CAR binding efficacy and off-target interactions for common CAR detection reagents.

Background: Chimeric Antigen Receptor (CAR)-T cell therapy is a highly innovative form of cell-based immunotherapy. To expand CAR-T therapies into additional disease indications, identification of novel tumor antigens and grafting of CARs on other types of immune cells, such as macrophages and natural killer (NK) cells are being pursued. Therefore, as this treatment modality continues to evolve, there is a need for highly specific detection reagents to interrogate CAR surface expression.

The Effect of Intraoperative Hypotension on Postoperative Renal Function.

Purpose Of Review: This review summarizes the most recent literature on the association between intraoperative hypotension (IOH) and the occurrence of postoperative acute kidney injury (AKI). It provides recommendations for the management of intraoperative blood pressure to reduce the incidence of postoperative AKI. Fluid management strategies, administration of vasopressor medications, and other methods for reducing the incidence of AKI are also briefly discussed.

Oxygen Reserve Index: Utility as an Early Warning for Desaturation in High-Risk Surgical Patients.

Background: Perioperative pulse oximetry hemoglobin saturation (Spo2) measurement is associated with fewer desaturation and hypoxia episodes. However, the sigmoidal nature of oxygen-hemoglobin dissociation limits the accuracy of estimation of the partial pressure of oxygen (Pao2) >80 mm Hg and correspondingly limits the ability to identify when Pao2 >80 mm Hg but falling. We hypothesized that a proxy measurement for oxygen saturation (Oxygen Reserve Index [ORI]) derived from multiwavelength pulse oximetry may allow additional warning time before critical desaturation or hypoxia.

Study of early warning for desaturation provided by Oxygen Reserve Index in obese patients.

Acute hemoglobin desaturation can reflect rapidly decreasing PaO. Pulse oximetry saturation (SpO) facilitates hypoxia detection but may not significantly decrease until PaO < 80 mmHg. The Oxygen Reserve Index (ORI) is a unitless index that correlates with moderately hyperoxic PaO.

Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus.

Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers, and is closely associated with poor prognosis and chemo- or radiotherapeutic resistance. Phosphorylation of Akt at S473 (ref.

Perioperative hypotension and myocardial ischemia: diagnostic and therapeutic approaches.

Although perioperative hypotension is a common problem, its true incidence is largely unknown. There is evidence that postoperative outcome, including the incidence of myocardial adverse events, may be linked to the prolonged episodes of perioperative hypotension. Despite this, there are very few comprehensive resources available in the literature regarding diagnosis and management of these not so uncommon clinical occurrences, especially during non-cardiac surgery.

Harnessing the tumor suppressor function of FOXO as an alternative therapeutic approach in cancer.

The promotion of cellular survival, dedifferentiation, and uncontrolled proliferation via the suppression of apoptotic effectors is a fundamental characteristic of tumor cells. As substrates that are negatively regulated by oncogenic signaling cascades driven by AKT, SGK (serum- and glucocorticoid-inducible kinase), IkB kinase (IKK), ERK, and cyclin-dependent kinases (CDK), forkhead box-class O (FOXO) transcription factors have emerged as bona fide tumor suppressors. These transcription factors indeed regulate a variety of cellular responses and themselves are regulated by reversible phosphorylation, acetylation, ubiquitination and miRNAs.

PEST motif serine and tyrosine phosphorylation controls vascular endothelial growth factor receptor 2 stability and downregulation.

The internalization and degradation of vascular endothelial growth factor receptor 2 (VEGFR-2), a potent angiogenic receptor tyrosine kinase, is a central mechanism for the regulation of the coordinated action of VEGF in angiogenesis. Here, we show that VEGFR-2 is ubiquitinated in response to VEGF, and Lys 48-linked polyubiquitination controls its degradation via the 26S proteosome. The degradation and ubiquitination of VEGFR-2 is controlled by its PEST domain, and the phosphorylation of Ser1188/Ser1191 is required for the ubiquitination of VEGFR-2.

Perioperative pharmacology in elderly patients.

Purpose Of Review: Populations across the world are getting older and requiring more surgery. Elderly patients present unique challenges to the anesthesiologist and anesthesia-care team. This review addresses some concerns when caring for an elderly patient.

Protein phosphatase 2A reactivates FOXO3a through a dynamic interplay with 14-3-3 and AKT.

Forkhead box transcription factor FOXO3a, a key regulator of cell survival, is regulated by reversible phosphorylation and subcellular localization. Although the kinases regulating FOXO3a activity have been characterized, the role of protein phosphatases (PP) in the control of FOXO3a subcellular localization and function is unknown. In this study, we detected a robust interaction between FOXO3a and PP2A.

Surgery in the patient with liver disease.

