Search

Cardiac sarcoidosis is associated with a high mortality rate. Given multiple barriers to obtaining cardiac PET imaging, we suspect individuals with access to this imaging modality are not representative of the Sarcoid patient population, which in the United States are predominantly Black females.To evaluate the demographics of patients with cardiac PET access and the cost-effectiveness of cardiac PET/MR imaging relative to standard of care.This is a retrospective, observational study. The demographic information of patients with suspected cardiac sarcoidosis and cardiac PET/CT imaging within a national registry of sarcoidosis were reviewed (n = 4561). An individual-level, continuous, time-state transition model was used for the evaluation of long-term cost-effectiveness for the combined cardiac PET/MR compared to standard of care cardiac MR followed by cardiac PET/CT.Patients who underwent cardiac PET in the national registry had 88.35% higher odds of being male (p 0.001) and 43.82% higher odds of being White (p = 0.003) than their counterparts who did not have cardiac PET imaging. Combined cardiac PET/MR had overall lower total lifetime costs ($8761 vs $10,777) and overall improved expected quality of life-years compared to the standard of care (0.77 vs 0.69).The findings suggest that patients with access to cardiac PET/CT are not representative of the patient population most likely to have cardiac sarcoidosis in this limited study evaluation. Universal insurance coverage should be considered for Cardiac PET imaging as same day cardiac PET and MR imaging has potential long-term cost and quality of life benefit.

Objectives: To measure the diagnostic accuracy of intraoperative frozen section examination of sentinel lymph nodes (SLN) in vulvar cancer and to describe associated patient outcomes. Methods: This retrospective cohort study included patients with invasive squamous cell carcinoma of the vulva who underwent SLN biopsy with intraoperative frozen section at one cancer centre from Jan 2008 - Feb 2020. Exclusion criteria were tumor size >4cm, multifocal tumor, palpable groin lymph nodes and neoadjuvant therapy. The SLN procedure was performed by injection of the primary vulvar tumor or scar with technetium-99m, ICG and/or blue dye. We compared the intraoperative SLN frozen section diagnosis and the paraffin section report for concordance. Recurrence location was described and recurrence free survival (RFS) was compared using the Kaplan-Meier method. Results: A total of 173 patients (258 groins) met inclusion and exclusion criteria. On frozen section, there were 36/258 positive groins on frozen section and 222 negative groins. On final pathology, there were 39/258 positive groin nodes: 30 macro-metastases, 7 micro-metastases, 2 isolated tumor cells (ITCs). There were 219 negative groins. The sensitivity and specificity for frozen section detecting any metastatic disease compared to final pathology, was 89.7% and 99.5%, respectively. The positive-predictive value (PPV) was 97.2% and the negative-predictive-value (NPV) was 98.2%. There were 4 cases of false negative frozen section where final pathology revealed two cases of ITCs, 1 micro-metastasis and 1 macro-metastasis. A total of 30 patients (17.3%) underwent a full inguinal femoral lymphadenectomy during the same operation due to the frozen section results and avoided a second operation. A total of 2 patients (1.2%) required a second operation for lymphadenectomy due to false negative results on frozen section. Median (range) follow up was 38.0 (1-137.8) months. Median RFS was 14.9 (3.6 to 98.2) months. There were 46 recurrences in the study population, of which 29 were confined to the vulva, 9 groin recurrences and 8 distant recurrences. Among patients with a negative SLN biopsy on both frozen section and final pathology, there were 10 (3.9 %) groin and/or distant recurrences. A total of 6 nodal recurrences were ipsilateral, 1 was contralateral, 2 were bilateral and 1 recurrence was distant. After exclusion of patients with local recurrence only, the RFS at 3 years was 91.6% (95% CI 86.2-97.4%) for patients with negative SLN on frozen section and 64.6% (95% CI 46.5-89.7%) for positive SLN on frozen section. On final pathology, patients with negative SLN had a 3-year RFS of 91.7% (95% CI 86.3-97.4%), macro-metastases 58.4% (95% CI 38.5-87.7%), and micro-metastases/ITCs was 100%. Conclusions: Intraoperative frozen section of SLNs in vulvar cancer is an accurate intraoperative guide to determine if complete inguinal femoral lymphadenectomy should be performed. SLN biopsy reduced the need for a second surgical procedure and does not appear to compromise patient outcomes.

18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) underperforms in detecting prostate cancer (PCa) due to inherent characteristics of primary and metastatic tumors, including relatively low rate of glucose utilization. Consequently, alternate PCa PET imaging agents targeting other aspects of PCa cell biology have been developed for clinical practice. The most common dedicated PET imaging tracers include 68Ga/18F prostate-specific membrane antigen (PSMA), 11C-Choline, and 18F-fluciclovine (Axumin™). This review will describe how these agents target specific inherent characteristics of PCa and explore the current literature for these agents for both primary and recurrent PCa, comparing the advantages and limitations of each tracer. Both 11C-Choline and 18F-Fluciclovine PET have been shown to detect nodal and osseous disease at higher rates compared to FDG-PET but offer no additional benefit in detecting prostate disease, especially in primary staging. As a result, PSMA PET, specifically 68Ga-PSMA-11, has emerged as a key imaging option for both primary and recurrent cancer. PSMA PET may be more sensitive than MRI at the local level and more sensitive than 11C-Choline and 18F-Fluciclovine PET for distant disease. Furthermore, compared to 11C-Choline and 18F-Fluciclovine PET, 68Ga-PSMA-11 PET has higher detection rates at low PSA levels (

Copy number variation (CNV) at 7q11.23 causes distinct disorders with both contrasting and overlapping phenotypic features of some but not all of the genes encompassed by the CNV. The spectrum of cognitive disabilities, psychopathology and altered behaviours associated with 7q11.23 CNV provides a tantalizing window of opportunity to better understand the molecular bases for complex human cognitive function and social behaviour. Study of individuals with atypical CNVs has narrowed the field of candidate genes, and the generation of mouse models has allowed further insight into their functions. Recent research has used high-throughput genomics techniques to interrogate the transcriptome and methylome, and initial strategies to correct gene transcription levels, pathophysiology and cognitive and behavioural phenotypes show promise.

