bluuebunny/crossref_metadata_2025_split huggingface dataset:
B cells imprint adoptively transferred CD8+T cells with enhanced tumor immunity
Authors: Smith Aubrey S , Knochelmann Hannah M , Wyatt Megan M , Rangel Rivera Guillermo O , Rivera-Reyes Amalia M , Dwyer Connor J , Ware Michael B , Cole Anna C , Neskey David M , Rubinstein Mark P , Liu Bei , Thaxton Jessica E , Bartee Eric , Paulos Chrystal M 
Published: January 2022

BackgroundAdoptive T cell transfer (ACT) therapy improves outcomes in patients with advanced malignancies, yet many individuals relapse due to the infusion of T cells with poor function or persistence. Toll-like receptor (TLR) agonists can invigorate antitumor T cell responses when administered directly to patients, but these responses often coincide with toxicities. We posited that TLR agonists could be repurposed ex vivo to condition T cells with remarkable potency in vivo, circumventing TLR-related toxicity.MethodsIn this study we investigated how tumor-specific murine CD8+T cells and human tumor infiltrating lymphocytes (TILs) are impacted when expanded ex vivo with the TLR9 agonist CpG.ResultsHerein we reveal a new way to reverse the tolerant state of adoptively transferred CD8+T cells against tumors using TLR-activated B cells. We repurposed the TLR9 agonist, CpG, commonly used in the clinic, to bolster T cell—B cell interactions during expansion for ACT. T cells expanded ex vivo from a CpG-treated culture demonstrated potent antitumor efficacy and prolonged persistence in vivo. This antitumor efficacy was accomplished without in vivo administration of TLR agonists or other adjuvants of high-dose interleukin (IL)-2 or vaccination, which are classically required for effective ACT therapy. CpG-conditioned CD8+T cells acquired a unique proteomic signature hallmarked by an IL-2RαhighICOShighCD39lowphenotype and an altered metabolic profile, all reliant on B cells transiently present in the culture. Likewise, human TILs benefitted from expansion with CpG ex vivo, as they also possessed the IL-2RαhighICOShighCD39lowphenotype. CpG fostered the expansion of potent CD8+T cells with the signature phenotype and antitumor ability via empowering a direct B–T cell interaction. Isolated B cells also imparted T cells with the CpG-associated phenotype and improved tumor immunity without the aid of additional antigen-presenting cells or other immune cells in the culture.ConclusionsOur results demonstrate a novel way to use TLR agonists to improve immunotherapy and reveal a vital role for B cells in the generation of potent CD8+T cell-based therapies. Our findings have immediate implications in the clinical treatment of advanced solid tumors.
Systemic high-dose dexamethasone treatment may modulate the efficacy of intratumoral viral oncolytic immunotherapy in glioblastoma models
Authors: Koch Marilin S , Zdioruk Mykola , Nowicki Michal O , Griffith Alec M , Aguilar Estuardo , Aguilar Laura K , Guzik Brian W , Barone Francesca , Tak Paul P , Tabatabai Ghazaleh , Lederer James A , Chiocca E Antonio , Lawler Sean 
Published: January 2022

