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Recent investigations of Morton Village, a Mississippian and Oneota community formed following Oneota migration into the central Illinois River valley around AD 1300, focus on evaluating the social context for the remarkable violence evidenced at the adjacent Norris Farms 36 cemetery. Here, we use the concepts of thirdspace and hybridity to examine three areas of village life: creation of the physical structure of the village, ritual, and foodways. Within these three areas, we identify transformations of Mississippian and Oneota practices that support the interpretation that villagers were engaged in the formation of a coalescent community.

Izencitinib (TD-1473), an oral, gut-selective pan-Janus kinase (JAK) inhibitor under investigation for treatment of inflammatory bowel diseases, was designed for optimal efficacy in the gastrointestinal tract while minimizing systemic exposures and JAK-related safety findings. The nonclinical safety of izencitinib was evaluated in rat and dog repeat-dose and rat and rabbit reproductive and developmental toxicity studies. Systemic exposures were compared with JAK inhibitory potency to determine effects at or above pharmacologic plasma concentrations (≥1× plasma average plasma concentration [Cave]:JAK 50% inhibitory concentration [IC50] ratio). In rats and dogs, 1000 and 30 mg/kg/day izencitinib, respectively, produced minimal systemic findings (ie, red/white cell changes) and low systemic concentrations (approximately 1× plasma Cave:JAK IC50 ratio) with an 8× nonclinical:clinical systemic area under the curve (AUC) margin compared with exposures at the highest clinically tested dose (300 mg, quaque die, once daily, phase 1 study in healthy volunteers). In dogs, it was possible to attain sufficient systemic exposures to result in immunosuppression characteristic of systemic JAK inhibition, but at high AUC margins (43×) compared with systemic exposures observed at the highest tested dose in humans. No adverse findings were observed in the gastrointestinal tract or systemic tissues. Izencitinib did not affect male or female fertility. Izencitinib did not affect embryonic development in rats and rabbits as commonly reported with systemic JAK inhibition, consistent with low maternal systemic concentrations (2–6× plasma Cave:JAK IC50 ratio, 10–33× nonclinical:clinical AUC margin) and negligible fetal exposures. In conclusion, the izencitinib gut-selective approach resulted in minimal systemic findings in nonclinical species at pharmacologic, clinically relevant systemic exposures, highlighting the impact of organ-selectivity in reducing systemic safety findings.

After 15 years of existence, the ACVP/STP Coalition for Veterinary Pathology Fellows will dissolve, primarily due to lack of renewed financial sponsorship. While in operation, the Coalition organized 32 new training position for veterinary pathologists, supported by $7.4 M from sponsors, including pharmaceutical and biotechnology companies, contract research organizations, private individuals and allied veterinary pathology support groups. All residual funds will be donated to ACVP and STP with the understanding that the two organizations will use these funds to enhance training by collaborating on outreach efforts, thus maintaining the legacy and spirit of the Coalition.

Past studies have documented the ability of cardiopulmonary exercise testing to detect cardiac dysfunction in symptomatic patients with coronary artery disease. Firefighters are at high risk for work-related cardiac events. This observational study investigated the association of subclinical cardiac dysfunction detected by cardiopulmonary exercise testing with modifiable cardiometabolic risk factors in asymptomatic firefighters.As part of mandatory firefighter medical evaluations, study subjects were assessed at 2 occupational health clinics serving 21 different fire departments. Mixed effects logistic regression analyses were used to estimate odds ratios (ORs) and account for clustering by fire department.Of the 967 male firefighters (ages 20-60 years; 84% non-Hispanic white; 14% on cardiovascular medications), nearly two-thirds (63%) had cardiac dysfunction despite having normal predicted cardiorespiratory fitness (median peak VOSubclinical cardiac dysfunction detected by cardiopulmonary exercise testing is a common finding in career firefighters and is associated with substantially reduced cardiorespiratory fitness and cardiometabolic risk factors. These individuals should be targeted for aggressive risk factor modification to increase cardiorespiratory fitness as part of an outpatient prevention strategy to improve health and safety.

Identification of a novel catalyst–allenoate pair allows enantioselective [2+2] cycloaddition of α-methylstyrene. To understand the origin of selectivity, a detailed mechanistic investigation was conducted. Herein, two competing reaction pathways are proposed, which operate simultaneously and funnel the alkenes to the same axially chiral cyclobutanes. In agreement with the Woodward–Hoffmann rules, this mechanistic curiosity can be rationalized through a unique symmetry operation that was elucidated by deuteration experiments. In the case of 1,1-diarylalkenes, distal communication between the catalyst and alkene is achieved through subtle alteration of electronic properties and conformation. In this context, a Hammett study lends further credibility to a concerted mechanism. Thus, extended scope exploration, including β-substitution on the alkene to generate two adjacent stereocenters within the cyclobutane ring, is achieved in a highly stereospecific and enantioselective fashion (33 examples, up to >99:1 er).

The application of thioallenoates to catalytic enantioselective [2+2]-cycloadditions with unactivated alkenes is reported.In many cases, the thioallenoates examined exhibit superior reactivity and selectivity compared to the alkoxy analogs generally used in these cycloadditions.

