Phosphatidylinositol 4-kinase␤ (PI4K␤) plays an essential role in maintaining the structural integrity of the Golgi complex. In a search for PI4K␤-interacting proteins, we found that PI4K␤ specifically interacts with the GTP-bound form of the small GTPase rab11. The PI4K␤-rab11 interaction is of functional significance because inhibition of rab11 binding to PI4K␤ abolished the localization of rab11 to the Golgi complex and significantly inhibited transport of vesicular stomatitis virus G protein from the Golgi complex to the plasma membrane. We propose that a novel function of PI4K␤ is to act as a docking protein for rab11 in the Golgi complex, which is important for biosynthetic membrane transport from the Golgi complex to the plasma membrane.

The program had to be flexible enough to meet the educational requirements and class schedules of the different health professions' education programs. The target community spoke limited English, so providing interpretation services using bilingual Marshallese community health workers was integral to the program's success.

Purpose This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax®) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available. Methods Twenty-one patients with peritoneal malignancies received Nanotax® in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50–275 mg/m2) of Cremophor-free Nanotax® were administered intraperitoneally for one to six cycles (every 28 days). Results Intraperitoneal (IP) administration of Nanotax® did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration–time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450–2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax® IP treatment. Conclusions Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax® provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity.

Pacific Islanders face many health disparities, including higher rates of cardiovascular disease, cancer, obesity, and diabetes compared to other racial and ethnic groups. Specifically, the Marshallese population suffers disproportionately from type 2 diabetes, with rates 400% higher than the general US population. As part of an ongoing community-based participatory research (CBPR) partnership, 148 participants were recruited for a study examining genetic variants to better understand diabetes. Participants provided a saliva specimen in an Oragene® DNA self-collection kit. Each participant provided approximately 2 mL volume of saliva and was asked qualitative questions about their experience. The study yielded a recruitment rate of 95.5%. Among the 148 persons who participated, 143 (96.6%) agreed to be contacted for future studies; 142 (95.9%) agreed to have their samples used for future IRB-approved studies; and 144 (97.3%) gave permission for the researchers to link information from this study to other studies in which they had participated. Qualitative responses showed that the majority of participants were willing to participate because of their desire to contribute to the health of their community and to understand the genetic influence related to diabetes. This study demonstrates willingness to participate in genetic research among Marshallese living in Arkansas. Willingness was likely enhanced because the feasibility study was part of a larger CBPR effort. This study is important to community stakeholders who have voiced a desire to collaboratively conduct genetic research related to diabetes, perinatal outcomes, and cancer.

Two groups of male Wistar rats were treated 16 times (every 3rd day) subcutaneously with a defined mixture of polychlorinated dibenzo-p-dioxins (PCDDs) or of polychlorinated dibenzofurans (PCDFs). These mixtures contained no measurable amount of 2,3,7,8-TCDD. Each single dose was calculated to contain either 57 ng I-TEq (international 2,3,7,8-T4CDD toxicity equivalencies)/kg body weight of the PCDD mixture or 39 ng I-TEq/kg body weight of the PCDF mixture. Both mixtures contained a large excess of non-2,3,7,8-substituted congeners. The activities of ethoxyresorufin O-deethylase (EROD) in liver microsomes were correlated with the corresponding concentrations of PCDDs or PCDFs in hepatic tissue. Data were compared with results obtained after single injections of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-T4CDD). As expected, a complex kinetic situation resulted, because of the different tissue distributions and elimination half-lives of the various congeners: (1) 2,3,7,8-substituted PCDDs: the time course of the concentrations in liver and adipose tissue was similar for all congeners, the levels increased during the treatment period and decreased after treatment. Tissue concentrations of all 2,3,7,8-substituted PCDDs were considerably higher in liver than in adipose tissue. The liver/adipose tissue concentration ratios increased with the degree of chlorination. The ratio of 1,2,3,7,8-P5CDD was much lower than those of all other 2,3,7,8-substituted congeners. (2) 2,3,7,8-substituted PCDFs: 1,2,3,7,8-P5CDF was rapidly eliminated from liver and adipose tissue while 2,3,4,7,8-P5CDF largely persisted after the treatment period in both tissues. 2,3,7,8-T4CDF was eliminated even more rapidly than 1,2,3,7,8-P5CDF and could not be detected after treatment in both tissues. Time courses of the concentrations of 2,3,4,7,8-P5CDF, H6CDFs, H7CDFs and OCDF in liver and adipose tissue were similar: the levels of all congeners increased during the treatment period but no clear-cut decrease was observed within 34 days after the last treatment. Tissue concentrations of all 2,3,7,8-substituted PCDFs were higher in liver than in adipose tissue. The liver/adipose tissue concentration ratios increased with the degree of chlorination. The ratios of 2,3,7,8-T4CDF and 1,2,3,7,8-P5CDF were much lower than those of all other 2,3,7,8-substituted congeners. (3) non-2,3,7,8-substituted PCDDs and PCDFs: a number of non-2,3,7,8-substituted PCDD and PCDF congeners were found in both tissues in concentrations below 1 ng/g. In adipose tissue nearly all congeners were found during the treatment period showing a decrease after the treatment. In liver samples, many higher chlorinated PCDF congeners (with >4 chlorine atoms) could be detected. Most of those substituted in three of the four 2, 3, 7 and 8-positions persisted after treatment. In contrast, only one 1,4,6,9-substituted isomer of each PCDD homologue group was found during treatment with high recoveries after the third injection, but a rapid decline occurred already during the treatment period....

