Search Results (44)

Background and aims: Recent advances in acute stroke interventions have highlighted the importance of accurate determination of infarct volume in the evaluation of acute stroke patients, carrying important prognostic and therapeutic implications for treatment planning, outcome prediction, and evaluation of the success of therapeutic interventions. However, there is no consensus on the methodologies employed to measure cerebral infarct volume. We aimed to assess the reproducibility and reliability of methods employed in the clinical determination of infarct volume in acute ischaemic stroke. Methods: We carried out a systematic review of studies assessing methodologies for the determination of infarct volume in the acute phase (<24 h). We searched Medline PubMed, Scopus, Cinahl, Cochrane Library, Web of Science, and Embase for studies examining image-based diagnosis of acute ischaemic stroke < 24 h by CT or MRI. Data on patient cohorts, imaging type, time from symptoms onset, methodologies and quantification strategies, rater reliability, accuracy, sensitivity, and specificity were compared. Results: We identified eighteen eligible studies with a total of 3298 ischaemic stroke patients assessing a variety of manual, semi-automated, and fully-automated methods. The ABC/2 method was found to be highly reliable, reproducible, and accurate, and provides the best manual estimate of infarction, but has a tendency to under- or overestimate infarct volume. Semi-automated and automated approaches with user refinement showed excellent inter-rater and intra-rater correlation. However, differences in operating algorithms and lack of standardisation of image acquisition parameters, quality, and format may impact performance and reproducibility. Conclusions: Of all methods, automated and semi-automated approaches utilising rater judgment and refinement represent the most robust approaches, with semi-automated tools demonstrating consistent and repeatable results. We recommend a standardised reporting of study methodologies for the accurate interpretation and comparison of efficacy of therapeutic interventions and patient outcomes, especially in a multi-centre setting. This may allow for more effective evaluation of stroke therapies and accelerate ischaemic stroke treatment decisions. Full article

Background and Purpose: Accurate and reproducible methods for assessing infarct volume in acute ischaemic stroke have important therapeutic and prognostic implications for the choice and success of acute therapeutic interventions. However, there is no international consensus on the methodology employed in infarct volume assessment. We aimed to assess the reliability of the ABC/2 score and e-ASPECTS in the determination of infarct volume in acute ischaemic stroke. Methods: Infarct volume was measured from NCCT in stroke patients recruited ≤12 h of symptoms onset and at 24 h using the ABC/2 method. Automated ischaemic volume measurements were carried out using e-ASPECTS software. Measurements using ABC/2 were compared with e-ASPECTS to assess volume differences and reliability using Lin’s concordance correlation coefficient. Results: Thirty-three patients with CT < 12 h from onset of symptoms and follow-up at 24 h were included in the analysis. Use of ABC/2 demonstrated low agreement between observers (0.490, CI 0.236–0.743, p < 0.001) on admission (<12 h). High agreement was found between observers at 24 h (0.724, CI 0.564–0.884, p < 0.001). High agreement was observed between the mean observed infarct volumes using ABC/2 and e-ASPECTS on admission (0.794, CI 0.691–0.898, p < 0.001). Conclusions: Our results suggest that e-ASPECTS is a reliable platform for ischaemic volume determination particularly in the hyperacute phase to inform management. However, the use of ABC/2 represents an alternative approach to e-ASPECTS in the rapid and reliable estimation of ischaemic infarct volume to inform prognosis and treatment decisions, particularly in cases of delayed presentation where infarction is established and arterial territory boundaries are easily identifiable. Full article

