Observation of New Isotopes in the Fragmentation of

Five previously unknown isotopes (^{182,183}Tm, ^{186,187}Yb, ^{190}Lu) were produced, separated, and identified for the first time at the Facility for Rare Isotope Beams (FRIB) using the Advanced Rare Isotope Separator (ARIS). The new isotopes were formed through the interaction of a ^{198}Pt beam with a carbon target at an energy of 186 MeV/u and with a primary beam power of 1.5 kW. Event-by-event particle identification of A, Z, and q for the reaction products was performed by combining measurements of the energy loss, time of flight, magnetic rigidity Bρ, and total kinetic energy. The ARIS separator has a novel two-stage design with high resolving power to strongly suppress contaminant beams. This successful new isotope search was performed less than one year after FRIB operations began and demonstrates the discovery potential of the facility which will ultimately provide 400 kW of primary beam power.

New

The discrepancy between observations from γ-ray astronomy of the ^{60}Fe/^{26}Al γ-ray flux ratio and recent calculations is an unresolved puzzle in nuclear astrophysics. The stellar ß-decay rate of ^{59}Fe is one of the major nuclear uncertainties impeding us from a precise prediction. The important Gamow-Teller strengths from the low-lying states in ^{59}Fe to the ^{59}Co ground state are measured for the first time using the exclusive measurement of the ^{59}Co(t,^{3}He+γ)^{59}Fe charge-exchange reaction. The new stellar decay rate of ^{59}Fe is a factor of 3.5±1.1 larger than the currently adopted rate at T=1.2 GK. Stellar evolution calculations show that the ^{60}Fe production yield of an 18 solar mass star is decreased significantly by 40% when using the new rate. Our result eliminates one of the major nuclear uncertainties in the predicted yield of ^{60}Fe and alleviates the existing discrepancy of the ^{60}Fe/^{26}Al ratio.

Navigating systemic therapy for metastatic castration-naïve prostate cancer.

INTRODUCTION: The last decade has seen a remarkable shift in the treatment landscape of advanced prostate cancer, none more so than in the management of metastatic castration-naïve disease. METHODS: This narrative review will examine existing and emerging evidence supporting systemic therapy use for metastatic castration-naïve prostate cancer (mCNPC) and provide guidance on the selection of these agents with respect to optimising patient outcomes. RESULTS: The addition of either docetaxel (chemohormonal approach) or an AR pathway inhibitor (abiraterone, enzalutamide or apalutamide) is a reasonable standard of care option for men commencing long-term ADT for mCNPC. While the issue of disease volume as a predictive biomarker for docetaxel benefit has previously been debated, recent data support consideration of upfront docetaxel in all patients, regardless of metastatic burden. Decisions regarding systemic treatment for men with mCNPC should be based on comprehensive consideration of disease, patient and logistical factors. Multiple novel therapeutics for mCNPC are currently under active investigation. CONCLUSION: The introduction of potent systemic therapy earlier in the mCNPC disease course has resulted in dramatic improvements in clinical outcomes for patients. As the management of mCNPC continues to evolve, the future remains promising, with the expectation of ongoing improvements to patient outcomes and quality of life.

Studies of pear-shaped nuclei using accelerated radioactive beams.

There is strong circumstantial evidence that certain heavy, unstable atomic nuclei are 'octupole deformed', that is, distorted into a pear shape. This contrasts with the more prevalent rugby-ball shape of nuclei with reflection-symmetric, quadrupole deformations. The elusive octupole deformed nuclei are of importance for nuclear structure theory, and also in searches for physics beyond the standard model; any measurable electric-dipole moment (a signature of the latter) is expected to be amplified in such nuclei. Here we determine electric octupole transition strengths (a direct measure of octupole correlations) for short-lived isotopes of radon and radium. Coulomb excitation experiments were performed using accelerated beams of heavy, radioactive ions. Our data on (220)Rn and (224)Ra show clear evidence for stronger octupole deformation in the latter. The results enable discrimination between differing theoretical approaches to octupole correlations, and help to constrain suitable candidates for experimental studies of atomic electric-dipole moments that might reveal extensions to the standard model.

Localizing the Shape Transition in Neutron-Deficient Selenium.

