Citations

AbstractBackgroundThe feasibility, safety and outcomes of robotic presacral neurectomy were evaluated.MethodsA retrospective analysis was performed of 33 patients with midline chronic pelvic pain, who underwent robotic presacral neurectomy. Data were collected during the period March 2004–March 2010.ResultsAll patients underwent robotic presacral neurectomy and additional robotic procedures. Mean operating time for robotic presacral neurectomy was 5.8 (range 4.4–6.9) min. Mean blood loss, including concomitant procedures, was 39 (range 15–150) ml. Most patients were discharged the same day (60%) and mean hospital stay was 0.39 (range 0–2) days. There were no conversions or intra‐operative complications. There were two postoperative complications: one pelvic abscess and one Clostridium difficile colitis. Pain improvement was reported by 73% (22/30) of patients.ConclusionRobotic presacral neurectomy is safe and feasible, resulting in improvement of pelvic pain in selected patients. Copyright © 2011 John Wiley & Sons, Ltd.

Abstract Background: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium. Methods: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression. Results: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08–1.14, P = 7 × 10−18) for invasive breast cancer and 1.10 (95% CI = 1.01–1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99–1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12–1.20, P = 1 × 10−18 vs. OR = 1.03, 95% CI = 0.99–1.07, P = 0.2 for PR-negative disease; Pheterogeneity = 2 × 10−7); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14–1.25), 1.13 (1.09–1.16), and 1.04 (0.99–1.08) for grade 1, 2, and 3/4, respectively; Ptrend = 5 × 10−7]. Conclusion: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer. Impact: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants. Cancer Epidemiol Biomarkers Prev; 20(10); 2222–31. ©2011 AACR.

The chromosomal translocation t (11;14)(q13;q32) leading to cyclin-D1 overexpression plays an essential role in the development of mantle cell lymphoma (MCL), an aggressive tumor that remains incurable with current treatment strategies. Cyclin-D1 has been postulated as an effective therapeutic target, but the evaluation of this target has been hampered by our incomplete understanding of its oncogenic functions and by the lack of valid MCL murine models. To address these issues, we generated a cyclin-D1–driven mouse model in which cyclin-D1 expression can be regulated externally. These mice developed cyclin-D1–expressing lymphomas capable of recapitulating features of human MCL. We found that cyclin-D1 inactivation was not sufficient to induce lymphoma regression in vivo; however, using a combination of in vitro and in vivo assays, we identified a novel prosurvival cyclin-D1 function in MCL cells. Specifically, we found that cyclin-D1, besides increasing cell proliferation through deregulation of the cell cycle at the G 1 –S transition, sequestrates the proapoptotic protein BAX in the cytoplasm, thereby favoring BCL2’s antiapoptotic function. Accordingly, cyclin-D1 inhibition sensitized the lymphoma cells to apoptosis through BAX release. Thus, genetic or pharmacologic targeting of cyclin-D1 combined with a proapoptotic BH3 mimetic synergistically killed the cyclin-D1–expressing murine lymphomas, human MCL cell lines, and primary lymphoma cells. Our study identifies a role of cyclin-D1 in deregulating apoptosis in MCL cells, and highlights the potential benefit of simultaneously targeting cyclin-D1 and survival pathways in patients with MCL. This effective combination therapy also might be exploited in other cyclin-D1–expressing tumors.

BACKGROUND: Many patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) have had recent healthcare interventions prior to developing ALI/ARDS. OBJECTIVE: To determine the timing of ALI/ARDS onset in relation to hospital admission and other healthcare interventions. METHODS: We conducted a population-based observational cohort study with a validated electronic surveillance tool, and identified patients with possible ALI/ARDS among critically ill adults at Mayo Clinic hospitals that provide critical care services for Olmsted County, Minnesota, in 2006. Trained investigators independently reviewed electronic medical records and confirmed the presence and timing of ALI/ARDS based on the American-European consensus definition. RESULTS: Of 124 episodes of ALI in 118 patients, only 5 did not fulfill the ARDS criteria. The syndrome developed a median 30 hours (IQR 10–82 h) after hospital admission in 79 patients (67%). ARDS was present on admission in 39 patients (33%), of whom 14 had recent hospitalization, 6 were transferred from nursing homes, and 3 had recent out-patient contact (1 antibiotic prescription, 1 surgical intervention, and 1 chemotherapy). Only 16 ARDS patients (14%) did not have known recent contact with a healthcare system. Compared to ARDS on admission, hospital-acquired ARDS was more likely to occur in surgery patients (54% vs 15%, P < .001), and had longer adjusted hospital stay (mean difference 8.9 d, 95% CI 0.3–17.4, P = .04). CONCLUSIONS: ARDS in the community most often develops either during hospitalization or in patients who recently had contact with a healthcare system. These findings have important implications for potential preventive strategies.

Abstract The CD3ε cytoplasmic tail contains a conserved proline-rich sequence (PRS) that influences TCR–CD3 expression and signaling. Although the PRS can bind the SH3.1 domain of the cytosolic adapter Nck, whether the PRS is constitutively available for Nck binding or instead represents a cryptic motif that is exposed via conformational change upon TCR–CD3 engagement (CD3Δc) is currently unresolved. Furthermore, the extent to which a cis-acting CD3ε basic amino acid-rich stretch (BRS), with its unique phosphoinositide-binding capability, might impact PRS accessibility is not clear. In this study, we found that freshly harvested primary thymocytes expressed low to moderate basal levels of Nck-accessible PRS (“open-CD3”), although most TCR–CD3 complexes were inaccessible to Nck (“closed-CD3”). Ag presentation in vivo induced open-CD3, accounting for half of the basal level found in thymocytes from MHC+ mice. Additional stimulation with either anti-CD3 Abs or peptide–MHC ligands further elevated open-CD3 above basal levels, consistent with a model wherein antigenic engagement induces maximum PRS exposure. We also found that the open-CD3 conformation induced by APCs outlasted the time of ligand occupancy, marking receptors that had been engaged. Finally, CD3ε BRS–phosphoinositide interactions played no role in either adoption of the initial closed-CD3 conformation or induction of open-CD3 by Ab stimulation. Thus, a basal level of open-CD3 is succeeded by a higher, induced level upon TCR–CD3 engagement, involving CD3Δc and prolonged accessibility of the CD3ε PRS to Nck.