Critical heat flux (CHF) is a primary parameter for nuclear fuel design and plant operation safety. CHF values are normally obtained from fuel bundle integral departure from nucleate boiling (DNB) or dryout experiments. These experiments are expensive, and detailed measurements (bubble dynamics, void fraction distribution, etc.) are difficult to obtain, particularly under typical pressurized water reactor (PWR) conditions of high pressure and temperature. Therefore, it is highly desirable that computational tools such as computational fluid dynamics (CFD) provide detailed flow and heat transfer information that will efficiently facilitate design improvements of PWR fuel designs.For the CFD studies described in this paper, an Eulerian-Eulerian two-phase modeling approach was adopted to predict DNB in a fuel assembly with mixing vane grids. Subcooled flow boiling was simulated using heat flux partition modeling and phase interactions. Direct addition of heat to the vapor was activated when the local...

Signet-ring cell carcinomas (SRCCs) tend to present at higher stages and thus are generally associated with a worse prognosis. It has been postulated that a deficiency of E-cadherin may be causal in the pathogenesis of SRCC in animal models. In this study, we systemically analyzed the expression of E-cadherin and β-catenin, a key component of the cadherin complex, in 137 consecutive SRCCs of various organ systems to explore the significance of these molecules in the pathogenesis and progression of SRCCs. Seventy-six percent of SRCCs showed loss or reduced E-cadherin expression. Aberrant β-catenin expression, defined as loss of membranous expression and nuclear/cytoplasmic subcellular localization, was observed in 60% of these cases, with the altered β-catenin expression observed most commonly in the breast (93%) and least in the lung (38%) primaries. Further, the aberrant β-catenin was significantly associated with pathologic nodal stage (P=0.002) and clinical stage (P=0.02). Our findings demonstrated that reduced membranous E-cadherin and aberrant β-catenin expression were frequent events in SRCCs of various organs, and that the altered β-catenin expression was significantly associated with advanced disease. The observations further support the importance of these molecules in the pathogenesis of SRCCs, and indicate the fundamental role of the Wnt/β-catenin signaling pathway in the progression of these tumors. Further investigations of the downstream molecules in this cascade may provide potential novel therapeutic targets for this aggressive tumor type.

In utero hematopoietic cell transplantation (IUHCT) is a novel nonmyeloablative approach that results in donor-specific tolerance and mixed allogeneic chimerism. Clinical application is limited by low levels of donor cell engraftment. Competition from endogenous hematopoietic stem cells (HSCs) for limited "space" in fetal hematopoietic organs remains a significant barrier to successful IUHCT. AMD3100, a CXCR4 inhibitor, and firategrast, an α4β1 and α4β7 integrin inhibitor (α4β1/7), have been shown to disrupt HSC retention in the postnatal hematopoietic niche. We hypothesized that maternal administration of AMD3100 and/or firategrast prior to IUHCT would mobilize endogenous HSCs from the fetal liver (FL) and result in preferential FL homing of donor HSCs and enhanced long-term engraftment following IUHCT in an allogeneic mouse model. We demonstrate that (1) both agents cross the placenta with rapidly detectable fetal serum concentrations following maternal administration; (2) firategrast treatment alone or with AMD3100 mobilizes endogenous HSCs from the FL and results in increased FL homing of donor HSCs following IUHCT; and (3) enhanced donor HSC homing following firategrast treatment translates into increased long-term multilineage donor cell engraftment. This approach highlights the potential of mobilization strategies to overcome barriers to successful engraftment and increase the clinical promise of IUHCT.

Using a comprehensive next-generation sequencing pipeline (143 genes), Oncomine Comprehensive v.2, we analyzed genetic alterations on a set of vulvar squamous cell carcinomas (SCCs) with emphasis on the primary and metastatic samples from the same patient, to identify amenable therapeutic targets. Clinicopathologic features were reported and genomic DNA was extracted from 42 paraffin-embedded tumor tissues of 32 cases. PD-L1 expression was evaluated in 20 tumor tissues (10 cases with paired primary and metastatic tumors). Fifteen (88%) of 17 successfully analyzed HPV-unrelated SCCs harbored TP53 mutations. 2 different TP53 mutations had been detected in the same tumor in 4 of 15 cases. Other recurrent genetic alterations in this group of tumors included CDKN2a mutations (41%), HRAS mutations (12%), NOTCH1 mutations (12%) and BIRC3 (11q22.1-22.2) amplification (12%). Six HPV-related tumors harbored PIK3CA, BAP1, PTEN, KDR, CTNNB1, and BRCA2 mutations, of which, one case also contained TP53 mutation. Six cases showed identical mutations in paired primary site and distant metastatic location and four cases displayed different mutational profiles. PD-L1 expression was seen in 6 of 10 primary tumors and all 6 paired cases showed discordant PD-L1 expression in the primary and metastatic sites. Our results further confirmed the genetic alterations that are amenable to targeted therapy, offering the potential for individualized management strategies for the treatment of these aggressive tumors with different etiology. Discordant PD-L1 expression in the primary and metastatic vulvar SCCs highlights the importance of evaluation of PD-L1 expression in different locations to avoid false negative information provided for immunotherapy.

