Outcomes of Venovenous Extracorporeal Membrane Oxygenation in Viral Acute Respiratory Distress Syndrome.

Our study assessed the relationship between the duration of venovenous extracorporeal membrane oxygenation (V-V ECMO) and patient outcomes. We studied patients undergoing V-V ECMO support for acute respiratory distress syndrome (ARDS) between 2009 and 2017 who were reported to the Extracorporeal Life Support Organization registry. We evaluated survival, major bleeding, renal failure, pulmonary complications, mechanical complications, neurologic complications, infection, and duration of V-V ECMO support. Multivariable regression modeling assessed risk factors for adverse events. Of the 4,636 patients studied, the mean support duration was 12.2 ± 13.7 days. There was a progressive increase in survival after the initiation of V-VECMO, peaking at a survival rate of 73% at 10 days of support. However, a single-day increase in V-V ECMO duration was associated with increased bleeding events (odds ratio [OR] 1.038; 95% confidence interval [CI]: 1.029-1.047; p < 0.0001), renal failure (OR 1.018; 95% CI: 1.010-1.027; p < 0.0001), mechanical complications (OR 1.065; 95% CI: 1.053-1.076; p < 0.0001), pulmonary complications (OR 1.04; 95% CI: 1.03-1.05; p < 0.0001), and infection (OR 1.04; 95% CI: 1.03-1.05; p < 0.0001). V-V ECMO progressively increases survival for ARDS over the first 10 days of support. Thereafter, rising complications associated with prolonged durations of support result in a progressive decline in survival.

The Potential of Topoisomerase Inhibitor-Based Antibody-Drug Conjugates.

DNA topoisomerases are essential enzymes that stabilize DNA supercoiling and resolve entanglements. Topoisomerase inhibitors have been widely used as anti-cancer drugs for the past 20 years. Due to their selectivity as topoisomerase I (TOP1) inhibitors that trap TOP1 cleavage complexes, camptothecin and its derivatives are promising anti-cancer drugs. To increase accumulation of TOP1 inhibitors in cancer cells through the targeting of tumors, TOP1 inhibitor antibody-drug conjugates (TOP1-ADC) have been developed and marketed. Some TOP1-ADCs have shown enhanced therapeutic efficacy compared to prototypical anti-cancer ADCs, such as T-DM1. Here, we review various types of camptothecin-based TOP1 inhibitors and recent developments in TOP1-ADCs. We then propose key points for the design and construction of TOP1-ADCs. Finally, we discuss promising combinatorial strategies, including newly developed approaches to maximizing the therapeutic potential of TOP1-ADCs.

AZD2014, a dual mTOR inhibitor, attenuates cardiac hypertrophy in vitro and in vivo.

Cardiac hypertrophy is one of the most common genetic heart disorders and considered a risk factor for cardiac morbidity and mortality. The mammalian target of rapamycin (mTOR) pathway plays a key regulatory function in cardiovascular physiology and pathology in hypertrophy. AZD2014 is a small-molecule ATP competitive mTOR inhibitor working on both mTORC1 and mTORC2 complexes. Little is known about the therapeutic effects of AZD2014 in cardiac hypertrophy and its underlying mechanism. Here, AZD2014 is examined in in vitro model of phenylephrine (PE)-induced human cardiomyocyte hypertrophy and a myosin-binding protein-C (Mybpc3)-targeted knockout (KO) mouse model of cardiac hypertrophy. Our results demonstrate that cardiomyocytes treated with AZD2014 retain the normal phenotype and AZD2014 attenuates cardiac hypertrophy in the Mybpc3-KO mouse model through inhibition of dual mTORC1 and mTORC2, which in turn results in the down-regulation of the Akt/mTOR signaling pathway.

Peptide Adjuvant to Invigorate Cytolytic Activity of NK Cells in an Obese Mouse Cancer Model.

Cancer patients who are overweight compared to those with normal body weight have obesity-associated alterations of natural killer (NK) cells, characterized by poor cytotoxicity, slow proliferation, and inadequate anti-cancer activity. Concomitantly, prohibitin overexpressed by cancer cells elevates glucose metabolism, rendering the tumor microenvironment (TME) more tumor-favorable, and leading to malfunction of immune cells present in the TME. These changes cause vicious cycles of tumor growth. Adoptive immunotherapy has emerged as a promising option for cancer patients; however, obesity-related alterations in the TME allow the tumor to bypass immune surveillance and to down-regulate the activity of adoptively transferred NK cells. We hypothesized that inhibiting the prohibitin signaling pathway in an obese model would reduce glucose metabolism of cancer cells, thereby changing the TME to a pro-immune microenvironment and restoring the cytolytic activity of NK cells. Priming tumor cells with an inhibitory the prohibitin-binding peptide (PBP) enhances cytokine secretion and augments the cytolytic activity of adoptively transferred NK cells. NK cells harvested from the PBP-primed tumors exhibit multiple markers associated with the effector function of active NK cells. Our findings suggest that PBP has the potential as an adjuvant to enhance the cytolytic activity of adoptively transferred NK cells in cancer patients with obesity.

