Elevated serum CEA is associated with liver metastasis and distinctive circulating tumor DNA alterations in patients with castration-resistant prostate cancer.

BACKGROUND: Elevated serum carcinoembryonic antigen (CEA) is used to identify "treatment emergent" forms of castration-resistant prostate cancer (CRPC) such as aggressive variant prostate cancer (AVPC). However, its individual utility as a prognostic marker and the genetic alterations associated with its expression have not been extensively studied in CRPC. METHODS: This study retrospectively analyzed clinical outcomes and circulating tumor DNA profiles in 163 patients with CRPC and elevated or normal serum CEA. These same patients were then classified as AVPC or non-AVPC and compared to determine the uniqueness of CEA-associated gene alterations. RESULTS: Patients with elevated CEA demonstrated higher rates of liver metastasis (37.5% vs. 19.1%, p = 0.02) and decreased median overall survival from CRPC diagnosis (28.7 vs. 73.2 mo, p < 0.0001). In addition, patients with elevated CEA were more likely to harbor copy number amplifications (CNAs) in AR, PIK3CA, MYC, BRAF, CDK6, MET, CCNE1, KIT, RAF1, and KRAS. Based on variant allele frequency we also defined "clonal" single-nucleotide variants (SNVs) thought to be driving disease progression in each patient and found that CEA expression was negatively correlated with clonal AR SNVs and positively correlated with clonal TP53 SNVs. Of these genetic associations, only the increases in clonal TP53 SNVs and KRAS amplifications were recapitulated among patients with AVPC when compared to patients without AVPC. CONCLUSIONS: Together these findings suggest that CEA expression in CRPC is associated with aggressive clinical behavior and gene alterations distinct from those in AVPC.

Comprehensive Genomic Profiling of Cell-Free DNA in Men With Advanced Prostate Cancer: Differences in Genomic Landscape Based on Race.

Advanced prostate cancer (aPC) in Black men was reported to present with aggressive features and to be associated with poor prognosis. Herein, we compared the cell-free DNA (cfDNA) genomic landscape of aPC in Black vs White men. Patients (pts) with aPC from 6 academic institutions and available cfDNA comprehensive genomic profiling (CGP) were included. Association between mutated genes and race was evaluated using Barnard's test and a Probabilistic Graphical Model (PGM) machine learning approach. Analysis included 743 aPC pts (217 Black, 526 White) with available cfDNA CGP. The frequency of alterations in the androgen receptor gene was significantly higher in Black vs White men (55.3% vs 35% respectively, P < .001). Additionally, alterations in EGFR, MYC, FGFR1, and CTNNB1 were present at higher frequencies in Black men. PGM analysis and Barnard's test were concordant. Findings from the largest cohort of Black men with aPC undergoing cfDNA CGP may guide further drug development in these men.

Electric current paths in a Si:P delta-doped device imaged by nitrogen-vacancy diamond magnetic microscopy.

The recently-developed ability to control phosphorous-doping of silicon at an atomic level using scanning tunneling microscopy, a technique known as atomic precision advanced manufacturing (APAM), has allowed us to tailor electronic devices with atomic precision, and thus has emerged as a way to explore new possibilities in Si electronics. In these applications, critical questions include where current flow is actually occurring in or near APAM structures as well as whether leakage currents are present. In general, detection and mapping of current flow in APAM structures are valuable diagnostic tools to obtain reliable devices in digital-enhanced applications. In this paper, we used nitrogen-vacancy (NV) centers in diamond for wide-field magnetic imaging (with a few-mm field of view and micron-scale resolution) of magnetic fields from surface currents flowing in an APAM test device made of a P delta-doped layer on a Si substrate, a standard APAM witness material. We integrated a diamond having a surface NV ensemble with the device (patterned in two parallel mm-sized ribbons), then mapped the magnetic field from the DC current injected in the APAM device in a home-built NV wide-field microscope. The 2D magnetic field maps were used to reconstruct the surface current densities, allowing us to obtain information on current paths, device failures such as choke points where current flow is impeded, and current leakages outside the APAM-defined P-doped regions. Analysis on the current density reconstructed map showed a projected sensitivity of ∼0.03 A m-1, corresponding to a smallest-detectable current in the 200µm wide APAM ribbon of ∼6µA. These results demonstrate the failure analysis capability of NV wide-field magnetometry for APAM materials, opening the possibility to investigate other cutting-edge microelectronic devices.

