Faculty Bibliography

We have designed lectin functionalized Lipo-polymerosome bearing Amphotericin B (Lec-AmB-L-Psome) for specific internalization via lectin receptors over-expressed on infected macrophages of mononuclear phagocytic system (MPS) for the effective management of intramacrophage diseases such as Visceral Leishmaniasis. The lipo-polymerosome composed of glycol chitosan-stearic acid copolymer (GC-SA25%) and model lipid cholesterol, was surface functionalized with lectin by EDC/NHS carbodiimide coupling method. Our designed Lec-AmB-L-Psome showed >2 fold enhanced uptake and significantly higher internalization in macrophages as compared to AmB-L-Psome. Importantly, pharmacokinetic and organ distribution studies illustrate significantly higher accumulation of Lec-AmB-L-Psome in MPS especially in liver, spleen and lung as compared to AmB-L-Psome, Ambisome and Fungizone. The IC50 value demonstrated that Lec-AmB-L-Psome has 1.63, 2.23 and 3.43 times higher activity as compared to AmB-L-Psome (p<0.01), Ambisome (p<0.05) and Fungizone (p<0.05), respectively. Additionally, the Lec-AmB-L-Psome showed significantly higher splenic parasite inhibition (78.66+/-3.08%) compared to Fungizone and Ambisome that caused only 56.54+/-3.91% (p<0.05) and 66.46+/-2.08% (p<0.05) parasite inhibition, respectively in Leishmania-infected hamsters. The toxicity profile revealed that Lec-AmB-L-Psome is safe delivery system with diminished nephrotoxicity which is a limiting factor of Fungizone application. Taken together these studies suggest this surface functionalized self assembled Lec-AmB-L-Psome can open new platform to specifically target macrophages for effective management of intramacrophage diseases.

INTRODUCTION: Pathophysiologic changes associated with diabetes impair new blood vessel formation and wound healing. Mesenchymal stem cells derived from adipose tissue (ASCs) have been used clinically to promote healing, although it remains unclear whether diabetes impairs their functional and therapeutic capacity. METHODS: In this study, we examined the impact of diabetes on the murine ASC niche, as well as on the potential of isolated cells to promote neovascularization in vitro and in vivo. A novel single cell analytical approach was used to interrogate ASC heterogeneity and subpopulation dynamics in this pathologic setting. RESULTS: Our results demonstrate that diabetes alters the ASC niche in situ, and that diabetic ASCs are compromised in their ability to establish a vascular network both in vitro and in vivo. Moreover, these diabetic cells were ineffective in promoting soft tissue neovascularization and wound healing. Single cell transcriptional analysis identified a subpopulation of cells which was diminished in both type 1 and type 2 models of diabetes. These cells were characterized by the high expression of genes known to be important for new blood vessel growth. CONCLUSIONS: Perturbations in specific cellular subpopulations, visible only on a single cell level, represent a previously unreported mechanism for the dysfunction of diabetic ASCs. These data suggest that the utility of autologous ASCs for cell-based therapies in diabetic patients may be limited, and that interventions to improve cell function before application are warranted.

In this commentary, Michelle Arbeitman et al., examine the topic of the Genetics of Sex as explored in this month's issues of GENETICS and G3: Genes|Genomes|Genetics. These inaugural articles are part of a joint Genetics of Sex collection (ongoing) in the GSA journals.

Inflammation contributes to many of the characteristics of plaques implicated in the pathogenesis of acute coronary syndromes. Moreover, inflammatory pathways not only regulate the properties of plaques that precipitate acute coronary syndromes but also modulate the clinical consequences of the thrombotic complications of atherosclerosis. This synthesis will provide an update on the fundamental mechanisms of inflammatory responses that govern acute coronary syndromes and also highlight the ongoing balance between proinflammatory mechanisms and endogenous pathways that can promote the resolution of inflammation. An appreciation of the countervailing mechanisms that modulate inflammation in relation to acute coronary syndromes enriches our fundamental understanding of the pathophysiology of this important manifestation of atherosclerosis. In addition, these insights provide glimpses into potential novel therapeutic interventions to forestall this ultimate complication of the disease.