Targeted delivery of heat shock protein 90 inhibitors prevents growth of HER2-positive tumor.

Heat shock protein 90 (HSP90) plays a crucial role in the survival of cancer cells. When an inhibitor blocks the signaling pathway of HSP90, its client proteins are degraded, destabilized, and inactivated. Although HSP90 inhibitors are in various clinical trials, there are no HSP90 inhibitor-immunoconjugates due to the difficulty in chemical modification of HSP90 inhibitors. Here we show that biological affinity binding enables the incorporation of HSP90 inhibitors to an antibody without the need for chemical conjugation. We constructed a recombinant fusion protein composed of an anti-HER2 scFv and an HSP90 inhibitor-binding domain (HER2 scFv-HBD). The HBD spontaneously captures a HSP90 inhibitor, resulting in the formation of an HER2 scFv-HBD/HSP90 inhibitor complex. In an HER2-positive cancer mouse model, targeted delivery of HSP90 inhibitors was confirmed and improved anti-cancer efficacy was observed. We have proven the promise of tumor-directed HSP90 inhibition as a new form of targeted therapy.

Short-Term Risk of Bilateral Internal Mammary Artery Grafting in Diabetic Patients.

This study compares the morbidity and mortality at 30 days following the use of bilateral internal mammary arteries (BIMA) vs a single internal mammary artery (SIMA) at the time of coronary artery bypass grafting (CABG) in patients with a preoperative HbA1c. Patients undergoing CABG from January 2008 to December 2016 reported to the Society of Thoracic Surgeons database were retrospectively reviewed. The patients were divided into 2 groups: use of BIMA or use of SIMA and propensity matched. To assess the effect of preoperative HbA1c, both groups were further divided into 5 subgroups: patients without diabetes mellitus (DM), or patients with DM and a preoperative HbA1c level in one of four groups (< 7%, 7-9%, 9-11%, or >11%). The postoperative outcomes in both the BIMA and SIMA groups were compared. There were 700,504 and 28,115 patients with measured preoperative HbA1c levels in the SIMA and BIMA groups, respectively. Propensity score matching identified 23,635 comparable patients in each group for analysis. There was no difference in postoperative mortality between the BIMA and SIMA groups (1.3% vs 1.2%). The incidences of sternal wound infection (SWI) in patients undergoing placement of BIMA vs SIMA were: 0.8% vs 0.4% with no DM (P < 0.0001), 1.9% vs 1.0% with HbA1c < 7% (P < 0.001), 2.4% vs 1.2% with HbA1c 7-9% (P < 0.001), 2.8% vs 1.4% with HbA1c 9-11% (P = 0.02), 4.1% vs 1.5% with HbA1c > 11% (P = 0.01). Based on the incidence of SWI, BIMA is a reasonable approach with an HbA1c<7%.

The Role of Adjuvant Therapy in Advanced Thymic Carcinoma: A National Cancer Database Analysis.

BACKGROUND: There is area of controversy and variability in the recommendation for the role of adjuvant therapy after R0 resection of a Masaoka stage IIB and III thymic carcinoma. This study investigated the role of adjuvant therapy in patients who had complete surgical resection for thymic carcinoma. METHODS: Patients with stage IIB and III thymic carcinoma who underwent curative resection were queried and categorized according to Masaoka-Koga stage groups from the National Cancer Database. Patients were grouped by treatment status (surgery only or surgery followed by adjuvant therapy). Kaplan-Meier estimates of overall survival and univariate and multivariate Cox proportional hazards regression analyses were performed. RESULTS: From 2004 to 2013, 632 surgical patients with stage IIB and III thymic carcinoma were selected for analysis. In stage IIB patients, the adjuvant therapy group had improved survival compared with the surgery only group (P = .01), although no survival difference was observed in patients who had R0 resection between the 2 groups (P = .59). In multivariate analysis, age (P < .001) and grade III and IV (P = .02) negatively impacted survival; the adjuvant therapy improved survival (P < .02). For stage III cancer, the adjuvant therapy group had improved survival compared with the OS group regardless of margin status. In multivariate analysis, tumor size exceeding 70 mm (P = .02) and positive margin (P < .01) negatively affected survival; adjuvant therapy improved survival (P < .01). CONCLUSIONS: Adjuvant therapy showed no benefit in patients with stage IIB cancer who had R0 resection. Use of adjuvant therapy should be strongly considered for stage IIB cancer patients with positive margins and all stage III thymic cancer patients.