Neutron-deficient selenium isotopes are thought to undergo a rapid shape change from a prolate deformation near the line of beta stability towards oblate deformation around the line of N=Z. The point at which this shape change occurs is unknown, with inconsistent predictions from available theoretical models. A common feature in the models is the delicate nature of the point of transition, with the introduction of even a modest spin to the system sufficient to change the ordering of the prolate and oblate configurations. We present a measurement of the quadrupole moment of the first-excited state in radioactive ^{72}Se-a potential point of transition-by safe Coulomb excitation. This is the first low-energy Coulomb excitation to be performed with a rare-isotope beam at the reaccelerated beam facility at the National Superconducting Cyclotron Laboratory. By demonstrating a negative spectroscopic quadrupole moment for the first-excited 2^{+} state, it is found that any low-spin shape change in neutron-deficient selenium does not occur until ^{70}Se.

Observation of the Isovector Giant Monopole Resonance via the

The (^{10}Be,^{10}B^{*}[1.74 MeV]) charge-exchange reaction at 100 AMeV is presented as a new probe for isolating the isovector (ΔT=1) nonspin-transfer (ΔS=0) response of nuclei, with ^{28}Si being the first nucleus studied. By using a secondary ^{10}Be beam produced by fast fragmentation of ^{18}O nuclei at the NSCL Coupled Cyclotron Facility, applying the dispersion-matching technique with the S800 magnetic spectrometer to determine the excitation energy in ^{28}Al, and performing high-resolution γ-ray tracking with the Gamma-Ray Energy Tracking In-beam Nuclear Array (GRETINA) to identify the 1022-keV γ ray associated with the decay from the 1.74-MeV T=1 isobaric analog state in ^{10}B, a ΔS=0 excitation-energy spectrum in ^{28}Al was extracted. Monopole and dipole contributions were determined through a multipole-decomposition analysis, and the isovector giant dipole resonance and isovector giant monopole resonance (IVGMR) were identified. The results show that this probe is a powerful tool for studying the elusive IVGMR, which is of interest for performing stringent tests of modern density functional theories at high excitation energies and for constraining the bulk properties of nuclei and nuclear matter. The extracted distributions were compared with theoretical calculations based on the normal-modes formalism and the proton-neutron relativistic time-blocking approximation. Calculated cross sections based on these strengths underestimate the data by about a factor of 2, which likely indicates deficiencies in the reaction calculations based on the distorted wave Born approximation.

High Precision Determination of the ß Decay Q(EC) Value of (11)C and Implications on the Tests of the Standard Model.

We report the determination of the Q(EC) value of the mirror transition of (11)C by measuring the atomic masses of (11)C and (11)B using Penning trap mass spectrometry. More than an order of magnitude improvement in precision is achieved as compared to the 2012 Atomic Mass Evaluation (Ame2012) [Chin. Phys. C 36, 1603 (2012)]. This leads to a factor of 3 improvement in the calculated Ft value. Using the new value, Q(EC)=1981.690(61) keV, the uncertainty on Ft is no longer dominated by the uncertainty on the Q(EC) value. Based on this measurement, we provide an updated estimate of the Gamow-Teller to Fermi mixing ratio and standard model values of the correlation coefficients.

Benefit from cytoreductive nephrectomy and the prognostic role of neutrophil-to-lymphocyte ratio in patients with metastatic renal cell carcinoma.

BACKGROUND: The role of cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of targeted therapies is currently undefined. In recent years, neutrophil-to-lymphocyte ratio (NLR) has emerged as a prognostic marker in several cancers, including mRCC. In this multicentre retrospective study, we aim to assess the impact of CN in mRCC and the value of NLR in risk stratification and patient selection. METHODS: Retrospective data from patients with de novo mRCC from four large Australian hospitals were collected. Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses were performed using the Cox proportional hazards method. RESULTS: Our study identified 91 de novo mRCC patients. Patients who underwent CN (n = 46, 51%) were more likely to be younger (59.0 years vs 64.6 years, P = 0.019) and to have received systemic therapy (91% vs 76%, P = 0.043). Median overall survival (mOS) was significantly improved in patients who underwent CN (23.0 months vs 10.9 months, hazard ratios (HR) 0.33, 95% confidence interval (CI) 0.20-0.55, P < 0.0001). Patients with NLR ≥ 5 also had inferior mOS (6.2 months vs 16.7 months, HR 1.94, 95% CI 1.14-3.29, P = 0.014). CN was associated with substantially improved survival in patients with both NLR < 5 (mOS 31.1 months vs 7.0 months, HR 0.41, 95% CI, 0.18-0.64, P = 0.0009) and NLR ≥ 5 (mOS 10.9 months vs 2.3 months, HR 0.33, 95% CI, 0.11-0.69, P = 0.009). Significant survival benefits associated with CN were maintained in multivariate analyses (HR 0.39, 95% CI 0.22-0.70, P = 0.0014). CONCLUSIONS: CN is associated with significantly improved overall survival in de novo mRCC. The incremental survival benefit associated with CN was seen irrespective of NLR.

