Interdependent Citizens: The Ethics of Care in Pandemic Recovery

The crisis of Covid-19 has forced us to notice two things: our human interdependence and American society's tolerance for what Nancy Krieger has called “inequalities embodied in health inequities,” reflected in data on Covid-19 mortality and geographies. Care is integral to our recovery from this catastrophe and to the development of sustainable public health policies and practices that promote societal resilience and reduce the vulnerabilities of our citizens. Drawing on the insights of Joan Tronto and Eva Feder Kittay, we argue that the ethics of care offers a critical alternative to utilitarian and deontological approaches and provides a street-ready framework for integration into public health deliberations to anchor public policy and investments concerning the recovery and future well-being of America's citizens and society.     

Percutaneous ventricular assist device placement during active cardiopulmonary resuscitation for severe refractory cardiogenic shock after acute myocardial infarction

Cardiogenic shock after acute myocardial infarction is associated with a high mortality rate despite modern reperfusion methods and intra-aortic balloon pump support. For myocardial infarction patients in cardiogenic shock that is refractory to intra-aortic ballon pump counterpulsation and pressors (severe refractory cardiogenic shock), there are limited means to rapidly provide additional hemodynamic support. We present the case of a 49-year-old man who presented with an anterior wall acute myocardial infarction complicated by cardiogenic shock. After resuscitation and stabilization with intra-aortic balloon pump and pressor support, the patient underwent successful emergent percutaneous transluminal coronary angioplasty and stenting of the left anterior descending coronary artery. Forty-eight hours later, the patient again went into severe refractory cardiogenic shock; pulseless electrical activity arrest followed. Cardiopulmonary resuscitation was started, and the patient underwent urgent placement of a TandemHeart percutaneous ventricular assist device. The device enabled the reversal of terminal hemodynamic collapse during active cardiopulmonary resuscitation, subsequent stabilization of the patient, and discharge of the patient from the hospital after device removal. In this patient, the percutaneous ventricular assist device was successful in the treatment of severe refractory cardiogenic shock after acute myocardial infarction.     

Skeletal muscle glucose metabolism and inflammation in the development of the metabolic syndrome

Insulin resistance and metabolic dysfunction in skeletal muscle play a major role in the development of the metabolic syndrome and type 2 diabetes. Numerous mechanisms have been proposed to explain the pathophysiology of obesity-linked metabolic dysfunction and this review will focus on the contributing role of adiponectin and inflammation. The beneficial effects of adiponectin on both insulin action and inflammation are now well documented and will be reviewed. More recent work provided new insights into adiponectin signaling mechanisms. The development of strategies to mimic adiponectin action holds promise that adiponectin-based compounds may translate into effective therapeutic applications. We will also discussed the novel role of long chain ω-3 PUFA-derived resolution mediators, which in addition to resolving inflammation, can also exert glucoregulatory effects in models of obesity and insulin resistance. We will focus on one resolution mediator, protectin DX (PDX), which was recently shown to act as a muscle interleukin-6 secretagogue. PDX and its isomer PD1 also enhance adiponectin expression and action. Ultimately, it is via a better understanding the molecular mechanisms of action via which inflammation, insulin resistance and metabolic dysfunction occur in skeletal muscle, and also how they crosstalk with each other, that we can generate new and improved therapies for obesity-linked metabolic complications.     

AFP, AFP-L3, DCP, and GP73 as markers for monitoring treatment response and recurrence and as surrogate markers of clinicopathological variables of HCC

Background

Alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), des-γ-carboxy prothrombin (DCP), and Golgi protein-73 (GP73) have been used or proposed as tumor markers for hepatocellular carcinoma (HCC).

Methods

They were measured in 96 patients undergoing hepatectomy for HCC to investigate their treatment response and association with variables linked with tumor invasiveness and/or prognosis. Values at 1 month post-surgery in the 77 patients without recurrence within 6 postoperative months were adopted as those after surgery.

Results

GP73 levels did not change after hepatectomy, but levels of other markers decreased and areas under receiver operating characteristic curves (95% CI) were: 0.64 (0.56–0.72), 0.63 (0.55–0.71), 0.79 (0.73–0.86), and 0.63 (0.55–0.71) for AFP, AFP-L3, DCP, and combination of AFP and AFP-L3, respectively. Cutoff points giving specificities of 96.1% (sensitivities at these points) were: 124 ng/mL (28.1%), 10% (21.9%), and 60 mAU/mL (52.1%), for AFP, AFP-L3, and DCP, respectively. The combination of AFP and AFP-L3 provided a sensitivity of 26.0% at a specificity of 96.1%. The increased DCP value was, or tended to be, associated with a larger tumor, vascular invasion, intrahepatic metastases, and a lower grade of tumor cell differentiation. Although similar associations were found between AFP and vascular invasion as well as a lower grade of tumor cell differentiation, no such relationship was found with AFP-L3.

Conclusions

DCP is a more effective tumor marker than AFP and AFP-L3. AFP-L3 showed comparable accuracy to AFP but no benefit was found in their combination. GP73 did not play a significant role in this context. Indices of tumor invasiveness were most closely associated with DCP.     

Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells

An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD(+) leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML.