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Comparison of AR RISH in bone and soft tissue metastases from the same patient.

Location of the mutations/deletions in TP53 gene detected by sequencing stratified p53 immunostaining result. (A) Location of the TP53 missense mutations that were detected by p53 immunostaining, showing a higher occurrence at hotspots in the DNA binding domain. (B) Location of the missense mutations, frameshifts, nonsense and splice site variants that were not detected by p53 IHC.

Supplementary Tables

Purpose: RNA expression of androgen receptor splice variants may be a biomarker of resistance to novel androgen deprivation therapies in castrate-resistant prostate cancer (CRPC). We analytically validated an RNA in situ hybridization (RISH) assay for total AR and AR-V7 for use in formalin-fixed paraffin-embedded (FFPE) prostate tumors.Experimental Design: We used prostate cell lines and xenografts to validate chromogenic RISH to detect RNA containing AR exon 1 (AR-E1, surrogate for total AR RNA species) and cryptic exon 3 (AR-CE3, surrogate for AR-V7 expression). RISH signals were quantified in FFPE primary tumors and CRPC specimens, comparing to known AR and AR-V7 status by IHC and RT-PCR.Results: The quantified RISH results correlated significantly with total AR and AR-V7 levels by RT-PCR in cell lines, xenografts, and autopsy metastases. Both AR-E1 and AR-CE3 RISH signals were localized in nuclear punctae in addition to the expected cytoplasmic speckles. Compared with admixed benign glands, AR-E1 expression was significantly higher in primary tumor cells with a median fold increase of 3.0 and 1.4 in two independent cohorts (P < 0.0001 and P = 0.04, respectively). While AR-CE3 expression was detectable in primary prostatic tumors, levels were substantially higher in a subset of CRPC metastases and cell lines, and were correlated with AR-E1 expression.Conclusions: RISH for AR-E1 and AR-CE3 is an analytically valid method to examine total AR and AR-V7 RNA levels in FFPE tissues. Future clinical validation studies are required to determine whether AR RISH is a prognostic or predictive biomarker in specific clinical contexts. Clin Cancer Res; 22(18); 4651–63. ©2016 AACR.

Demographic and clinical-pathologic characteristics of eligible patients in intermediate/high risk radical prostatectomy cohort

MSH2/6 immunostains in a formalin fixed and paraffin embedded primary prostate tumor with single copy MSH2 loss by sequencing. Standard tissue section of tumor with apparent single copy somatic gene inactivation of MSH2 (MSH2 c. 1728del), showing loss of both MSH2 and MSH6 immunostaining, with intact staining in stromal cells and lymphocytes for both markers. All photomicrographs are reduced from 200x.

Purpose: Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects.Experimental Design: A total of 1,133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS).Results: Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9–10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (P < 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed MSH2 loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in MSH2. Tumors with MSH2 loss had a higher density of infiltrating CD8+ lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm2; P = 0.008), and CD8+ density was correlated with mutation burden among cases with MSH2 loss (r = 0.72, P = 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls.Conclusions: Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts. Clin Cancer Res; 23(22); 6863–74. ©2017 AACR.