Meningiomas are the most common non-malignant primary intracranial tumors, accounting for nearly 40% of all primary brain tumors, usually expressing high levels of somatostatin receptors (SSTR), particularly SSTR2. Because 68Ga-DOTATATE targets SSTR2, it is increasingly used clinically for meningioma evaluation. While previous apparent lack of SSTR expression in meningiomas has been reported in isolated cases, these prior studies utilized Indium-111 (111In) Octreotide, which is of lesser diagnostic accuracy compared to 68Ga-DOTATATE, as well as Technetium-99m (99mTc)-DTPA scintigraphy, which necessitates an intact blood-tumor-permeability barrier. This paper presents a histopathologic proven atypical meningioma, WHO Grade II, with low level avidity on 68Ga-DOTATATE PET/MRI, subsequently proven to be SSTR2-negative by immunohistochemistry, with a review and discussion of the current literature and imaging implications.

The clinical utility of gallium 68 (68Ga)-PSMA PET for the diagnosis and management of prostate cancer is driven in part by radioisotope availability and production costs. This study evaluates the equivalence between the two manufacturing processes for 68Ga-PSMA: 68Ga-PSMA-cyclotron (from a solid target) and 68Ga-PSMA-generator. A prospective, single-arm, single-institution non-randomized study was conducted where 16 patients with prostate adenocarcinoma underwent PET/CTs consecutively within 12 to 48 hours with each type of manufactured 68Ga-PSMA between December 2020 and June 2021. The intraclass correlation coefficients suggested acceptable reliability in all lesion parameters (ICC > 0.70). Bland-Altman analysis demonstrated acceptable bias levels for all lesion parameters. Thereby 68Ga-cyclotron (solid target) and 68Ga-generator production methods tagged to the same PSMA ligand resulted in scans which were deemed to be equivalent in detecting PSMA+ lesions in our study. As cyclotron-produced, solid- target 68Ga can be made in large (Ci) quantities, it is a promising tool for future application in 68Ga-PSMA PET scans with the potential to decrease radiotracer production costs and increase isotope availability. ispartof: TRANSLATIONAL ONCOLOGY vol:28 ispartof: location:United States status: published

The first definitely interstellar object 1I/‘Oumuamua (previously A/2017 U1) observed in our solar system provides the opportunity to directly study material from an other star system. Can such objects be intercepted? The challenge of reaching the object within a reasonable timeframe is formidable due to its high heliocentric hyperbolic excess velocity of about 26 km/s; much faster than any vehicle yet launched. This paper presents a high-level analysis of potential near-term options for a mission to 1I/‘Oumuamua and potential similar objects. Reaching 1I/‘Oumuamua via a spacecraft launched in a reasonable timeframe of 5-10 years (launch in 2022-2027) requires an Earth departure hyperbolic excess velocity between 33 and 76 km/s for mission durations between 30 and 5 years, respectively. Different mission durations and their velocity requirements are explored with respect to the launch date, assuming direct impulsive transfer to the intercept trajectory. In addition, missions using a powered Jupiter gravity assist combined with a solar Oberth manoeuvre are explored, using solid rocket engines and Parker Solar Probe heat shield technology. For such a mission, a Falcon Heavy-class launcher would be able to launch a spacecraft of dozens of kilograms towards 1I/‘Oumuamua, if launched in 2021. An additional Saturn gravity assist would allow for the launch of a New Horizons-class spacecraft. Further technology options are outlined, ranging from electric propulsion, and more advanced options such as laser electric propulsion, solar and laser sails. To maximize science return, decelerating the spacecraft at ’Oumuamua is highly desirable, compared to the minimal science return from a flyby. Electric and magnetic sails could be used for this purpose. It is concluded that although reaching the object is challenging, there seem to be feasible options based on current and near-term technology.

Personality and individual differences have rarely played a role in human reasoning research, and the sparse previous work has focused on Big 5 personality factors and reasoning in a very general sense. The present research expands this by using the HEXACO model of personality as well as more specific traits (interpersonal trust and reciprocation ideology), and examines conditional reasoning across three theoretically significant domains (social contract, precaution, and descriptive contents). Across two studies, greater trust (higher interpersonal trust and less reciprocation wariness) was associated with better reasoning about conditional rules in general. Concurrently, greater conscientiousness and honesty-humility were differentially predictive of reasoning about social contracts and precautions, but not descriptive contents. Openness was associated with reasoning performance in Study 1 but not in Study 2, and other traits of interest in prior studies (extraversion, emotionality) consistently did not emerge as important predictors. Further research should examine in more detail the effects of individual differences and personality on reasoning, and if certain traits may predict domain specific reasoning abilities. Such findings can provide both a new and informative method for assessing theories of human reasoning, as well as integrate the fields of human reasoning and personality.

Multiperiodic Fourier series solutions of integrable nonlinear wave equations are applied to the study of ocean waves for scientific and engineering purposes. These series can be used to compute analytical formulae for the stochastic properties of nonlinear equations, in analogy to the standard approach for linear equations. Here I emphasize analytically computable results for the correlation functions, power spectra and coherence functions of a nonlinear random process associated with an integrable nonlinear wave equation. The multiperiodic Fourier series have the advantage that the coherent structures of soliton physics are encoded in the formulation, so that solitons, breathers, vortices, etc. are contained in the temporal evolution of the nonlinear power spectrum and phases. I illustrate the method for the Korteweg-deVries and nonlinear SchrOdinger equations. Applications of the method to the analysis of data are discussed.

In type-2 diabetes (T2D), severely reduced islet syntaxin-1A (Syn-1A) levels contribute to insulin secretory deficiency. We generated β-cell-specific Syn-1A-KO (Syn-1A-βKO) mice to mimic β-cell Syn-1A deficiency in T2D. Glucose tolerance tests showed that Syn-1A-βKO mice exhibited blood glucose elevation corresponding to reduced blood insulin levels. Perifusion of Syn-1A-βKO islets showed impaired first- and second-phase glucose-stimulated insulin secretion (GSIS) resulting from reduction in readily releasable pool and granule pool refilling. To unequivocally determine the β-cell exocytotic defects caused by Syn-1A deletion, EM and total internal reflection fluorescence microscopy showed that Syn-1A-KO β-cells had a severe reduction in the number of secretory granules (SGs) docked onto the plasma membrane (PM) at rest and reduced SG recruitment to the PM after glucose stimulation, the latter indicating defects in replenishment of releasable pools required to sustain second-phase GSIS. Whereas reduced predocked SG fusion accounted for reduced first-phase GSIS, selective reduction of exocytosis of short-dock (but not no-dock) newcomer SGs accounted for the reduced second-phase GSIS. These Syn-1A actions on newcomer SGs were partly mediated by Syn-1A interactions with newcomer SG VAMP8.

