Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential permeability of a human brain tumor xenograft in the nude rat: impact of tumor size and method of administration on optimizing delivery of biologically diverse agents.

To assess how to maximize drug delivery to intracerebral tumors and surrounding brain, this study examined the effects of route and method of administration and tumor size on the distribution of three agents in a nude rat intracerebral tumor xenograft model. Aminoisobutyric acid (M(r) 103), methotrexate (M(r) 454), and dextran 70 (M(r) 70,000) were administered i.v. or intra-arterially (i.a.) with or without osmotic blood-brain barrier disruption (BBBD) at 8, 12, or 16 days after tumor cell inoculation (n = 72). A 2.2- to 2.5-fold increase in delivery to tumor and surrounding brain was observed when i.a. was compared with i.v. , and a 2.5- to 7.6-fold increase was observed when BBBD was compared with the saline control. The combined effect of i.a. administration and BBBD was to increase delivery 6.3-16.7-fold. The greatest benefit of BBBD was seen in animals with 8-day tumors, whereas BBBD had less benefit in improving delivery to intracerebral tumor and brain around tumor as the tumors grew larger. Regional delivery decreased as the molecular weight of the agent increased. Based on these results, we suggest that i.a. administration of antitumor agents may be adequate to obtain initial responses in large, very permeable, intracerebral tumors. However, in smaller, less permeable tumors or after an initial response to treatment, there may be a significant therapeutic advantage to i.a. agent administration and BBBD.
High‐risk HPV types and head and neck cancer

Although HPV16 has been strongly implicated in oropharyngeal carcinogenesis, the role of other high‐risk HPV types in the etiology of head and neck cancer remains unclear. To date, few data exist addressing the nature of the association between antibodies to oncogenic proteins of non‐HPV16 HPVs in relation to head and neck cancer. We examined the relationship between multiple HPV types (HPV6, 11, 16, 18, 31, 33, 45, 52, 58) and head and neck squamous cell carcinoma (HNSCC) in a large population‐based case–control study (1069 cases and 1107 controls). Serological measures for HPV types included antibodies to L1, E6 and/or E7. In a secondary analysis, we excluded HPV16 seropositive subjects to examine independent associations with other high‐risk HPVs. All analyses were adjusted for age, race, sex, education, smoking and alcohol consumption. Statistically significant associations were observed for HPV16, 18, 33 and 52 and risk of HNSCC after mutually adjusting for HPV types. Among HPV16 seronegative subjects, elevated risks of HNSCC were observed for HPV18 E6 (OR = 4.19, 95% CI = 1.26–14.0), HPV33 E6 (OR = 7.96, 95% CI = 1.56–40.5) and HPV52 E7 (OR = 3.40, 95% CI = 1.16–9.99). When examined by tumor type, associations with HPV18 and HPV33 remained statistically significant for oropharyngeal cancer, and HPV52 was associated with oral cancer. In addition, magnitude of associations for HNSCC increased markedly with increasing number of seropositive high‐risk HPV infections. High‐risk HPV types, other than HPV16, are likely to be involved in the etiology of HNSCC.
Bile acids inhibit interleukin‐6 signaling via gp130 receptor‐dependent and ‐independent pathways in rat liver

Interleukin‐6 (IL‐6) is a major regulator of the acute phase reaction in the liver and is thought to mediate protective effects in response to hepatotoxins. In this study, the influence of bile acids on IL‐6 signal transduction was analyzed. It was shown that hydrophobic bile acids such as glycochenodeoxycholate (GCDC) inhibited IL‐6–induced tyrosine phosphorylation of signal transducer and activator of transcription (STAT) 3 in hepatocytes and in perfused rat liver. This inhibition was accompanied by GCDC‐mediated downregulation of glycoprotein (gp) 130 expression, whereas gp130 and suppressor of cytokine signaling 3 messenger RNA and gp80 protein levels remained unaffected. The GCDC‐induced downregulation of gp130 protein expression was insensitive to inhibition of proteasomal or lysosomal protein degradation but turned out to be sensitive to inhibition of caspase‐3 or caspase‐8 activity. Accordingly, treatment of cell extracts with active recombinant caspase‐3 led to a decay of immunoreactive gp130. Moreover, activation of caspases by CD95 ligand or hyperosmotic stress also resulted in a downregulation of gp130 levels. This indicates that caspase activation antagonizes IL‐6 signaling by decay of gp130 levels. However, caspase inhibition did not prevent GCDC‐dependent inhibition of IL‐6–induced STAT3 activation, which turned out to be at least partially sensitive to suppression of p38MAPK activation. In conclusion, hydrophobic bile acids compromise IL‐6 signaling through both a caspase‐mediated downregulation of gp130 and a p38MAPK‐dependent inhibition of STAT3 phosphorylation. This may contribute to bile acid–induced hepatotoxicity in cholestasis through counteracting the known hepatoprotective effects of IL‐6. (HEPATOLOGY 2006;44:1206–1217.)
Hepatitis C virus (HCV) core protein enhances the immunogenicity of a co‐delivered DNA vaccine encoding HCV structural antigens in mice

