bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation
Authors: Sardar Debosmita , Cheng Yi-Ting , Woo Junsung , Choi Dong-Joo , Lee Zhung-Fu , Kwon Wookbong , Chen Hsiao-Chi , Lozzi Brittney , Cervantes Alexis , Rajendran Kavitha , Huang Teng-Wei , Jain Antrix , Arenkiel Benjamin R. , Maze Ian , Deneen Benjamin
Published: June 2023

Neuronal activity drives alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. We found that neuronal activity induces widespread transcriptional up-regulation and down-regulation in astrocytes, highlighted by the identification of
Slc22a3
as an activity-inducible astrocyte gene that encodes neuromodulator transporter Slc22a3 and regulates sensory processing in the mouse olfactory bulb. Loss of astrocytic Slc22a3 reduced serotonin levels in astrocytes, leading to alterations in histone serotonylation. Inhibition of histone serotonylation in astrocytes reduced the expression of γ-aminobutyric acid (GABA) biosynthetic genes and GABA release, culminating in olfactory deficits. Our study reveals that neuronal activity orchestrates transcriptional and epigenomic responses in astrocytes while illustrating new mechanisms for how astrocytes process neuromodulatory input to gate neurotransmitter release for sensory processing.
Modification of ground-state chemical reactivity via light–matter coherence in infrared cavities
Authors: Ahn Wonmi , Triana Johan F. , Recabal Felipe , Herrera Felipe , Simpkins Blake S.
Published: June 2023

Reaction-rate modifications for chemical processes due to strong coupling between reactant molecular vibrations and the cavity vacuum have been reported; however, no currently accepted mechanisms explain these observations. In this work, reaction-rate constants were extracted from evolving cavity transmission spectra, revealing resonant suppression of the intracavity reaction rate for alcoholysis of phenyl isocyanate with cyclohexanol. We observed up to an 80% suppression of the rate by tuning cavity modes to be resonant with the reactant isocyanate (NCO) stretch, the product carbonyl (CO) stretch, and cooperative reactant-solvent modes (CH). These results were interpreted using an open quantum system model that predicted resonant modifications of the vibrational distribution of reactants from canonical statistics as a result of light–matter quantum coherences, suggesting links to explore between chemistry and quantum science.
Regulating light pollution: More than just the night sky
Authors: Morgan-Taylor Martin
Published: June 2023

Impacts on ecology, health, energy, and climate are critical
Gastrointestinal Microbial Ecology of Weaned Piglets Fed Diets with Different Levels of Glyphosate
Authors: Rani Sundas , Sørensen Martin Tang , Estellé Jordi , Noel Samantha Joan , Nørskov Natalja , Krogh Uffe , Foldager Leslie , Højberg Ole
Published: June 2023

Glyphosate residues can be found in feed made from genetically modified glyphosate-resistant crops treated with glyphosate or from conventional crops, desiccated with glyphosate before harvest. If these residues affect the gut microbiota to an extent that is unfavorable to livestock health and productivity, the widespread use of glyphosate on feed crops may need to be reconsidered.
Highly Cross-Reactive and Protective Influenza A Virus H3N2 Hemagglutinin- and Neuraminidase-Specific Human Monoclonal Antibodies
Authors: Piepenbrink Michael , Oladunni Fatai , Nogales Aitor , Khalil Ahmed M. , Fitzgerald Theresa , Basu Madhubanti , Fucile Christopher , Topham David J. , Rosenberg Alexander F. , Martinez-Sobrido Luis , Kobie James J.
Published: June 2023

Influenza A virus (IAV) infections continue to cause substantial morbidity and mortality despite the availability of seasonal vaccines. The extensive genetic variability in seasonal and potentially pandemic influenza strains necessitates new vaccine strategies that can induce universal protection by focusing the immune response on generating protective antibodies against conserved targets within the influenza virus hemagglutinin and neuraminidase proteins.
Towards Response ADAptive Radiotherapy for organ preservation for intermediate-risk rectal cancer (preRADAR): protocol of a phase I dose-escalation trial
Authors: Verweij Maaike E , Tanaka Max D , Kensen Chavelli M , van der Heide Uulke A , Marijnen Corrie A M , Janssen Tomas , Vijlbrief Tineke , van Grevenstein Wilhelmina M U , Moons Leon M G , Koopman Miriam , Lacle Miangela M , Braat Manon N G J A , Chalabi Myriam , Maas Monique , Huibregtse Inge L , Snaebjornsson Petur , Grotenhuis Brechtje A , Fijneman Remond , Consten Esther , Pronk Apollo , Smits Anke B , Heikens Joost T , Eijkelenkamp Hidde , Elias Sjoerd G , Verkooijen Helena M , Schoenmakers Maartje M C , Meijer Gert J , Intven Martijn , Peters Femke P
Published: June 2023

Introduction

Organ preservation is associated with superior functional outcome and quality of life (QoL) compared with total mesorectal excision (TME) for rectal cancer. Only 10% of patients are eligible for organ preservation following short-course radiotherapy (SCRT, 25 Gy in five fractions) and a prolonged interval (4–8 weeks) to response evaluation. The organ preservation rate could potentially be increased by dose-escalated radiotherapy. Online adaptive magnetic resonance-guided radiotherapy (MRgRT) is anticipated to reduce radiation-induced toxicity and enable radiotherapy dose escalation. This trial aims to establish the maximum tolerated dose (MTD) of dose-escalated SCRT using online adaptive MRgRT.