Variation in Ultrasound Diagnostic Thresholds for Carotid Stenosis in the United States.

BACKGROUND: Individuals with carotid stenosis enter surveillance or are considered for surgery on the basis of disease severity assessed by ultrasound. However, there is variation in the ultrasound diagnostic thresholds used to determine disease severity. Our objective was to describe this variation and its potential impact on patients. METHODS: To describe the variation in carotid ultrasound diagnostic thresholds, we examined testing protocols from 338 accredited vascular testing centers in the United States. To determine the potential impact of this variation, we applied the range of thresholds to carotid ultrasound parameters from 2 groups: a population-based sample ≥65 years of age in the Cardiovascular Health Study (n=4791), and a cohort of patients who underwent surgery for asymptomatic carotid stenosis in the Vascular Quality Initiative registry (n=28 483). RESULTS: Internal carotid artery peak systolic velocity was used by all centers to assess disease severity, with 60 distinct thresholds in use. The peak systolic velocity threshold for moderate (≥50%) stenosis ranged from 110 to 245 cm/s (median, 125; 5th and 95th percentile, 125 and 150), and the threshold for severe (≥70%) stenosis ranged from 175 to 340 cm/s (median, 230; 5th and 95th percentile, 230 and 275). In the population-based sample, the 5th percentile threshold would assign a diagnosis of moderate carotid stenosis to twice as many individuals as the 95th percentile threshold (7.9% versus 3.9%; relative risk, 2.01 [CI, 1.70-2.38]). In the surgical cohort, 1 in 10 (9.8%) patients had peak systolic velocity values that warranted the diagnosis of severe carotid stenosis at centers in the 5th percentile, but not in the 95th. CONCLUSIONS: The diagnostic threshold for carotid stenosis varies considerably. Whether or not a person is said to have moderate stenosis and enters surveillance, and whether or not they have severe stenosis and are candidates for surgery, can depend on which center performs their ultrasound.

Optimization of duplex velocity criteria for diagnosis of internal carotid artery (ICA) stenosis: A report of the Intersocietal Accreditation Commission (IAC) Vascular Testing Division Carotid Diagnostic Criteria Committee.

Diagnostic criteria to classify severity of internal carotid artery (ICA) stenosis vary across vascular laboratories. Consensus-based criteria, proposed by the Society of Radiologists in Ultrasound in 2003 (SRUCC), have been broadly implemented but have not been adequately validated. We conducted a multicentered, retrospective correlative imaging study of duplex ultrasound versus catheter angiography for evaluation of severity of ICA stenosis. Velocity data were abstracted from bilateral duplex studies performed between 1/1/2009 and 12/31/2015 and studies were interpreted using SRUCC. Percentage ICA stenosis was determined using North American Symptomatic Carotid Endarterectomy Trial (NASCET) methodology. Receiver operating characteristic analysis evaluated the performance of SRUCC parameters compared with angiography. Of 448 ICA sides (from 224 patients), 299 ICA sides (from 167 patients) were included. Agreement between duplex ultrasound and angiography was moderate (κ = 0.42), with overestimation of degree of stenosis for both moderate (50-69%) and severe (⩾ 70%) ICA lesions. The primary SRUCC parameter for ⩾ 50% ICA stenosis of peak-systolic velocity (PSV) of ⩾ 125 cm/sec did not meet prespecified thresholds for adequate sensitivity, specificity, and accuracy (sensitivity 97.8%, specificity 64.2%, accuracy 74.5%). Test performance was improved by raising the PSV threshold to ⩾ 180 cm/sec (sensitivity 93.3%, specificity 81.6%, accuracy 85.2%) or by adding the additional parameter of ICA/common carotid artery (CCA) PSV ratio ⩾ 2.0 (sensitivity 94.3%, specificity 84.3%, accuracy 87.4%). For ⩾ 70% ICA stenosis, analysis was limited by a low number of cases with angiographically severe disease. Interpretation of carotid duplex examinations using SRUCC resulted in significant overestimation of severity of ICA stenosis when compared with angiography; raising the PSV threshold for ⩾ 50% ICA stenosis to ⩾ 180 cm/sec as a single parameter or requiring the ICA/CCA PSV ratio ⩾ 2.0 in addition to PSV of ⩾ 125 cm/sec for laboratories using the SRUCC is recommended to improve the accuracy of carotid duplex examinations.

