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Magnesium and its alloys are the most investigated materials for solid-state hydrogen storage in the form of metal hydrides, but there are still unresolved problems with the kinetics and thermodynamics of hydrogenation and dehydrogenation of this group of materials. Severe plastic deformation (SPD) methods, such as equal-channel angular pressing (ECAP), high-pressure torsion (HPT), intensive rolling and fast forging, have been widely used to enhance the activation, air resistance, and hydrogenation/dehydrogenation kinetics of Mg-based hydrogen storage materials by introducing ultrafine/nanoscale grains and crystal lattice defects. These severely deformed materials, particularly in the presence of alloying additives or second-phase nanoparticles, can show not only fast hydrogen absorption/desorption kinetics but also good cycling stability. It was shown that some materials that are apparently inert to hydrogen can absorb hydrogen after SPD processing. Moreover, the SPD methods were effectively used for hydrogen binding-energy engineering and synthesizing new magnesium alloys with low thermodynamic stability for reversible low/room-temperature hydrogen storage, such as nanoglasses, high-entropy alloys, and metastable phases including the high-pressure {\gamma}-MgH2 polymorph. This article reviews recent advances in the development of Mg-based hydrogen storage materials by SPD processing and discusses their potential in future applications.

PURPOSE In the United States, the National Cancer Institute National Cancer Clinical Trials Network (NCTN) groups have conducted publicly funded oncology research for 50 years. The combined impact of all adult network group trials has never been systematically examined. METHODS We identified randomized, phase III trials from the adult NCTN groups, reported from 1980 onward, with statistically significant findings for ≥ 1 clinical, time-dependent outcomes. In the subset of trials in which the experimental arm improved overall survival, gains in population life-years were estimated by deriving trial-specific hazard functions and hazard ratios to estimate the experimental treatment benefit and then mapping this trial-level benefit onto the US cancer population using registry and life-table data. Scientific impact was based on citation data from Google Scholar. Federal investment costs per life-year gained were estimated. The results were derived through December 31, 2020. RESULTS One hundred sixty-two trials comprised of 108,334 patients were analyzed, representing 29.8% (162/544) of trials conducted. The most common cancers included breast (34), gynecologic (28), and lung (14). The trials were cited 165,336 times (mean, 62.2 citations/trial/year); 87.7% of trials were cited in cancer care guidelines in favor of the recommended treatment. These studies were estimated to have generated 14.2 million (95% CI, 11.5 to 16.5 million) additional life-years to patients with cancer, with projected gains of 24.1 million (95% CI, 19.7 to 28.2 million) life-years by 2030. The federal investment cost per life-year gained through 2020 was $326 in US dollars. CONCLUSION NCTN randomized trials have been widely cited and are routinely included in clinical guidelines. Moreover, their conduct has predicted substantial improvements in overall survival in the United States for patients with oncologic disease, suggesting they have contributed meaningfully to this nation's health. These findings demonstrate the critical role of government-sponsored research in extending the lives of patients with cancer.

G protein-coupled receptors (GPCRs) are key modulators of cell signaling. Multiple GPCRs are present in the heart where they regulate cardiac homeostasis including processes such as myocyte contraction, heart rate and coronary blood flow. GPCRs are pharmacological targets for several cardiovascular disorders including heart failure (HF) such as beta-adrenergic receptor (βAR) blockers and angiotensin II receptor (AT1R) antagonists. The activity of GPCRs are finely regulated by GPCR kinases (GRKs), which phosphorylate agonist-occupied receptors and start the process of desensitization. Among the seven members of the GRK family, GRK2 and GRK5 are predominantly expressed in the heart, where they exhibit both canonical and non-canonical functions. Both kinases are known to be increased in cardiac pathologies and contribute to pathogenesis through their roles in different cellular compartments. Lowering or inhibiting their actions mediate cardioprotective effects against pathological cardiac growth and failing heart. Therefore, given their importance in cardiac dysfunction, these kinases are drawing attention as promising targets for the treatment of HF, which needs improved therapies. Over the past three decades, broad knowledge on GRK inhibition in HF has been gained by studies using genetically engineered animal models or through gene therapy with peptide inhibitors or using small molecule inhibitors. In this mini review, we summarize the work focusing on GRK2 and GRK5 but also discuss a couple of the non-abundant cardiac subtypes and their multi-functional roles in the normal and diseased heart and the potential and therapeutic targets.