Despite mounting evidence that large intramural leiomyomas decrease fecundity during in vitro fertilization cycles, few studies have demonstrated a mechanism for this impact. We hypothesize that large intramural leiomyomas (IM) decrease the expression of endometrial implantation factors during the window of implantation. We prospectively recruited sub-fertile patients with IM 3 cm or greater in size planning myomectomy and performed endometrial biopsies the day of planned myomectomy (n = 9). Preoperative screening demonstrated no intercavitary lesions. Control endometrial samples were obtained from young, normally menstruating women free of uterine leiomyomas (n = 8). Endometrial samples were obtained in the mid-secretory phase (average cycle day for control patients and intramural leiomyoma patients were 24.5 and 21.3, respectively). Expression of implantation markers HOXA10, leukemia inhibitory factor (LIF), ER-α, and PR was compared using quantitative immunohistochemistry. Standard descriptive statistics were used to compare H-scores between the cohorts. Patients with intramural leiomyomas were found to have decreased LIF compared to controls (p value

A method for the [2 + 2] cycloaddition of terminal alkenes with allenoates is presented. This process allows for the rapid synthesis of 1,3-substituted cyclobutanes in high yield under simple and robust reaction conditions.

The purpose of this study was to evaluate the safety, efficacy, and immunogenicity of a plasmid vaccine, pNGVL4a-CRT-E7(detox), administered either intradermally, intramuscularly, or directly into the cervical lesion, in patients with HPV16-associated CIN2/3.Eligible patients with HPV16(+) CIN2/3 were enrolled in treatment cohorts evaluating pNGVL4a-CRT-E7(detox), administered by either particle-mediated epidermal delivery (PMED), intramuscular injection (IM), or cervical intralesional injection, at study weeks 0, 4, and 8. Patients were monitored for local injection site and systemic toxicity. A standard therapeutic resection was performed at week 15. The primary endpoints were safety and tolerability. Secondary endpoints included histologic regression and change in cervical HPV viral load. Exploratory endpoints included immune responses in the blood and in the target tissue.Thirty-two patients with HPV16(+) CIN2/3 were enrolled onto the treatment phase of the study, and were vaccinated. Twenty-two of 32 patients (69%) experienced vaccine-specific related adverse events. The most frequent vaccine-related events were constitutional and local injection site in nature, and were grade 1 or less in severity. Histologic regression to CIN 1 or less occurred in 8 of 27 (30%) patients who received all vaccinations and underwent LEEP. In subject-matched comparisons, intraepithelial CD8+ T cell infiltrates increased after vaccination in subjects in the intralesional administration cohort.pNGVL4a-CRT-E7(detox) was well-tolerated, elicited the most robust immune response when administered intralesionally, and demonstrated preliminary evidence of potential clinical efficacy.

Small cell neuroendocrine carcinoma (SCNEC) of the uterine cervix is a rare but extremely aggressive tumor. While high-risk human papillomavirus (HPV) is involved at an early stage of oncogenesis in many tumors, additional driving events have been postulated to facilitate the progression of SCNECs. Identification of oncogenic drivers could guide targeted therapy of this neoplasm. Clinicopathologic features of 10 cervical SCNECs are reported. Analyses included immunohistochemical evaluation of p16, p53, synaptophysin, and chromogranin expression; in situ hybridizations and polymerase chain reaction for high-risk HPV and/or HPV 18; and next-generation sequencing based on a 637-gene panel. The patients ranged in age from 28 to 68 years (mean, 45.6 y; median, 40.5 y). All tumors had diffuse p16 and synaptophysin expression. All but 1 tumor was positive for chromogranin (extent of staining ranged from focal to diffuse). HPV 18 was detected in 6 tumors and HPV 35 in 1 tumor. At least 1 driver mutation was detected in 8 tumors. Four cases harbored TP53 somatic mutations, 3 of which correlated with an aberrant p53 staining pattern. Four PIK3CA mutations (p.G106A, p.N345T, p.E545K, and p.E545D) were detected in 3 tumors, 2 of which also harbored TP53 mutations. Oncogenic driver mutations involving KRAS, Erbb2, c-Myc, NOTCH1, BCL6, or NCOA3 were detected in 4 tumors. Mutations in caretaker tumor suppressors PTEN, RB1, BRCA1, BRCA2, and ARID1B were also identified in 4 tumors that commonly coharbored activating oncogenic mutations. Targeted next-generation gene sequencing identified genetic alterations involving the MAPK, PI3K/AKT/mTOR, and TP53/BRCA pathways in SCNECs. The presence of genetic alterations that are amenable to targeted therapy in SCNECs offers the potential for individualized management strategies for treatment of this aggressive tumor.

