Lung-to-Heart Nano-in-Micro Peptide Promotes Cardiac Recovery in a Pig Model of Chronic Heart Failure.

BACKGROUND: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. OBJECTIVES: In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. METHODS: Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. RESULTS: DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. CONCLUSIONS: The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart.

Wearable Technologies and Stress: Toward an Ethically Grounded Approach.

The widespread use of digital technologies that can be worn on our bodies-wearables-is presented as a turning point for various areas of biomedical research and healthcare, such as stress. The ability to constantly measure these parameters, the perceived quality of measurement, and their individual and personal level frame wearable technology as a possibly crucial step in the direction of a more accurate and objective definition and measurement of stress for clinical, research, and personal purposes. In this paper, we discuss the hypothesis that the use of wearables for stress is also beneficial from an ethical viewpoint. We start by situating wearables in the context of existing methods and limitations of stress research. On this basis, we discuss the ethics of wearables for stress by applying ethical principles from bioethics (beneficence, non-maleficence, autonomy, justice), which allows us to identify ethical benefits as well as challenges in this context. As a result, we develop a more balanced view of the ethics of wearables for stress, which we use to present recommendations and indications with a focus on certification, accessibility, and inclusion. This article is, thus, a contribution towards ethically grounded wearable and digital health technology for stress.

Comprehensive genome profiling by next generation sequencing of circulating tumor DNA in solid tumors: a single academic institution experience.

Background: Recently, new evidence of the next-generation sequencing (NGS) liquid biopsy utility in clinical practice has been developed. This assay is emerging as a new promising tool to use as a noninvasive biomarker for cancer mutation profiling. Additional data supporting the clinical validity of cell free DNA (cfDNA) based testing is necessary to inform optimal use of these assays in the clinic. Materials and methods: A total of 398 cancer patients were analyzed by FoundationOne Liquid Analysis (F1LA), a genomic profiling assay and by standard NGS diagnostic ThermoFisher platform. The association between diagnostic technique was evaluated using a Poisson regression model. FoundationOne Liquid (F1L) and FoundationOne Liquid CDx (F1LCDx) detect 70 and 324 cancer-related genes alterations, respectively, including genomic signatures tumor fraction, blood tumor mutational burden (only for the 324 genes version), and microsatellite instability high status. Both assays used a single DNA extraction method to obtain cfDNA. The real-life clinical impact and feasibility of F1L and F1LCDx were evaluated across different solid tumors in our department. Results: Between 1 January 2019 and 28 February 2021, 398 samples of different tumor types from 398 patients were analyzed (overall success rate: 92%, in FoundationOne Liquid CDx Analysis success rate: 97%). Most frequent molecular alterations were TP53 (74), APC (40), DNMT3A (39), KRAS (23). The comprehensive clinical impact of F1LA compared with standard diagnostic was 64.7% versus 22.1% [risk ratio (RR) = 2.94; p < 0.001] and the potential clinical impact was 58.6% versus 11.0% (RR = 5.32; p < 0.001), respectively. Furthermore, some clinical cases were selected, in which F1LA detected actionable alterations offering an unexpected therapeutic choice. Conclusions: Although additional studies are needed to better select patients and setting, NGS F1LA is a useful, noninvasive, and repeatable assay to guide therapeutic choice in oncology. It provides a snapshot of cancer heterogeneity profile that could be incorporated in routinely clinical practice.

Blood Pressure Continuous Measurement through a Wearable Device: Development and Validation of a Cuffless Method.

The present study aims to develop and validate a cuffless method for blood pressure continuous measurement through a wearable device. The goal is achieved according to the time-delay method, with the guiding principle of the time relation it takes for a blood volume to travel from the heart to a peripheral site. Inversely proportional to the blood pressure, this time relation is obtained as the time occurring between the R peak of the electrocardiographic signal and a marker point on the photoplethysmographic wave. Such physiological signals are recorded by using L.I.F.E. Italia's wearable device, made of a sensorized shirt and wristband. A linear regression model is implemented to estimate the corresponding blood pressure variations from the obtained time-delay and other features of the photoplethysmographic wave. Then, according to the international standards, the model performance is assessed, comparing the estimates with the measurements provided by a certified digital sphygmomanometer. According to the standards, the results obtained during this study are notable, with 85% of the errors lower than 10 mmHg and a mean absolute error lower than 7 mmHg. In conclusion, this study suggests a time-delay method for continuous blood pressure estimates with good performance, compared with a reference device based on the oscillometric technique.

1,2-Benzisothiazole Derivatives Bearing 4-, 5-, or 6-Alkyl/arylcarboxamide Moieties Inhibit Carbonic Anhydrase Isoform IX (CAIX) and Cell Proliferation under Hypoxic Conditions.

Three novel series of 1,2-benzisothiazole derivatives have been developed as inhibitors of carbonic anhydrase isoform IX. Compounds 5c and 5j, tested in vitro on the human colon cell line HT-29, blocked the growth of cells cultured under chemically induced hypoxic conditions, displaying a specific activity against cancer cells characterized by CAIX up-regulation. Moreover, a synergistic activity of 5c with SN-38 (the active metabolite of irinotecan) and 5-fluorouracil on cell proliferation under hypoxic conditions was demonstrated.