This work experimentally quantifies the relationship between metrics of the local reaction rate and flame thickness for turbulent premixed flames in the corrugated flamelet and thickened preheat zone/thin reaction zones regime using data from simultaneous 10 kHz tomographic particle image velocimetry (TPIV), hydroxyl planar laser induced fluorescence (OH PLIF), and formaldehyde (CH2O) PLIF. Two reaction rate metrics are presented, which are based on tracking fluid elements in a Lagrangian manner as they traverse from the flame leading edge to the reaction zone. This yields both a fluid residence time in the flame (τc) and a metric of the flame speed (S). τc in the thickened preheat zone regime was reduced by nearly 40% compared with the corrugated flamelet despite the flame being broader, indicating a substantial increase in the local reaction rate. The joint PDFs of S and local flame thickness showed a positive linear correlation between these quantities, which can be explained by turbulent diffusivity arguments. These data provide guidelines for reaction rate models, as well as a quantitative means of comparing local behavior between experiments and simulations.

Prostate cancer (PCa) is frequently diagnosed in men, and dysregulation of microRNAs is characteristic of many cancers. MicroRNA-1207-3p is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, the role of microRNA-1207-3p in PCa is unclear. We discovered that microRNA-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells. Increased expression of microRNA-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of FNDC1, a protein which contains a conserved protein domain of fibronectin (FN1). FNDC1, FN1, and the androgen receptor (AR) are significantly overexpressed in PCa cell lines and human PCa, and positively correlate with aggressive PCa. Prostate tumor FN1 expression in patients that experienced PCa-specific death is significantly higher than in patients that remained alive. Furthermore, FNDC1, FN1 and AR are concomitantly overexpressed in metastatic PCa. Consequently, these studies have revealed a novel microRNA-1207-3p/FNDC1/FN1/AR regulatory pathway in PCa.

MicroRNAs (miRNAs) have been found to be dysregulated in prostate cancer (PCa). In this study, we investigated if miR-1207-3p is capable of distinguishing between indolent and aggressive PCa and if it contributes to explaining the disproportionate aggressiveness of PCa in men of African ancestry (moAA). A total of 404 patients with primary adenocarcinoma of the prostate were recruited between 1988 and 2003 at the Moffitt Cancer Center, Tampa, FL, USA. Patient clinicopathological features and demographic characteristics such as race were identified. RNA samples from 404 postprostatectomy prostate tumor tissue samples were analyzed by real-time quantitative reverse transcription polymerase chain reaction for the mRNA expression of miR-1207-3p. miR-1207-3p expression in PCa that resulted in overall death or PCa-specific death is significantly higher than in PCa cases that did not. The same positive correlation holds true for other clinical characteristics such as biochemical recurrence, Gleason score, clinical stage, and prostate-specific antigen level. Furthermore, miR-1207-3p expression was significantly less in moAA in comparison to Caucasian men. We also evaluated whether miR-1207-3p is associated with clinical outcomes adjusted for age at diagnosis and tumor stage in the modeling. Using competing risk regression, the PCa patients with a high miR-1207-3p expression (≥6 vs 3) had a high risk to develop PCa recurrence (hazard rate = 2.5, P < .001) adjusting for age at diagnosis and tumor stage. In conclusion, miR-1207-3p is a promising novel prognostic biomarker for PCa. Furthermore, miR-1207-3p may also be important in explaining the disproportionate aggressiveness of PCa in moAA.

Purpose To compare the performance of 4 metrics of metabolic response on FDG-PET/CT against RECIST 1.0 for determining response and predicting overall survival (OS) following 90 Y resin microspheres radioembolization of colorectal liver metastases (CLM). Methods We conducted an IRB-waived retrospective review of our radioembolization database to identify patients with unresectable CLM treated between December 2009 and December 2013. We included patients who had both PET/CT and contrast enhanced CT (CECT) available at baseline and on the first follow-up post-radioembolization. On baseline CECT up to five target tumors were chosen per patient according to RECIST 1.0. Four metrics of FDG-avidity (SUVmax, SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG)) on PET/CT were measured for the same target tumors. Using RECIST 1.0, patients were classified as no progression (partial response or stable disease) and progression. For each PET metric, a cut-off point of ≥30% decrease was chosen to define response. OS was calculated from the time of radioembolization using Kaplan-Meier methodology. The log-rank test was used for univariate analysis to identify predictors of OS. Results The study enrolled 49 patients with 119 target tumors; a median of 2 (range: 1–5) tumors were selected per patient. Median OS was 12.7 months (95%CI: 7.2-16.7). Response by MTV (P=0.035) and TLG (P=0.044) reached statistical significance in predicting OS. Response by SUVmax (P=0.21), SUVpeak (P=0.20) or no progression by RECIST 1.0 (P=0.44) did not predict OS. Conclusion Metabolic response based on changes in MTV and TLG can predict OS post-radioembolization of CLM.

