Diagnostic potential of exosomal extracellular vesicles in oncology.

Liquid biopsy can detect circulating cancer cells or tumor cell-derived DNA at various stages of cancer. The fluid from these biopsies contains extracellular vesicles (EVs), such as apoptotic bodies, microvesicles, exomeres, and exosomes. Exosomes contain proteins and nucleic acids (DNA/RNA) that can modify the microenvironment and promote cancer progression, playing significant roles in cancer pathology. Clinically, the proteins and nucleic acids within the exosomes from liquid biopsies can be biomarkers for the detection and prognosis of cancer. We review EVs protein and miRNA biomarkers identified for select cancers, specifically melanoma, glioma, breast, pancreatic, hepatic, cervical, prostate colon, and some hematological malignancies. Overall, this review demonstrates that EV biomolecules have great potential to expand the diagnostic and prognostic biomarkers used in Oncology; ultimately, EVs could lead to earlier detection and novel therapeutic targets. Clinical implicationsEVs represent a new paradigm in cancer diagnostics and therapeutics. The potential use of exosomal contents as biomarkers for diagnostic and prognostic indicators may facilitate cancer management. Non-invasive liquid biopsy is helpful, especially when the tumor is difficult to reach, such as in pancreatic adenocarcinoma. Moreover, another advantage of using minimally invasive liquid biopsy is that monitoring becomes more manageable. Identifying tumor-derived exosomal proteins and microRNAs would allow a more personalized approach to detecting cancer and improving treatment.

Multi-functional auto-fluorescent nanogels for theranostics.

Here in the present article, the state of art for nanotechnology-enabled nanogel theranostics and the upcoming concepts in nanogel-based therapeutics are summarized. The benefits, innovation, and prospects of nanogel technology are also briefly presented.

A Comparative Analysis of Different HIV Viral Load Suppression Definitions Among Clients Receiving Care in the Miami-Dade Ryan White HIV/AIDS Program.

The study's objective was to examine variations in viral load (VL) suppression definitions among clients in the Ryan White Program (RWP). Data from clients enrolled in the RWP during 2017 were examined to calculate the proportion of virally suppressed clients using three definitions: recent viral suppression, defined as having a suppressed VL (< 200 copies/mL) in the last test in 2017; maintained viral suppression, having a suppressed VL for both the first and last tests in 2017; and sustained viral suppression, having all tests in 2017 showing suppression. Relative differences across all three definitions were computed. Recent viral suppression measures were higher than maintained and sustained viral suppression measures by 7.0% and 10.1%, respectively. Significant relative differences in definitions by demographic, socioeconomic and clinical status were observed. It may be beneficial for care planning to report not only estimates of recent viral suppression but maintained and sustained viral suppression as well.

Does l-citrulline supplementation improve exercise blood flow in older adults?

NEW FINDINGS: What is the central question of this study? Does short-term supplementation with l-citrulline in order to increase l-arginine improve exercise blood flow and peripheral dilatation responses to exercise in older adults? What is the main finding and its importance? l-Citrulline increased femoral blood flow by 11% and vascular conductance by 14% during lower-limb exercise in older men, whereas no changes were observed in older women. This modest improvement in bulk muscle blood flow in older men has implications for altering muscle metabolism that may result in enhanced exercise tolerance in older adults. l-Citrulline (Cit) increases l-arginine (Arg), the primary substrate for nitric oxide biosynthesis. We tested the hypothesis that muscle blood flow during exercise would be enhanced by Cit supplementation in older adults. Femoral artery blood flow was measured during calf exercise using Doppler ultrasound, and vascular conductance (FVC) was calculated in 25 older adults (13 women and 12 men) before and after 14 days of Cit (6 g day-1 ) and placebo (maltodextrin) in a randomized, double-blind, crossover study. Plasma [Arg] and resting blood pressure were also measured before and after each condition. Women and men were analysed separately because of significant sex-by-condition interactions for the change in exercise blood flow and FVC. Plasma [Arg] was increased by 30 and 35% after Cit (P < 0.01) in women and men, respectively, with no change after placebo. Citrulline lowered diastolic blood pressure in men (75 ± 9 versus 71 ± 6 mmHg, P = 0.02), but this variable remained unchanged in women. Blood flow and FVC during exercise at higher workloads were increased after Cit in men (flow, 521 ± 134 versus 584 ± 166 ml min-1 , P = 0.04; FVC, 5.0 ± 1.5 versus 5.8 ± 1.7 m, min mmHg-1 , P = 0.01) but were not different after placebo. These variables were not altered by Cit in women. Adjusting for baseline diastolic blood pressure removed (P = 0.10) the difference in FBF and FVC following Cit in men. These results indicate that l-citrulline has a modest effect of improving muscle blood flow during submaximal exercise in older men.

