Abstract
Background: Racial disparities in prostate cancer (PCa) incidence and mortality are well known. PCa is known to be more aggressive in African American men (AAM) compared to European American ...men (EAM) in terms of higher incidence and mortality rates. Here we validate a tumor gene expression pan-cancer race model in men with PCa and further characterize genomic differences that may contribute to disparate clinical outcomes.
Methods: We obtained deidentified genome-wide expression profiles from clinical use of the Decipher RP test in 9,953 men from the GRID registry database. A subset of men (n=313) had known race status. A pan-cancer race model, developed to predict patient AAM race from analysis of gene expression patterns in 4,162 tumors from retrospective cohorts with known race status, was applied to the prospective cohort for race prediction. Hallmarks of cancer, immune modulators, AR activity, and prognostic gene signatures available in the GRID were used to gain a molecular perspective on PCa racial disparities.
Results: The race model was independently validated in the subset of men with known race and had an AUC of 0.98 for differentiating AAM from EAM. The model was then applied to the 9,640 GRID patients with unknown race status and classified 6,831 as EAM, 1,058 as AAM, and 1,751 as having indeterminate race. Characterizing the molecular subtypes, we found known and predicted AAM to be enriched with SPINK1+ tumors (21% and 24%, respectively) compared to predicted EAM (8%). In contrast, while ERG+ was found 22% and 19% in known and predicted AAM, respectively, compared to 46% in predicted EAM. Based on PAM50 prostate cancer classifier, 61% of AAM were classified as basal-like tumors, whereas 41% were basal-like in EAM. Similarly, 28% of AAM had low AR-A while only 11% of EAM had low AR-A. AAM tumors had higher levels of immune infiltration signatures as well as higher scores for inflammatory and interferon gamma responses, NF-KB mediated tumor necrosis factor (TNF) activity, and interleukin 6 (IL6) signaling activity scores. AAM had lower DNA repair glycolysis scores compared to EAM.
Conclusion: Known and predicted AAM were enriched with SPINK1+ tumors, higher immune infiltration and activation but lower ERG+, DNA repair, and AR activity tumors. Using such large GRID data with known race, we will further understand the underlying causes associated with prostate cancer racial disparities.
Citation Format: Walter Rayford, Jennifer Jordan, Mandeep Takhar, Mohammed Alshalalfa, Darlene Dai, Nicholas Erho, Mark D. Greenberger, Elai Davicioni. Genomic variations associated with prostate cancer in large cohort of African American men abstract. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B098.
Summary The American Academy of Dermatology and the American Society of Plastic Surgeons, with the support of other sister societies, conducted the Facial Soft-Tissue Fillers: Assessing the State of ...the Science conference in December of 2009. The American Academy of Dermatology and the American Society of Plastic Surgeons established a panel of leading experts in the field of soft-tissue fillers—from researchers to clinicians—and other stakeholders for the conference to examine and discuss issues of patient safety, efficacy, and effectiveness in relation to the approved and off-label use of soft-tissue fillers, and other factors, including the training and level of experience of individuals administering fillers. This report represents the systematic literature review that examines comprehensively the available evidence and gaps in the evidence related to soft-tissue fillers, to inform and support the work of the state-of-the-science conference panel. This evidence-based medicine review will serve as the foundation for future evidence-based medicine reports in this growing field.
Manganese superoxide dismutase plasmid liposomes (MnSOD-PL) confer organ-specific in vivo ionizing irradiation protection. To prepare for potential intravenous clinical trials of systemic MnSOD-PL ...for radioprotection in humans, plasmid and bacterial sequences were removed and a new minicircle construct was tested. Minicircle MnSOD was purified and then cotransfected into 32D cl 3 murine interleukin-3-dependent hematopoietic progenitor cells along with another plasmid carrying the neo gene. Cells were selected in G418 (50 microg/ml) and cloned by limiting dilution. Biochemical analysis of minicircle MnSOD-transfected cells showed an MnSOD biochemical activity level of 5.8 +/- 0.5 U/mg compared with 2.7 +/- 0.1 U/mg for control 32D cl 3 cells (p = 0.0039). 32D-mc-MnSOD cells were as radioresistant as full-length MnSOD-PL transgene-expressing 2C6 cells, relative to 32D cl 3 parent cells, with an increased shoulder on the radiation survival curve (n = 4.8 +/- 0.2 and n = 4.6 +/- 0.2, respectively, compared with 1.5 +/- 0.5 for 32D cl 3 cells; p = 0.007). C57BL/6NHsd mice received intraoral mc-MnSOD-PL, mc-DsRed-PL control, full-length MnSOD-PL, or blank-PL and then were irradiated 24 hr later with 31 Gy to the esophagus. Mice receiving mc-MnSOD-PL showed increased survival compared with control mice or mice treated with mc-DsRed-PL (p = 0.0003 and 0.039, respectively), and comparable to full-length MnSOD-PL. Intravenous, systemic administration of mc-MnSOD-PL protected mice from total body irradiation (9.75 Gy). Therefore, minicircle DNA containing the human MnSOD transgene confers undiminished radioprotection in vitro and in vivo.
