Month: April 2024

Abstract

Background

Tyrosine kinase inhibitors (TKIs) targeting fms-like tyrosine kinase 3 (Flt3) such as quizartinib were specifically designed for acute myeloid leukemia treatment, but also multi-targeting TKIs applied to solid tumor patients inhibit Flt3. Flt3 is expressed in the heart and its activation is cytoprotective in myocardial infarction (MI) in mice.

Objectives

We sought to test whether Flt3-targeting TKI treatment aggravates cardiac injury after MI.

Methods and results

Compared to vehicle, quizartinib (10 mg/kg/day, gavage) did not alter cardiac dimensions or function in healthy mice after four weeks of therapy. Pretreated mice were randomly assigned to MI or sham surgery while receiving quizartinib or vehicle for one more week. Quizartinib did not aggravate the decline in ejection fraction, but significantly enhanced ventricular dilatation one week after infarction. In addition, apoptotic cell death was significantly increased in the myocardium of quizartinib-treated compared to vehicle-treated mice. In vitro, quizartinib dose-dependently decreased cell viability in neonatal rat ventricular myocytes and in H9c2 cells, and increased apoptosis as assessed in the latter. Together with H₂O_2, quizartinib potentiated the phosphorylation of the pro-apoptotic mitogen activated protein kinase p38 and augmented H₂O₂-induced cell death and apoptosis beyond additive degree. Pretreatment with a p38 inhibitor abolished apoptosis under quizartinib and H₂O₂.

Conclusion

Quizartinib potentiates apoptosis and promotes maladaptive remodeling after MI in mice at least in part via a p38-dependent mechanism. These findings are consistent with the multi-hit hypothesis of cardiotoxicity and make cardiac monitoring in patients with ischemic heart disease under Flt3- or multi-targeting TKIs advisable.

Abstract

Background

Tyrosine kinase inhibitors (TKIs) targeting fms-like tyrosine kinase 3 (Flt3) such as quizartinib were specifically designed for acute myeloid leukemia treatment, but also multi-targeting TKIs applied to solid tumor patients inhibit Flt3. Flt3 is expressed in the heart and its activation is cytoprotective in myocardial infarction (MI) in mice.

Objectives

We sought to test whether Flt3-targeting TKI treatment aggravates cardiac injury after MI.

Methods and results

Compared to vehicle, quizartinib (10 mg/kg/day, gavage) did not alter cardiac dimensions or function in healthy mice after four weeks of therapy. Pretreated mice were randomly assigned to MI or sham surgery while receiving quizartinib or vehicle for one more week. Quizartinib did not aggravate the decline in ejection fraction, but significantly enhanced ventricular dilatation one week after infarction. In addition, apoptotic cell death was significantly increased in the myocardium of quizartinib-treated compared to vehicle-treated mice. In vitro, quizartinib dose-dependently decreased cell viability in neonatal rat ventricular myocytes and in H9c2 cells, and increased apoptosis as assessed in the latter. Together with H₂O_2, quizartinib potentiated the phosphorylation of the pro-apoptotic mitogen activated protein kinase p38 and augmented H₂O₂-induced cell death and apoptosis beyond additive degree. Pretreatment with a p38 inhibitor abolished apoptosis under quizartinib and H₂O₂.

Conclusion

Quizartinib potentiates apoptosis and promotes maladaptive remodeling after MI in mice at least in part via a p38-dependent mechanism. These findings are consistent with the multi-hit hypothesis of cardiotoxicity and make cardiac monitoring in patients with ischemic heart disease under Flt3- or multi-targeting TKIs advisable.

Abstract

Although many studies link mineral deposit formation to rifting and hydrothermal processes, we present a study that focuses on the relationship between crustal necking and mineral deposit formation. Necking corresponds to the timing, location, and process of rift localization and abrupt crustal and lithospheric thinning. Although necking is well identified and described from present-day rifted margins and has been modeled numerically, little is known about the necking process and its possible link to ore deposit formation. We present observations from the Mont-Blanc fossil detachment system, one of the few exposed examples of a necking detachment fault. We show that fluids flowed along the fault zone and leached metals (mainly Pb and Zn). This process was associated with the hydrothermal breakdown of feldspar and biotite at temperatures of 200 °C and salinities ranging from 5 to 20 eq. wt% with a H₂O-NaCl (-KCl) composition. The resulting metal-rich fluids reacted with mainly carbonate-rich units to form Pb-Zn ore deposits in basement and sedimentary cover rocks. A direct link can, therefore, be demonstrated between fluid and reaction-assisted breakdown of silicates, metal transfer and trapping along detachment faults, and the overlying sedimentary rocks during necking. Similar ore deposits can be found throughout the inner External Crystalline Massif of the Western Alps, interpreted as the former necking domain of the Alpine Tethys. This leads to the suggestion that necking and Pb-Zn deposit formation may be closely linked, a hypothesis, if correct, that has the potential to predict additional Pb-Zn-Ba-F resources in rifts, rifted margins, and reactivated fossil rifted margins forming collisional mountain belts.

Abstract

In previous analyses of regional underdevelopment, aspects such as technological progress, the implications of growth theory, depreciation (especially capital), capital input, and technology input have been completely ignored. Desmet and Ortίn analyze rational underdevelopment using a Ricardian model. This study investigates the underdevelopment of regions in the light of the Solow model. Two regions with two sectors are considered for the model. The regions are characterized by different technological equipment. The first region is industrial. The second region has an agricultural character. When a new technology is available, both regions can benefit under certain conditions. Financial transfers between regions equalize incomes. The security of transfer payments is positive; the increase in income levels without an increase in productivity is negative. The regions have different depreciation rates, factors, and technology endowments. Enlargement to a growth theoretical model framework (Solow model) should demonstrate the effects of an economy’s investments, constant depreciation rates, population growth, and technological progress. This will make it possible to see how the new influencing factors influence the utility of the two regions.

Abstract

Purpose

Compare extracranial internal carotid artery flow rates and intracranial collateral use between conventional ≥ 50% carotid stenosis and carotid near-occlusion, and between symptomatic and asymptomatic carotid near-occlusion.

Methods

We included patients with ≥ 50% carotid stenosis. Degree of stenosis was diagnosed on CTA. Mean blood flow rates were assessed with four-dimensional phase-contrast MRI.

Results

We included 110 patients of which 83% were symptomatic, and 38% had near-occlusion. Near-occlusions had lower mean internal carotid artery flow (70 ml/min) than conventional ≥ 50% stenoses (203 ml/min, P < .001). Definite use of ≥ 1 collateral was found in 83% (35/42) of near-occlusions and 10% (7/68) of conventional stenoses (P < .001). However, there were no differences in total cerebral blood flow (514 ml/min vs. 519 ml/min, P = .78) or ipsilateral hemispheric blood flow (234 vs. 227 ml/min, P = .52), between near-occlusions and conventional ≥ 50% stenoses, based on phase-contrast MRI flow rates. There were no differences in total cerebral or hemispheric blood flow, or collateral use, between symptomatic and asymptomatic near-occlusions.

Conclusion

Near-occlusions have lower internal carotid artery flow rates and more collateral use, but similar total cerebral blood flow and hemispheric blood flow, compared to conventional ≥ 50% carotid stenosis.