In the present study, recombinant HCV (hepatitis C virus) core proteins enhanced the immune response elicited by a co‐delivered DNA vaccine encoding HCV core and envelope proteins. A mixture of the plasmid pIDKE2 and Co.173, a protein comprising the first 173 amino acids of HCV core, in particular induces a strong humoral response, including antibodies that recognized peptides representing hypervariable region I from different viral isolates. Moreover, positive lymphoproliferative responses against the HCV structural proteins, encoded by the plasmid, were detected after two doses with this mixture. When the HCV core protein used in the mixture with pIDKE2 was Co.120, a protein comprising the first 120 amino acids of the viral antigen, a strong humoral response and a positive lymphoproliferative response were also detected. The effectiveness of this formulation was tested in vivo by measuring the protection against infection with a recombinant vaccinia virus expressing HCV core protein. A 2 log reduction in vaccinia‐virus titre was observed in mice immunized with the mixture of pIDKE2 and Co.120. Humoral and cellular immune responses elicited for the mixture of pIDKE2 with either Co.173 or Co.120 was stronger and more diverse than those generated by individual components. In conclusion, our results indicate that formulations comprising both DNA constructs and protein subunit vaccine candidates are able to elicit strong humoral and cellular immunity against several antigens. Particularly, HCV core protein might be used as a feasible vehicle/adjuvant for DNA vaccines.
How (Good) Was It to Be the King? Current Research on the Archaeology of Palaces in Ancient America

These two books concern a growing field of research in precolumbian archaeology—the study of palaces and elite residences, and in so doing broach two seminal issues in anthropology—social differentiation and the secularization of power, or, perhaps more correctly, the possible specificity of political power as an entity Independent from religious power in ancient complex societies. In Peru, this field was explored by the Chan Chan-Moche Valley Project (Moseley and Day 1982) and the successive palace model devised by Geoffrey Conrad (1981). This model combines archaeological and ethnohistorical data, and proposes that each ruler of a dynasty would build their own palace, which would become his mausoleum; his successor would then repeat this process. A similar model may reasonably be applied to the Wari (Isbell 2000, 2001), the Ychsma (Eeckhout 1999), and the Inca (Niles 1999). In Mesoamerica, there are numerous colonial accounts concerning Aztec palaces, but comparatively few archaeological remains. This may be a matter of definition; the term "palace" is sometimes used somewhat indiscriminately and without explicit justification (i.e., the Quetzalpapalotl Palace at Teotihuacan, the Palace of Mitla, etc). Early Maya archaeologists' typologies concerning monumental Maya ruins—which can be summarized as "pyramid = temple" and "structure on low platform = residence"— have proven to be remarkably durable, yet considerable progress has been made in recent decades, resulting in the Americas' most abundant literature on the subject (i.e., Chase and Chase 1992; Christie 2003; Inomata and Houston 2001).
Role of pelvic sensory signalling during delivery in postpartum mental health

