Delivery Mechanism Research Articles

Abstract 4011: Locoregional GPC3 chimeric antigen receptor (CAR)-T cell therapy is associated with improved tumor control in hepatocellular carcinoma by enhancing CAR-T cell trafficking and functionality

Abstract Despite the rapid development of anti-cancer immunotherapy, the prognosis of hepatocellular carcinoma (HCC) patients is far from satisfactory. Glypican-3 (GPC3) CAR-T cell therapy has shown varied patient response. One of the potential reasons of low response rates may be due to the limited CAR-T cell infiltration. Therefore, locoregional GPC3 CAR-T therapy has been a promising option, with a hope of enhancing CAR-T cell tumor penetration. In this study, the therapeutic efficacy and underlying mechanisms of locoregional GPC3 CAR-T cell delivery were explored using HCC mouse xenografts. Orthotopic NOD-scid IL2Rgnull (NSG) HCC models were established by tumor fragment implantation into the liver. CAR-T cell injections were performed via the tail vein and portal vein to simulate systemic and locoregional administrations, respectively. Compared to the systemic treatment, locoregional therapy could better control the tumor growth, and was associated with improved liver function. In addition, the locoregional therapy group demonstrated a higher percentage of tumor-infiltrating CAR-T cells which showed an increased expression level of the cytotoxicity marker GZMB and a reduced level of the exhaustion marker LAG3. Moreover, significantly higher IFN-gamma level was found in the blood of the locoregional therapy group, indicating a better CAR-T cell functionality. In conclusion, we have demonstrated that locoregional administration of CAR-T cells is associated with increased CAR-T cell infiltration and better therapeutic efficacy. Additionally, CAR-T cells being injected locoregionally are correlated with enhanced functionality and reduced exhaustion phenotype. These findings highlight the potential of locoregional GPC3 CAR-T therapy as a promising treatment strategy for HCC patients. Citation Format: Jue Wang, Kinching Tsang, Jiale Qiu, Bo Feng. Locoregional GPC3 chimeric antigen receptor (CAR)-T cell therapy is associated with improved tumor control in hepatocellular carcinoma by enhancing CAR-T cell trafficking and functionality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4011.

Gaps and opportunities in addressing the needs of older adults in the Philippines and Vietnam: a qualitative exploration of health and social workers' experiences in urban care settings.

Despite numerous government initiatives, concerns and disparities among older adults have continually been growing. Empirical studies focused on older adults in the Philippines and Vietnam appear minimal and mostly regarding perceptions of aging. An effective geriatric care strongly relies on functional service providers requiring their perspectives to be explored toward inclusive service delivery. To investigate the perceived gaps and opportunities in geriatric care service delivery among health and social care workers in selected urban areas in the Philippines and Vietnam. A qualitative case study approach drawn on social constructivism theory, examined working experiences, observed characteristics of older adults, geriatric services and needs, difficulties on service delivery, and recommended solutions. A total of 12 semi-structured interviews and 29 focus group discussions were conducted in the Philippines, with 174 health and social care workers, while in Vietnam, there were 23 semi-structured interviews and 29 focus group discussions with 124 participants. An inductive thematic analysis was employed. Interview participants highlighted the increasing unmet needs such as accessibility, availability, and acceptability of geriatric care services. The implementation of interventions on the older population faced multiple challenges, including issues related to older adult conundrums and dilemmas in geriatric care providers and facilities. The participants from the two countries felt that strengthening implementation of collaboration toward an integrated geriatric care structure and expansion of training and capability in handling older adults can be potential in addressing the gaps at both individual and institutional levels. Additionally, a committed leadership was viewed to be the important step to effectively operationalize the strategy. Health and social workers emphasized that the needs of older adults are exacerbated by various challenges within a fragmented geriatric care system. To address this issue, an establishment of an integrated service delivery mechanism with dedicated leadership is needed. The findings from this study may help develop appropriate solutions for addressing the health and social care needs of older adults in similar settings across Southeast Asia. Further examination of the impact of these challenges and solutions on service delivery and the wellbeing of older adults is essential.