Social and clinical determinants of physical activity in prostate cancer survivors.

PURPOSE: Physical activity is important for enhancing quality of life and cancer control among prostate cancer survivors. The purpose of this study was to characterize adherence to physical activity guidelines among African American and white prostate cancer survivors based on social and clinical determinants and psychosocial factors. METHODS: Observational study of meeting guidelines for moderate intensity physical activity in a retrospective cohort of African American and white prostate cancer survivors (n = 89). RESULTS: Thirty-four percent of survivors met the recommended guidelines for moderate intensity physical activity. There were no racial differences in physical activity between African American and white prostate cancer survivors; however, the likelihood of meeting guidelines was associated significantly with stage of disease, self-rated health, and perceptions of stress. Survivors who had stage pT2c or higher disease had a significantly reduced likelihood of meeting recommended guidelines for physical activity (OR = 0.27, 95% CI = 0.08, 0.86, p = 0.03). The likelihood of meeting guidelines was also reduced among survivors who rated their health as being the same or worse than before they were diagnosed with prostate cancer (OR = 0.32, 95% CI = 0.11, 0.96, p = 0.04). As perceived stress increased, the likelihood of being physically active according to guidelines also decreased (OR = 0.48, 95% CI = 0.26, 0.89, p = 0.02). CONCLUSION: The results of this study underscore the need to develop, implement, and evaluate strategies to enhance physical activity among prostate cancer survivors, regardless of their racial background. Complementary and alternative strategies for physical activity may be one strategy for enhancing activity levels and managing stress among prostate cancer survivors.

Comprehensive Analysis of AR Alterations in Circulating Tumor DNA from Patients with Advanced Prostate Cancer.

BACKGROUND: Somatic alterations in circulating tumor DNA (ctDNA) may be associated with treatment response or prognosis in prostate cancer (PCa). The goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in ctDNA from patients with PCa and to further understand the somatic genetic heterogeneity of advanced prostate cancer. PATIENTS AND METHODS: This study included a heterogeneous group of 892 patients with advanced PCa (predominantly castrate-resistant prostate cancer) with AR alterations detected in ctDNA that underwent next-generation sequencing of 54 to 73 genes via Guardant360 testing (Guardant Health, Inc., Redwood City, CA). Distribution and summary of AR alterations detected, the association of AR alterations with other genes, and a pathway analysis are reported. RESULTS: The median absolute plasma copy number of AR amplifications was 3.3 (range, 1.2-165.2). Many patients had multiple AR mutations; a total of 112 unique mutations were identified in AR, including L702H (25%), T878A (14%), H875Y (11%), W742C (8%), W742L (4%), F877L (2%), and T878S (2%). Other ctDNA gene alterations in the Guardant assays included TP53 (50%), MYC (34%), BRAF (32%), PIK3CA (29%), MET (25%), CDK6 (26%), EGFR (24%), FGFR1 (21%), and APC (12%). Many of these non-AR alterations are not tissue verified in other studies. AR amplification cosegregated with alterations in MYC (p < .001), BRAF (p < .001), PIK3CA (p < .001), MET (p < .001), CDK6 (p < .001), EGFR (p < .001), FGFR1 (p = .391), and more. Alterations in APC were significantly associated with mutations in AR (p < .001). CONCLUSION: Several AR alterations and concomitant non-AR alterations that associate with drug resistance were detected. These findings provide additional insights into the heterogeneity of advanced prostate cancer. IMPLICATIONS FOR PRACTICE: The goal was to characterize androgen receptor gene (AR) amplifications and mutations detected in circulating tumor DNA (ctDNA) from patients with prostate cancer in relation to non-AR gene alterations detected in the ctDNA landscape. The study included 892 patients with prostate cancer with AR alterations in ctDNA. AR alterations were significantly associated with other gene alterations detected in ctDNA. The common AR mutations found are linked to resistance to abiraterone, enzalutamide, or bicalutamide. Characterization of the circulating AR landscape and gene alterations provides potential additional insight into the somatic genetic heterogeneity of advanced prostate cancer.