Imaging assessment of cardioprotection mediated by a dodecafluoropentane oxygen-carrier administered during myocardial infarction.

INTRODUCTION: The objective of this study was to investigate the cardioprotective effects of a dodecafluoropentane (DDFP)-based perfluorocarbon emulsion (DDFPe) as an artificial carrier for oxygen delivery to ischemic myocardium, using 99mTc-duramycin SPECT imaging. METHODS: Rat hearts with Ischemia-reperfusion (I/R) was prepared by coronary ligation for 45-min followed by reperfusion. The feasibility of 99mTc-duramycin in detecting myocardial I/R injury and its kinetic profile were first verified in the ischemic hearts with 2-h reperfusion (n = 6). DDFPe (0.6 mL/kg) was intravenously administered at 10 min after coronary ligation in fifteen rats and saline was given in thirteen rats as controls. 99mTc-duramycin SPECT images were acquired in the DDFPe-treated hearts and saline controls at 2-h (DDFPe-2 h, n = 7 and Saline-2 h, n = 6) or 24-h (DDFPe-24 h, n = 8 and Saline-24 h, n = 7) of reperfusion. RESULTS: SPECT images, showing "hot-spot" 99mTc-duramycin uptake in the ischemic myocardium, exhibited significantly lower radioactive retention and smaller hot-spot size in the DDFPe-2 h and DDFPe-24 h hearts compared to controls. The infarcts in the Saline-24 h hearts extended significantly relative to measurements in the Saline-2 h. The extension of infarct size did not reach a statistical difference between the DDFPe-2 h and DDFPe-24 h hearts. Ex vivo measurement of 99mTc-duramycin activity (%ID/g) was lower in the ischemic area of DDFPe-2 h and DDFPe-24 h than that of the Saline-2 h and Saline-24 h hearts (P < 0.05). The area of injured myocardium, delineated by the uptake of 99mTc-duramycin, extended more substantially outside the infarct zone in the controls. CONCLUSIONS: Significant reduction in myocardial I/R injury, as assessed by 99mTc-duramycin cell death imaging and histopathological analysis, was induced by DDFPe treatment after acute myocardial ischemia. 99mTc-duramycin imaging can reveal myocardial cell death in ischemic hearts and may provide a tool for the non-invasive assessment of cardioprotective interventions.

Is There a Role for Cancer-Directed Surgery in Early-Stage Sarcomatoid or Biphasic Mesothelioma?

BACKGROUND: Benefits of surgical resection for early-stage nonepithelioid malignant pleural mesothelioma (MPM) have not been clearly elucidated. This study investigated whether cancer-directed surgery affects overall survival compared with nonsurgical therapies for T1-T2 N0 M0 sarcomatoid or biphasic MPM patients. METHODS: Adult patients with clinical stage I or II MPM were identified in the National Cancer Database from 2004 to 2103. Patients who underwent cancer-directed surgery were matched by propensity score with patients who had received chemotherapy/radiotherapy or no treatments. Overall survival was compared using a Cox proportional hazard regression model. RESULTS: From National Cancer Database queries, 878 patients with clinical stage I or II MPM with sarcomatoid (n = 524) or biphasic (n = 354) histology were identified. Overall median survival was 5.5 months for patients with sarcomatoid mesothelioma. The cancer-directed surgery improved overall survival compared with no operation (median survival, 7.56 months vs 4.21 months, respectively; p < 0.01). In the biphasic group, median overall survival was 12.2 months. Again, the cancer-directed surgery improved survival compared with no operation (15.8 months vs 9.3 months, p < 0.01). For both histologies, the cancer-directed surgery improved overall survival compared with those who underwent chemotherapy or radiotherapy, or both, without resection (p < 0.05). Perioperative mortality was 6.0% at 30 days and 21.4% at 90 days. CONCLUSIONS: The cancer-directed surgery is associated with improved survival in early-stage MPM patients with nonepithelioid histology compared with those who did not undergo resection or chose medical therapy. Given the high perioperative mortality, a careful patient selection and multidisciplinary evaluation is recommended.

