Predictors of Post-induction Hypotension for Patients With Pulmonary Hypertension.

Purpose The purpose is to identify predictors of post-induction hypotension (PIH) during general anesthesia in a population of patients with varying degrees of pulmonary hypertension (PH). Methods This is a single-center, retrospective, observational study of perioperative data obtained via electronic health records from patients with PH undergoing surgery over a five-year period. Baseline patient characteristics, peri-induction management variables, and pre-induction mean arterial pressure (MAP) were statistically analyzed using Kruskal-Wallis rank sum tests, Pearson's chi-squared tests, and logistic regression analysis to identify risk factors for PIH. We further assessed the relationship between PH and PIH using propensity score matching. Primary outcomes include a percent decrease in post-induction blood pressure as well as a post-induction nadir with a threshold of 55 mm Hg. Results Eight hundred fifty-seven patients in the cohort stratified by severity of PH reveal that advanced age (p < 0.001), higher BMI (P = 0.002), higher American Society of Anesthesiologists (ASA) score (P = 0.001), and renal and cardiac comorbidities (P < 0.001) are associated with PH severity. None of our tested parameters were significantly predictive for PIH in patients with PH. Right heart failure was found to be weakly and non-significantly predictive of PIH in patients with PH (P = 0.052, odds ratio [OR] = 1.116). Diabetes (P = 0.007, OR = 0.919) and maintenance of spontaneous ventilation (P = 0.012, OR = 0.925) were associated with decreased rates of PIH. Conclusion Hypotension after induction of general anesthesia in patients with PH is a serious problem, yet statistically significant risk factors were not identified. History of diabetes and preservation of spontaneous ventilation had a significant but weak effect of decreasing rates of PIH. This pilot study was limited by retrospective design and warrants further analysis with a prospective cohort.

Transport between im/mobile fractions shapes the speed and profile of cargo distribution in neurons.

Neuronal function requires continuous distribution of ion channels and other proteins throughout large cell morphologies. Protein distribution is complicated by immobilization of freely diffusing subunits such as on lipid rafts or in postsynaptic densities. Here, we infer rates of immobilization for the voltage-gated potassium channel Kv4.2. Fluorescence recovery after photobleaching quantifies protein diffusion kinetics, typically reported as a recovery rate and mobile fraction. We show that, implicit in the fluorescence recovery, are rates of particle transfer between mobile and immobile fractions (im/mobilization). We performed photobleaching of fluorescein-tagged ion channel Kv4.2-sGFP2 in over 450 dendrites of rat hippocampal cells. Using mass-action models, we infer rates of Kv4.2-sGFP2 im/mobilization. Using a realistic neuron morphology, we show how these rates shape the speed and profile of subunit distribution. The experimental protocol and model inference introduced here is widely applicable to other cargo and experimental systems.

Paradoxical relationships between active transport and global protein distributions in neurons.

Neural function depends on continual synthesis and targeted trafficking of intracellular components, including ion channel proteins. Many kinds of ion channels are trafficked over long distances to specific cellular compartments. This raises the question of whether cargo is directed with high specificity during transit or whether cargo is distributed widely and sequestered at specific sites. We addressed this question by experimentally measuring transport and expression densities of Kv4.2, a voltage-gated transient potassium channel that exhibits a specific dendritic expression that increases with distance from the soma and little or no functional expression in axons. In over 500 h of quantitative live imaging, we found substantially higher densities of actively transported Kv4.2 subunits in axons as opposed to dendrites. This paradoxical relationship between functional expression and traffic density supports a model-commonly known as the sushi belt model-in which trafficking specificity is relatively low and active sequestration occurs in compartments where cargo is expressed. In further support of this model, we find that kinetics of active transport differs qualitatively between axons and dendrites, with axons exhibiting strong superdiffusivity, whereas dendritic transport resembles a weakly directed random walk, promoting mixing and opportunity for sequestration. Finally, we use our data to constrain a compartmental reaction-diffusion model that can recapitulate the known Kv4.2 density profile. Together, our results show how nontrivial expression patterns can be maintained over long distances with a relatively simple trafficking mechanism and how the hallmarks of a global trafficking mechanism can be revealed in the kinetics and density of cargo.

A melanin-mediated cancer immunotherapy patch.

Melanin is capable of transforming 99.9% of the absorbed sunlight energy into heat, reducing the risk of skin cancer. We here develop a melanin-mediated cancer immunotherapy strategy through a transdermal microneedle patch. B16F10 whole tumor lysate containing melanin is loaded into polymeric microneedles that allow sustained release of the lysate upon insertion into the skin. In combination with the near-infrared light irradiation, melanin in the patch mediates the generation of heat, which further promotes tumor-antigen uptake by dendritic cells, and leads to enhanced antitumor vaccination. We found that the spatiotemporal photoresponsive immunotherapy increases infiltration of polarized T cells and local cytokine release. These immunological effects increase the survival of mice after tumor challenge and elicited antitumor effects toward established primary tumor and distant tumor. Collectively, melanin generates local heat, boosts T cell activities by transdermal vaccines, and promotes antitumor immune responses.

Tailoring Biomaterials for Cancer Immunotherapy: Emerging Trends and Future Outlook.

Cancer immunotherapy, as a paradigm shift in cancer treatment, has recently received tremendous attention. The active cancer vaccination, immune checkpoint blockage (ICB) and chimeric antigen receptor (CAR) for T-cell-based adoptive cell transfer are among these developments that have achieved a significant increase in patient survival in clinical trials. Despite these advancements, emerging research at the interdisciplinary interface of cancer biology, immunology, bioengineering, and materials science is important to further enhance the therapeutic benefits and reduce side effects. Here, an overview of the latest studies on engineering biomaterials for the enhancement of anticancer immunity is given, including the perspectives of delivery of immunomodulatory therapeutics, engineering immune cells, and constructing immune-modulating scaffolds. The opportunities and challenges in this field are also discussed.

Anaerobe-Inspired Anticancer Nanovesicles.

Anaerobic bacteria, such as Clostridium and Salmonella, can selectively invade and colonize in tumor hypoxic regions (THRs) and deliver therapeutic products to destroy cancer cells. Herein, we present an anaerobe nanovesicle mimic that can not only be activated in THRs but also induce hypoxia in tumors by themselves. Moreover, inspired by the oxygen metabolism of anaerobes, we construct a light-induced hypoxia-responsive modality to promote dissociation of vehicles and activation of bioreductive prodrugs simultaneously. In vitro and in vivo experiments indicate that this anaerobe-inspired nanovesicle can efficiently induce apoptotic cell death and significantly inhibit tumor growth. Our work provides a new strategy for engineering stimuli-responsive drug delivery systems in a bioinspired and synergistic fashion.

Stimuli-Responsive Polymersomes for Biomedical Applications.

Polymersomes, the structural analogues of liposomes, are hollow structures enclosed by a bilayer membrane made from amphiphilic copolymers. Polymersomes have been proposed to mimic the structure and properties of cellular membranes and viral capsids. Excellent robustness and stability, chemical versatility for tunable membrane properties and surface functionalization make polymersomes attractive candidates for drug delivery, diagnostic imaging, nanoreactor vessels, and artificial organelles. In further biomimetic strategies, stimuli-responsive polymersomes that can recognize various external physical or internal biological environmental stimuli and conduct "on demand" release in dose-, spatial-, and temporal-controlled fashions have been widely developed. This Perspective focuses on recent advances in stimuli-responsive polymersomes and their potential biomedical applications. Representative examples of each stimulus, the advantages and limitations of different strategies, and the future opportunities and challenges are discussed.