The first synthesis of hebelophyllene E is presented, along with assignment of its previously unknown relative configuration through synthesis of epi-ent-hebelophyllene E. Development of a catalytic enantioselective [2+2] cycloaddition of alkenes and allenoates provides access to the required chiral geminal dimethylcyclobutanes. Key to its success is the identification of a novel oxazaborolidine catalyst which promotes the cycloaddition in high enantioselectivities with good functional-group tolerance (9 examples, up to 97:3 e.r.). Thus, a late-stage cycloaddition using a fully functionalized alkene, followed by a diastereoselective reduction allows a concise entry to this class of natural products.

Cyclobutane und Cyclobutene sind wichtige Strukturmotive, die in zahlreichen biologisch bedeutenden Verbindungen vorkommen, und nutzliche Zwischenstufen in der chemischen Synthese. Entsprechend haben sich [2+2]-Cycloadditionen zur Synthese von Cyclobutanen und Cyclobutenen als besonders nutzliche Umwandlungen erwiesen. In den letzten 10 Jahren ist die Zahl der Publikationen zu katalytischen enantioselektiven [2+2]-Cycloadditionen gestiegen. Diese Reaktionen machen eine Vielzahl zuvor nicht erhaltlicher enantiomerenangereicherter chemischer Verbindungen zuganglich. In diesem Kurzaufsatz wird uber die Fortschritte bei katalytischen enantioselektiven [2+2]-Cycloadditionen fur die Synthese von Cyclobutanen und Cyclobutenen berichtet.

Cyclobutanes and cyclobutenes are important structural motifs found in numerous biologically significant molecules, and they are useful intermediates for chemical synthesis. Consequently, [2+2] cycloadditions to access cyclobutanes and cyclobutenes have been established to be particularly useful transformations. Within the last 10 years, an increase in the frequency of publications for catalytic enantioselective [2+2] cycloadditions has occurred. These reactions provide access to a wide array of enantiomerically enriched chemical diversity that was not previously attainable. Described in this review are the advances made in catalytic enantioselective [2+2] cycloadditions to access cyclobutanes and cyclobutenes.

Catalytic enantioselective [2 + 2] cycloadditions between allenoates and alkenes is disclosed. The method functions well for a variety of alkenes, and the products are generated with excellent levels of enantioselectivity. One of the most significant aspects of the present method is that unactivated alkenes are suitable substrates for this method, which is distinctly different from nearly all other catalytic enantioselective [2 + 2] cycloaddition methods.

To investigate whether tumor cells could be detected in the vagina of women with serous ovarian cancer through TP53 analysis of DNA samples collected by placement of a vaginal tampon.Women undergoing surgery for a pelvic mass were identified in the gynecologic oncology clinic. They placed a vaginal tampon before surgery, which was removed in the operating room. Cells were isolated and DNA was extracted from both the cells trapped within the tampon and the primary tumor. In patients with serous carcinoma, the DNA was interrogated for the presence of TP53 mutations using a method capable of detecting rare mutant alleles in a mixture of mutant and wild-type DNA.Thirty-three patients were enrolled. Eight patients with advanced serous ovarian cancer were included for analysis. Three had a prior tubal ligation. TP53 mutations were identified in all eight tumor samples. Analysis of the DNA from the tampons revealed mutations in three of the five patients with intact tubes (sensitivity 60%) and in none of the three patients with tubal ligation. In all three participants with mutation detected in the tampon specimen, the tumor and the vaginal DNA harbored the exact same TP53 mutation. The fraction of DNA derived from exfoliated tumor cells ranged from 0.01% to 0.07%.In this pilot study, DNA derived from tumor was detected in the vaginas of 60% of patients with ovarian cancer with intact fallopian tubes. With further development, this approach may hold promise for the early detection of this deadly disease.

// Zachary C. Dobbin 1,2 , Ashwini A. Katre 1 , Adam D. Steg 1 , Britt K. Erickson 1 , Monjri M. Shah 1 , Ronald D. Alvarez 1 , Michael G. Conner 3 , David Schneider 4 , Dongquan Chen 5 and Charles N. Landen 6 1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alabama at Birmingham 2 NIH Medical Scientist Training Program, University of Alabama at Birmingham 3 Department of Pathology, University of Alabama at Birmingham 4 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham 5 Division of Preventative Medicine, Department of Medicine, University of Alabama at Birmingham 6 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Virginia, Charlottesville, VA Correspondence: Charles N. Landen Jr, email: // Keywords : Ovarian Cancer, Patient-derived xenograft, cancer stem cells, chemoresistance, animal models of cancer Received : August 08, 2014 Accepted : August 18, 2014 Published : August 19, 2014 Abstract A cornerstone of preclinical cancer research has been the use of clonal cell lines. However, this resource has underperformed in its ability to effectively identify novel therapeutics and evaluate the heterogeneity in a patient’s tumor. The patient-derived xenograft (PDX) model retains the heterogeneity of patient tumors, allowing a means to not only examine efficacy of a therapy, but also basic tenets of cancer biology in response to treatment. Herein we describe the development and characterization of an ovarian-PDX model in order to study the development of chemoresistance. We demonstrate that PDX tumors are not simply composed of tumor-initiating cells, but recapitulate the original tumor’s heterogeneity, oncogene expression profiles, and clinical response to chemotherapy. Combined carboplatin/paclitaxel treatment of PDX tumors enriches the cancer stem cell populations, but persistent tumors are not entirely composed of these populations. RNA-Seq analysis of six pair of treated PDX tumors compared to untreated tumors demonstrates a consistently contrasting genetic profile after therapy, suggesting similar, but few, pathways are mediating chemoresistance. Pathways and genes identified by this methodology represent novel approaches to targeting the chemoresistant population in ovarian cancer

