Recent advances in searching c-Myc transcriptional cofactors during tumorigenesis

Background: The mechanism by which c-Myc exerts its oncogenic functions is not completely clear and different hypotheses are still under investigation. The knowledge of the capacity of c-Myc to bind exclusively E-box sequences determined the discrepancy between, on the one hand, genomic studies showing the binding of c-Myc to all active promoters and, on the other hand, the evidence that only 60% or less of the binding sites have E-box sequences. Main body: In this review, we provide support to the hypothesis that the cooperation of c-Myc with transcriptional cofactors mediates c-Myc-induced cellular functions. We produce evidence that recently identified cofactors are involved in c-Myc control of survival mechanisms of cancer cells. Conclusion: The identification of new c-Myc cofactors could favor the development of therapeutic strategies able to compensate the difficulty of targeting c-Myc

Relationship between Planthoppers (\u3ci\u3eNilaparvata lugens\u3c/i\u3e and \u3ci\u3eSogatella furcifera\u3c/i\u3e) and Rice Diseases

The locational preference of the brown planthopper (BPH) Nilaparvata lugens (Still) and the whitebacked plant hopper (WBPH) Sogatella furcifera (Horvath) was studied on rice cultivars IR22 and IR36 as an integral part of subsequent research on insect-fungal pathogen relationships. The BPH was observed to stay consistently on the basal portion while the WBPH showed a general preference for the upper portion regardless of varieties, rice growth stages and insect population density levels. The habitat preference of both species (BPH and WBPH) was found not to be affected by the presence of the other species when both species are present on the same host plant. Five rice cultivars with different reactions to BPH biotype 2 were used in the study on BPH-Rhizoctonia solani relationship: IR22 and TN1 (susceptible); Triveni and ASD7 (moderately resistant); and IR42 (resistant). Test plants were inoculated with R. solani (Kuhn) 3~4days after insect infestation. Sheath blight disease severity/incidence was significantly higher in the treatment where BPH+R. solani were together than in the treatment with only the pathogen. Symptom expression of the disease in the BPH-pathogen combination was faster and mycelial growth was more profuse inducing the formation of more infection structures. Regardless of varietal reaction to BPH biotype 2, the degree of hopperburn was significantly higher in the combination of the two pests as compared with that of BPH alone. There could be a synergistic relationship between the insect pest and the pathogen indicated by a positive interaction between the two species

GD2 redirected CAR T and activated NK-cell-mediated secretion of IFNγovercomes MYCN-dependent IDO1 inhibition, contributing to neuroblastoma cell immune escape

Immune escape mechanisms employed by neuroblastoma (NB) cells include secretion of immunosuppressive factors disrupting effective antitumor immunity. The use of cellular therapy to treat solid tumors needs to be implemented. Killing activity of anti-GD2 Chimeric Antigen Receptor (CAR) T or natural killer (NK) cells against target NB cells was assessed through coculture experiments and quantified by FACS analysis. ELISA assay was used to quantify interferon-gamma (IFN gamma) secreted by NK and CAR T cells. Real Time PCR and Western Blot were performed to analyze gene and protein levels modifications. Transcriptional study was performed by chromatin immunoprecipitation and luciferase reporter assays on experiments of mutagenesis on the promoter sequence. NB tissue sample were analyzed by IHC and Real Time PCR to perform correlation study. We demonstrate that Indoleamine-pyrrole 2,3-dioxygenase1 (IDO1), due to its ability to convert tryptophan into kynurenines, is involved in NB resistance to activity of immune cells. In NB, IDO1 is able to inhibit the anti-tumor effect displayed by of both anti-GD2 CAR (GD2.CAR) T-cell and NK cells, mainly by impairing their IFN gamma production. Furthermore, inhibition of MYCN expression in NB results into accumulation of IDO1 and consequently of kynurenines, which negatively affect the immune surveillance. Inverse correlation between IDO1 and MYCN expression has been observed in a wide cohort of NB samples. This finding was supported by the identification of a transcriptional repressive role of MYCN on IDO1 promoter. The evidence of IDO1 involvement in NB immune escape and its ability to impair NK and GD2.CAR T-cell activity contribute to clarify one of the possible mechanisms responsible for the limited efficacy of these immunotherapeutic approaches. A combined therapy of NK or GD2.CAR T-cells with IDO1 inhibitors, a class of compounds already in phase I/II clinical studies, could represent a new and still unexplored strategy capable to improve long-term efficacy of these immunotherapeutic approaches

AATF/Che-1 RNA polymerase II binding protein overexpression reduces the anti-tumor NK-cell cytotoxicity through activating receptors modulation

