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BigScience Biomedical Datasets 110

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22239943_0

Hypoxic events frequently occur in the aquatic environment in association with micro pollutants , including heavy metals .

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Only a few studies are however available on the uptake and biological responses of heavy metals under hypoxic conditions .

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To elucidate the phenomenon , mirror carp Cyprinus carpio L .

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( 16.13-16.22 g ) were exposed chronically to dietary copper ( Cu ; 250 and 500 mg kg dry wt.(-1) ) for 30 d under normoxic ( 8.25 mg O(2) L(-1) ) and hypoxic ( mg O(2) L(-1) ) conditions and adopting an integrated approach , sub-lethal biomarker responses were determined at different levels of biological organisation .

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Level of oxidative DNA damage ( as determined by modified Comet assay ) showed strong significant difference following exposure to dietary Cu level under normoxic ( 1.6-fold ) as well as under hypoxic condition at both Cu levels ( 2.1 and 2.5-folds respectively ) .

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Significant difference was also observed for haematological parameters ( i.e. increased red and white blood cells , haematocrit value and haemoglobin concentration ) .

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Quantitative histology revealed alterations in tissues ( i.e. liver and gills ) for hypoxic and all dietary Cu treatment groups under both normoxic and hypoxic conditions suggesting a compensatory response to these organs ( p<0.05 ) .

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The order of Cu accumulation in tissues ( as determined by ICP-OES ) was liver>intestine>kidney>gill .

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Interestingly , SGR under both normoxic and hypoxic conditions reduced with elevating Cu levels ( p=0.019 ) .

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Overall , the results provide evidence for enhanced toxicological responses in fish following exposure to Cu either alone or in combination with hypoxic condition and lends support to the evolving viewpoint that many water quality guidelines should be revisited in terms of new ecotoxicological criteria .

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20839428_0

A 51-year-old previously healthy man , an ex-smoker , was admitted to the authors ' medical department with a 3-month history of dry cough ; intermittent fever ; painless , ulcerated cutaneous lesions over the trunk and limbs ( Figure 1 ) ; and progressive weight loss .

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He was of Greek descent .

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His medical history was remarkable for nasal polyps , which were surgically removed 15 years earlier .

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Initially , he had been treated with antibiotics , without improvement .

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Several days before admission , chest radiography revealed pulmonary infiltrates in the left lower lobe .

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On admission , physical examination revealed a well-orientated man in mild distress , with inspiratory rhonchi at the lower part of the left lung and scattered erythematous nodules of variable size , some of which were ulcerated .

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Laboratory values were notable for leukopenia , 3.3 x 10(9)/L ; total protein , 5.9 g/dL ; globulin , 2.2 g/dL ; serum glutamic oxaloacetic transaminase , 86 IU/L ; serum glutamic pyruvic transaminase , 71 IU/L ; and lactate dehydrogenase , 519 U/L .

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Computed tomograph ( CT ) of the chest showed multiple alveolar opacities bilaterally ( Figure 2 ) .

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Fiberoptic bronchoscopy did not reveal any important pathologic findings .

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Results of bronchial biopsy , cytology of bronchoalveolar lavage , washing , brushing , and sputum following bronchoscopy were negative .

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CT of the brai and sinonasal area revealed an abnormal low-density mass in the left nasal area .

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CT findings of the abdomen were negative , as were results of a bone marrow biopsy .

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There was no evidence of immunosuppression .

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The differential diagnosis , considering the evidence described , included granulomatous or infectious diseases , angiocentric lymphoproliferative lesions , and lymphomas .

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Biopsy of a skin lesion showed lymphoproliferative infiltration of the dermis with a follicular and angiocentric growth pattern and regional epidermal necrosis .

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Immunohistochemical stains showed that the tumor cell were positive for CD56 and CD3 ( cytoplasmic positivity ) and expressed the cytotoxic proteins T-cell intracellular antigen and granzyme B ( Figure 3 ) They lacked TdT , CD34 , CD7 , CD8 , TCL-1 , and CD123 .

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Findings from an in situ hybridization study for Epstein-Barr virus were negative .

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Give this result , molecular analysis ofT-cell receptor ( TCR ) gene rearrangements was performed using polymerase chain reaction-based TCR-gamma gene , wit negative results .

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The morphology and the immunophenotype were consistent with natural killer/T-cell lymphoma , nasal-type .

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Nasal involvement must be first excluded to proceed to the diagnosis of nasal-type natural killer-cell lymphoma .

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Indeed , histologic examination of the nasal mass revealed its polypoid nature .

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Thus , the authors were led to the diagnosis of extranodal extranasal natural killer/T-cell lymphoma , nasal-type , CD56-positive , Ep stein-Barr virus-negative , TCR-negative .

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The patient received combination chemotherapy and completed 4 cycles of cyclophosphamide , doxorubicin vincristine , and prednisone every 14 days for 2 months .

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Skin lesions improved , and there was no fever soon after the initiation of therapy .

