SHOC2 scaffold protein modulates daunorubicin-induced cell death through p53 modulation in lymphoid leukemia cells

SHOC2 scaffold protein has been mainly related to oncogenic ERK signaling through the RAS-SHOC2-PP1 phosphatase complex. In leukemic cells however, SHOC2 upregulation has been previously related to an increased 5-year event-free survival of pediatric pre-B acute lymphoid leukemia, suggesting that SHOC2 could be a potential prognostic marker. To address such paradoxical function, our study investigated how SHOC2 impact leukemic cells drug response. Our transcriptome analysis has shown that SHOC2 can modulate the DNA-damage mediated by p53. Notably, upon genetic inhibition of SHOC2 we observed a significant impairment of p53 expression, which in turn, leads to the blockage of key apoptotic molecules. To confirm the specificity of DNA-damage related modulation, several anti-leukemic drugs has been tested and we did confirm that the proposed mechanism impairs cell death upon daunorubicin-induced DNA damage of human lymphoid cells. In conclusion, our study uncovers new insights into SHOC2 function and reveals that this scaffold protein may be essential to activate a novel mechanism of p53-induced cell death in pre-B lymphoid cells

Allergic Rhinitis and its Associated Co-Morbidities at Bugando Medical Centre in Northwestern Tanzania; A Prospective Review of 190 Cases.

Allergic rhinitis is one of the commonest atopic diseases which contribute to significant morbidity world wide while its epidemiology in Tanzania remains sparse. There was paucity of information regarding allergic rhinitis in our setting; therefore it was important to conduct this study to describe our experience on allergic rhinitis, associated co-morbidities and treatment outcome in patients attending Bugando Medical Centre. This was descriptive cross-sectional study involving all patients with a clinical diagnosis of allergic rhinitis at Bugando Medical Centre over a three-month period between June 2011 and August 2011. Data was collected using a pre-tested coded questionnaire and analyzed using SPSS statistical computer software version 17.0. A total of 190 patients were studied giving the prevalence of allergic rhinitis 14.7%. The median age of the patients was 8.5 years. The male to female ratio was 1:1. Adenoid hypertrophy, tonsillitis, hypertrophy of inferior turbinate, nasal polyps, otitis media and sinusitis were the most common co-morbidities affecting 92.6% of cases and were the major reason for attending hospital services. Sleep disturbance was common in children with adenoids hypertrophy (χ2 = 28.691, P = 0.000). Allergic conjunctivitis was found in 51.9%. The most common identified triggers were dust, strong perfume odors and cold weather (P < 0.05). Strong perfume odors affect female than males (χ2 = 4.583, P = 0.032). In this study family history of allergic rhinitis was not a significant risk factor (P =0.423). The majority of patients (68.8%) were treated surgically for allergic rhinitis co morbidities. Post operative complication and mortality rates were 2.9% and 1.6% respectively. The overall median duration of hospital stay of in-patients was 3 days (2 - 28 days). Most patients (98.4%) had satisfactory results at discharge. The study shows that allergic rhinitis is common in our settings representing 14.7% of all otorhinolaryngology and commonly affecting children and adolescent. Sufferers seek medical services due to co-morbidities of which combination of surgical and medical treatment was needed. High index of suspicions in diagnosing allergic rhinitis and early treatment is recommended

Antiproliferative effects of Tubi-bee propolis in glioblastoma cell lines

Propolis is a resin formed by a complex chemical composition of substances that bees collect from plants. Since ancient times, propolis has been used in folk medicine, due to its biological properties, that include antimicrobial, anti-inflammatory, antitumoral and immunomodulatory activities. Glioblastoma is the most common human brain tumor. Despite the improvements in GBM standard treatment, patients’ prognosis is still very poor. The aim of this work was to evaluate in vitro the Tubi-bee propolis effects on human glioblastoma (U251 and U343) and fibroblast (MRC-5) cell lines. Proliferation, clonogenic capacity and apoptosis were analyzed after treatment with 1 mg/mL and 2 mg/mL propolis concentrations for different time periods. Additionally, glioblastoma cell lines were submitted to treatment with propolis combined with temozolomide (TMZ). Data showed an antiproliferative effect of tubi-bee propolis against glioblastoma and fibroblast cell lines. Combination of propolis with TMZ had a synergic anti-proliferative effect. Moreover, propolis caused decrease in colony formation in glioblastoma cell lines. Propolis treatment had no effects on apoptosis, demonstrating a cytostatic action. Further investigations are needed to elucidate the molecular mechanism of the antitumor effect of propolis, and the study of its individual components may reveal specific molecules with antiproliferative capacity