In this setting, SCIT would be indicated.7 SLIT is considered much safer than SCIT in that almost no serious systemic reactions have occurred.1,8,9 A serious anaphylactic reaction occurred in a ...patient being treated with multiple allergens prepared from commercially available US extracts.10 Furthermore, with SLIT, patients have experienced lip swelling (up to 10-fold normal size),11 uvular edema not requiring treatment,5 or laryngeal edema.9 However, the preponderance of published data (treatment with a single class of allergen) does not suggest that the oral, mucosal pruritus progresses to serious oropharygneal edema. Allergist-immunologists face many issues, including the remote practice of allergy,15 and this issue will be made more challenging by the availability of SLIT in the United States. Because less than 50% of patients with antiallergen IgE antibodies develop clinical reactivity when evaluated over many years, patients with rhinitis symptoms may receive a laboratory-based diagnosis and then SLIT (or SCIT).
Summary The American Academy of Dermatology and the American Society of Plastic Surgeons, with the support of other sister societies, conducted the Facial Soft-Tissue Fillers: Assessing the State of ...the Science conference in December of 2009. The American Academy of Dermatology and the American Society of Plastic Surgeons established a panel of leading experts in the field of soft-tissue fillers—from researchers to clinicians—and other stakeholders for the conference to examine and discuss issues of patient safety, efficacy, and effectiveness in relation to the approved and off-label use of soft-tissue fillers, and other factors, including the training and level of experience of individuals administering fillers. This report summarizes the deliberations and key points made by the panel and presenters to the panel, and includes a summary of the panel’s near-term and longer term recommendations for next steps to help guide future efforts to address the safety, efficacy, and effectiveness of facial soft-tissue fillers. This report represents the panel’s assessment of the medical knowledge available on facial soft-tissue fillers at the time of the conference.
Skin is the largest human organ, and it provides a first line of defense that includes physical, chemical, and immune mechanisms to combat environmental stress. Radiation is a prevalent environmental ...stressor. Radiation-induced skin damage ranges from photoaging and cutaneous carcinogenesis caused by UV exposure, to treatment-limiting radiation dermatitis associated with radiotherapy, to cutaneous radiation syndrome, a frequently fatal consequence of exposures from nuclear accidents. The major mechanism of skin injury common to these exposures is radiation-induced oxidative stress. Efforts to prevent or mitigate radiation damage have included development of antioxidants capable of reducing reactive oxygen species. Mitochondria are particularly susceptible to oxidative stress, and mitochondrial-dependent apoptosis plays a major role in radiation-induced tissue damage. We reasoned that targeting a redox cycling nitroxide to mitochondria could prevent reactive oxygen species accumulation, limiting downstream oxidative damage and preserving mitochondrial function. Here we show that in both mouse and human skin, topical application of a mitochondrially targeted antioxidant prevents and mitigates radiation-induced skin damage characterized by clinical dermatitis, loss of barrier function, inflammation, and fibrosis. Further, damage mitigation is associated with reduced apoptosis, preservation of the skin’s antioxidant capacity, and reduction of irreversible DNA and protein oxidation associated with oxidative stress.
The Mars Phoenix Lander was equipped with a 2.4 m Robotic Arm (RA) with an Icy Soil Acquisition Device capable of excavating trenches in soil deposits, grooming hard icy soil surfaces with a scraper ...blade, and acquiring icy soil samples using a rasp tool. A camera capable of imaging the scoop interior and a thermal and electrical conductivity probe were also included on the RA. A dozen trench complexes were excavated at the northern plains landing site and 31 samples (including water‐ice‐bearing soils) were acquired for delivery to instruments on the Lander during the 152 sol mission. Deliveries included sprinkling material from several centimeters height to break up cloddy soils on impact with instrument portals. Excavations were done on the side of the Humpty Dumpty and the top of the Wonderland polygons, and in nearby troughs. Resistive forces encountered during backhoe operations show that soils above the 3–5 cm deep icy soil interfaces are stronger with increasing depth. Further, soils are similar in appearance and properties to the weakly cohesive crusty and cloddy soils imaged and excavated by the Viking Lander 2, which also landed on the northern plains. Adsorbed H2O is inferred to be responsible for the variable nature and cohesive strength of the soils. Backhoe blade chatter marks on excavated icy soil surfaces, combined with rasp motor currents, are consistent with laboratory experiments using grain‐supported icy soil deposits, as is the relatively rapid decrease in icy soil strength over time as the ice sublimated on Mars.