Abstract 4137: Feasibility of a novel image guided injection tool for non-surgical implantation of orthotopic tumors

Abstract The purpose of this study was to evaluate a novel device for non-surgical implantation of tumor cells using ultrasonic (US) image guidance. There are a variety of mouse model cancer types (e.g. sub-cu, orthotopic, genetically engineered). Orthotopic tumors are increasingly prevalent but usually require surgery, which reduces throughput and injures the surrounding anatomy. Injections are an alternative to surgery, but usually require image guidance or extensive training. US guided injection systems exist, but are suboptimal because they require significant training, as the US beam is not necessarily coplanar with needle location or trajectory, reducing accuracy and throughput. We tested a new approach to image guided injection which ensures that the US beam is coplanar with the needle. To test the efficacy of the image guided injection device across a variety of common orthotopic tumors, we delivered luc-tagged cells to the prostate (2.5e5 cells in 40 µL, PC3, N=8), liver (2e6 cells in 100 µL, Hep G2, N=5), and brain (1.75e5 cells in 100 µL, U87-MG, N=3). The brain tumor model was introduced via intracardiac injection to simulate metastases. Between 3 and 8 mice were injected for each tumor model. For injection, animals were anesthetized and positioned on motion stage. A 1 mL syringe was mounted to the adjustable injection gantry with the needle co-planar with the US beam, and the target organ was visualized with US. Cells were delivered to the targets using the US live stream as a guide. Between 1 to 3 weeks after the injections, tumors were confirmed via BLI with an IVIS (Revvity, Waltham, MA, USA). For each of the three tumor cell lines, animal preparation and injections could be performed in 10 mins by recently-trained novice users. All three cell lines could be effectively delivered to the orthotopic host tissues, and this was confirmed by using BLI of the cells. This study represents the first time a co-planar US beam and needle delivery mechanism was used for the purpose of non-surgical implantation of orthotopic tumors. Future developments of this platform could include improvements to automation of needle placement and trajectory to ensure successful payload delivery by novice users. Citation Format: Thomas M. Kierski, Juan D. Rojas, Nathan Beaumont, Theresa Charity, Robert D. Marek, Kenneth H. Young, Gregory M. Palmer, Ryan C. Gessner, Tomek J. Czernuszewicz. Feasibility of a novel image guided injection tool for non-surgical implantation of orthotopic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4137.

Effectiveness of Spontaneous Pushing versus Valsalva Pushing in the Second Stage of Labor on Maternal and Neonatal Outcomes: A Systematic Review and Meta-analysis

Vaginal birth is a natural process, but maternal pushing is an essential factor in the mechanism and process of delivery. This systematic review examined the evidence comparing the effectiveness of two methods of pushing techniques (spontaneous push­ing versus Valsalva pushing) on maternal and neonatal outcomes in the second stage of labor. A literature search of Scopus, PubMed, ScienceDirect, CINAHL, PsycINFO, and ThaiJo for articles published between 2012 and 2023 revealed 12 studies with a focus on maternal pushing during the second stage, but four with neonatal outcomes (APGAR scores) and maternal outcomes (fatigue and duration of labor). Meta-analysis of the four studies did not support the benefit of spontaneous pushing in reducing the duration of labor but did support spontaneous pushing in lessening maternal fatigue two hours postpartum. Spontaneous pushing did not directly benefit the neonatal APGAR scores at 1 or 5 minutes postpartum. The result that spontaneous pushing did not shorten labor was unexpected; this is contrary to other studies that have reported a shorter labor duration. The small number of studies makes it difficult to conclude the effectiveness of either pushing technique. Further evidence is necessary to include possible confounding variables postpartum, including women’s choice, advanced assessments of neonatal outcomes, and maternal recovery beyond the immediate postpartum period.

Healthcare Accessibility and Utilization by Women in Indian Prisons

Prison healthcare assumes significance as prisons are characterized by disharmony between goals of penal and medical agenda. The present study aimed at understanding the healthcare delivery mechanisms across three prisons in the Indian state of West Bengal. Semi-structured interviews were conducted among 90 imprisoned women to analyze their experiences of accessing healthcare and assess their satisfaction with the treatment received. While 42.2 percent of the women perceived healthcare accessibility to be easy, 30 percent expressed satisfaction with the treatment received. A perceived deterioration of health post-imprisonment was found among 67.77 percent. The study revealed how prison environments and practices infiltrate healthcare delivery patterns and have direct implications for the health of women. The paper recommends the delivery of a holistic model of correctional healthcare that is sensitive to the gender-specific needs of women.