OBJECTIVE. Carcinosarcomas are rare and aggressive ovarian malignancies. Treatment recommendations, which include surgical cytoreduction followed by platinum based chemotherapy, have been based on small amounts of retrospective data or extrapolated from experience with high-grade epithelial ovarian adenocarcinoma. Our objective was to determine the effects of radical primary cytoreduction on progression-free survival (PFS) and overall survival (OS). METHODS. Following IRB approval, records of women with ovarian carcinosarcomas diagnosed between 2000 and 2012 at our institution were reviewed. Demographics, tumor characteristics, treatments, PFS, and OS were collected. Patients were divided into three groups based on the amount of residual disease: N1 cm of disease, ≤1 cm of disease, or no visible disease. Chi-square and student’s t-test were used to compare variables among groups. Kaplan–Meier survival curves were generated and compared with the log-rank test. RESULTS. 51 patients with ovarian carcinosarcoma were identified and all underwent primary cytoreductive surgery. Following surgical cytoreduction, 18 patients (35%) had no visible disease, 20 (39%) had ≤1 cm of disease, and 13 (25%) had >1 cm of residual disease. Median PFS varied significantly among groups: 29 vs. 21 vs. 2 months (p = 0.036) as did median OS: 57 vs. 32 vs. 11 months (p = 0.015). When patients with stage 3 disease were analyzed separately, median OS still varied significantly among groups: 57 versus 31 versus 3 months (p = 0.009). CONCLUSION. Degree of surgical cytoreduction appears to correlate with PFS and OS. Radical surgery resulting in no visible disease is recommended for the upfront surgical treatment of ovarian carcinosarcoma.

We report a case of extramedullary hematopoiesis (EMH) in uterine leiomyoma and associated numerous intravascular thrombi. A 29-year-old nulliparous female presented with heavy vaginal bleeding and a hematocrit of 22%. No bone marrow biopsy has been performed. She had a history of uterine leiomyomata and menorrhagia for a year. A transvaginal ultrasound confirmed the presence of a uterine leiomyoma. The patient was treated conservatively with oral contraceptive pills due to desire for fertility. However, she continued to have heavy vaginal bleeding and developed bilateral upper extremity deep vein thrombosis and multiple superficial vein thromboses after two months. An exploratory laparotomy with uterine myomectomy was performed. Gross examination of the specimen revealed a single nodular mass measuring10.0×9.5×7.5 cm with a white-tan swirling cut surface. Microscopic examination revealed benign smooth muscle consistent with leiomyoma and numerous intravascular thrombi both with areas of EMH. Immunohistochemical stains confirmed the presence of all three benign lineages of hematopoietic cells. Occurrence of EMH in uterine leiomyoma and intravascular thrombi is very rare. It may be related to systemic hematopoietic stimulation due to severe chronic anemia and local presence of hematopoietic growth factors and/or cytokines.

Advanced cases of epithelial ovarian, primary peritoneal, and primary tubal malignancies have a relatively poor prognosis and collectively remain the most deadly of all gynecologic malignancies. Although traditionally thought of as one disease process, ongoing research suggests that there is not 1 single site or cell type from which these cancers arise. A majority of the serous tumors appear to originate from dysplastic lesions in the distal fallopian tube. Therefore, what we have traditionally considered “ovarian” cancer may in fact be tubal in origin. In this article, we will review epithelial ovarian cancer classification and genetics, theories regarding cells of origin with a focus on tubal intraepithelial carcinoma, and implications for prevention and screening.

The purpose of the present study is to present new hydraulic benchmark data obtained for PWR rod bundles for the purpose of benchmarking computational fluid dynamics (CFD) models of the rod bundle. The flow field in a PWR fuel assembly downstream of structural grids which have mixing vane grids attached is very complex due to the geometry of the subchannel and the high axial component of the velocity field relative to the secondary flows which are used to enhance the heat transfer performance of the rod bundle. Westinghouse has a CFD methodology to model PWR rod bundles that was developed with prior benchmark test data. As improvements in testing techniques have become available, further PWR rod bundle testing is being performed to obtain advanced data which have high spatial and temporal resolution. This paper presents the advanced testing and benchmark data that has been obtained by Westinghouse through collaboration with Texas A&M University.

• HVO focuses on the education, surgical training and development of research skills of surgical oncology residents.