Nef exosomes isolated from the plasma of individuals with HIV-associated dementia (HAD) can induce Aß(1-42) secretion in SH-SY5Y neural cells.

In the era of combined antiretroviral therapy (CART), many of the complications due to HIV-1 infection have diminished. One exception is HIV-associated neurocognitive disorder (HAND). HAND is a spectrum of disorders in cognitive function that ranges from asymptomatic disease to severe dementia (HAD). The milder form of HAND has actually remained the same or slightly increased in prevalence in the CART era. Even in individuals who have maintained undetectable HIV RNA loads, viral proteins such as Nef and Tat can continue to be expressed. In this report, we show that Nef protein and nef messenger RNA (mRNA) are packaged into exosomes that remain in circulation in patients with HAD. Plasma-derived Nef exosomes from patients with HAD have the ability to interact with the neuroblastoma cell line SH-SY5Y and deliver nef mRNA. The mRNA can induce expression of Nef in target cells and subsequently increase expression and secretion of beta-amyloid (Aß) and Aß peptides. Increase secretion of amyloid peptide could contribute to cognitive impairment seen in HAND.

Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1)-facilitated HIV restriction in astrocytes is regulated by miRNA-181a.

BACKGROUND: Although highly active antiretroviral therapy (HAART) has significantly reduced the morbidity and mortality in HIV patients, virus continues to reside in the central nervous system (CNS) reservoir. Hence, a complete eradication of virus remains a challenge. HIV productively infects microglia/macrophages, but astrocytes are generally restricted to HIV infection. The relative importance of the possible replication blocks in astrocytes, however, is yet to be delineated. A recently identified restriction factor, sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1), restricts HIV infection in resting CD4(+)T cells and in monocyte-derived dendritic cells. However, SAMHD1 expression and HIV-1 restriction activity regulation in the CNS cells are unknown. Though, certain miRNAs have been implicated in HIV restriction in resting CD4(+)T cells, their role in the CNS HIV restriction and their mode of action are not established. We hypothesized that varying SAMHD1 expression would lead to restricted HIV infection and host miRNAs would regulate SAMHD1 expression in astrocytes. RESULTS: We found increased SAMHD1 expression and decreased miRNA expression (miR-181a and miR-155) in the astrocytes compared to microglia. We report for the first time that miR-155 and miR-181a regulated the SAMHD1 expression. Overexpression of these cellular miRNAs increased viral replication in the astrocytes, through SAMHD1 modulation. Reactivation of HIV replication was accompanied by decrease in SAMHD1 expression. CONCLUSIONS: Here, we provide a proof of concept that increased SAMHD1 in human astrocytes is in part responsible for the HIV restriction, silencing of which relieves this restriction. At this time, this concept is of theoretical nature. Further experiments are needed to confirm if HIV replication can be reactivated in the CNS reservoir.

Enhanced blood-brain barrier transmigration using a novel transferrin embedded fluorescent magneto-liposome nanoformulation.