Methods and analysis

The preRADAR is a multicentre phase I trial with a 6+3 dose-escalation design. Patients with intermediate-risk rectal cancer (cT3c-d(MRF-)N1M0 or cT1-3(MRF-)N1M0) interested in organ preservation are eligible. Patients are treated with a radiotherapy boost of 2×5 Gy (level 0), 3×5 Gy (level 1), 4×5 Gy (level 2) or 5×5 Gy (level 3) on the gross tumour volume in the week following standard SCRT using online adaptive MRgRT. The trial starts on dose level 1. The primary endpoint is the MTD based on the incidence of dose-limiting toxicity (DLT) per dose level. DLT is a composite of maximum one in nine severe radiation-induced toxicities and maximum one in three severe postoperative complications, in patients treated with TME or local excision within 26 weeks following start of treatment. Secondary endpoints include the organ preservation rate, non-DLT, oncological outcomes, patient-reported QoL and functional outcomes up to 2 years following start of treatment. Imaging and laboratory biomarkers are explored for early response prediction.

Ethics and dissemination

The trial protocol has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. The primary and secondary trial results will be published in international peer-reviewed journals.

Trial registration number

WHO International Clinical Trials Registry (NL8997;https://trialsearch.who.int).
Cardiotocography in practice: a qualitative study to explore obstetrical care professionals’ experiences with using cardiotocography information in Dutch practice
Authors: Romijn A , Bakker P C A M , Teunissen P W
Published: June 2023

Objective

This study aimed to explore obstetric care professionals’ experiences with using cardiotocograph (CTG) information and how they employ this tool in their practice.

Design

Qualitative study, involving 30 semi-structured interviews and two focus group sessions. Conventional content analysis was used for data analysis.

Setting

Amsterdam University Medical Centers in the Netherlands.

Participants

In total, 43 care professionals participated. The respondents included obstetricians, residents in obstetrics and gynaecology, junior physicians, clinical midwives and nurses.

Findings

Three main categories were identified that influenced the use of cardiotocography in practice; (1) individual characteristics involving knowledge, experience and personal beliefs; (2) teams involving collaboration in and between shifts and (3) work environment involving equipment, culture and continuing development.

Conclusion

This study underlines the importance of teamwork when working with cardiotocography in practice. There is a particular need to create shared responsibility among team members for cardiotocography interpretation and appropriate management, which should be addressed in educational programmes and regular multidisciplinary meetings, to allow learning from colleagues’ perspectives.
Differential clinicopathological features, treatments and outcomes in patients with Exon 19 deletion and Exon 21 L858R EGFR mutation-positive adenocarcinoma non-small-cell lung cancer
Authors: Batra Ullas , Biswas Bivas , Prabhash Kumar , Krishna M. Vamshi
Published: June 2023

The most common oncogenic driver in non-small-cell lung cancer (NSCLC) is the epidermal growth factor receptor (EGFR) gene mutations that occur more frequently among Asians (30%–50%) as opposed to Caucasians (10%–15%). Lung cancer is one of the most prevalent cancers in India, with a reported adenocarcinoma positivity ranging between 26.1% and 86.9% in NSCLC patients. The prevalence ofEGFRmutations in adenocarcinoma patients (36.9%) in India is higher than that of Caucasian patients and lower than that of East Asian patients. The exon 19 deletion (Ex19del) is more common than exon 21 L858R mutations in Indian patients with NSCLC. Studies have shown that the clinical behaviour of patients with advanced NSCLC differs betweenEGFREx19del and exon 21 L858R mutation status. In this study, we investigated the differences in clinicopathological features and survival outcomes after first line and second-line treatment withEGFRtyrosine kinase inhibitors (EGFRTKIs) in NSCLC patients with Ex19del and exon 21 L858REGFRmutation status. This study also focuses on the role and potential benefits of dacomitinib, a second-generation irreversibleEGFRTKI, in patients with Ex19del and exon 21 L858REGFRmutation-positive advanced NSCLC in Indian settings.
Neurodiversity in elite sport: a systematic scoping review
Authors: Hoare Erin , Reyes Jonathan , Olive Lisa , Willmott Catherine , Steer Emma , Berk Michael , Hall Kate
Published: June 2023