In numerical simulations of fuel rod bundle flow fields, the unsteady Navier–Stokes equations have to be solved in order to determine the time (phase) dependent characteristics of the flow. In order to validate the simulations results, detailed comparison with experimental data must be done. Experiments investigating complex flows in rod bundles with spacer grids that have mixing devices (such as flow mixing vanes) have mostly been performed using single-point measurements. In order to obtain more details and insight on the discrepancies between experimental and numerical data as well as to obtain a global understanding of the causes of these discrepancies, comparisons of the distributions of complete phase-averaged velocity and turbulence fields for various locations near spacer-grids should be performed. The experimental technique Particle Image Velocimetry (PIV) is capable of providing such benchmark data. This paper describes an experimental database obtained using two-dimensional Time Resolved Particle Image Velocimetry (TR-PIV) measurements within a 5 × 5 PWR rod bundle with spacer-grids that have flow mixing vanes. One of the unique characteristic of this set-up is the use of the Matched Index of Refraction technique employed in this investigation to allow complete optical access to the rod bundle. This unique feature allows flow visualization and measurement within the bundle without rod obstruction. This approach also allows the use of high temporal and spatial non-intrusive dynamic measurement techniques namely TR-PIV to investigate the flow evolution below and immediately above the spacer. The experimental data presented in this paper includes explanation of the various cases tested such as test rig dimensions, measurement zones, the test equipment and the boundary conditions in order to provide appropriate data for comparison with Computational Fluid Dynamics (CFD) simulations. Turbulence parameters of the obtained data are presented in order to gain insight of the physical phenomena.

One aspect of the AP1000 ® 1 reactor design is the reduction in the number of major components and simplification in manufacturing. One design change relative to current Westinghouse reactors of similar size is the reduction in the number of reactor vessel outlet nozzles/hot legs leaving the upper plenum from three to two. With regard to fuel performance, this design difference creates a different flow field in the AP1000 reactor vessel upper plenum (the region above the core). The flow exiting core and entering the upper plenum must turn 90°, flow laterally through the upper plenum around support structures, and exit through one of the two outlet nozzles. While the flow in the top of the core is mostly axial, there is some lateral flow component as the core flow reacts to the flow field and pressure distribution in the upper plenum. The pressure distribution in the upper plenum varies laterally depending upon various factors including the proximity to the outlet nozzles. To determine how the lateral flow in the top of the AP1000 core compares to current Westinghouse reactors, a computational fluid dynamics (CFD) model of the flow in the upper portion of the AP1000 reactor vessel including the top region of the core, the upper plenum, the reactor vessel outlet nozzles, and a portion of the hot legs was created. Due to geometric symmetry, the computational domain was reduced to a quarter (from the top view) that includes ¼ of the top of the core, ¼ of the upper plenum, and ½ of an outlet nozzle. Results from this model include predicted velocity fields and pressure distributions throughout the model domain. The flow patterns inside and around guide tubes clearly demonstrate the influence of lateral flow due to the presence of the outlet nozzles. From these results, comparisons of AP1000 flow versus current Westinghouse plants were performed. Field performance information from current Westinghouse plants will be shown to demonstrate an experience base of acceptable core lateral flows. From this experience base and the AP1000 CFD results, acceptability of the AP1000 upper plenum design on the fuel performance of the AP1000 fuel design will be demonstrated.

An unexpected [4+2] cycloaddition of aryl allenes and simple acrylate derivatives is reported. This process functions well with a variety of allenes and acrylates to generate bi- and tricyclic dihydronaphthalene derivatives through a nonconventional bond disconnection.

To determine fuel assembly mechanical damping under PWR conditions during a postulated seismic event or LOCA, fuel assembly flowing water damping tests were needed. Since flowing water damping values are high, pluck tests were used in which the fuel assembly was deflected, pluck mechanism retracted, and fuel assembly vibration decay observed and measured. To allow for the pluck vibration to occur, an oversized flow housing was utilized, which allowed additional flow to bypass the fuel assembly in the gaps between the assembly and the flow housing walls that would otherwise flow through the bundle rodded region. Since a direct measurement of the average bundle flow velocity could not be made, a method was developed for determining the flowrate through the bundle using fuel assembly lift force measurements. This paper will present the method for determining the actual flowrate that was used in recent testing. The use of custom load cells that were designed for this testing to measure the fuel assembly lift force will be described in this paper. Additionally, the paper will show how the correlation between total test flow and bundle flow was developed from a series of flow calibration tests at different hydraulic conditions. This correlation was then used to prescribe the loop flow setpoints necessary to achieve targeted bundle flow velocities during the pluck test series.

An unexpected [4+2] cycloaddition of aryl allenes and simple acrylate derivatives is reported. This process functions well with a variety of allenes and acrylates to generate bi- and tricyclic dihydronaphthalene derivatives through a nonconventional bond disconnection.

Malignant transformation in a mature cystic teratoma (MCT) is rare, with a reported incidence of approximately 1% to 3%. To our knowledge, no case has been reported previously with the invasion of malignant tumor of MCT into the adjacent small intestine. We report a case of squamous cell carcinoma arising within a MCT and invading into the adjacent small bowel. The patient is a 73-yr-old African American woman who noted the presence of a relatively asymptomatic abdominal mass over the past 40 yr. The mass had become more symptomatic over the past several months, with right-sided abdominal pain and constipation. She underwent an exploratory laparatomy, which demonstrated a cystic abdominal mass measuring 24 cm in diameter and weighing 8 kg. The mass contained necrotic debris, a cloudy fluid, hair, and cartilage. It was adherent to the small intestine in an area associated with focal thickening of the cystic wall of the mass. Histologically, the mass demonstrated a MCT within which arose a well-differentiated squamous cell carcinoma. At the point of attachment to the small intestine, histologic sections demonstrated a transmural invasion of the squamous cell carcinoma into the attached segment of the small intestine through the muscularis propria and the submucosa reaching the mucosal surface. Thirteen regional lymph nodes were isolated near the portion of the small intestine involved with the tumor; however, none of them exhibited metastatic carcinoma.