The blood-brain barrier (BBB) is considered as the primary impediment barrier for most drugs. Delivering therapeutic agents to the brain is still a big challenge to date. In our study, a dual mechanism, receptor mediation combined with external non-invasive magnetic force, was incorporated into ferrous magnet-based liposomes for BBB transmigration enhancement. The homogenous magnetic nanoparticles (MNPs), with a size of ∼10 nm, were synthesized and confirmed by TEM and XRD respectively. The classical magnetism assay showed the presence of the characteristic superparamagnetic property. These MNPs encapsulated in PEGylated fluorescent liposomes as magneto-liposomes (MLs) showed mono-dispersion, ∼130 ± 10 nm diameter, by dynamic laser scattering (DLS) using the lipid-extrusion technique. Remarkably, a magnetite encapsulation efficiency of nearly 60% was achieved. Moreover, the luminescence and hydrodynamic size of the MLs was stable for over two months at 4 ° C. Additionally, the integrity of the ML structure remained unaffected through 120 rounds of circulation mimicking human blood fluid. After biocompatibility confirmation by cytotoxicity evaluation, these fluorescent MLs were further embedded with transferrin and applied to an in vitro BBB transmigration study in the presence or absence of external magnetic force. Comparing with magnetic force- or transferrin receptor-mediated transportation alone, their synergy resulted in 50-100% increased transmigration without affecting the BBB integrity. Consequently, confocal microscopy and iron concentration in BBB-composed cells further confirmed the higher cellular uptake of ML particles due to the synergic effect. Thus, our multifunctional liposomal magnetic nanocarriers possess great potential in particle transmigration across the BBB and may have a bright future in drug delivery to the brain.

HIV Latency and Nanomedicine Strategies for Anti-HIV Treatment and Eradication.

Antiretrovirals (ARVs) reduce Human Immunodeficiency Virus (HIV) loads to undetectable levels in infected patients. However, HIV can persist throughout the body in cellular reservoirs partly due to the inability of some ARVs to cross anatomical barriers and the capacity of HIV-1 to establish latent infection in resting CD4+ T cells and monocytes/macrophages. A cure for HIV is not likely unless latency is addressed and delivery of ARVs to cellular reservoir sites is improved. Nanomedicine has been used in ARV formulations to improve delivery and efficacy. More specifically, researchers are exploring the benefit of using nanoparticles to improve ARVs and nanomedicine in HIV eradication strategies such as shock and kill, block and lock, and others. This review will focus on mechanisms of HIV-1 latency and nanomedicine-based approaches to treat HIV.

HIV-1 and opiates modulate miRNA profiles in extracellular vesicles.

Opiate abuse increases the risk of HIV transmission and exacerbates HIV neuropathology by increasing inflammation and modulating immune cell function. Exosomal EVs(xEV) contain miRNAs that may be differentially expressed due to HIV infection or opiate abuse. Here we develop a preliminary exosomal-miRNA biomarker profile of HIV-infected PBMCs in the context of opiate use. PBMCs infected with HIV were treated with increasing dosages of morphine for 72 hours, the culture supernatants were collected, and the exosomes isolated using differential centrifugation. Exosomal miRNAs were extracted, expression levels determined via Nanostring multiplexed microRNA arrays, and analyzed with Webgestalt. The effect of the exosomes on neuronal function was determined by measuring calcium. Preliminary findings show that HIV-1 infection altered the miRNA profile of PBMC-derived EVs concurrently with opiate exposure. MicroRNA, hsa-miR-1246 was up-regulated 12-fold in the presence of morphine, relative to uninfected control. PBMCs infected with HIV-1 MN, an X4-tropic HIV-1 strain and exposed to morphine, displayed a trend which suggests potential synergistic effects between HIV-1 infection and morphine exposure promoting an increase in viral replication. Dose-dependent differences were observed in miRNA expression as a result of opiate exposure. The xEVs derived from PBMCs exposed to morphine or HIV modulated neuronal cell function. SH-SY5Y cells, treated with xEVs derived from ART-treated PBMCs, exhibited increased viability while for SH-SY5Ys exposed to xEVs derived from HIV-1 infected PBMCs viability was decreased compared to the untreated control. Exposing SH-SY5Y to xEVs derived from HIV-infected PBMCs resulted in significant decrease in calcium signaling, relative to treatment with xEVs derived from uninfected PBMCs. Overall, HIV-1 and morphine induced differential miRNA expression in PBMC-derived exosomes, potentially identifying mechanisms of action or novel therapeutic targets involved in opiate use disorder, HIV neuropathology, TNF signaling pathway, NF-κB signaling pathway, autophagy, and apoptosis in context of HIV infection.

