Bevacizumab Eye Drop Treatment Stimulates Tear Secretion in Rats Through Changes in VEGF and NGF Lacrimal Gland Levels

VEGF and NGF are known to modulate corneal healing, neovascularisation and tear secretion. While a VEGF-NGF cross talk has been recently shown to modulate corneal healing in rats, it is not known whether it also plays a role in the regulation of lacrimal function. In this study we aim to investigate the effects of anti-VEGF eye drop treatment on lacrimal gland function and on the local expression of VEGF and NGF in rats. Tear function was measured in 3 months old rats by modified Schirmer test at baseline and after 3 weeks of topical anti-VEGF eye drop treatment. Whole lacrimal glands from rats were removed after treatment and analysed by ELISA for VEGF and NGF levels. To investigate if the effects of anti-VEGF were mediated by changes in the NGF-pathway, we repeated the experiments in RCS rats, a strain with NGF-pathway impairment associated with decreased tear flow. After topical treatment with anti-VEGF eye drops, an increase in tear secretion was observed in both wild-type and RCS rats. A significant decrease of VEGF levels was also observed in lacrimal glands of both RCS and SD rats, accompanied by a significant increase in NGF levels. Inhibition of VEGF at the ocular surface in rats results in changes of tear function and lacrimal gland levels of VEGF and NGF. Further studies on the VEGF/NGF cross-talk at the ocular surface may expand our knowledge on the pathogenesis of several diseases characterized by tear dysfunction.     

'Click' synthesis of a triazole-based inhibitor of Met functions in cancer cells

The use of Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition permitted the synthesis of a new compound that is able to inhibit the HGF-induced scattering of MDCK (epithelial cells) and in vitro tumorigenesis of H1437 (non-small-cell lung cancer) and GTL-16 (human gastric carcinoma). In agreement with biochemical and biological results, docking studies within the ATP binding site of Met suggested for the new synthesized compound a binding mode similar to that of the active compound Triflorcas previously reported.     

A novel survival-based tissue microarray of pancreatic cancer validates MUC1 and mesothelin as biomarkers

Background

One–fifth of patients with seemingly ‘curable’ pancreatic ductal adenocarcinoma (PDA) experience an early recurrence and death, receiving no definable benefit from a major operation. Some patients with advanced stage tumors are deemed ‘unresectable’ by conventional staging criteria (e.g. liver metastasis), yet progress slowly. Effective biomarkers that stratify PDA based on biologic behavior are needed. To help researchers sort through the maze of biomarker data, a compendium of ∼2500 published candidate biomarkers in PDA was compiled (PLoS Med, 2009. 6(4) p. e1000046).

Methods and Findings

Building on this compendium, we constructed a survival tissue microarray (termed s-TMA) comprised of short-term (cancer-specific death <12 months, n = 58) and long-term survivors (>30 months, n = 79) who underwent resection for PDA (total, n = 137). The s-TMA functions as a biological filter to identify bona fide prognostic markers associated with survival group extremes (at least 18 months separate survival groups). Based on a stringent selection process, 13 putative PDA biomarkers were identified from the public biomarker repository. Candidates were tested against the s-TMA by immunohistochemistry to identify the best markers of tumor biology. In a multivariate model, MUC1 (odds ratio, OR = 28.95, 3+ vs. negative expression, p = 0.004) and MSLN (OR = 12.47, 3+ vs. negative expression, p = 0.01) were highly predictive of early cancer-specific death. By comparison, pathologic factors (size, lymph node metastases, resection margin status, and grade) had ORs below three, and none reached statistical significance. ROC curves were used to compare the four pathologic prognostic features (ROC area = 0.70) to three univariate molecular predictors (MUC1, MSLN, MUC2) of survival group (ROC area = 0.80, p = 0.07).

Conclusions

MUC1 and MSLN were superior to pathologic features and other putative biomarkers as predicting survival group. Molecular assays comparing cancers from short and long survivors are an effective strategy to screen biomarkers and prioritize candidate cancer genes for diagnostic and therapeutic studies.     