Purpose: TP53 missense mutations may help to identify prostate cancer with lethal potential. Here, we preanalytically, analytically, and clinically validated a robust IHC assay to detect subclonal and focal TP53 missense mutations in prostate cancer.Experimental Design: The p53 IHC assay was performed in a CLIA-accredited laboratory on the Ventana Benchmark immunostaining system. p53 protein nuclear accumulation was defined as any p53 nuclear labeling in >10% of tumor cells. Fifty-four formalin-fixed paraffin embedded (FFPE) cell lines from the NCI-60 panel and 103 FFPE prostate cancer tissues (88 primary adenocarcinomas, 15 metastases) with known TP53 mutation status were studied. DU145 and VCaP xenografts were subjected to varying fixation conditions to investigate the effects of preanalytic variables. Clinical validation was performed in two partially overlapping radical prostatectomy cohorts.Results: p53 nuclear accumulation by IHC was 100% sensitive for detection of TP53 missense mutations in the NCI-60 panel (25/25 missense mutations correctly identified). Lack of p53 nuclear accumulation was 86% (25/29) specific for absence of TP53 missense mutation. In FFPE prostate tumors, the positive predictive value of p53 nuclear accumulation for underlying missense mutation was 84% (38/45), whereas the negative predictive value was 97% (56/58). In a cohort of men who experienced biochemical recurrence after RP, the multivariable HR for metastasis among cases with p53 nuclear accumulation compared with those without was 2.55 (95% confidence interval, 1.1–5.91).Conclusions: IHC is widely available method to assess for the presence of deleterious and heterogeneous TP53 missense mutations in clinical prostate cancer specimens. Clin Cancer Res; 23(16); 4693–703. ©2017 AACR.

supplemental legend

RNA-seq reads spanning selected AR junctions in the RNA-seq data of CRPC samples from GSE50630, which was depleted of ribosomal RNA but not enriched for polyA transcripts

Conduction defects requiring permanent pacemaker insertion (PPI) are one of the most common complications after transcatheter aortic valve implantation (TAVI). The purpose of this study was to identify the incidence and predictors of this complication as well as to assess clinical outcomes of patients requiring PPI after TAVI in an Arab population. In this single-center, retrospective cohort analysis, all patients who underwent TAVI from 2010 to 2018 were reviewed; seventy-four independent variables were collected per patient, and multivariate analysis was performed to identify predictors. In-hospital outcomes were examined as well as 30-day and 1-year endpoints as defined by the Valve Academic Research Consortium-2. There were 48 of 170 patients (28.2%) who required PPI within 30 days of TAVI. The median time from TAVI to PPI was 2 days (interquartile range: 0 to 5 days). Positive predictors of 30-day PPI were prior right bundle branch block (odds ratio [OR]: 4.10; 95% confidence interval [CI]: 0.37 to 0.79; p

Consecutive traffic signalized intersections can increase vehicle stops, producing vehicle accelerations on arterial roads and potentially increasing vehicle fuel consumption levels. Eco-driving systems are one method to improve vehicle energy efficiency with the help of vehicle connectivity. In this paper, an eco-driving system is developed that computes a fuel-optimized vehicle trajectory while traversing more than one signalized intersection. The system is designed in a modular and scalable fashion allowing it to be implemented in large networks without significantly increasing the computational complexity. The proposed system utilizes signal phasing and timing (SPaT) data that are communicated to connected vehicles (CVs) together with real-time vehicle dynamics to compute fuel-optimum trajectories. The proposed algorithm is incorporated in the INTEGRATION microscopic traffic assignment and simulation software to conduct a comprehensive sensitivity analysis of various variables, including: system market penetration rates (MPRs), demand levels, phase splits, offsets and traffic signal spacings on the system performance. The analysis shows that at 100\% MPR, fuel consumption can be reduced by as high as 13.8\%. Moreover, higher MPRs and shorter phase lengths result in larger fuel savings. Optimum demand levels and traffic signal spacings exist that maximize the effectiveness of the algorithm. Furthermore, the study demonstrates that the algorithm works less effective when the traffic signal offset is closer to its optimal value. Finally, the study highlights the need for further work to enhance the algorithm to deal with over-saturated traffic conditions., Comment: In review in the IEEE Transactions on Intelligent Transportation Systems