Background: Animal research demonstrates that pelvic sensory signalling at parturition initiates behavioural and emotional changes that are protective for mother and offspring. In contrast, research with humans has found no effect of caesarean delivery (i.e. procedure that blocks pelvic signalling) on mother's mental health. The lack of effect may reflect little consideration for the use of epidurals, another intervention that blocks pelvic signalling. The following study examines whether blocking pelvic signalling during delivery predicts postpartum depression symptomatology. Method: Longitudinal mental health data were collected prospectively from 142 primiparous women who had a caesarean delivery and/or received epidural anaesthesia (Intervention) or delivered vaginally without anaesthesia (No‐Intervention). Measurements began in late pregnancy and continued through the first postpartum year. Results: Intervention mothers reported more depressive symptoms at the end of the first postpartum year compared to those in the No‐Intervention group. This effect was independent of socio‐cultural factors known to predict levels of depressive symptoms. Conclusion: These results suggest that pelvic sensory signalling may help to prepare women for the postpartum period. Considering there are many factors influencing the mental health of mothers, the present finding suggest that populations vulnerable to postpartum depression should consider a delivery without intervention, when medically permissible.
Differential effects of cyclic and constant stress on ATP release and mucociliary transport by human airway epithelia

In the lungs, the first line of defence against bacterial infection is the thin layer of airway surface liquid (ASL) lining the airway surface. The superficial airway epithelium exhibits complex regulatory pathways that blend ion transport to adjust ASL volume to maintain proper mucociliary clearance (MCC). We hypothesized that stresses generated by airflow and transmural pressures during breathing govern ASL volume by regulating the rate of epithelial ATP release. Luminal ATP, via interactions with apical membrane P2‐purinoceptors, regulates the balance of active ion secretion versus absorption to maintain ASL volume at optimal levels for MCC. In this study we tested the hypothesis that cyclic compressive stress (CCS), mimicking normal tidal breathing, regulates ASL volume in airway epithelia. Polarized tracheobronchial epithelial cultures from normal and cystic fibrosis (CF) subjects responded to a range of CCS by increasing the rate of ATP release. In normal airway epithelia, the CCS‐induced increase in ASL ATP concentration was sufficient to induce purinoceptor‐mediated increases in ASL height and MCC, via inhibition of epithelial Na+‐channel‐mediated Na+ absorption and stimulation of Cl− secretion through CFTR and the Ca2+‐activated chloride channels. In contrast, static, non‐oscillatory stress did not stimulate ATP release, ion transport or MCC, emphasizing the importance of rhythmic mechanical stress for airway defence. In CF airway cultures, which exhibit basal ASL depletion, CCS was partially effective, producing less ASL volume secretion than in normal cultures, but a level sufficient to restore MCC. The present data suggest that CCS may (1) regulate ASL volume in the normal lung and (2) improve clearance in the lungs of CF patients, potentially explaining the beneficial role of exercise in lung defence.
Identification of a new marker of hepatocellular carcinoma by serum protein profiling of patients with chronic liver diseases

Surface‐enhanced laser desorption ionization time‐of‐flight mass spectrometry (SELDI‐TOF MS) is a proteomic technique that enables the profiling of proteins present in any biological material studied. We used this approach to identify new biomarkers of hepatocellular carcinoma (HCC) in the sera of patients with cirrhosis. Sera from 82 patients with cirrhosis, either without (n = 38) or with (n = 44) HCC, were analyzed by SELDI‐TOF MS, and the results of the two groups were compared. The most efficient protein peaks leading to discrimination of patients with HCC were selected (receiver operative characteristic curves). The highest‐scoring peak combination was established in a first group of serum samples (multinomial regression) and was tested in an independent group. The protein corresponding to the highest discrimination was purified and characterized further. The intensity of 30 protein peaks significantly differed between cirrhotic patients with and without HCC. An algorithm including the six highest‐scoring peaks allowed correct classification (presence or absence of HCC) of 92.5% of patients in the test sample set and 90% in the validation sample set. The highest discriminating peak (8,900 Da) was purified further and was characterized as the C‐terminal part of the V10 fragment of vitronectin. An in vitro study suggested that the increase of the 8,900‐Da fragment in the serum of patients with HCC may proceed from the cleavage of native vitronectin with metalloproteases, a family of enzymes whose activity is enhanced in HCC. In conclusion, global protein profiling is an efficient approach that enabled us to identify a catalytic fragment of vitronectin as a new serum marker of HCC in patients with chronic liver diseases. (HEPATOLOGY 2005;41:40–47.)
Solid waste disposal in urban areas and health - the case of Belo Horizonte, Brazil

