Success rates of re-excision after positive margins for invasive lobular carcinoma of the breast.

Rates of positive margins after surgical resection of invasive lobular carcinoma (ILC) are high (ranging from 18 to 60%), yet the efficacy of re-excision lumpReceptor subtypeectomy for clearing positive margins is unknown. Concerns about the diffuse nature of ILC may drive increased rates of completion mastectomy to treat positive margins, thus lowering breast conservation rates. We therefore determined the success rate of re-excision lumpectomy in women with ILC and positive margins after surgical resection. We identified 314 cases of stage I-III ILC treated with breast conserving surgery (BCS) at the University of California, San Francisco. Surgical procedures, pathology reports, and outcomes were analyzed using univariate and multivariate statistics and Cox-proportional hazards models. We evaluated outcomes before and after the year 2014, when new margin management consensus guidelines were published. Positive initial margins occurred in 118 (37.6%) cases. Of these, 62 (52.5%) underwent re-excision lumpectomy, which cleared the margin in 74.2%. On multivariate analysis, node negativity was significantly associated with successful re-excision (odds ratio [OR] 3.99, 95% CI 1.15-13.81, p = 0.029). After 2014, we saw fewer initial positive margins (42.7% versus 25.5%, p = 0.009), second surgeries (54.6% versus 20.2%, p < 0.001), and completion mastectomies (27.7% versus 4.5%, p < 0.001). In this large cohort of women with ILC, re-excision lumpectomy was highly successful at clearing positive margins. Additionally, positive margins and completion mastectomy rates significantly decreased over time. These findings highlight improvements in management of ILC, and suggest that completion mastectomy may not be required for those with positive margins after initial BCS

Association between preseason training and performance in elite Australian football

Purpose: To examine the association between preseason training variables and subsequent in-season performance in an elite Australian football team. Methods: Data from 41 elite male Australian footballers (mean [SD] age = 23.4 [3.1] y, height =188.4 [7.1] cm, and mass = 86.7 [7.9] kg) were collected from 1 Australian Football League (AFL) club. Preseason training data (external load, internal load, fitness testing, and session participation) were collected across the 17-wk preseason phase (6 and 11 wk post-Christmas). Champion Data© Player Rank (CDPR), coaches’ ratings, and round 1 selection were used as in-season performance measures. CDPR and coaches’ ratings were examined over the entire season, first half of the season, and the first 4 games. Both Pearson and partial (controlling for AFL age) correlations were calculated to assess if any associations existed between preseason training variables and in-season performance measures. A median split was also employed to differentiate between higher- and lower-performing players for each performance measure. Results: Preseason training activities appeared to have almost no association with performance measured across the entire season and the first half of the season. However, many preseason training variables were significantly linked with performance measured across the first 4 games. Preseason training variables that were measured post-Christmas were the most strongly associated with in-season performance measures. Specifically, total on-field session rating of perceived exertion post-Christmas, a measurement of internal load, displayed the greatest association with performance. Conclusion: Late preseason training (especially on-field match-specific training) is associated with better performance in the early season

Subglacial Drainage Evolution Modulates Seasonal Ice Flow Variability of Three Tidewater Glaciers in Southwest Greenland

B.J.D was funded in the form of a PhD studentship provided by the Scottish Association for Geosciences, Environment and Society (SAGES) and the University of St Andrews, UK. J.M.L is supported by a UKRI Future Leaders Fellowship (Grant No. MR/S017232/1). D.F would like to acknowledge the support of this work through the EPSRC and ESRC Centre for Doctoral Training on Quantification and Management of Risk and Uncertainty in Complex Systems Environments Grant No. (EP/L015927/1).Surface‐derived meltwater can access the bed of the Greenland Ice Sheet, causing seasonal velocity variations. The magnitude, timing and net impact on annual average ice flow of these seasonal perturbations depends on the hydraulic efficiency of the subglacial drainage system. We examine the relationships between drainage system efficiency and ice velocity, at three contrasting tidewater glaciers in southwest Greenland during 2014‐2019, using high‐resolution remotely sensed ice velocities, modelled surface melting, subglacial discharge at the terminus and results from buoyant plume modelling. All glaciers underwent a seasonal speed‐up, which usually coincided with surface melt‐onset, and subsequent slow‐down, which usually followed inferred subglacial channelisation. The amplitude and timing of these speed variations differed between glaciers, with the speed‐up being larger and more prolonged at our fastest study glacier. At all glaciers, however, the seasonal variations in ice flow are consistent with inferred changes in hydraulic efficiency of the subglacial drainage system, and qualitatively indicative of a flow regime in which annually‐averaged ice velocity is relatively insensitive to inter‐annual variations in meltwater supply – so‐called ‘ice flow self‐regulation’. These findings suggest that subglacial channel formation may exert a strong control on seasonal ice flow variations, even at fast‐flowing tidewater glaciers.Publisher PDFPeer reviewe