Germ cell tumors (GCT) are the most common malignancy in men in the third and fourth decades of life. The occurrence of malignant GCT in men aged 50 years or over is rare, and their histopathologic characteristics and outcome is insufficiently characterized in the medical literature. Hence, we report the histopathologic features and clinical outcome of malignant GCTs in men aged ≥50 years at our institution.We performed a retrospective search of our database from 2005 to 2021 to identify men aged 50 years or older with malignant GCT. Cases of spermatocytic tumor were excluded. Clinical and histopathologic features of the tumors were reviewed.Forty-seven cases were identified, showing a sharp decline in incidence over the age of 65. Thirty-nine (83 %) tumors were testicular while eight (17 %) were non-testicular in presentation. Cases included 26 (55 %) seminomas, 15 (32 %) non-seminoma/mixed malignant GCT, and 5 (11 %) regressed testicular germ cell tumors. The most common component in mixed malignant GCTs was embryonal carcinoma (77 %), followed by seminoma and yolk sac tumor (62 % each). Germ cell neoplasia in situ (GCNIS) accompanied 57 % of the cases. Aggressive pathologic features, including lymphovascular invasion, retroperitoneal/lymph node involvement and higher stage at presentation, were identified in a significant proportion of cases (36/47, 77 %). Clinical follow up showed six patients (14 %) died of disease-related causes.Our findings expand and corroborate the previously reported data on malignant GCT in older men. Unique characteristics include tendency for higher stage at presentation with adverse pathologic features and more aggressive clinical course.

Purpose: Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects. Experimental Design: A total of 1,133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS). Results: Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9–10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (P < 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed MSH2 loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in MSH2. Tumors with MSH2 loss had a higher density of infiltrating CD8+ lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm2; P = 0.008), and CD8+ density was correlated with mutation burden among cases with MSH2 loss (r = 0.72, P = 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls. Conclusions: Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts. Clin Cancer Res; 23(22); 6863–74. ©2017 AACR.

Purpose: TP53 missense mutations may help to identify prostate cancer with lethal potential. Here, we preanalytically, analytically, and clinically validated a robust IHC assay to detect subclonal and focal TP53 missense mutations in prostate cancer. Experimental Design: The p53 IHC assay was performed in a CLIA-accredited laboratory on the Ventana Benchmark immunostaining system. p53 protein nuclear accumulation was defined as any p53 nuclear labeling in >10% of tumor cells. Fifty-four formalin-fixed paraffin embedded (FFPE) cell lines from the NCI-60 panel and 103 FFPE prostate cancer tissues (88 primary adenocarcinomas, 15 metastases) with known TP53 mutation status were studied. DU145 and VCaP xenografts were subjected to varying fixation conditions to investigate the effects of preanalytic variables. Clinical validation was performed in two partially overlapping radical prostatectomy cohorts. Results: p53 nuclear accumulation by IHC was 100% sensitive for detection of TP53 missense mutations in the NCI-60 panel (25/25 missense mutations correctly identified). Lack of p53 nuclear accumulation was 86% (25/29) specific for absence of TP53 missense mutation. In FFPE prostate tumors, the positive predictive value of p53 nuclear accumulation for underlying missense mutation was 84% (38/45), whereas the negative predictive value was 97% (56/58). In a cohort of men who experienced biochemical recurrence after RP, the multivariable HR for metastasis among cases with p53 nuclear accumulation compared with those without was 2.55 (95% confidence interval, 1.1–5.91). Conclusions: IHC is widely available method to assess for the presence of deleterious and heterogeneous TP53 missense mutations in clinical prostate cancer specimens. Clin Cancer Res; 23(16); 4693–703. ©2017 AACR.

African-American (AA) men have a higher risk of lethal prostate cancer (PCa) compared to European-American (EA) men. However, the molecular basis of this difference, if any, remains unclear. In EA PCa, PTEN loss, but not ERG rearrangement, has been associated with poor outcomes in most studies. Although ERG rearrangement is less common in AA compared to EA PCa, the relative frequency of PTEN loss and the association of PTEN/ERG molecular subtypes with outcomes is unknown for AA PCa. We examined PTEN/ERG status by immunohistochemistry in self-identified AA patients undergoing radical prostatectomy at Johns Hopkins with tumor tissue available on tissue microarray (TMA; n=169) and matched these cases by pathologic parameters to 169 EA patients from the same TMAs. The rate of PTEN loss was significantly lower in AA compared to EA PCa (18% vs 34%; p=0.001), similar to the lower rate of ERG expression (25% vs 51%; p0.001). To examine the association of PTEN/ERG status with oncologic outcomes, we created an additional TMA of 87 AA tumors with Gleason score4 + 3 = 7. Among the total population of AA men with outcome data from all TMAs (n=222), PTEN loss was associated with higher risk of biochemical recurrence (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.33-3.82) and metastasis (HR 3.90, 95% CI 1.46-10.4) in multivariable models.PTEN and ERG alterations in prostate cancer are less likely in African-American than in European-American men. However, PTEN loss remains associated with poor prostate cancer outcomes among African-American men.