BackgroundIntratumoral viral oncolytic immunotherapy is a promising new approach for the treatment of a variety of solid cancers. CAN-2409 is a replication-deficient adenovirus that delivers herpes simplex virus thymidine kinase to cancer cells, resulting in local conversion of ganciclovir or valacyclovir into a toxic metabolite. This leads to highly immunogenic cell death, followed by a local immune response against a variety of cancer neoantigens and, next, a systemic immune response against the injected tumor and uninjected distant metastases. CAN-2409 treatment has shown promising results in clinical studies in glioblastoma (GBM). Patients with GBM are usually given the corticosteroid dexamethasone to manage edema. Previous work has suggested that concurrent dexamethasone therapy may have a negative effect in patients treated with immune checkpoint inhibitors in patients with GBM. However, the effects of dexamethasone on the efficacy of CAN-2409 treatment have not been explored.MethodsIn vitro experiments included cell viability and neurosphere T-cell killing assays. Effects of dexamethasone on CAN-2409 in vivo were examined using a syngeneic murine GBM model; survival was assessed according to Kaplan-Meier; analyses of tumor-infiltrating lymphocytes were performed with mass cytometry (CyTOF - cytometry by time-of-flight). Data were analyzed using a general linear model, with one-way analysis of variance followed by Dunnett’s multiple comparison test, Kruskal-Wallis test, Dunn’s multiple comparison test or statistical significance analysis of microarrays.ResultsIn a mouse model of GBM, we found that high doses of dexamethasone combined with CAN-2409 led to significantly reduced median survival (29.0 days) compared with CAN-2409 treatment alone (39.5 days). CyTOF analyses of tumor-infiltrating immune cells demonstrated potent immune stimulation induced by CAN-2409 treatment. These effects were diminished when high-dose dexamethasone was used. Functional immune cell characterization suggested increased immune cell exhaustion and tumor promoting profiles after dexamethasone treatment.ConclusionOur data suggest that concurrent high-dose dexamethasone treatment may impair the efficacy of oncolytic viral immunotherapy of GBM, supporting the notion that dexamethasone use should be balanced between symptom control and impact on the therapeutic outcome.
Fc-null anti-PD-1 monoclonal antibodies deliver optimal checkpoint blockade in diverse immune environments
Authors: Moreno-Vicente Julia , Willoughby Jane E , Taylor Martin C , Booth Steven G , English Vikki L , Williams Emily L , Penfold Christine A , Mockridge C Ian , Inzhelevskaya Tatyana , Kim Jinny , Chan H T Claude , Cragg Mark S , Gray Juliet C , Beers Stephen A 
Published: January 2022

BackgroundDespite extensive clinical use, the mechanisms that lead to therapeutic resistance to anti-programmed cell-death (PD)-1 monoclonal antibodies (mAbs) remain elusive. Here, we sought to determine how interactions between the Fc region of anti-PD-1 mAbs and Fcγ receptors (FcγRs) affect therapeutic activity and how these are impacted by the immune environment.MethodsMouse and human anti-PD-1 mAbs with different Fc binding profiles were generated and characterized in vitro. The ability of these mAbs to elicit T-cell responses in vivo was first assessed in a vaccination setting using the model antigen ovalbumin. The antitumor activity of anti-PD-1 mAbs was investigated in the context of immune ‘hot’ MC38 versus ‘cold’ neuroblastoma tumor models, and flow cytometry performed to assess immune infiltration.ResultsEngagement of activating FcγRs by anti-PD-1 mAbs led to depletion of activated CD8 T cells in vitro and in vivo, abrogating therapeutic activity. Importantly, the extent of this Fc-mediated modulation was determined by the surrounding immune environment. Low FcγR-engaging mouse anti-PD-1 isotypes, which are frequently used as surrogates for human mAbs, were unable to expand ovalbumin-reactive CD8 T cells, in contrast to Fc-null mAbs. These results were recapitulated in mice expressing human FcγRs, in which clinically relevant hIgG4 anti-PD-1 led to reduced endogenous expansion of CD8 T cells compared with its engineered Fc-null counterpart. In the context of an immunologically ‘hot’ tumor however, both low-engaging and Fc-null mAbs induced long-term antitumor immunity in MC38-bearing mice. Finally, a similar anti-PD-1 isotype hierarchy was demonstrated in the less responsive ‘cold’ 9464D neuroblastoma model, where the most effective mAbs were able to delay tumor growth but could not induce long-term protection.ConclusionsOur data collectively support a critical role for Fc:FcγR interactions in inhibiting immune responses to both mouse and human anti-PD-1 mAbs, and highlight the context-dependent effect that anti-PD-1 mAb isotypes can have on T-cell responses. We propose that engineering of Fc-null anti-PD-1 mAbs would prevent FcγR-mediated resistance in vivo and allow maximal T-cell stimulation independent of the immunological environment.
Theoretical investigation of the mechanism of DMAP-promoted [4 + 2]-annulation of prop-2-ynylsulfonium with isatoic anhydride
Authors: Lu Nan , Liang Hui , Miao Chengxia , Lan Xiaozheng , Qian Ping 
Published: January 2022

