The additive effect of intravitreal dexamethasone combined with bevacizumab in refractory diabetic macular edema.

PURPOSE: To evaluate the short-term structural and visual outcomes and side effects associated with intravitreal dexamethasone (IVD) combined with bevacizumab (IVB) in treating patients with diabetic macular edema (DME) and an inadequate response to anti-vascular endothelial growth factor (anti-VEGF) agents. METHODS: In this prospective interventional case series, a total of 81 eyes of 81 patients with type 2 diabetes mellitus (T2DM) and refractory DME were included and assigned to one of two groups: I) those receiving three monthly intravitreal injections of combined bevacizumab and dexamethasone (IVB+IVD) and II) those receiving three monthly intravitreal injections of bevacizumab alone (IVB). The primary outcome was the inter-group difference in central macular thickness (CMT); secondary outcomes included best-corrected visual acuity (BCVA), baseline optical coherence tomography (OCT) biomarkers, and intraocular pressure (IOP) one month after the last injection. RESULTS: Reduction in CMT and improvement in BCVA were significantly greater in the IVB+IVD group than the IVB group (109.88±156.25 vs. 43±113.67, respectively, P=0.03; and -0.13±0.23 vs. -0.01±0.17, respectively, P=0.008). Presence of neurosensory retinal detachment (NSD) (P<0.001) and complete inner segment/outer segment junction (IS-OS) disruption (P=0.049) on baseline OCT scans were associated with further CMT reductions in response to IVD. Conversely, identifiable epiretinal membrane (ERM) (P=0.002) and multiple hyperreflective foci (>20) (P=0.049) were associated with smaller reductions in CMT. Vitreomacular traction correlated with worse visual outcomes in the IVB+IVD group (P=0.003). The intergroup IOP difference was not clinically significant. CONCLUSION: In patients with refractory DME, addition of IVD to the standard IVB regimen can improve visual and structural outcomes without increasing the risk of endophthalmitis, IOP rise, or intraocular inflammation. Patients with NSD are more likely to respond well to IVD. The presence of ERM may predict poor treatment response.

MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes.

MUC1 (CD227), a membrane tethered mucin glycoprotein, is overexpressed in >60% of human pancreatic cancers (PCs), and is associated with poor prognosis, enhanced metastasis and chemoresistance. The objective of this study was to delineate the mechanism by which MUC1 induces drug resistance in human (BxPC3 and Capan-1) and mouse (KCKO, KCM) PC cells. We report that PC cells that express high levels of MUC1 exhibit increased resistance to chemotherapeutic drugs (gemcitabine and etoposide) in comparison with cells that express low levels of MUC1. This chemo resistance was attributed to the enhanced expression of multidrug resistance (MDR) genes including ABCC1, ABCC3, ABCC5 and ABCB1. In particular, levels of MRP1 protein encoded by the ABCC1 gene were significantly higher in the MUC1-high PC cells. In BxPC3 and Capan-1 cells MUC1 upregulates MRP1 via an Akt-dependent pathway, whereas in KCM cells MUC1-mediated MRP1 upregulation is via an Akt-independent mechanism. In KCM, BxPC3 and Capan-1 cells, the cytoplasmic tail motif of MUC1 associates directly with the promoter region of the Abcc1/ABCC1 gene, indicating a possible role of MUC1 acting as a transcriptional regulator of this gene. This is the first report to show that MUC1 can directly regulate the expression of MDR genes in PC cells, and thus confer drug resistance.

The origin of nitrogen incorporated into compounds in the rumen bacteria of steers given protein- and urea-containing diets.

1. Two young Friesian steers fitted with rumen cannulas were each given three different isonitrogenous and isoenergetic diets for successive periods of 2-3 weeks. The diets consisted mainly of straw and tapioca, with the nitrogen supplied mainly as decorticated groundnut meal(DCGM; diet A), in approximately equal amounts of DCGM and urea (diet B), or entirely as urea (diet C). 2. At the end of each period on a given diet, part of the dietary urea of a morning feed was replaced by a solution of [15N]urea which was infused into the rumen. Samples of rumen contents were removed just before giving the 15N dose and at 1,3,5,7 and 24 h afterwards, concentrations of ammonia and its 15N enrichment were determined and samples of mixed bacteria were prepared. Amino acids, ammonia derived mainly from amide groups, and hexosamines were prepared by ion-exchange chromatography of acid-hydrolysates of the bacteria and analysed for 15N. 3. Approximate estimates of net bacterial N synthesis were made from turnover data for rumen fluid and 15N enrichments in rumen fractions. From the determined efficiency of incorporation of urea-N into bacteria recovered at the duodenum, it was calculated that on diets A, B and C respectively 82%, 37% and 0% of the bacterial N was derived from dietary protein or other non-urea sources. 4. [15N]urea was converted rapidly to ammonia and the 15N then incorporated into bacterial amide-N; it appeared at a slower rate in total bacterial non-amide-N. Rates of incorporation into non-amide-N were highest for glutamic acid, aspartic acid and alanine, and generally lowest for proline (pro), histidine (his), phenylalanine(phe), arginine(arg), methionine(met) and galactosamine. A similar ranking was also generally observed for relative 15N abundances (15N atoms % excess in N component divided by 15N atoms % excess in total bacterial N) achieved after several hours. Relative 15N abundances in his, arg and pro increased with decreasing protein (DCGM) in the diet but those in the other protein amino acids, including the poorly labelled met, phe (and its derivative tyrosine) did not. 5. It was concluded that different extents of labelling of the amino acids (at least those present mainly in protein) indicated that different amounts of preformed units (amino acids or peptides) were used. When an adequate supply of such units was available (particularly on diet A) pro, arg, his, met and phe were derived in this way to a greater extent than the other amino acids, but whereas synthesis of pro, arg and his increased on the low-protein diet C, that of met and phe did not. Thus met and phe may be limiting for bacterial growth on diets low in protein and high in non-protein-N. 6. Differences in the extent of labelling of other bacterial N components may be due to different turnover rates.