Validation of ferroptosis in canine cancer cells to enable comparative oncology and translational medicine.

Ferroptosis is a cell death mechanism that has attracted significant attention as a potential basis for the development of new cancer therapies. Validation of ferroptosis biology in species commonly used in translation and pre-clinical development is a necessary foundation for enabling the advancement of such ferroptosis modulating drugs. Here, we demonstrate that canine cancer cells exhibit sensitivity to a wide range of ferroptosis-inducing perturbations in a manner indistinguishable from human cancer cells, and recapitulate characteristic patterns of ferroptotic response across tumor types seen in the human setting. The foundation provided herein establishes the dog as a relevant efficacy and toxicology model for ferroptosis and creates new opportunities to leverage the canine comparative oncology paradigm to accelerate the development of ferroptosis-inducing drugs for human cancer patients.

Sex differences in the extent of acute axonal pathologies after experimental concussion.

Although human females appear be at a higher risk of concussion and suffer worse outcomes than males, underlying mechanisms remain unclear. With increasing recognition that damage to white matter axons is a key pathologic substrate of concussion, we used a clinically relevant swine model of concussion to explore potential sex differences in the extent of axonal pathologies. At 24 h post-injury, female swine displayed a greater number of swollen axonal profiles and more widespread loss of axonal sodium channels than males. Axon degeneration for both sexes appeared to be related to individual axon architecture, reflected by a selective loss of small caliber axons after concussion. However, female brains had a higher percentage of small caliber axons, leading to more extensive axon loss after injury compared to males. Accordingly, sexual dimorphism in axonal size is associated with more extensive axonal pathology in females after concussion, which may contribute to worse outcomes.

Alternating rabacfosadine and doxorubicin for treatment of naïve canine lymphoma.

The current standard of care treatment for canine lymphoma is a multi-agent, CHOP-based chemotherapy protocol. Single agent doxorubicin (DOX) is less burdensome; however, multi-agent chemotherapy protocols are often superior. The recently approved drug rabacfosadine (RAB, Tanovea) provides an attractive option for combination therapy with DOX, as both drugs demonstrate efficacy against lymphoma and possess different mechanisms of action. A previous study evaluating alternating RAB/DOX reported an overall response rate (ORR) of 84%, with a median progression-free survival time (PFS) of 194 days. The aim of this prospective trial was to evaluate the same protocol in an additional population of dogs. Fifty-nine dogs with treatment naïve lymphoma were enrolled. RAB (1.0 mg/kg IV) was alternated with DOX (30 mg/m2 IV) every 21 days for up to six total treatments (3 cycles). Response assessment and adverse event (AE) evaluation were performed every 21 days using VCOG criteria. The ORR was 93% (79% CR, 14% PR). The median time to maximal response was 21.5 days; median PFS was 199 days. T cell immunophenotype and lack of treatment response were predictive of inferior outcomes. AEs were mostly gastrointestinal. Six dogs developed presumed or confirmed pulmonary fibrosis; four were grade 5. One dog experienced grade 3 extravasation injury with RAB that resolved with supportive treatment. These data mirror those of the previously reported RAB/DOX study, and support the finding that alternating RAB/DOX is a reasonable treatment option for canine lymphoma.

Gaps in the wall of a perivascular space act as valves to produce a directed flow of cerebrospinal fluid: a hoop-stress model.

The flow of cerebrospinal fluid (CSF) along perivascular spaces (PVSs) is an important part of the brain's system for clearing metabolic waste. Astrocyte endfeet bound the PVSs of penetrating arteries, separating them from brain extracellular space. Gaps between astrocyte endfeet might provide a low-resistance pathway for fluid transport across the wall. Recent studies suggest that the astrocyte endfeet function as valves that rectify the CSF flow, producing the net flow observed in pial PVSs by changing the size of the gaps in response to pressure changes. In this study, we quantify this rectification based on three features of the PVSs: the quasi-circular geometry, the deformable endfoot wall, and the pressure oscillation inside. We provide an analytical model, based on the thin-shell hoop-stress approximation, and predict a pumping efficiency of about 0.4, which would contribute significantly to the observed flow. When we add the flow resistance of the extracellular space (ECS) to the model, we find an increased net flow during sleep, due to the known increase in ECS porosity (decreased flow resistance) compared to that in the awake state. We corroborate our analytical model with three-dimensional fluid-solid interaction simulations.

