Search Results (66)

The activation of immunosuppressed antigen-presenting cells (APCs) in the tumor microenvironment is a key goal in modern cancer immunotherapy. Our laboratory utilizes a liposome-based immunotherapy platform that binds endogenous complement to deliver antigen, adjuvant, and therapeutic agents to APCs in vivo. The liposomes contain external linker groups, which readily bind complement protein C3, and mediate liposomal uptake via complement receptor 3 into APCs. To test the ability of a model antigen to bind to these external linker groups on C3-liposomes and elicit a robust adaptive immune response, we conjugated a modified ovalbumin peptide (OVA-C) to the liposomes and incorporated a toll-like receptor (TLR) 4 agonist, monophosphoryl lipid A (MPLA), in the liposomal membrane. Adaptive immune responses from C57BL/6 mice were analyzed by ELISA and ELISpot. Mice vaccinated with OVA-C liposomes elicited significantly greater humoral and cellular adaptive responses relative to controls. Furthermore, female mice vaccinated with MPLA + OVA-C liposomes produced significantly more IgG antibodies than males vaccinated with the same liposomes. In conclusion, antigen binding on the exterior of C3-liposomes markedly improves antigen loading efficiency and still allows for complement C3-targeted delivery to APCs. These data demonstrate the initiation of a robust cellular and humoral immune response using a new liposomal delivery platform. Full article

The ability to walk is often lost after neural injury, leading to multiple secondary complications that reduce quality of life and increase healthcare costs. The current rehabilitation interventions primarily focus on restoring leg movements through intensive training on a treadmill or using robotic devices, but ignore engaging the arms. Several groups have recently shown that simultaneous arm and leg (A&L) cycling improves walking function and interlimb connectivity. These findings highlight the importance of neuronal pathways between the arm (cervical) and leg (lumbar) control regions in the spinal cord during locomotion, and emphasize the need for activating these pathways to improve walking after neural injury or disease. While the findings to date provide important evidence about actively including the arms in walking rehabilitation, these strategies have yet to be optimized. Moreover, improvements beyond A&L cycling alone may be possible with conjunctive targeted strategies to enhance spinal interlimb connectivity. The aim of this review is to highlight the current evidence for improvements in walking function and neural interlimb connectivity after neural injury or disease with cycling-based rehabilitation paradigms. Furthermore, strategies to enhance the outcomes of A&L cycling as a rehabilitation strategy are explored. These include the use of functional electrical stimulation-assisted cycling in acute care settings, utilizing non-invasive transcutaneous spinal cord stimulation to activate previously inaccessible circuitry in the spinal cord, and the use of paired arm and leg rehabilitation robotics. This review aims to consolidate the effects of exercise interventions that incorporate the arms on improved outcomes for walking, functional mobility, and neurological integrity, underscoring the importance of integrating the arms into the rehabilitation of walking after neurological conditions affecting sensorimotor function. Full article

Relativistic quantum metrology provides a framework within which we can quantify the quality of measurement and estimation procedures while accounting for both quantum and relativistic effects. The chief measure for describing such procedures is the Fisher information, which quantifies how sensitive a given estimation is to a variance in some underlying parameter. Recently, the Fisher information has been used to quantify the spacetime information accessible to two-level quantum particle detectors. We have previously shown that such a system is capable of discerning black hole mass for static black holes in 2 + 1 dimensions. Here, we extend these results to the astrophysically interesting case of rotating black holes and show that the Fisher information is also sensitive to the rotation of a black hole. Full article