A rationally designed nuclei-targeting FAPI 04-based molecular probe with enhanced tumor uptake for PET/CT and fluorescence imaging.

Fibroblast activation protein inhibitor (FAPI) -based probes have been widely studied in the diagnosis of various malignant tumors with positron emission tomography/computed tomography (PET/CT). However, current imaging studies of FAPI-based probes face challenges in rapid clearance rate and potential false-negative results. Furthermore, FAPI has been rarely explored in optical imaging. Considering this, further modifications are imperative to improve the properties of FAPI-based probes to address existing limitations and broaden their application scenarios. In this study, we rationally introduced methylene blue (MB) to FAPIs, thereby imparting nuclei-targeting and fluorescence imaging capabilities to the probes. Furthermore, we evaluated the added value of FAPI-based fluorescence imaging to traditional PET/CT, exploring the potential application of FAPI-based probes in intraoperative fluorescence imaging. A new FAPI-based probe, namely NOTA-FAPI-MB, was designed for both PET/CT and fluorescence imaging by conjugation of MB. The targeting efficacy of the probe was evaluated on fibroblast activation protein (FAP)-transfected cell line and human primary cancer-associated fibroblasts (CAFs). Subsequently, PET/CT and fluorescence imaging were conducted on tumor-bearing mice. The tumor detection and boundary delineation were assessed by fluorescence imaging of tissues from hepatocellular carcinoma (HCC) patients. NOTA-FAPI-MB demonstrated exceptional targeting ability towards FAP-transfected cells and CAFs in comparison to NOTA-FAPI. This benefit arises from the cationic methylene blue (MB) affinity for anionic nucleic acids. PET/CT imaging of tumor-bearing mice revealed significantly higher tumor uptake of [18F]F-NOTA-FAPI-MB (standard uptake value of 2.20 ± 0.31) compared to [18F]F-FDG (standard uptake value of 1.66 ± 0.14). In vivo fluorescence imaging indicated prolonged retention at the tumor site, with retention lasting up to 24h. In addition, the fluorescent probes enabled more precise lesion detection and tumor margin delineation than clinically used indocyanine green (ICG), achieving a 100.0% (6/6) tumor-positive rate for NOTA-FAPI-MB while 33.3% (2/6) for ICG. These findings highlighted the potential of NOTA-FAPI-MB in guiding intraoperative surgical procedures. The NOTA-FAPI-MB was successfully synthesized, in which FAPI and MB simultaneously contributed to the targeting effect. Notably, the nuclear delivery mechanism of the probes improved intracellular retention time and targeting efficacy, broadening the imaging time window for fluorescence imaging. In vivo PET/CT demonstrated favorable performance of NOTA-FAPI-MB compared to [18F]F-FDG. This study highlights the significance of fluorescence imaging as an adjunct technique to PET/CT. Furthermore, the encouraging results obtained from the imaging of human HCC tissues hold promise for the potential application of NOTA-FAPI-MB in intraoperative fluorescent surgery guidance within clinical settings.

System dynamics analysis of Retailer's emergency strategies when facing irrational demand and supply disruption

Emergency events, such as epidemics, typhoons, and floods, can lead to increased demand instability, resulting in a higher risk of supply–demand imbalances in supply chains. Companies often face challenges in managing irrational demand and supply disruptions due to their limited experience. In this paper, we utilize system dynamics (SD) and susceptible-infected-recovered (SIR) model to examine the phenomenon of irrational consumer demand within the context of supply disruption. Specifically, we focus on analyzing such demand patterns across three external supply scenarios: sufficient, stable, and learning types. Furthermore, we consider emergency strategies (pricing, transshipment, and hybrid) for the retailer based on the consideration of either delayed or non-delayed delivery mechanisms. The results show that the upsurge of irrational demand following an emergency outbreak is usually short term and enormous. A higher level of panic effect leads to increased irrational demand, whereas a stronger conformity effect results in faster increases and declines of such demand during early and later stages, respectively. Furthermore, the emergency strategies should aim to mitigate the negative impacts of the disruption retailer operations and improve the retailer's emergency capabilities. Numerical analysis indicates that the retailer can increase its profit in the sufficient-type external supply scenario by adopting a pricing strategy that incorporates a delayed delivery mechanism. When facing a stable-type scenario, the recommendation is the hybrid strategy. In a learning-type scenario, the retailer should consider using the hybrid strategy with non-delayed delivery as the default option, but use a pricing strategy if delayed delivery is necessary.