An Ultrathin, Fast-Response, Large-Scale Liquid-Crystal-Facilitated Multi-Functional Reconfigurable Metasurface for Comprehensive Wavefront Modulation.

The rapid advancement of prevailing communication/sensing technologies necessitates cost-effective millimeter-wave arrays equipped with a massive number of phase-shifting cells to perform complicated beamforming tasks. Conventional approaches employing semiconductor switch/varactor components or tunable materials encounter obstacles such as quantization loss, high cost, high complexity, and limited adaptability for realizing large-scale arrays. Here, a low-cost, ultrathin, fast-response, and large-scale solution relying on metasurface concepts combined together with liquid crystal (LC) materials requiring a layer thickness of only 5 µm is reported. Rather than immersing resonant structures in LCs, a joint material-circuit-based strategy is devised, via integrating deep-subwavelength-thick LCs into slow-wave structures, to achieve constitutive metacells with continuous phase shifting and stable reflectivity. An LC-facilitated reconfigurable metasurface sub-system containing more than 2300 metacells is realized with its unprecedented comprehensive wavefront manipulation capacity validated through various beamforming functions, including beam focusing/steering, reconfigurable vortex beams, and tunable holograms, demonstrating a milli-second-level function-switching speed. The proposed methodology offers a paradigm shift for modulating electromagnetic waves in a non-resonating broadband fashion with fast-response and low-cost properties by exploiting functionalized LC-enabled metasurfaces. Moreover, this extremely agile metasurface-enabled antenna technology will facilitate a transformative impact on communication/sensing systems and empower new possibilities for wavefront engineering and diffractive wave calculation/inference.

Preparing Patients for Oral Immunotherapy (PPOINT): International Delphi consensus for procedural preparation and consent.

BACKGROUND: Despite the promise of oral immunotherapy (OIT) to treat food allergies, this procedure is associated with potential risk. There is no current agreement about what elements should be included in the preparatory or consent process. OBJECTIVE: We developed consensus recommendations about the OIT process considerations and patient-specific factors that should be addressed before initiating OIT and developed a consensus OIT consent process and information form. METHODS: We convened a 36-member Preparing Patients for Oral Immunotherapy (PPOINT) panel of allergy experts to develop a consensus OIT patient preparation, informed consent process, and framework form. Consensus for themes and statements was reached using Delphi methodology, and the consent information form was developed. RESULTS: The expert panel reached consensus for 4 themes and 103 statements specific to OIT preparatory procedures, of which 76 statements reached consensus for inclusion specific to the following themes: general considerations for counseling patients about OIT; patient- and family-specific factors that should be addressed before initiating OIT and during OIT; indications for initiating OIT; and potential contraindications and precautions for OIT. The panel reached consensus on 9 OIT consent form themes: benefits, risks, outcomes, alternatives, risk mitigation, difficulties/challenges, discontinuation, office policies, and long-term management. From these themes, 219 statements were proposed, of which 189 reached consensus, and 71 were included on the consent information form. CONCLUSION: We developed consensus recommendations to prepare and counsel patients for safe and effective OIT in clinical practice with evidence-based risk mitigation. Adoption of these recommendations may help standardize clinical care and improve patient outcomes and quality of life.

ImmunoChemoradiation for Non-Small Cell Lung Cancer: A Meta-Analysis of Factors Influencing Survival Benefit in Combination Trials.

