabling further study in a clinical trial. TIME features such as low CD8/FoxP3 ratio and high PD-1 expression within FoxP3 cells warrant study as potential biomarkers of successful TIL expansion.
50 National trends in the surgical management of renal cell carcinoma in Germany
Authors: Steiner Clara , Fahlenbrach Claus , Gilfrich Christian , Günster Christian , Jeschke Elke , Popken Gralf , Roigas Jan , Gratzke Christian , Stolzenburg Jens-Uwe , Leicht Hanna
Published: August 2024

Background

The incidence of RCC is increasing worldwide. For most patients with localized RCC, surgery remains the preferred treatment option. We aimed to investigate whether international trends towards minimally invasive procedures and nephron-sparing surgery are reflected in Germany.

Methods

Pseudonymized inpatient billing data from the AOK (Allgemeine Ortskrankenkassen), a non-profit oriented health insurance organization in Germany, was used for the conduct of the study. A total of 43,936 RCC cases were identified in which either a partial nephrectomy (PN, n = 20,030) or radical nephrectomy (RN, n = 21,906) was performed between 2012 and 2021. The proportions of different surgical procedures over time, as well as mortality (90 days), transfusion rate, reinterventions, and general postsurgical complications (30 days), were evaluated. Due to the use of pseudonymized data, no ethics vote was required.

Results

During the period of observation, there was a significant shift from RN to PN, with an increase in the proportion of PN among all procedures from 41.0% (1,918/4,684) in 2012 to 57.4% (2,274/3,960) in 2021 (p <0.001). Open surgery decreased for PN and RN but still accounted for the majority of all procedures (2021: 53.2% of PN and 65% of RN). Mortality was higher among patients with RN compared to PN (in hospital: 1.9% vs. 0.6%, 90 days: 4.7% vs. 1.2%). While general complication rates were similar (19.4% after PN versus 20.4% after RN), the reintervention rate was slightly higher after PN at 10.7% than after RN at 7.9%. Transfusion rates decreased significantly in several subgroups, favoring PN and minimally invasive approaches. Open surgical procedures were associated with higher unadjusted complication rates.

Conclusions

Despite shifts in favor of nephron-sparing surgery and minimally invasive surgery during the study period, open surgery remained the dominant surgical option for the treatment of renal cell carcinoma in Germany as of 2021. The adoption of laparoscopic and robotic-assisted techniques appears to reduce overall perioperative morbidity and consequently improve the quality of care in Germany. Further studies are required to examine patient level trends between type of surgical procedure, complication rates, and oncologic outcomes. Optimizing the assessment of the quality of care would enable further improvement of the quality itself.
59 Risk Factors of Immune Related Adverse Events in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors
Authors: Chehade Razane El Hajj , Semaan Karl , Saliby Renee Maria , Saad Eddy , Nawfal Rashad , Machaalani Marc , Eid Marc , Yekeduz Emre , Steiner Clara , Sun Maxine , Kaymakcalan Marina , Choueiri Toni K
Published: August 2024

Background

Immune checkpoint inhibitor (ICI) based combinations have become the standard of care for first-line treatment in patients with metastatic renal cell carcinoma (mRCC). However, ICI can be responsible for immune-related adverse events (irAEs). Herein, we aimed to identify risk factors of immune related adverse events (irAEs) in patients treated with current first line (1L) combination of ICIs (ICI+ICI) or ICI with vascular endothelial growth factor (VEGF) targeted therapy (ICI+VEGF).

Methods

Data was collected retrospectively from patients treated for mRCC at Dana-Farber Cancer Institute, either receiving dual ICI or ICI+VEGF as 1L treatment regimen. Patients were categorized into two groups: those who developed grade ≥ 2 irAEs and those with grade 1 or no AEs. Time to toxicity (TT) was defined as the primary outcome. Univariate Cox regression analysis was initially conducted to identify potential predictive factors associated with irAEs. Subsequently, significant variables related to treatment adverse events were included in a multivariate Cox regression analysis with adjustments for multiple baseline factors.

Results

Among the 158 patients included, 122 (77.2%) were male, and 36 (22.8%) were female. Median age of patients at the treatment start date of therapy was 61 years (Q1-Q3: 62-69). A total of 57 (36.1%) patients developed grade ≥ 2 irAEs. The median follow-up of patients was 25.7 months.

Univariate analysis showed that diabetes, male sex, and ccRCC may indeed influence the development of irAEs with a trend towards significance. However, thrombocytosis could be a protective factor against developing irAEs (p <0.05, Table).

Upon multivariate analysis, only ccRCC remained significant as a risk factor for irAEs compared to other subtypes, with a HR of 2.93 (95% CI:1.05-8.18, p = 0.04) (Table).

Table: Cox regression analysis for assessment of risk factors associated with irAEs

Conclusions

In this real-world study, we investigated potential clinical risk factors at baseline related to irAEs in patients with mRCC undergoing ICI-combination therapy. ccRCC histology was significantly associated with a higher risk of developing irAEs compared to other RCC subtypes. The retrospective design and the number of patients could be potential limitations of our findings.
Ozone Priming Enhanced Low Temperature Tolerance of Wheat (Triticum Aestivum L.) based on Physiological, Biochemical and Transcriptional Analyses
Authors: Dai Bing , Wang Hongyan , Li Weiqiang , Zhang Peng , Liu Tianhao , Li Xiangnan
Published: August 2024

Low temperature significantly inhibits plant growth in wheat (Triticum aestivum L.), prompting the exploration of effective strategies to mitigate low temperature stress. Several priming methods enhance low temperature stress tolerance; however, the role of ozone priming remains unclear in wheat. Here we found ozone priming alleviated low temperature stress in wheat. Transcriptome analysis showed that ozone priming positively modulated the ‘photosynthesis-antenna proteins’ pathway in wheat under low temperature. This was confirmed by the results of ozone-primed plants, which had higher trapped energy flux and electron transport flux per reaction, and less damage to chloroplasts than non-primed plants under low temperature. Ozone priming also mitigated the overstimulation of glutathione metabolism and induced the accumulation of total ascorbic acid and glutathione, as well as maintaining redox homeostasis in wheat under low temperature. Moreover, gene expressions and enzyme activities in glycolysis pathways were upregulated in ozone priming compared with non-priming after the low temperature stress. Furthermore, exogenous antibiotics significantly increased low temperature tolerance, which further proved that the inhibition of ribosome biogenesis by ozone priming was involved in low temperature tolerance in wheat. In conclusion, ozone priming enhanced wheat’s low temperature tolerance through promoting light-harvesting capacity, redox homeostasis and carbohydrate metabolism, as well as inhibiting ribosome biogenesis.