Retargeting the Coxsackievirus and Adenovirus Receptor to the Apical Surface of Polarized Epithelial Cells Reveals the Glycocalyx as a Barrier to Adenovirus-Mediated Gene Transfer

Lumenal delivery of adenovirus vectors (AdV) results in inefficient gene transfer to human airway epithelium. The human coxsackievirus and adenovirus receptor (hCAR) was detected by immunofluorescence selectively at the basolateral surfaces of freshly excised human airway epithelial cells, suggesting that the absence of apical hCAR constitutes a barrier to adenovirus-mediated gene delivery in vivo. In transfected polarized Madin-Darby canine kidney cells, wild-type hCAR was expressed selectively at the basolateral membrane, whereas hCAR lacking the transmembrane and/or cytoplasmic domains was expressed on both the basolateral and apical membranes. Cells expressing apical hCAR still were not efficiently transduced by AdV applied to the apical surface. However, after the cells were treated with agents that remove components of the apical surface glycocalyx, AdV transduction occurred. These results indicate that adenovirus can infect via receptors located at the apical cell membrane but that the glycocalyx impedes interaction of AdV with apical receptors

Artemin, a Novel Member of the GDNF Ligand Family, Supports Peripheral and Central Neurons and Signals through the GFRα3–RET Receptor Complex

AbstractThe glial cell line–derived neurotrophic factor (GDNF) ligands (GDNF, Neurturin [NTN], and Persephin [PSP]) signal through a multicomponent receptor system composed of a high-affinity binding component (GFRα1–GFRα4) and a common signaling component (RET). Here, we report the identification of Artemin, a novel member of the GDNF family, and demonstrate that it is the ligand for the former orphan receptor GFRα3–RET. Artemin is a survival factor for sensory and sympathetic neurons in culture, and its expression pattern suggests that it also influences these neurons in vivo. Artemin can also activate the GFRα1–RET complex and supports the survival of dopaminergic midbrain neurons in culture, indicating that like GDNF (GFRα1–RET) and NTN (GFRα2–RET), Artemin has a preferred receptor (GFRα3–RET) but that alternative receptor interactions also occur

Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults.

New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved

Oxidative Stress-Induced STIM2 Cysteine Modifications Suppress Store-Operated Calcium Entry

Store-operated calcium entry (SOCE) through STIM-gated ORAI channels governs vital cellular functions. In this context, SOCE controls cellular redox signaling and is itself regulated by redox modifications. However, the molecular mechanisms underlying this calcium-redox interplay and the functional outcomes are not fully understood. Here, we examine the role of STIM2 in SOCE redox regulation. Redox proteomics identify cysteine 313 as the main redox sensor of STIM2 in vitro and in vivo. Oxidative stress suppresses SOCE and calcium currents in cells overexpressing STIM2 and ORAI1, an effect that is abolished by mutation of cysteine 313. FLIM and FRET microscopy, together with MD simulations, indicate that oxidative modifications of cysteine 313 alter STIM2 activation dynamics and thereby hinder STIM2-mediated gating of ORAI1. In summary, this study establishes STIM2-controlled redox regulation of SOCE as a mechanism that affects several calcium-regulated physiological processes, as well as stress-induced pathologies

Epigenetic Drugs Can Stimulate Metastasis through Enhanced Expression of the Pro-Metastatic Ezrin Gene

Ezrin has been reported to be upregulated in many tumors and to participate in metastatic progression. No study has addressed epigenetic modification in the regulation of Ezrin gene expression, the importance of which is unknown. Here, we report that highly metastatic rhabdomyosarcoma (RMS) cells with high levels of Ezrin have elevated acetyl-H3-K9 and tri-methyl-H3-K4 as well as reduced DNA methylation at the Ezrin gene promoter. Conversely, poorly metastatic RMS cells with low levels of Ezrin have reduced acetyl-H3-K9 and elevated methylation. Thus epigenetic covalent modifications to histones within nucleosomes of the Ezrin gene promoter are linked to Ezrin expression, which in fact can be regulated by epigenetic mechanisms. Notably, treatment with histone deacetylase (HDAC) inhibitors or DNA demethylating agents could restore Ezrin expression and stimulate the metastatic potential of poorly metastatic RMS cells characterized by low Ezrin levels. However, the ability of epigenetic drugs to stimulate metastasis in RMS cells was inhibited by expression of an Ezrin-specific shRNA. Our data demonstrate the potential risk associated with clinical application of broadly acting covalent epigenetic modifiers, and highlight the value of combination therapies that include agents specifically targeting potent pro-metastatic genes