PURPOSE: Adding immune checkpoint blockade (ICB) to concurrent chemoradiotherapy (cCRT) has improved overall survival (OS) for inoperable locally advanced non-small cell lung cancer. Trials of cCRT-ICB are heterogeneous for factors such as tumor stage and histology, programmed cell death ligand-1 (PDL-1) status, and cCRT-ICB schedules. We therefore aimed to determine the ICB contribution to survival across studies and identify factors associated with survival gain. METHODS AND MATERIALS: Data were collated from cCRT-ICB clinical studies published 2018 to 2022 that treated 2196 patients with non-small cell lung cancer (99% stage 3). Associations between 2-year OS and ICB, CRT, patient and tumor factors were investigated using metaregression. A published model of survival after radiation therapy (RT) or CRT was extended to include ICB effects. The model was fitted simultaneously to the cCRT-ICB data and data previously compiled for RT/CRT treatments alone. The net ICB contribution (OS gain) and its associations with factors were described by fitted values of ICB terms added to the model. Statistical significance was determined by likelihood-ratio testing. RESULTS: The gain in 2-year OS from ICB was 9.9% overall (95% CI, 7.6%, 12.2%; P = .018). Both OS gain and 2-year OS itself rose with increasing planned ICB duration (P = .008, .002, respectively) and with tumor PDL-1 ≥ 1% (P = .034, .023). Fitted OS gains were also greater for patients with stage 3B/C disease (P = .021). OS gain was not associated with tumor histology, patient performance status, radiation therapy dose, ICB drug type (anti-PDL-1 vs anti-programmed cell death-1), or whether ICB began concurrently with or after cCRT. CONCLUSIONS: Fitted gains in 2-year OS due to ICB were higher in cohorts with greater fractions of stage 3B/C patients and patients with tumor PDL-1 ≥ 1%. OS gain was also significantly higher in a single cohort with a planned ICB duration of 2 years rather than 1, but was not associated with whether ICB treatment began during versus after CRT.

Pre-hospital emergency medicine: a spectrum of imaging findings.

The goal of emergency medical services (EMS) is to provide urgent medical care and stabilization prior to patient transport to a healthcare facility for definitive treatment. The number and variety of interventions performed in the field by EMS providers continues to grow as early management of severe injuries and critical illness in the pre-hospital setting has been shown to improve patient outcomes. The sequela of many field interventions, including those associated with airway management, emergent vascular access, cardiopulmonary resuscitation (CPR), patient immobilization, and hemorrhage control may be appreciated on emergency department admission imaging. Attention to these imaging findings is important for the emergency radiologist, who may be the first to identify a malpositioned device or an iatrogenic complication arising from pre-hospital treatment. Recognition of these findings may allow for earlier corrective action to be taken in the acute care setting. This review describes common EMS interventions and their imaging findings.

In the face of ambiguity: intrinsic brain organization in development predicts one's bias toward positivity or negativity.

Exacerbated negativity bias, including in responses to ambiguity, represents a common phenotype of internalizing disorders. Individuals differ in their propensity toward positive or negative appraisals of ambiguity. This variability constitutes one's valence bias, a stable construct linked to mental health. Evidence suggests an initial negativity in response to ambiguity that updates via regulatory processes to support a more positive bias. Previous work implicates the amygdala and prefrontal cortex, and regions of the cingulo-opercular system, in this regulatory process. Nonetheless, the neurodevelopmental origins of valence bias remain unclear. The current study tests whether intrinsic brain organization predicts valence bias among 119 children and adolescents (6 to 17 years). Using whole-brain resting-state functional connectivity, a machine-learning model predicted valence bias (r = 0.20, P = 0.03), as did a model restricted to amygdala and cingulo-opercular system features (r = 0.19, P = 0.04). Disrupting connectivity revealed additional intra-system (e.g. fronto-parietal) and inter-system (e.g. amygdala to cingulo-opercular) connectivity important for prediction. The results highlight top-down control systems and bottom-up perceptual processes that influence valence bias in development. Thus, intrinsic brain organization informs the neurodevelopmental origins of valence bias, and directs future work aimed at explicating related internalizing symptomology.

Intergenomic signatures of coevolution between Tasmanian devils and an infectious cancer.