Double-Balloon Catheter–Mediated Transarterial Chemotherapy Delivery in a Swine Model: A Mechanism Recruiting the Vasa Vasorum for Localized Therapies

PurposeTreatment of hypovascular tumors, such as pancreatic adenocarcinoma, is challenging owing to inefficient drug delivery. This report examines the potential mechanism of localized drug delivery via transarterial microperfusion (TAMP) using a proprietary adjustable double-balloon occlusion catheter in a porcine model. Materials and MethodsAdult Yorkshire swine (N = 21) were used in the Institutional Animal Care & Use Committee–approved protocols. The RC-120 catheter (RenovoRx, Los Altos, California) was positioned into visceral, femoral, and pulmonary arteries with infusion of methylene blue dye, gemcitabine, or gold nanoparticles. Transmural delivery was compared under double-balloon occlusion with and without side-branch exclusion, single-balloon occlusion, and intravenous delivery. Intra-arterial pressure and vascular histologic changes were assessed. ResultsInfusion with double-balloon occlusion and side-branch exclusion provided increased intra-arterial pressure in the isolated segment and enhanced perivascular infusate penetration with minimal vascular injury. Infusates were predominantly found in the vasa vasorum by electron microscopy. ConclusionsTAMP enhanced transmural passage mediated by localized increase in arterial pressure via vasa vasorum.

Quantum-secure content key delivery mechanism for DRM system

Quantum-secure content key delivery mechanism for DRM system

A Contemporary View of Menopausal Hormone Therapy.

Enthusiasm for the use of hormones to ameliorate symptoms of perimenopause and menopause has waxed and waned over the years. Both treatment for symptoms and training of women's health care practitioners in the management of menopause have sharply declined since publication of the Women's Health Initiative initial results in 2002. Findings from that trial, which treated a population of older, asymptomatic patients, have been extrapolated over the past 21 years to all estrogen products, all menopausal women, and all delivery mechanisms. Our patients deserve a more nuanced, individualized approach. Conjugated equine estrogens and medroxyprogesterone acetate are no longer the predominant medications or medications of choice available for management of menopausal symptoms. All hormones are not equivalent any more than all antiseizure medications or all antihypertensives are equivalent; they have different pharmacodynamics, duration of action, and affinity for receptors, among other things, all of which translate to different risks and benefits. Consideration of treatment with the right formulation, at the right dose and time, and for the right patient will allow us to recommend safe, effective, and appropriate treatment for people with menopausal symptoms.

It may all come down to the mechanisms of nanoparticle delivery

It may all come down to the mechanisms of nanoparticle delivery

Vascular Endothelial Cell-Derived Exosomal Sphingosylphosphorylcholine Attenuates Myocardial Ischemia-Reperfusion Injury through NR4A2-Mediated Mitophagy.

Cardiomyocyte survival is a critical contributing process of host adaptive responses to cardiovascular diseases (CVD). Cells of the cardiovascular endothelium have recently been reported to promote cardiomyocyte survival through exosome-loading cargos. Sphingosylphosphorylcholine (SPC), an intermediate metabolite of sphingolipids, mediates protection against myocardial infarction (MI). Nevertheless, the mechanism of SPC delivery by vascular endothelial cell (VEC)-derived exosomes (VEC-Exos) remains uncharacterized at the time of this writing. The present study utilized a mice model of ischemia/reperfusion (I/R) to demonstrate that the administration of exosomes via tail vein injection significantly diminished the severity of I/R-induced cardiac damage and prevented apoptosis of cardiomyocytes. Moreover, SPC was here identified as the primary mediator of the observed protective effects of VEC-Exos. In addition, within this investigation, in vitro experiments using cardiomyocytes showed that SPC counteracted myocardial I/R injury by activating the Parkin and nuclear receptor subfamily group A member 2/optineurin (NR4A2/OPTN) pathways, in turn resulting in increased levels of mitophagy within I/R-affected myocardium. The present study highlights the potential therapeutic effects of SPC-rich exosomes secreted by VECs on alleviating I/R-induced apoptosis in cardiomyocytes, thereby providing strong experimental evidence to support the application of SPC as a potential therapeutic target in the prevention and treatment of myocardial infarction.

Natural Compounds and Biomimetic Engineering to Influence Fibroblast Behavior in Wound Healing.