Protein cargo of Nef-containing exosomal extracellular vesicles may predict HIV-associated Neurocognitive Impairment status.

Exosomal extracellular vesicles (xEVs) in plasma and cerebrospinal fluid (CSF) of aviremic people living with HIV/AIDS (PLWHA) contain the HIV Negative factor (Nef) protein. However, the role of xEVs and Nef-containing-xEVs(xEV-Nef) in HIV-associated neuropathology is unknown. Here we performed a cross-sectional analysis of the content of xEVs derived from matched serum and CSF samples of PLWHAs diagnosed with either asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). The overall objective was to determine whether the content of the matched xEVs derived plasma or CSF correlated with the neurocognitive impairment (NCI) status. The size and protein content of the xEVs were characterized via dynamic light scattering (DLS) and LC-MS/MS, respectively. xEV size was not significantly different between ANI, MND, or HAD groups. CSF of PLWHAs with NCI contained significantly more xEVs than matched plasma. xEV-Nef CSF concentration was elevated in PLWHAs with NCI and correlated with CD4 T-cell count. Plasma-derived xEV protein profiles from PLWHAs with ANI or MND differed from PLWHAs without NCI. Over-representation analysis using Reactome and KEGG databases show proteins involved in pathways associated with heme scavenging, signaling(MAP kinase and integrin-alpha),Toll-like receptor regulation, clot formation, complement, and cytosolic calcium level were elevated in MND. Pathways upregulated within the ANI group involved high-density lipid (HDL) remodeling, post-translational protein phosphorylation, and platelet activation. Overall, the data shows that xEV protein profiles of ANI and MND differ, suggesting protein profiles of peripheral xEVs, xEV-Nef, and CD4 T-cell count may discern NCI status.

Person-time spent with HIV viral load above 1500 copies/mL among Miami-Dade County Ryan White Program clients, 2017-2019: a retrospective analysis.

HIV transmission risk significantly increases at HIV viral load (VL) >1500 copies/mL. We sought to determine the percentage of person-time spent with VL >1500 copies/mL (pPT >1500) and the associations of demographic, clinical, and psychosocial factors and this outcome among persons with HIV receiving care. A retrospective analysis of data from clients enrolled in the Ryan White Program from 2017 to 2019 was performed. We assessed pPT >1500 in HIV care by utilizing consecutive VL pairs and calculating the length of time between each pair and the corresponding time spent for the observation period. The association between pPT >1500 and selected client characteristics were analyzed using a random-effects zero-inflated negative binomial model. Among the 6390 clients, 42% were aged 50 or older, 52% MSM, and 59% Hispanic. Overall, 7.5% of clients spent, on average, 27.4 days per year at substantial risk of transmitting HIV. Younger age, AIDS diagnosis, and reported drug use in the preceding 12 months were associated with higher pPT >1500. Tailored interventions should be implemented to meet the unique HIV needs of groups with consistent viremia to significantly minimize transmission risk.

Recent Advances in Nanotherapeutics for Neurological Disorders.

Neurological disorders remain a significant health and economic burden worldwide. Addressing the challenges imposed by existing drugs, associated side- effects, and immune responses in neurodegenerative diseases is essential for developing better therapies. The immune activation in a diseased state has complex treatment protocols and results in hurdles for clinical translation. There is an immense need for the development of multifunctional nanotherapeutics with various properties to address the different limitations and immune interactions exhibited by the existing therapeutics. Nanotechnology has proven its potential to improve therapeutic delivery and enhance efficacy. Promising advancements have been made in developing nanotherapies that can be combined with CRISPR/Cas9 or siRNA for a targeted approach with unique potential for clinical translation. Engineering natural exosomes derived from mesenchymal stem cells (MSCs), dendritic cells (DCs), or macrophages to both deliver therapeutics and modulate the immune responses to tumors or in neurodegenerative disease (ND) can allow for targeted personalized therapeutic approaches. In the present review, we summarize and overview the recent advances in nanotherapeutics in addressing the existing treatment limitations and neuroimmune interactions for developing ND therapies and provide insights into the upcoming advancements in nanotechnology-based nanocarriers.