Coevolution is common and frequently governs host-pathogen interaction outcomes. Phenotypes underlying these interactions often manifest as the combined products of the genomes of interacting species, yet traditional quantitative trait mapping approaches ignore these intergenomic interactions. Devil facial tumor disease (DFTD), an infectious cancer afflicting Tasmanian devils (Sarcophilus harrisii), has decimated devil populations due to universal host susceptibility and a fatality rate approaching 100%. Here, we used a recently developed joint genome-wide association study (i.e., co-GWAS) approach, 15 y of mark-recapture data, and 960 genomes to identify intergenomic signatures of coevolution between devils and DFTD. Using a traditional GWA approach, we found that both devil and DFTD genomes explained a substantial proportion of variance in how quickly susceptible devils became infected, although genomic architectures differed across devils and DFTD; the devil genome had fewer loci of large effect whereas the DFTD genome had a more polygenic architecture. Using a co-GWA approach, devil-DFTD intergenomic interactions explained ~3× more variation in how quickly susceptible devils became infected than either genome alone, and the top genotype-by-genotype interactions were significantly enriched for cancer genes and signatures of selection. A devil regulatory mutation was associated with differential expression of a candidate cancer gene and showed putative allele matching effects with two DFTD coding sequence variants. Our results highlight the need to account for intergenomic interactions when investigating host-pathogen (co)evolution and emphasize the importance of such interactions when considering devil management strategies.

Age-Related Food Aversion and Anxiety Represent Primary Patient Barriers to Food Oral Immunotherapy.

BACKGROUND: Although oral immunotherapy (OIT) for food allergy is a reasonable treatment option, barriers to this procedure's implementation have not been extensively evaluated from a patient perspective. OBJECTIVE: We evaluated the barriers patients face during OIT administration, including anxiety and taste aversion, and the role of health care professionals, especially dietitians. METHODS: A survey in Canada and the United States involved families currently enrolled in food OIT programs. RESULTS: Of responses from 379 participants, fear of reaction was the most common barrier to OIT initiation, with 45.6% reporting it being a "very significant" barrier with other fears reported. However, taste aversion represented the prominent obstacle to continuation. Taste aversion was associated with a slower buildup (P = .02) and a reduction in dose (P = .002). Taste aversion was a strongly age-dependent barrier for initiation (P < .001) and continuation (P < .002), with older children over 6 years of age reporting it as a very significant barrier (P < .001). Boredom was reported as a concern for specific allergens such as peanut, egg, sesame, and hazelnuts (P < .05), emphasizing the need for diverse food options. Notably, 59.9% of respondents mixed OIT foods with sweet items. Despite these dietary concerns, dietitians were underutilized, with only 9.5% of respondents having seen a dietitian and the majority finding dietitian support helpful with greater certainty about the exact dose (P < .001). CONCLUSIONS: Taste aversion and anxiety represent primary patient-related barriers to OIT. Taste aversion was highly age dependent, with older patients being more affected. Dietitians and psychology support were underutilized, representing a critical target to improve adherence and OIT success.

Qualitative and quantitative spermatic cord abnormalities at CT predict symptomatic scrotal pathology.

PURPOSE: To evaluate quantitative and qualitative spermatic cord CT abnormalities and presence of unilateral or bilateral symptomatic scrotal pathology (SSP) at ultrasound. METHODS: This retrospective study included 122 male patients (mean age 47.8 years) undergoing scrotal ultrasound within 24 h of contrast-enhanced CT (n = 85), non-contrast CT (NECT, n = 32) or CT-Urogram (n = 5). CECT quantitative analysis assessed differential cord enhancement using maximum Hounsfield unit measurements. Three fellowship trained body radiologists independently assessed qualitative cord abnormalities for both CECT and NECT. Qualitative and quantitative findings were compared with the presence of SSP. Reader performance, interobserver agreement and reader confidence were assessed for NECT and CECT. Quantitative cutoff points were identified which maximized accuracy, specificity, negative predictive value, and other measures. RESULTS: SSP was present in 36/122 patients (29.5%). Positive cases were unilateral in 30 (83.3%) and bilateral in 6 (16.6%). At quantitative assessment, 25% differential cord enhancement had the highest diagnostic accuracy (88.9%), with 90.5% positive predictive value, 88.4% negative predictive value, 96.8% specificity, and 70.4% sensitivity. At qualitative evaluation, CECT reader performance was excellent (aggregate AUC = 0.86; P < .001); NECT was poorly discriminatory, although remained significant (aggregate AUC = 0.67; P = .002). Readers had significantly higher confidence levels with CECT (P < .001). Qualitative inter-observer agreement was high for both CECT and NECT (ICC = 0.981 and 0.963, respectively). CONCLUSION: Simple quantitative assessment of differential cord enhancement is highly accurate and specific for SSP at CECT. Qualitative abnormalities at CECT and NECT are also both predictors of SSP, however, CECT significantly out-performs non-contrast exams.