Ultrasound for Lower Extremity Deep Venous Thrombosis: Multidisciplinary Recommendations From the Society of Radiologists in Ultrasound Consensus Conference.

Venous ultrasound is the standard imaging test for patients suspected of having acute deep venous thrombosis (DVT). There is variability and disagreement among authoritative groups regarding the necessary components of the test. Some protocols include scanning the entire lower extremity, whereas others recommend scans limited to the thigh and knee supplemented with serial testing. Some protocols use gray-scale ultrasound alone, whereas others include Doppler interrogation. Point-of-care ultrasound is recommended in some settings, and there is heterogeneity of these protocols as well. Heterogeneity of recommendations can lead to errors including incorrect application of guidelines, confusion among requesting physicians, and incorrect follow-up. In October 2016, the Society of Radiologists in Ultrasound convened a multidisciplinary panel of experts to evaluate the current evidence to develop recommendations regarding ultrasound protocols for DVT and the terminology used to communicate results to clinicians. Recommendations were made after open discussion and by unanimous consensus.The panel recommends a comprehensive duplex ultrasound protocol from thigh to ankle with Doppler at selected sites rather than a limited or complete compression-only examination. This protocol is currently performed in many facilities and is achievable with standard ultrasound equipment and personnel. The use of these recommendations will increase the diagnosis of calf DVT and provide better data to explain the presenting symptoms. The panel recommends a single point-of-care protocol that minimizes underdiagnoses of proximal DVT.The panel recommends the term chronic postthrombotic change to describe the residual material that persists after the acute presentation of DVT to avoid potential overtreatment of prior thrombus.Adoption of a single standardized comprehensive duplex ultrasound and a single point-of-care examination will enhance patient safety and clinicians' confidence.

Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. METHODS: Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated. RESULTS: Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. CONCLUSIONS: ctDNA frequently was detected in this large cohort of "real-world" patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.

Advanced glycation end products are elevated in estrogen receptor-positive breast cancer patients, alter response to therapy, and can be targeted by lifestyle intervention.

PURPOSE: Lifestyle factors associated with personal behavior can alter tumor-associated biological pathways and thereby increase cancer risk, growth, and disease recurrence. Advanced glycation end products (AGEs) are reactive metabolites produced endogenously as a by-product of normal metabolism. A Western lifestyle also promotes AGE accumulation in the body which is associated with disease phenotypes through modification of the genome, protein crosslinking/dysfunction, and aberrant cell signaling. Given the links between lifestyle, AGEs, and disease, we examined the association between dietary-AGEs and breast cancer. METHODS: We evaluated AGE levels in bio-specimens from estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer patients, examined their role in therapy resistance, and assessed the ability of lifestyle intervention to reduce circulating AGE levels in ER+ breast cancer survivors. RESULTS: An association between ER status and AGE levels was observed in tumor and serum samples. AGE treatment of ER+ breast cancer cells altered ERα phosphorylation and promoted resistance to tamoxifen therapy. In a proof of concept study, physical activity and dietary intervention was shown to be viable options for reducing circulating AGE levels in breast cancer survivors. CONCLUSIONS: There is a potential prognostic and therapeutic role for lifestyle derived AGEs in breast cancer. Given the potential benefits of lifestyle intervention on incidence and mortality, opportunities exist for the development of community health and nutritional programs aimed at reducing AGE exposure in order to improve breast cancer prevention and treatment outcomes.