Macromolecular properties of cepacian in water and in dimethylsulfoxide

Cepacian is the exopolysaccharide produced by the majority of the so far investigated clinical strains of the Burkholderia cepacia complex. This is a group of nine closely related bacterial species that might cause serious lung infections in cystic fibrosis patients, in some cases leading to death. In this paper the aggregation ability and the conformational properties of cepacian chain were investigated to understand its role in biofilm formation. Viscosity and atomic force microscopy studies in water and in mixed (dimethylsulfoxide/water) solvent indicated the formation of double stranded molecular structures in aqueous solutions. Inter-residue short distances along cepacian chain were investigated by NOE NMR, which showed that two side chains of cepacian were not conformationally free due to strong interactions with the polymer backbone. These interactions were attributed to hydrogen bonding and contributed to structure rigidity.     

Cardiovascular evaluation,including resting and exercise electrocardiography,before participation in competitive sports: cross sectional study

Objective To evaluate the clinical usefulness of complete preparticipation cardiovascular screening in a large cohort of sports participants.Design Cross sectional study of data over a five year period.Setting Institute of Sports Medicine in Florence, Italy.Participants 30 065 (23 570 men) people seeking to obtain clinical eligibility for competitive sports.Main outcome measures Results of resting and exercise 12 lead electrocardiography.Results Resting 12 lead ECG patterns showed abnormalities in 1812 (6%) participants, with the most common abnormalities (>80%) concerning innocent ECG changes. Exercise ECG showed an abnormal pattern in 1459 (4.9%) participants. Exercise ECG showed cardiac anomalies in 1227 athletes with normal findings on resting ECG. At the end of screening, 196 (0.6%) participants were considered ineligible for competitive sports. Among the 159 participants who were disqualified at the end of the screening for cardiac reasons, a consistent proportion (n=126, 79.2%) had shown innocent or negative findings on resting 12 lead ECG but clear pathological alterations during the exercise test. After adjustment for possible confounders, logistic regression analysis showed that age >30 years was significantly associated with an increased risk of being disqualified for cardiac findings during exercise testing.Conclusions Among people seeking to take part in competitive sports, exercise ECG can identify those with cardiac abnormalities. Follow-up studies would show if disqualification of such people would reduce the incidence of CV events among athletes.     

Mating Systems of Psychotria tenuinervis (Rubiaceae): Distance from Anthropogenic and Natural Edges of Atlantic Forest Fragment

The aim of this study was to determine and compare the mating systems among Psychotria tenuinervis populations at anthropogenic edges, natural edges, and the forest interior using allozyme electrophoresis of naturally pollinated progeny arrays. P. tenuinervis showed low outcrossing rates, varying from 37% to 50% of the mating attributable to outcrossing and 50% to 63% attributable to self-fertilization, in the three habitats. The forest interior had the highest outcrossing rate (t _m = 0.50 and t _s = 0.43) among the three habitats. However, there were no differences in either multilocus or single-locus rates among the three habitats, indicating that the contribution of biparental inbreeding to the apparent selfing rate in these populations was very low. The multilocus (t _m) and single-locus (t _s) outcrossing rates for the P. tenuinervis in the sample plots within each habitat showed great heterogeneity. In conclusion, edge creation seems not to influence its mating systems. Additionally, although P. tenuinervis is a distylous species, the population’s inbreeding can be attributed almost entirely to self-fertilization.     

Combined use of dopamine and prostaglandin A1 in patients with acute renal failure and hepatorenal syndrome

Dopamine and prostaglandin A₁ were infused intravenously in 4 patients with the hepatorenal syndrome, in 1 patient with acute tubular necrosis, and 1 patient with cortical necrosis. Large doses of prostaglandin A₁ decreased arterial blood pressure preventing increase in dosage; in contrast, high doses of dopamine elevated blood pressure. When the two drugs were administered conjointly, much larger doses of each agent could be administered without change in arterial blood pressure. Significant improvement of renal function was not observed in any of these critically ill patients during or within 24 hours after dopamine and prostaglandin A₁ administration. This study demonstrated that extremely large doses of these vasodilating agents can be safely administered conjointly.