Cell surface engineering and application in cell delivery to heart diseases.

Cell-based therapy has expanded its influence in cancer immunotherapy, regenerative medicine, and tissue engineering. Due to their secretory functions, differentiation capabilities, specific homing effects through chemotaxis, distinctive therapeutic potentials, and ex vivo expandability, cells have become an attractive reagent for advanced therapeutic strategies. Therefore, the ability to modify cells and manipulate their functions according to intended therapeutic designs has been the central scientific interest in the field of biomedical research. Many innovative methods have been developed with genetic modification of cells being the most advanced cell surface engineering technique. Although genetic modification is a powerful tool, it has a limited applicability due to the permanent modifications made on cells. Alternatively, many endeavors have been made to develop surface engineering techniques that can circumvent the limitations of genetic modification. In this review, current methods of non-genetic cell surface modification, including chemical conjugations, polymeric encapsulation, hydrophobic insertion, enzymatic and metabolic addition, will be introduced. Moreover, cell surface engineering plausible for cardiac remodeling and the future prospective will be discussed at the end.

One-Step Method for Instant Generation of Advanced Allogeneic NK Cells.

Conventional combinatorial anticancer therapy has shown promising outcomes; still, a significant interest in developing new methods to reinforce and possibly merge chemotherapy and immunotherapy persists. Here, a new one-step method that immediately modifies immune cells into a targeted form of chemoimmunotherapy through spontaneous and rapid incorporation of hydrophobized antibody-drug conjugates (ADCs) on the surface of immune cells is presented. Therapeutic objectives of this approach include targeted delivery of a potent chemotherapeutic agent to avoid adverse effects, enhancing the mobilization of infused immune cells toward tumor sites, and preserving the intense cytotoxic activities of immune cells against tumor cells. The embedding of hydrophobized ADCs on the immune cell membrane using the strategy in this study provides noninvasive, nontoxic, and homogenous modifications that transiently arm immune cells with highly potent cytotoxic drugs targeted toward cancer cells. The resulting surface-engineered immune cells with ADCs significantly suppress the tumor growth and drive the eradication of target cancer cells through combinatorial anticancer effects. This novel strategy allows convenient and timely preparation of advanced chemoimmunotherapy on a single immune cell to treat various types of cancer.

Abundance, localization, and functional correlates of the advanced glycation end-product carboxymethyl lysine in human myocardium.

Advanced glycation end-products (AGEs) play a role in the pathophysiology of diabetes mellitus (DM) and possibly hypertension (HTN). In experimental DM, AGEs accumulate in myocardium. Little is known about AGEs in human myocardium. We quantified abundance, localization, and functional correlates of the AGE carboxymethyl lysine (CML) in left ventricular (LV) myocardium from patients undergoing coronary bypass grafting (CBG). Immunoelectron microscopy was used to quantify CML in epicardial biopsies from 98 patients (71 M, 27 F) with HTN, HTN + DM or neither (controls), all with normal LV ejection fraction. Myofilament contraction-relaxation function was measured in demembranated myocardial strips. Echocardiography was used to quantify LV structure and function. We found that CML was abundant within cardiomyocytes, but minimally associated with extracellular collagen. CML counts/µm2 were 14.7% higher in mitochondria than the rest of the cytoplasm (P < 0.001). There were no significant sex or diagnostic group differences in CML counts [controls 45.6 ± 3.6/µm2 (±SEM), HTN 45.8 ± 3.6/µm2, HTN + DM 49.3 ± 6.2/µm2; P = 0.85] and no significant correlations between CML counts and age, HgbA1c or myofilament function indexes. However, left atrial volume was significantly correlated with CML counts (r = 0.41, P = 0.004). We conclude that in CBG patients CML is abundant within cardiomyocytes but minimally associated with collagen, suggesting that AGEs do not directly modify the stiffness of myocardial collagen. Coexistent HTN or HTN + DM do not significantly influence CML abundance. The correlation of CML counts with LAV suggests an influence on diastolic function independent of HTN, DM or sex whose mechanism remains to be determined.

Primary Cystic Pleuropulmonary Synovial Sarcoma Presenting as Recurrent Pneumothorax.

Primary pleuropulmonary synovial sarcomas are quite rare, representing 0.1-0.5% of all pulmonary malignancies. We report an entirely cystic monophasic synovial sarcoma in a 25-year-old male who presented with recurrent pneumothorax and no evidence of a mass lesion on imaging. The purpose of this case report is to increase awareness of neoplasms clinically presenting as a pneumothorax with no imagining evidence of a mass-forming lesion and emphasize the significance of fluorescent in situ hybridization testing in nontypical synovial sarcoma cases.

