Very Small Embryonic-Like Stem Cells Transform Into Cancer Stem Cells and Are Novel Candidates for Detecting/Monitoring Cancer by a Simple Blood Test.

Cancer continues to remain a "Black Box," as there is no consensus on how it initiates, progresses, metastasizes, or recurs. Many imponderables exist about whether somatic mutations initiate cancer, do cancer stem cells (CSCs) exist, and if yes, are they a result of de-differentiation or originate from tissue-resident stem cells; why do cancer cells express embryonic markers, and what leads to metastasis and recurrence. Currently, the detection of multiple solid cancers through liquid biopsy is based on circulating tumor cells (CTCs) or clusters, or circulating tumor DNA (ctDNA).

Extremely Active Nano-formulation of Resveratrol (XAR™) attenuates and reverses chemotherapy-induced damage in mice ovaries and testes.

Background: Fertility preservation and restoration in cancer patients/survivors is the need of present times when increased numbers of patients get cured of cancer but face infertility as a serious side effect. Resveratrol has beneficial effects on chemoablated ovaries and testes in mice but has failed to enter the clinics because of extremely poor bioavailability. The present study was undertaken to evaluate the protective and curative effects of Extremely active Resveratrol (XAR™)- a nano-formulation of resveratrol with significantly improved bioavailability- on mouse ovary and testis after chemotherapy.

Quest for Pan-Cancer Diagnosis/Prognosis Ends with HrC Test Measuring Oct4A in Peripheral Blood.

Cancer is a devastating disease whose incidence has increased in recent times and early detection can lead to effective treatment. Existing detection tools suffer from low sensitivity and specificity, and are high cost, invasive and painful procedures. Cancers affecting different tissues, ubiquitously express embryonic markers including Oct-4A, whose expression levels have also been correlated to staging different types of cancer.

Microdevice integrating innate and adaptive immune responses associated with antigen presentation by dendritic cells.

Dendritic cells are the principal antigen presenting cells that are responsible for acquiring and transporting antigen from the peripheral tissue to the secondary lymphoid tissue. There they present it to T cells which ultimately initiate an antigen specific immune response. , the migration of dendritic cells (DCs) and T cell activation are intimately linked.

Perspectives on Non-Animal Alternatives for Assessing Sensitization Potential in Allergic Contact Dermatitis.

Skin sensitization remains a major environmental and occupational health hazard. Animal models have been used as the gold standard method of choice for estimating chemical sensitization potential. However, a growing international drive and consensus for minimizing animal usage have prompted the development of methods to assess chemical sensitivity.

Development of Metabolic Indicators of Burn Injury: Very Low Density Lipoprotein (VLDL) and Acetoacetate Are Highly Correlated to Severity of Burn Injury in Rats.

Hypermetabolism is a significant sequela to severe trauma such as burns, as well as critical illnesses such as cancer. It persists in parallel to, or beyond, the original pathology for many months as an often-fatal comorbidity. Currently, diagnosis is based solely on clinical observations of increased energy expenditure, severe muscle wasting and progressive organ dysfunction.

Metabolic profiling based quantitative evaluation of hepatocellular metabolism in presence of adipocyte derived extracellular matrix.

The elucidation of the effect of extracellular matrices on hepatocellular metabolism is critical to understand the mechanism of functional upregulation. We have developed a system using natural extracellular matrices [Adipogel] for enhanced albumin synthesis of rat hepatocyte cultures for a period of 10 days as compared to collagen sandwich cultures. Primary rat hepatocytes isolated from livers of female Lewis rats recover within 4 days of culture from isolation induced injury while function is stabilized at 7 days post-isolation.

Subnormothermic machine perfusion at both 20°C and 30°C recovers ischemic rat livers for successful transplantation.

Background: Utilizing livers from donors after cardiac death could significantly expand the donor pool. We have previously shown that normothermic (37°C) extracorporeal liver perfusion significantly improves transplantation outcomes of ischemic rat livers. Here we investigate whether recovery of ischemic livers is possible using sub-normothermic machine perfusion at 20°C and 30°C.

In situ metabolic flux analysis to quantify the liver metabolic response to experimental burn injury.

Trauma such as burns induces a hypermetabolic response associated with altered central carbon and nitrogen metabolism. The liver plays a key role in these metabolic changes; however, studies to date have evaluated the metabolic state of liver using ex vivo perfusions or isotope labeling techniques targeted to specific pathways. Herein, we developed a unique mass balance approach to characterize the metabolic state of the liver in situ, and used it to quantify the metabolic changes to experimental burn injury in rats.

Impact of co-culture on pancreatic differentiation of embryonic stem cells.

Promise of cellular therapy for type 1 diabetes has inspired the search for transplantable cell sources, and embryonic stem cells (ESCs) have emerged as strong candidates. We have developed a directed differentiation protocol to obtain insulin-producing cells from ESCs. The ESCs are first induced towards a homogeneous monolayer of definitive endoderm-like cells by co-culture with primary hepatocytes.