The presence of sanitary or controlled landfill in urban areas and its implications for the health of the population that lives in its bordering area has been little investigated. The presence of these deposits, with design or operational problems, can end up providing a likely location for the proliferation of diverse vectors and favouring uncontrolled emissions, which may affect health, both for the people that work and live in these places and those that live nearby. This paper describes a study carried out in the city of Belo Horizonte, Brazil, with the objective of associating the presence of the BR 040 sanitary landfill, located in the urban environment, and the health of the neighbouring population. There were 475 possibilities of occurrences studied, covering 19 different combinations for association between the exposure factor and the groupings of researched diseases (respiratory diseases, diarrhoea and skin diseases). However, of this total only 33 results were shown to be significant in showing the existence of an association. For these results, the variable exposures identified as a risk factor showed an odds ratio ranging between 1.20 and 13.75. Although without an evidenced relationship, respiratory diseases appeared as a relevant outcome in the study, as they were present in 23 of the 33 studied combinations in which the results were significant.
CYCLOSPORINE METABOLISM BY P450IIIA IN RAT ENTEROCYTES—ANOTHER DETERMINANT OF ORAL BIOAVAILABILITY?

Cyclosporine is converted to its major metabolites (M-17, M-1, and M-21) in human liver by enzymes belonging to the P450IIIA subfamily. These enzymes are also present in rat and human enterocytes; however, the possibility that CsA is metabolized in enterocytes has not been previously investigated. We therefore directly compared metabolism of 3H-CsA in microsomes prepared from liver and jejunal enterocytes. M-17, M-1, and M-21 were the major CsA metabolites produced by enterocyte microsomes. This metabolism appeared to be catalyzed by P450IIIA, because pretreatment of rats with the P450IIIA inducer dexamethasone significantly increased the rate of CsA metabolism in enterocyte microsomes and preincubation of enterocyte microsomes with anti-P450IIIA IgG inhibited the production of CsA metabolites by greater than 95%. To determine if enterocyte P450IIIA metabolizes CsA in vivo, rats were pretreated with the P450IIIA inducer dexamethasone, the P450IIIA inhibitor erythromycin, or vehicle alone. At laparotomy, 2 mg/kg of 3H-CsA was injected into a sealed loop of jejunum, and after collection of the mesenteric venous blood draining this segment for 45 min, the production of M-17 and M-1 was measured. In the control group, a mean of 3.9% of the recovered radioactivity was found as M-1 and M-17. In the rats pretreated with dexamethasone, a mean of 8.4% of the radioactivity was found as M-1 and M-17 (P less than 0.05 relative to control) and this decreased to 2.3% in the group pretreated with erythromycin (P = 0.08 relative to control). We conclude that P450IIIA in jejunal enterocytes readily metabolizes CsA. Furthermore, the metabolism of CsA by enterocytes in vivo is substantial and likely contributes to "first pass metabolism" of orally administered CsA. Our observations provide novel hypotheses to explain some important drug interactions and interpatient differences in CsA dosing requirements.
Surface Proteome Analysis of a Natural Isolate of Lactococcus lactis Reveals the Presence of Pili Able to Bind Human Intestinal Epithelial Cells*

Surface proteins of Gram-positive bacteria play crucial roles in bacterial adhesion to host tissues. Regarding commensal or probiotic bacteria, adhesion to intestinal mucosa may promote their persistence in the gastro-intestinal tract and their beneficial effects to the host. In this study, seven Lactococcus lactis strains exhibiting variable surface physico-chemical properties were compared for their adhesion to Caco-2 intestinal epithelial cells. In this test, only one vegetal isolate TIL448 expressed a high-adhesion phenotype. A nonadhesive derivative was obtained by plasmid curing from TIL448, indicating that the adhesion determinants were plasmid-encoded. Surface-exposed proteins in TIL448 were analyzed by a proteomic approach consisting in shaving of the bacterial surface with trypsin and analysis of the released peptides by LC-MS/MS. As the TIL448 complete genome sequence was not available, the tryptic peptides were identified by a mass matching approach against a database including all Lactococcus protein sequences and the sequences deduced from partial DNA sequences of the TIL448 plasmids. Two surface proteins, encoded by plasmids in TIL448, were identified as candidate adhesins, the first one displaying pilin characteristics and the second one containing two mucus-binding domains. Inactivation of the pilin gene abolished adhesion to Caco-2 cells whereas inactivation of the mucus-binding protein gene had no effect on adhesion. The pilin gene is located inside a cluster of four genes encoding two other pilin-like proteins and one class-C sortase. Synthesis of pili was confirmed by immunoblotting detection of high molecular weight forms of pilins associated to the cell wall as well as by electron and atomic force microscopy observations. As a conclusion, surface proteome analysis allowed us to detect pilins at the surface of L. lactis TIL448. Moreover we showed that pili appendages are formed and involved in adhesion to Caco-2 intestinal epithelial cells.
Reduced hemoglobin on day of peripheral blood progenitor cell collection is associated with low graft content of vascular progenitors and increased toxicity after autologous hematopoietic stem cell transplantation