Dose-Dependent Tranexamic Acid Blunting of Penumbral Leukocyte Mobilization and Blood-Brain Barrier Permeability Following Traumatic Brain Injury: An In Vivo Murine Study.

BACKGROUND: Early posttraumatic brain injury (TBI) tranexamic acid (TXA) may reduce blood-brain barrier (BBB) permeability, but it is unclear if this effect is fixed regardless of dose. We hypothesized that post-TBI TXA demonstrates a dose-dependent reduction of in vivo penumbral leukocyte mobilization, BBB microvascular permeability, and enhancement of neuroclinical recovery. METHODS: CD1 male mice (n = 40) were randomly assigned to TBI by controlled cortical impact (injury [I]) or sham TBI (S), followed by intravenous bolus of either saline (placebo [P]) or TXA (15, 30, or 60 mg/kg). At 48 h, in vivo pial intravital microscopy visualized live penumbral BBB microvascular leukocytes and albumin leakage. Neuroclinical recovery was assessed by Garcia Neurological Test scores and animal weight changes at 24 h and 48 h after injury. RESULTS: I + TXA60 reduced live penumbral leukocyte rolling compared with I + P (p < 0.001) and both lower TXA doses (p = 0.017 vs. I + TXA15, p = 0.012 vs. I + TXA30). Leukocyte adhesion was infrequent and similar across groups. Only I + TXA60 significantly reduced BBB permeability compared with that in the I + P (p = 0.004) group. All TXA doses improved Garcia Test scores relative to I + P at both 24 h and 48 h (p < 0.001 vs. I + P for all at both time points). Mean 24-h body weight loss was greatest in the I + P (- 8.7 ± 1.3%) group and lowest in the I + TXA15 (- 4.4 ± 1.0%, p = 0.051 vs. I + P) group. CONCLUSIONS: Only higher TXA dosing definitively abrogates penumbral leukocyte mobilization, preserving BBB integrity post TBI. Some neuroclinical recovery is observed, even with lower TXA dosing. Better outcomes with higher dose TXA after TBI may occur secondary to blunting of leukocyte-mediated penumbral cerebrovascular inflammation.

The forensic imaging technique of age progression used within missing people cases: The Italian Missing Children association realizing age progression for Missing Child Kenya.

The age progression technique allows to update identification photos of individuals who have been missing for years. This method is based on the study of the facial variation and on the dynamics of facial growth. Knowledge about changes in the distribution of facial fat and the tone of the cartilage allows realistic predictions of the facial appearance after many years. Beside these elements, age progression is also supported by similar characters between family members. This is why photos of the missing and family members are used to create an age progression, making the new identikit accurate. Non-profit associations are crucial for the dissemination of information on the problem of missing persons. In Italy, the Italian Missing Children association provides for free an age progression service with the support of forensic anthropology. With the activation of a protocol, consisting of guidelines, and a form for the request for age progression by family members, the Italian Missing Children has started a collaboration with Missing Child Kenya. It allowed to disseminate up-to-date photos of the presumed current appearance of the missing children in Kenya. Thus, in the present study some cases are reported, in which age progression technique was applied. The photos provided by Italian Missing Children were shown in video documentaries made by Missing Child Kenya, allowing to continue the dissemination of age progression photo during the Covid quarantines and to keep the population active in the search for the missing.

Expanding the Spectrum of NR4A3 Fusion-Positive Gynecologic Leiomyosarcomas.