Spin-orbit Interactions for Singlet-Triplet Qubits in Silicon.

Spin-orbit coupling is relatively weak for electrons in bulk silicon, but enhanced interactions are reported in nanostructures such as the quantum dots used for spin qubits. These interactions have been attributed to various dissimilar interface effects, including disorder or broken crystal symmetries. In this Letter, we use a double-quantum-dot qubit to probe these interactions by comparing the spins of separated singlet-triplet electron pairs. We observe both intravalley and intervalley mechanisms, each dominant for [110] and [100] magnetic field orientations, respectively, that are consistent with a broken crystal symmetry model. We also observe a third spin-flip mechanism caused by tunneling between the quantum dots. This improved understanding is important for qubit uniformity, spin control and decoherence, and two-qubit gates.

Intersocietal Accreditation Commission Accreditation Status of Outpatient Cerebrovascular Testing Facilities Among Medicare Beneficiaries: The VALUE Study.

OBJECTIVES: Accreditation of cerebrovascular ultrasound laboratories by the Intersocietal Accreditation Commission (IAC) and equivalent organizations is supported by the Joint Commission certification of stroke centers. Limited information exists on the accreditation status and geographic distribution of cerebrovascular testing facilities in the United States. Our study objectives were to identify the proportion of IAC-accredited outpatient cerebrovascular testing facilities used by Medicare beneficiaries, describe their geographic distribution, and identify variations in cerebrovascular testing procedure types and volumes by accreditation status. METHODS: As part of the VALUE (Vascular Accreditation, Location, and Utilization Evaluation) Study, we examined the proportion of IAC-accredited facilities that conducted cerebrovascular testing in a 5% Centers for Medicare and Medicaid Services random Outpatient Limited Data Set in 2011 and investigated their geographic distribution using geocoding. RESULTS: Among 7327 outpatient facilities billing Medicare for cerebrovascular testing, only 22% (1640) were IAC accredited. The proportion of IAC-accredited cerebrovascular testing facilities varied by region (χ(2)[3] = 177.1; P < .0001), with 29%, 15%, 13%, and 10% located in the Northeast, South, Midwest, and West, respectively. However, of the total number of cerebrovascular outpatient procedures conducted in 2011 (38,555), 40% (15,410) were conducted in IAC-accredited facilities. Most cerebrovascular testing procedures were carotid duplex, with 40% of them conducted in IAC-accredited facilities. CONCLUSIONS: The proportion of facilities conducting outpatient cerebrovascular testing accredited by the IAC is low and varies by region. The growing number of certified stroke centers should be accompanied by more accredited outpatient vascular testing facilities, which could potentially improve the quality of stroke care.

Luteolin, ellagic acid and punicic acid are natural products that inhibit prostate cancer metastasis.

