Search Results (84)

Background: T-cell-engaging bispecific (TCB) antibodies represent a promising therapy that utilizes T-cells to eliminate cancer cells independently of the major histocompatibility complex. Despite their success in hematologic cancers, challenges such as cytokine release syndrome (CRS), off-tumor toxicity, and resistance limit their efficacy in solid tumors. Optimizing biodistribution is key to overcoming these challenges. Methods: A physiologically based pharmacokinetic (PBPK) model was developed that incorporates T-cell transmigration, retention, receptor binding, receptor turnover, and cellular engagement. Preclinical biodistribution data were modeled using two TCB formats: one lacking tumor target binding and another with target arm binding, each with varying CD3 affinities in a transgenic tumor-bearing mouse model. Results: The PBPK model successfully described the distribution of activated T-cells and various TCB formats. It accurately predicted preclinical biodistribution patterns, demonstrating that higher CD3 affinity leads to faster clearance from the blood and increased accumulation in T-cell-rich organs, often reducing tumor exposure. Simulations of HER2-CD3 TCB doses (0.1 µg to 100 mg) revealed monotonic increases in synapse AUC within the tumor. A bell-shaped dose-Cmax relationship for synapse formation was observed, and Tmax was delayed at higher doses. Blood PK was a reasonable surrogate for tumor synapse at low doses but less predictive at higher doses. Conclusions: We developed a whole-body PBPK model to simulate the biodistribution of T-cells and TCB molecules. The insights from this model provide a comprehensive understanding of the factors affecting PK, synapse formation, and TCB activity, aiding in dose optimization and the design of effective therapeutic strategies. Full article

In early-phase dose-finding clinical trials, integrating patient-reported outcomes (PROs) is essential for enhancing patient-centered decision-making. This short communication advocates for several key practices to achieve such integration. Firstly, foster patient-centered communication that ensures patient understanding of the potential benefits of early-phase trials, thereby mitigating therapeutic misconceptions. Secondly, (a) facilitate partnerships to understand and address the underlying reasons for discrepancies between clinician and patient reports of adverse events and (b) facilitate partnerships among clinical trialists, statisticians, clinicians, patients, and advocates to gain diverse perspectives of adverse events and in so doing ensure that patients comprehend how their data will be used. Thirdly, optimize trial design and data collection by (a) determining optimal and feasible frequencies for PRO collection to minimize patient burden while maintaining data integrity and (b) effectively incorporating concordant PROs to guide dose recommendation decisions and adapt trial designs and statistical methods accordingly. Future research will involve investigating the application of these practices in patients within the Virginia Commonwealth University (VCU) Massey Comprehensive Cancer Center Catchment Area. By integrating these recommendations, early-phase dose-finding clinical trials have the potential to achieve more informed and patient-centered objectives. Full article

There is currently a lack of regulation of the caffeine found in cola and energy drinks by the FDA, which fails to protect the consumers of these products. Due to this lack of regulation, cola and energy drinks can have noticeable differences in their caffeine content when compared to the average amount per serving labelled on the product. In this study, we demonstrate the ability to analyse caffeine rapidly in under 20 s, and with HPLC pressures under 3500 psi (241 bar). To facilitate a high-throughput routine HPLC analysis of the caffeine content found in energy and cola drinks, two HPLC column technologies are studied, a conventional run HPLC column, and a newly commercialised Radial Flow Splitting end fitted HPLC column. The Radial Flow Splitting fitted column demonstrated the following benefits: a 37% reduction in pressure, an increased signal intensity sensitivity of 35%, a reduced analysis time by 20%, and improved metrics in assay precision based on triplicate injections associated with retention time, peak area, and peak height precision %RSD values. Both rapid HPLC methods offer greater opportunity for expanded beverage testing, which can ultimately help protect the consumer. The quantified energy drinks that were tested had a higher caffeine content, on average, than the labelled caffeine content, with an approximately ±16 mg difference per serving size for the energy drinks. In the case of the cola drinks, which did not include caffeine levels on the food label, we compared the levels to the USDA guidance and found up to double the recommended amount of caffeine in one serving for the samples studied. This highlights the need to have stricter regulations for caffeinated beverages to protect consumers and provide transparency regarding the caffeine content. Full article