Liver dysfunction is a prominent entity in Western medicine that has historically affected patients suffering from chronic viral or alcoholic hepatitis. The incidence of these conditions has not changed dramatically in recent years but the overall number of patients with liver dysfunction has increased considerably with the emergence of the obesity epidemic. Nonalcoholic fatty liver disease (NAFLD) has become increasingly recognized as the most common cause of chronic liver disease in the United States.

Surgery in the patient with liver disease.

Liver dysfunction is a prominent entity in Western medicine that has historically affected patients suffering from chronic viral or alcoholic hepatitis. The incidence of these conditions has not changed dramatically in recent years but the overall number of patients with liver dysfunction has increased considerably with the emergence of the obesity epidemic. Nonalcoholic fatty liver disease (NAFLD) has become increasingly recognized as the most common cause of chronic liver disease in the United States.

Experimental approaches to investigate the proteasomal degradation pathways involved in regulation of apoptosis.

Ubiquitin-mediated proteolysis plays a major role in a variety of cellular functions, including cell metabolism, cell cycle progression, cellular response to DNA damage, and programmed cell death. In most cases, the crucial regulators involved in the control of these diverse cellular functions are modified by specific E3 ubiquitin ligases through the attachment of multiple ubiquitin molecules, a signal that triggers the subsequent destruction by the 26S proteasome complex. Recent studies revealed that the proteasomal degradation pathway regulates the cellular apoptosis process on multiple levels.

FoxO tumor suppressors and BCR-ABL-induced leukemia: a matter of evasion of apoptosis.

Numerous studies have revealed that the BCR-ABL oncoprotein abnormally engages a multitude of signaling pathways, some of which may be important for its leukemogenic properties. Central to this has been the determination that the tyrosine kinase function of BCR-ABL is mainly responsible for its transforming potential, and can be targeted with small molecule inhibitors, such as imatinib mesylate (Gleevec, STI-571). Despite this apparent success, the development of clinical resistance to imatinib therapy, and the inability of imatinib to eradicate BCR-ABL-positive malignant hematopoietic progenitors demand detailed investigations of additional effector pathways that can be targeted for CML treatment.

A critical role for the E3-ligase activity of c-Cbl in VEGFR-2-mediated PLCgamma1 activation and angiogenesis.

Activation of phospholipase Cgamma1 (PLCgamma1) by vascular endothelial growth factor receptor-2 (VEGFR-2) in endothelial cells in part is responsible for angiogenesis in vivo. The cellular mechanisms exerting negative control over PLCgamma1 activation, however, remain unaddressed. Here by using in vitro and in vivo binding assays, we show that the Casitas B-lineage lymphoma (c-Cbl) E3 ubiquitin ligase constitutively associates with PLCgamma1 via its C-terminal domain and conditionally interacts with VEGFR-2 via the N-terminal/TKB domain.

The carboxyl terminus of VEGFR-2 is required for PKC-mediated down-regulation.

Vascular endothelial growth factor receptor-2 (VEGFR-2/Flk-1) is a receptor tyrosine kinase (RTK) whose activation regulates angiogenesis. The regulatory mechanisms that attenuate VEGFR-2 signal relay are largely unknown. Our study shows that VEGFR-2 promotes phosphorylation of c-Cbl, but activation, ubiquitylation, and down-regulation of VEGFR-2 are not influenced by c-Cbl activity.

Substitution of C-terminus of VEGFR-2 with VEGFR-1 promotes VEGFR-1 activation and endothelial cell proliferation.

VEGFR-1 is devoid of ligand-dependent tyrosine autophosphorylation and its activation is not associated with proliferation of endothelial cells. The molecular mechanism responsible for this characteristic of VEGFR-1 is not known. In this study, we show that VEGFR-1 is devoid of ligand-dependent downregulation and failed to stimulate intracellular calcium release, cell migration and angiogenesis in vitro.

Cardiac output monitoring during off-pump coronary artery bypass grafting.

Objective: To evaluate and compare monitors of cardiac output during repositioning and stabilization of the heart for off-pump coronary artery bypass (OPCAB) surgery.

Design: Prospective, observational, clinical study.

Setting: University teaching hospital.

The carboxyl terminus controls ligand-dependent activation of VEGFR-2 and its signaling.

Vascular endothelial growth factor receptor-2 (VEGFR-2/FLK-1) is a receptor tyrosine kinase whose activation stimulates angiogenesis. We recently generated a chimeric VEGFR-2 in which the extracellular domain of VEGFR-2 was replaced with the extracellular domain of human colony stimulating factor-1 receptor and expressed in endothelial cells. To study the contribution of the carboxyl terminus to activation of VEGFR-2, we created a panel of truncated receptors in which the carboxyl terminus of VEGFR-2 was progressively deleted.

Anesthetic management in fibrodysplasia ossificans progressiva (FOP): a case report.

Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder of connective tissue, which has significant implications on anesthetic management of affected patients, e.g., application of difficult airway algorithm, avoiding any trauma during venous cannulation.