Throughout history, natural products have played a significant role in wound healing. Fibroblasts, acting as primary cellular mediators in skin wound healing, exhibit behavioral responses to natural compounds that can enhance the wound healing process. Identifying bioactive natural compounds and understanding their impact on fibroblast behavior offers crucial translational opportunities in the realm of wound healing. Modern scientific techniques have enabled a detailed understanding of how naturally derived compounds modulate wound healing by influencing fibroblast behavior. Specific compounds known for their wound healing properties have been identified. Engineered biomimetic compounds replicating the natural wound microenvironment are designed to facilitate normal healing. Advanced delivery methods operating at micro- and nano-scales have been developed to effectively deliver these novel compounds through the stratum corneum. This review provides a comprehensive summary of the efficacy of natural compounds in influencing fibroblast behavior for promoting wound regeneration and repair. Additionally, it explores biomimetic engineering, where researchers draw inspiration from nature to create materials and devices mimicking physiological cues crucial for effective wound healing. The review concludes by describing novel delivery mechanisms aimed at enhancing the bioavailability of natural compounds. Innovative future strategies involve exploring fibroblast-influencing pathways, responsive biomaterials, smart dressings with real-time monitoring, and applications of stem cells. However, translating these findings to clinical settings faces challenges such as the limited validation of biomaterials in large animal models and logistical obstacles in industrial production. The integration of ancient remedies with modern approaches holds promise for achieving effective and scar-free wound healing.

Neutrophil hitchhiking: Riding the drug delivery wave to treat diseases.

Neutrophils are a crucial component of the innate immune system and play a pivotal role in various physiological processes. From a physical perspective, hitchhiking is considered a phenomenon of efficient transportation. The combination of neutrophils and hitchhikers has given rise to effective delivery systems both in vivo and in vitro, thus neutrophils hitchhiking become a novel approach to disease treatment. This article provides an overview of the innovative and feasible application of neutrophils as drug carriers. It explores the mechanisms underlying neutrophil function, elucidates the mechanism of drug delivery mediated by neutrophil-hitchhiking, and discusses the potential applications of this strategy in the treatment of cancer, immune diseases, inflammatory diseases, and other medical conditions.

Nitric oxide nano-reactor DNMF/PLGA enables tumor vascular microenvironment and chemo-hyperthermia synergetic therapy

BackgroundBreast cancer ranks first among malignant tumors, of which triple-negative breast cancer (TNBC) is characterized by its highly invasive behavior and the worst prognosis. Timely diagnosis and precise treatment of TNBC are substantially challenging. Abnormal tumor vessels play a crucial role in TNBC progression and treatment. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis, while effective NO delivery can normalize the tumor vasculature. Accordingly, we have proposed here a tumor vascular microenvironment remodeling strategy based on NO-induced vessel normalization and extracellular matrix collagen degradation with multimodality imaging-guided nanoparticles against TNBC called DNMF/PLGA.ResultsNanoparticles were synthesized using a chemotherapeutic agent doxorubicin (DOX), a NO donor L-arginine (L-Arg), ultrasmall spinel ferrites (MnFe2O4), and a poly (lactic-co-glycolic acid) (PLGA) shell. Nanoparticle distribution in the tumor was accurately monitored in real-time through highly enhanced magnetic resonance imaging and photoacoustic imaging. Near-infrared irradiation of tumor cells revealed that MnFe2O4 catalyzes the production of a large amount of reactive oxygen species (ROS) from H2O2, resulting in a cascade catalysis of L-Arg to trigger NO production in the presence of ROS. In addition, DOX activates niacinamide adenine dinucleotide phosphate oxidase to generate and supply H2O2. The generated NO improves the vascular endothelial cell integrity and pericellular contractility to promote vessel normalization and induces the activation of endogenous matrix metalloproteinases (mainly MMP-1 and MMP-2) so as to promote extravascular collagen degradation, thereby providing an auxiliary mechanism for efficient nanoparticle delivery and DOX penetration. Moreover, the chemotherapeutic effect of DOX and the photothermal effect of MnFe2O4 served as a chemo-hyperthermia synergistic therapy against TNBC.ConclusionThe two therapeutic mechanisms, along with an auxiliary mechanism, were perfectly combined to enhance the therapeutic effects. Briefly, multimodality image-guided nanoparticles provide a reliable strategy for the potential application in the fight against TNBC.Graphical

On the uncertainty quantification of the active uterine contraction during the second stage of labor simulation.