Background: Loss of brain-derived neurotrophic factor (BDNF)/TrkB (tropomyosin kinase receptor B) signaling accounts for brain and cardiac disorders. In neurons, β-adrenergic receptor stimulation enhances local BDNF expression. It is unclear if this occurs in a pathophysiological relevant manner in the heart, especially in the β-adrenergic receptor-desensitized postischemic myocardium. Nor is it fully understood whether and how TrkB agonists counter chronic postischemic left ventricle (LV) decompensation, a significant unmet clinical milestone. Methods: We conducted in vitro studies using neonatal rat and adult murine cardiomyocytes, SH-SY5Y neuronal cells, and umbilical vein endothelial cells. We assessed myocardial ischemia (MI) impact in wild type, β3AR knockout, or myocyte-selective BDNF knockout (myoBDNF KO) mice in vivo (via coronary ligation [MI]) or in isolated hearts with global ischemia-reperfusion (I/R). Results: In wild type hearts, BDNF levels rose early after MI ( Conclusions: BDNF loss underscores chronic postischemic heart failure. TrkB agonists can improve ischemic LV dysfunction via replenished myocardial BDNF content. Direct cardiac β3AR stimulation, or β-blockers (via upregulated β3AR), is another BDNF-based means to fend off chronic postischemic heart failure.

Non-pharmacologic adjuncts to opioid analgesics for burn wound debridement enhance safety and cost effectiveness in care. The current study explored the feasibility of using a custom portable water-friendly immersive VR hardware during burn debridement in adults, and tested whether interactive VR would reduce pain more effectively than nature stimuli viewed in the same VR goggles.Forty-eight patients with severe burn injuries (44 adults and 4 children) had their burn injuries debrided and dressed in a wet wound care environment on Study Day 1, and 13 also participated in Study Day 2.The study used a within-subject design to test two hypotheses (one hypothesis per study day) with the condition order randomized. On Study Day 1, each individual (n = 44 participants) spent 5 min of wound care in an interactive immersive VR environment designed for burn care, and 5 min looking at still nature photos and sounds of nature in the same VR goggles. On Study Day 2 (n = 12 adult participants and one adolescent from Day 1), each participant spent 5 min of burn wound care with no distraction and 5 min of wound care in VR, using a new water-friendly VR system. On both days, during a post-wound care assessment, participants rated and compared the pain they had experienced in each condition. OUTCOME MEASURES ON STUDY DAYS 1 AND 2: Worst pain during burn wound care was the primary dependent variable. Secondary measures were ratings of time spent thinking about pain during wound care, pain unpleasantness, and positive affect during wound care.On Study Day 1, no significant differences in worst pain ratings during wound care were found between the computer-generated world (Mean = 71.06, SD = 26.86) vs. Nature pictures conditions (Mean = 68.19, SD = 29.26; t 1, NS). On secondary measures, positive affect (fun) was higher, and realism was lower during computer-generated VR. No significant differences in pain unpleasantness or "presence in VR" between the two conditions were found, however. VR VS. NO VR. (STUDY DAY 2): Participants reported significantly less worst pain when distracted with adjunctive computer generated VR than during standard wound care without distraction (Mean = 54.23, SD = 26.13 vs 63.85, SD = 31.50, t(11) = 1.91, p .05, SD = 17.38). In addition, on Study Day 2, "time spent thinking about pain during wound care" was significantly less during the VR condition, and positive affect was significantly greater during VR, compared to the No VR condition.The current study is innovative in that it is the first to show the feasibility of using a custom portable water-friendly immersive VR hardware during burn debridement in adults. However, contrary to predictions, interactive VR did not reduce pain more effectively than nature stimuli viewed in the same VR goggles.

