A novel echocardiographic parameter considering left ventricular afterload during V-A ECMO support.

BACKGROUND: Left ventricular stroke work index (LVSWI) and cardiac power index (CPI) account for the haemodynamic load of the left ventricle and are promising prognostic values in cardiogenic shock. However, accurately and non-invasively measuring these parameters during veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is challenging and potentially biased by the extracorporeal circulation. This study aimed to investigate, in an ovine model of cardiogenic shock, whether Pressure-Strain Product (PSP), a novel speckle-tracking echocardiography parameter, (1) can correlate with pressure-volume catheter-based LVSWI and CPI, and (2) can be load-independent during the flow modification of V-A ECMO. METHODS: Nine Dorset-cross ewes (51 ± 4 kg) were included. After cardiogenic shock was induced, full support V-A ECMO (X L/min based on 60 mL/kg/min) commenced. At seven time points during 24-h observation, echocardiographic parameters as well as pressure-volume catheter-based LVSWI and CPI were simultaneously measured with X and following X-1 L/min of ECMO flow. PSP was calculated by multiplying global circumferential strain or global radial strain, and mean arterial pressure, for PSPcirc or PSPrad, respectively. RESULTS: PSPcirc showed a stronger correlation with LVSWI (correlation coefficient, CC = .360, p < .001) and CPI (CC = .283, p < .001) than other echocardiographic parameters. The predictability of PSPcirc for pressure-volume catheter-based LVSWI (AUC .82) and CPI (AUC .80) was also higher than other echocardiographic parameters. No statistically significant differences were identified between the two ECMO flow variations in PSPcirc (p = .558). CONCLUSIONS: A novel echocardiographic parameter, PSP, may non-invasively predict pressure-volume catheter-based LVSWI and CPI in a load-independent manner in a cardiogenic shock supported by V-A ECMO.

Echocardiographic surrogate of left ventricular stroke work in a model of brain stem death donors.

BACKGROUND: The commonest echocardiographic measurement, left ventricular ejection fraction, can not necessarily predict mortality of recipients following heart transplantation potentially due to afterload dependency. Afterload-independent left ventricular stroke work index (LVSWI) is alternatively recommended by the current guideline; however, pulmonary artery catheters are rarely inserted in organ donors in most jurisdictions. We propose a novel non-invasive echocardiographic parameter, Pressure-Strain Product (PSP), as a potential surrogate of catheter-based LVSWI. This study aimed to investigate if PSP could correlate with catheter-based LVSWI in an ovine model of brain stem death (BSD) donors. The association between PSP and myocardial mitochondrial function in the post-transplant hearts was also evaluated. METHODS: Thirty-one female sheep (weight 47 ± 5 kg) were divided into two groups; BSD (n = 15), and sham neurologic injury (n = 16). Echocardiographic parameters including global circumferential strain (GCS) and global radial strain (GRS) and pulmonary artery catheter-based LVSWI were simultaneously measured at 8-timepoints during 24-h observation. PSP was calculated as a product of GCS or GRS, and mean arterial pressure for PSPcirc or PSPrad, respectively. Myocardial mitochondrial function was evaluated following 6-h observation after heart transplantation. RESULTS: In BSD donor hearts, PSPcirc (n = 96, rho = .547, p < .001) showed the best correlation with LVSWI among other echocardiographic parameters. PSPcirc returned AUC of .825 to distinguish higher values of cardiomyocyte mitochondrial function (cut-off point; mean value of complex 1,2 O2 Flux) in post-transplant hearts, which was greater than other echocardiographic parameters. CONCLUSIONS: PSPcirc could be used as a surrogate of catheter-based LVSWI reflecting mitochondrial function.

Tigilanol tiglate is an oncolytic small molecule that induces immunogenic cell death and enhances the response of both target and non-injected tumors to immune checkpoint blockade.

BACKGROUND: Tigilanol tiglate (TT) is a protein kinase C (PKC)/C1 domain activator currently being developed as an intralesional agent for the treatment of various (sub)cutaneous malignancies. Previous work has shown that intratumoral (I.T.) injection of TT causes vascular disruption with concomitant tumor ablation in several preclinical models of cancer, in addition to various (sub)cutaneous tumors presenting in the veterinary clinic. TT has completed Phase I dose escalation trials, with some patients showing signs of abscopal effects. However, the exact molecular details underpinning its mechanism of action (MoA), together with its immunotherapeutic potential in oncology remain unclear. METHODS: A combination of microscopy, luciferase assays, immunofluorescence, immunoblotting, subcellular fractionation, intracellular ATP assays, phagocytosis assays and mixed lymphocyte reactions were used to probe the MoA of TT in vitro. In vivo studies with TT used MM649 xenograft, CT-26 and immune checkpoint inhibitor refractory B16-F10-OVA tumor bearing mice, the latter with or without anti-programmed cell death 1 (PD-1)/anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mAb treatment. The effect of TT at injected and non-injected tumors was also assessed. RESULTS: Here, we show that TT induces the death of endothelial and cancer cells at therapeutically relevant concentrations via a caspase/gasdermin E-dependent pyroptopic pathway. At therapeutic doses, our data demonstrate that TT acts as a lipotoxin, binding to and promoting mitochondrial/endoplasmic reticulum (ER) dysfunction (leading to unfolded protein responsemt/ER upregulation) with subsequent ATP depletion, organelle swelling, caspase activation, gasdermin E cleavage and induction of terminal necrosis. Consistent with binding to ER membranes, we found that TT treatment promoted activation of the integrated stress response together with the release/externalization of damage-associated molecular patterns (HMGB1, ATP, calreticulin) from cancer cells in vitro and in vivo, characteristics indicative of immunogenic cell death (ICD). Confirmation of ICD in vivo was obtained through vaccination and rechallenge experiments using CT-26 colon carcinoma tumor bearing mice. Furthermore, TT also reduced tumor volume, induced immune cell infiltration, as well as improved survival in B16-F10-OVA tumor bearing mice when combined with immune checkpoint blockade. CONCLUSIONS: These data demonstrate that TT is an oncolytic small molecule with multiple targets and confirms that cell death induced by this compound has the potential to augment antitumor responses to immunotherapy.

Development has the answer: Unraveling psychiatric disorders via thalamocortical organoids.

Dissecting the role of the thalamus in neuropsychiatric disorders requires new models to analyze complex genetic interactions. In this issue of Cell Stem Cell, Shin et al. use patient-derived thalamocortical organoids to investigate 22q11.2 microdeletion impact on thalamic development, revealing significant transcriptional dysregulation linked to psychiatric disorders.