Background: Mucin-1 (MUC1) is a glycoprotein that is hypoglycosylated and overexpressed in most adenocarcinomas, making it a promising target for cancer vaccines. Our group previously demonstrated that C3 (OPSS)-liposomes enhance antigen uptake by antigen-presenting cells (APCs) via the complement C3 pathway and, when combined with toll-like receptor (TLR) agonists, reduce tumor growth in murine cancer models. Methods: In the present study, we evaluate the immunogenicity of MUC1 peptide vaccines encapsulated in C3-liposomes, with and without TLR agonists, using MUC1-tolerant transgenic mice challenged with Lewis lung carcinoma (LLC.MUC1) cells. To assess vaccine effectiveness, tumor volumes were measured, and flow cytometry and ELISA and ELISPOT assays were used to assess the immune response. Results: Both male and female C57BL/6 transgenic mice vaccinated with MUC1 C3-liposomes developed significantly smaller tumors than those vaccinated with free MUC1 peptide or PBS. Notably, a sex-dependent response emerged in mice vaccinated with MUC1 C3-liposomes with TLR agonists (TLR4, TLR7/8, and TLR9); male mice exhibited greater tumor suppression than females. Flow cytometry analysis revealed that female mice had significantly higher levels of CD11b⁺, LY6C⁺, and LY6G⁺ MDSC cells, suggesting a potential mechanism for the sex difference. Additionally, MUC1 C3-liposome vaccination elicited robust adaptive immune responses, including significantly higher levels of IFN-γ-producing T cells and MUC1-specific IgG antibodies compared to non-encapsulated MUC1 or TLR adjuvant-only formulations. Conclusions: These findings underscore the potential of C3-liposome-based antigen vaccines to enhance anti-tumor immunity and highlight the impact of sex differences in vaccine efficacy. Full article

Background: Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy (HCM) remains challenging. Late gadolinium enhancement (LGE) on cardiac MRI signifies myocardial fibrosis and is linked to adverse outcomes in HCM. However, the threshold of LGE that is clinically significant remains a subject of debate. We hypothesized that even small amounts of LGE (≥ 5%) or a history of syncope are associated with worse outcomes. Methods: Between May 2018 and June 2023, HCM patients were prospectively enrolled at the Medical University of Vienna, Austria, a tertiary referral center. The primary endpoint was a composite of new-onset ventricular tachycardia, appropriate ICD therapy, and all-cause mortality. Results: In total, 230 patients were included. The median age of patients was 56 (IQR 44, 64) years, 40% (n = 94) were female, and 43% (n = 84) had significant left ventricular outflow tract obstruction (LVOTO). Over a median follow-up of 3.2 years, 29 patients (13%) met the composite endpoint. While the ESC HCM risk score was not associated with the primary endpoint, both LGE > 5% (Adj. HR 6.16) and a history of at least one syncope (Adj. HR 3.40) were independently associated with the primary endpoint. These associations were consistent across patients with and without LVOTO. Conclusions: In conclusion, our findings indicate that the combination of a history of syncope together with small amounts of LGE (≥ 5%) in cardiac MRI are associated with unfavorable clinical outcomes in HCM patients Full article

For several decades, dopamine agonist therapy has been the mainstay of treatment for prolactinomas, with surgery generally considered a second line for cases failing medical therapy due to intolerance or resistance. There is increasing recognition of the burden of long-term DA therapy; many patients experience debilitating side effects, and emerging evidence demonstrates that the prevalence of impulse control disorders has been vastly underreported. Long-term DA therapy is associated with significant costs to patients and healthcare systems, which is projected to exceed that of surgery in many circumstances. Recent advancements in surgical approaches, including endoscopic transsphenoidal surgery, have led to improved surgical outcomes (82–100% remission rates; serious complication rates < 2%), prompting a reappraisal of the role of surgery for prolactinoma. Favourable surgical outcomes have been observed in both remission and complication rates for microprolactinomas and well-circumscribed macroprolactinomas, leading to consideration of surgery as an earlier, or first-line, option in the treatment paradigm. Potential advantages of surgical management should be weighed against institutional case volume and expertise, the risk of perioperative complications, and the need for adjuvant medical therapy post-operatively. Ultimately, patients and care-providers should engage in shared decision-making following informed discussion about the risks and benefits of both medical and surgical approaches. Full article

Leptospirosis, a global zoonotic disease caused by Leptospira spp., presents high morbidity and mortality risks, especially in tropical regions like Thailand. Military personnel deployed in endemic areas, such as during the Cobra Gold Joint exercise, face heightened exposure. This study assessed Leptospira’s prevalence in rodents and environmental reservoirs at military training sites from 2017 to 2022. A surveillance program was conducted at Engineering Civil Assistance Program (ENCAP) training sites using real-time PCR, dark-field microscopy, and 16S rRNA gene sequencing to detect Leptospira in rodents and environmental samples. Results showed a 1.3% infection rate in rodents (15 of 1161), while Leptospira was detected in 10.2% of water samples (42 of 413) and 23.1% of soil samples (30 of 130). Diverse Leptospira interrogans strains circulated among rodents, and three groups of naturally circulating Leptospira strains were detected in environmental reservoirs. These findings underscore Leptospira’s survival and transmission potential within exercise sites, informing Force Health Protection (FHP) decisions. By integrating pre-exercise data on primary hosts and environmental reservoirs with historical local outbreak records and research on risk factors, this study identifies key areas for public health intervention and potential mitigation strategies. Full article