PURPOSE Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4–blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy. PATIENTS AND METHODS In a phase III trial, patients with treatment-naive BRAFV600-mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety. RESULTS A total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A ( P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B ( P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated. CONCLUSION Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

Problem definition: Bargaining situations are ubiquitous in economics and management. We consider the problem of bargaining for a fair ex ante distribution of random profits arising from a cooperative effort of a fixed set of risk-averse agents. Our approach integrates optimal managerial decision making into bargaining situations with random outcomes and explicitly models the impact of risk aversion. The proposed solution rests on a firm axiomatic foundation and yet allows to compute concrete bargaining solutions for a wide range of practically relevant problems. Methodology/results: We model risk preferences using coherent acceptability functionals and base our bargaining solution on a set of axioms that can be considered a natural extension of Nash bargaining to our setting. We show that the proposed axioms fully characterize a bargaining solution, which can be efficiently computed by solving a stochastic optimization problem. We characterize special cases where random payoffs of players are simple functions of overall project profit. In particular, we show that, for players with distortion risk functionals, the optimal bargaining solution can be represented by an exchange of standard options contracts with the project profit as the underlying asset. We illustrate the concepts in the paper with a detailed example of risk-averse households that jointly invest into a solar plant. Managerial implications: We demonstrate that there is no conflict of interest between players about management decisions and that risk aversion facilitates cooperation. Furthermore, our results on the structure of optimal contracts as a basket of option contracts provides valuable guidance for negotiators. Supplemental Material: The online appendix is available at https://doi.org/10.1287/msom.2021.1076 .

The presence of a 22q11.2 microdeletion (22q11.2 deletion syndrome [22q11DS]) ranks among the greatest known genetic risk factors for the development of psychotic disorders. There is emerging evidence that the cerebellum is important in the pathophysiology of psychosis. However, there is currently limited information on cerebellar neuroanatomy in 22q11DS specifically.High-resolution 3T magnetic resonance imaging was acquired in 79 individuals with 22q11DS and 70 typically developing control subjects (N = 149). Lobar and lobule-level cerebellar volumes were estimated using validated automated segmentation algorithms, and subsequently group differences were compared. Hierarchical clustering, principal component analysis, and graph theoretical models were used to explore intercerebellar relationships. Cerebrocerebellar structural connectivity with cortical thickness was examined via linear regression models.Individuals with 22q11DS had, on average, 17.3% smaller total cerebellar volumes relative to typically developing subjects (p.0001). The lobules of the superior posterior cerebellum (e.g., VII and VIII) were particularly affected in 22q11DS. However, all cerebellar lobules were significantly smaller, even after adjusting for total brain volumes (all cerebellar lobules p.0002). The superior posterior lobule was disproportionately associated with cortical thickness in the frontal lobes and cingulate cortex, brain regions known be affected in 22q11DS. Exploratory analyses suggested that the superior posterior lobule, particularly Crus I, may be associated with psychotic symptoms in 22q11DS.The cerebellum is a critical but understudied component of the 22q11DS neuroendophenotype.

Summary The authors of a recent study identified noncanonical peptides (NCP) presented by cancer cells’ HLA and observed lack of reactivity to these antigens by endogenous tumor-reactive T cells. In vitro sensitization generated NCP-reactive T cells that recognized epitopes shared by a majority of cancers tested, providing opportunities for novel therapies to shared antigens. See related article by Lozano-Rabella et al., p. xxx

This work reports the first record of Batrachochytrium dendrobatidis (Bd) infection in the endangered La Banderita marsupial frog Gastrotheca gracilis from the Southern Yungas Andean forest. We analysed swab samples from the oral discs of 20 tadpoles and histological sections from two post-metamorphic individuals. We found 60 % of the tadpoles to be infected, and the histological sections revealed the presence of zoosporangia of Bd in different maturation stages. The signs of infection confirm the presence of Bd, which may pose a threat to the endangered La Banderita marsupial frog populations. Keywords: conservation, Batrachochytrium dendrobatidis, chytridfungus infection, Hemiphractidae, tadpoles