Uterine contractions in the myometrium occur at multiple scales, spanning both organ and cellular levels. This complex biological process plays an essential role in the fetus delivery during the second stage of labor. Several finite element models of active uterine contractions have already been developed to simulate the descent of the fetus through the birth canal. However, the developed models suffer severe reliability issues due to the uncertain parameters. In this context, the present study aimed to perform the uncertainty quantification (UQ) of the active uterine contraction simulation to advance our understanding of pregnancy mechanisms with more reliable indicators. A uterus model with and without fetus was developed integrating a transversely isotropic Mooney-Rivlin material with two distinct fiber orientation architectures. Different contraction patterns with complex boundary conditions were designed and applied. A global sensitivity study was performed to select the most valuable parameters for the uncertainty quantification (UQ) process using a copula-based Monte Carlo method. As results, four critical material parameters ( ) of the active uterine contraction model were identified and used for the UQ process. The stress distribution on the uterus during the fetus descent, considering first and second fiber orientation families, ranged from 0.144 to 1.234MPa and 0.044 to 1.619MPa, respectively. The simulation outcomes revealed also the segment-specific contraction pattern of the uterus tissue. The present study quantified, for the first time, the effect of uncertain parameters of the complex constitutive model of the active uterine contraction on the fetus descent process. As perspectives, a full maternal pelvis model will be coupled with reinforcement learning to automatically identify the delivery mechanism behind the cardinal movements of the fetus during the active expulsion process.

Nanotechnology in plant nutrition: Ensuring sustainable agriculture through nanofertilizers

AbstractFertilizers play a crucial role in enhancing the productivity of plants. However, low nutrient use efficiencies of conventional fertilizers (CFs) associated with several losses have led to widespread multi‐nutrient deficiencies in the soil and lower productivity. Furthermore, their excess application has caused serious damage to the soil and environment. Recently, nanotechnology has broadened its applicability in plant nutrition and has paved a way for the production of nanoparticle‐induced fertilizers. Therefore, nanofertilizers stand out as promising alternative to CFs for sustainable agriculture. Nanofertilizers are composed of nanoparticles that contain macro‐ and micronutrients and deliver them in a controlled way to the plant's rhizosphere. This contributes to the enhanced nutrient utilization efficiency. This review delves into the effect of nanotechnology‐based nanofertilizers in different forms and dosages on soil properties and plant development. Additionally, the mechanism underlying absorption of nanofertilizers and their advantages and limitations have also been discussed. A thorough comparison between conventional and nanofertilizers has also been made in this review in terms of their nutrient delivery mechanism, efficiency and application. As the use of nanoparticle‐embedded fertilizers in plant nutrition is still in its infancy, this review can serve as a guide for future investigations to enhance the knowledge of the use of nanoparticles in the mineral nutrition of different crops.

Distribution and suitability of pulmonary surfactants as a vehicle for topically applied antibodies in healthy and SARS-CoV-2 infected rodent lungs

The use of natural pulmonary surfactants (PS) as a drug delivery vehicle for biologics is a more recent therapeutic modality. Herein, we tested different contents of PS regarding their physicochemical properties under stress conditions. The PS content of 12.25 mg/ml (Formulation B) showed desired properties such as an isotonic osmolality ∼300 mOsm/kg and an acceptable viscosity of 8.61 cSt, being lower than in commercially available PS solutions. Formulation B passed the specifications of surface lowering capacities of >80 % total lung capacity and physiologically desired formulation properties were independent of the antibody used in the composition. The identified formulation showed the capability of significantly increasing the oxygen saturation in ex vivo isolated perfused rat lungs, compared to a control and up to 30 min post lavage. In the in vivo setting, we showed that intratracheal administration of a human mAB with and without pulmonary surfactant led to higher amounts of delivered antibody within the alveolar tissue compared to intravenous administration. The antibody with the PS formulation remained longer in the alveolar tissues than the antibody without the PS formulation. Further, SARS-CoV-2 infected Golden Syrian hamsters showed that the intranasally applied antibody reached the site of infection in the alveoli and could be detected in the alveolar region 24 h after the last administration. With this work, we demonstrated that pulmonary surfactants can be used as a pulmonary drug delivery mechanism for antibodies and may subsequently improve the antibody efficacy by increasing the residence time at the desired site of action in the alveolar tissue.