Syntaxin-3 regulates newcomer insulin granule exocytosis and compound fusion in pancreatic beta cells.

AIMS/HYPOTHESIS: The molecular basis of the exocytosis of secretory insulin-containing granules (SGs) during biphasic glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells remains unclear. Syntaxin (SYN)-1A and SYN-4 have been shown to mediate insulin exocytosis. The insulin-secretory function of SYN-3, which is particularly abundant in SGs, is unclear. METHODS: Mouse pancreatic islets and INS-1 cells were treated with adenovirus carrying Syn-3 (also known as Stx3) or small interfering RNA targeting Syn-3 in order to examine insulin secretion by radioimmunoassay. The localisation and distribution of insulin granules were examined by confocal and electron microscopy. Dynamic single-granule fusion events were assessed using total internal reflection fluorescence microscopy (TIRFM). RESULTS: Depletion of endogenous SYN-3 inhibited insulin release. TIRFM showed no change in the number or fusion competence of previously docked SGs but, instead, a marked reduction in the recruitment of newcomer SGs and their subsequent exocytotic fusion during biphasic GSIS. Conversely, overexpression of Syn-3 enhanced both phases of GSIS, owing to the increase in newcomer SGs and, remarkably, to increased SG-SG fusion, which was confirmed by electron microscopy. CONCLUSIONS/INTERPRETATION: In insulin secretion, SYN-3 plays a role in the mediation of newcomer SG exocytosis and SG-SG fusion that contributes to biphasic GSIS.

Fine structure of the giant M1 resonance in 90Zr.

The M1 excitations in the nuclide 90Zr have been studied in a photon-scattering experiment with monoenergetic and linearly polarized beams from 7 to 11 MeV. More than 40 J(π)=1+ states have been identified from observed ground-state transitions, revealing the fine structure of the giant M1 resonance with a centroid energy of 9 MeV and a sum strength of 4.17(56) µ(N)(2). The result for the total M1 strength and its fragmentation are discussed in the framework of the three-phonon quasiparticle-phonon model.

Retrospective cohort study of an outbreak of cryptosporidiosis caused by a rare Cryptosporidium parvum subgenotype.

The occurrence of a gastrointestinal illness among a class of 96 undergraduate veterinary students in New Zealand prompted laboratory and questionnaire-based investigations. Cryptosporidium parvum was the only enteropathogen identified in 4/7 faecal specimens analysed. The C. parvum isolates carried a rare IIa GP60 allele, indicating a point-source outbreak. The infection source could not be microbiologically traced, but the investigation suggested contact with calves during a practical class as the most likely exposure. A total of 25/80 respondents to a questionnaire were defined as cases using a clinical case definition (31% attack rate). The inferred median incubation period was 5 days (range 0-11 days), and the median illness duration was 5-6 days (range 2-23 days), corroborating previous observations in experimental cryptosporidiosis. Disease was self-limiting, characterized by abdominal discomfort, diarrhoea, and in some cases, vomiting. Originating from a rural area and having had previously handled ruminants were associated with a significant risk reduction in males. All the three students who reported chronic use of steroid inhalers for treatment of asthma were cases. This case highlighted, once again, the potential hazard for explosive outbreaks of cryptosporidiosis.

The utility of the brief ECT cognitive screen (BECS) for early prediction of cognitive adverse effects from ECT: A CARE network study.

Although highly effective, electroconvulsive therapy (ECT) often produces cognitive side effects which can be a barrier for patients. Monitoring cognitive side effects during the acute course is therefore recommended to identify patients at increased risk for adverse outcomes. The Brief ECT Cognitive Screen (BECS) is a brief instrument designed to measure emerging cognitive side effects from ECT. The aim of this study was to examine the clinical utility of the BECS for predicting adverse cognitive outcomes in real world clinic settings. The study included data collated from four participating sites in the Clinical Alliance for ECT and Related treatments (CARE) network. The BECS was administered at pre ECT and post 3 or 4 ECT. The primary outcome was a ≥4 point decrease on the Montreal Cognitive Assessment (MoCA) from pretreatment to post ECT. Logistic multiple regression analyses examined the BECS and other relevant clinical and demographic and treatment factors as predictors. The final analysis included 623 patients with diverse indications for ECT including 53.6% with major depression and 33.7% with schizophrenia or schizoaffective disorder. A higher total score on the BECS significantly predicted decline in Total Scores on the MoCA [B = 0.25 (0.08), p = 0.003], though not decline in MoCA Delayed Recall scores (p > 0.1). Other significant predictors included higher pretreatment MoCA Total Scores and female gender for verbal anterograde memory decline. This study confirmed that the BECS has clinical utility for identifying patients with both reduced and increased risk for adverse cognitive outcomes from ECT.