Cardiovascular diseases (CVDs) represent the leading cause of death globally. Despite major advances in the field of pharmacological CVD treatments, particularly in the field of heart failure (HF) research, case numbers and overall mortality remain high and have trended upwards over the last few years. Thus, identifying novel molecular targets for developing HF therapeutics remains a key research focus. G protein-coupled receptors (GPCRs) are critical myocardial signal transducers which regulate cardiac contractility, growth, adaptation and metabolism. Additionally, GPCR dysregulation underlies multiple models of cardiac pathology, and most pharmacological therapeutics currently used in HF target these receptors. Currently-approved treatments have improved patient outcomes, but therapies to stop or reverse HF are lacking. A recent focus on GPCR intracellular-regulating proteins such as GPCR kinases (GRKs) has uncovered GRK2 as a promising target for combating HF. Current literature strongly establishes increased levels and activity of GRK2 in multiple models of CVD. Additionally, the GRK2 interactome includes numerous proteins which interact with differential domains of GRK2 to modulate both beneficial and deleterious signaling pathways in the heart, indicating that these domains can be targeted with a high level of specificity unique to various cardiac pathologies. These data support the premise that GRK2 should be at the forefront of a novel investigative drug search. This perspective reviews cardiac GPCRs, describes the structure and functions of GRK2 in cardiac function and maladaptive pathology, and summarizes the ongoing and future research for targeting this critical kinase across cellular, animal and human models of cardiac dysfunction and HF.

Com o intuito de avaliar a eficácia dos programas de prevenção e controle dos carcinomas de colo uterino, realizou-se um estudo comparativo de sua incidência nos últimos 13 anos. Foram estudados 131 prontuários de pacientes portadoras de câncer de colo uterino, sendo 53 (40,5%) incipientes e 78 (59,5%) avançados. Todas as doentes foram atendidas no Hospital das Clínicas da UFMG, em 1979 (n=73) e em 1992 (n=58). Houve um aumento (p=0,048) no número de diagnósticos de carcinoma incipiente e uma diminuição (p=0,048) no número de cânceres avançados. A idade mediana das pacientes com carcinoma incipiente foi de 38,0 anos, em 1979, e de 36,0 anos em 1992. Todavia, a idade mediana do diagnóstico do carcinoma avançado não se alterou, mantendo-se em 50,0 anos. Esses dados sugerem que, apesar de uma eficácia maior dos programas e métodos de prevenção e controle das neoplasias do colo uterino, eles não conseguiram atingir satisfatoriamente a população. Esses programas deveriam atingir mulheres começando antes dos trinta anos.

The subtleties of human perception, as measured by vision scientists through the use of psychophysics, are important clues to the internal workings of visual recognition. For instance, measured reaction time can indicate whether a visual stimulus is easy for a subject to recognize, or whether it is hard. In this paper, we consider how to incorporate psychophysical measurements of visual perception into the loss function of a deep neural network being trained for a recognition task, under the assumption that such information can enforce consistency with human behavior. As a case study to assess the viability of this approach, we look at the problem of handwritten document transcription. While good progress has been made towards automatically transcribing modern handwriting, significant challenges remain in transcribing historical documents. Here we describe a general enhancement strategy, underpinned by the new loss formulation, which can be applied to the training regime of any deep learning-based document transcription system. Through experimentation, reliable performance improvement is demonstrated for the standard IAM and RIMES datasets for three different network architectures. Further, we go on to show feasibility for our approach on a new dataset of digitized Latin manuscripts, originally produced by scribes in the Cloister of St. Gall in the the 9th century.

Hematite, the mineral that gives color to bright red iron ochres, occurs naturally, but there is much evidence that early humans sometimes artificially produced hematite by heating a related mineral, goethite, in wood fires. This represents an important cognitive and technological advance in early human prehistory. Thus, there is a need to distinguish natural hematite from hematite generated by heating goethite in a wood fire. Measuring the line widths of powder X-ray diffraction (XRD) in hematite has been explored, and synthetic goethite heated in a modern furnace has been used as a model system for studying this process. We now show that to be an inappropriate model. Although chemically identical, natural goethite is physically different from and much more variable than goethite produced in a laboratory. Furthermore, by replicating the process using Stone Age technology, we show that heating goethite in a wood fire complicates the interpretation of XRD line widths of the resulting hematite. We conclude that strategies other than powder XRD are necessary to draw conclusions about the ancient processing of iron ochres.

