•Cell-free therapy using MSC-CM can offer an exciting approach in regenerative medicine.•Therapeutic role of cytokine and growth factors present in MSC-CM in clinical studies.•Cell-free therapy ...offers a significant advantage over cells based therapy and other conventional pharmaceutics.
Mesenchymal Stem Cells (MSCs) have been shown to be a promising candidate for cell-based therapy. The therapeutic potential of MSCs, towards tissue repair and wound healing is essentially based on their paracrine effects. Numerous pre-clinical and clinical studies of MSCs have yielded encouraging results. Further, these cells have been shown to be relatively safe for clinical applications. MSCs harvested from numerous anatomical locations including the bone marrow, adipose tissue, Wharton’s jelly of the umbilical cord etc., display similar immunophenotypic profiles. However, there is a large body of evidence showing that MSCs secrete a variety of biologically active molecules such as growth factors, chemokines, and cytokines. Despite the similarity in their immunophenotype, the secretome of MSCs appears to vary significantly, depending on the age of the host and niches where the cells reside. Thus, by implication, proteomics-based profiling suggests that the therapeutic potential of the different MSC populations must also be different. Analysis of the secretome points to its influence on varied biological processes such as angiogenesis, neurogenesis, tissue repair, immunomodulation, wound healing, anti-fibrotic and anti-tumour for tissue maintenance and regeneration. Though MSC based therapy has been shown to be relatively safe, from a clinical standpoint, the use of cell-free infusions can altogether circumvent the administration of viable cells for therapy. Understanding the secretome of in vitro cultured MSC populations, by the analysis of the corresponding conditioned medium, will enable us to evaluate its utility as a new therapeutic option. This review will focus on the accumulating evidence that points to the therapeutic potential of the conditioned medium, both from pre-clinical and clinical studies. Finally, this review will emphasize the importance of profiling the conditioned medium for assessing its potential for cell-free therapy therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mesenchymal stem cells (MSCs) have immense potential for cell-based therapy of acute and chronic pathological conditions. MSC transplantation for cell-based therapy requires a substantial number of ...cells in the range of 0.5-2.5 × 10
cells/kg body weight of an individual. A prolific source of MSCs followed by in vitro propagation is therefore an absolute prerequisite for clinical applications. Umbilical cord tissue (UCT) is an abundantly available prolific source of MSC that are fetal in nature and have higher potential for ex-vivo expansion. However, the ex-vivo expansion of MSCs using a xenogeneic supplement such as fetal bovine serum (FBS) carries the risk of transmission of zoonotic infections and immunological reactions. We used platelet lysate (PL) as a xeno-free, allogeneic replacement for FBS and compared the biological and functional characteristics of MSC processed and expanded with PL and FBS by explant and enzymatic method. UCT-MSCs expanded using PL displayed typical immunophenotype, plasticity, immunomodulatory property and chromosomal stability. PL supplementation also showed 2-fold increase in MSC yield from explant culture with improved immunomodulatory activity as compared to enzymatically dissociated cultures. In conclusion, PL from expired platelets is a viable alternative to FBS for generating clinically relevant numbers of MSC from explant cultures over enzymatic method.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Monocyte-derived and tissue-resident macrophages are ontogenetically distinct components of the innate immune system. Assessment of their respective functions in pathology is complicated by changes ...to the macrophage phenotype during inflammation. Here we find that Cxcr4-CreER enables permanent genetic labeling of hematopoietic stem cells (HSCs) and distinguishes HSC-derived monocytes from microglia and other tissue-resident macrophages. By combining Cxcr4-CreER-mediated lineage tracing with Cxcr4 inhibition or conditional Cxcr4 ablation in photothrombotic stroke, we find that Cxcr4 promotes initial monocyte infiltration and subsequent territorial restriction of monocyte-derived macrophages to infarct tissue. After transient focal ischemia, Cxcr4 deficiency reduces monocyte infiltration and blunts the expression of pattern recognition and defense response genes in monocyte-derived macrophages. This is associated with an altered microglial response and deteriorated outcomes. Thus, Cxcr4 is essential for an innate-immune-system-mediated defense response after cerebral ischemia. We further propose Cxcr4-CreER as a universal tool to study functions of HSC-derived cells.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We study the dynamic implications of capital investment in innovative capacity (IC) on future stock returns, investment, and profitability by modeling the unique effects of IC investment on uncertain ...option generation/exercise and postexercise revenue. The model highlights the diverse effects of IC investment on expected returns in different postinvestment regimes and yields the novel prediction that, under the neoclassical assumption of nonincreasing revenue returns, IC investment is positively related to subsequent cumulative stock returns with a lag. The model also predicts a positive effect of IC investment on future investment and profitability. We find strong empirical support for these predictions.