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Reevaluatio after the fourth cycle , however , disclosed pulmonary infiltrations as well as leukemic infiltration of the central nervous system .

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The patient had receive systemic salvage chemotherapy and intrathecal infusions of methotrexate .

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Although the lung lesions had diminished at that time , the patient develope paraplegia , his clinical course rapidly deteriorated , and he eventually died .

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MicroRNAs ( miRs ) are small non-coding RNAs that recently emerged as potent regulators of gene expression .

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The members of the miR-17-92 cluster have been shown to control endothelial cell functions and neovascularization ; however , the regulation and function of the cluster in endothelial cell lineage commitment has not been explored .

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This project aimed to test the role of the miR-17-92 cluster during endothelial differentiation .

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We demonstrate that miR-17 , miR-18 , miR-19 and miR-20 are increased upon the induction of endothelial cell differentiation of murine embryonic stem cells or induced pluripotent stem cells .

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In contrast , miR-92a and the primary miR-17-92 transcript were downregulated .

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The inhibition of each individual miR of the cluster by cholesterol-modified antagomirs did not affect endothelial marker gene expression .

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Moreover , the combination of all antagomirs had no effect .

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These findings illustrate that although the miR-17-92 cluster regulates vascular integrity and angiogenesis , none of the members has a significant impact on the endothelial differentiation of pluripotent stem cells .

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22593574_0

The solution structure of the complex of enzyme IIA of the N,N'-diacetylchitobiose ( Chb ) transporter with the histidine phosphocarrier protein HPr has been solved by NMR .

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The IIA(Chb)-HPr complex completes the structure elucidation of representative cytoplasmic complexes for all four sugar branches of the bacterial phosphoryl transfer system ( PTS ) .

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The active site His-89 of IIA(Chb) was mutated to Glu to mimic the phosphorylated state .

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IIA(Chb)(H89E) and HPr form a weak complex with a K(D) of mM .

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The interacting binding surfaces , concave for IIA(Chb) and convex for HPr , complement each other in terms of shape , residue type , and charge distribution , with predominantly hydrophobic residues , interspersed by some uncharged polar residues , located centrally , and polar and charged residues at the periphery .

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The active site histidine of HPr , His-15 , is buried within the active site cleft of IIA(Chb) formed at the interface of two adjacent subunits of the IIA(Chb) trimer , thereby coming into close proximity with the active site residue , H89E , of IIA(Chb) .

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A His89-P-His-15 pentacoordinate phosphoryl transition state can readily be modeled without necessitating any significant conformational changes , thereby facilitating rapid phosphoryl transfer .

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Comparison of the IIA(Chb)-HPr complex with the IIA(Chb)-IIB(Chb) complex , as well as with other cytoplasmic complexes of the PTS , highlights a unifying mechanism for recognition of structurally diverse partners .

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This involves generating similar binding surfaces from entirely different underlying structural elements , large interaction surfaces coupled with extensive redundancy , and side chain conformational plasticity to optimize diverse sets of intermolecular interactions .

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1433375_0

Immunosuppression of humoral and cellular responses following chronic oral exposure to 1 , 5 , 10 , and 20 ppm N-nitrosodimethylamine ( NDMA ) was examined in CD-1 mice .

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Monitoring of cumulative mortality and the incidence of peritoneal ascites in animals showed an NDMA dose-related mortality and hepatotoxicity .

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No visible changes in immunological parameters were noted at the 1 ppm NDMA dose .

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Immunosuppression of immunoglobulin M ( IgM ) antibody response by NDMA to sheep red blood cells ( SRBC ) was time-related , dose-related , and could be reversed within 30 d by removal of the chemical from the drinking water .

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Cellular immune response , monitored by allogeneic stimulation of cells in mixed lymphocyte reaction ( MLR ) , was markedly suppressed by 10 and 20 ppm NDMA .

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Thus , chronic exposure to NDMA , except for the low-hepatotoxic doses of nitrosamine , resulted in a marked and persistent immunosuppression of cellular and humoral responses in CD-1 mice .

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In conclusion , chronic exposure to the hepatotoxic ( ascite-inducing ) doses of NDMA suppressed humoral and cellular immunity .

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The persistent immunosuppression could be reversed after the removal of NDMA from the drinking water .

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Although no direct NDMA-related cancer was reported in humans , our data point to a potential epigenetic carcinogenicity of nitrosamines due to chronic immunosuppression .

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AIMS Tumour cell growth results from a disturbance in the balance between the rate of proliferation and cell death .

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In this study , proteins involved in the regulation of cell cycle arrest and apoptosis were studied as possible factors responsible for uncontrolled cell growth in colorectal cancer .

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METHODS The expression of proteins involved in these processes was investigated in 48 metastases from patients with colorectal cancer and compared with eight normal colon mucosa samples and 14 primary tumours .

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Both primary tumours and metastases were obtained from eight patients .

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The expression of thymidylate synthase ( TS ) , p53 , retinoblastoma protein ( Rb ) , Fas receptor , Fas ligand , bcl-2 , mcl-1 , bax , and bcl-x was measured using immunohistochemistry .