Background/Objectives: Immunocytokines (ICKs) are antibody–cytokine fusion proteins that deliver cytokines directly to tumors to increase immune responses, which are otherwise absent or limited by the delivery of antibodies alone. Tumor-associated glycoprotein-72 (TAG72) is overexpressed in numerous solid tumors. Methods: An anti-TAG72-IL-2 fusion protein was expressed in mammalian cells and tested in vitro for binding and bioactivity, and in vivo in two models. Results: In vitro studies showed high antigen specificity against TAG-72-positive tumor cell lines and IL-2 activity in CD25 (IL-2R)-positive reporter cells. To study the anti-tumor activity of huCC49-IL-2 in an immunocompetent model, the TAG-72 expression was established in murine mammary and colorectal cells by transfection with murine st6galnac-I gene (mSTn). Four daily doses of anti-TAG72-IL-2 monotherapy for TAG-72-expressing orthotopic murine mammary tumors in immunocompetent mice resulted in minimal whole-body toxicity and significant tumor growth reduction mediated by tumor infiltration of IFNγ⁺ CD8⁺ T cells. When mammary tumors were pretreated with image-guided fractionated radiation therapy (IGRT) followed by anti-TAG72-IL-2 therapy, an improved tumor growth inhibition was observed along with an increased tumor infiltration of IFNγ⁺ CD8⁺ T cells and a significant reduction in Foxp3⁺ CD4⁺ cells. Anti-TAG72-IL-2 monotherapy in TAG-72⁺ colorectal tumors led to a significant tumor reduction but also cures (4/7), with a rejection of rechallenges with both TAG-72-positive and -negative MC38 cells, thus demonstrating evidence of immune memory and antigen spreading. Conclusions: antiTAG-72-IL-2 therapy showed strong anti-tumor effects driven by activated CD8⁺ T cells making it a promising approach to the treatment of TAG-72⁺ tumors. Full article

On 4 September 2024, the Reagan-Udall Foundation for the FDA (FDA Foundation) in collaboration with the Food and Drug Administration (FDA) and the Gates Foundation hosted a workshop titled “Scientific Advancements in Gene Therapies: Opportunities for Global Regulatory Convergence”. The event brought together a diverse group of experts, including international regulatory bodies, regulated industries, healthcare professionals, patients, academic researchers and global health advocates, to discuss the rapid advancements in gene therapy and the pressing need for equitable access in low-and middle-income countries (LMICs), with sickle cell disease (SCD) serving as the model disorder for the discussions. Although there has been significant progress in gene therapy, such as breakthroughs in clustered regularly interspaced short palindromic repeats (CRISPR)-based technologies and FDA-approved therapies, access to these therapies remain limited in underresourced regions. The workshop addressed critical challenges, including the high cost of therapies, regulatory gaps and barriers and ethical concerns regarding informed consent and public engagement in LMICs. This paper highlights the critical discussion points from the workshop with a focus on exploring strategies for global regulatory convergence, the role of international collaborations and the potential pathways to making gene therapies affordable and accessible to all. Full article

The complex interwoven crises of climate disruption and biodiversity loss demand not only rapid technological innovation for sustainable development but also major shifts in consumption and behaviour, implying a need for responses rooted in ethical values and a reorientation of attitudes towards the more-than-human world. In this context, given the global significance of faith communities and institutions as motivators and moral authorities, it is important that faith leaders state the challenges for sustainable development and suggest pathways forward to protect the environment and people that live in it. Building on his landmark encyclical of 2015, Laudato Si’, Pope Francis issued Laudate Deum, an apostolic exhortation on the climate crisis, and followed this up with a message to COP 28 for leaders to show leadership in facing up to the climate challenge. We argue that the interventions of Pope Francis point to the crucial importance of an approach to sustainable development that can integrate faith perspectives on social and ecological ethics with the knowledge generated by the natural sciences and by environmental systems science. The interdependence revealed by the emerging scientific understanding of human, animal, and ecosystem life implies the bioethics of care and stewardship, which have the potential to bring people together across religious and disciplinary divides. Unlike other analyses, we argue that it is important to understand how life was created if we are to care for it effectively and sustainably. We also put forward the case for more sustainable land use and the production of more sustainable foods. This article is written from the perspective of the Catholic Church, including its approach to moral theology, but we argue that the implications of the analysis are relevant to all faith communities and religious institutions seeking to promote sustainable development. Full article