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BFBNIB, FZAB, GIS, IJS, INZLJ, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZRSKP
A novel tetra-4-{(
E
)-(8-aminonaphthalen-1-yl)iminomethyl}-2-methoxyphenol Co(
ii
) phthalocyanine (CoTANImMMPPc) was synthesized using a precursor protocol and characterized
via
electroanalytical ...and spectroscopic techniques. The FT-IR spectra of the synthesized compounds showed significant peaks corresponding to the functional groups of the precursors and phthalocyanine (Pc) compound. The mass and NMR spectra confirmed the formation of the target precursor compounds. A film of CoTANImMMPPc was deposited on the surface of an electrode and applied for the detection and monitoring of
l
-alanine and
l
-arginine. The cyclic voltammetric studies of
l
-alanine and
l
-arginine using the (CoTANImMMPPc/MWCNTs/GC) electrode showed a linear response in the range of 50-500 nM and the limit of detection was found to be 1.5 and 1.2 nM, respectively. Differential pulse voltammetry and chronoamperometry showed that the catalytic response for
l
-alanine and
l
-arginine is in the range of 50-500 nM with an LoD of 1.8 and 2.3 nM, respectively. The oxidation-active CoTANImMMPPc film significantly enhanced the current response in the chronoamperometric method and displayed a selective and sensitive response towards
l
-alanine and
l
-arginine in the presence of various other bio-molecules. The developed electrode showed good working stability and was applied for the analysis of real samples, which yielded satisfactory results. Therefore, CoTANImMMPPc-MWCNTs/GCE shows good analytical performance, is economical and produced
via
a simple synthetic method and can be applied as a sensor for the detection of
l
-alanine and
l
-arginine.
A novel CoTANImMMPPc complex was synthesized using a precursor protocol and characterized
via
electroanalytical and spectroscopic techniques with enhanced electrocatalytic behaviour of α-amino acids.
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IJS, KILJ, NUK, UL, UM, UPUK
Cancer is among the highly complex disease and renal cell carcinoma is the sixth-leading cause of cancer death. In order to understand complex diseases such as cancer, diabetes and kidney diseases, ...high-throughput data are generated at large scale and it has helped in the research and diagnostic advancement. However, to unravel the meaningful information from such large datasets for comprehensive and minute understanding of cell phenotypes and disease pathophysiology remains a trivial challenge and also the molecular events leading to disease onset and progression are not well understood. With this goal, we have collected gene expression datasets from publicly available dataset which are for two different stages (I and II) for renal cell carcinoma and furthermore, the TCGA and cBioPortal database have been utilized for clinical relevance understanding. In this work, we have applied computational approach to unravel the differentially expressed genes, their networks for the enriched pathways. Based on our results, we conclude that among the most dominantly altered pathways for renal cell carcinoma, are PI3K-Akt, Foxo, endocytosis, MAPK, Tight junction, cytokine-cytokine receptor interaction pathways and the major source of alteration for these pathways are MAP3K13, CHAF1A, FDX1, ARHGAP26, ITGBL1, C10orf118, MTO1, LAMP2, STAMBP, DLC1, NSMAF, YY1, TPGS2, SCARB2, PRSS23, SYNJ1, CNPPD1, PPP2R5E. In terms of clinical significance, there are large number of differentially expressed genes which appears to be playing critical roles in survival.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A hybrid nanosystem with impeccable cellular imaging and antioxidant functionality is demonstrated. The microwave irradiation-derived molybdenum trioxide nanoparticles (MoO3 NPs) were ...surface-functionalized with the cationic dye molecule, methylene blue (MB), which enables superior UV–visible absorbance and fluorescence emission wavelengths potential for bioimaging. The radical scavenging property of the pristine MoO3 NPs and MoO3–MB NPs were studied in vivo using Caenorhabditis elegans as the model system. Heat shock-induced oxidative stress in C. elegans was significantly resolved by the MoO3–MB NPs, in agreement with the in vitro radical scavenging study by electron paramagnetic resonance spectroscopy. Hybrid nanostructures of MoO3–MB demonstrate synergistic benefits in intracellular imaging with intrinsic biocompatibility and antioxidant behavior, which can facilitate application as advanced healthcare materials toward bioimaging and clinical therapeutics.