Sexual minority women (e.g., lesbian, bisexual, pansexual) have increased risk of experiencing various mental health problems compared to sexual minority men and heterosexual individuals. Sexual minority women (SMW) have also been found to have lower self-esteem than heterosexual women, which could contribute to poorer mental health. Previous findings suggest that role models could potentially be used to improve LGBTQ+ wellbeing. The current exploratory study investigated SMW’s experiences about the impact of role models or the lack of them and their views about how role models could be used to increase the self-esteem of SMW in potential interventions. Semi-structured qualitative interviews were conducted with 17 SMW. Using thematic analyses, four themes about characteristics of role models were developed: “Similar to me”, “Self-confident about being different”, “Strong and kind”, and “Source of learning and support”. Three themes about the impact of role models were identified: “Increased self-esteem”, “Inspiring personal growth”, and “Lack of role models: I don’t belong”. Content analyses indicated a wide range of ideas about how role models could be used within individual or group self-esteem interventions. Future research could apply these findings to develop or enhance interventions to increase the self-esteem of SMW. Full article

In 2021, the World Health Organization classified isocitrate dehydrogenase (IDH) mutant gliomas as a distinct subgroup of tumors with genetic changes sufficient to enable a complete diagnosis. Patients with an IDH mutant glioma have improved survival which has been further enhanced by the advent of targeted therapies. IDH enzymes contribute to cellular metabolism, and mutations to specific catalytic residues result in the neomorphic production of D-2-hydroxyglutarate (D-2-HG). The accumulation of D-2-HG results in epigenetic alterations, oncogenesis and impacts the tumor microenvironment via immunological modulations. Here, we summarize the molecular, cellular, and clinical implications of IDH mutations in gliomas as well as current diagnostic techniques. Full article

The development of a sensitive and specific blood test for the early detection of breast cancer is crucial to improve screening and patient outcomes. Existing methods, such as mammography, have limitations, necessitating the exploration of alternative approaches, including circulating factors. Using 598 prospectively collected blood samples, a multivariate plasma-derived lipid biomarker signature was developed that can distinguish healthy control individuals from those with breast cancer. Liquid chromatography with high-resolution and tandem mass spectrometry (LC-MS/MS) was employed to identify lipids for both extracellular vesicle-derived and plasma-derived signatures. For each dataset, we identified a signature of 20 lipids using a robust, statistically rigorous feature selection algorithm based on random forest feature importance applied to cross-validated training samples. Using an ensemble of machine learning models, the plasma 20-lipid signature generated an area under the curve (AUC) of 0.95, sensitivity of 0.91, and specificity of 0.79. The results from this study indicate that lipids extracted from plasma can be used as target analytes in the development of assays to detect the presence of early-stage breast cancer. Full article

Hamstring injuries (HSIs) are prevalent in sports that involve changes in direction, kicking, and sprinting. These injuries are a major cause of time lost from competition, practice, and training, as well as increased healthcare costs. In a Division I collegiate football program, the authors implemented a multifactorial approach that included repeated performance assessments, detailed data analysis, and a flexible strength and conditioning regimen. Over a three-year period, this resulted in no game time loss due to HSI. This model can be adapted and implemented across sports settings. Full article

The Module-0 Demonstrator is a single-phase 600 kg liquid argon time projection chamber operated as a prototype for the DUNE liquid argon near detector. Based on the ArgonCube design concept, Module-0 features a novel 80k-channel pixelated charge readout and advanced high-coverage photon detection system. In this paper, we present an analysis of an eight-day data set consisting of 25 million cosmic ray events collected in the spring of 2021. We use this sample to demonstrate the imaging performance of the charge and light readout systems as well as the signal correlations between the two. We also report argon purity and detector uniformity measurements and provide comparisons to detector simulations. Full article

