Aerosol technology to mimic dry powder inhalation in vitro using pulmonary cell models.

Inhaled therapy confers key advantages for the treatment of topical pulmonary diseases and offers potential for systemic delivery of medicines. Dry powder inhalers (DPIs) are generally the preferred devices for pulmonary delivery due to improved stability and satisfactory patient compliance. However, the mechanisms governing drug powder dissolution and availability in the lung and poorly understood. Here, we report a new in vitro system to study epithelial absorption of inhaled dry powders in lung barrier models of the upper and lower airway. The system is based on a CULTEX® RFS (Radial Flow System) cell exposure module joined to a Vilnius aerosol generator and allows the coupling of drug dissolution and permeability assessments. The cellular models recapitulate the barrier morphology and function of healthy and diseased pulmonary epithelium and incorporate the mucosal barrier to enable the investigation of drug powder dissolution in biorelevant conditions. With this system, we found differences in permeability across the airway tree and pinpointed the impact of diseased barriers in paracellular drug transport. Furthermore, we identified a different rank order of permeability for compounds tested in solution or powder form. These results highlight the value of this in vitro drug aerosolization setup for use in research and development of inhaled medicines.

Lipid metabolism in tumor immunology and immunotherapy.

Lipids are a diverse class of biomolecules that have been implicated in cancer pathophysiology and in an array of immune responses, making them potential targets for improving immune responsiveness. Lipid and lipid oxidation also can affect tumor progression and response to treatment. Although their importance in cellular functions and their potential as cancer biomarkers have been explored, lipids have yet to be extensively investigated as a possible form of cancer therapy. This review explores the role of lipids in cancer pathophysiology and describes how further understanding of these macromolecules could prompt novel treatments for cancer.

The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy.

Immunotherapy has revolutionized cancer treatment and revitalized efforts to harness the power of the immune system to combat a variety of cancer types more effectively. However, low clinical response rates and differences in outcomes due to variations in the immune landscape among patients with cancer continue to be major limitations to immunotherapy. Recent efforts to improve responses to immunotherapy have focused on targeting cellular metabolism, as the metabolic characteristics of cancer cells can directly influence the activity and metabolism of immune cells, particularly T cells. Although the metabolic pathways of various cancer cells and T cells have been extensively reviewed, the intersections among these pathways, and their potential use as targets for improving responses to immune-checkpoint blockade therapies, are not completely understood. This review focuses on the interplay between tumor metabolites and T-cell dysfunction as well as the relationship between several T-cell metabolic patterns and T-cell activity/function in tumor immunology. Understanding these relationships could offer new avenues for improving responses to immunotherapy on a metabolic basis.

Corrigendum: Lipid metabolism in tumor immunology and immunotherapy.

[This corrects the article DOI: 10.3389/fonc.2023.1187279.].

Bone morphogenetic proteins, activins, and growth and differentiation factors in tumor immunology and immunotherapy resistance.

The TGF-ß superfamily is a group of secreted polypeptides with key roles in exerting and regulating a variety of physiologic effects, especially those related to cell signaling, growth, development, and differentiation. Although its central member, TGF-ß, has been extensively reviewed, other members of the family-namely bone morphogenetic proteins (BMPs), activins, and growth and differentiation factors (GDFs)-have not been as thoroughly investigated. Moreover, although the specific roles of TGF-ß signaling in cancer immunology and immunotherapy resistance have been extensively reported, little is known of the roles of BMPs, activins, and GDFs in these domains. This review focuses on how these superfamily members influence key immune cells in cancer progression and resistance to treatment.

Predicting Route of Delivery Using Quantification of Maternal Expulsive Efforts in the Second Stage of Labor.