Background Docetaxel remains a standard of care for metatsatic castration resistant porstate cancer (mCRPC) and has radiosensitizing properties. The dose limiting toxicity (DLT) of radioimmunotherapy is myelosuppression; dose fractionation of 177Lu-J591 allows similar administered doses with less toxicity. This study (NCT00916123) was designed to determine the safety, DLT, and maximum tolerated dose of fractionated 177Lu-J591 administered concurrently with standard docetaxel. Methods Men with progressive mCRPC received docetaxel 75 mg/m2 every 3 weeks with escalating 2 fractionated doses of 177Lu-J591 (1.48 GBq/m2 up to max of 2.96 GBq/m2) with cycle 3. Cycle 4 of docetaxel was planned 6 weeks after cycle 3 to allow for recovery from 177Lu-J591-associated hematologic toxicity. DLT was defined as delay in docetaxel >3 weeks, prolonged myelosuppression or need for >2 platelet transfusions, febrile neutropenia, or grade ≥3 nonhematological toxicity following 177Lu-J591. PSA was assessed prior to each cycle and serial computed tomography (CT) and bone scan were performed. Results Fifteen men with progressive mCRPC received dose-escalated targeted radionuclide therapy in 4 cohorts up to the highest planned dose (2.96 GBq/m2). No DLT was seen at any dose level. Grade 4 neutropenia without fever occurred in 8 (53.5%) and thromboytopenia in 2 (13.3%), with 2 receiving prophylactic platelet transfusion. No grade ≥3 nonhematological toxicity was observed. 11 (73.3%) had >50% PSA decline, with 78.6% having favorable circulating tumor cell counts after 177Lu-J591. All patients had targeting of known sites of disease by planar 177Lu-J591 imaging. Conclusion The combination of 177Lu-J591 delivered as a single fractionated cycle with docetaxel/prednisone is feasible in patients with mCRPC. Without preselection for prostate-specific membrane antigen, accurate targeting of known sites of disease and a strong preliminary efficacy signal was observed.

Defining protein-protein interactions is fundamental to the understanding of gene function. Protein-fragment complementation assays have been used for the analysis of protein-protein interactions in various organisms. The split-dihydrofolate reductase (DHFR) protein-fragment complementation assay utilises two complementary fragments of the enzyme fused to a pair of potentially interacting proteins. If these proteins interact, the DHFR fragments associate, fold into their native structure, reconstitute their function and confer resistance to antifolate drugs. We show that murine DHFR fragments fused to interacting proteins reconstitute a functional enzyme and confer resistance to the antifolate drug WR99210 in Plasmodium falciparum. These data demonstrate that the split-DHFR method can be used to detect in vivo protein-protein interactions in the parasite. Additionally, we show that split-DHFR fragments can be used as selection markers, permitting simultaneous selection of two plasmids in the presence of a single antifolate drug. Taken together, these experiments show that split-DHFR represents a valuable tool for the characterisation of Plasmodium protein function and genetic manipulation of the parasite.

Background PSMA is overexpressed in PC with limited expression in other organs. PC is radiosensitive with dose-response. Dose-fractionation allows delivery of higher total dose per cycle, may result in less radioresistance due to repopulation compared with doses 6-12 wks apart. Initial Ph I safety results of the dose-escalation portion of this study [ESMO 2018] were without DLT at all dose levels. Methods Entry criteria: progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and taxane (or unfit/refuse chemo) without limit of # prior therapies, adequate organ function, ECOG performance status 0-2. No preselection for PSMA expression. Treatment was a single cycle of fractionated dose 177Lu-PSMA-617 on D1 and D15. In the Ph I dose-escalation cohort, men received 7.4 to 22 GBq. In Ph II, a Simon 2 stage design enrolled pts at the 22.2 GBq dose level. Pre- and post-treatment 68Ga-PSMA11 PET/CT and post-treatment 177Lu-PSMA-617 imaging was performed in addition to standard serial CT and bone scans. Cellsearch CTC count at baseline and 12 wks. Results 44 men (29 in Ph I, 15 in Ph II; total 21 at 22.2 GBq) with median age 69 (range 55-91), median PSA 182.97 (range 0.89-5541) were treated. 93% with bone, 45% nodal, 18% lung, 9% liver, 9% other visceral metastases. 55% with at least 1 prior chemo regimen, 52% >1 prior potent AR therapy, 27% with Ra223, 30% sip-T, 5% 177Lu-J591; 66% Halabi poor risk, 30% intermed risk. With follow up ongoing, 61% with >50% PSA decline (71.4% at 22.2 GBq), median overall survival 16 months (95% CI 11-NR). Of 26 with paired CTC counts, 57.7% decreased, 7.7% stable, 34.6% increased; 34.6% converted from detectable to undetectable at 12 weeks). 61.4% with all grade xerostomia, 29.5% fatigue, 25% thrombocytopenia, 25% anemia, 25% pain, 15.5% nausea. While not required for eligibility, all pts had some PSMA uptake in at least 1 site on PSMA PET, with 2.2% highest lesion SUV 5x liver. Conclusions A single fractionated cycle of up to 22.2 GBq of 177Lu-PSMA-617 is safe, with encouraging early efficacy signals, even without selection for PSMA expression by imaging. A trend for dose-response was observed. Clinical trial identification NCT03042468. Legal entity responsible for the study Well Cornell Medicine. Funding Weill Cornell Medicine, Prostate Cancer Foundation, US Department of Defense, US National Institutes of Health, Endocyte. Disclosure S.T. Tagawa: Advisory / Consultancy, Research grant / Funding (institution): Endocyte. H. Beltran: Advisory / Consultancy: Endocyte. S. Vallabhajosula: Research grant / Funding (institution): Endocyte; Full / Part-time employment: NCM USA. O. Sartor: Research grant / Funding (institution): Endocyte. All other authors have declared no conflicts of interest.

Stereotypic behavior in horses, including cribbing and weaving, can be attributed to a number of different factors including the number of hours in a stall, number of grazing opportunities, number of times fed hay in a day, and the ability to touch other horses. By providing environmental enrichment that allows for feed availability for a longer time period, a reduction of stereotypic behaviors could be seen. A behavioral tool, a tongue-activated liquid dispenser, was tested to determine whether the device itself could reduce stereotypic behaviors. Four horses, two weavers and two cribbers were studied over a 4-day period. Each horse acted as it's own control in a randomized block design. On average, data trended toward a treatment effect depending on the day.