Prostate cancer (PCa) is the second cause of cancer deaths in men in the USA. When the cancer recurs, early stages can be controlled with hormone ablation therapy to delay the rate of cancer progression but, over time, the cancer overcomes its hormone dependence, becomes highly aggressive and metastasizes. Clinical trials have shown that pomegranate juice (PJ) inhibits PCa progression. We have previously shown that the PJ components luteolin (L), ellagic acid (E) and punicic acid (P) together inhibit growth of hormone-dependent and -independent PCa cells and inhibit their migration and chemotaxis towards CXCL12, a chemokine that is important in PCa metastasis. On the basis of these findings, we hypothesized that L+E+P inhibit PCa metastasis in vivo. To test this possibility, we used a severe combined immunodeficiency mouse model in which luciferase-expressing human PCa cells were injected subcutaneously near the prostate. Tumor progression was monitored with bioluminescence imaging weekly. We found that L+E+P inhibits PC-3M-luc primary tumor growth, inhibits the CXCL12/CXCR4 axis for metastasis and none of the tumors metastasized. In addition, L+E+P significantly inhibits growth and metastasis of highly invasive Pten (-/-) ;K-ras (G12D) prostate tumors. Furthermore, L+E+P inhibits angiogenesis in vivo, prevents human endothelial cell (EC) tube formation in culture and disrupts preformed EC tubes, indicating inhibition of EC adhesion to each other. L+E+P also inhibits the angiogenic factors interleukin-8 and vascular endothelial growth factor as well as their induced signaling pathways in ECs. In conclusion, these results show that L+E+P inhibits PCa progression and metastasis.

Derivatives of imidazotriazine and pyrrolotriazine C-nucleosides as potential new anti-HCV agents.

Previous investigations identified 2'-C-Me-branched ribo-C-nucleoside adenosine analogues, 1, which contains a pyrrolo[2,1-f][1,2,4]triazin-4-amine heterocyclic base, and 2, which contains an imidazo[2,1-f][1,2,4]triazin-4-amine heterocyclic base as two compounds with promising anti-HCV in vitro activity. This Letter describes the synthesis and evaluation of a series of novel analogues of these compounds substituted at the 2-, 7-, and 8-positions of the heterocyclic bases. A number of active new HCV inhibitors were identified but most compounds also demonstrated unacceptable cytotoxicity. However, the 7-fluoro analogue of 1 displayed good potency with a promising cytotherapeutic margin.

Accreditation status and geographic location of outpatient vascular testing facilities among Medicare beneficiaries: the VALUE (Vascular Accreditation, Location & Utilization Evaluation) study.

OBJECTIVE: There is limited information on the accreditation status and geographic distribution of vascular testing facilities in the US. The Centers for Medicare & Medicaid Services (CMS) provide reimbursement to facilities regardless of accreditation status. The aims were to: (1) identify the proportion of Intersocietal Accreditation Commission (IAC) accredited vascular testing facilities in a 5% random national sample of Medicare beneficiaries receiving outpatient vascular testing services; (2) describe the geographic distribution of these facilities. METHODS: The VALUE (Vascular Accreditation, Location & Utilization Evaluation) Study examines the proportion of IAC accredited facilities providing vascular testing procedures nationally, and the geographic distribution and utilization of these facilities. The data set containing all facilities that billed Medicare for outpatient vascular testing services in 2011 (5% CMS Outpatient Limited Data Set (LDS) file) was examined, and locations of outpatient vascular testing facilities were obtained from the 2011 CMS/Medicare Provider of Services (POS) file. RESULTS: Of 13,462 total vascular testing facilities billing Medicare for vascular testing procedures in a 5% random Outpatient LDS for the US in 2011, 13% (n=1730) of facilities were IAC accredited. The percentage of IAC accredited vascular testing facilities in the LDS file varied significantly by US region, p<0.0001: 26%, 12%, 11%, and 7% for the Northeast, South, Midwest, and Western regions, respectively. CONCLUSIONS: Findings suggest that the proportion of outpatient vascular testing facilities that are IAC accredited is low and varies by region. Increasing the number of accredited vascular testing facilities to improve test quality is a hypothesis that should be tested in future research.

Endovascular repair of an asymptomatic aortic pseudoaneurysm after penetrating injury.

Penetrating injuries to the aorta usually result in immediate life-threatening hemorrhage. Because these lesions are typically either fatal or identified and controlled surgically, chronic pseudoaneurysms after penetrating aortic trauma are rare. Most of these patients present with rupture or local complications, and management before the endovascular era has historically been open repair. As such, there are limited data to guide the modern management of an asymptomatic, posttraumatic aortic pseudoaneurysm. Here, we describe a 54-year-old man who was diagnosed with an incidental, supraceliac aortic pseudoaneurysm 14 years after an abdominal stab wound. He underwent successful and uncomplicated endovascular repair.

