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BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC. ispartof: CANCER vol:129 issue:5 pages:697-713 ispartof: location:United States status: published

Coastal aeolian sediment transport is influenced by supply-limiting factors caused by sediment sorting by grain size. Sorting processes can lead to coarsening of the bed surface and influence the formation of aeolian ripples. However, the influence sorting processes and bedforms might have on the magnitude of the transport is not fully understood. This study explores sorting processes and their influence on the magnitude and mode of aeolian transport by using sediment tracers. Sand was painted in different colors according to particle size and placed on a supratidal beach in Noordwijk, the Netherlands. Several experiments were conducted with varying wind speeds. Surface sampling and cameras tracked the sand color movement on the bed surface, and wind velocity was measured. The tracer experiments showed that ripples developed in moderate wind conditions. Once the ripples had formed, the supply of finer tracer grains in the downwind direction decreased over time, while the supply of coarser grains remained constant. A linear relationship between ripple migration speed and wind speed was found. For higher wind speeds, no ripples or differences in transport of grain size fractions were observed. Instead, alternating phases of erosion and deposition of the bed surface were observed, which could not be related to local variations in wind velocity. Based on these results and literature, a conceptual model was developed for an active bed surface layer with two transport regimes corresponding to moderate (I) and high (II) wind speeds. The conceptual model is intended to guide the selection of aeolian sediment transport models as a function of wind speed, bed characteristics, and upwind sediment supply. For Regime I, transport could be modeled using a linear relationship between sediment transport and wind speed and for Regime II using a third power relationship in combination with a process-based model accounting for supply limitations.

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Researchers are currently debating whether theories of addiction explain compulsive overeating of highly processed (HP) foods (i.e., industrially created foods high in refined carbohydrates and/or fat), which contributes to obesity and diet-related disease. A subset of individuals consumes HP foods with behavioral phenotypes that mirror substance use disorders. Withdrawal, the emergence of aversive physical and psychological symptoms upon reduction or cessation of substance use, is a core component of addiction that was central to historical debates about other substances' addictive potential (e.g., nicotine and cocaine). However, no one has systematically considered evidence for whether HP foods cause withdrawal, which represents a key knowledge gap regarding the utility of addiction models for understanding compulsive overeating. Thus, we reviewed evidence for whether animals and humans exhibit withdrawal when reducing or eliminating HP food intake. Controlled experimental evidence indicates animals experience HP food withdrawal marked by neural reward changes and behaviors consistent with withdrawal from other addictive substances. In humans, preliminary evidence supports subjective withdrawal-like experiences. However, most current human research is limited to retrospective recall. Further experimental research is needed to evaluate this construct. We outline future research directions to investigate HP food withdrawal in humans and consider potential clinical implications.

Regulatory T cells (Tregs) play a critical role in immune regulation and peripheral tolerance. While different types of Tregs have been identified in both mice and humans, much of our understanding about how these cells maintain immune homeostasis is derived from animal models. In this study, we examined two distinct human lymphoid organs to understand how repeated exposure to infections at the mucosal surface influences the phenotype and tissue localization of Tregs. We show that while Tregs in both tonsils and spleen express a tissue-resident phenotype, they accumulate in greater numbers in tonsils. Tonsillar-resident Tregs exhibit a highly suppressive phenotype with significantly increased expression of CD39, ICOS and CTLA-4 compared with their counterparts in circulation or in the spleen. Functionally, resident Tregs are able effectively to suppress T cell proliferation. We further demonstrate that tonsillar-resident Tregs share key features of T follicular helper cells. Spatial analysis reveals that the vast majority of resident Tregs are localized at the border of the T-zone and B cell follicle, as well as within the lymphocyte pockets enriched with resident memory T cells. Together our findings suggest that resident Tregs are strategically co-localized to maintain immune homeostasis at sites of recurrent inflammation.

Non-viral vectors represent versatile and immunologically safer alternatives for nucleic acid delivery. Nanoneedles and high-aspect ratio nanostructures are unconventional but interesting delivery systems, in which delivery is mediated by surface interactions. Herein, nanoneedles are synergistically combined with polysaccharide-polyplex nanofilms and enhanced transfection efficiency is observed, compared to polyplexes in suspension. Different polyplex-polyelectrolyte nanofilm combinations are assessed and it is found that transfection efficiency is enhanced when using polysaccharide-based polyanions, rather than being only specific for hyaluronic acid, as suggested in earlier studies. Moreover, results show that enhanced transfection is not mediated by interactions with the CD44 receptor, previously hypothesized as a major mechanism mediating enhancement via hyaluronate. In cardiac tissue, nanoneedles are shown to increase the transfection efficiency of nanofilms compared to flat substrates; while in vitro, high transfection efficiencies are observed in nanostructures where cells present large interfacing areas with the substrate. The results of this study demonstrate that surface-mediated transfection using this system is efficient and safe, requiring amounts of nucleic acid with an order of magnitude lower than standard culture transfection. These findings expand the spectrum of possible polyelectrolyte combinations that can be used for the development of suitable non-viral vectors for exploration in further clinical trials.