The Helping to End Addiction Long-termIn 2020, the National Institutes of Health (NIH) held the Target Validation for Non-Addictive Therapeutics Development for Pain workshop to gather insights from key opinion leaders in academia, industry, and venture-financing.The result was a roadmap for pain target validation focusing on three modalities: 1) human evidence; 2) assay development

The postprandial glycemic response is an important metabolic health factor, which, from laboratory studies, is known to change from low to high over the course of the day, and from which negative health outcomes have been linked to nightly eating. We applied interstitial continuous glucose monitoring to examine the glycemic response to a standardized carbohydrate-rich snack (198 kcal) across the day in a real-life setting. Twenty-four healthy participants (12 men, 12 women, 27–61 y old) consumed the snack nine times during 6 d in a crossover design, altering the time of consumption between morning, afternoon and evening. The snack was consumed in the participant’s own environment with a preceding fast of at least 2.5 h between their customary main meals and practices. Linear mixed models were used with fixed effect of timing, and participant as random effect, to assess incremental area under the curve, peak value and time-to-peak of the glycemic response. Overall, the highest glycemic excursions were observed in the morning, while a more dampened but prolonged response was observed in the evening. These findings do not concur with previously published laboratory studies. This implies that results obtained under controlled experimental conditions in laboratories cannot be generalized directly to predict chrononutritional effects on the glycemic response in healthy individuals and their daily routines.

Urinary tract infections are among the most common human bacterial infections and place a significant burden on healthcare systems due to associated morbidity, cost, and antibiotic use. Despite being a facultative anaerobe, uropathogenic Escherichia coli (UPEC), the primary cause of urinary tract infections, requires aerobic respiration to establish infection in the bladder. By combining bacterial genetics with cell culture and murine models of infection, we demonstrate that the widely conserved respiratory quinol oxidase cytochrome bd is required for intracellular infection of urothelial cells. Through a series of genetic, biochemical, and functional assays, we show that intracellular oxygen scavenging by cytochrome bd alters mitochondrial physiology by reducing the efficiency of mitochondrial respiration, stabilizing the hypoxia inducible transcription factor HIF-1, and promoting a shift toward aerobic glycolysis. This bacterially induced rewiring of host metabolism antagonizes apoptosis, thereby protecting intracellular bacteria from urothelial cell exfoliation and preserving their replicative niche. These results reveal the metabolic basis for intracellular bacterial pathogenesis during urinary tract infection and identify subversion of mitochondrial metabolism as a bacterial strategy to facilitate persistence within the urinary tract.

Purpose/Objective Multiple tumorous lesions in one pituitary gland are rare and mostly described in case reports. Their incidences and combinations are defined in larger collectives. Therefore, we analyzed our large collection for double tumors and combinations of tumors, cysts, and inflammation. Methods The German Registry of Pituitary Tumors, including cases from 1990 to 2018, served as the database. Our collection comprises a total of 16,283 cases up until the end of 2018. Of these cases, 12,673 originated from surgical and 3,610 from autopsy material. All specimens were fixed in formalin and embedded in paraffin. The sections were stained with hematoxylin–eosin and PAS. Monoclonal (prolactin, TSH, FSH, LH, and α subunit) or polyclonal (GH and ACTH) antibodies were used to detect pituitary hormones in the lesions. Since 2017, antibodies against the transcription factors Pit-1, T-Pit, and SF-1 have been used in difficult cases. The criteria of the 2017 WHO classification have been basic principles for classification since 2018 (Osamura et al. 2017). For differentiation of other sellar tumors, such as meningiomas, chordomas, or metastases, the use of additional antibodies was necessary. For these cases, it was possible to use a broad antibody spectrum. Autopsy pituitaries were generally studied by H&E and PAS sections. If any lesions were demonstrated in these specimens, additional immunostaining was performed. Results Multiple tumorous lesions with more than one pituitary neuroendocrine tumor (PitNET) respectively adenoma make up 1.4% (232 cases) in our collection. Within the selected cases, synchronous multiple pituitary neuroendocrine tumors (PitNETs) account for 17.3%, PANCH cases (pituitary adenoma with neuronal choristoma) for 14.7%, PitNETs and posterior lobe tumors for 2.2%, PitNETs and metastases for 5.2%, PitNETs and mesenchymal tumors for 2.6%, PitNETs and cysts for 52.2%, and PitNETs and primary inflammation for 6.0%. The mean patient age was 53.8 years, with a standard deviation of 18.5 years. A total of 55.3% of the patients were female and 44.7% were male. From 1990 to 2018, there was a continuous increase in the number of multiple tumorous lesions. Conclusion From our studies, we conclude that considering possible tumorous double lesions during surgeries and in preoperative X-ray analyses is recommended.