Spectral structure of the pygmy dipole resonance.

High-sensitivity studies of E1 and M1 transitions observed in the reaction 138Ba(gamma,gamma{'}) at energies below the one-neutron separation energy have been performed using the nearly monoenergetic and 100% linearly polarized photon beams of the HIgammaS facility. The electric dipole character of the so-called "pygmy" dipole resonance was experimentally verified for excitations from 4.0 to 8.6 MeV. The fine structure of the M1 "spin-flip" mode was observed for the first time in N=82 nuclei.

Genetic diversity and zoonotic potential of Cryptosporidium parvum causing foal diarrhea.

Cryptosporidium isolates from diarrheic foals in New Zealand (n = 9) were identified as C. parvum, subtyped at two polymorphic loci, and compared with human (n = 45) and bovine (n = 8) isolates. Foal C. parvum isolates were genetically diverse, markedly similar to human and bovine isolates, and carried GP60 IIaA18G3R1 alleles, indicating a zoonotic potential.

A family with osteoporosis pseudoglioma syndrome due to compound heterozygosity of two novel mutations in the LRP5 gene.

Osteoporosis pseudoglioma syndrome (OPPG) is an autosomal recessive disorder due to mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Here, we report two novel missense mutations found in a southern Chinese family of a non-consanguineous marriage. Three out of four children had blindness, low bone mineral density (BMD) and multiple fractures in their childhood. Genotyping by DNA sequencing demonstrated 2 new mutations in exon 7 of the LRP5 gene. Tryptophans at amino acid residue positions 478 and 504 were replaced by arginine (W478R) and cysteine (W504C), respectively. While the parents that possessed either heterozygous W478R or W504C were apparently normal, all affected subjects were compound heterozygotes for the W478R and W504C mutations in the LRP5 gene. W478R is located immediately C-terminal to the third YWTD repeat of the second YWTD/EGF domain in LRP5, while W504C is located between the third and the fourth YWTD repeats of the second YWTD/EGF domain in LRP5. Using LRP5-related proteins, such as the low-density lipoprotein receptor (LDLR) and nidogen as reference models, a homology model of LRP5 suggested that the observed mutations may affect the molecular interactions of LRP5 and so lead to the observed OPPG phenotypes.

Classification of BRCA1 missense variants of unknown clinical significance.

BACKGROUND: BRCA1 is a tumour suppressor with pleiotropic actions. Germline mutations in BRCA1 are responsible for a large proportion of breast-ovarian cancer families. Several missense variants have been identified throughout the gene but because of lack of information about their impact on the function of BRCA1, predictive testing is not always informative. Classification of missense variants into deleterious/high risk or neutral/low clinical significance is essential to identify individuals at risk. OBJECTIVE: To investigate a panel of missense variants. METHODS AND RESULTS: The panel was investigated in a comprehensive framework that included (1) a functional assay based on transcription activation; (2) segregation analysis and a method of using incomplete pedigree data to calculate the odds of causality; (3) a method based on interspecific sequence variation. It was shown that the transcriptional activation assay could be used as a test to characterise mutations in the carboxy-terminus region of BRCA1 encompassing residues 1396-1863. Thirteen missense variants (H1402Y, L1407P, H1421Y, S1512I, M1628T, M1628V, T1685I, G1706A, T1720A, A1752P, G1788V, V1809F, and W1837R) were specifically investigated. CONCLUSIONS: While individual classification schemes for BRCA1 alleles still present limitations, a combination of several methods provides a more powerful way of identifying variants that are causally linked to a high risk of breast and ovarian cancer. The framework presented here brings these variants nearer to clinical applicability.

Increased retinoic acid receptor gamma expression suppresses the malignant phenotype and alters the differentiation potential of human neuroblastoma cells.