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IJS, KILJ, NUK, PNG, UL, UM
8.
On the Secrecy Capacity of Fading Channels Gopala, P.K.; Lifeng Lai; El Gamal, H.
IEEE transactions on information theory,
10/2008, Volume:
54, Issue:
10
Journal Article
Peer reviewed
Open access
We consider the secure transmission of information over an ergodic fading channel in the presence of an eavesdropper. Our eavesdropper can be viewed as the wireless counterpart of Wyner's wiretapper. ...The secrecy capacity of such a system is characterized under the assumption of asymptotically long coherence intervals. We first consider the full channel state information (CSI) case, where the transmitter has access to the channel gains of the legitimate receiver and the eavesdropper. The secrecy capacity under this full CSI assumption serves as an upper bound for the secrecy capacity when only the CSI of the legitimate receiver is known at the transmitter, which is characterized next. In each scenario, the perfect secrecy capacity is obtained along with the optimal power and rate allocation strategies. We then propose a low-complexity on/off power allocation strategy that achieves near-optimal performance with only the main channel CSI. More specifically, this scheme is shown to be asymptotically optimal as the average signal-to-noise ratio (SNR) goes to infinity, and interestingly, is shown to attain the secrecy capacity under the full CSI assumption. Overall, channel fading has a positive impact on the secrecy capacity and rate adaptation, based on the main channel CSI, is critical in facilitating secure communications over slow fading channels.
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and an attractive therapeutic target for cancer and other human diseases. Despite 20 years of persistent research ...efforts, targeting STAT3 has been very challenging. We report herein the structure-based discovery of potent small-molecule STAT3 degraders based upon the proteolysis targeting chimera (PROTAC) concept. We first designed SI-109 as a potent, small-molecule inhibitor of the STAT3 SH2 domain. Employing ligands for cereblon/cullin 4A E3 ligase and SI-109, we obtained a series of potent PROTAC STAT3 degraders, exemplified by SD-36. SD-36 induces rapid STAT3 degradation at low nanomolar concentrations in cells and fails to degrade other STAT proteins. SD-36 achieves nanomolar cell growth inhibitory activity in leukemia and lymphoma cell lines with high levels of phosphorylated STAT3. A single dose of SD-36 results in complete STAT3 protein degradation in xenograft tumor tissue and normal mouse tissues. SD-36 achieves complete and long-lasting tumor regression in the Molm-16 xenograft tumor model at well-tolerated dose-schedules. SD-36 is a potent, selective, and efficacious STAT3 degrader.
Ecohydrological systems may be characterized as nonlinear, complex, open dissipative systems. Such systems consist of many coupled processes, and the couplings change depending on the system state or ...scale in space and time at which the system is analyzed. The arrangement of couplings in a complex system may be represented as a network of information flow and feedback between variables that measure system processes. The occurrence of feedback on such a network provides sufficient conditions for self-organized and nonlinear behaviors to emerge. We adapt an information-theoretic statistical method called transfer entropy for the purposes of robustly measuring the directionality, relative strength, statistical significance, and time scale of information flow between pairs of ecohydrological variables using time series data. A process network may be delineated where variables are cast as nodes and information flows as weighted directional links between them. The process network captures key couplings and time scales and represents the state of the complex system as a whole, including functional groups of variables (subsystems) and synchronization resulting from feedbacks. It is therefore able to identify interactions which are not detectable using methods which examine the system using one relationship at a time. We assemble an information flow process network using July 2003 FLUXNET data for a Midwestern corn-soybean ecohydrological system in a healthy, peak growing season state and compare the results with those using July 2005 data for the same site during a severe drought. We find that the process network during drought is substantially decoupled, and regional-scale information feedback is reduced during the drought. We conclude that the proposed process network methodology is able to identify the differences between two states of an ecohydrological system on the basis of variations in the pattern of feedback coupling on the network.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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