The critical role of G protein–coupled receptor kinase 2 (GRK2) in regulating cardiac function has been well documented for >3 decades. Targeting GRK2 has therefore been extensively studied as a novel approach to treating cardiovascular disease. However, little is known about its role in hemostasis and thrombosis. We provide here the first evidence that GRK2 limits platelet activation and regulates the hemostatic response to injury. Deletion of GRK2 in mouse platelets causes increased platelet accumulation after laser-induced injury in the cremaster muscle arterioles, shortens tail bleeding time, and enhances thrombosis in adenosine 5′-diphosphate (ADP)-induced pulmonary thromboembolism and in FeCl3-induced carotid injury. GRK2−/− platelets have increased integrin activation, P-selectin exposure, and platelet aggregation in response to ADP stimulation. Furthermore, GRK2−/− platelets retain the ability to aggregate in response to ADP restimulation, indicating that GRK2 contributes to ADP receptor desensitization. Underlying these changes in GRK2−/− platelets is an increase in Ca2+ mobilization, RAS-related protein 1 activation, and Akt phosphorylation stimulated by ADP, as well as an attenuated rise of cyclic adenosine monophosphate levels in response to ADP in the presence of prostaglandin I2. P2Y12 antagonist treatment eliminates the phenotypic difference in platelet accumulation between wild-type and GRK2−/− mice at the site of injury. Pharmacologic inhibition of GRK2 activity in human platelets increases platelet activation in response to ADP. Finally, we show that GRK2 binds to endogenous Gβγ subunits during platelet activation. Collectively, these results show that GRK2 regulates ADP signaling via P2Y1 and P2Y12, interacts with Gβγ, and functions as a signaling hub in platelets for modulating the hemostatic response to injury.

This special Issue of the Journal of Cross-Cultural Psychology celebrates the 50th anniversary of the founding of the International Association for Cross-Cultural Psychology (IACCP) in 1972. This article seeks to provide a summary of the main influences that led to its founding, and the events and activities that followed. In this article, we search for the many relationships between cultural and behavioral phenomena, beginning around the turn of the 20th century, and continuing to the present. This review follows a chronological sequence and is organized according to the main events that led to the founding of IACCP.

Background Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody–drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. Methods In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. Results There were 639 randomized patients (median age 60, range 22–84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82–1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70–1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56–0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61–0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3–4), causing 12% to discontinue. Conclusions Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.

Surplus Production Models of North Atlantic swordfish have been used in addition to age structured virtual population analyses by ICCAT's SCRS to evaluate the status of the resource and to provide a basis for management advice. Production models require a standardized index of relative abundance in terms of biomass. The standardized biomass index of abundance developed for the 2006, 2008 and 2012 ICCAT SCRS meetings for North Atlantic swordfish was revised and updated with data through 2015. Generalized Linear Modeling (GLM) procedures were used to standardize swordfish catch (biomass) and effort (number of hooks) data from the major longline fleets operating in the North Atlantic; United States, EU-Spain, Canada, Japan, Morocco and EU-Portugal. As in past analyses, main effects included: year, area, quarter, a nation-operation variable accounting for gear and operational differences thought to influence swordfish catchability, and a target variable to account for trips where fishing operations varied according to the main target species. Interactions among main factors were also evaluated. 0

While the conceptual underpinnings of the circular economy (CE) date back to the 1970s, the concept has recently become a major discourse in contemporary sustainability debates. The idea of CE, as it is now understood, is thus rather new and remains in conceptual development. Moreover, it is a contested concept with many different circular visions competing in the discursive sphere. Many researchers have evidenced that dominant CE propositions focus on technocentric solutions and do not address crucial social, political, and ecological implications. This opinion paper seeks to help address this gap by going to the root of the CE metaphor and asking: What do circles, cycles, and flows mean for an economy and a society? To answer this question, this article unpacks the idea of cycles, loops, and flows by analysing what socio-ecological cycles are most relevant for sustainability and circularity. It thus finds a set of seven cycles that are key to better understanding CE and its relation to human and planetary well-being (biogeochemical, ecosystem, resource, power, wealth, knowledge, and care cycles). This article then analyses how and whether dominant CE discourses currently address these cycles. This paper proposes the idea of a circular society as an umbrella concept that can help us better address the critical ecological, social, and political implications of a circularity transition. Moreover, this article develops a set of interrelated strategies to operationalise the circular society concept. This paper thus hopes to contribute to expanding the imaginary regarding the concept of circularity that can help the cross-pollination of ideas, solutions, and approaches to face the manyfold socio-ecological challenges of the twenty-first century.