Prostate cancer remains a significant global health concern, with over 1.4 million new cases diagnosed and more than 330,000 deaths each year. The primary clinical challenge that contributes to poor patient outcomes involves the failure to accurately predict and treat at the onset of metastasis, which remains an incurable stage of the disease. This review discusses the emerging paradigm that prostate cancer metastasis is driven by a dysregulation of critical molecular machinery that regulates endosome-lysosome homeostasis. Endosome and lysosome compartments have crucial roles in maintaining normal cellular function but are also involved in many hallmarks of cancer pathogenesis, including inflammation, immune response, nutrient sensing, metabolism, proliferation, signalling, and migration. Here we discuss new insight into how alterations in the complex network of trafficking machinery, responsible for the microtubule-based transport of endosomes and lysosomes, may be involved in prostate cancer progression. A better understanding of endosome-lysosome dynamics may facilitate the discovery of novel strategies to detect and manage prostate cancer metastasis and improve patient outcomes. Full article

Competition between bacterial species is a major factor shaping microbial communities. It is possible but remains largely unexplored that competition between bacterial pathogens can be mediated through antagonistic effects of bacterial effector proteins on host systems, particularly the actin cytoskeleton. Using Salmonella Typhimurium invasion into cells as a model, we demonstrate that invasion is inhibited if the host actin cytoskeleton is disturbed by actin-specific toxins, namely, Vibrio cholerae MARTX actin crosslinking (ACD) and Rho GTPase inactivation (RID) domains, Photorhabdus luminescens TccC3, and Salmonella’s own SpvB. We noticed that ACD, being an effective inhibitor of tandem G-actin-binding assembly factors, is likely to inhibit the activity of another Vibrio effector, VopF. In reconstituted actin polymerization assays and by live-cell microscopy, we confirmed that ACD potently halted the actin nucleation and pointed-end elongation activities of VopF, revealing competition between these two V. cholerae effectors. These results suggest that bacterial effectors from different species that target the same host machinery or proteins may represent an effective but largely overlooked mechanism of indirect bacterial competition in host-associated microbial communities. Whether the proposed inhibition mechanism involves the actin cytoskeleton or other host cell compartments, such inhibition deserves investigation and may contribute to a documented scarcity of human enteric co-infections by different pathogenic bacteria. Full article

This study examines the complex interplay of genetic and environmental interactions that shape chronic illness risk. Evidence is mounting for the role of genetic expression and the immune response in the pathogenesis of chronic disease. In the Rio Grande Valley of south Texas, where 90% of the population is Mexican American, chronic illnesses (including obesity, diabetes, nonalcoholic liver disease, and depression) are reaching epidemic proportions. This study leverages an ongoing family study of the genetic determinants of risk for obesity, diabetes, hypertension, hyperlipidemia, and depression in a Mexican American population. Data collected included blood pressure, BMI, hepatic transaminases, HbA1c, depression (BDI-II), acculturation/marginalization (ARSMA-II), and liver health as assessed by elastography. Heritability and genotype-by-environment (G×E) interactions were analyzed, focusing on the marginalization/separation measure of the ARSMA-II. Significant heritabilities were found for traits such as HbA1c (h² = 0.52), marginalization (h² = 0.30), AST (h² = 0.25), ALT (h² = 0.41), and BMI (h² = 0.55). Genotype-by-environment interactions were significant for HbA1c, AST/ALT ratio, BDI-II, and CAP, indicating that genetic factors interact with marginalization to influence these traits. This study found that acculturation stress exacerbates the genetic response to chronic illness. These findings underscore the importance of considering G×E interactions in understanding disease susceptibility and may inform targeted interventions for at-risk populations. Further research is warranted to elucidate the underlying molecular pathways and replicate these findings in diverse populations. Full article

Currently, more than 55 million people around the world suffer from dementia, and Alzheimer’s Disease and Related Dementias (ADRD) accounts for nearly 60–70% of all those cases. The spread of Alzheimer’s Disease (AD) pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of ADRD’s causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA), in the induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that the NSCs’ ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR-corrected p-value ≤ 0.05 and fold change absolute ≥ 2.0) differentially expressed (DE). The pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways, protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF-6), and inositol-requiring enzyme-1 (IRE1), were significantly activated and cooperatively regulated the NSCs’ transcriptional response to ER stress. Our results show that IRE1/X-box binding protein 1 (XBP1) mediated transcriptional regulation of the E2F transcription factor 1 (E2F1) gene, and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in ER stress-challenged NSCs. The ER stress-challenged NSCs also showed the activation of C/EBP homologous protein (CHOP)-mediated apoptosis and the dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that the ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD. Full article