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Background The lack of reliable data on gastric emptying of solid food during labor has led to some discrepancies between current guidelines regarding fasting for solid food in the parturient. This prospective comparative study aimed to test the hypothesis that the gastric emptying rate of a light meal would be reduced in parturients receiving epidural analgesia and with no labor analgesia compared with nonpregnant and pregnant women. Methods Ten subjects were enrolled and tested in each group: nonpregnant women, term pregnant women, parturients with no labor analgesia, and parturients with epidural labor analgesia. After a first ultrasound examination was performed to ensure an empty stomach, each subject ingested a light meal (125 g yogurt; 120 kcal) within 5 min. Then ultrasound measurements of the antral area were performed at 15, 60, 90, and 120 min. The rate of gastric emptying at 90 min was calculated as [(antral area90 min / antral area15 min) – 1] × 100, and half-time to gastric emptying was also determined. For the Parturient–Epidural group, the test meal was ingested within the first hour after the induction of epidural analgesia. Results The median (interquartile range) rate of gastric emptying at 90 min was 52% (46 to 61), 45% (31 to 56), 7% (5 to 10), and 31% (17 to 39) for nonpregnant women, pregnant women, parturients without labor analgesia, and parturients with labor epidural analgesia, respectively (P < 0.0001). The rate of gastric emptying at 90 min was statistically significant and lower in the Parturient–Epidural group than in the Nonpregnant and Pregnant Control groups. In addition, the rate of gastric emptying at 90 min was statistically significant and lower in the Parturient–No-Epidural group than in the Parturient–Epidural group. Conclusions Gastric emptying in parturients after a light meal was delayed, and labor epidural analgesia seems not to worsen but facilitates gastric emptying. This should be taken into consideration when allowing women in labor to consume a light meal. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Introduction Sorafenib is a multi-kinase inhibitor affecting pathways involved in tumor progression and angiogenesis. We conducted a phase II trial of Sorafenib in platinum-treated extensive stage small cell lung cancer (SCLC) patients to determine the tumor response rate, toxicity and overall survival. Methods Patients with histologically confirmed, measurable disease, Zubrod performance status 0–1 and no more than 1 prior platinum based treatment were eligible. Patients were stratified by platinum-sensitivity status: sensitive (progression >90 days after platinum) or refractory (progression during or ≤90 days after platinum). Pts were treated with sorafenib 400mg PO BID continuously on a 28 day cycle. Results Of 89 pts registered; 82 were evaluable for toxicity assessment and 83 were evaluable for response There were 4 partial responses seen among the 38 patients in the platinum sensitive stratum, for an estimated response rate of 11% (95% confidence interval: 3% – 25%); and one partial response among the 45 patients in the platinum refractory stratum for an estimated response rate of 2% (95% confidence interval: 0% – 12%). The median overall survival estimates were 5.3 months (95% confidence interval: 3.3–7.5 months) and 6.7 months (95% confidence interval: 6.1–9.1 months) for the platinum-refractory and platinum-sensitive strata respectively. Nineteen patients discontinued treatment due to adverse events or side effects from therapy. Conclusions Based on the lack of disease control seen in our trial, further investigation of single-agent sorafenib in the SCLC population is not recommended. Combination trials of Sorafenib and chemotherapy are ongoing.