Corneal transparency and avascularity are essential for vision. The avascular cornea transitions into the vascularized conjunctiva at the limbus. Here, we explore a limbal stromal cell sub-population that expresses ABCB5 and has mesenchymal stem cell characteristics. Human primary corneal stromal cells were enriched for ABCB5 by using FACS sorting. ABCB5+ cells expressed the MSC markers CD90, CD73, and CD105. ABCB5+ but not ABCB5− cells from the same donor displayed evidence of pluripotency with a significantly higher colony-forming efficiency and the ability of trilineage differentiation (osteogenic, adipogenic, and chondrogenic). The ABCB5+ cell secretome demonstrated lower levels of the pro-inflammatory protein MIF (macrophage migration inhibitory factor) as well as of the pro-(lymph)angiogenic growth factors VEGFA and VEGFC, which correlated with reduced proliferation of Jurkat cells co-cultured with ABCB5+ cells and decreased proliferation of blood and lymphatic endothelial cells cultured in ABCB5+ cell-conditioned media. These data support the hypothesis that ABCB5+ limbal stromal cells are a putative MSC population with potential anti-inflammatory and anti-(lymph)angiogenic effects. The therapeutic modulation of ABCB5+ limbal stromal cells may prevent cornea neovascularization and inflammation and, if transplanted to other sites in the body, provide similar protective properties to other tissues. Full article

Onychomycosis is a recalcitrant fungal infection of the nail unit that can lead to secondary infections and foot complications. Accurate pathogen identification by confirmatory testing is recommended to improve treatment outcomes. In this study, we reviewed the records of 710,541 patients whose nail specimens were sent to a single molecular diagnostic laboratory between 2015 and 2024. PCR testing revealed a more comprehensive spectrum of pathogens than previously reported, which was corroborated by the demonstration of fungal invasion on histopathology. Consistent with our current understanding, the T. rubrum complex (54.3%) are among the most common pathogens; however, a significant portion of mycology-confirmed diagnoses were caused by the T. mentagrophytes complex (6.5%), Aspergillus (7.0%) and Fusarium (4.5%). Females were significantly more likely to be infected with non-dermatophytes molds (NDMs; OR: 2.0), including Aspergillus (OR: 3.3) and Fusarium (OR: 2.0), and yeasts (OR: 1.5), including Candida albicans (OR: 2.0) and C. parapsilosis (OR 1.6), than males. The T. mentagrophytes complex became more prevalent with age, and conversely the T. rubrum complex became less prevalent with age. Patients aged ≥65 years also demonstrated a higher likelihood of contracting onychomycosis caused by NDMs (OR: 1.6), including Aspergillus (OR: 2.2), Acremonium (OR: 3.5), Scopulariopsis (OR: 2.9), Neoscytalidium (OR: 3.8), and yeasts (OR: 1.8), including C. albicans (OR: 1.9) and C. parapsilosis (OR: 1.7), than young adults. NDMs (e.g., Aspergillus and Fusarium) and yeasts were, overall, more likely to cause superficial onychomycosis and less likely to cause dystrophic onychomycosis than dermatophytes. With regards to subungual onychomycosis, Aspergillus, Scopulariopsis and Neoscytalidium had a similar likelihood as dermatophytes. The advent of molecular diagnostics enabling a timely and accurate pathogen identification can better inform healthcare providers of appropriate treatment selections and develop evidence-based recommendations. Full article

During animal embryogenesis, one of the earliest specification events distinguishes extraembryonic (EE) from embryonic tissue fates: the serosa in the case of the insects. While it is well established that the homeodomain transcription factor Zen1 is the critical determinant of the serosa, the subsequent realization of this tissue’s identity has not been investigated. Here, we examine serosal differentiation in the beetle Tribolium castaneum based on the quantification of morphological and morphogenetic features, comparing embryos from a Tc-zen1 RNAi dilution series, where complete knockdown results in amnion-only EE tissue identity. We assess features including cell density, tissue boundary morphology, and nuclear size as dynamic readouts for progressive tissue maturation. While some features exhibit an all-or-nothing outcome, other key features show dose-dependent phenotypic responses with trait-specific thresholds. Collectively, these findings provide nuance beyond the known status of Tc-Zen1 as a selector gene for serosal tissue patterning. Overall, our approach illustrates how the analysis of tissue maturation dynamics from live imaging extends but also challenges interpretations based on gene expression data, refining our understanding of tissue identity and when it is achieved. Full article