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It has been established that many chemotherapeutic agents are associated with a variety of ocular side effects. As an antineoplastic agent, 5-fluorouracil (5-FU) is the chemotherapeutic agent that is frequently linked with cicatricial ectropion. Capecitabine is a prodrug of 5-FU and has a more favorable side effect profile than 5-FU. Frequent side effects of capecitabine include gastrointestinal events and hand–foot–mouth syndrome; cicatricial ectropion is rather uncommon. Enzyme deficiencies affecting the capecitabine metabolism have been reported to be associated with exaggerated generalized systemic and cutaneous side effects; however, there are no cases in the literature reporting capecitabine-induced isolated bilateral-progressive ectropion. Although cessation of the agent is frequently sufficient for the treatment of ectropion, close follow-up is indicated in such patients as permanent damage may occur if the problem is left untreated. We report a case of capecitabine-induced bilateral cicatricial ectropion refractory to treatment cessation, ultimately requiring surgical treatment.

Mehmet Demir, Ersin Oba, Efe Can, Mahmut Odabasi, Semra Tiryaki, Erhan Ozdal, Hakan SensozEye Clinic, Sisli Etfal Training and Research Hospital, Istanbul, TurkeyPurpose: The inspection of foveal and parafoveal thickness in healthy pregnant women in the last trimester.Materials and methods: This study included 40 healthy pregnant women in their last trimester (study group: 40 women, 80 eyes) and 37 nonpregnant women (control group: 37 women, 74 eyes). Visual acuity, intraocular pressure, slit lamp examination of anterior and posterior segments, and visual field examination with automated perimetry were performed in both groups. Foveal and parafoveal thickness in the four quadrants (upper, nasal, temporal, and inferior parafoveal) and peripapillary retinal nerve fiber layer were measured by optical coherence tomography. There were no systemic or ocular problems in either group. Findings were analyzed with statistical software. A P value

Membrane contact sites (MCS), close membrane apposition between organelles, are platforms for interorganellar transfer of lipids including cholesterol, regulation of lipid homeostasis, and co-ordination of endocytic trafficking. Sphingosine kinases (SphKs), two isoenzymes that phosphorylate sphingosine to the bioactive sphingosine-1-phosphate (S1P), have been implicated in endocytic trafficking. However, the physiological functions of SphKs in regulation of membrane dynamics, lipid trafficking and MCS are not known. Here, we report that deletion of SphKs decreased S1P with concomitant increases in its precursors sphingosine and ceramide, and markedly reduced endoplasmic reticulum (ER) contacts with late endocytic organelles. Expression of enzymatically active SphK1, but not catalytically inactive, rescued the deficit of these MCS. Although free cholesterol accumulated in late endocytic organelles in SphK null cells, surprisingly however, cholesterol transport to the ER was not reduced. Importantly, deletion of SphKs promoted recruitment of the ER-resident cholesterol transfer protein Aster-B (also called GRAMD1B) to the plasma membrane (PM), consistent with higher accessible cholesterol and ceramide at the PM, to facilitate cholesterol transfer from the PM to the ER. In addition, ceramide enhanced in vitro binding of the Aster-B GRAM domain to phosphatidylserine and cholesterol liposomes. Our study revealed a previously unknown role for SphKs and sphingolipid metabolites in governing diverse MCS between the ER network and late endocytic organelles versus the PM to control the movement of cholesterol between distinct cell membranes.

Enhanced ceramide glycosylation catalyzed by glucosylceramide synthase (GCS) limits therapeutic efficiencies of antineoplastic agents including doxorubicin in drug-resistant cancer cells. Aimed to determine the role of GCS in tumor response to chemotherapy, a new mixed-backbone oligonucleotide (MBO-asGCS) with higher stability and efficiency has been generated to silence human GCS gene. MBO-asGCS was taken up efficiently in both drug-sensitive and drug-resistant cells, but it selectively suppressed GCS overexpression, and sensitized drug-resistant cells. MBO-asGCS increased doxorubicin sensitivity by 83-fold in human NCI/ADR-RES, and 43-fold in murine EMT6/AR1 breast cancer cells, respectively. In tumor-bearing mice, MBO-asGCS treatment dramatically inhibited the growth of multidrug-resistant NCI/ADR-RE tumors, decreasing tumor volume to 37%, as compared with scrambled control. Furthermore, MBO-asGCS sensitized multidrug-resistant tumors to chemotherapy, increasing doxorubicin efficiency greater than 2-fold. The sensitization effects of MBO-asGCS relied on the decreases of gene expression and enzyme activity of GCS, and on the increases of C(18)-ceramide and of caspase-executed apoptosis. MBO-asGCS was accumulation in tumor xenografts was greater in other tissues, excepting liver and kidneys; but MBO-asGCS did not exert significant toxic effects on liver and kidneys. This study, for the first time in vivo, has demonstrated that GCS is a promising therapeutic target for cancer drug resistance, and MBO-asGCS has the potential to be developed as an antineoplastic agent.