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Proliferation was determined by Ki67 staining , whereas apoptosis was assessed by M30 immunostaining , which recognises cleaved cytokeratin 18 .

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RESULTS In the limited number of cases in which paired comparisons were possible , the expression of TS and Ki67 was significantly higher in metastases than in the matched primary tumour samples ( p = 0.014 and 0.016 , respectively ) , whereas Rb expression was lower in metastases than in primary tumours ( p = 0.024 ) .

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Fas receptor expression was high in normal mucosa but absent in primary tumours and metastases , whereas the opposite was seen for p53 .

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The expression of bax , mcl-1 , and bcl-x in normal mucosa was more apical than that seen in malignant cells , where a more diffuse expression pattern was seen ( p < 0.04 ) .

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Apoptosis was more abundant in primary tumours than in metastases .

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CONCLUSIONS These results demonstrate that proliferation and apoptosis are disturbed during colorectal cancer progression , and this is accompanied by loss of Rb and Fas expression , the accumulation of p53 and TS , and changes in the expression patterns of bax , mcl-1 , and bcl-xl .

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21116101_0

The radioprotective effects of dimethyl sulfoxide ( DMSO ) have been known for many years , and the suppression of hydroxyl ( OH ) radicals induced by ionizing radiation has been thought to be the main cause of this effect .

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However , the DMSO concentration used was very high , and might be toxic , in earlier studies .

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In the present study , we administered a lower , non-toxic concentration ( 0.5% , i.e. , 64 mM ) of DMSO before irradiation and examined its radioprotective effects .

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Colony formation assay and micronucleus assay showed significant radioprotective effects in CHO , but not in xrs5 , which is defective in the repair function of DNA double-strand breaks .

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The levels of phosphorylated H2AX and the formation of 53BP1 foci 15 minutes after irradiation , which might reflect initial DNA double-strand breaks , in DMSO-treated CHO cells were similar to those in non-treated cells , suggesting that the radioprotective effects were not attributable to the suppression of general indirect action in the lower concentration of DMSO .

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On the other hand , 2 hours after irradiation , the average number of 53BP1 foci , which might reflect residual DNA double-strand breaks , was significantly decreased in DMSO-treated CHO cells compared to non-treated cells .

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The results indicated that low concentration of DMSO exerts radioprotective effects through the facilitation of DNA double-strand break repair rather than through the suppression of indirect action .

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Androgens regulate both the physiological development of the prostate and the pathology of prostatic diseases .

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However , the mechanisms by which androgens exert their regulatory activities on these processes are poorly understood .

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In this study , we have determined that androgens regulate overall cell metabolism and cell growth , in part , by increasing autophagy in prostate cancer cells .

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Importantly , inhibition of autophagy using either pharmacological or molecular inhibitors significantly abrogated androgen-induced prostate cancer cell growth .

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Mechanistically , androgen-mediated autophagy appears to promote cell growth by augmenting intracellular lipid accumulation , an effect previously demonstrated to be necessary for prostate cancer cell growth .

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Further , autophagy and subsequent cell growth is potentiated , in part , by androgen-mediated increases in reactive oxygen species .

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These findings demonstrate a role for increased fat metabolism and autophagy in prostatic neoplasias and highlight the potential of targeting underexplored metabolic pathways for the development of novel therapeutics .

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Cis-diamminedichloroplatinum ( II ) ( cisplatin ) is a well characterized antitumor drug used for the treatment of a variety of human cancers .

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The cytotoxicity of cisplatin is mainly mediated through the formation of DNA adducts , which are also believed to be responsible for the secondary malignancies produced by the drug .

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The aim of this study was to determine the in vivo mutagenic activity of cisplatin in the lacZ plasmid-based transgenic mouse model .

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The mutant frequency ( MF ) and the spectrum of mutations induced by cisplatin in the mouse liver were analyzed and compared to controls .

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The mean MF in the lacZ gene was increased 2-fold in mice treated with a single 6 mg/kg body weight dose of cisplatin and sacrificed after 17 and 28 days ( P = 0.001 and P < 0.0001 ) .

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Restriction analysis and sequencing of mutant DNA showed that cisplatin was able to induce both large deletions and point mutations .

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A specific profile of base substitution and frameshift mutations was identified in treated mice , consisting primarily of G:C-->A:T transitions at GpG and ApG sites , the preferential DNA binding sites of cisplatin , and single basepair deletions/insertions .

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The present results provide the first evidence that cisplatin has mutagenic activity in vivo and induces a characteristic pattern of mutations in the mouse liver .

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This mutagenicity may be responsible for its tumorigenic activity .

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A prominent feature of inflammatory diseases is endothelial dysfunction .

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Factors associated with endothelial dysfunction include proinflammatory cytokines , adhesion molecules , and matrix degrading enzymes .

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At the transcriptional level , they are regulated by the histone deacetylase sirtuin ( SIRT ) 1 via its actions on the proinflammatory transcription factor nuclear factor-κB ( NF-κB ) .