Statistical genetic models of genotype-by-environment (G×E) interaction can be divided into two general classes, one on G×E interaction in response to dichotomous environments (e.g., sex, disease-affection status, or presence/absence of an exposure) and the other in response to continuous environments (e.g., physical activity, nutritional measurements, or continuous socioeconomic measures). Here we develop a novel model to jointly account for dichotomous and continuous environments. We develop the model in terms of a joint genotype-by-sex (for the dichotomous environment) and genotype-by-social determinants of health (SDoH; for the continuous environment). Using this model, we show how a depression variable, as measured by the Beck Depression Inventory-II survey instrument, is not only underlain by genetic effects (as has been reported elsewhere) but is also significantly determined by joint G×Sex and G×SDoH interaction effects. This model has numerous applications leading to potentially transformative research on the genetic and environmental determinants underlying complex diseases. Full article

COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly impacted public health and the economy worldwide. Most of the currently licensed COVID-19 vaccines act by inhibiting the receptor-binding function of the SARS-CoV-2 spike protein. The constant emergence of SARS-CoV-2 variants resulting from mutations in the receptor-binding domain (RBD) leads to vaccine immune evasion and underscores the importance of broadly acting COVID-19 vaccines. Inactivated whole virus vaccines can elicit broader immune responses to multiple epitopes of several antigens and help overcome such immune evasions. We prepared a psoralen-inactivated SARS-CoV-2 vaccine (SARS-CoV-2 PsIV) and evaluated its immunogenicity and efficacy in nonhuman primates (NHPs) when administered with the Advax-CpG adjuvant. We also evaluated the SARS-CoV-2 PsIV as a booster shot in animals vaccinated with a DNA vaccine that can express the full-length spike protein. The Advax-CpG-adjuvanted SARS-CoV-2 PsIV elicited a dose-dependent neutralizing antibody response in the NHPs, as measured using a serum microneutralization assay against the SARS-CoV-2 Washington strain and the Delta variant. The animals vaccinated with the DNA vaccine followed by a boosting dose of the SARS-CoV-2 PsIV exhibited the highest neutralizing antibody responses and were able to quickly clear infection after an intranasal challenge with the SARS-CoV-2 Delta variant. Overall, the data show that the Advax-CpG-adjuvanted SARS-CoV-2 PsIV, either by itself or as a booster shot following nucleic acid (NA) vaccines, has the potential to protect against emerging variants. Full article

Traumatic heterotopic ossification (HO) is frequently observed in Service Members following combat-related trauma. Estimates suggest that ~65% of wounded warriors who suffer limb loss or major extremity trauma will experience some type of HO formation. The development of HO delays rehabilitation and can prevent the use of a prosthetic. To date there are limited data to suggest a standard mechanism for preventing HO. This may be due to inadequate animal models not producing a similar bone structure as human HO. We recently showed that traumatic HO growth is possible in an ovine model. Within that study, we demonstrated that 65% of sheep developed a human-relevant hybrid traumatic HO bone structure after being exposed to a combination of seven combat-relevant factors. Although HO formed, we did not determine which traumatic factor contributed most. Therefore, in this study, we performed individual and various combinations of surgical/traumatic factors to determine their individual contribution to HO growth. Outcomes showed that the presence of mature biofilm stimulated a large region of bone growth, while bone trauma resulted in a localized bone response as indicated by jagged bone at the linea aspera. However, it was not until the combinatory factors were included that an HO structure similar to that of humans formed more readily in 60% of the sheep. In conclusion, data suggested that traumatic HO growth can develop following various traumatic factors, but a combination of known instigators yields higher frequency size and consistency of ectopic bone. Full article