This analysis will explore the corporate governance of the Kuwait Finance House. Given that the institution is a market leader, it encompasses the revolutionary financial mall concept whereby it groups together partners such as telecommunication, insurance and also credit card providers. The concept of the financial mall is providing a degree of ease through convenient services for customers, automated systems and also financial advisors. The analysis will explore the major challenge that Kuwait Finance House is facing and also the conflict of interest between the managers and the shareholders. The analysis will utilize descriptive research study whereby interviews will be conducted to get a scope of the operation of the institution. The analysis will offer recommendations such as involvement of the customers before internal growth investment. It should also establish the reason for the conflict between the shareholders and the managers and also why the financial house requires corporate governance. Given the bank has a separate clause that defines their creation of wealth for the shareholder, the conflict between the manager will eventually result in a stunted growth of the customer deposit, shareholder equity and the total assets which are important financial indicators.

Introduction: Left Main Coronary Artery (LMCA) disease is prognostically the most important coronary lesion. LMCA differs from the other coronaries in having high elastin content. Aortic Pulsatility (AP) is an independent predictor of cardiovascular events in CAD. We hypothesized that pulsatile stress may be an independent determinant of disease in the LMCA. Methods: This was a prospective cohort study in patients undergoing coronary angiography between the years 2011 and 2016 (n = 4633, 25% female) at King Abdul Aziz Cardiac Center, Riyadh, Saudi Arabia. We excluded patients with acute myocardial infarction, cardiogenic shock and significant valvular disease. Aortic systolic and diastolic blood pressures (BP) were measured in the ascending aorta. Mean Arterial Pressure (MAP) by direct integration of the BP curve and Pulse pressure (PP) as difference between systolic and diastolic BP. AP was calculated as PP/MAP. CAD was defined as > 50% stenosis in any major vessel. Results: Six percent of the population had LMCA disease (mean age 60 ± 11 years, 25% female). LMCA disease was associated with higher PP (69 ± 22 vs. 58 ± 18, p < 0.0001) despite similar MAP (94 ± 16 vs. 94.5 ± 14, p = 0.92) compared with non-LMCA disease. AP was significantly higher (0.72 ± 0.30) in LMCA disease compared with; 3-vd (0.63 ± 0.32); 2-vd (0.61 ± 0.28), 1-vd (0.58 ± 0.31) and non-obstructive CAD (0.52 ± 0.26) (p < 0.0001). In a stepwise regression model, AP was an independent predictor of LMCA disease (R2=0.68, P < 0.0001) even when adjusted for potential confounders, including MAP, age and gender. Conclusions: LMCA disease is independently associated with high AP. Considering aortic pulsatile stress to be an independent cardiovascular prognosticator, stiffness of the LMCA may play an important role in plaque formation, hitherto ignored.