Anogenital inflammation is a critical risk factor for HIV acquisition. The primary preventative HIV intervention, pre-exposure prophylaxis (PrEP), is ineffective in blocking transmission in anogenital inflammation. Pre-existing sexually transmitted diseases (STIs) and anogenital microbiota dysbiosis are the leading causes of inflammation, where inflammation is extensive and often asymptomatic and undiagnosed. Dendritic cells (DCs), as potent antigen-presenting cells, are among the first to capture HIV upon its entry into the mucosa, and they subsequently transport the virus to CD4 T cells, the primary HIV target cells. This increased HIV susceptibility in inflamed tissue likely stems from a disrupted epithelial barrier integrity, phenotypic changes in resident DCs and an influx of inflammatory HIV target cells, including DCs and CD4 T cells. Gaining insight into how HIV interacts with specific inflammatory DC subsets could inform the development of new therapeutic strategies to block HIV transmission. However, little is known about the early stages of HIV capture and transmission in inflammatory environments. Here, we review the currently characterised inflammatory-tissue DCs and their interactions with HIV. Full article

With a warmer and drier climate, there has been an increase in wildfire events in the Northwest U.S., posing a potential health risk to downwind communities. The Lewis–Clark Valley (LCV), a small metropolitan area on the Washington/Idaho border in the United States Intermountain West region, was studied over the time period of 2017–2018. The main objective was to determine the community’s exposure to particulate matter (PM_2.5) and volatile organic compounds (VOCs) during wildfire smoke events and to estimate the associated health risk. VOCs were analyzed previously in the LCV using sorbent tube sampling and thermal-desorption gas-chromatography mass-spectrometry (TD-GC-MS) during several local smoke events in the 2017–2018 fire seasons. PM_2.5 measurements were obtained from nearby agency monitors. PM_2.5 reached up to 200 µg/m³ in 2017 and over 100 µg/m³ in 2018 in the LCV, and has been observed to be increasing at a rate of 0.10 µg m⁻³/yr over the past two decades. Benzene, a carcinogen and air toxic, was measured with concentrations up to 11 µg/m³, over ten times the normal level in some instances, in the LCV. The health risk in the LCV from benzene was calculated at seven extra cancers per million for lifetime exposure and thirteen extra cancers per million considering all air toxics measured. The other cities monitored showed similar lifetime cancer risk, due to benzene of about 6–7 extra cancers per million. This work is important, as it measures ground-level exposures of VOCs and demonstrates decreases in PM_2.5 air quality over time in the region. Full article

Stellar and black hole feedback heat and disperse surrounding cold gas clouds, launching gas flows off circumnuclear and galactic disks, producing a dynamic interstellar medium. On large scales bordering the cosmic web, feedback drives enriched gas out of galaxies and groups, seeding the intergalactic medium with heavy elements. In this way, feedback shapes galaxy evolution by shutting down star formation and ultimately curtailing the growth of structure after the peak at redshift 2–3. To understand the complex interplay between gravity and feedback, we must resolve both the key physics within galaxies and map the impact of these processes over large scales, out into the cosmic web. The Advanced X-ray Imaging Satellite (AXIS) is a proposed X-ray probe mission for the 2030s with arcsecond spatial resolution, large effective area, and low background. AXIS will untangle the interactions of winds, radiation, jets, and supernovae with the surrounding interstellar medium across the wide range of mass scales and large volumes driving galaxy evolution and trace the establishment of feedback back to the main event at cosmic noon. This white paper is part of a series commissioned for the AXIS Probe mission concept; additional AXIS white papers can be found at the AXIS website. Full article

In this review, we outline our current understanding of the mechanisms involved in the absorption, storage, and transport of dietary vitamin A to the eye, and the trafficking of rhodopsin protein to the photoreceptor outer segments, which encompasses the logistical backbone required for photoreceptor cell function. Two key mechanisms of this process are emphasized in this manuscript: ocular and systemic vitamin A membrane transporters, and rhodopsin transporters. Understanding the complementary mechanisms responsible for the generation and proper transport of the retinylidene protein to the photoreceptor outer segment will eventually shed light on the importance of genes encoded by these proteins, and their relationship on normal visual function and in the pathophysiology of retinal degenerative diseases. Full article

Females of reproductive age constitute one of the largest demographics of the hip arthroscopy population, but it is unclear as to how pregnancy planning affects decision-making regarding surgery or vice versa. The purpose of this study was to assess perceived risks to pregnancy from hip pain and/or hip arthroscopy among reproductive-age females who underwent arthroscopic treatment of femoroacetabular impingement syndrome (FAIS). A cross-sectional study was conducted involving females aged 18–44 years who underwent hip arthroscopy for the treatment of FAIS, with a single surgeon included in the study. Subjects completed a survey that assessed obstetric and gynecologic history, decision-making regarding the planning and timing of hip surgery and pregnancy, and perceived risks to pregnancy from hip pain and/or hip surgery. Subjects were classified as nulligravid (Group 1), pregnant at least once before hip surgery but never again following hip surgery (Group 2), or pregnant at least once following hip surgery (Group 3). A total of 85 patients were enrolled with a mean age of 32.3 ± 6.5 years at the time of surgery. The mean follow-up time was 51.9 ± 34.5 months. There were 39 subjects in Group 1 (45.9%), 20 in Group 2 (23.5%), and 26 in Group 3 (30.6%). About half of all subjects expressed “some” to “a lot of” concern that their hip pain could get worse during pregnancy (49.4%), and about half had “no concern” that hip arthroscopy would affect the health of their fetus/baby (54.1%). Reproductive-age females undergoing hip arthroscopy for FAIS generally consider the procedure to be safe with respect to future pregnancy outcomes. Full article