The mechanism for DMAP-promoted [4 + 2]-annulation of prop-2-ynylsulfonium with isatoic anhydride is investigated using the M06-2X functional. The reaction comprises isomerization of prop-2-ynylsulfonium in stage 1. Stage 2 includes DMAP-promoted deprotonation, nucleophilic addition, ring opening, and decarboxylation. Three steps of intramolecular cycloaddition, DMAP-promoted protonation, and dealkylation occur in stage 3, generating methylated DMAP and neutral thioether, which undergo double-bond isomerization to yield 3-methylthio-4-quinolone. The ability of DMAP to promote the reaction lies in the barrier decrease for alkyne isomerization, deprotonation/protonation of allenes, and dealkylation as effective bases for transferring protons and methyl groups. The roles of prop-2-ynylsulfonium and isatoic anhydride were demonstrated to be C2 and C4 synthons via Multiwfn analysis on the frontier molecular orbital. An alternative path was also confirmed by the Mayer bond order of the vital transition states.
O que um Lied de Schoenberg pode nos ensinar sobre uma Sonata de Santoro?
Authors: Souza Rodolfo Coelho de 
Published: January 2022

A análise da canção Sommermüg Op. 48 No 1 de Arnold Schoenberg nos mostra que as técnicas dodecafônicas empregadas pelo compositor, no período em que o método já tinha atingido sua maturidade, exibem uma variedade bem maior de estratégias composicionais do que nos ensinam os manuais. A segmentação da série em conjuntos com funções complementares de contraponto melódico e sustentação harmônica é uma delas. Sua busca por construções simétricas é outra preocupação a que se dá menos atenção do que ele teria desejado.
A análise de Schoenberg nos propiciou revisitar a Sonata 1942 para piano de Claudio Santoro, uma das obras pioneiras do estilo dodecafônico na música brasileira. O exame detalhado da técnica usada na obra revela um compositor jovem já no domínio completo do método dodecafônico, o que nos levou a cogitar os motivos que induziram nossa musicologia a acusá-lo de desconhecer ou desconsiderar a ortodoxia do estilo. Concluímos que, entre outras razões, essa crítica indevida se deveu a uma preferência da Academia pelo estilo de Webern, um autor que àquela altura não poderia ter servido de modelo a Santoro.
Single Circuit in V1 Capable of Switching Contexts During Movement Using an Inhibitory Population as a Switch
Authors: Voina Doris , Recanatesi Stefano , Hu Brian , Shea-Brown Eric , Mihalas Stefan 
Published: January 2022

Abstract
As animals adapt to their environments, their brains are tasked with processing stimuli in different sensory contexts. Whether these computations are context dependent or independent, they are all implemented in the same neural tissue. A crucial question is what neural architectures can respond flexibly to a range of stimulus conditions and switch between them. This is a particular case of flexible architecture that permits multiple related computations within a single circuit.
Here, we address this question in the specific case of the visual system circuitry, focusing on context integration, defined as the integration of feedforward and surround information across visual space. We show that a biologically inspired microcircuit with multiple inhibitory cell types can switch between visual processing of the static context and the moving context. In our model, the VIP population acts as the switch and modulates the visual circuit through a disinhibitory motif. Moreover, the VIP population is efficient, requiring only a relatively small number of neurons to switch contexts. This circuit eliminates noise in videos by using appropriate lateral connections for contextual spatiotemporal surround modulation, having superior denoising performance compared to circuits where only one context is learned. Our findings shed light on a minimally complex architecture that is capable of switching between two naturalistic contexts using few switching units.
Recognition and Redistribution in Aristotle’s Account of Stasis
Authors: Cairns Douglas , Canevaro Mirko , Mantzouranis Kleanthis 
Published: January 2022

Abstract
In Politics 5.1–3, Aristotle sees different conceptions of proportional equality and justice as the fundamental causes of stasis and metabolē (constitutional change). His account shows what happens to notions of ‘particular’ justice when they become causes of individual and collective action in pursuit of moral and political revolution. The whole discussion of the causes of stasis should be read through the filter of individual/group motivation – as a reflection of what goes on in the heads of those who engage in stasis. Movements towards political change are motivated by ingrained conceptions of proportional equality and fair distribution of honour and wealth. Aristotle’s approach, therefore, may be compared to Axel Honneth’s, that social justice should be seen in terms of the distribution of dignity and respect as well as of material resources.
Cyrus’ Beehive: Ruling Eros and with Eros in Xenophon’s Cyropaedia
Authors: Pageau-St-Hilaire Antoine 
Published: January 2022