Introduction: Invasive intra-aortic pressures are the gold standard for accurate Blood Pressure (BP) measurement. Hypertension management is guided by brachial cuff BP although its accuracy has been questioned. Hypothesis: We hypothesized that there may be a discrepancy between brachial and invasive intra-aortic BPs. Methods: Invasive intra-aortic and brachial cuff pressures were recorded in some 3000 patients undergoing coronary angiography (mean age 58.6 ± 28, 23% female) between 2010 and 2016, at King Abdul AzizCardiac Centre, Riyadh, Saudi Arabia. Clinical and angiographic data were collected from electronic medical records (Apollo Lx®). Results: Cuff brachial BP underestimated intra-aortic systolic BP (−6.2 mm Hg;95% CI:−7.2 to −5.4 mmHg; p < 0.0001),but overestimated intra-aortic diastolic BP (2.5 mm Hg; 95% CI:1.5 to 3.8 mm Hg;p < 0.001). The discrepancy betweenintra-aortic and brachial systolic BP was significantly higher in women than men ( −15 mm Hg; 95% CI: −14 to −17 mm Hg vs. −3.9 mm Hg;95% CI: −2.8 to −4.1 mm Hg, p < 0.0001). Intra-aortic diastolic BP was overestimated by cuff BP in men (0.9 mm Hg; 95% CI;0.74 to 1.26, p < 0.0.001) but underestimated in women ( −3.6 mm Hg;95% CI:−3 to −4 mm Hg, p < 0.0001). While brachial BP correctly estimated intra-aortic systolic BP in subjects 50 yr-olds ( −8.6 mm Hg; 95% CI: −8.1 to −9.5 mm Hg, p < 0.0001). Conclusions: Brachial BP underestimates intra-aortic systolic BP, particularly in women, older subjects and at higher BPs with implications for HTN mangagement.

Introduction: Degenerative cervical spine disorders are referred to one or more of the following process: decrease in signal intensity of disc, posterior disc protrusion, anterior compression of spinal cord and dura, disc space narrowing, foraminal stenosis or osteophytosis. They are asymptomatic in most of the cases. However, the symptoms may vary between different populations. The aim of this study is to find out the pattern of degenerative cervical spine disease at King Abdulaziz university hospital. Material and Method: This was a Retrospective study From January 2005 to December 2010, the medical files of the patients were reviewed for demographic data (age and gender), clinical presentation, duration of symptoms, physical examination and progression of disease, radiological examinations with evidence of degenerative cervical. The results were presented in mean ± standard deviation; the correlation between variables was calculated by using Spearman’s formula for the nonparametric values. Results: A total of 120 cases were reviewed. 63 (52.5%) were females and 57 (47.5%) were males. The mean age was 55.2± 12.8 years. The most common degenerative cervical spine changes were found at C 5-6 levels. The younger patients tended to have higher cervical spine level involvement P=0.0. The mean duration of symptoms was 41months. The younger patients tended to present more with the weakness and numbness p = 0.002, p = 0.005, respectively. 35 (29.1%) of patients found to have lost reflexes and 17 (14.1%) had exaggerated reflexes. Conclusion: Younger age group presents with more numbness, weakness and higher level in the cervical spine involvement. May be the new life style with more use of handheld devices and bad flexion posture of the neck plays a role in this aspect Further biomechamical studies need to be conducted to explore the effect of head posture on the cervical spine. The mean duration of symptoms prior to presentation was 41 months seems to be long, an education campaign need to be conducted to the community about the degenerative cervical disease risk factors, prevention and early recognition.

Network-wide fuel consumption along arterial roadways increases as the number of vehicle stops caused by traffic signals increase. Eco-Cooperative Adaptive Cruise Control for Multiple Signals (Eco-CACC-MS) systems are being introduced to increase vehicle fuel consumption savings in the vicinity of signalized intersections. These Eco-CACC-MS systems utilize traffic Signal Phasing and Timing (SPaT) data received from vehicle-to-infrastructure (V2I) communication and vehicle queue predictions to compute and transmit fuel-optimum vehicle trajectories to vehicles traveling through the vicinity of the signalized intersections. This study used INTEGRATION microscopic traffic assignment and simulation software to evaluate the Eco-CACC-MS algorithm to assess its network-wide environmental and energy impacts. A simulation sensitivity analysis showed that the Eco-CACC-MS algorithm reduces fuel consumption up to 13% with a 100% market penetration rate compared with Eco-CACC. The analyses also examined multi-lane networks, different demand levels, and different signal offsets. The significance analysis section showed the significance difference in the saving of Eco-CACC-MS and Eco-CACC. However, the algorithm may cause an increase in fuel consumption with oversaturated networks; thus, further work is needed to enhance the algorithm for these conditions.