The neurobiology of anorexia nervosa remains incompletely understood. Here we utilized PET imaging with the radiotracer [(11)C]raclopride to measure striatal dopamine type 2 (D2) receptor availability in patients with anorexia nervosa. 25 women with anorexia nervosa who were receiving treatment in an inpatient program participated, as well as 25 control subjects. Patients were scanned up to two times with the PET tracer [(11)C]raclopride: once while underweight, and once upon weight restoration. Control subjects underwent one PET scan. In the primary analyses, there were no significant differences between underweight patients (n=21) and control subjects (n=25) in striatal D2 receptor binding potential. Analysis of subregions (sensorimotor striatum, associative striatum, limbic striatum) did not reveal differences between groups. In patients completing both scans (n=15), there were no detectable changes in striatal D2 receptor binding potential after weight restoration. In this sample, there were no differences in striatal D2 receptor binding potential between patients with anorexia nervosa and control subjects. Weight restoration was not associated with a change in striatal D2 receptor binding. These findings suggest that disturbances in reward processing in this disorder are not attributable to abnormal D2 receptor characteristics, and that other reward-related neural targets may be of greater relevance.

Epigenetic dysfunction has been implicated in a growing list of disorders that include cancer, neurodevelopmental disorders, and neurodegeneration. Williams syndrome (WS) and 7q11.23 duplication syndrome (Dup7) are rare neurodevelopmental disorders with broad phenotypic spectra caused by deletion and duplication, respectively, of a 1.5-Mb region that includes several genes with a role in epigenetic regulation. We have identified striking differences in DNA methylation across the genome between blood cells from children with WS or Dup7 and blood cells from typically developing (TD) children. Notably, regions that were differentially methylated in both WS and Dup7 displayed a significant and symmetrical gene-dose-dependent effect, such that WS typically showed increased and Dup7 showed decreased DNA methylation. Differentially methylated genes were significantly enriched with genes in pathways involved in neurodevelopment, autism spectrum disorder (ASD) candidate genes, and imprinted genes. Using alignment with ENCODE data, we also found the differentially methylated regions to be enriched with CCCTC-binding factor (CTCF) binding sites. These findings suggest that gene(s) within 7q11.23 alter DNA methylation at specific sites across the genome and result in dose-dependent DNA-methylation profiles in WS and Dup7. Given the extent of DNA-methylation changes and the potential impact on CTCF binding and chromatin regulation, epigenetic mechanisms most likely contribute to the complex neurological phenotypes of WS and Dup7. Our findings highlight the importance of DNA methylation in the pathogenesis of WS and Dup7 and provide molecular mechanisms that are potentially shared by WS, Dup7, and ASD.

Highlights • High theta and low gamma activity in the dynamic pain connectome is linked to chronic pain. • High alpha-band activity is present when neuropathic pain is likely. • Spectral frequency band strength distinguish neuropathic from non-neuropathic pain., We previously identified alpha frequency slowing and beta attenuation in the dynamic pain connectome related to pain severity and interference in patients with multiple sclerosis-related neuropathic pain (NP). Here, we determined whether these abnormalities, are markers of aberrant temporal dynamics in non-neuropathic inflammatory pain (non-NP) or when NP is also suspected. We measured resting-state magnetoencephalography (MEG) spectral density in 45 people (17 females, 28 males) with chronic back pain due to ankylosing spondylitis (AS) and 38 age/sex matched healthy controls. We used painDETECT scores to divide the chronic pain group into those with only non-NP (NNP) and those who likely also had a component of NP in addition to their inflammatory pain. We also assessed pain severity, pain interference, and disease activity with the Brief Pain Inventory and Bath AS Disease Activity Index (BASDAI). We examined spectral power in the dynamic pain connectome, including nodes of the ascending nociceptive pathway (ANP), default mode (DMN), and salience networks (SN). Compared to the healthy controls, the AS patients exhibited increased theta power in the DMN and decreased low-gamma power in the DMN and ANP, but did not exhibit beta-band attenuation or peak-alpha slowing. The NNP patients were not different from HCs. Compared to both healthy controls and NNP, NP patients had increased alpha power in the ANP. Increased alpha power within the ANP was associated with reduced BASDAI in the NNP group, and increased pain in the mixed-NP group within the DMN, SN, and ANP. Thus, high theta and low gamma activity may be markers of chronic pain but high alpha-band activity may relate to particular features of neuropathic chronic pain.

Photoperiod is essential in manipulating sexual maturity and reproductive performance in avian species. Light can be perceived by photoreceptors in the retina of the eye, pineal gland, and hypothalamus. However, the relative sensitivity and specificity of each organ to wavelength, and consequently the physiological effects, may differ. The purpose of this experiment was to test the impacts of light wavelengths on reproduction, growth, and stress in laying hens maintained in cages and to determine whether the retina of the eye is necessary. Individual cages in 3 optically isolated sections of a single room were equipped with LED strips providing either pure green, pure red or white light (red, green, and blue) set to 10 lx (hens levels). The involvement of the retina on mediating the effects of light wavelength was assessed by using a naturally blind line (Smoky Joe) of chickens. Red and white lights resulted in higher estradiol concentrations after photostimulation, indicating stronger ovarian activation, which translated into a significantly lower age at first egg when compared with the green light. Similarly, hens maintained under red and white lights had a longer and higher peak production and higher cumulative egg number than hens under green light. No significant difference in BW gain was observed until sexual maturation. However, from 23 wk of age onward, birds exposed to green light showed higher body growth, which may be the result of their lower egg production. Although corticosterone levels were higher at 20 wk of age in hens under red light, concentrations were below levels that can be considered indicative of stress. Because no significant differences were observed between blind and sighted birds maintained under red and white light, the retina of the eye did not participate in the activation of reproduction. In summary, red light was required to stimulate the reproductive axis whereas green light was ineffective, and the effects of stimulatory wavelengths do not appear to require a functional retina of the eye.

Prostate cancer (CaP) is the most common noncutaneous malignancy affecting men in North America. Despite significant efforts, conventional imaging of CaP does not contribute to patient management as much as imaging performed for other common cancers. Given the lack of specificity in conventional imaging techniques, one possible solution is to screen for CaP-specific antigenic targets and generate agents able to specifically bind. Prostate-specific membrane antigen (PSMA) is overexpressed in CaP tissue, with low levels of expression in the small intestine, renal tubular cells, and salivary gland. The first clinical agent for targeting PSMA was 111 In-capromab, involving an antibody recognizing the internal domain of PSMA. The second- and third-generation humanized PSMA binding antibodies have the potential to overcome some of the limitations inherent to capromab penditide (i.e., inability to bind to live CaP cells). One example is the humanized monoclonal antibody J591 (Hu mAb J591) that was developed primarily for therapeutic purposes but also has interesting imaging characteristics, including the identification of bone metastases in CaP. The major disadvantage of use of mAb for imaging is slow target recognition and background clearance in an appropriate time frame for diagnostic imaging. Urea-based compounds, such as small molecule inhibitors may also present promising agents for CaP imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Two such small-molecule inhibitors targeting PSMA, MIP-1072, and MIP-1095 have exhibited high affinity for PSMA. The uptake of 123 I-MIP-1072 and 123 I-MIP-1095 in CaP xenografts have imaged successfully with favorable properties amenable to human trials. While advances in conventional imaging will continue, Ab and small molecule imaging exemplified by PSMA targeting have the greatest potential to improve diagnostic sensitivity and specificity.