Lentinan-loaded GelMA hydrogel accelerates diabetic wound healing through enhanced angiogenesis and immune microenvironment modulation

Diabetic wound healing is a substantial clinical challenge, characterized by delayed angiogenesis and unresolved inflammation. Lentinan, a polysaccharide extracted from shiitake mushrooms, has the potential to regulate both macrophage polarization and angiogenesis, though this aspect remains inadequately explored. To facilitate lentinan's clinical utility, we have developed a GelMA hydrogel encapsulated with lentinan (10 μM), offering a controlled release mechanism for sustained lentinan delivery at the wound site. Application of the lentinan-encapsulated delivery system topically significantly expedites wound closure compared to control groups. Furthermore, histological examination demonstrates enhanced neovascularization and reduced inflammation in lentinan-treated wounds, as evidenced by increased M2 macrophage infiltration. Moreover, our results indicated that lentinan-induced AMPK activation promotes DAF16 expression, enhancing the resistance of macrophages and HUVECs to oxidative stress in high-glucose environments, thereby promoting M2 macrophage polarization and angiogenesis. All these findings underscore lentinan's capacity to modulate macrophage polarization and angiogenesis via the AMPK/DAF16 pathway, ultimately facilitating the healing of diabetic wounds.

Federal Business Subsidies: Explosive Growth Since 2014

Federal business subsidies have risen 140 per cent over the nine years ending in 2023–24, compared to 17 per cent over the previous nine years. New programs accounted for over half the growth. Clean economy measures, which rose $7 billion from 2014–15 to 2023–24, were the major contributor to growth in new programs. Even without the new climate change measures, business subsidies would have doubled over the period. Subsidies are likely to reach about $50 billion in 2027–28, which would represent 54 per cent of corporate income tax revenue, up from 42 per cent in 2014–15. Other key findings are: Small and medium-sized enterprises benefit disproportionately from subsidies. These firms account for about half of output in Canada but receive approximately two-thirds of business subsidies. Clean economy measures account for almost a fifth of business subsidies. The agri-food sector receives the second largest share, approximately 15 per cent, which is substantial relative to its four per cent output share. Business subsidies are concentrated in a small number of programs. In the current fiscal year, the top 10 programs (out of almost 150 programs) account for almost 60 per cent of subsidies, and the top 20 for almost 80 per cent. Spending programs account for a surprisingly small share of business subsidies — approximately 30 per cent in the current fiscal year. The tax system is the most important delivery mechanism (45 per cent), while government business enterprises and refundable tax credits account for just over 10 per cent each. What are taxpayers getting in return for the massive spending on subsidies? They are certainly getting more of the activities that are being subsidized and less of the activities that arenot. However, this change in the composition of economic activity won’t necessarily improve well-being because market prices generally allocate society’s scarce resources to their best uses. That is, if markets are functioning properly, subsidies harm rather than help economic performance. On the other hand, if subsidy programs address a market failure, the resulting reallocation of activity may be more efficient. Federal business subsidies that have the potential to improve economic performance, or more generally, to enhance well-being, because they address a market failure accounted for 64 per cent of business subsidies in 2023–24. However, measures accounting for about two-thirds of this spending fail a benefit-cost test — they are not successful in raising Canadians’ real income. These programs should be reviewed to determine if they can be restructured to deliver a positive net benefit. If not, they should be eliminated. Measures accounting for 36 per cent of total spending in 2023–24 are not intended to correct a market failure and are therefore transferring income from one group of Canadians to another while harming economic performance. These measures include general business subsidies and initiatives providing income support. These measures should be carefully reviewed to determine if their income redistribution effects can be justified in the context of the real income loss they cause. Since 2019–20, subsidies implemented to mitigate the impact of climate change and to creategood jobs by subsidizing high-productivity, high-wage industries have grown in importance andwill continue to do so. Climate change mitigation measures should only be implemented if they complement carbon pricing, the government’s main and most cost-effective instrument for reducing emissions. If they meet this minimum condition, climate change mitigation measures should be assessed based on their relative cost-effectiveness in reducing emissions. The proposition that subsidies intended to create good jobs are sound public policy is controversial. The impact of these measures should be tested against the data before additional funds are committed.