BACKGROUND: Tissue damage after hematopoietic stem cell transplantation (HSCT) occurs as a result of high‐dose chemotherapy and radiation. The aim was to determine the importance of pretransplant anemia on toxicity and red blood cell (RBC) transfusion requirements after autologous HSCT.
Anti-B7-1 blocks mononuclear cell adherence in vasa recta after ischemia.

BACKGROUND Blocking the costimulatory pathway by CTLA-4 Ig, reactive with both B7-1 and B7-2 costimulatory molecules, protects the kidney during acute ischemia/reperfusion injury. This study investigated whether and how B7-1 and/or B7-2 proteins are involved in renal ischemia/reperfusion injury (IRI). METHODS Uninephrectomized rats were submitted to warm renal ischemia (30 min) and received control monoclonal antibody (mAb; 17E3), anti-B7-1 (3H5), anti-B7-2 (24F), a combination of anti-B7-1/B7-2, or CTLA-4 Ig. Renal function, morphology, and the kinetics of inflammatory cells were studied for a ten-day period. Binding sites of the injected antibodies were detected by secondary staining with anti-mouse Ab. RESULTS Compared with controls, acute renal failure (ARF) in the anti-B7-1 group was attenuated both functionally and morphologically. Anti-B7-1/B7-2 and CTLA-4 Ig also were protective in IRI. ARF was not altered by anti-B7-2 treatment. Two hours after reperfusion, B7-1 was expressed along the endothelial cells of the ascending vasa recta. Expression of B7-1 increased over time during the first 24 hours and decreased thereafter. Two hours after reperfusion, adherence/accumulation of T cells and monocytes/macrophages was found in the vasa recta of the ischemic kidney. Anti-B7-1-treated animals had fewer T cells and monocytes/macrophages in the vasa recta compared with controls. Leukocyte accumulation in these vessels after anti-B7-2 treatment was not different from IRI controls. CONCLUSION These observations strongly support the key role of the B7-1 protein in the protection of renal IRI through inhibition of T cell and monocyte adherence at the level of the ascending vasa recta.
Antibody Binding to CD4 Induces Rac GTPase Activation and Alters T Cell Migration

The use of nondepleting Abs specific for CD4 and CD8 is an effective strategy to tolerize CD4+ and CD8+ T cells in a tissue-specific manner. We reported that coreceptor therapy reverses diabetes in new onset NOD mice. A striking feature of coreceptor-induced remission is the purging of T cells from the pancreatic lymph nodes (PLN) and islets of NOD mice. Evidence indicates that Abs binding to the coreceptors promotes T cell egress from these tissues. The present study examined how coreceptor therapy affects the migration of CD4+ T cells residing in the PLN of NOD mice. Anti-CD4 Ab treatment resulted in an increased frequency of PLN but not splenic CD4+ T cells that exhibited a polarized morphology consistent with a migratory phenotype. Furthermore, PLN CD4+ T cells isolated from anti-CD4 versus control Ab-treated animals displayed increased in vitro chemotaxis to chemoattractants such as sphingosine-1-phosphate and CXCL12. Notably, the latter was dependent on activation of the small Rho GTPases Rac1 and Rac2. Rac1 and Rac2 activation was increased in Ab-bound CD4+ T cells from the PLN but not the spleen, and knockdown of Rac expression blocked the heightened reactivity of Ab-bound PLN CD4+ T cells to CXCL12. Interestingly, Rac1 and Rac2 activation was independent of Rac guanine nucleotide exchange factors known to regulate T cell activity. Therefore, Ab binding to CD4 initiates a novel pathway that involves inflammation-dependent activation of Rac and establishment of altered T cell migratory properties.