Background Preoperative (neoadjuvant) chemotherapy and radiotherapy are more effective than similar postoperative treatment for oesophageal, gastric, and rectal cancers, perhaps because of more effective micrometastasis eradication and reduced risk of incomplete excision and tumour cell shedding during surgery. The FOxTROT trial aims to investigate the feasibility, safety, and efficacy of preoperative chemotherapy for colon cancer. Methods In the pilot stage of this randomised controlled trial, 150 patients with radiologically staged locally advanced (T3 with >= 5 mm invasion beyond the muscularis propria or T4) tumours from 35 UK centres were randomly assigned (2:1) to preoperative (three cycles of OxMdG [oxaliplatin 85 mg/m(2), l-folinic acid 175 mg, fluorouracil 400 mg/m(2) bolus, then 2400 mg/m(2) by 46 h infusion] repeated at 2-weekly intervals followed by surgery and a further nine cycles of OxMdG) or standard postoperative chemotherapy (12 cycles of OxMdG). Patients with KRAS wild-type tumours were randomly assigned (1:1) to receive panitumumab (6 mg/kg; every 2 weeks with the first 6 weeks of chemotherapy) or not. Treatment allocation was through a central randomisation service using a minimised randomisation procedure including age, radiological T and N stage, site of tumour, and presence of defunctioning colostomy as stratification variables. Primary outcome measures of the pilot phase were feasibility, safety, and tolerance of preoperative therapy, and accuracy of radiological staging. Analysis was by intention to treat. This trial is registered, number ISRCTN 87163246. Findings 96% (95 of 99) of patients started and 89% (85 of 95) completed preoperative chemotherapy with grade 3-4 gastrointestinal toxicity in 7% (seven of 94) of patients. All 99 tumours in the preoperative group were resected, with no significant differences in postoperative morbidity between the preoperative and control groups: 14% (14 of 99) versus 12% (six of 51) had complications prolonging hospital stay (p=0.81). 98% (50 of 51) of postoperative chemotherapy patients had T3 or more advanced tumours confirmed at post-resection pathology compared with 91% (90 of 99) of patients following preoperative chemotherapy (p=0.10). Preoperative therapy resulted in significant downstaging of TNM5 compared with the postoperative group (p=0.04), including two pathological complete responses, apical node involvement (1% [one of 98] vs 20% [ten of 50], p

This paper explores the enigma of cancer of unknown primary (CUP) in relation to rapidly improving molecular diagnostic approaches. It is based on the first global collaboration meeting on improving research and clinical outcomes in CUP organized by the CUP Foundation. We review the difficulties of classifying this widely heterogeneous disease and the available diagnostic and pathological evaluative techniques, focusing on molecular profiling. Retrospective studies in CUP patients are shown to provide indirect validation of the accuracy of several platforms of gene expression profiling assays that may identify CUP subsets that respond favorably to active chemotherapy regimens. This review concludes that the recent major improvements in pathologic and molecular diagnostics, coupled with new improved therapies for several specific advanced solid tumors, need to be harmonized with more evidence from clinical–translational trials. All patients with CUP could thus be appropriately managed without the constant uncertainty that has previously severely hampered patient care and optimal outcomes. The longer-term objective is to understand the biology of highly metastatic disease, leading to the development of future global therapeutic programs. Current clinical studies, such as CUP-ONE, will address some of these issues.

The ability of random mutagenesis techniques to annotate the mammalian genome can be hampered due to genetic redundancy and compensatory pathways that mask heterozygous mutations under homeostatic conditions. The objective of this study was to devise a pharmacologically sensitized screen using the chemotherapeutic drug, 5-fluorouracil (5FU), to induce cytopenia. 5FU dose was optimized in the 129/SvImJ, C57BL/6J, BALB/cJ, and C3H/HeJ strains of laboratory mice. N-ethyl-N-nitrosourea (ENU) mutagenesis was performed on 129/SvImJ males and phenotypic variants were identified by backcrossing on to the C57BL/6J background. G1 animals were challenged with 100 μg/g 5FU and phenodeviants with altered platelet recovery were monitored. Of 546 G1 animals tested, 15 phenodeviants were identified that displayed increased baseline platelet number, a platelet overshoot, or delayed platelet recovery, thereby demonstrating the utility of this approach for uncovering mutations in megakaryocyte and platelet development. Four G1 mice were selected for further analysis. The phenotypes were heritable in all four strains and genetic mapping identified a chromosome location in two of the three G2 lines tested. In conclusion, our group has developed a sensitized random mutagenesis screen utilizing 5FU and has shown that the strain combination of 129/SvImJ × C57BL/6J is robust for identification of founder lines with defects in megakaryocyte and platelet development.

During the blood stage of its lifecycle, the malaria parasite resides and replicates inside a membrane vacuole within its host cell, the human erythrocyte. The parasite exports many proteins across the vacuole membrane and into the host cell cytoplasm. Most exported proteins are characterized by the presence of a Host Targeting (HT) motif, also referred to as a Plasmodium Export Element (PEXEL), which corresponds to the consensus sequence RxLxE/D/Q. During export the HT motif is cleaved by an unknown protease. Here, we generate parasite lines expressing HT motif containing proteins that are localized to different compartments within the parasite or host cell. We find that the HT motif in a protein that is retained in the parasite endoplasmic reticulum, is cleaved and N-acetylated as efficiently as a protein that is exported. This shows that cleavage of the HT motif occurs early in the secretory pathway, in the parasite endoplasmic reticulum.