Elite football is associated with the increased risk of illness, although targeted supplementation can reduce illness risk. This study assessed the effects of a supplement containing turmeric root within a black pepper and fat-soluble blend, vitamin C and vitamin D, on upper respiratory symptoms (URS), gastrointestinal symptoms (GIS), muscle soreness, and markers of inflammation and gut permeability in elite male footballers. Twenty-three footballers completed 3 weeks of no intervention (CON), followed by 16 weeks of daily consuming 60 mL of a commercially available supplement containing raw turmeric root (17.5 g, estimated to contain 700 mg of curcumin), vitamin C (1000 mg), and vitamin D3 (3000 IU/75 mcg) (SUP). URS and GIS were measured daily. Immediately (0 h), 40, and 64 h after six competitive matches (two in CON, four in SUP), the subjective soreness and plasma concentrations of creatine kinase [CK], c-reactive protein [CRP], and intestinal fatty-acid binding protein [I-FABP] were assessed. URS incidence (p < 0.001), GIS (p < 0.05), and plasma [I-FABP] at 0 h (p < 0.05) were greater during CON versus SUP. At 40 h, [CRP] was greater than 0 h during CON (p < 0.01) but not SUP (p = 0.204). There were no differences in soreness or [CK]. This study indicates that turmeric root, vitamin C, and vitamin D supplementation over 16 weeks can reduce URS, GIS, and post-match [I-FABP] in elite footballers. Full article

Background: This study aimed to determine the prevalence of potentially inappropriate prescribing (PIP) and potential prescribing omissions (PPOs) and their association with ADR-related hospital admissions in patients aged ≥ 65 years admitted acutely to the hospital. Methods: Information on medications and morbidities was extracted from the Adverse Drug Reactions in an Ageing Population (ADAPT) cohort (N = 798: N = 361 ADR-related admissions; 437 non-ADR-related admissions). PIP and PPOs were assessed using Beers Criteria 2019 and STOPP/START version 2. Multivariable logistic regression (adjusted odds ratios (aOR), 95%CI) was used to examine the association between PIP, PPOs and ADR-related admissions, adjusting for covariates (age, gender, comorbidity, polypharmacy). Results: In total, 715 (90%; 95% CI 87–92%) patients had ≥1 Beers Criteria, 555 (70%; 95% CI 66–73%) had ≥ 1 STOPP criteria and 666 patients (83%; 95% CI 81–86%) had ≥ 1 START criteria. Being prescribed at least one Beers (aOR = 1.66, 95% CI = 1.00–2.77), or meeting STOPP (aOR = 1.07, 95% CI = 0.79–1.45) or START (aOR = 0.72; 95%CI = 0.50–1.06) criteria or the number of PIP/PPO criteria met was not significantly associated with ADR-related admissions. Patients prescribed certain drug classes (e.g., antiplatelet agents, diuretics) per individual PIP criteria were more likely to have an ADR-related admission. Conclusion: There was a high prevalence of PIP and PPOs in this cohort but no association with ADR-related admissions. Full article

Antibody–drug conjugates (ADCs) constitute a rapidly expanding category of biopharmaceuticals that are reshaping the landscape of targeted chemotherapy. The meticulous process of selecting therapeutic targets, aided by specific monoclonal antibodies’ high specificity for binding to designated antigenic epitopes, is pivotal in ADC research and development. Despite ADCs’ intrinsic ability to differentiate between healthy and cancerous cells, developmental challenges persist. In this study, we present a rationalized pipeline encompassing the initial phases of the ADC development, including target identification and validation. Leveraging an in-house, computationally constructed ADC target database, termed ADC Target Vault, we identified a set of novel ovarian cancer targets. We effectively demonstrate the efficacy of Surface Plasmon Resonance (SPR) technology and in vitro models as predictive tools, expediting the selection and validation of targets as ADC candidates for ovarian cancer therapy. Our analysis reveals three novel robust antibody/target pairs with strong binding and favourable antibody internalization rates in both wild-type and cisplatin-resistant ovarian cancer cell lines. This approach enhances ADC development and offers a comprehensive method for assessing target/antibody combinations and pre-payload conjugation biological activity. Additionally, the strategy establishes a robust platform for high-throughput screening of potential ovarian cancer ADC targets, an approach that is equally applicable to other cancer types. Full article