OBJECTIVE: To investigate the association between the number of pushing contractions and the likelihood of spontaneous vaginal delivery, operative vaginal delivery, cesarean delivery and maternal and neonatal complications. METHODS: This was a retrospective analysis of patients who entered the second stage of labor with singleton, term pregnancies at Harbor-UCLA Medical Center from January 1, 2017, to December 31, 2019. Probabilities of spontaneous vaginal delivery, operative vaginal delivery, and cesarean delivery were calculated for each hour of pushing and for every 10 maternal pushing contractions. Maternal and neonatal morbidities were assessed in relation to second-stage pushing contractions. RESULTS: Four hundred thirty-nine nulliparous and 424 multiparous patients who entered the second stage of labor were included. Nulliparous patients had significantly more pushing contractions than multiparous patients (20.3±1.8 vs 7.8±1.0 pushes, P<.001). In nulliparous patients, 91.8% (326/355 patients) of spontaneous vaginal deliveries and 50.0% (12/24 patients) of cesarean deliveries occurred by 40 pushing contractions. In multiparous patients, 94.3% (369/391) of spontaneous vaginal deliveries and 50.0% of cesarean deliveries (4/8) occurred by 20 pushing contractions. The probabilities of cesarean delivery were at their highest after 80 pushing contractions in nulliparous patients and after 50 pushing contractions in multiparous patients. In both nulliparous and multiparous patients, there was no significant change in maternal and neonatal composite morbidities as the number of pushing contractions increased. CONCLUSION: Results from this study suggest that pushing contractions may be a viable alternative method for prediction of the likelihood of spontaneous vaginal delivery and probabilities of operative vaginal delivery and cesarean delivery for patients reaching the second stage of labor. Providing patients with a goal for expected number of pushing contractions may be of motivational benefit.

Cryptococcus Meningoencephalitis With Severe Localizing Neurological Deficits Mimicking a Large Right Middle Cerebral Artery Infarct in a HIV Patient.

Immunocompromised patients with Cryptococcal meningoencephalitis can develop focal neurological signs and symptoms. Stroke and abscess are usually the leading etiologies. Definitively localized non-fluctuating deficits mimicking a large middle cerebral artery (MCA) infarct without corresponding MRI findings is rare. Localized lobar cerebritis may be the underlying etiology. Despite having many different kinds of sequences, a significant pathological process can still evade MRI's detection. Diffusion-weighted imaging (DWI) abnormality has also been seen in pathology other than ischemic stroke.

Translational Aspects of Nuclear Factor-Kappa B and Its Modulation by Thalidomide on Early and Late Radiation Sequelae in Urinary Bladder Dysfunction.

PURPOSE: This preclinical study aimed to investigate the role of nuclear factor (NF)-κB in early and late radiogenic sequelae of urinary bladder dysfunction in mice. Thalidomide was applied either during the early or late response phase to determine potential effects of NF-κB inhibition on functional bladder impairment. METHODS AND MATERIALS: After pelvic irradiation on day 0, female C3H/Neu mice were observed over a period of 360 days and radiation response was evaluated for alterations in bladder functionality and NF-κB activation. Functionality was determined in graded dose experiments (14-24 Gy) and assessed by micturition frequency analysis and transurethral cystotonometry to reveal alterations in voiding and volume. The induction of the NF-κB proteins p50 and p65 was evaluated by immunohistochemistry in response to a single dose of 23 Gy (ED90). Thalidomide (100 mg/kg/d) was applied intraperitoneally in 3 treatment groups: daily from day 1 to 15, daily from day 16 to 30, and in 2-day-intervals from day 150 to 180. RESULTS: Immunohistochemical analysis showed a biphasic activation of p50 and p65 during the early radiation cystitis phase (day 1-30). After a transient decrease, p50, but not p65, was reactivated permanently leading to increased levels, which suggests an occurrence of chronic inflammation correlated with functional impairment. Both early thalidomide treatments reduced NF-κB activation and shifted the ED50 value for early radiation cystitis and late radiation sequelae to higher doses. CONCLUSIONS: These data clearly demonstrate the involvement of NF-κB signaling in the pathogenesis of radiation-induced urinary bladder dysfunction. Additionally, this study emphasizes that biological targeting of early radiogenic processes has enormous effect on chronic symptoms. The late administration of thalidomide showed no significant effect on functionality.