An Overview of Miami CDEIPI and a Showcase of Team Science and Cutting-Edge Research Driven by Students.

BACKGROUND: The Miami-CFAR Diversity, Equity & Inclusion Pathway Initiative (Miami CDEIPI) is designed to promote a diverse scientific workforce that reflects the communities at the highest risk of HIV in South Florida. SETTING AND METHODS: The focus of the Miami CDEIPI is to help train the next generation of Underrepresented Minorities (URM) and Black, Indigenous, People of Color (BIPOC) in HIV/AIDS-related research through a team science experience. The Miami CDEIPI objectives are to facilitate the interaction of URM/BIPOC students with the network of CFAR-affiliated investigators and to enable these students to access the cutting-edge technologies at the Miami-CFAR and the Sylvester Comprehensive Cancer Center and other resources at the University of Miami. RESULTS: Five URM/BIPOC students supported by the program in year 1 have been carrying out projects in collaboration with mentors at their parent institution and Miami-CFAR investigators. The students used the state-of-the-art laboratories and core facilities. They began their research with a proposal designed to integrate the cutting-edge technologies now available to them. Their training included participation in Miami-CFAR-sponsored activities such as seminars, an annual conference, and a national HIV workshop. Candidates in the Miami CDEIPI are in the process of developing their research proposals, integrating cutting-edge technologies into their doctoral dissertation research. Their projects are now in the completion phase. CONCLUSIONS: The Miami CDEIPI focuses its resources on one of the conspicuous gaps in the career paths of URM/BIPOC researchers-the dearth of leading URM/BIPOC scientists in the field. The Miami CDEIPI provides a professional network that supports the participation of URM/BIPOC trainees in innovative research and career skill training.

Inability of plasmacytoid dendritic cells to directly lyse HIV-infected autologous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligand.

The function of plasmacytoid dendritic cells (PDC) in chronic human immunodeficiency virus type 1 (HIV-1) infection remains controversial with regard to its potential for sustained alpha interferon (IFN-alpha) production and induction of PDC-dependent tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity of HIV-infected cells. We address these areas by a study of chronically HIV-1-infected subjects followed through antiretroviral therapy (ART) interruption and by testing PDC cytolytic function against autologous HIV-infected CD4(+) T cells. Rebound in viremia induced by therapy interruption showed a positive association between TRAIL and viral load or T-cell activation, but comparable levels of plasma IFN-alpha/beta were found in viremic ART-treated and control subjects. While PDC from HIV-infected subjects expressed less interferon regulator factor 7 (IRF-7) and produced significantly less IFN-alpha upon Toll-like receptor 7/9 (TLR7/9) engagement than controls, membrane TRAIL expression in PDC from HIV(+) subjects was increased. Moreover, no significant increase in death receptor 5 (DR5) expression was seen in CD4(+) T cells from viremic HIV(+) subjects compared to controls or following in vitro infection/exposure to infectious and noninfectious virus or exogenous IFN-alpha, respectively. Although activated PDC killed the DR5-expressing HIV-infected Sup-T1 cell line, PDC did not lyse primary autologous HIV(+) CD4(+) T cells yet could provide accessory help for NK cells in killing HIV-infected autologous CD4(+) T cells. Taken together, our data show a lack of sustained high levels of soluble IFN-alpha in chronic HIV-1 infection in vivo and document a lack of direct PDC cytolytic activity against autologous infected or uninfected CD4(+) T cells.

Circulating monocytes in HIV-1-infected viremic subjects exhibit an antiapoptosis gene signature and virus- and host-mediated apoptosis resistance.