Recurrent gene fusions have been observed in epithelioid and myxoid variants of uterine leiomyosarcoma. PGR::NR4A3 fusions were recently described in a subset of epithelioid leiomyosarcomas exhibiting rhabdoid morphology. In this study, we sought to expand the clinical, morphologic, immunohistochemical, and genetic features of gynecologic leiomyosarcomas harboring NR4A3 rearrangements with PGR and novel fusion partners. We identified 9 gynecologic leiomyosarcomas harboring PGR::NR4A3, CARMN::NR4A3, ACTB::NR4A3, and possible SLCO5A1::NR4A3 fusions by targeted RNA sequencing. Tumors frequently affected premenopausal women, involving the uterine corpus, uterine cervix, or pelvis. All were similarly characterized by lobules of monomorphic epithelioid and/or spindled cells arranged in sheets, cords, trabeculae, and micro- and macrocysts associated with abundant myxoid matrix and hemorrhage, creating labyrinth-like or pulmonary edema-like architecture. Myogenic differentiation with frequent estrogen receptor and progesterone receptor staining and no CD10 expression characterized all tumors. All cases showed high NR4A3 RNA expression levels and NOR1 (NR4A3) nuclear staining similar to salivary gland acinic cell carcinomas and a subset of extraskeletal myxoid chondrosarcomas harboring NR4A3 rearrangements. NOR1 (NR4A3) immunohistochemistry may serve as a useful diagnostic marker of NR4A3 fusion-positive gynecologic leiomyosarcomas.

NNDB: An Expanded Database of Nearest Neighbor Parameters for Predicting Stability of Nucleic Acid Secondary Structures.

Nearest neighbor thermodynamic parameters are widely used for RNA and DNA secondary structure prediction and to model thermodynamic ensembles of secondary structures. The Nearest Neighbor Database (NNDB) is a freely available web resource (https://rna.urmc.rochester.edu/NNDB) that provides the functional forms, parameter values, and example calculations. The NNDB provides the 1999 and 2004 set of RNA folding nearest neighbor parameters. We expanded the database to include a set of DNA parameters and a set of RNA parameters that includes m6A in addition to the canonical RNA nucleobases. The site was redesigned using the Quarto open-source publishing system. A downloadable PDF version of the complete resource and downloadable sets of nearest neighbor parameters are available.

Father figure: Study of the age progression process from old pictures and its value in forensic sciences.

The application of age progression to the search for missing persons demonstrates its usefulness in being able to reconstruct the aged face based on the current age of a person who has been missing for many years. Age progression takes into account facial physiognomic elements and their changes over time. Based on these premises, the present study aims to investigate the evolution of somatic features, from childhood to adulthood, of one of the authors' father using photos at different ages of him. Sixteen photos were collected depicting an individual of Italian origin between the age of 1 and 72. The photos were processed in Adobe© Photoshop software to graphically highlight the shape development of individual physiognomic elements. The shape of the face, eyebrows, eyes, nose, mouth, and cheeks were analysed in detail using a morphological approach. The ageing processes that occurred in this case were discussed on the basis of the literature. The present study demonstrates the in-depth analysis of the dynamics of facial growth in a single case. Nonetheless, aging is different for each individual, so further studies are necessary to observe facial development on as many subjects as possible.

Chiral optical solitons in an electrically active multiferroic guiding structure.

A stack of a dielectric planar waveguide with a Kerr-type nonlinearity, sandwiched between two oxide-based helical multiferroic layers is shown to support electrically-controlled chiral solitons. These findings follow from analytical and full numerical simulations. The analytical scheme delivers explicit material parameters for the guided mode soliton and unveils how the soliton propagation characteristics are controlled by tuning the multiferroic helicity and amplitude of the injected electromagnetic wave. Silicon and CS2 are considered as the optical media in the guiding region enclosed by the multiferroic slabs. CS2 has very similar nonlinearity characteristics to silicon but in the linear regime it exhibits a smaller refractive index in the THz frequency range. The scattering simulations are performed using our developed numerical code based on the rigorous coupled wave method and the results for the dispersion curve for the guided mode agree very well with the analytical formula that we derive in this work. The results demonstrate a case of nonlinear pulse generation with field-controlled, nontrivial topological properties.