This paper provides an overview of results generated by the static test expansion–deflection rocket nozzle (STERN) project. The engine propellants were gaseous air and hydrogen, with a design chamber pressure and thrust of 102 bar and 5 kN respectively. The maximum chamber pressure achieved was restricted to 55 bar absolute, due to a conservative approach in the test programme dictated by the uncertainty in heat transfer to the pintle. Despite this, the programme achieved many successes, including the first tests of an ED nozzle in the UK; the production of significant amounts of data for both the analysis of the performance of the nozzle and the verification of analysis codes; and an improved compensation performance over that apparent from earlier work, including demonstration of attached flow to the exit plane for all chamber pressures. Whilst the wake pressure was not as high as hoped, ranging between 70% and 95% of ambient and apparently inversely related to chamber pressure, this result is still sufficiently encouraging to warrant further investigation of the type. As importantly, the data derived from the experiments, including performance analysis and wall pressure variations in time and space, are now being made available to the wider academic community, something which for commercial reasons appears to be a unique occurrence for this type of nozzle.

Infantile spasms (IS) is the most severe and common form of epilepsy occurring in the first year of life. At least half of IS cases are idiopathic in origin, with others presumed to arise because of brain insult or malformation. Here, we identify a locus for IS by high-resolution mapping of 7q11.23-q21.1 interstitial deletions in patients. The breakpoints delineate a 500 kb interval within the MAGI2 gene (1.4 Mb in size) that is hemizygously disrupted in 15 of 16 participants with IS or childhood epilepsy, but remains intact in 11 of 12 participants with no seizure history. MAGI2 encodes the synaptic scaffolding protein membrane-associated guanylate kinase inverted-2 that interacts with Stargazin, a protein also associated with epilepsy in the stargazer mouse.

Objective The purpose of our study is to describe patterns of care of invasive vulvar carcinoma in the province of Ontario, Canada. Our ultimate goal is to improve vulvar cancer care by understanding variations in care and their impact on outcome. In this pilot study, we specifically evaluate the use of groin node dissection (GND). Methods The provincial cancer registry was used to identify incident cases of vulvar carcinoma diagnosed between 1994 and 2003. These cases were linked to physician billings claims and hospital discharge records to identify treatment given in the first year after diagnosis. Results The cohort included 978 women with vulvar carcinoma. 85% had at least one surgical procedure. 62% of these had a GND. GND was more likely in those who were treated by a gynecologic oncologist or who had less co-morbid illness. Approximately 25% received radiotherapy. Conclusion The rate of GND appears to be low. As proper management of the groins is critical for most patients with vulvar cancer, this observation raises concerns about the quality of treatment received by patients with vulvar carcinoma. Further investigation is required to verify the observations made in this hypothesis generating study.

The SecY complex associates with the ribosome to form a protein translocation channel in the bacterial plasma membrane. We have used cryo-electron microscopy and quantitative mass spectrometry to show that a nontranslating E. coli ribosome binds to a single SecY complex. The crystal structure of an archaeal SecY complex was then docked into the electron density maps. In the resulting model, two cytoplasmic loops of SecY extend into the exit tunnel near proteins L23, L29, and L24. The loop between transmembrane helices 8 and 9 interacts with helices H59 and H50 in the large subunit RNA, while the 6/7 loop interacts with H7. We also show that point mutations of basic residues within either loop abolish ribosome binding. We suggest that SecY binds to this primary site on the ribosome and subsequently captures and translocates the nascent chain.

Gefitinib and irinotecan in patients with fluoropyrimidine-refractory, irinotecan-naive advanced colorectal cancer: a phase I-II study Background: To establish the recommended dose level (RDL) and to evaluate the efficacy and safety of gefitinib plus irinotecan in patients with advanced fluoropyrimidine-refractory colorectal cancer (CRC). Patients and methods: Patients with advanced CRC progressing on or within 12 weeks of fluoropyrimidine-based chemotherapy, irinotecan naive and performance status of two or less were recruited. During dose-finding phase, dose-limiting toxicity (DLT) was encountered at dose level 1, therefore subsequent dose de-escalation and pharmacokinetic (PK) studies were carried out. The RDL was then expanded in a multicentre setting to further evaluate safety and efficacy. Results: From June 2002 to February 2005, 39 patients were treated in total with 27 at the RDL. The RDL was established at irinotecan 225 mg/m(2) every 3 weeks and gefitinib 250 mg daily. The DLTs were neutropenia and diarrhoea. For the patients treated at RDL, the objective tumour response rate was 11.1% (95% confidence interval 2.4% to 29.2%) and median survival was 9.3 months. PK studies indicated that the addition of irinotecan to gefitinib resulted in an average of 50% increase in exposure to gefitinib (P < 0.05), but gefitinib did not alter the PK profiles of irinotecan or SN-38. Grade 3-4 toxic effects in all patients included diarrhoea (35.9%), lethargy (15.4%), neutropenia (15.4%), febrile neutropenia (10.3%) and skin rash (7.7%). Conclusions: Irinotecan and gefitinib at this dose schedule was tolerable, but gefitinib did not appear to add substantial efficacy to irinotecan.

Recently two numerical spectral methods, based on the use of the Fast Fourier Transform algorithm, have been found to be useful for studying the statistical properties of a large number of interacting random waves: the first one is known as the Higher Order Spectral (HOS) method and the second is based on the computation of the dynamical equation arising from the Hamiltonian description of surface gravity waves. Here we show analytically the relation between these two methods; more in particular, starting from the HOS approach and writing the corresponding evolution equations in spectral space, after a proper symmetrization of the coupling coefficients in the resulting integral terms, the Hamiltonian dynamical equations are recovered.