IntroductionAATF/Che-1 over-expression in different tumors is well known and its effect on tumorigenicity is mainly due to its central role demonstrated in the oncogenic pathways of solid tumors, where it controls proliferation and viability. The effect exerted by tumors overexpressing Che-1 on the immune response has not yet been investigated.MethodsStarting from ChIP-sequencing data we confirmed Che-1 enrichment on Nectin-1 promoter. Several co-cultures experiments between NK-cells and tumor cells transduced by lentiviral vectors carrying Che-1-interfering sequence, analyzed by flow-cytometry have allowed a detailed characterization of NK receptors and tumor ligands expression.ResultsHere, we show that Che-1 is able to modulate the expression of Nectin-1 ligand at the transcriptional level, leading to the impairment of killing activity of NK-cells. Nectin-1 down-modulation induces a modification in NK-cell ligands expression able to interact with activating receptors and to stimulate NK-cell function. In addition, NK-cells from Che-1 transgenic mice, confirming a reduced expression of activating receptors, exhibit impaired activation and a preferential immature status.DiscussionThe critical equilibrium between NK-cell ligand expression on tumor cells and the interaction with NK cell receptors is affected by Che-1 over-expression and partially restored by Che-1 interference. The evidence of a new role for Che-1 as regulator of anti-tumor immunity supports the necessity to develop approaches able to target this molecule which shows a dual tumorigenic function as cancer promoter and immune response modulator

Geochemical composition of dust from Qatar peninsula

Atmospheric dust samples have been collected from different areas in Qatar and analyzed for major and trace element composition. This region of the Arabian Gulf represents an area largely affected by dust from natural and anthropogenic sources. Twenty one samples were collected during 2014 and 2015 from Al-Khor, Katara, Sealine, Al-Waab, and Qatar University by passive and active sampling techniques. Some bulk samples were collected during the massive megastorm that occurred in April 2015. Back trajectories were determined for each sample set using the NOAA HYSPLIT model over a 50 hour time interval. Samples were equally divided between northerly (n=12; northern Saudi Arabia, Kuwait or Iraq) and southerly (n=8; SE Saudi Arabia, United Arab Emirates and Oman) sources. One sample is expected to originate from westward, in Saudi Arabia. There is more variability noticed in source locations throughout the winter months (October to March), with more of them coming from the south (9 times) compared to summer months (April to September) for twice only. Dust samples were microwave-assisted, total acid digested (HF+HCl+HNO3) and oxidized with H2O2 before analyses were conducted by ICP-OES. Only 12 out of 23 elements (Al, Ca, Fe, K, Mg, Na, Ag, As, Ba, Be, Cd, Co, Cr, Cu, Li, Mn, Mo, Ni, Pb, Sr, V, Zn, P) of the Qatari dust samples were enriched relative to Upper Continental Crust (UCC). Calcium was especially enriched to a level of 400% relative to UCC. About 33% of the total sample mass was CaCO3, reflecting the composition of surface rocks in the source areas. Of the elements typically associated with anthropogenic activity, Ag, Ni, and Zn were the most enriched relative to UCC, with enrichment factors of 182%, 233%, and 209%, respectively. Other metals like Pb and V were not significantly enriched, with enrichment factors not exceeding 25% and 3%, respectively. Major elements (Al, Mn and Fe) were depleted relative to UCC due to the strong enrichment of CaCO3, with enrichment factors of -58%, -35% and -5%, respectively. Samples with northern and southern origins were separated to investigate if the elemental composition could be used to identify source/origin. Only three elements were observed to have a statistical difference. Pb and Na were higher in the samples collected from the south while Cr was higher in those from the north. This study aims to investigate present-day geochemistry of dust particles and its effect on the marine environment of the Arabian Gulf. The geochemical composition of dust is essential component for correcting lithogenic input to water column suspended matter samples.qscienc

Microbiological testing of adults hospitalised with community-acquired pneumonia: An international study

This study aimed to describe real-life microbiological testing of adults hospitalised with community-acquired pneumonia (CAP) and to assess concordance with the 2007 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) and 2011 European Respiratory Society (ERS) CAP guidelines. This was a cohort study based on the Global Initiative for Methicillin-resistant Staphylococcus aureus Pneumonia (GLIMP) database, which contains point-prevalence data on adults hospitalised with CAP across 54 countries during 2015. In total, 3702 patients were included. Testing was performed in 3217 patients, and included blood culture (71.1%), sputum culture (61.8%), Legionella urinary antigen test (30.1%), pneumococcal urinary antigen test (30.0%), viral testing (14.9%), acute-phase serology (8.8%), bronchoalveolar lavage culture (8.4%) and pleural fluid culture (3.2%). A pathogen was detected in 1173 (36.5%) patients. Testing attitudes varied significantly according to geography and disease severity. Testing was concordant with IDSA/ATS and ERS guidelines in 16.7% and 23.9% of patients, respectively. IDSA/ATS concordance was higher in Europe than in North America (21.5% versus 9.8%; p<0.01), while ERS concordance was higher in North America than in Europe (33.5% versus 19.5%; p<0.01). Testing practices of adults hospitalised with CAP varied significantly by geography and disease severity. There was a wide discordance between real-life testing practices and IDSA/ATS/ERS guideline recommendations