Actinobacillus pleuropneumoniae is the causative agent of pleuropneumonia, an economically important lung disease in pigs. In draft genomes of two Cypriot clinical A. pleuropneumoniae isolates (MIDG3457 and MIDG3459), we previously identified single genomic regions with homology to Mu-like bacteriophage and presented preliminary evidence of active phage. Here, updated Phastest genomic analysis identified two loci in both MIDG3457 and MIDG3459 that were predicted to encode proteins with high homology to, and whose organisation was characteristic of, Mu-like phages. Phylogenetically, the closest matches were with Mannheimia Vb and Glaesserella SuMu phages. Phastest scored the loci as “complete”, indicating they produced active phage. PCR amplification of the Mu-like phage c and tail genes from DNase-treated polyethylene glycol 8000 (PEG)-precipitated supernatants of MIDG3457 and MIDG3459 (grown in either Brain Heart Infusion-NAD or Grace’s Insect Medium-NAD broth) indicated the presence of intact virions. The phages from MIDG3457 and MIDG3459 were named PluMu 3457-1, 3457-2, and PluMu 3459-1 and PluMu 3459-2, respectively. Transmission electron microscopy (TEM) of the PEG-precipitated supernatants of broth-grown MIDG3459 identified virions with icosahedral heads and tails, consistent with other Mu-like phages. We conclude that MIDG3459 produces an active Mu-like phage. Full article

The sand fly, Phlebotomus papatasi (Scopoli, 1786), is a major vector for Leishmania major in the Middle East, which has impacted human health and US military operations in the area, demonstrating the need to develop effective sand fly control and repellent options. Here, we report the results of spatial repellency and avoidance experiments in a static air olfactometer using the female P. papatasi testing essential oils of Lippia graveolens (Mexican oregano), Pimenta dioica (allspice), Amyris balsamifera (amyris), Nepeta cataria (catnip), Mentha piperita (peppermint), and Melaleuca alternifolia (tea tree); the 9–12 carbon saturated fatty acids (nonanoic acid, decanoic acid, undecanoic acid, and dodecanoic acid); and the synthetic repellents DEET and IR3535. The materials applied at 1% exhibited varying activity levels but were not significantly different in mean repellency and avoidance from DEET and IR3535, except in regards to nonanoic acid. Some materials, particularly nonanoic and undecanoic acids, produced sand fly mortality. The observed trends in mean repellency over exposure time included the following: (1) P. dioica oil, M. alternifolia oil, decanoic acid, undecanoic acid, DEET, and IR3535 exhibited increasing mean repellency over time; (2) oils of N. cataria, A. balsamifera, M. piperita, and dodecanoic acid exhibited relatively constant mean repellency over time; and (3) L. graveolens oil and nonanoic acid exhibited a general decrease in mean repellent activity over time. These studies identified the essential oils of N. cataria and A. balsamifera as effective spatial repellents at reduced concentrations compared to those of DEET. Additional research is required to elucidate the modes of action and potential synergism of repellents and essential oil components for enhanced repellency activity. Full article

Whether brain temperature noninvasively extracted by magnetic resonance imaging has a role in identifying brain changes in the later phases of mild to moderate traumatic brain injury (TBI) is not known. This prospective study aimed to evaluate if TBI patients in subacute and chronic phases had altered brain temperature measured by whole-brain magnetic resonance spectroscopic imaging (WB-MRSI) and if the measurable brain temperature had any relationship with cognitive function scores. WB-MRSI was performed on eight TBI patients and fifteen age- and sex-matched control subjects. Brain temperature (T) was extracted from the brain’s major metabolites and compared between the two groups. The T of the patients was tested for correlation with cognitive function test scores. The results showed significantly lower brain temperature in the TBI patients (p < 0.05). Brain temperature derived from N-acetylaspartate (T_NAA) strongly correlated with the 2 s paced auditory serial addition test (PASAT-2s) score (p < 0.05). The observation of lower brain temperature in TBI patients may be due to decreased metabolic activity resulting from glucose and oxygen depletion. The correlation of brain temperature with PASAT-2s may imply that noninvasive brain temperature may become a noninvasive index reflecting cognitive performance. Full article