Mechanisms that may allow circulating monocytes to persist as CD4 T cells diminish in HIV-1 infection have not been investigated. We have characterized steady-state gene expression signatures in circulating monocytes from HIV-infected subjects and have identified a stable antiapoptosis gene signature comprised of 38 genes associated with p53, CD40L, TNF, and MAPK signaling networks. The significance of this gene signature is indicated by our demonstration of cadmium chloride- or Fas ligand-induced apoptosis resistance in circulating monocytes in contrast to increasing apoptosis in CD4 T cells from the same infected subjects. As potential mechanisms in vivo, we show that monocyte CCR5 binding by HIV-1 virus or agonist chemokines serves as independent viral and host modulators resulting in increased monocyte apoptosis resistance in vitro. We also show evidence for concordance between circulating monocyte apoptosis-related gene expression in HIV-1 infection in vivo and available datasets following viral infection or envelope exposure in monocyte-derived macrophages in vitro. The identification of in vivo gene expression associated with monocyte resistance to apoptosis is of relevance to AIDS pathogenesis since it would contribute to: 1) maintaining viability of infection targets and long-term reservoirs of HIV-1 infection in the monocyte/macrophage populations, and 2) protecting a cell subset critical to host survival despite sustained high viral replication.

Extracellular Vesicles in the Pathogenesis of Viral Infections in Humans.

Most cells can release extracellular vesicles (EVs), membrane vesicles containing various proteins, nucleic acids, enzymes, and signaling molecules. The exchange of EVs between cells facilitates intercellular communication, amplification of cellular responses, immune response modulation, and perhaps alterations in viral pathogenicity. EVs serve a dual role in inhibiting or enhancing viral infection and pathogenesis. This review examines the current literature on EVs to explore the complex role of EVs in the enhancement, inhibition, and potential use as a nanotherapeutic against clinically relevant viruses, focusing on neurotropic viruses: Zika virus (ZIKV) and human immunodeficiency virus (HIV). Overall, this review's scope will elaborate on EV-based mechanisms, which impact viral pathogenicity, facilitate viral spread, and modulate antiviral immune responses.

Bioengineered Exosomal Extracellular Vesicles in Cancer Therapeutics.

Liquid or blood-based biopsy is a less invasive and more efficient method in which to clinicians can identify diagnostic, prognostic, and therapeutic responsive biomarkers in cancer patients. Circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), RNAs, proteins, metabolites, and extracellular vesicles (EVs) are all potential biomarkers found in liquid biopsies. All nucleated cells including healthy, virally infected, and cancer cells release EVs. Since the early 1980s, evidence has mounted to support the pathophysiological role of EVs in cancer. Here we focus on the smallest of the EV, the exosome, and their clinical relevance as nanotherapeutics for cancers. Exosomes obtained from tumors have been reported to promote and/or facilitate malignancy of cancers especially in terms of metastatic potential. Exosomal EVs have also contributed to the development of therapeutic resistance. Recent studies demonstrate that intrinsic and bioengineered exosomes can serve as effective therapeutic agents that disrupt cancer progression. Here we review the current literature regarding the utilization of bioengineered exosomes for therapeutics to treat prevalent cancers such as melanoma, glioma, breast, pancreatic, hepatic, cervical, prostate, and colon cancers. Overall, studies reviewed show that bioengineered exosomes are effective and promising for targeted cancer therapy.

Magnetic Nanoparticle and Exosomal Therapeutic (M-NEXT) Effects on HIV-Associated Neurotoxicity.

