The Tpr protein regulates export of mRNAs with retained introns that traffic through the Nxf1 pathway.

Post-transcriptional regulation of mRNA includes restriction mechanisms to prevent export and expression of mRNAs that are incompletely spliced. Here we present evidence that the mammalian protein Tpr is involved in this restriction. To study the role of Tpr in export of mRNA with retained introns, we used reporters in which the mRNA was exported either via the Nxf1/Nxt1 pathway using a CTE or via the Crm1 pathway using Rev/RRE. Our data show that even modest knockdown of Tpr using RNAi leads to a significant increase in export and translation from the mRNA containing the CTE. In contrast, Tpr perturbation has no effect on export of mRNA containing the RRE, either in the absence or presence of Rev. Also, no effects were observed on export of a completely spliced mRNA. Taken together, our results indicate that Tpr plays an important role in quality control of mRNA trafficked on the Nxf1 pathway.

Implementation and evaluation of a new surgical residency model.

BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) duty-hour requirements prompted program directors to rethink the organizational structure of their residency programs. Many surgical educators have expressed concerns that duty-hour restrictions would negatively affect quality of resident education. This article summarizes evaluation research results collected to study the impact of our reengineered residency program designed to preserve important educational activities while meeting duty-hour accreditation requirements. STUDY DESIGN: The traditional residency structure was redesigned to include a mixture of apprenticeship, small team, and night-float models. Impact evaluation data were collected using operative case logs, standardized test scores, quality assurance data, resident perception surveys, a faculty survey, and process evaluation measures. RESULTS: PGY1s and PGY2s enjoyed a substantial increase in operative cases. Operative cases increased overall and no resident has failed to meet ACGME volume or distribution requirements. American Board of Surgery In-Training Examination performance improved for PGY1s and PGY2s. Patient outcomes measures, including monthly mortality and number of and charges for admissions, showed no changes. Anonymously completed rotation evaluation forms showed stable or improved resident perceptions of case load, continuity, operating room teaching, appropriate level of faculty involvement and supervision, encouragement to attend conferences, and general assessment of the learning environment. A quality-of-life survey completed by residents before and after implementation of the new program structure showed substantial improvements. Faculty surveys showed perceived increases in work hours and job dissatisfaction. New physician assistant and nurse positions directly attributed to duty-hour restrictions amounted to about 0.2 full-time equivalent per resident. CONCLUSIONS: Duty-hour restrictions produce new challenges and might require additional resources but need not cause a deterioration of surgical residents' educational experience.

Sam68 enhances the cytoplasmic utilization of intron-containing RNA and is functionally regulated by the nuclear kinase Sik/BRK.

Cells normally restrict the nuclear export and expression of intron-containing mRNA. In many cell lines, this restriction can be overcome by inclusion of cis-acting elements, such as the Mason-Pfizer monkey virus constitutive transport element (CTE), in the RNA. In contrast, we observed that CTE-mediated expression from human immunodeficiency virus Gag-Pol reporters was very inefficient in 293 and 293T cells. However, addition of Sam68 led to a dramatic increase in the amount of Gag-Pol proteins produced in these cells. Enhancement of CTE function was not seen when a Sam68 point mutant (G178E) that is defective for RNA binding was used. Additionally, the effect of Sam68 was inhibited in a dose-dependent manner by coexpression of an activated form of the nuclear kinase Sik/BRK that hyperphosphorylated Sam68. RNA analysis showed that cytoplasmic Gag-Pol-CTE RNA levels were only slightly enhanced by the addition of Sam68, compared to a 60- to 70-fold increase in the levels of Gag-Pol protein expression. Thus, in this system, Sam68 functioned to enhance the cytoplasmic utilization of RNA containing the CTE. These results suggest that Sam68 may interact with specific RNAs in the nucleus to provide a "mark" that affects their cytoplasmic fate. They also provide further evidence of links between signal transduction and RNA utilization.

Core body temperature during competition in the heat: National Boys' 14s Junior Championships.

OBJECTIVE: To examine on-court core body temperature (T(C)) and sweat loss, as well as pre- and post-play hydration status, in elite adolescent tennis players during a national championships event in a hot climate. METHODS: Eight healthy, fit, young male tennis players (mean (SD) age 13.9 (0.9) years; mass 56.0 (10.7) kg; height 169.2 (14.7) cm) were evaluated during first-round singles competition at the National Boys' 14s Junior Championships in the heat (wet-bulb globe temperature (WBGT) 29.6 (0.4) degrees C). Five of those same players were also evaluated during a same-day doubles match (WBGT 31.3 (0.5) degrees C). RESULTS: During doubles (4.37 (0.35) h after singles), pre-play urine specific gravity (USG) (1.025 (0.002); p = 0.06) and total sweat loss (1.9 (0.2) litres; p = 0.10) tended to be higher before and during doubles, respectively, compared to singles. However, percentage change in body mass (-0.5 (0.3) %) tended to be comparatively less (p = 0.08), even though the doubles matches were generally longer (106.6 (11.2) vs 78.8 (10.9) min; p = 0.09) and the degree minutes total was greater (p = 0.04). T(C) increased (p<0.001) during singles and remained elevated, even after 10 min following the end of play. Notably, pre-play (singles) USG was strongly associated (p = 0.005) with the players' final T(C) (38.7 (0.3) degrees C) recorded at the end of singles play. CONCLUSION: Junior tennis players who begin a match not well hydrated could have progressively increasing thermal strain and a greater risk for exertional heat illness as the match advances.