Polymersomes are vesicular structures self-assembled from amphiphilic block copolymers and are considered an alternative to liposomes for applications in drug delivery, immunotherapy, biosensing, and as nanoreactors and artificial organelles. However, the limited availability of systematic stability, protein fouling (protein corona formation), and blood circulation studies hampers their clinical translation. Poly(2-oxazoline)s (POx) are valuable antifouling hydrophilic polymers that can replace the current gold-standard, poly(ethylene glycol) (PEG), yet investigations of POx functionality on nanoparticles are relatively sparse. Herein, a systematic study is reported of the structural, dynamic and antifouling properties of polymersomes made of poly(2-methyl-2-oxazoline)-block-poly(dimethylsiloxane)-block-poly(2-methyl-2-oxazoline) (PMOXA-b-PDMS-b-PMOXA). The study relates in vitro antifouling performance of the polymersomes to atomistic molecular dynamics simulations of polymersome membrane hydration behavior. These observations support the experimentally demonstrated benefit of maximizing the length of PMOXA (degree of polymerization (DP) > 6) while keeping PDMS at a minimal length that still provides sufficient membrane stability (DP > 19). In vitro macrophage association and in vivo blood circulation evaluation of polymersomes in zebrafish embryos corroborate these findings. They further suggest that single copolymer presentation on polymersomes is outperformed by blends of varied copolymer lengths. This study helps to rationalize design rules for stable and low-fouling polymersomes for future medical applications.

Aim To conduct a prospective, consecutive cohort study to evaluate the incidence of allergen-specific and total immunoglobulin E (IgE) in a paediatric population undergoing adenotonsillectomy for sleep-disordered breathing. Methods A total of 64 consecutive patients presenting for adenotonsillectomy at a single centre were recruited over a period of 3 months. All patients underwent adenotonsillectomy and had allergen-specific and total IgE serum testing at the time of anaesthesia induction. Pre-operative history and examination were conducted to determine clinical allergy. Caregivers completed the Sleep-Related Breathing Disorder scale of the Paediatric Sleep Questionnaire and the Mini Rhinoconjunctivitis Quality of Life Questionnaire at baseline and at 6 weeks post-operatively. Results A total of 37 (57.8%) patients had either allergen-specific or total IgE positivity. House dust mite was the most prevalent allergen-specific IgE finding, being present in moderate to high levels in 14 (21.9%) patients. A total of 17 (26.6%) patients had a history of atopy, while 34 (53.1%) had examination findings suggestive of allergy. Neither serum IgE testing nor clinical history and examination were independently associated with residual symptoms post adenotonsillectomy. Patients with concomitant serum IgE positivity and clinical allergy had higher residual symptom scores compared to those who did not using both Sleep-Related Breathing Disorder scale of the Paediatric Sleep Questionnaire (P = 0.035) and Mini Rhinoconjunctivitis Quality of Life Questionnaire (P = 0.02) questionnaires. Conclusions Our prospective, consecutive cohort of patients reflect a greater incidence of serum IgE positivity compared to historical figures. When utilised with clinical findings on history and examination, serum IgE is a useful adjunct that is associated with greater residual symptoms post-adenotonsillectomy.

AMPA receptors are tetrameric glutamate‐gated ion channels that mediate a majority of fast excitatory neurotransmission in the brain. They exist as calcium‐impermeable (CI‐) and calcium‐permeable (CP‐) subtypes, the latter of which lacks the GluA2 subunit. CP‐AMPARs display an array of distinctive biophysical and pharmacological properties that allow them to be functionally identified. This has revealed that they play crucial roles in diverse forms of central synaptic plasticity. Here we summarise the functional hallmarks of CP‐AMPARs and describe how these are modified by the presence of auxiliary subunits that have emerged as pivotal regulators of AMPARs. A lasting change in the prevalence of GluA2‐containing AMPARs, and hence in the fraction of CP‐AMPARs, is a feature in many maladaptive forms of synaptic plasticity and neurological disorders. These include modifications of glutamatergic transmission induced by inflammatory pain, fear conditioning, cocaine exposure, and anoxia‐induced damage in neurons and glia. Furthermore, defective RNA editing of GluA2 can cause altered expression of CP‐AMPARs and is implicated in motor neuron damage (amyotrophic lateral sclerosis) and the proliferation of cells in malignant gliomas. A number of the players involved in CP‐AMPAR regulation have been identified, providing useful insight into interventions that may prevent the aberrant CP‐AMPAR expression. Furthermore, recent molecular and pharmacological developments, particularly the discovery of TARP subtype‐selective drugs, offer the exciting potential to modify some of the harmful effects of increased CP‐AMPAR prevalence in a brain region‐specific manner., figure legend AMPARs containing GluA2 (red subunits) are Ca2+‐impermeable (CI‐AMPARs). Those that lack GluA2 are Ca2+‐permeable (CP‐AMPARs) and are implicated in diverse forms of synaptic plasticity and disease. Both native CP‐ and CI‐AMPARs contain various auxiliary subunits (shown as yellow, green or turquoise) that affect AMPAR function and play a role in the regulation of relative CP‐/CI‐AMPAR prevalence. Image based on PDB model 6NJM.