To investigate relationships between weight loss and weight loss maintenance with cardiac autonomic function and exercise in obesity, 39 adults (45.7±10.7 years; BMI: 34.2±3.4 kg/m2) participated in a 10-week, medical weight loss program combined with aerobic exercise. A subset (n=18) participated in an aerobic exercise weight loss maintenance program (550 or 970 MET minutes/week) for 18 additional weeks. Primary outcomes included markers of cardiac autonomic function assessed by heart rate variability (HRV) (i.e., SDNN, RMSSD, HFln). Following weight loss, we observed significant improvements for SDNN (48.2±19.1 vs. 55.1±25.9 ms, p=0.03) RMSSD (37.7±24.0 vs. 47.9±29.1 ms, p=0.002), and HFln (5.88±1.34 vs. 6.32±1.28 ms, p=0.001). Regression analyses showed fasting insulin concentration predicted 24% and 27% of the variance in RMSSD (r2=0.236, p=0.007) and HFln (r2=0.274, p=0.004), respectively. Following weight loss maintenance, no significant changes in HRV were observed. Changes in LDL (r=–0.54, p=0.04) and non-HDL (r=–0.77, p=0.001) were inversely associated with RMSSD changes. Clinically significant weight loss via caloric restriction and aerobic exercise improved HRV markers of cardiac vagal modulation. Following weight loss maintenance, we did not observe any further changes in HRV. Thus, our data suggests commonly prescribed exercise volumes contribute to maintenance of parasympathetic modulation following medical weight loss programming and exercise.

Severe pain is a widespread health problem in need of novel treatment approaches. In the current study we used real water to give virtual objects (i.e., animated virtual water) more realistic physical properties (wet liquid qualities). Healthy volunteers aged 18–34 participated in a within-subject randomized study comparing participants’ worst pain during brief thermal stimuli with (1) No Immersive Virtual Reality (VR), versus (2) during VR + no tactile feedback versus (3) VR + real water (with tactile feedback from co-located real objects). Tactile feedback significantly decreased pain intensity (VR analgesia, p

Laboratory models are critical to basic and translational microbiology research. Models serve multiple purposes, from providing tractable systems to study cell biology to allowing the investigation of inaccessible clinical and environmental ecosystems. Although there is a recognized need for improved model systems, there is a gap in rational approaches to accomplish this goal. We recently developed a framework for assessing the accuracy of microbial models by quantifying how closely each gene is expressed in the natural environment and in various models. The accuracy of the model is defined as the percentage of genes that are similarly expressed in the natural environment and the model. Here, we leverage this framework to develop and validate two generalizable approaches for improving model accuracy, and as proof of concept, we apply these approaches to improve models of Pseudomonas aeruginosa infecting the cystic fibrosis (CF) lung. First, we identify two models, an in vitro synthetic CF sputum medium model (SCFM2) and an epithelial cell model, that accurately recapitulate different gene sets. By combining these models, we developed the epithelial cell-SCFM2 model which improves the accuracy of over 500 genes. Second, to improve the accuracy of specific genes, we mined publicly available transcriptome data, which identified zinc limitation as a cue present in the CF lung and absent in SCFM2. Induction of zinc limitation in SCFM2 resulted in accurate expression of 90% of P. aeruginosa genes. These approaches provide generalizable, quantitative frameworks for microbiological model improvement that can be applied to any system of interest.

Human polyomaviruses, such as JCPyV and BKPyV, cause significant morbidity and mortality in immunocompromised or immunomodulated patients. There are no treatments for polyomavirus-induced diseases other than restoration of immune function. We discovered that the oxindole GW-5074 potently inhibits infection by both JCPyV and BKPyV. Further optimization of this compound could result in the development of antiviral therapies for polyomavirus-induced diseases.

