Cardiac hypertrophy is generated in response to hemodynamic overload by altering steady-state protein metabolism such that the rate of protein synthesis exceeds the rate of protein degradation. To ...determine the relative contributions of protein synthesis and degradation in regulating cardiac hypertrophy in mice, a continuous infusion strategy was developed to measure myocardial protein synthesis rates in vivo. Osmotic mini-pumps were implanted in the abdominal cavity to infuse radiolabeled leucine in mice that are conscious and ambulatory. Protein synthesis rates were calculated by measuring incorporation of leucine into myocardial protein over 24 h prior to each time point and dividing by the specific radioactivity of plasma leucine. Compared to sham-operated controls, fractional rates of protein synthesis (
K
s
) increased significantly at days 1 and 3 of TAC, but was lower on day 7 and returned to control values by day 14. These changes coincided with the curvilinear increase in LV mass that characterizes the hypertrophic response. Fractional rates of protein degradation (
K
d
) were calculated by subtracting the rate of myocardial growth from the corresponding
K
s
value.
K
d
fell at days 1 and 3 of TAC, increased at day 7 and returned to control on day 14. Thus, the increase in LV mass generated in response to pressure overload is caused by acceleration of
K
s
and suppression of
K
d
. As the growth rate slows, a new steady-state is achieved once the hypertrophic response is completed.
Innovations and Challenges in Renal Cancer, chaired by Michael B. Atkins, was held April 28 to 29, 2006 in Cambridge, Massachusetts. The conference brought together leading experts in the fields of ...cancer research, medical oncology, urology, immunology, radiology, and immunotherapy, with the goal of advancing the field of renal cancer treatment by critiquing new data from ongoing clinical trials and stimulating communication among those involved in basic and clinical research. The conference proceedings published in this educational supplement to Clinical Cancer Research are intended to provide timely information and recommendations on important aspects of renal cancer genetics and biology and advances in prognostic classification and treatment.
Treatment of a large, symptomatic skull metastasis requires surgical excision and in many cases postoperative radiation therapy. Immediate reconstruction of the skull for cerebral protection usually ...involves cranioplasty with titanium mesh and/or methyl methacrylate. Preoperative synthetic cranioplasty technology is yet to evolve sufficiently to allow computer-generated prostheses to precisely fit a defined craniectomy defect created at the time of tumor removal. We document the techniques used for simultaneous craniectomy and composite cranioplasty in the setting of a large occipital renal cell skull metastasis. Preoperative computed tomography (CT) and magnetic resonance (MR) imaging identified the pathological anatomy of an occipital skull metastasis presenting as an exophytic scalp mass. Preoperative angiography and embolization was performed followed by craniectomy in the semi-sitting position and composite cranioplasty using titanium mesh and methyl methacrylate. A series of steps in the surgical procedure are outlined to assist with safely and accurately performing the craniectomy and cranioplasty to guarantee the best surgical and cosmetic outcome. Postoperative CT imaging confirmed excellent contours of the cranioplasty. The method described herein allows for a single-step surgical procedure to excise a large skull metastasis and create a structurally sound and cosmetically acceptable composite cranioplasty. This method can also be used for the excision and repair of other skull tumors or anomalies requiring excision.
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Over the past years it has emerged that acute myeloid leukemia (AML) is a disease often driven by multiple co-occurring genomic lesions. It is a great challenge to understand the logic of these ...mutational patterns and how the particular constellation of genomic risk factors affects a patient's outcome in conjunction with common clinical variables such as blood counts.
Here we present a novel prognostic framework based genomic sequencing data of 111 cancer genes matched with detailed diagnostic, treatment and survival data from 1,540 patients with AML enrolled in three different trials run by the German-Austrian AML Study Group (AML-HD 98A, AML-HD 98B, and AMLSG 07-04). A systematic evaluation of risk modeling strategies reveals that much of the risk determining overall survival is captured in our comprehensive panel of genomic and prognostic clinical variables. Cox proportional hazards models with random effects achieved the highest cross-validated prognostic accuracy (Harrel's concordance C=0.72), better than models with variable selection (C=0.70 for AIC and BIC), and clearly superior to the ELN risk classification (C=0.63).
It emerges that patient risk is the aggregate of many small and few large factors, such as previously established mutations in NPM1, CEBPA-/-, FLT3ITD and TP53; fusion genes generated by t(15;17), inv(16), and inv(3) rearrangements; and complex karyotype, del(5q) and trisomy 21. Multiple risk factors act mostly additively, with the exception of gene-gene interaction terms, including NPM1:FLT3ITD:DNMT3A (n=93; HR=1.50; P<0.03; Wald test, Benjamini-Yekutieli adjusted) that indicate the presence of epistatic effects on outcome. We found substantial heterogeneity in the presence of risk factors with almost unique constellations for each patient. We observed that approximately 2/3 of the predicted inter-patient risk variation was related to genomic factors (balanced rearrangements, copy number changes and point mutations), the remainder being mostly attributed to diagnostic blood counts, demographic data and treatment. Hence a large share, but not all, prognostic information seems to be determined by genomic factors.