Prevalence and etiology of community-acquired pneumonia in immunocompromised patients

Background. The correct management of immunocompromised patients with pneumonia is debated. We evaluated the prevalence, risk factors, and characteristics of immunocompromised patients coming from the community with pneumonia. Methods. We conducted a secondary analysis of an international, multicenter study enrolling adult patients coming from the community with pneumonia and hospitalized in 222 hospitals in 54 countries worldwide. Risk factors for immunocompromise included AIDS, aplastic anemia, asplenia, hematological cancer, chemotherapy, neutropenia, biological drug use, lung transplantation, chronic steroid use, and solid tumor. Results. At least 1 risk factor for immunocompromise was recorded in 18% of the 3702 patients enrolled. The prevalences of risk factors significantly differed across continents and countries, with chronic steroid use (45%), hematological cancer (25%), and chemotherapy (22%) the most common. Among immunocompromised patients, community-acquired pneumonia (CAP) pathogens were the most frequently identified, and prevalences did not differ from those in immunocompetent patients. Risk factors for immunocompromise were independently associated with neither Pseudomonas aeruginosa nor non\u2013community-acquired bacteria. Specific risk factors were independently associated with fungal infections (odds ratio for AIDS and hematological cancer, 15.10 and 4.65, respectively; both P = .001), mycobacterial infections (AIDS; P = .006), and viral infections other than influenza (hematological cancer, 5.49; P < .001). Conclusions. Our findings could be considered by clinicians in prescribing empiric antibiotic therapy for CAP in immunocompromised patients. Patients with AIDS and hematological cancer admitted with CAP may have higher prevalences of fungi, mycobacteria, and noninfluenza viruses

Burden and risk factors for Pseudomonas aeruginosa community-acquired pneumonia:a Multinational Point Prevalence Study of Hospitalised Patients

Pseudornonas aeruginosa is a challenging bacterium to treat due to its intrinsic resistance to the antibiotics used most frequently in patients with community-acquired pneumonia (CAP). Data about the global burden and risk factors associated with P. aeruginosa-CAP are limited. We assessed the multinational burden and specific risk factors associated with P. aeruginosa-CAP. We enrolled 3193 patients in 54 countries with confirmed diagnosis of CAP who underwent microbiological testing at admission. Prevalence was calculated according to the identification of P. aeruginosa. Logistic regression analysis was used to identify risk factors for antibiotic-susceptible and antibiotic-resistant P. aeruginosa-CAP. The prevalence of P. aeruginosa and antibiotic-resistant P. aeruginosa-CAP was 4.2% and 2.0%, respectively. The rate of P. aeruginosa CAP in patients with prior infection/colonisation due to P. aeruginosa and at least one of the three independently associated chronic lung diseases (i.e. tracheostomy, bronchiectasis and/or very severe chronic obstructive pulmonary disease) was 67%. In contrast, the rate of P. aeruginosa-CAP was 2% in patients without prior P. aeruginosa infection/colonisation and none of the selected chronic lung diseases. The multinational prevalence of P. aeruginosa-CAP is low. The risk factors identified in this study may guide healthcare professionals in deciding empirical antibiotic coverage for CAP patients

Relationship between Planthoppers (\u3ci\u3eNilaparvata lugens\u3c/i\u3e and \u3ci\u3eSogatella furcifera\u3c/i\u3e) and Rice Diseases

The locational preference of the brown planthopper (BPH) Nilaparvata lugens (Still) and the whitebacked plant hopper (WBPH) Sogatella furcifera (Horvath) was studied on rice cultivars IR22 and IR36 as an integral part of subsequent research on insect-fungal pathogen relationships. The BPH was observed to stay consistently on the basal portion while the WBPH showed a general preference for the upper portion regardless of varieties, rice growth stages and insect population density levels. The habitat preference of both species (BPH and WBPH) was found not to be affected by the presence of the other species when both species are present on the same host plant. Five rice cultivars with different reactions to BPH biotype 2 were used in the study on BPH-Rhizoctonia solani relationship: IR22 and TN1 (susceptible); Triveni and ASD7 (moderately resistant); and IR42 (resistant). Test plants were inoculated with R. solani (Kuhn) 3~4days after insect infestation. Sheath blight disease severity/incidence was significantly higher in the treatment where BPH+R. solani were together than in the treatment with only the pathogen. Symptom expression of the disease in the BPH-pathogen combination was faster and mycelial growth was more profuse inducing the formation of more infection structures. Regardless of varietal reaction to BPH biotype 2, the degree of hopperburn was significantly higher in the combination of the two pests as compared with that of BPH alone. There could be a synergistic relationship between the insect pest and the pathogen indicated by a positive interaction between the two species