Hemodialysis Affects Phenotype and Proliferation of CD4-Positive T Lymphocytes

CD4+ T lymphocytes of patients with chronic kidney disease (CKD) are characterized by reduced levels of crucial surface antigens and changes in the cell cycle parameters. Recombinant human erythropoietin (rhEPO) normalizes their altered phenotype and proliferative capacity. Mechanisms leading to the deficient responses of T lymphocytes are still not clear but it is postulated that immunological changes are deepened by hemodialysis (HD). Study of activation parameters of CD4+ T lymphocytes in hemodialyzed and predialysis CKD patients could bring insight into this problem. Two groups of patients, treated conservatively (predialysis, PD) and hemodialyzed (HD), as well as healthy controls, were included into the study; neither had received rhEPO. Proportions of main CD4+CD28+, CD4+CD25+, CD4+CD69+, CD4+CD95+, and CD4+HLA-DR+ lymphocyte subpopulations and proliferation kinetic parameters were measured with flow cytometry, both ex vivo and in vitro. No differences were seen in the proportions of main CD4+ lymphocyte subpopulations (CD4+CD28+, CD4+CD25+, CD4+HLA-DR+, CD4+CD69+, CD4+CD95+) between all examined groups ex vivo. CD4+ T lymphocytes of HD patients exhibited significantly decreased expression of co-stimulatory molecule CD28 and activation markers CD25 and CD69 after stimulation in vitro when compared with PD patients and healthy controls. HD patients showed also decreased percentage of CD4+CD28+ lymphocytes proliferating in vitro; these cells presented decreased numbers of finished divisions after 72 h of stimulation in vitro and had longer G0→G1 time when compared to healthy controls. CD4+ T lymphocytes of PD patients and healthy controls were characterized by similar cell cycle parameters. Our study shows that repeated hemodialysis procedure influences phenotype and proliferation parameters of CD4+ T lymphocytes

Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium

Defences against the bacteria that usually infect the endometrium of postpartum cattle are impaired when there is metabolic energy stress, leading to endometritis and infertility. The endometrial response to bacteria depends on innate immunity, with recognition of pathogen-associated molecular patterns stimulating inflammation, characterised by secretion of interleukin (IL)-1β, IL-6 and IL-8. How metabolic stress impacts tissue responses to pathogens is unclear, but integration of energy metabolism and innate immunity means that stressing one system might affect the other. Here we tested the hypothesis that homeostatic pathways integrate energy metabolism and innate immunity in bovine endometrial tissue. Glucose deprivation reduced the secretion of IL-1β, IL-6 and IL-8 from ex vivo organ cultures of bovine endometrium challenged with the pathogen-associated molecular patterns lipopolysaccharide and bacterial lipopeptide. Endometrial inflammatory responses to lipopolysaccharide were also reduced by small molecules that activate or inhibit the intracellular sensor of energy, AMP-activated protein kinase (AMPK). However, inhibition of mammalian target of rapamycin, which is a more global metabolic sensor than AMPK, had little effect on inflammation. Similarly, endometrial inflammatory responses to lipopolysaccharide were not affected by insulin-like growth factor-1, which is an endocrine regulator of metabolism. Interestingly, the inflammatory responses to lipopolysaccharide increased endometrial glucose consumption and induced the Warburg effect, which could exacerbate deficits in glucose availability in the tissue. In conclusion, metabolic energy stress perturbed inflammatory responses to pathogen-associated molecular patterns in bovine endometrial tissue, and the most fundamental regulators of cellular energy, glucose availability and AMPK, had the greatest impact on innate immunity

Snail1 factor behaves as a therapeutic target in renal fibrosis.

Kidney fibrosis is a devastating disease that leads to organ failure, and no specific treatment is available to preserve organ function. In fibrosis, myofibroblasts accumulate in the interstitium leading to massive deposition of extracellular matrix and organ disfunction. The origin of myofibroblasts is multiple and the contribution of renal epithelial cells after undergoing epithelial-to-mesenchymal transition (EMT) is still debated. In a model unable to reactivate the EMT inducer Snail1 upon damage, we show that Snail1 is required in renal epithelial cells for the development of fibrosis. Damage-mediated Snail1 reactivation induces a partial EMT that relays fibrotic and inflammatory signals to the interstitium through the activation of TGF-β and NF-B pathways. Snail1-induced fibrosis can be reverted in vivo and inhibiting Snail1 in a model of obstructive nephropathy highly ameliorates fibrosis. These results reconcile conflicting data on the role of EMT in renal fibrosis and provide avenues for the design of antifibrotic therapies.pre-print8435 K

Blocking TGF-β signaling pathway preserves mitochondrial proteostasis and reduces early activation of PDGFRβ+ pericytes in aristolochic acid induced acute kidney injury in wistar male rats

The platelet-derived growth factor receptor β (PDGFRβ)+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target.In this regard, we first confirmed the presence of PDGFRβ+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN) and thereafter we focused on the early fibrosis events of transforming growth factor β (TGFβ) inhibition in a rat model of AAN.Neutralizing anti-TGFβ antibody (1D11) and its control isotype (13C4) were administered (5 mg/kg, i.p.) at Days -1, 0, 2 and 4; AA (15 mg/kg, sc) was injected daily.At Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema) in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR) pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro.The early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRβ+ pericytes-derived myofibroblasts accumulation

User preferences for adaptive user interfaces in health information systems

An adaptive user interface requires identification of user requirements. Interface designers and engineers must understand end-user interaction with the system to improve user interface design. A combination of interviews and observations is applied for user requirement analysis in health information systems (HIS). Then, user preferences are categorized in this paper as either data entry, language and vocabulary, information presentation, or help, warning and feedback. The user preferences in these categories were evaluated using the focus group method. Focus group sessions with different types of HIS users comprising medical staff (with and without computer skills) and system administrators identified each user group’s preference for the initial adaptation of the HIS user interface. User needs and requirements must be identified to adapt the interface to users during data entry into the system. System designers must understand user interactions with the system to identify their needs and preferences. Without this, interface design cannot be adapted to users and users will not be comfortable using the system and eventually abandon its use