Abstract
This paper examines the role of love in Xenophon’s Cyropaedia. I argue that an essential aspect of Cyrus’ knowledgeable rule is a specific understanding of eros and a corresponding strategy to cope with the power of love. Specifically, I contend that by exploiting a common Greek distinction between the beloved and the lover, he articulates the view that lovers are subjects or even slaves to their beloved who deceive themselves into thinking that their attraction and the ensuing behaviors are voluntary. Accordingly, Cyrus attempts to avoid falling in love and to rule as a universally beloved leader. Reflecting on the implications of this solution, I finally suggest that Xenophon wishes to show the limits of Cyrus’ solution.
Cynicism as Immanent Critique: Diogenes and the Philosophy of Transvaluation
Authors: Gardner Darren 
Published: January 2022

Abstract
I argue that Diogenes and early Cynicism can be understood in an explicitly social and political context, where Cynic praxis, performative public action, can be seen to make visible oppositions inherent to the polity. In doing so, Diogenes’ praxis should be understood as a form of immanent critique, one that demonstrates, for example, that nature and custom (phusis and nomos) are interrelated oppositions in the polis. Cynicism here is understood as a form of immanent critique because Diogenes challenges the social norms of the polis without endorsing external universal standards or predetermined models, but from illuminating dynamics from within the polis and polity.
The Beautiful in Aristotle’s Ethics
Authors: Little David H. 
Published: January 2022

Abstract
This article argues for an aesthetic reading of to kalon, primarily as it appears in Aristotle’s Nicomachean Ethics. Aristotle uses to kalon to indicate that, to the morally serious, virtue is attractive and productive of a kind of pleasure. Read aesthetically, to kalon mitigates the tension between one’s own good and the common good. Aristotle shows how his students’ understanding of to kalon can be refined and thus preserved as an important and salutary feature of moral and political life.
Maternal Stressful Life Events During the Periconceptional Period and Orofacial Clefts: A Systematic Review and Meta-Analysis
Authors: Tran Christina , Crawford Andrew A. , Hamilton Alexander , French Clare E. , Wren Yvonne , Sandy Jonathan , Sharp Gemma 
Published: January 2022

Objective To assess whether women who experience stressful life events during the periconceptional period are at higher risk of giving birth to a baby with an orofacial cleft (OFC). Design Systematic review and meta-analysis of studies reporting the proportion of babies born with OFC to mothers exposed and unexposed to population-level or personal-level stressful life events during the periconceptional period. Six electronic databases were searched from inception to August 2020. Risk of bias was assessed using the Newcastle-Ottawa scale. Odds ratios (ORs) for the odds of OFC in babies of exposed mothers relative to unexposed controls were extracted and/or calculated. Random effects meta-analysis was undertaken, stratified by cleft subtype. Results Of 12 eligible studies, 8 examined experience of personal events and 4 examined population-level events. Studies demonstrated low-moderate risk of bias and there was indication of publication bias. There was some evidence that personal stressful life events were associated with greater odds of cleft lip and/or palate (six studies, OR 1.63, 95% confidence interval (CI) 1.16, 2.30, P = 0.001) and cleft palate only (six studies, OR 1.45, 95% CI 1.02, 2.06, P = 0.04). Population-level events were associated with higher odds of OFC in studies that did not specify subtype (three studies, OR 1.64, 95% CI 1.19, 2.25, P = 0.002), but subtype stratified analyses were underpowered. Heterogeneity was high. Conclusions Limited evidence indicated a weak positive association between maternal stressful life events during the periconceptional period and risk of OFC in the offspring, but further studies with greater consistency in research design are needed.
Cervix Uteri Cancer in Lebanon: Incidence, Temporal Trends, and Comparison to Countries From Different Regions in the World
Authors: Lakkis Najla A. , Osman Mona H. , Abdallah Reem M. 
Published: January 2022

