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BACKGROUND. The human bone marrow (BM) niche contains a population of mesenchymal stromal cells (MSCs) that provide physical support and regulate hematopoietic stem cell (HSC) homeostasis. [beta]-Thalassemia (BT) is a hereditary disorder characterized by altered hemoglobin beta-chain synthesis amenable to allogeneic HSC transplantation and HSC gene therapy. Iron overload (IO) is a common complication in BT patients affecting several organs. However, data on the BM stromal compartment are scarce. METHODS. MSCs were isolated and characterized from BM aspirates of healthy donors (HDs) and BT patients. The state of IO was assessed and correlated with the presence of primitive MSCs in vitro and in vivo. Hematopoietic supportive capacity of MSCs was evaluated by transwell migration assay and 2D coculture of MSCs with human CD3[4.sup.+] HSCs. In vivo, the ability of MSCs to facilitate HSC engraftment was tested in a xenogenic transplant model, whereas the capacity to sustain human hematopoiesis was evaluated in humanized ossicle models. RESULTS. We report that, despite iron chelation, BT BM contains high levels of iron and ferritin, indicative of iron accumulation in the BM niche. We found a pauperization of the most primitive MSC pool caused by increased ROS production in vitro which impaired MSC stemness properties. We confirmed a reduced frequency of primitive MSCs in vivo in BT patients. We also discovered a weakened antioxidative response and diminished expression of BM niche-associated genes in BT-MSCs. This caused a functional impairment in MSC hematopoietic supportive capacity in vitro and in cotransplantation models. In addition, BT-MSCs failed to form a proper BM niche in humanized ossicle models. CONCLUSION. Our results suggest an impairment in the mesenchymal compartment of BT BM niche and highlight the need for novel strategies to target the niche to reduce IO and oxidative stress before transplantation. FUNDING. This work was supported by the SR-TIGET Core grant from Fondazione Telethon and by Ricerca Corrente., Introduction [beta]-Thalassemia (BT) is one of the most common inherited monogenic disorders in the world, with an overall carrier rate of 1.5% of the world population, and 60,000 BT symptomatic [...]

It has been reported that endogenous retroviruses can contaminate human cell lines that have been passaged as xenotransplants in immunocompromised mice. We previously developed and described 2 human pancreatic β cell lines (EndoC-βH1 and EndoC-βH2) that were generated in this way. Here, we have shown that B10 xenotropic virus 1 (Bxv1), a xenotropic endogenous murine leukemia virus (MuLV), is present in these 2 recently described cell lines. We determined that Bxv1 was also present in SCID mice that were used for in vivo propagation of EndoC-βH1/2 cells, suggesting that contamination occurred during xenotransplantation. EndoC-βH1/2 cells released Bxv1 particles that propagated to human 293T and Mus dunni cells. Mobilization assays demonstrated that Bxv1 transcomplements defective MuLV-based retrovectors. In contrast, common rodent β cell lines, rat INS-1E and RIN-5F cells and mouse MIN6 and pTC3 cells, displayed either no or extremely weak xenotropic helper activity toward MuLV-based retrovectors, although xenotropic retrovirus sequences and transcripts were detected in both mouse cell lines. Bxv1 propagation from EndoC- βH1/2 to 293T cells occurred only under optimized conditions and was overall poorly efficient. Thus, although our data imply that MuLV-based retrovectors should be cautiously used in EndoC-βH1/2 cells, our results indicate that an involuntary propagation of Bxv1 from these cells can be easily avoided with good laboratory practices., Introduction Diabetes is caused by deficiency or malfunction of pancreatic p cells. Our understanding of the mechanisms underlying β cell maintenance and failure in humans has been hampered by the [...]

Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established [similar]1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 x 1 x 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses., Author(s): Hui Gao [1]; Joshua M Korn [1]; Stéphane Ferretti [2]; John E Monahan [3]; Youzhen Wang [4]; Mallika Singh [5]; Chao Zhang [4]; Christian Schnell [2]; Guizhi Yang [1]; [...]

Investigations confirm a reaction between a majority of human IgM antibodies, seen in the serum of healthy donors, with pig cells and galactose in (alpha1-3)Gal. The antibodies identified the same or extremely alike epitopes on the surface of blood and splenic lymphocytes in pig erythrocytes and aortic endothelial cells.

A small animal model was produced using human fetal brain transplantedto the anterior chamber of the eye of an immunosuppressed patient in order to study HIV-1 infection of the nervous system. Polymerase chain reaction analysisrevealed that pathological damage occurred only in neural xenografts infected with the HIV-1 virus. These findings are supportive of the hypothesis that macrophages and multinucleated giant cells mediate neurotoxicity.

The article discusses the need and impetus behind pushing for the clinical introduction of cross-species or xenotransplantation. The scientific and ethical implications that are necessary before any kind of clinical xenotransplantation trials and the barriers that come in the way are highlighted.

Advances in molecular biology and the need for organ donations has lead scientists to look at ways to transplant organs from animals to humans. Some experts believe these xenografts could be very dangerous for the human population since animal donors may carry viruses that can mutate in the human body and cause disease. Scientists have been unable to stop the human immune system from rejecting the donated organ. Drugs and other therapies that inhibit the immune system may make humans more sensitive to infections of the donor animal. Scientists are researching genetically engineered animals, such as pigs, whose organs would be protected against the human immune response. They are working on methods to eliminate human antibodies against pig organs, mask substances on the donor organ that cause an immune reaction and prepare humans to receive the organs by transplanting bone marrow cells from the donor animal.

Xenotransplantation is the transplantation of organs or tissues between different species. In Jun 1992 and Jan 1993, two women received baboon livers. Although neither patient survived, Thomas E. Starzl, a leading surgeon in the field of xenotransplantation, says these transplants may be feasible by 1994. A key factor in the success of any transplant is the migration of cells from the host into the transplanted organ and the migration of cells from the transplanted organ throughout the host. Essentially, successful organ transplants are also mini-bone marrow transplants. Using this knowledge, future organ recipients may also receive bone marrow from the donor to boost their immune system and lessen the chance of organ rejection. Although other researchers are skeptical, successful xenotransplantation could offer hope to the thousands of people on waiting lists for transplants.

Institute for Anatomy and Experimental Morphology, University Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany Purpose: The aim of this study is to investigate the effects of purified mistletoe lectin-I (pML-I) [...]

It was front-page news when medical science tried out yet another way to postpone our common and inevitable fate--TERMINALLY ILL MAN GETS BABOON'S LIVER IN UNTRIED OPERATION (New York Times, [...]