This study quantifies setup uncertainty in brain tumor patients who received image-guided proton therapy. Patients analyzed include 165 children, adolescents, and young adults (median age at radiotherapy: 9 years (range: 10 months to 24 years); 80 anesthetized and 85 awake) enrolled in a single-institution prospective study from 2020 to 2023. Cone-beam computed tomography (CBCT) was performed daily to calculate and correct manual setup errors, once per course after setup correction to measure residual errors, and weekly after treatments to assess intrafractional motion. Orthogonal radiographs were acquired consecutively with CBCT for paired comparisons of 40 patients. Translational and rotational errors were converted from 6 degrees of freedom to a scalar by a statistical approach that considers the distance from the target to the isocenter. The 95th percentile of setup uncertainty was reduced by daily CBCT from 10 mm (manual positioning) to 1–1.5 mm (after correction) and increased to 2 mm by the end of fractional treatment. A larger variation existed between the roll corrections reported by radiographs vs. CBCT than for pitch and yaw, while there was no statistically significant difference in translational variation. A quantile mixed regression model showed that the 95th percentile of intrafractional motion was 0.40 mm lower for anesthetized patients ($p=0.0016$). Considering additional uncertainty in radiation-imaging isocentricity, the commonly used total plan robustness of 3 mm against positional uncertainty would be appropriate for our study cohort. Full article

In April 2023, the superBIT telescope was lifted to the Earth’s stratosphere by a helium-filled super-pressure balloon to acquire astronomical imaging from above (99.5% of) the Earth’s atmosphere. It was launched from New Zealand and then, for 40 days, circumnavigated the globe five times at a latitude 40 to 50 degrees south. Attached to the telescope were four “drs” (Data Recovery System) capsules containing 5 TB solid state data storage, plus a gnss receiver, Iridium transmitter, and parachute. Data from the telescope were copied to these, and two were dropped over Argentina. They drifted 61 km horizontally while they descended 32 km, but we predicted their descent vectors within 2.4 km: in this location, the discrepancy appears irreducible below ∼2 km because of high speed, gusty winds and local topography. The capsules then reported their own locations within a few metres. We recovered the capsules and successfully retrieved all of superBIT’s data despite the telescope itself being later destroyed on landing. Full article

The era of 20 nm integrated circuits has arrived. There exist abundant heterogeneous micro/nano structures, with thicknesses ranging from hundreds of nanometers to sub-microns in the IC back end of the line stack, which put stringent demands on the reliability of the device. In this paper, the reliability issues of a 20 nm chip due to chip–package interaction during the reflow process is studied. A representative volume element of the detailed complex BEoL structure has been analyzed to obtain mechanical properties of the BEoL stack by adopting a sub-model analysis. For the first time, semi-elliptical cracks were used in conjunction with J-integral techniques to analyze the failure caused by Chip-to-Package Interaction for a 20 nm chip. The Energy Release Rate(ERR)for cracks at various interfaces and locations in the BEoL stack were calculated to predict the most likely mode and location of failure. We found that the ERR of interfacial cracks at the bottom surface of the interconnects are, on average, more than double those at the sidewalls, which are in turn more than double the number of cracks in the low-k inter-layer dielectric. A total of 500 cycles of thermal shock were conducted, which verified the predictions of the finite element simulations. Full article

Synchrotron Microbeam Radiation Therapy (MRT) is an innovative technique that spatially segments the synchrotron radiation field for cancer treatment. A microbeam peak dose is often hundreds of times the dose in the valley (the sub-millimeter region between the peaks of the microbeams). Peak and valley doses vary with increasing depth in tissue which effects tumor dose coverage. It remains to be seen whether the peak or valley is the primary factor in MRT cancer control. This study investigates how unilateral MRT doses can be modulated using a bolus, and identifies the valley dose as a primary factor in MRT cancer control. Fischer rats bearing 9 L gliosarcoma tumors were irradiated with MRT at the Imaging and Medical Beam Line of the Australian Synchrotron. MRT valley doses of 8–15 Gy (250–1040 Gy peak doses) were used to treat tumors with and without a 5 mm dose-modulating bolus. Long-term survival depended on the valley dose primarily (92% correlation), and the use of the bolus reduced the variance in animal survival and improved to the mean survival of rats treated with MRT by 47% and 18% using 15 Gy and 8 Gy valley doses, respectively. Full article