Compared with traditional conductive fillers, carbon nanotubes (CNTs) have unique advantages, i.e., excellent mechanical properties, high electrical conductivity and thermal stability. Nanocomposites as piezoresistive films provide an interesting approach for the realization of large area strain sensors with high sensitivity and low manufacturing costs. A polymer-based nanocomposite with carbon nanomaterials as conductive filler can be deposited on a flexible substrate of choice and this leads to mechanically flexible layers. Such sensors allow the strain measurement for both integral measurement on a certain surface and local measurement at a certain position depending on the sensor geometry. Strain sensors based on carbon nanostructures can overcome several limitations of conventional strain sensors, e.g., sensitivity, adjustable measurement range and integral measurement on big surfaces. The novel technology allows realizing strain sensors which can be easily integrated even as buried layers in material systems. In this review paper, we discuss the dependence of strain sensitivity on different experimental parameters such as composition of the carbon nanomaterial/polymer layer, type of polymer, fabrication process and processing parameters. The insights about the relationship between film parameters and electromechanical properties can be used to improve the design and fabrication of CNT strain sensors.

BACKGROUND: Dalbavancin, a lipoglycopeptide antibiotic agent that is active against gram-positive pathogens, has a long plasma half-life, allowing for once-weekly dosing. DISCOVER 1 and DISCOVER 2 were identically designed noninferiority trials of dalbavancin for the treatment of acute bacterial skin and skin-structure infection. METHODS: We randomly assigned patients to receive dalbavancin intravenously on days 1 and 8 or vancomycin intravenously for at least 3 days with the option to switch to oral linezolid to complete 10 to 14 days of therapy. The primary end point, early clinical response, required the cessation of spread of infection-related erythema and the absence of fever at 48 to 72 hours. Secondary end points at the end of therapy included clinical status and investigator's assessment of outcome. RESULTS: Analysis of the primary end point showed noninferiority of dalbavancin in both DISCOVER 1 and DISCOVER 2. In the pooled analysis, 525 of 659 patients (79.7%) in the dalbavancin group and 521 of 653 (79.8%) in the vancomycin-linezolid group had an early clinical response indicating treatment success (weighted difference, -0.1 percentage point; 95% confidence interval, -4.5 to 4.2). The outcomes were similar in the analyses by study and the pooled analyses of clinical status at the end of therapy and the investigator's assessment of outcome. For patients infected with Staphylococcus aureus, including methicillin-resistant S. aureus, clinical success was seen in 90.6% of the patients treated with dalbavancin and 93.8% of those treated with vancomycin-linezolid. Adverse events and study days with an adverse event were less frequent in the dalbavancin group than in the vancomycin-linezolid group. The most common treatment-related adverse events in either group were nausea, diarrhea, and pruritus. CONCLUSIONS: Once-weekly intravenous dalbavancin was not inferior to twice-daily intravenous vancomycin followed by oral linezolid for the treatment of acute bacterial skin and skin-structure infection. (Funded by Durata Therapeutics; DISCOVER 1 and DISCOVER 2 ClinicalTrials.gov numbers, NCT01339091 and NCT01431339.).

PGRN was previously reported to bind to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis. Here we present further evidences demonstrating the PGRN inhibition of TNF-alpha binding and activity, and clarifying the distinct mechanisms underlying TNF-alpha inhibition between PGRN and classic TNF-alpha-binding inhibitors. In addition, we present evidences indicating that three TNFR binding domains of PGRN act independently in binding to TNFR. Furthermore, changing the order of three TNFR-binding domains in Atsttrin, a PGRN-derived molecule composed of these TNFR-binding domains, does not affect its anti-inflammatory and anti-TNF activities in both collagen-induced inflammatory arthritis and human TNF-alpha transgenic mouse model. Taken together, these findings provide the additional molecular basis underlying PGRN/TNFR interaction and PGRN-mediated anti-inflammatory activity in various inflammatory diseases and conditions.

ADAMTS-18 is a member of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of proteases, which are known to play important roles in development, angiogenesis and coagulation; dysregulation and mutation of these enzymes have been implicated in many disease processes, such as inflammation, cancer, arthritis and atherosclerosis. Mutations of ADAMTS-18 have been linked to abnormal early eye development and reduced bone mineral density. In this review, we briefly summarize the structural organization and the expression of ADAMTS-18. We will also focus on the emerging role of ADAMTS-18 in several pathophysiological conditions which include: hematological diseases, tumorgenesis, osteogenesis, eye-related diseases, central nervous system disorders, and last but not least a research perspective of ADAMTS-18 and its potential as a promising diagnostic and therapeutic target.

SUMMARY: The recognition that the tumor microenvironment contributes to tumor survival, growth, and response to therapy provides the rationale for considering it a therapeutic target. The article by Alspach and colleagues in this issue provides evidence that p38MAPK acts posttranscriptionally to promote the tumor-permissive secretory phenotype of both cancer-associated and senescent fibroblasts, and that p38MAPK inhibitors already in clinical trials have significant therapeutic potential. Cancer Discov; 4(6); 637-9. (c)2014 AACR. See related article by Alspach et al., p. 716.