Chemotherapy-induced premature ovarian insufficiency (POI) impacts fertility and other aspects of women’s health. The OPTION trial tested whether administration of a gonadotropin-releasing hormone ...agonist during chemotherapy for early breast cancer reduced the risk of POI.
This was a prospective, randomized, parallel group study of the gonadotropin-releasing hormone agonist goserelin administered before and during chemotherapy for breast cancer with stage I–IIIB disease. The primary outcome was amenorrhoea between 12 and 24 months after randomization, supported by elevated follicle stimulating hormone concentrations to give an additional analysis as rate of POI.
A total of 227 patients were randomized and the primary analysis was conducted on 202 patients. Goserelin reduced the prevalence of amenorrhoea between 12 and 24 months to 22% versus 38% in the control group (P = 0.015) and the prevalence of POI to 18.5% versus 34.8% in the control group (P = 0.048). Follicle stimulating hormone concentrations were also lower in all women treated with goserelin at both 12 and 24 months (P = 0.027, P = 0.001, respectively). The effect of goserelin was not statistically significant in women >40 years. Assessment of the ovarian reserve using anti-Müllerian hormone showed a marked fall in both groups during treatment to median values of 5% of pretreatment levels in the control group and 7% in the goserelin group, which were not significantly different between groups.
This study shows that goserelin reduced the risk of POI in women treated with chemotherapy for early breast cancer, with particular efficacy in women aged ≤40 years old. The degree of ovarian protection also seems limited and the clinical significance for fertility and longer term prevention of estrogen deficiency-related outcomes needs to be determined.
We present 32 epochs of optical (3300−9700 Å) spectrophotometric observations of the nearby quintessential “normal” type Ia supernova (SN Ia) SN 2011fe in the galaxy M101, extending from −15 to +97 d ...with respect to B-band maximum, obtained by the Nearby Supernova Factory collaboration. SN 2011fe is the closest (μ = 29.04) and brightest (Bmax = 9.94 mag) SN Ia observed since the advent of modern large scale programs for the intensive periodic followup of supernovae. Both synthetic light curve measurements and spectral feature analysis attest to the normality of SN 2011fe. There is very little evidence for reddening in its host galaxy. The homogeneous calibration, intensive time sampling, and high signal-to-noise ratio of the data set make it unique. Thus it is ideal for studying the physics of SN Ia explosions in detail, and for furthering the use of SNe Ia as standardizable candles for cosmology. Several such applications are shown, from the creation of a bolometric light curve and measurement of the 56Ni mass, to the simulation ofdetection thresholds for unburned carbon, direct comparisons with other SNe Ia, and existing spectral templates.
Superoxide dismutases (SODs) are key components of the plant antioxidant defense system. While plastidic and cytosolic isoforms have been extensively studied, the importance of mitochondrial SOD at a ...cellular and whole-plant level has not been established. To address this, transgenic Arabidopsis (Arabidopsis thaliana) plants were generated in which expression of AtMSD1, encoding the mitochondrial manganese (Mn)SOD, was suppressed by antisense. The strongest antisense line showed retarded root growth even under control growth conditions. There was evidence for a specific disturbance of mitochondrial redox homeostasis in seedlings grown in liquid culture: a mitochondrially targeted redox-sensitive green fluorescent protein was significantly more oxidized in the MnSOD-antisense background. In contrast, there was no substantial change in oxidation of cytosolically targeted redox-sensitive green fluorescent protein, nor changes in antioxidant defense components. The consequences of altered mitochondrial redox status of seedlings were subtle with no widespread increase of mitochondrial protein carbonyls or inhibition of mitochondrial respiratory complexes. However, there were specific inhibitions of tricarboxylic acid (TCA) cycle enzymes (aconitase and isocitrate dehydrogenase) and an inhibition of TCA cycle flux in isolated mitochondria. Nevertheless, total respiratory CO₂ output of seedlings was not decreased, suggesting that the inhibited TCA cycle enzymes can be bypassed. In older, soil-grown plants, redox perturbation was more pronounced with changes in the amount and /or redox poise of ascorbate and glutathione. Overall, the results demonstrate that reduced MnSOD affects mitochondrial redox balance and plant growth. The data also highlight the flexibility of plant metabolism with TCA cycle inhibition having little effect on overall respiratory rates.
Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently ...updated AD Research Framework put forth by the National Institute on Aging–Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.
There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is ...lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma.
Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index.
In total, 17,930 LNs from 763 patients were examined. LN response classified as
(LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%),
(LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%),
(LNRS 4-5; n = 303, 39.7%), or
(no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio HR, 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%).
Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.