The programmed grooming model proposes that animals groom in response to an internal timing mechanism that has evolved to control ectoparasites. This model predicts that polygynous males will groom less frequently than smaller females (sexually dimorphic grooming) because (1) parasitism is more costly for smaller individuals (body size principle), and (2) during the breeding season, sexual selection has favoured males that reduce grooming to enhance vigilance for mates and rivals (vigilance principle). The proximate mechanism for vigilance-mediated suppression of grooming may be either time budget conflicts (males are too busy breeding to groom) or physiological suppression (the action of elevated testosterone). In this study, we examined the influence of body size, breeding activity and androgens on sexually dimorphic grooming in American bison, Bison bison. Bison were observed before (pre-rut) and during the breeding season (rut) at National Bison Range (NBR) and Fort Niobrara (FTN) national wildlife refuges; androgens were measured in FTN males. Females oral-groomed two to five times more than males during pre-rut, and 5–40 times more than tending males (guarding oestrous females) during the rut; tending males oral-groomed less than pre-rut males at both sites. Rutting activity of tending males was much greater than that of nontending or nonrutting males, but all males groomed at the same low rate. Androgen levels increased between pre-rut and rut for all males, but androgen levels of tending males were higher than those of nontending males. In a subsample of males for whom both androgen and grooming data were available, androgen levels were negatively correlated with oral-grooming rate, as predicted by the physiological suppression model. We conclude that effects of body size and sexually selected vigilance work independently and additively to produce sexually dimorphic grooming in bison. The vigilance-associated suppression of grooming rate in breeding males appears to be due to the action of elevated testosterone rather than conflicting time budgets.

We summarise the microphysical and optical parameters of some principal aerosol species obtained by instrumentation on the UK Met Office C-130 aircraft during international field campaigns since 1996. The aerosol species include Saharan dust, biomass burning aerosol, European continental pollution, eastern seaboard USA pollution, and clean maritime aerosol. The typical structure of the aerosol in the vertical from each airmass type is described. Microphysical parameters are described that comprise the mode radius and geometric standard deviation associated with 2–3 lognormal fits to the mean observed aerosol size distributions spanning the accumulation and coarse modes. Optical parameters comprising the aerosol single scattering albedo (which was both measured and derived from Mie theory), specific extinction coefficient, and asymmetry factor (which were derived from Mie theory) are also presented. Where available, evolution of the physical and optical properties of the aerosol has been highlighted. Comparisons with long-term ground-based AERONET aerosol retrievals show reasonable agreement. Our observations provide useful data for validating and improving global circulation models (GCMs) that use physically based aerosol representation and for validating satellite retrievals of the physical and optical properties of aerosols.

A large class of ATPases contains a RecA-like structural domain and uses the energy of nucleotide binding and hydrolysis to perform mechanical work, for example, to move polypeptides or nucleic acids. These ATPases include helicases, ABC transporters, clamp loaders, and proteases. The functional units of the ATPases contain different numbers of RecA-like domains, but the nucleotide is always bound at the interface between two adjacent RecA-like folds and the two domains move relative to one another during the ATPase cycle. The structures determined for different RecA-like motor ATPases begin to reveal how they move macromolecules.

This paper describes the design of a single wafer acoustic device using heterogeneous buried oxide wafer technology for use as a fuel level indicator. The fabrication is compatible with the electronics industry and utilises electron beam patterning with a further dry etch process step. The acoustic device is designed and modelled as a suspended plate with both modal and static load finite element analysis employed. Acoustic plate dimensions range from 720 to 1300 μm in diameter and supporting beam structures range from 10 to 30 μm in beam width. Electrostatic forces are simulated for the plate and acoustic data concerning the test volume has been collected and related to plate geometries and their resonant frequencies. Fuel level indication is made by following the resonant frequencies of the air volume above the liquid excited with a white noise source. Liquid level decreases causing a decrease in the resonant frequency of all modes or overtones. Mechanical plate resonance is used to track the frequency change using an array of plates with varying resonant frequencies.

Introduction La litteratie en sante se refere aux competences et ressources necessaires aux individus pour repondre aux demandes de sante complexes de la societe moderne : acceder, utiliser, comprendre, apprehender et evaluer les informations et services de sante pour maintenir ou ameliorer sa sante. Nous rapportons ici les premiers resultats d'exploration des profils de litteratie en sante a la Reunion via le HLQ (Health Literacy Questionnaire). Patients et Methodes Le HLQ, questionnaire aux proprietes psychometriques robustes, a ete traduit et valide pour la France et pour la Reunion. Il explore 9 dimensions en 44 items. A titre exploratoire, le questionnaire a ete administre en auto-remplissage ou avec aide en face a face a 191 patients consecutifs avec diabete de type 2 au CHU de Saint-Denis entre fevrier et juillet 2015. Resultats L'echantillon etait d'âge moyen 58±12 ans, 111 femmes, 80 hommes, 22 % sans emploi, 34 % retraites, 25 % ≤ ecole primaire. Les scores les plus eleves ont ete objectives pour « Se sentir soutenu et compris par les professionnels de sante » (score moyen 3,35±0,51 sur une echelle de 4) et « Capacite a s'engager avec les professionnels de sante » (score sur 5 : 3,86±0,63) et les plus bas pour « Evaluation de l'information en sante » (3,00±0,51, sur 4) et « Aptitude a trouver des informations de bonne qualite » (3,48±0,69, sur 5). Discussions Ces donnees sont les 1 res concernant les profils de litteratie en sante dans le diabete de type 2 en France. Elles revelent a la fois des leviers, notamment la capacite a s'engager avec les professionnels de sante, et des faiblesses telles que le niveau d'acces et d'utilisation des informations en sante. La prise en compte de ces resultats permettra de travailler sur les actions et priorites a mettre en œuvre pour repondre aux besoins specifiques de litteratie en sante des populations, notamment les plus vulnerabilisees.

Ozone is an important factor in urban pollution and represents a major concern for human health. The chemical reactivity of ozone toward biological targets and particularly its genotoxicity supports a possible link between exposure and cancer risk, but no molecular data exist on its mutagenic potential in human cells. Using a shuttle vector, we showed that ozone is indeed a potent mutagen and we characterized the mutation spectrum it produced in human cells. Almost all mutations are base substitutions, essentially located at G:Cs (75%), typical of reactive oxygen species (ROS), but occurring in a specific pattern, i.e. a similar extent of GC:TA (28%), GC:CG (23%) and GC:AT (23%). The targeted distribution of mutations and identification of hotspot sequences define the first molecular fingerprint of mutations induced by ozone in human cells. Possible applications derived from our results with respect to ozone genotoxicity should help determining quantifiable biomarkers of ozone exposure in human health, especially for carcinogenesis.