Human neuroblastoma (NB) tumor cell lines treated in vitro with the retinoid, all-trans-retinoic acid (aRA), form neurites and undergo growth arrest. Retinoids exert their diverse morphologic effects through a signalling pathway which involves the nuclear retinoid receptors. Defective retinoic acid receptor (RAR) function contributes to the malignant phenotype of several human and experimental tumors. Considerable evidence from gene disruption studies now suggests that one of the RARs, RAR gamma, may directly mediate some retinoid effects on embryonic and malignant cells. We, firstly, examined primary NB tumor tissue for a correlation between endogenous RAR gamma expression and clinical stage of the tumor and secondly, the effects of exogenous over-expression of the RAR gamma gene on a human NB tumor cell line. RAR gamma mRNA expression in 32 primary NB tumor tissue samples were significantly higher in clinically localised tumors compared with advanced or disseminated tumors. The human NB tumor cell line, BE(2)-C, was stably transfected with a mammalian expression vector (pREP4) over-expressing the human RAR gamma cDNA. Two selected clones over-expressing RAR gamma (BE/G1 and 2) exhibited a reduced growth rate compared to control cells. Tumorigenicity was inhibited for BE/G1 cells and there was a delayed onset to tumor formation for BE/G2 cells. aRA caused growth inhibition but not neuritic differentiation of the BE/G clones, while 9-cis-retinoic acid caused both growth arrest and neuritic differentiation. Taken together these results suggest that reduced endogenous RAR gamma expression may contribute to the malignant phenotype of human NB. In NB cells the retinoid signalling pathway for neuritic differentiation may be distinct from that causing growth inhibition.

Crystallization and preliminary X-ray diffraction analysis of the catalytic domain of Cex, an exo-beta-1,4-glucanase and beta-1,4-xylanase from the bacterium Cellulomonas fimi.

Single crystals of the catalytic domain of Cex, an exo-beta-1,4-glucanase and beta-1,4-xylanase from the cellulolytic bacterium Cellulomonas fimi, have been grown in the presence of polyethylene glycol 4000 using the vapour diffusion technique. The crystals, which diffract to better than 2.0 A resolution, belong to space group P4(1)2(1)2 or P4(3)2(1)2 and have cell constants: a = b = 88.21 A, c = 81.10 A; alpha = beta = gamma = 90 degrees.

Detection of evolving immunoglobulin heavy-chain gene rearrangements in acute lymphoblastic leukemia: a PCR-based assay employing overlapping DJH primers.

The use of the polymerase chain reaction (PCR) to amplify clonal immunoglobulin heavy-chain (IgH) gene rearrangements appears to be a particularly promising technique for detecting minimal residual disease (MRD). However, a major obstacle to successful implementation of this technique involves the problem of clonal evolution, in which instability of the VHDJH region leads to the generation of further rearrangements of the IgH gene over time. Such clonal evolution results in a high likelihood of false negative results when detecting MRD using clone-specific primers based on the rearrangement present at diagnosis. Since in acute lymphoblastic leukemia (ALL), clonal evolution commonly involves alterations of the VHD joining but not the DJH joining, we have devised a novel PCR strategy to circumvent the problem of false negativity in these evolved leukemias. The strategy, which involves construction of overlapping clone-specific DJH primers for use with a consensus VH segment primer, can be used to amplify both evolved and nonevolved ALL populations with high sensitivity and specificity. The method does not require radioactivity and should prove valuable for improving the effectiveness of PCR-based detection of residual leukemia.

Characterization of clonal immunoglobulin heavy chain and I cell receptor gamma gene rearrangements during progression of childhood acute lymphoblastic leukemia.

Instability of antigen receptor gene rearrangements during progression of acute lymphoblastic leukemia (ALL) has important implications for polymerase chain reaction (PCR)-based techniques using these genes for the detection of minimal residual disease (MRD). Antigen receptor gene instability may lead to false negative results in bone marrow samples taken during remission. Utilizing the PCR and consensus primers for rearranged immunoglobulin heavy chain (IgH) and T cell receptor gamma (TCR gamma) gene sequences, we analyzed the bone marrow samples at diagnosis and first relapse for 37 children with ALL. The incidence of clonal evolution at the IgH locus was 9/33 (27%) and at the TCR gamma locus 1/15 (7%). In four of the nine patients with clonal evolution at the IgH locus, the sequence at relapse retained the diversity and joining region (D-N-J) sequences from diagnosis. Patients with clonal evolution were characterized by a higher incidence of more than one IgH PCR band at diagnosis and by late relapse (> 18 months from diagnosis). These results suggest that, where possible, patients with more than one IgH PCR rearrangement at diagnosis should be monitored using another antigen receptor gene, such as TCR gamma, since evolution for this gene was found to be a rare event. By combining this approach with a strategy directed at the more stable D-N-J region of the IgH gene, MRD false negativity would have occurred in less than 10% of patients in the present study.