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Modulated electro-hyperthermia (mEHT) is an adjuvant cancer therapy that enables tumor-selective heating (+2.5 °C). In this study, we investigated whether mEHT accelerates the tumor-specific delivery of doxorubicin (DOX) from lyso-thermosensitive liposomal doxorubicin (LTLD) and improves its anticancer efficacy in mice bearing a triple-negative breast cancer cell line (4T1). The 4T1 cells were orthotopically injected into Balb/C mice, and mEHT was performed on days 9, 12, and 15 after the implantation. DOX, LTLD, or PEGylated liposomal DOX (PLD) were administered for comparison. The tumor size and DOX accumulation in the tumor were measured. The cleaved caspase-3 (cC3) and cell proliferation were evaluated by cC3 or Ki67 immunohistochemistry and Western blot. The LTLD+mEHT combination was more effective at inhibiting tumor growth than the free DOX and PLD, demonstrated by reductions in both the tumor volume and tumor weight. LTLD+mEHT resulted in the highest DOX accumulation in the tumor one hour after treatment. Tumor cell damage was associated with cC3 in the damaged area, and with a reduction in Ki67 in the living area. These changes were significantly the strongest in the LTLD+mEHT-treated tumors. The body weight loss was similar in all mice treated with any DOX formulation, suggesting no difference in toxicity. In conclusion, LTLD combined with mEHT represents a novel approach for DOX delivery into cancer tissue.

Cancers, chronic diseases and respiratory infections are major causes of mortality and present diagnostic and therapeutic challenges for health care. There is an unmet medical need for non-invasive, easy-to-use biomarkers for the early diagnosis, phenotyping, predicting and monitoring of the therapeutic responses of these disorders. Exhaled breath sampling is an attractive choice that has gained attention in recent years. Exhaled nitric oxide measurement used as a predictive biomarker of the response to anti-eosinophil therapy in severe asthma has paved the way for other exhaled breath biomarkers. Advances in laser and nanosensor technologies and spectrometry together with widespread use of algorithms and artificial intelligence have facilitated research on volatile organic compounds and artificial olfaction systems to develop new exhaled biomarkers. We aim to provide an overview of the recent advances in and challenges of exhaled biomarker measurements with an emphasis on the applicability of their measurement as a non-invasive, point-of-care diagnostic and monitoring tool.

Alterations of heart rate variability (HRV) are associated with various (patho)physiological conditions; therefore, HRV analysis has the potential to become a useful diagnostic module of wearable/telemedical devices to support remote cardiovascular/autonomic monitoring. Continuous pulse recordings obtained by photoplethysmography (PPG) can yield pulse rate variability (PRV) indices similar to HRV parameters; however, it is debated whether PRV/HRV parameters are interchangeable. In this study, we assessed the PRV analysis module of a digital arterial PPG-based telemedical system (SCN4ALL). We used Bland-Altman analysis to validate the SCN4ALL PRV algorithm to Kubios Premium software and to determine the agreements between PRV/HRV results calculated from 2-min long PPG and ECG captures recorded simultaneously in healthy individuals (n = 33) at rest and during the cold pressor test, and in diabetic patients (n = 12) at rest. We found an ideal agreement between SCN4ALL and Kubios outputs (bias < 2%). PRV and HRV parameters showed good agreements for interbeat intervals, SDNN, and RMSSD time-domain variables, for total spectral and low-frequency power (LF) frequency-domain variables, and for non-linear parameters in healthy subjects at rest and during cold pressor challenge. In diabetics, good agreements were observed for SDNN, LF, and SD2; and moderate agreement was observed for total power. In conclusion, the SCN4ALL PRV analysis module is a good alternative for HRV analysis for numerous conventional HRV parameters.

Angiotensin II (Ang II) has various cardiac effects and causes vasoconstriction. Ang II activates the type-1 angiotensin receptor-G q/11 signaling pathway resulting in the release of 2-arachidonoylglycerol (2-AG). We aimed to investigate whether cardiac Ang II effects are modulated by 2-AG-release and to identify the role of type-1 cannabinoid receptors (CB 1 R) in these effects. Expression of CB 1 R in rat cardiac tissue was confirmed by immunohistochemistry. To characterize short-term Ang II effects, increasing concentrations of Ang II (10 -9 -10 -7 M); whereas to assess tachyphylaxis, repeated infusions of Ang II (10 -7 M) were administered to isolated Langendorff-perfused rat hearts. Ang II infusions caused a decrease in coronary flow and ventricular inotropy, which was more pronounced during the first administration. CB agonist 2-AG and WIN55,212-2 administration to the perfusate enhanced coronary flow. The flow-reducing effect of Ang II was moderated in the presence of CB 1 R blocker O2050 and diacylglycerol-lipase inhibitor Orlistat. Our findings indicate that Ang II-induced cardiac effects are modulated by simultaneous CB 1 R-activation, most likely due to 2-AG-release during Ang II signalling. In this combined effect, the response to 2-AG via cardiac CB 1 R may counteract the positive inotropic effect of Ang II, which may decrease metabolic demand and augment Ang II-induced coronary vasoconstriction.

Sphingosine-1-phosphate (S1P) is a lysophospholipid mediator with diverse biological function mediated by S1P 1-5 receptors. Whereas S1P was shown to protect the heart against ischemia/reperfusion (I/R) injury, other studies highlighted its vasoconstrictor effects. We aimed to separate the beneficial and potentially deleterious cardiac effects of S1P during I/R and identify the signaling pathways involved. Wild type (WT), S1P 2 -KO and S1P 3 -KO Langendorff-perfused murine hearts were exposed to intravascular S1P, I/R, or both. S1P induced a 45% decrease of coronary flow (CF) in WT-hearts. The presence of S1P-chaperon albumin did not modify this effect. CF reduction diminished in S1P 3 -KO but not in S1P 2 -KO hearts, indicating that in our model S1P 3 mediates coronary vasoconstriction. In I/R experiments, S1P 3 deficiency had no influence on postischemic CF but diminished functional recovery and increased infarct size, indicating a cardioprotective effect of S1P 3 . Preischemic S1P exposure resulted in a substantial reduction of postischemic CF and cardiac performance and increased the infarcted area. Although S1P 3 deficiency increased postischemic CF, this failed to improve cardiac performance. These results indicate a dual role of S1P 3 involving a direct protective action on the myocardium and a cardiosuppressive effect due to coronary vasoconstriction. In acute coronary syndrome when S1P may be released abundantly, intravascular and myocardial S1P production might have competing influences on myocardial function via activation of S1P 3 receptors.