Kimura disease is a rare benign chronic inflammatory disorder of unknown etiology that typically involves lymph nodes and soft tissues. This disease is most common in middle-aged Asian men. Although the disorder most frequently involves the head and neck region, it has also been reported to involve the extremities. Lesions typically show follicular lymphocytic hyperplasia with prominent interfollicular venules and a mixed inflammatory infiltrate, including numerous eosinophils. We describe a case of Kimura disease in a 29-year-old female presenting with a slowly enlarging, painless soft tissue mass in her left wrist for five months. The lesion was non-tender, mobile, and compressible. Lab results were significant for peripheral blood eosinophilia and elevated IgE. Microscopically, the mass was circumscribed, with apparent fibrous capsule or pseudocapsule, prominent high-endothelial venules, and inflammatory cells consisting of lymphocytes and eosinophils. There were prominent secondary B-lymphocytic follicles with germinal centers containing many penetrating small blood vessels, and some follicles exhibiting follicle lysis and a small amount of eosinophilic extracellular material. Polykaryocytes were noted in many germinal centers. Angiolymphoid hyperplasia with eosinophilia, a main differential diagnosis of Kimura disease, was considered; however, the combined clinical and morphologic findings appeared to be more consistent with Kimura disease, particularly in the context of eosinophilia and elevated IgE level. Kimura disease may present as a rare cause of a soft tissue mass and a diagnostic challenge for clinicians and pathologists, especially in less common sites such as the wrist. Disclosures No relevant conflicts of interest to declare.

Background Prior acute coronary syndrome (ACS) registries in Saudi Arabia might not have accurately described the true demographics and cardiac care of patients with ACS. We aimed to evaluate the clinical characteristics, management, and outcomes of a representative sample of patients with acute myocardial infarction (AMI) in Saudi Arabia. Methods We conducted a 1-month snap-shot, prospective, multi-center registry study in 50 hospitals from various health care sectors in Saudi Arabia. We followed patients for 1 month and 1 year after hospital discharge. Patients with AMI included those with or without ST-segment elevation (STEMI or NSTEMI, respectively). This program survey will be repeated every 5 years. Results Between May 2015 and January 2017, we enrolled 2233 patients with ACS (mean age was 56 [standard deviation = 13] years; 55.6% were Saudi citizens, 85.7% were men, and 65.9% had STEMI). Coronary artery disease risk factors were high; 52.7% had diabetes mellitus and 51.2% had hypertension. Emergency Medical Services (EMS) was utilized in only 5.2% of cases. Revascularization for patients with STEMI included thrombolytic therapy (29%), primary percutaneous coronary intervention (PCI); (42.5%), neither (29%), or a pharmaco-invasive approach (3%). Non-Saudis with STEMI were less likely to undergo primary PCI compared to Saudis (35.8% vs. 48.7%; respectively, p

MI: Myocardial Infraction; CK: Creatinine kinase; LVEF: Left Ventricular Ejection Fraction; MR: Mitral Regurgitation; ERO: Effective Regurgitatant Volume; PISA: Proximal Isovelocity Surface Area: OM1: Obtuse Marginal Artery 1; OM2: Obtuse Marginal Artery 2; NYHA: New York Heart Association. PCI: percutaneous coronary intervention.