Magnetic resonance imaging (MRI) of the brain could be a key diagnostic and research tool for understanding the neuropsychiatric complications of COVID-19. For maximum impact, multi-modal MRI ...protocols will be needed to measure the effects of SARS-CoV-2 infection on the brain by diverse potentially pathogenic mechanisms, and with high reliability across multiple sites and scanner manufacturers. Here we describe the development of such a protocol, based upon the UK Biobank, and its validation with a travelling heads study. A multi-modal brain MRI protocol comprising sequences for T1-weighted MRI, T2-FLAIR, diffusion MRI (dMRI), resting-state functional MRI (fMRI), susceptibility-weighted imaging (swMRI), and arterial spin labelling (ASL), was defined in close approximation to prior UK Biobank (UKB) and C-MORE protocols for Siemens 3T systems. We iteratively defined a comparable set of sequences for General Electric (GE) 3T systems. To assess multi-site feasibility and between-site variability of this protocol, N = 8 healthy participants were each scanned at 4 UK sites: 3 using Siemens PRISMA scanners (Cambridge, Liverpool, Oxford) and 1 using a GE scanner (King's College London). Over 2,000 Imaging Derived Phenotypes (IDPs), measuring both data quality and regional image properties of interest, were automatically estimated by customised UKB image processing pipelines (S2 File). Components of variance and intra-class correlations (ICCs) were estimated for each IDP by linear mixed effects models and benchmarked by comparison to repeated measurements of the same IDPs from UKB participants. Intra-class correlations for many IDPs indicated good-to-excellent between-site reliability. Considering only data from the Siemens sites, between-site reliability generally matched the high levels of test-retest reliability of the same IDPs estimated in repeated, within-site, within-subject scans from UK Biobank. Inclusion of the GE site resulted in good-to-excellent reliability for many IDPs, although there were significant between-site differences in mean and scaling, and reduced ICCs, for some classes of IDP, especially T1 contrast and some dMRI-derived measures. We also identified high reliability of quantitative susceptibility mapping (QSM) IDPs derived from swMRI images, multi-network ICA-based IDPs from resting-state fMRI, and olfactory bulb structure IDPs from T1, T2-FLAIR and dMRI data.
These results give confidence that large, multi-site MRI datasets can be collected reliably at different sites across the diverse range of MRI modalities and IDPs that could be mechanistically informative in COVID brain research. We discuss limitations of the study and strategies for further harmonisation of data collected from sites using scanners supplied by different manufacturers. These acquisition and analysis protocols are now in use for MRI assessments of post-COVID patients (N = 700) as part of the ongoing COVID-CNS study.
Issue Title: The Hinode (Solar-B) Mission / Edited by Takashi Sakurai see e-mail The EUV Imaging Spectrometer (EIS) on Hinode will observe solar corona and upper transition region emission lines in ...the wavelength ranges 170-210 Å and 250-290 Å. The line centroid positions and profile widths will allow plasma velocities and turbulent or non-thermal line broadenings to be measured. We will derive local plasma temperatures and densities from the line intensities. The spectra will allow accurate determination of differential emission measure and element abundances within a variety of corona and transition region structures. These powerful spectroscopic diagnostics will allow identification and characterization of magnetic reconnection and wave propagation processes in the upper solar atmosphere. We will also directly study the detailed evolution and heating of coronal loops. The EIS instrument incorporates a unique two element, normal incidence design. The optics are coated with optimized multilayer coatings. We have selected highly efficient, backside-illuminated, thinned CCDs. These design features result in an instrument that has significantly greater effective area than previous orbiting EUV spectrographs with typical active region 2-5 s exposure times in the brightest lines. EIS can scan a field of 6×8.5 arcmin with spatial and velocity scales of 1 arcsec and 25 kms^sup -1^ per pixel. The instrument design, its absolute calibration, and performance are described in detail in this paper. EIS will be used along with the Solar Optical Telescope (SOT) and the X-ray Telescope (XRT) for a wide range of studies of the solar atmosphere. PUBLICATION ABSTRACT
Metabolic programming is important for B cell fate, but the bioenergetic requirement for regulatory B (B
) cell differentiation and function is unknown. Here we show that B
cell differentiation, ...unlike non-B
cells, relies on mitochondrial electron transport and homeostatic levels of reactive oxygen species (ROS). Single-cell RNA sequencing analysis revealed that TXN, encoding the metabolic redox protein thioredoxin (Trx), is highly expressed by B
cells, unlike Trx inhibitor TXNIP which was downregulated. Pharmacological inhibition or gene silencing of TXN resulted in mitochondrial membrane depolarization and increased ROS levels, selectively suppressing B
cell differentiation and function while favoring pro-inflammatory B cell differentiation. Patients with systemic lupus erythematosus (SLE), characterized by B
cell deficiencies, present with B cell mitochondrial membrane depolarization, elevated ROS and fewer Trx
B cells. Exogenous Trx stimulation restored B
cells and mitochondrial membrane polarization in SLE B cells to healthy B cell levels, indicating Trx insufficiency underlies B
cell impairment in patients with SLE.
Chiral amines are valuable building blocks for the pharmaceutical industry. ω-TAms have emerged as an exciting option for their synthesis, offering a potential “green alternative” to overcome the ...drawbacks associated with conventional chemical methods. In this review, we explore the application of ω-TAms for pharmaceutical production. We discuss the diverse array of reactions available involving ω-TAms and process considerations of their use in both kinetic resolution and asymmetric synthesis. With the aid of specific drug intermediates and APIs, we chart the development of ω-TAms using protein engineering and their contribution to elegant one-pot cascades with other enzymes, including carbonyl reductases (CREDs), hydrolases and monoamine oxidases (MAOs), providing a comprehensive overview of their uses, beginning with initial applications through to the present day.
Many important endemic and emerging diseases are transmitted by vectors that are biting arthropods. The functional traits of vectors can affect pathogen transmission rates directly and also through ...their effect on vector population dynamics. Increasing empirical evidence shows that vector traits vary significantly across individuals, populations, and environmental conditions, and at time scales relevant to disease transmission dynamics. Here, we review empirical evidence for variation in vector traits and how this trait variation is currently incorporated into mathematical models of vector-borne disease transmission. We argue that mechanistically incorporating trait variation into these models, by explicitly capturing its effects on vector fitness and abundance, can improve the reliability of their predictions in a changing world. We provide a conceptual framework for incorporating trait variation into vector-borne disease transmission models, and highlight key empirical and theoretical challenges. This framework provides a means to conceptualize how traits can be incorporated in vector borne disease systems, and identifies key areas in which trait variation can be explored. Determining when and to what extent it is important to incorporate trait variation into vector borne disease models remains an important, outstanding question.
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