The human immunodeficiency virus (HIV) envelope glycoprotein protein 120 (gp120) induces neurotoxicity associated with HIV-associated neurocognitive disorders (HAND). Mechanism of Gp120-mediated neurotoxicity is primarily apoptosis. Currently, there are no therapeutics that address gp120 neurotoxicity. A biocompatible, efficacious therapeutic that easily crosses the blood-brain barrier (BBB) is needed to treat neuronal toxicity observed in HIV-infected individuals. Magnetic nanoparticles (MNPs) have successfully delivered anti-HIV agents across in vitro BBB transwell model. However, MNPs at high doses may damage cells. Exosomal extracellular vesicles (xEVs) are endogenous nanocarriers capable of crossing the BBB. Unlike MNPs, xEVs interact with cells in a paracrine or juxtracrine manner, lacking long-range site specificity. Here we investigated the efficacy of an MNP and xEV-coupled therapeutic (M-NEXT) as a nanocarrier for targeted delivery of anti-HIV fusion agent across the BBB to inhibit HIV-gp120 associated neuropathology. M-NEXT consisting of MNPs encapsulated within xEV carrying T20 peptide on the surface was synthesized and characterized via zeta potential, dynamic light scattering, and TEM imaging. Preliminary efficacy studies using SH-SY5Y cocultured with the in vitro BBB model showed that the M-NEXT-T20-fusion peptide protected neurons from HIV gp120-mediated neurotoxicity. Additionally, BBB integrity and permeability assessed via trans-endothelial resistance (TEER) and a Dextran-FITC transport assay was unaffected. SH-SY5Y viability measured by XTT assay was not significantly modulated by M-NEXT. In summary, preliminary findings support M-NEXT as effective nanocarriers for delivery of anti-HIV gp120 associated neurotoxicity agents.

Physiologically Relevant Fluid-Induced Oscillatory Shear Stress Stimulation of Mesenchymal Stem Cells Enhances the Engineered Valve Matrix Phenotype.

Support of somatic growth is a fundamental requirement of tissue-engineered valves. However, efforts thus far have been unable to maintain this support long term. A key event that will determine the valve's long-term success is the extent to which healthy host tissue remodeling can occur on the valve soon after implantation. The construct's phenotypic-status plays a critical role in accelerating tissue remodeling and engineered valve integration with the host via chemotaxis. In the current study, human bone-marrow-derived mesenchymal stem cells were utilized to seed synthetic, biodegradable scaffolds for a period of 8 days in rotisserie culture. Subsequently, cell-seeded scaffolds were exposed to physiologically relevant oscillatory shear stresses (overall mean, time-averaged shear stress, ~7.9 dynes/cm2; overall mean, oscillatory shear index, ~0.18) for an additional 2 weeks. The constructs were found to exhibit relatively augmented endothelial cell expression (CD31; compared to static controls) but concomitantly served to restrict the level of the activated smooth muscle phenotype (α-SMA) and also produced very low stem cell secretion levels of fibronectin (p < 0.05 compared to static and rotisserie controls). These findings suggest that fluid-induced oscillatory shear stresses alone are important in regulating a healthy valve phenotype of the engineered tissue matrix. Moreover, as solid stresses could lead to increased α-SMA levels, they should be excluded from conditioning during the culture process owing to their associated potential risks with pathological tissue remodeling. In conclusion, engineered valve tissues derived from mesenchymal stem cells revealed both a relatively robust valvular phenotype after exposure to physiologically relevant scales of oscillatory shear stress and may thereby serve to accelerate healthy valve tissue remodeling in the host post-implantation.

Development of Multifunctional Biopolymeric Auto-Fluorescent Micro- and Nanogels as a Platform for Biomedical Applications.

The emerging field of theranostics for advanced healthcare has raised the demand for effective and safe delivery systems consisting of therapeutics and diagnostics agents in a single monarchy. This requires the development of multi-functional bio-polymeric systems for efficient image-guided therapeutics. This study reports the development of size-controlled (micro-to-nano) auto-fluorescent biopolymeric hydrogel particles of chitosan and hydroxyethyl cellulose (HEC) synthesized using water-in-oil emulsion polymerization technique. Sustainable resource linseed oil-based polyol is introduced as an element of hydrophobicity with an aim to facilitate their ability to traverse the blood-brain barrier (BBB). These nanogels are demonstrated to have salient features such as biocompatibility, stability, high cellular uptake by a variety of host cells, and ability to transmigrate across an in vitro BBB model. Interestingly, these unique nanogel particles exhibited auto-fluorescence at a wide range of wavelengths 450-780 nm on excitation at 405 nm whereas excitation at 710 nm gives emission at 810 nm. In conclusion, this study proposes the developed bio-polymeric fluorescent micro- and nano- gels as a potential theranostic tool for central nervous system (CNS) drug delivery and image-guided therapy.