Using multistage models with random effects we have assessed differential effects of prognostic variables at different stages of therapy. These models yield detailed predictions about the probability of being alive in induction, first complete remission and after relapse, as well as the mortality during each of the three stages. Importantly, our model computes how these probabilities change depending on a patient's constellation of risk factors. The resulting personalized predictions provide a quantitative risk assessment and allow evaluating the effect of treatment decisions such as allogeneic stem cell transplant versus standard chemotherapy in first complete remission.
Our analysis shows that detailed and accurate predictions can be made based on knowledge banks of genomic and clinical data. As a proof of principle we have implemented our prediction framework into a web portal to explore risk predictions. Our method is able to impute missing variables and quantify the uncertainty due to missingness and finite training data. Power calculations show that cohorts of 10,000 patients will be needed for precise clinical decision support.
McDermott:14M Genomics: Other: co-founder, stock-holder and consultant. Stratton:14M Genomics: Other: co-founder, stock-holder and consultant. Schlenk:Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Arog: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria. Campbell:14M genomics: Other: Co-founder and consultant.
Micro-Abstract ProleukinR Observational Study to Evaluate the Treatment Patterns and Clinical Response in Malignancy (PROCLAIMSM ) is the largest observational clinical database of high-dose ...interleukin-2 (HD IL-2)-treated patients in the US. Herein, the survival and outcome for patients with renal cell carcinoma receiving HD IL-2 in sequence with targeted therapy are described. HD IL-2 has an acceptable efficacy and safety profile in current clinical practice and remains a valuable therapy for patients with renal cell carcinoma.
Reports an error in "Examining the Interactive Effect of Posttraumatic Stress Disorder, Distress Tolerance, and Gender on Residential Substance Use Disorder Treatment Retention" by Matthew T. Tull, ...Kim L. Gratz, Scott F. Coffey, Nicole H. Weiss and Michael J. McDermott ( Psychology of Addictive Behaviors, Advanced Online Publication, Sep 3, 2012, np). There was a copyediting error in Table 1. In the column Treatment completers, the value in parenthesis for Frequency of criminal behavior should have been (9.70). All versions of this article have been corrected. (The following abstract of the original article appeared in record 2012-23737-001.) An extensive body of research has demonstrated that patients with a co-occurring posttraumatic stress disorder (PTSD) and substance use disorder (SUD) diagnosis are at high risk for a wide range of negative clinical outcomes, including treatment noncompletion. However, no studies to date have explored the effect of a PTSD-SUD diagnosis on residential SUD treatment completion, as well as potential moderators of this effect. Consequently, the goal of this study was to examine the interactive effect of a PTSD diagnosis, distress tolerance (DT), and gender on residential SUD treatment retention. Participants were 214 substance-dependent patients consecutively admitted to a residential SUD treatment facility. Participants were administered diagnostic interviews, completed a laboratory-based measure of DT, and were followed throughout the course of treatment. Although no significant main effects were found, results did reveal a significant PTSD × gender × DT interaction. Post hoc analyses indicated that, among men, those with a current diagnosis of PTSD and low DT completed a significantly lower proportion of residential SUD treatment compared to all other groups. The implications of the study's findings for identifying ways to improve residential SUD treatment retention among patients with a PTSD-SUD diagnosis are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved) (Source: journal abstract)
Data are limited regarding the prevalence of substance use among adolescents in rural and ethnically diverse communities. This study examined rates and sociodemographic correlates of lifetime ...substance use among adolescents in Mississippi, a rural state that is the poorest in the country (21.3% poverty rate) and has the largest proportion of African Americans per capita (36.3%).
Participants in this cross-sectional study were 6349 adolescents (6th through 12th grade) who reported on lifetime tobacco, alcohol, marijuana, cocaine, inhalant, hallucinogen, and methamphetamine use.
Lifetime smoking (10.2% to 44.5%), alcohol (23.2% to 72.0%), and marijuana use (7.9% to 39.2%) increased steadily when comparing students in 6th to 12th grade. Substances with more serious abuse potential (cocaine 6.7% to 11.1%, inhalants 12.2% to 17.9%, hallucinogens 4.4% to 12.1%, and methamphetamine 3.0% to 6.7%) displayed more modest increases across grade. Adolescents who classified their race/ethnicity as "Other" (i.e., not white, black/African American, Asian, or Hispanic/Latino/Latina) demonstrated more than 2-fold increased likelihood of methamphetamine use (odds ratio OR = 2.42), and increased risk for use of any illicit substance (OR = 1.49). In general, males demonstrated an increased risk for use across substances (OR = 1.15-1.94), and higher income was associated with a decreased likelihood of illicit substance use (OR = 0.51-0.67). Living in a more populated area was associated with an increased likelihood of alcohol (OR = 1.43), marijuana (OR = 2.11), and cocaine use (OR = 2.06), and use of any illicit substance (OR = 1.54).
Mississippi adolescents reported higher rates of lifetime cocaine, inhalant, hallucinogen, and methamphetamine use across all grade levels compared with national surveys. Male gender, low income, and residence in more populated areas were associated with increased use of several substances. Findings demonstrate the need for prevention and intervention programs targeting impoverished rural and ethnically diverse communities.
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