Purpose: RNA expression of androgen receptor splice variants may be a biomarker of resistance to novel androgen deprivation therapies in castrate-resistant prostate cancer (CRPC). We analytically validated an RNA in situ hybridization (RISH) assay for total AR and AR-V7 for use in formalin-fixed paraffin-embedded (FFPE) prostate tumors. Experimental Design: We used prostate cell lines and xenografts to validate chromogenic RISH to detect RNA containing AR exon 1 (AR-E1, surrogate for total AR RNA species) and cryptic exon 3 (AR-CE3, surrogate for AR-V7 expression). RISH signals were quantified in FFPE primary tumors and CRPC specimens, comparing to known AR and AR-V7 status by IHC and RT-PCR. Results: The quantified RISH results correlated significantly with total AR and AR-V7 levels by RT-PCR in cell lines, xenografts, and autopsy metastases. Both AR-E1 and AR-CE3 RISH signals were localized in nuclear punctae in addition to the expected cytoplasmic speckles. Compared with admixed benign glands, AR-E1 expression was significantly higher in primary tumor cells with a median fold increase of 3.0 and 1.4 in two independent cohorts (P < 0.0001 and P = 0.04, respectively). While AR-CE3 expression was detectable in primary prostatic tumors, levels were substantially higher in a subset of CRPC metastases and cell lines, and were correlated with AR-E1 expression. Conclusions: RISH for AR-E1 and AR-CE3 is an analytically valid method to examine total AR and AR-V7 RNA levels in FFPE tissues. Future clinical validation studies are required to determine whether AR RISH is a prognostic or predictive biomarker in specific clinical contexts. Clin Cancer Res; 22(18); 4651–63. ©2016 AACR.

This paper presents pervious concrete mixed with silica fume used to evaluate the role played by silica fume in enhancing the performance of the pervious concrete including compressive strength and freezing and thawing resistance. The purpose of this paper is to determine a set of promising pervious mixtures that can be used to withstand the cold climate of Flagstaff, AZ and can be adopted by agencies in Northern Arizona.

Hypercholesterolemia is a common problem among transplant recipients. Despite package-insert warnings about the potential side effects of the use of statins in patients with chronic liver disease, they are often prescribed for liver transplant recipients. Unlike statins, ezetimibe acts through inhibition of enterohepatic recirculation of lipids. We report the effectiveness and safety of ezetimibe among liver transplant recipients because this has been evaluated previously only in kidney and heart transplant patients. A consecutive cohort of 25 liver graft recipients with serum low-density lipoprotein (LDL) levels100 mg/dL (2.5 mmol/L) after a mean (+/-standard deviation) of 55 +/- 21 months following liver transplantation received ezetimibe (10 mg orally every day) for at least 6 months. Serum lipid profiles, liver and renal function tests, and dosages and blood levels of the immunosuppression drugs at baseline, 3 months, and 6 months were prospectively collected. The overall mean age was 58 +/- 12 years, and 56% were males. Statin therapy and fibrates were already being used in 32% and 20% of recipients for elevated LDL and/or triglycerides, respectively. The immunosuppression regimen included cyclosporine in 48% of subjects, tacrolimus in 32%, sirolimus in 48%, and mycophenolate mofetil in 44%; only 12% were on oral prednisone with a maximum daily dose of 5 mg. After ezetimibe was started, an 18% reduction in LDL values was observed [at baseline, 147 +/- 35 mg/dL (3.8 +/- 0.9 mmol/L), and at 6 months, 120 +/- 31 mg/dL (3.1 +/- 0.8 mmol/L); P = 0.010]. After 6 months, an additional 32% achieved the target LDL level of100 mg/dL. None of the remaining variables, including immunosuppression drug levels, varied significantly during ezetimibe therapy. None of the subjects required adjustments in their pharmacological dosages. One discontinued ezetimibe 3 months later because of cost, 2 subjects had minimal nausea, 1 subject had myalgias without a rise in creatine phosphokinase, and 1 subject had a transient elevation (3-5 times) in liver enzymes from baseline with increases in the total and indirect bilirubin levels. In conclusion, among liver transplant recipients, hypercholesterolemia can be effectively treated with ezetimibe with few side effects and no interaction with immunosuppressive regimens.