Cyclobutanes and cyclobutenes are important structural motifs found in numerous biologically significant molecules, and they are useful intermediates for chemical synthesis. Consequently, [2+2] cycloadditions to access cyclobutanes and cyclobutenes have been established to be particularly useful transformations. Within the last 10 years, an increase in the frequency of publications for catalytic enantioselective [2+2] cycloadditions has occurred. These reactions provide access to a wide array of enantiomerically enriched chemical diversity that was not previously attainable. Described in this review are the advances made in catalytic enantioselective [2+2] cycloadditions to access cyclobutanes and cyclobutenes.

One aspect of the Westinghouse AP1000™ 1 reactor design is the reduction in the number of major components and simplification in manufacturing. One design change relative to current Westinghouse reactors of similar size is that AP1000 reactor vessel has two nozzles/hot legs instead of three. With regard to fuel performance, this design difference creates a different flow field in the reactor vessel upper plenum. The flow exiting from the core and entering the upper plenum must turn toward one of the two outlet nozzles and flow laterally around numerous control rod guide tubes and support columns. Also, below the upper plenum are the upper core plate and the top core region of the 157 fuel assemblies and 69 guidetube assemblies. To determine how the lateral flow in the top of the core and upper plenum compares to the current reactors a CFD model of the flow in the upper portion of the AP1000 reactor vessel was created. Before detailed CFD simulations of the flow in the entire upper plenum and top core regions were performed, conducting local simulations for smaller sections of the domain provided crucial and detailed physical aspects of the flow. These sub-domain models were used to perform mesh sensitivities and to assess what geometrical details may be eliminated from the larger model in order to reduce mesh size and computational requirements. In this paper, CFD analysis is presented for two subdomain models: the top core region and control rod guide tube region. These models are chosen for simulation because guide tube and top core region (including top grid, top nozzle, and hold-down device) are the major components of upper plenum effecting the flow patterns and pressure distribution. The top core region, corresponding to ¼ of fuel assembly, includes components as upper part of the fuel assemblies (top grid, fuel rods, top nozzle), core component hold-down devices, and upper core plates. These components distribute the core flow to different sections of guidetube regions. Mesh sensitivity studies have been conducted for each individual part in order to determine the proper geometrical simplifications. Pressure drop measurement data are compared with the predicted CFD results and act as a guideline for the mesh selection. The guidetube region includes control rod guidetubes themselves, adjacent support columns and open regions. In this study, two models of subdomains are analyzed: (1) a ¼ section of one control rod guide tube by itself and (2) a representative unit cell containing two ¼ sections of adjacent control rod guide tubes and one ¼ section of a neighboring support column. Predicted flow rates at each of the outflow locations in conjunction with results from the mesh sensitivity studies provide guidance on (1) what geometry to preserve or remove, (2) what geometry can be simplified to reduce the required mesh, and (3) an estimate of the total mesh required to model the entire upper plenum and top fuel domain. The commercial CFD code STAR-CCM+ is employed to generate the computational mesh, to solve the Reynolds-averaged Navier–Stokes equations for incompressible flow with a Realizable k–ɛ turbulence model, and to post-process the results.

This paper presents the CFD modeling methodology and validation for steady-state, normal operation in a PWR fuel assembly. This work is part of a program that is developing a CFD methodology for modeling and predicting single-phase and two-phase flow conditions downstream of structural grids that have mixing devices. The purpose of the mixing devices (mixing vanes in this case) is to increase turbulence and improve heat transfer characteristics of the fuel assembly. The detailed CFD modeling methodology for single-phase flow conditions in PWR fuel assemblies was developed using the STAR-CD CFD code. This methodology includes the details of the computational mesh, the turbulence model used, and the boundary conditions applied to the model. The methodology was developed by benchmarking CFD results versus small-scale experiments. The experiments use PIV to measure the lateral flow field downstream of the grid, and thermal testing to determine the heat transfer characteristics of the rods downstream of the grid. The CFD results and experimental data presented in the paper provide validation of the single-phase flow modeling methodology. Two-phase flow CFD models are being developed to investigate two-phase conditions in PWR fuel assemblies, and these can be presented at a future CFD Workshop.

