PURPOSE. Excessive accumulation of lipofuscin is associated with pathogenesis of atrophic age-related macular degeneration (AMD) and Stargardt disease. Pharmacologic inhibition of the retinol-induced interaction of retinol-binding protein 4 (RBP4) with transthyretin (TTR) in the serum may decrease the uptake of serum retinol to the retina and reduce formation of lipofuscin bisretinoids. We evaluated in vitro and in vivo properties of the new nonretinoid RBP4 antagonist, A1120.METHODS. RBP4 binding potency, ability to antagonize RBP4-TTR interaction, and compound specificity were analyzed for A1120 and for the prototypic RBP4 antagonist fenretinide. A1120 ability to inhibit RPE65-mediated isomerohydrolase activity was assessed in the RPE microsomes. The in vivo effect of A1120 administration on serum RBP4, visual cycle retinoids, lipofuscin bisretinoids, and retinal visual function was evaluated using a combination of biochemical and electrophysiologic techniques.RESULTS. In comparison to fenretinide, A1120 did not act as a RARa agonist, while exhibiting superior in vitro potency in RBP4 binding and RBP4-TTR interaction assays. A1120 did not inhibit isomerohydrolase activity in the RPE microsomes. A1120 dosing in mice induced 75% reduction in serum RBP4, which correlated with reduction in visual cycle retinoids and ocular levels of lipofuscin fluorophores. A1120 dosing did not induce changes in kinetics of dark adaptation. CONCLUSIONS. A1120 significantly reduces accumulation of lipofuscin bisretinoids in the Abca4À/À animal model. This activity correlates with reduction in serum RBP4 and visual cycle retinoids confirming the mechanism of action for A1120.In contrast to fenretinide, A1120 does not act as a RARa agonist indicating a more favorable safety profile for this nonretinoid compound. (Invest Ophthalmol Vis Sci. 2013; 54:85-95)

Accumulation of lipofuscin in the retina is associated with pathogenesis of atrophic age-related macular degeneration and Stargardt disease. Lipofuscin bisretinoids (exemplified by N-retinylidene-N-retinylethanolamine) seem to mediate lipofuscin toxicity. Synthesis of lipofuscin bisretinoids depends on the influx of retinol from serum to the retina. Compounds antagonizing the retinol-dependent interaction of retinol-binding protein 4 (RBP4) with transthyretin in the serum would reduce serum RBP4 and retinol and inhibit bisretinoid formation. We recently showed that A1120 (3), a potent carboxylic acid based RBP4 antagonist, can significantly reduce lipofuscin bisretinoid formation in the retinas of Abca4–/– mice. As part of the NIH Blueprint Neurotherapeutics Network project we undertook the in vitro exploration to identify novel conformationally flexible and constrained RBP4 antagonists with improved potency and metabolic stability. We also demonstrate that upon acute and chronic dosing in rats, 43, a potent cyclopentyl fused pyrrolidine antagonist, reduced circulating plasma RBP4 protein levels by approximately 60%.

Famitinib is generally well tolerated. Famitinib demonstrates a wide spectrum of antitumor activities, which warrants further study in renal cell carcinoma, GIST, hepatocellular carcinoma and soft tissue sarcoma. The recommended dose for future phase II clinical trials is 25 mg.

Data presented here demonstrate that administration of TACI-Ig significantly attenuates progression of experimental arthritis, with reductions in inflammatory response and bone and joint destruction.

Phosphorylation of PTEN plays an important role in carcinogenesis and progression of gastric cancer. However, the underlying mechanism of PTEN phosphorylation regulation remains largely elusive. In the present study, PDZK1 was identified as a novel binding protein of PTEN by association of PTEN through its carboxyl terminus and PDZ domains of PDZK1. By direct interaction with PTEN, PDZK1 inhibited the phosphorylation of PTEN at S380/T382/T383 cluster and further enhanced the capacity of PTEN to suppress PI3K/AKT activation. PDZK1 suppressed gastric cancer cell proliferation by diminishing PI3K/AKT activation via inhibition of PTEN phosphorylation in vitro and in vivo. The expression of PDZK1 was frequently downregulated in gastric cancer specimens and correlated with progression and poor prognosis of gastric cancer patients. Downregulation of PDZK1 was associated with PTEN inactivation, AKT signaling and cell proliferation activation in clinical specimens. Thus, low levels of PDZK1 in gastric cancer specimens lead to increase proliferation of gastric cancer cells via phosphorylation of PTEN at the S380/T382/T383 cluster and constitutively activation of PI3K/AKT signaling, which results in poor prognosis of gastric cancer patients.