Background Invasive cervix uteri cancer is the fourth most common malignancy in women globally. This study investigates the incidence and trends of cervix uteri cancer in Lebanon, a country in the Middle East, and compares these rates to regional and global ones. Methods Data on cervix uteri were obtained from the Lebanese national cancer registry for the currently available years 2005 to 2016. The calculated age-standardized incidence and age-specific rates were expressed as per 100,000 population. Results From 2005 to 2016, cervix uteri cancer was the tenth most common cancer among women. Its age-standardized incidence rate fluctuated narrowly between 3.5 and 5.7 per 100,000, with the lowest rate in 2013 and the highest rate in 2012. The age-specific incidence rate had 2 peaks, the highest peak at age group 70–74 years and the second at age group 50–59 years. The annual percent change (+.05%) showed a non-statistically significant trend of increase. The age-standardized incidence rate of cervix uteri cancer in Lebanon was comparable to that of the Western Asia region that has the lowest incidence rate worldwide. The rate was intermediate as compared to other countries in the Middle East and North Africa Region and relatively similar to the ones in Australia, North America, and some Western European countries. Conclusion The incidence rates of invasive cervix uteri are low in Lebanon. This could be attributed to the low prevalence of human papilloma virus infection and other sexually transmitted infections among Lebanese women, and the opportunistic screening practices. It is important to adopt a comprehensive approach to decrease the potential burden of cervix uteri, especially with the rising patterns of risky sexual behaviors. This includes improving awareness, enhancing access to preventive services, developing clinical guidelines, and training health care providers on these guidelines.
Navigational health literacy among people with chronic illness
Authors: Griese Lennert , Schaeffer Doris , Berens Eva-Maria 
Published: January 2022

Objectives People with chronic illness are particularly dependent on navigating and using the health care system. This requires navigational health literacy (HL-NAV). The article aims to examine the distribution and predictors of HL-NAV in a sample of chronically ill individuals. Methods Data of 1,105 people with chronic illness from the general population in Germany were collected in December 2019 and January 2020. HL-NAV was assessed by 12 items (score 0–100). Bivariate and multiple linear regression analysis were performed. Results HL-NAV score was 39.1 (SD 27.3). In bivariate analyses, HL-NAV was lower among chronically ill persons aged 65 or above, with low education, limited functional health literacy, low social status, financial deprivation, poor social support, multiple chronic conditions, and an illness duration of 6–10 years. In multivariate analyses, advanced age, lower education, less functional health literacy, lower social status, and less social support remained associated with lower HL-NAV. Discussion The results underline the importance of promoting HL-NAV among people with chronic illness. Strategies should aim at strengthening individual competencies taking into account the social and situational factors but also at reducing the demands placed on chronically ill people by providing user-friendly and trustworthy information on the health care system along the illness trajectory.
Qualitative evaluation of the symptoms and quality of life impacts of long-chain fatty acid oxidation disorders
Authors: Williams-Hall Rebecca , Tinsley Katie , Kruger Eliza , Johnson Chloe , Bowden Alexandra , Cimms Tricia , Gater Adam 
Published: January 2022

Background: Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of rare autosomal-recessive genetic disorders characterized by metabolic deficiencies in which the body is unable to convert long-chain fatty acids into energy. To date, however, there is limited understanding of the patient experience of LC-FAOD. Methods: The symptoms, observable signs, and quality of life (QoL) impacts associated with LC-FAOD were explored via a focus group ( n = 8) and semi-structured interviews ( n = 6) with patients and caregivers of patients with LC-FAOD, and interviews ( n = 4) with expert clinicians. Data were analyzed via thematic analysis and summarized in a conceptual model. Results: Participants reported a wide range of signs and symptoms associated with LC-FAOD, broadly categorized as musculoskeletal, endocrine/nutritional/metabolic, neurological, gastrointestinal/digestive, sensory, cardiovascular, respiratory, urological, and constitutional. LC-FAOD were reported to have a significant impact on various aspects of patients’ lives including physical functioning, participation in daily activities, emotional/psychological wellbeing, and social functioning. Lifestyle modifications (such as diet and exercise restrictions) were necessary because of the condition. Symptoms were typically episodic in presentation often arising or exacerbated during catabolic conditions such as prolonged exercise, fasting, physiological stress, and illness/infection. Symptoms were also commonly reported to lead to emergency room visits, hospitalization, and clinical complications. Conclusion: LC-FAOD have a considerable impact on patients’ lives. There is a high degree of concordance in the signs, symptoms, and impacts of LC-FAOD reported by patients, caregivers, and clinicians; however, there were many symptoms and impacts that were only reported by patients and caregivers, thus demonstrating that insights from patient/caregiver experience data are integral for informing medical product development and facilitating patient-centered care.