Charge sensed Pauli blockade in a metal-oxide-semiconductor lateral double quantum dot.

We report Pauli blockade in a multielectron silicon metal-oxide-semiconductor double quantum dot with an integrated charge sensor. The current is rectified up to a blockade energy of 0.18 ± 0.03 meV. The blockade energy is analogous to singlet-triplet splitting in a two electron double quantum dot. Built-in imbalances of tunnel rates in the MOS DQD obfuscate some edges of the bias triangles. A method to extract the bias triangles is described, and a numeric rate-equation simulation is used to understand the effect of tunneling imbalances and finite temperature on charge stability (honeycomb) diagram, in particular the identification of missing and shifting edges. A bound on relaxation time of the triplet-like state is also obtained from this measurement.

Cryogenic platform to investigate strong microwave cavity-spin coupling in correlated magnetic materials.

We present a comprehensive exploration of loop-gap resonators for electron spin resonance (ESR) studies, enabling investigations into the hybridization of solid-state magnetic materials with microwave polariton modes. The experimental setup, implemented in aPhysical Property Measurement Systemby Quantum Design, allows for measurements of ESR spectra at temperatures as low as 2 Kelvin. The versatility of continuous wave ESR spectroscopy is demonstrated through experiments on CuSO4⋅5H2O and MgCr2O4, showcasing the g-tensor and magnetic susceptibilities of these materials. The study delves into the challenges of fitting spectra under strong hybridization conditions and underscores the significance of proper calibration and stabilization. The detailed guide provided serves as a valuable resource for laboratories interested in exploring hybrid quantum systems through microwave resonators.

A phase I study of docetaxel plus synthetic lycopene in metastatic prostate cancer patients.

PURPOSE: Our preclinical studies showed that lycopene enhanced the anti-prostate cancer efficacy of docetaxel in animal models. A phase I trial (NCT0149519) was conducted to identify an optimum dose of synthetic lycopene in combination with docetaxel (and androgen blockade [androgen deprivation therapy, ADT]), and to evaluate its effect on the safety and pharmacokinetics of docetaxel in men with metastatic prostate cancer. METHODS: Subjects were treated with 21-day cycles of 75 mg/m2 docetaxel (and ADT), plus lycopene at 30, 90 or 150 mg/day. A Bayesian model averaging continual reassessment method was used to guide dose escalation. Pharmacokinetics of docetaxel and multiple correlative studies were carried out. RESULTS: Twenty-four participants were enrolled, 18 in a dose escalation cohort to define the maximum tolerated dose (MTD), and six in a pharmacokinetic cohort. Docetaxel/ADT plus 150 mg/day synthetic lycopene resulted in dose-limiting toxicity (pulmonary embolus) in one out of 12 participants with an estimated probability of .106 and thus was chosen as the MTD. Lycopene increased the AUCinf and Cmax of plasma docetaxel by 9.5% and 15.1%, respectively. Correlative studies showed dose-related changes in circulating endothelial cells and vascular endothelial growth factor A, and reduction in insulin-like growth factor 1R phosphorylation, associated with lycopene therapy. CONCLUSIONS: The combination of docetaxel/ADT and synthetic lycopene has low toxicity and favourable pharmacokinetics. The effects of lycopene on biomarkers provide additional support for the toxicity-dependent MTD definition. HIGHLIGHTS: The maximum tolerated dose was identified as 150 mg/day of lycopene in combination with docetaxel/ADT for the treatment of metastatic prostate cancer patients. Small increases in plasma exposure to docetaxel were observed with lycopene co-administration. Mechanistically significant effects were seen on angiogenesis and insulin-like growth factor 1 signalling by lycopene co-administration with docetaxel/ADT.