Adipocyte-derived basement membrane extract with biological activity: applications in hepatocyte functional augmentation in vitro.

Natural and synthetic biomaterials utilized in tissue engineering applications require a dynamic interplay of complex macromolecular compositions of hydrated extracellular matrices (ECMs) and soluble growth factors. The challenges in utilizing synthetic ECMs is the effective control of temporal and spatial complexity of multiple signal presentation, as compared to natural ECMs that possess the inherent properties of biological recognition, including presentation of receptor-binding ligands, susceptibility to cell-triggered proteolytic degradation, and remodeling. We have developed a murine preadipocyte differentiation system for generating a natural basement membrane extract (Adipogel) comprising ECM proteins (collagen IV, laminin, hyaluronan, and fibronectin) and including relevant growth factors (hepatocyte growth factor, vascular endothelial growth factor, and leukemia inhibitory factor).

Enrichment of hepatocyte-like cells with upregulated metabolic and differentiated function derived from embryonic stem cells using S-NitrosoAcetylPenicillamine.

The generation of a large number of fully functional hepatocytes from a renewable cell source can provide an unlimited resource for bioartificial liver devices and cell replacement therapies. We have established a directed differentiation system using sodium butyrate treatment to generate an enriched population of hepatocyte-like cells from embryonic stem cells. A metabolic analysis of the hepatocyte populations revealed glycolytic and mitochondrial phenotypes similar to mouse hepatoma cells, implying that these cells represent an immature hepatocyte phenotype.

Augmentation of EB-directed hepatocyte-specific function via collagen sandwich and SNAP.

The development of implantable engineered liver tissue constructs and ex vivo hepatocyte-based therapeutic devices are limited by an inadequate hepatocyte cell source. In our previous studies, embryoid body (EB)-mediated stem cell differentiation spontaneously yielded populations of hepatocyte lineage cells expressing mature hepatocyte markers such as albumin (ALB) and cytokeratin-18 (CK18). However, these cultures neither yielded a homogenous hepatocyte lineage population nor exhibited detoxification function typical of a more mature hepatocyte lineage cell.

Recovery of warm ischemic rat liver grafts by normothermic extracorporeal perfusion.

Liver transplantation is currently the only established treatment of end-stage liver disease, but it is limited by a severe shortage of viable donor livers. Donors after cardiac death (DCD) are an untapped source that could significantly increase the pool of available livers. Preservation of these DCD livers by conventional static cold storage (SCS) is associated with an unacceptable risk of primary nonfunction and delayed graft failure.

Retinal pigment epithelium differentiation of stem cells: current status and challenges.

Degeneration and loss of retinal pigment epithelium (RPE) is the cause of a number of degenerative retinal diseases, including age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy, leading to blindness that affects three million Americans as of now. Transplantation of RPE aims to restore retinal structure and the interaction between the RPE and photoreceptors, which is fundamental to sight. Although a significant amount of progress has been made in the past 20 years in autologous RPE transplantation, sources for RPE cells are limited.

Functional modulation of ES-derived hepatocyte lineage cells via substrate compliance alteration.

Pluripotent embryonic stem cells represent a promising renewable cell source to generate a variety of differentiated cell types including hepatocyte lineage cells, and may ultimately be incorporated into extracorporeal bioartificial liver devices and cell replacement therapies. Recently, we and others have utilized sodium butyrate to directly differentiate hepatocyte-like cells from murine embryonic stem cells cultured in a monolayer configuration. However, to incorporate stem cell technology into clinical and pharmaceutical applications, and hopefully increase the therapeutic potential of these differentiated cells for liver disease treatment, a major challenge remains in sustaining differentiated functions for an extended period of time in their secondary culture environment.

What came first: fully functional or metabolically mature liver?

Hepatocytes, which constitute about 70% of the liver cell population, perform complex metabolic functions such as plasma protein synthesis and transport, xenobiotic metabolism, glucose homeostasis, urea synthesis, and ketogenesis. The process of liver development is marked by distinct changes in mitochondrial mass, activity, and function, especially during the transition from the fetal to the adult phenotype. The identification of the biochemical mechanisms implicated in hepatic development in vitro using embryonic stem cells is critical because it can unravel the relationship between metabolic changes and cell-specific functional differentiation.

Control of hepatic differentiation via cellular aggregation in an alginate microenvironment.

Integral to the development of embryonic stem cell therapeutic strategies for hepatic disorders is the identification and establishment of a controllable hepatic differentiation strategy. In order to address this issue we have established an alginate microencapsulation approach which provides a means to modulate the differentiation process through changes in key encapsulation parameters. We report that a wide array of hepatocyte specific markers is expressed by cells differentiated during a 23-day period within an alginate bead microenvironment.