A collaborative effort to assess factors affecting newborn survival at neonatal intensive care units (NICUs) was made by studying 1948 newborns admitted to nine NICUs in the city of São Paulo between ...1 June and 30 November 1991. Data on the study subjects were obtained using a standardized form. This was the first activity undertaken by a network of neonatologists (the Paulista Collaborative Group on Neonatal Care) dedicated to jointly evaluating and improving neonatal care in that city. The study results showed an overall mortality of 59 deaths per 1000 neonates, with survival improving as gestational age and birthweight rose. Other variables significantly affecting survival were a poor maternal obstetric history (a previous stillbirth or neonatal death, or two or more spontaneous abortions); birth asphyxia (Apgar at 5 minutes <7); respiratory distress syndrome; severe infections; and major malformations. However, multiple logistic regression analysis showed that the rates of neonatal survival in the nine NICUs differed even when these factors were considered. Potential sources of this variability included undetermined population differences in neonatal disease severity and medical care. These results suggest a need for greater efforts to identify and reduce risk factors associated with neonatal mortality, and to adequately evaluate the medical care provided in NICUs. Within this context, the collaborative network of neonatologists established in São Paulo provides a sound organizational structure for evaluating and improving the effectiveness of neonatal care.
Cancer-initiating cells (CICs) that are responsible for tumor initiation, propagation, and resistance to standard therapies have been isolated from human solid tumors, including colorectal cancer ...(CRC). The aim of this study was to obtain an immunological profile of CRC-derived CICs and to identify CIC-associated target molecules for T cell immunotherapy. We have isolated cells with CIC properties along with their putative non-CIC autologous counterparts from human primary CRC tissues. These CICs have been shown to display "tumor-initiating/stemness" properties, including the expression of CIC-associated markers (e.g., CD44, CD24, ALDH-1, EpCAM, Lgr5), multipotency, and tumorigenicity following injection in immunodeficient mice. The immune profile of these cells was assessed by phenotype analysis and by in vitro stimulation of PBMCs with CICs as a source of Ags. CICs, compared with non-CIC counterparts, showed weak immunogenicity. This feature correlated with the expression of high levels of immunomodulatory molecules, such as IL-4, and with CIC-mediated inhibitory activity for anti-tumor T cell responses. CIC-associated IL-4 was found to be responsible for this negative function, which requires cell-to-cell contact with T lymphocytes and which is impaired by blocking IL-4 signaling. In addition, the CRC-associated Ag COA-1 was found to be expressed by CICs and to represent, in an autologous setting, a target molecule for anti-tumor T cells. Our study provides relevant information that may contribute to designing new immunotherapy protocols to target CICs in CRC patients.
The aim of the study was to show
in vitro
the greater inertness to the corrosion body fluid of TiNbN coating than the CoCrMo alloy substrate. The prosthetic component under study was a femoral ...component of total knee prosthesis in CoCrMo alloy coated in TiNbN with Physical Vapor Deposition technique immersed in static Hank’s balanced salt solution (HBS) (pH = 6) for at least 34 months at a constant temperature of 37 °C. Another uncoated prosthetic component of CoCrMo alloy with the same type and size was left in static immersion in the same solution and for the same period of time. Scanning electron microscope (SEM) analysis was performed to investigate adhesion and proliferation at 24, 48, 72 h after seeding of 10
4
sub-confluents osteoblast-like cells (SaOS-2) cells on scaffold. The results of the study showed a reduction in the concentration of the metal ions released from the TiNbN-coated femoral component surface compared to the uncoated surface in the HBS solution. The overall reduction of the ions for the TiNbN-coated femoral component compared to the uncoated one was 80.1 ± 2%, 62.5% ± 8% and 48% ± 10% for Co, Cr, Mo, respectively (
p
< 0.01). SEM analysis confirmed the healthy state of the cells, the cellular adhesion and proliferation of SaOS-2 on the TiNbN-coated specimen. Although the results observed
in vitro
for the TiNbN coating are encouraging, clinical studies are certainly needed to be performed in order to understand how these positive findings can be translated
in vivo
and to determine the clinical benefit of TiNbN coating.