Objective 'Comfort eating' has been used to explain real-world food choices, suggesting that individuals are drawn to energy-dense ('unhealthy') snacks when experiencing negative affect. However, this concept has rarely been studied, particularly in real-world settings. Similarly, the effects of snacking on subsequent affect are also poorly understood. The present study aimed to examine the association between affect and snacking in daily life. Methods One hundred and forty-one adults recorded their food intake in real time for ~14 days using a study issued mobile phone. Participants also responded to randomly timed assessments. During both types of assessments, participants indicated their current level of affect. By anchoring off snacking events, the trajectory of affect in the hours leading up to - and following - snacking was explored. Results In the three hours leading up to a healthy snack, affect was stable. In contrast, affect fell during the hours leading up to an unhealthy snack. The interaction between snack type and time was significant. A similar, but opposite, pattern was seen following snacking: where affect decreased after unhealthy snacking, affect increased following healthy snack intake. Conclusion The findings are consistent with the hypothesis of comfort eating, with unhealthy snacking being preceded by worsening affect. Unhealthy snacking did not, however, lead to affect improvements afterwards, which questions the 'effectiveness' of comfort eating. The intake of healthy snacks however was associated with positive affective experiences. These findings could function as a component of interventions aiming at improving dietary behaviours.

Surgery for adult obstructive sleep apnoea (OSA) plays a key role in contemporary management paradigms, most frequently as either a second‐line treatment or in a facilitatory capacity. This committee, comprising two sleep surgeons and three sleep physicians, was established to give clarity to that role and expand upon its appropriate use in Australasia. This position statement has been reviewed and approved by the Australasian Sleep Association (ASA) Clinical Committee.

Coral reefs represent an efficient natural mechanical coastal defense against ocean waves. The focus of this study is La Saline fringing coral reef, located in the microtidal West of La Réunion Island in the Indian Ocean, frequently exposed to Southern Ocean swell and cyclonic events. The aim is to provide a better understanding of the reef's coastal defense characteristics for several Southern Ocean swell events. Pressure sensors were placed across the reef to measure water level fluctuations and to study wave transformation. A numerical model (XBeach surfbeat), validated using field observations, was used to deepen understanding of wave transformation, wave setup and runup. Field measurements and model outputs show that as gravity waves dissipate over the reef, and frequency-dependent dissipation of infragravity waves by bottom-friction occurs, the reef acts as a low-pass filter. Wave-induced setup is found to be the dominant hydrodynamic component. Setup and runup are each 98% and 79% driven by the offshore significant wave height, and 2% and 21% driven by the tide. The modulation of the water level by setup is the main contributor to runup in the fringing reef. At semidiurnal timescales, setup and runup are in antiphase with tidal variations as lower water levels result in higher gravity wave energy dissipation, setup and runup. Simple-to-use transfer functions relating incident wave characteristics to these hydrodynamic components are proposed. The effects of bottom friction and water level on the defensive capacity of the coral reef highlight future implications of structural damage and sea level rise. Key Points Study of wave transformation over La Saline fringing reef, a natural coastal defense against Southern Ocean swell and cyclonic events As gravity waves dissipate over the fringing reef, significant energy transfer to infragravity and very low frequency bands occurs Wave setup and runup are greater for higher offshore wave height (HS0) and lower water level. Modeled runup scales as ≈20% of HS0 Plain Language Summary Coral reefs protect the coastline from ocean waves. The protective characteristics of reefs are site-dependent as they vary according to a number of parameters such as coral health, water depth, oceanic and meteorological conditions. La Saline fringing reef on La Reunion Island is frequently exposed to Southern Ocean swell and cyclonic events. Accompanied by numerical modeling efforts, pressure sensors placed across the reef allow to study water level fluctuations for a range of swell events and tides. Results show that waves transform as they break and dissipate over the reef, as the energy of higher-frequency waves is transferred toward lower frequencies. At the study site, offshore significant wave height is the main driver of the reef hydrodynamics. The tide also contributes by modulating the water level over the reef flat. In the context of predicted sea level rise in recent climate change scenarios, as well as possible reef health decline, present study results suggest that the protective capacity of the La Saline fringing reef could decline, thus altering future reef hydrodynamics and associated sediment transport.