Improvement in Context: Exploring Aims, Improvement Priorities, and Environmental Considerations in a National Sample of Programs Using "Small Data".

BACKGROUND: In 2013, the Accreditation Council for Graduate Medical Education (ACGME) transitioned into a new accreditation system to reduce burden, focus on outcomes, and promote innovation and improvement. One component is a self-study that includes aims, an environmental assessment, and setting improvement priorities. The ACGME initiated voluntary site visits following the self-study. OBJECTIVE: We explored common themes in program aims and assessment of their environment. METHODS: Using grounded theory, inductive and deductive qualitative methods, and truth grounding, we analyzed data from voluntary site visits of 396 core and subspecialty programs between June 2015 and September 2017, with a focus on common themes. RESULTS: We report common themes for aims and the dimensions of the environmental assessment. Themes for strengths include a collegial, supportive learning environment; responsive leaders; and experiences that prepare residents for unsupervised practice. Improvement priorities encompass low learner engagement and "content mismatch" in didactic education, balancing education and service at a time of growing clinical volumes, and improving the utility of assessment systems. Common opportunities encompass collaborations that improve education, involving alumni and harnessing technology to enrich education, while threats include an unsustainable effort for many program leaders, clinical pressures on faculty, and loss of external sites important for education. Linked dimensions of the environmental assessment suggest benefit in a growing focus on learners, and approaches to ensure a humanistic learning environment that allows for growth, self-determination, and inclusion. CONCLUSIONS: The findings highlight actionable themes for the environmental assessment. We discuss implications for programs, institutions, and the ACGME.

A Phase I and pharmocokinetic study of exatecan mesylate administered as a protracted 21-day infusion in patients with advanced solid malignancies.

PURPOSE: The purpose of this study was to assess the feasibility of administering exatecan, a water-soluble, potent camptothecin analogue, as a protracted 21-day continuous i.v. infusion (CIVI). The study also sought to determine the maximum tolerated dose (MTD) of exatecan on a 21-day CIVI schedule, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Exatecan dose-schedule development was performed in two stages using the modified Continual Reassessment Method and single patient cohorts. First, patients with advanced solid malignancies were treated with exatecan (0.15 mg/m(2)/day) as a CIVI for 5 days, and the duration of the CIVI was incrementally increased from 5 to 21 days. In the second stage of the study, the dose was incrementally increased to derive a tolerable dose of exatecan administered as 21-day CIVI. The MTD was defined for both minimally pretreated (MP) and heavily pretreated (HP) patients as the highest dose level at which the incidence of dose-limiting toxicity does not exceed 20%. RESULTS: Thirty-one patients were treated with 100 courses of exatecan at 6 dose-schedule levels. The incidence of the principal dose-limiting toxicities, neutropenia and thrombocytopenia, was unacceptably high at exatecan doses exceeding 0.15 mg/m(2)/day as a 21-day CIVI, which was determined to be the MTD for both MP and HP patients. The pharmacokinetics of exatecan were dose-proportional, and mean [coefficient of variation (percentage) steady-state concentration (plasma concentration at steady-state)] values ranged from 6.88 (80.6) to 19.41 (74.2) ng/ml at exatecan dose levels ranging from 0.15 to 0.30 mg/m(2)/day, which are similar to IC(50) values against human tumor cell lines treated for shorter periods. Mean pharamacokinetic parameters for total exatecan derived from a compartmental model included clearance and volume of distribution values of 1.39 (86.9) liters/h/m(2) and 39.66 (197.4) liters, respectively. Two HP patients with non-small cell lung and unknown primary carcinomas had partial responses, and objective evidence of anticancer activity and clinical benefit were noted in several other individuals. CONCLUSIONS: The administration of exatecan as a 21-day CIVI at doses as high as 0.15 mg/m(2)/day is safe and feasible for both MP and HP patients. The characteristics of the myelosuppressive effects of exatecan on this schedule, the paucity of severe nonhematological toxicities, and documented anticancer activity in several drug-refractory malignancies warrant further evaluation of the merits of administering exatecan by either a CIVI or alternate drug delivery systems to achieve protracted systemic exposure.

A phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for five days every three weeks to patients with metastatic adenocarcinoma of the colon or rectum.

BACKGROUND: To evaluate the antitumor activity, toxicities, and pharmacokinetics (PK) of DX-8951f administered as a 30-min infusion daily for 5 days every 3 weeks in patients with fluorouracil-resistant metastatic colorectal carcinoma. PATIENTS AND METHODS: Sixteen patients were enrolled. All had metastatic colorectal carcinoma resistant to or progressing after chemotherapy containing 5-fluorouracil and no prior chemotherapy with camptothecin derivatives. DX-8951f was administered until disease progression or unacceptable toxicity. Responses were assessed after every two courses. RESULTS: Fifteen patients were evaluable. Fifty-one courses of therapy were delivered (median 2). Responses were one minor response, six stable disease, and eight progressive disease. The principal adverse event was neutropenia, with grade 3 and 4 toxicities in three and eight patients, respectively. Non-hematologic toxicities were mild to moderate; the most common were fatigue, nausea, and diarrhea. Plasma concentrations of DX-8951 were well described using a linear two-compartment PK model. There was no evidence of nonlinearity in the elimination of PK or auto-inhibition or induction of DX-8951 clearance over the 5 days of administration. CONCLUSIONS: DX-8951f at this dose and schedule had no significant activity in this patient population. The toxicity profile, mainly hematologic, was consistent with previous reports. The clearance and volume of distribution were not different from those previously reported.