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Background. Inhalation therapy is the main treatment for asthma and chronic obstructive pulmonary disease (COPD) patients. Owing to the poor inhaler technique in using inhalers, we assessed the effect of a multidimensional pharmaceutical care on inhalation technique in patients with asthma and COPD. Materials and Methods. A 3-month controlled parallel-group study was undertaken in asthma and COPD patients using dry powder inhalers (DPIs). Patients in the intervention group received multidimensional pharmaceutical care, including establishment of a special dispensing window, face-to-face demonstration and education, brochure education, videos education, online consultation and education, and follow-up reeducation. Patients in the control group received usual pharmaceutical care. The inhaler technique score, correctness of inhaler usage, beliefs about medicines questionnaire (BMQ) score, asthma control test (ACT), and COPD assessment test (CAT) were measured pre- and postintervention. Quality of life improvement evaluated according to score changes of ACT in asthma and CAT in COPD and patient satisfaction were measured postintervention. Results. 259 patients finished the study with 133 in the intervention group and 126 in the control group. Compared to preintervention and control group postintervention, the inhaler technique score, correctness of inhaler usage, and ACT score significantly increased in the intervention group postintervention, while the BMQ score and CAT score decreased significantly P < 0.05 . Significant improvements in quality of life and patient satisfaction were found P < 0.05 . Conclusion. This study showed the multidimensional pharmaceutical care for asthma and COPD patients were effective in improving inhalation technique. By providing pharmaceutical care, pharmacists might help asthma and COPD patients to acquire better quality of life.

ObjectiveRecent studies have reported increased mortality for right-sided colon cancers; however, the results are conflicting for different stage tumors. We examined the differences in clinicopathology between right- and left-sided colon cancers and the relationships between colon cancer location (right- and left-side) and 5-year disease-free survival (DFS) and overall survival (OS).MethodsWe identified patients from 2005 to 2008 with stage II/III colon cancer who underwent surgery for curative intent. We explored the impact of the tumor location on the postoperative DFS and OS using univariate and multivariate analyses.ResultsOf 627 patients, 50.6% (317/627) had right-sided colon cancer. These patients were more likely to have weight loss, second primary tumor, elevated preoperative carbohydrate antigen 19-9 (CA19-9), increased incidence of non-adenocarcinoma, more poorly differentiated tumors, vascular invasion, defective mismatch repair, and a lighter smoking history (P < 0.05). Right-sided colon cancer had a higher recurrence incidence compared with left-sided cancer (30.6% vs. 23.2%, P = 0.037), particularly with multiple metastatic sites in the first recurrence (17.5% vs. 5.6%, P = 0.020). Kaplan–Meier survival curves demonstrated a significant difference in the 5-year DFS rate between right- and left-sided cancers across all stages (68.1% vs. 75.2%, P = 0.043). However, there was no significant difference in the 5-year OS rate between the two groups (73.8% vs. 79.0%, P = 0.103). Subgroup analysis demonstrated that patients with left-sided colon cancer had a significantly better 5-year DFS and OS rates compared with those with right-sided disease at stage III (64.3% vs. 46.8%, P = 0.002; 69.5% vs. 53.5%, P = 0.006, respectively); there were no significant differences in the 5-year DFS and OS rates at stage II (85.2% vs. 85.9%, P = 0.819; 89.8% vs. 88.5%, P = 0.803, respectively). Adjusted Cox regression analysis showed no significant differences in the 5-year OS and DFS rates for stage II [hazard ratio (HR) = 1.203, 95% confidence interval (CI): 0.605–2.391, P = 0.598; HR = 0.980, 95% CI: 0.542–1.774, P = 0.948, respectively] or all stages combined (HR = 0.867, 95% CI: 0.613–1.227, P = 0.421; HR = 0.832, 95% CI: 0.606–1.142, P = 0.255, respectively). However, stage III left-sided cancer had higher 5-year OS and DFS rates (HR = 0.626, 95% CI: 0.414–0.948, P = 0.027; HR = 0.630, 95% CI: 0.428–0.926, P = 0.019, respectively).ConclusionWe found that right- and left-sided colon cancers had significantly different clinicopathological characteristics. Right-sided colon cancer had a higher incidence of recurrence than left-sided disease. Patients with stage III right-sided colon cancer had a worse prognosis compared with those with stage III left-sided colon cancer.