Citations

Ubiquitin (Ub) sorting receptors facilitate the targeting of ubiquitinated membrane proteins into multivesicular bodies (MVBs). Ub-binding domains (UBDs) have been described in several endosomal sorting complexes required for transport (ESCRT). Using available structural information, we have investigated the role of the multiple UBDs within ESCRTs during MVB cargo selection. We found a novel UBD within ESCRT-I and show that it contributes to MVB sorting in concert with the known UBDs within the ESCRT complexes. These experiments reveal an unexpected level of coordination among the ESCRT UBDs, suggesting that they collectively recognize a diverse set of cargo rather than act sequentially at discrete steps.

Abstract IL-17-producing CD8+ T cells (Tc17) appear to play a role in a range of conditions, such as autoimmunity and cancer. Thus far, Tc17 cells have been only marginally studied, resulting in a paucity of data on their biology and function. We demonstrate that Tc17 and Th17 cells share similar developmental characteristics, including the previously unknown promoting effect of IL-21 on Tc17 cell differentiation and IL-23-dependent expression of IL-22. Both STAT1 and STAT4 are required for optimal development of Tc17 cells and maximal secretion of cytokines. Tc17 cells are cytotoxic, and they can be either pathogenic or nonpathogenic upon adoptive transfer in the model of autoimmune diabetes. Tc17 cells treated with TGF-β1 plus IL-6 are not diabetogenic, whereas IL-23-treated cells potently induce the disease. IL-17A and IL-17F are necessary but not sufficient for diabetes induction by Tc17 cells. Tc17 cells treated with TGF-β1 plus IL-6 or IL-23 likely differ in pathogenicity due to their disparate capacity to attract other immune cells and initiate inflammation.

Purpose The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated. Patients and Methods Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m2 every 3 weeks) or arm B (FOLFOX4). Results A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias. Conclusion In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy.

Purpose We conducted a phase II study of combination of the anti–insulin-like growth factor 1 receptor antibody CP-751,871 with paclitaxel and carboplatin (PCI) in advanced treatment-naïve non–small-cell lung cancer (NSCLC). Patients and Methods Patients were randomly assigned (2:1) to paclitaxel 200 mg/m2, carboplatin (area under the plasma concentration-time curve of 6), and CP-751,871 10 to 20 mg/kg (PCI10, PCI20) or paclitaxel and carboplatin alone (PC) every 3 weeks for up to six cycles. PCI10-20 patients could continue CP-751,871 (figitumumab) treatment after chemotherapy discontinuation. Patients treated with PC experiencing disease progression were eligible to receive CP-751,871 at investigator's discretion. An additional nonrandomized single-arm cohort of 30 patients with nonadenocarcinoma tumor histology receiving PCI20 was enrolled on completion of the randomized study. Results A total of 156 patients were enrolled onto the randomized portion of the study. Safety and efficacy information are available for 151 patients (98 patients treated with PCI and 53 patients treated with PC). Forty-eight patients treated with PCI received PCI10 and 50 patients received PCI20 in two sequential stages. Twenty of 53 patients treated with PC received CP-751,871 after disease progression. PCI was well tolerated. Fifty-four percent of patients treated with PCI and 42% of patients treated with PC had objective responses. Sixteen of 23 patients assessable for efficacy in the nonrandomized single-arm extension cohort also responded to treatment. Of note, 14 of 18 randomly assigned and 11 of 14 nonrandomly assigned patients treated with PCI with squamous cell carcinoma histology had response to treatment, including nine objective responses in bulky disease. Responses were also observed in two patients with squamous histology receiving CP-751,871 on PC discontinuation. PCI20/PC hazard ratio for progression-free survival was 0.8 to 0.56, according to censorship. Conclusion These data suggest that PCI20 is safe and effective in patients with NSCLC.

Despite the vast number of individuals living with gastroesophageal reflux disease (GERD), establishing a diagnosis can be difficult. Detailed patient history and symptom review are critical. Nurses can play an integral role in gathering information that may lead to a definitive diagnosis. In addition to the classic symptoms of GERD—acid reflux and heartburn—several atypical conditions may also be present. Understanding the diverse and subtle nature of presenting symptoms can assist in establishing a GERD diagnosis. This column examines the atypical presentations of GERD, including laryngopharyngeal symptoms, chronic cough, asthma, and dental erosions. J Contin Educ Nurs 2009;40(3):103–104.

The nursing profession has a long history of helping to advance health care. This column describes contributions of the first nurses associated with a major medical center in the Midwest and their vision to build and staff a hospital to support the medical practice of a local physician and his two sons. The story comes to life as a readers' theater featured in department-wide orientation to the Department of Nursing. J Contin Educ Nurs 2009;40(3):105–106.