BackgroundImmune effector cell-associated neurotoxicity syndrome (ICANS) is an adverse event commonly observed in cancer patients receiving CAR-T cell therapies. Despite the clinical features of ...ICANS being recognizable, its pathophysiology remains poorly understood, current hypothesis are mainly based on findings in autopsies performed on individuals who suffered fatal neurotoxicity after CAR-T cell therapy and preclinical models are limited. Recently, a syngeneic mouse model of CAR-related neurotoxicity has been described; unfortunately, it does not allow to study ICANS that develops upon interaction of human CAR-T cells with human immune and tumor cells.MethodsHere we proposed a humanized mouse model, previously characterized for its ability to recapitulate CAR-related cytokine release syndrome (CRS) toxicity, in which we observed the development of multifocal brain haemorrhages, reminiscent of neurotoxic manifestations observed in patients with high-grade ICANS.ResultsInterestingly, we found that microhaemorrhages did not occur in mice treated with untransduced T cells, while they were observed in about the 45% of mice treated with human CD19 CAR-T cells. Moreover, we observed that this event is associated with CRS severity, as it occurs in patients, and by assessing the number and dimensions of microhaemorrhages by brain tissue area we found them to be greater in terms of extension and incidence in the cerebellum.By magnetic resonance imaging we observed the onset of hypointense lesions in deep brain structures and noteworthily an extravasation event of the injected contrast agent occurred, suggesting changes in blood vessels permeability. Moreover, according to the most affected mentioned brain areas, we find changes in locomotor abilities likely providing a clinical relevance to the phenomena occurring in the brain.ConclusionsThese findings suggest that our humanized mouse model is promisingly able to recapitulate ICANS-related complications, thus providing us with a preclinical tool to deepen ICANS pathophysiology studying.
Forkhead box P3 (FOXP3) is a key transcription factor in regulatory T (Treg) cell function. FOXP3 gene mutations cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, ...a fatal autoimmune syndrome. FOXP3 has also been proposed to act in effector T (Teff) cells, but to date, this role has not been confirmed.
We sought to evaluate the effect of reduced FOXP3 expression on human Treg and Teff cell development and correlate it with IPEX syndrome immune pathology.
We developed a model of humanized mice (huMice) in which the human hematopoietic system is stably knocked down or knocked out for the FOXP3 gene (knockdown KD/knockout KO huMice).
Because FOXP3-KD/KO was not 100% effective, residual FOXP3 expression in hematopoietic stem progenitor cells was sufficient to give rise to Treg cells with normal expression of FOXP3. However, numerous defects appeared in the Teff cell compartment. Compared with control mice, FOXP3-KD/KO huMice showed altered thymocyte differentiation, with KD/KO thymocytes displaying significantly reduced T-cell receptor (TCR) signaling strength and increased TCR repertoire diversity. Peripheral KD/KO Teff cells were expanded and showed signs of homeostatic proliferation, such as a significantly contracted TCR repertoire, a severely reduced naive compartment, decreased telomeric repeat-binding factor 2 expression, and a skew toward a TH2 profile, resembling an aged immune system. Consistent with results in FOXP3-KD/KO huMice, analysis of patients with IPEX syndrome provided evidence of defects in the Teff cell compartment at both the thymic and peripheral levels.
These findings support an intrinsic role for human FOXP3 in controlling thymocyte maturation and peripheral expansion of Teff cells and reveal a previously undescribed pathogenic mechanism through an altered Teff cell compartment in patients with IPEX syndrome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract To investigate the signs of inflammatory processes in Alzheimer's disease (AD), we examined peripheral blood mononuclear cells (PBMC) from 51 AD patients (29 with mild and 22 with moderately ...severe dementia) and 51 age-matched healthy controls (HC), using flow cytometry to analyse the absolute number and the percentage of T, B and NK cells. We also studied the surface expression of CD25, CD28, CD57, CD71, CD45RA and CD45RO markers on cells CD4+ and CD8+. In 30 AD patients and 20 HC the production of IL-2, IFN-γ, IL-10 and TNF-α by PBMC after stimulation with 25–35, 1–40 and 1–16 beta-amyloid (βA) fragments was also evaluated. A significant decrease in circulating B and CD8+CD28− cells, as well as an increase in CD8+ cells expressing CD71+ and CD28+, was observed in AD patients. A significant decrease in IL-10 production was also found after stimulation of PMBC with βA 1–40. The decreased IL-10 production was not related to disease severity. The observed imbalance of immune peripheral cell subpopulations and decreased IL-10 production point to a reduction of suppressor cell function in AD patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Wiskott–Aldrich Syndrome (WAS) is a life-threatening X-linked disease characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancies. Gene therapy could represent a therapeutic ...option for patients lacking a suitable bone marrow (BM) donor. In this study, we analyzed the long-term outcome of WAS gene therapy mediated by a clinically compatible lentiviral vector (LV) in a large cohort of wasnull mice. We demonstrated stable and full donor engraftment and Wiskott–Aldrich Syndrome protein (WASP) expression in various hematopoietic lineages, up to 12 months after gene therapy. Importantly, we observed a selective advantage for T and B lymphocytes expressing transgenic WASP. T-cell receptor (TCR)-driven T-cell activation, as well as B-cell's ability to migrate in response to CXCL13, was fully restored. Safety was evaluated throughout the long-term follow-up of primary and secondary recipients of WAS gene therapy. WAS gene therapy did not affect the lifespan of treated animals. Both hematopoietic and nonhematopoietic tumors arose, but we excluded the association with gene therapy in all cases. Demonstration of long-term efficacy and safety of WAS gene therapy mediated by a clinically applicable LV is a key step toward the implementation of a gene therapy clinical trial for WAS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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