We determined factors associated with morbidity and outcomes of a series of non-small cell lung cancer (NSCLC) patients treated with dose-escalated chemoradiotherapy at the University of Pittsburgh ...Lung Cancer Program.
The records of 170 stage III NSCLC patients treated with definitive intent were retrospectively reviewed. All patients received four-dimensional CT simulation scan and had respiratory gating if tumor movement exceeded 5 mm. Overall survival (OS), locoregional control (LRC), and freedom from distant metastasis (FFDM) were calculated using log-rank and Cox regression analysis.
For the present series of patients, median follow-up was 36.6 months, median survival 27.4 months, and the 2- and 4-year OS was 56.0 and 30.7%, respectively. The 4-year LRC and FFDM were 43.9 and 40.7%, respectively. No benefit was associated with irradiation doses above 66 Gy in OS (
= 0.586), LRC (
= 0.440), or FFDM (
= 0.230). On univariate analysis, variables associated with worse survival included: clinical stage IIIB (
= 0.037), planning target volume (PTV) over 450 cc (
< 0.001), heart V
over 40% (
= -0.048), and esophageal mean dose over 20% (
= 0.024), V
(
= -0.015), and V
(
= -0.011). On multivariable analysis, PTV above 450 cc (52.2 vs. 25.3 months,
< 0.001) and esophageal V
>20% (43.8 vs. 21.3 months,
= -0.01) were associated with lower survival. Grade 2 or higher acute lung toxicity and esophagitis were detected in 9.5 and 59.7%, respectively of patients. Grade 2 or higher acute lung toxicity was reduced if lung V
was ≤65 (7.4 vs. 23.8%,
= 0.03). Grade 2 or higher acute esophagitis was reduced if V
≤ 20% (62 vs. 81.3%,
= 0.018). The use of intensity-modulated radiation therapy was more frequent in stage IIIB compared to stage IIIA patients (56.5 vs. 39.5%,
= 0.048) and was associated with a higher lung V
and V
.
The outcomes of a program of dose-escalated chemoradiotherapy for unresectable stage IIIA and IIIB NSCLC patients were consistent with other studies and showed no benefit to radiation doses above 66 Gy. Furthermore, maintaining low esophageal V
and lung V
were associated with lower morbidity and mortality.
Family members of patients with coronary artery disease (CAD) have higher risk of vascular events. We conducted a trial to determine if a family heart-health intervention could reduce their risk of ...CAD.
We assessed coronary risk factors and randomized 426 family members of patients with CAD to a family heart-health intervention (n = 211) or control (n = 215). The intervention included feedback about risk factors, assistance with goal setting and counselling from health educators for 12 months. Reports were sent to the primary care physicians of patients whose lipid levels and blood pressure exceeded threshold values. All participants received printed materials about smoking cessation, healthy eating, weight management and physical activity; the control group received only these materials. The main outcomes (ratio of total cholesterol to high-density lipoprotein HDL cholesterol; physical activity; fruit and vegetable consumption) were assessed at 3 and 12 months. We examined group and time effects using mixed models analyses with the baseline values as covariates. The secondary outcomes were plasma lipid levels (total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol and triglycerides); glucose level; blood pressure; smoking status; waist circumference; body mass index; and the use of blood pressure, lipid-lowering and smoking cessation medications.
We found no effect of the intervention on the ratio of total cholesterol to HDL cholesterol. However, participants in the intervention group reported consuming more fruit and vegetables (1.2 servings per day more after 3 mo and 0.8 servings at 12 mo; p < 0.001). There was a significant group by time interaction for physical activity (p = 0.03). At 3 months, those in the intervention group reported 65.8 more minutes of physical activity per week (95% confidence interval CI 47.0-84.7 min). At 12 months, participants in the intervention group reported 23.9 more minutes each week (95% CI 3.9-44.0 min).
A health educator-led heart-health intervention did not improve the ratio of total cholesterol to HDL cholesterol but did increase reported physical activity and fruit and vegetable consumption among family members of patients with CAD. Hospitalization of a spouse, sibling or parent is an opportunity to improve cardiovascular health among other family members.
clinicaltrials.gov, no NCT00552591.
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