Neuroblastoma is a common pediatric cancer, where preclinical studies have suggested chemotherapy resistance is driven by a mesenchymal-like gene expression program. However, the poor clinical outcomes imply we need a better understanding of the relationship between patient tumors and preclinical models. Here, we generated single-cell RNA-seq maps of neuroblastoma cell lines, patient-derived xenograft models (PDX), and a genetically engineered mouse model (GEMM). We developed an unsupervised machine learning approach to compare the gene expression programs found in preclinical models to a large cohort of human neuroblastoma tumors. The dominant adrenergic programs were well preserved in preclinical models, but contrary to previous reports do not unambiguously map to an obvious cell of origin. The mesenchymal-like program was less clearly preserved, and primarily restricted to cancer-associated fibroblasts and Schwann-like cellsin vivo. Surprisingly however, we identified a subtle, weakly expressed, mesenchymal-like program in otherwise adrenergic cancer cells in some high-risk tumors. This program appears distinct from mesenchymal cell lines but was maintained in PDX and a similar program could be chemotherapy-induced in our GEMM after only 24 hours, suggesting an uncharacterized therapy-escape mechanism. Collectively, our findings advance the understanding of neuroblastoma heterogeneity and can inform the development of new treatments.

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Therapeutic cancer vaccines targeting melanoma-associated antigens are commonly immunogenic but are rarely effective in promoting objective clinical responses. To identify critical molecules for activation of effective antitumor immunity, we have profiled autologous dendritic cell (DC) vaccines used to treat 35 patients with melanoma. We showed that checkpoint molecules induced by ex vivo maturation correlated with in vivo DC vaccine activity. Melanoma patient DCs had reduced expression of cell surface inducible T-cell costimulator ligand (ICOSL) and had defective intrinsic NF-κB signaling. Chromatin immunoprecipitation assays revealed NF-κB–dependent transcriptional regulation of ICOSL expression by DCs. Blockade of ICOSL on DCs reduced priming of antigen-specific CD8+ and CD4+ T cells from naïve donors in vitro. Concentration of extracellular/soluble ICOSL released from vaccine DCs positively correlated with patient clinical outcomes, which we showed to be partially regulated by ADAM10/17 sheddase activity. These data point to the critical role of canonical NF-κB signaling, the regulation of matrix metalloproteinases, and DC-derived ICOSL in the specific priming of cognate T-cell responses in the cancer setting. This study supports the implementation of targeted strategies to augment these pathways for improved immunotherapeutic outcomes in patients with cancer.

Supplementary Figure from Sensory Nerves Impede the Formation of Tertiary Lymphoid Structures and Development of Protective Antimelanoma Immune Responses

Peripheral neurons comprise a critical component of the tumor microenvironment (TME). The role of the autonomic innervation in cancer has been firmly established. However, the effect of the afferent (sensory) neurons on tumor progression remains unclear. Utilizing surgical and chemical skin sensory denervation methods, we showed that afferent neurons supported the growth of melanoma tumors in vivo and demonstrated that sensory innervation limited the activation of effective antitumor immune responses. Specifically, sensory ablation led to improved leukocyte recruitment into tumors, with decreased presence of lymphoid and myeloid immunosuppressive cells and increased activation of T-effector cells within the TME. Cutaneous sensory nerves hindered the maturation of intratumoral high endothelial venules and limited the formation of mature tertiary lymphoid-like structures containing organized clusters of CD4+ T cells and B cells. Denervation further increased T-cell clonality and expanded the B-cell repertoire in the TME. Importantly, CD8a depletion prevented denervation-dependent antitumor effects. Finally, we observed that gene signatures of inflammation and the content of neuron-associated transcripts inversely correlated in human primary cutaneous melanomas, with the latter representing a negative prognostic marker of patient overall survival. Our results suggest that tumor-associated sensory neurons negatively regulate the development of protective antitumor immune responses within the TME, thereby defining a novel target for therapeutic intervention in the melanoma setting.

Supplementary Data from Sensory Nerves Impede the Formation of Tertiary Lymphoid Structures and Development of Protective Antimelanoma Immune Responses

Supplementary Tables 1-2