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Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding and alpelisib-mediated changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Together, our findings uncover a regulatory crosstalk between post-translational modifications that fine-tunes KMT2D function at the chromatin. This provides a rationale for the use of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors in the treatment of ER+/ PIK3CA mutant breast cancer. [Display omitted] • KMT2D is methylated at K1330 by SMYD2 • There is crosstalk between phosphorylation of KMT2D at S1331 and methylation at K1330 • Loss of SMYD2 abrogates PI3Ki-induced KMT2D chromatin binding and ER-dependent transcription • Inhibition of KMT2D methylation sensitizes cells and tumors to PI3K/AKT inhibition Blawski et al. show that KMT2D is methylated by the lysine methyltransferase SMYD2 at K1330. SMYD2 loss attenuates PI3K inhibitor-induced KMT2D chromatin binding at estrogen-receptor (ER) loci and ER-dependent transcription. SMYD2 inhibition sensitizes cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy through KMT2D K1330 methylation. [ABSTRACT FROM AUTHOR]

Background: The role of panel reactive antibody (PRA) in lung transplant recipients has not been clearly defined in a large population. We sought to determine how panel reactive antibody level affects survival in lung transplant recipients. Methods: The United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research files from 1987 through 2005 were analyzed. Demographic data, pretransplant PRA, relevant clinical indicators, and survival were examined. Results: Of the 12,751 first lung transplant recipients during this period, pretransplant PRA levels were reported for 10,237 patients. Panel reactive antibody was more than 0% in 1748 patients; of these, PRA was 1% to 10% in 1259 (72%), 11% to 25% in 249 (14%), and more than 25% in 240 (14%). Using the Kaplan-Meier method, survival decreased with increasing PRA and was significant when PRA exceeded 25% compared with the rest of the cohort. On multivariable analysis, PRA was associated with increased 30-day (hazard ratio, 2.6) and overall mortality (hazard ratio, 1.3). Importantly, this effect was not seen when a cohort from 1998 through 2005 was analyzed. Conclusions: The UNOS database has provided the largest series of lung transplant patients stratified by PRA. Our analysis demonstrates that PRA level exceeding 25% is a predictor of death. However, newer laboratory and management techniques may attenuate this effect with better outcomes in the modern era. [Copyright &y& Elsevier]

Objective: Lung transplantation has been increasingly applied to patients over the age of 60 years. Importantly, the procedure of choice, single versus bilateral lung transplantation, remains unclear. Therefore, the purpose of this study was to examine short- and midterm outcomes in this age group with particular attention to procedure type. Methods: All first lung transplant recipients, 60 years of age or older, reported to the United Network for Organ Sharing from 1998 to 2004 were divided into two groups: bilateral and single lung transplantation. A retrospective review of pertinent baseline characteristics, clinical parameters, and outcomes was performed. Kaplan–Meier methodology was used to estimate and Cox proportional hazards regression modeling was used to compare posttransplant survival between these groups. Additionally, propensity scores analysis was performed. Results: During the study period, 1656 lung transplant recipients were 60 years of age or older (mean 62.7 ± 2.4 years, median 62 years). Of these, 364 (28%) had bilateral and 1292 (78%) had single lung transplantation. Survival was not statistically different between the two groups. In the multivariate analysis, bilateral versus single lung transplantation was not a predictor of mortality. Idiopathic pulmonary fibrosis and a donor tobacco history of more than 20 pack-years were significantly associated with mortality (P = .003, CI 1.12–1.76; and P = .006, CI 1.09–1.63; respectively). Conclusions: The survival of lung transplant recipients 60 years of age or older who underwent bilateral versus single lung transplantation is comparable. These data suggest that type of procedure is not a predictor of mortality in this age group. Idiopathic pulmonary fibrosis and donor cigarette use of more than 20 pack-years were independently associated with mortality. [Copyright &y& Elsevier]

Background: A low prevalence of high-level clinical studies in the surgical literature has been reported previously. We reviewed a recent sample of surgical publications to assess the current status of clinical research. Study design: A 3-month sample of journal articles in Archives of Surgery, Surgery, and Annals of Surgery in 2005 was evaluated by two independent reviewers to determine the distribution of articles in established evidence classes. Results: A total of 133 publications were identified in the three journals during the time periods reviewed, including 101 clinical articles and 30 basic science articles. Among the clinical papers, there were 8 class I studies (7.9%), 34 class II studies (33.7%), and more than half were class III studies (59 of 101, or 58.4%). Conclusions: The low prevalence of high-level evidence to guide surgical management of patients persists in major general surgery journals. We believe that education about proper research methodology is not only important for researchers, but is also important for practicing surgeons, and can have important health policy implications as well. [Copyright &y& Elsevier]