This study aimed at evaluating the expression of tyrosine kinase receptors c-kit, (platelet-derived growth factor receptor-alpha (PDGFR-alpha), and PDGFR-beta in ovarian granulosa cell tumors (GCTs).Primary ovarian GCT specimens were obtained for immunohistochemical staining.The expressions of c-kit, PDGFR-alpha, and PDGFR-beta were analyzed and scored by a semiquantitative (SQ) method. Normal ovarian tissue from the same patients' specimens served as internal controls.A total of 21 specimens were available for evaluation. C-kit was expressed in only 2 samples, whereas both PDGFR-alpha and PDGFR-beta stained positive in 100% of tumors. PDGFR targets demonstrated strong positive expression in intensity and amount of tissue stained. Normal ovarian tissue demonstrated complete absence of staining for all 3 antibodies evaluated.The data demonstrated significant expression of PDGFR targets of imatinib mesylate in GCTs, whereas normal ovarian tissues had a complete absence of staining.This expression profile provides the rationale to investigate the role of imatinib mesylate in PDGFR-positive GCTs.

In this report, we present the case of a 32-year-old woman with Wegener's granulomatosis of the uterine cervix, review the literature, and discuss the differential diagnosis.

A new and highly enantioselective method for catalytic [2 + 2] cycloadditions between unactivated alkenes and allenoates is disclosed.

Describe the effect of 50 mcg vaginal 17-β-estradiol (E2) cream on vaginal maturation, serum estrogen levels, atrophic symptoms, and biomarkers of oxidative stress and tissue remodeling in postmenopausal women without prolapse.Seventeen women, 65 years or older, applied intravaginal E2 cream nightly for eight weeks, then twice weekly for eight weeks. Vaginal biopsies, serial blood draws, and atrophic symptoms were obtained at baseline, eight, and sixteen weeks. Changes in atrophic symptoms, vaginal maturation indices (VMI), and serum E2 were measured. Immunohistochemical staining characterized levels of transforming growth factor-beta (TGF-β), nuclear factor kappa B (NFKB), inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and thrombospondin (TSP).Serum E2 levels (pg/ml) were unchanged from baseline (mean (SD)) 7.7 (3.3) to eight 9.7 (5.7) and sixteen 8.7 (5.8) (p=0.24) weeks. VMI (mean (SD)) improved from baseline 34.2 (18.3) to eight 56.7 (13.1) and sixteen 54.5 (11.3) (p0.001) weeks with no difference between eight and sixteen weeks. Vaginal dryness (p=0.03) and itching (p=0.02) improved. Tissue biomarker levels did not change (TGF-β p=0.35, NFKB p=0.74, eNOS p=0.80, iNOS p=0.24, TSP p=0.80).Vaginal E2 improved atrophic symptoms and VMI without elevating serum E2. Tissue remodeling biomarkers did not change.

The Ebola virus disease (EVD) is a serious illness characterized by fever, severe vomiting and diarrhea, and, in severe cases, multi-organ failure requiring mechanical ventilation and renal replacement therapy. The current outbreak has centered in West Africa and affected over 15,000 individuals. EVD is transmitted by direct contact with blood or other infectious bodily fluid, and as such, numerous heath care workers caring for patients with EVD have become infected. During the current outbreak, a number of patients have received advanced supportive care for EVD in Europe and North America and therefore survived. Now, many hospitals in Europe and North America are planning to accept care for patients with EVD. In this review, we discussed the key issues related to the planning and delivery of advanced supportive care in patients with EVD with a focus on the factors necessary to provide renal replacement therapy (RRT). Since success in the treatment of patients with EVD rests on both patient outcome and prevention of transmission of disease to health care workers, we extensively discussed the modes of Ebola virus transmission and recommended protocols to protect health care workers. Experience now indicates that with appropriate planning and protocols, it is possible to successfully treat EVD patients with advanced supportive care (mechanical ventilation and RRT) while avoiding transmission to health care providers. Video Journal Club “Cappuccino with Claudio Ronco” at http://www.karger.com/?doi=371530.

To prospectively evaluate in a blinded fashion the accuracy of frozen section in endometrial cancer.Sixty patients with endometrial cancer or complex atypical hyperplasia were consecutively enrolled. Intraoperatively, a frozen section was obtained, processed, and stored for interpretation by blinded pathologists. Final pathologic diagnosis was conducted in the usual fashion with the pathologists blinded to frozen results. Histologic grade and myometrial invasion on frozen section was correlated with final pathology.Median age was 61 years (range, 39-82 years). Fifty-seven percent of patients were white, and mean body mass index was 40 mg/kg2. Depth of invasion on frozen correlated with final pathology in 67% (95% confidence interval [CI] 55-79%). Twenty-eight percent (95% CI 17-39%) of patients were upstaged from frozen to final. Patients with no invasion on frozen were upstaged in 46% (95% CI 28-64%). Histologic grade on frozen correlated with final pathology in 58% (95% CI 46-70%); 38% (95% CI 26-50%) of patients were upgraded by final grade. Patients with frozen grade 1 histology or less were upgraded in 61% (95% CI 45-77%). Clinically relevant upstaging occurred in 11 patients (18%) (95% CI 8-28%).Frozen section for histologic grade and depth of myometrial invasion in endometrial cancer correlates poorly with final pathology. Because a large number of patients are potentially understaged with the use of frozen section with a subsequent risk of over and under treatment, we recommend consideration of comprehensive surgical staging for all patients with endometrial cancer.II-2.