Excessive Surgical Adhesive Mimicking Aortic Root Abscess: A Case Report.

Aortic root abscess is a complication of aortic valve endocarditis that is associated with a high morbidity and mortality. The diagnosis usually is made with transesophageal echocardiography, which is highly sensitive and specific for the disease. We present a case of suspected aortic root abscess 1 week after mechanical aortic valve replacement for native valve endocarditis. The diagnosis was made by the use of transesophageal echocardiography but surgical inspection revealed that the paravalvular fluid collection was excessive surgical adhesive. We discuss the clinical significance and differential diagnosis of aortic root abscess in the setting of infective endocarditis.

Bioprosthetic Aortic Paravalvular Leak: Is Valve-in-Valve Another Solution?

Paravalvular leak (PVL) following aortic valve implantation is a rare complication but may cause potentially serious consequences. It occurs in 2%-10% of surgical aortic valve replacements and 7%-17% of surgical mitral valve replacements. Transcatheter valve replacement data show that significant PVL occurs in 6%-8% of cases. The management of significant PVL has traditionally involved repeat surgical repair. However, many of these patients are considered too high risk to undergo a repeat surgical procedure; hence, a percutaneous transcatheter approach has often been utilized to treat these patients. Vascular plugs have been used to close PVLs, with variable results; the procedure is complex and technically demanding. Transcatheter aortic valve replacement, using a valve-in-valve approach, may provide an alternative approach for bioprosthetic PVL in the aortic position.

Direct Incorporation of Functional Peptides into M-DNA through Ligand-to-Metal Charge Transfer.

Conventional nonviral gene delivery methods suffer from the toxicity of the cationic nature of polymeric carriers. There is a significant need for a new method of gene delivery that overcomes the limitations and allows targeted gene delivery. In this study, we have developed a new method to incorporate functional peptides into DNA without the need for chemical conjugations by utilizing a ligand-to-metal charge transfer (LMCT) transition, which occurs between divalent metal ions and the sulfhydryl group in cysteine. To apply the LMCT transition to the incorporation of cysteine-containing targeting peptides into DNA, divalent metal ions must be first introduced to DNA. Zn2+ ions spontaneously intercalate into the DNA base pairs in the pH range of 7.0-8.5, resulting in the conversion of normal B-DNA to metal-bound DNA (M-DNA). We found that the Zn2+ ions present in M-DNA could interact with the sulfhydryl groups in cysteines of targeting peptides through the LMCT transition, and the M-DNA/peptide complex could specifically transfect the target cells.

Cell surface-engineering to embed targeting ligands or tracking agents on the cell membrane.

The key challenge to improve the efficacy of cell therapy is how to efficiently modify cells with a specific molecule or compound that can guide the cells to the target tissue. To address this, we have developed a cell surface engineering technology to non-invasively modify the cell surface. This technology can embed a wide variety of bioactive molecules on any cell surface and allow for the targeting of a wide range of tissues in a variety of disease states. Using our cell surface engineering technology, mesenchymal stem cells (MSC)s were modified with: 1) a homing peptide or a recombinant protein to facilitate the migration of the cells toward a specific molecular target; or 2) magnetic resonance imaging (MRI) contrast agents to allow for in vivo tracking of the cells. The incorporation of a homing peptide or a targeting ligand on MSCs facilitated the migration of the cells toward their molecular target. MRI contrast agents were successfully embedded on the cell surfaces without adverse effects to the cells and the contrast agent-labeled cells were detectable by MRI. Our technology is a promising method of cell surface engineering that is applicable to a broad range of cell therapies.

Pulmonary arterial hypertension in primary amyloidosis.

Amyloidosis involves extravascular deposition of fibrillar proteins within tissues and organs. Primary light chain amyloidosis represents the most common form of systemic amyloidosis involving deposition of monoclonal immunoglobulin light chains. Although pulmonary amyloid deposition is common in primary amyloidosis, clinically significant pulmonary amyloidosis is uncommon, and elevated pulmonary artery pressures are rarely observed in the absence of other underlying etiologies for pulmonary hypertension, such as elevated filling pressures secondary to cardiac amyloid. In this case report, we present a patient with primary light chain amyloidosis and pulmonary arterial hypertension in the setting of pulmonary vascular and right ventricular myocardial amyloid deposition.