The objective of this systematic scoping review is to understand the extent and scope of evidence regarding neurodiversity in elite sport. This systematic scoping review considered epidemiological studies, com

mentary and viewpoints papers, systematic review and meta-analyses, and any intervention or clinical treatment, management and practice studies in relation to neurodiversity in elite sport. Case studies and grey literature were ineligible for review. Neurodivergence included neurodevelopmental disorders such as autism spectrum disorder, attention-deficit hyperactivity disorder (ADHD) and specific learning disorders. Elite sport was defined as Olympic, Paralympic, national, international, professional and semiprofessional sport. The final 23 studies included in this review comprised 10 observational studies, 4 systematic/narrative reviews, 6 commentary/position statements and 3 qualitative studies. The literature reflected a major focus on ADHD as a risk factor for concussion and prognosis for postconcussion recovery. Further, there was a focus on the medical management of ADHD, regarding adherence to sporting antidoping regulations. One study focused on the experience of autism in athletes in elite sport settings through qualitative interviews. One study focused on anxiety disorders in elite athletes, with ADHD emerging as a major risk factor. There is a strong rationale for future research to build on the evidence for neurodiversity in elite sport to foster supportive and inclusive elite sporting environments.
Anticoagulant in atrial fibrillation patients with prior intracranial haemorrhage: a meta-analysis
Authors: Cai Huiya , Chen Guoquan , Hu Wei , Jiang Chunjiao
Published: June 2023

Background

The benefit of resuming anticoagulation in atrial fibrillation (AF) patients with prior intracranial haemorrhage (ICH) and which anticoagulant to choose are controversial.

Summary of review

PubMed, Embase, Web of Science and the Cochrane Library were searched from their inception until 13 February 2022. Thirteen eligible articles (17 600 participants) were collected, including 11 real-world studies (n=17 296) and 2 randomised controlled trials (RCTs) (n=304). Compared with no anticoagulants, oral anticoagulation (OAC) was not associated with an increased risk of ICH recurrence (HR 0.85 (95% CI 0.57 to 1.25), p=0.41), but with a significantly increased risk of major bleeding (HR 1.66 (95% CI 1.20 to 2.30), p<0.01). Meanwhile, OAC was associated with a reduced risk of ischaemic stroke/systemic thromboembolism (IS/SE) (HR 0.54 (95% CI 0.42 to 0.70), p<0.01) and all-cause death (HR 0.38 (95% CI 0.28 to 0.52), p<0.01) compared with no anticoagulants. Furthermore, compared with warfarin, non-vitamin K antagonist oral anticoagulants (NOACs) were associated with a significant reduction of ICH recurrence (HR 0.64 (95% CI 0.49 to 0.85), p<0.01), while the risk of IS/SE and all-cause mortality were comparable between warfarin and NOACs.

Conclusions

For patients with AF with prior ICH, OAC is associated with a significant reduction in IS/SE and all-cause mortality without increasing ICH recurrence, but may increase major bleeding risk. Compared with warfarin, NOACs had a better safety profile and comparable efficacy. Further larger RCTs are warranted to validate these findings.
Fault tolerance evaluation of model-free controllers with application to unmanned aerial vehicles
Authors: Saied Majd , Kassem Mohammad , Mazeh Hussein , Shraim Hassan , Francis Clovis
Published: June 2023

Although important improvements in the area of robust control of nonlinear systems have been presented in the literature, most of the developed controllers suffer from complexity and large dependency on accurate mathematical formulation of the models. Recently, model-free robust control techniques were introduced and have shown good performance when applied to multi-input–multi-output systems. The model-free approach is characterized by the nonuse of any prior knowledge about the underlying structure and/or associated parameters of the dynamical system. Therefore, the major criteria for assessing the effectiveness of these controllers are related to their ability to handle unknown inputs and disturbances, as well as achieving the desired tracking performance in presence of faults and malfunctions. This work considers the development of robust fault-tolerant controllers based on the model-free approach and their application to multirotor unmanned aerial vehicles’ (UAVs) systems. The different controllers based on intelligent proportional-derivative (iPD), intelligent backstepping (iBackstepping), and adaptive control are compared in terms of performance, ease of implementation and parameters tuning. The simulated results, tested on Matlab/Simulink on a full nonlinear model of a hexarotor UAV, validate the theoretical advantages of the adaptive approach with respect to multiple criteria such as improved tracking performance in case of existence of actuators faults when compared to the iPD and iBackstepping control methods at the cost of increased complexity.
Graph Neural Rough Differential Equations for Traffic Forecasting
Authors: Choi Jeongwhan , Park Noseong
Published: June 2023

Traffic forecasting is one of the most popular spatio-temporal tasks in the field of machine learning. A prevalent approach in the field is to combine graph convolutional networks and recurrent neural networks for the spatio-temporal processing. There has been fierce competition and many novel methods have been proposed. In this article, we present the method of spatio-temporal graph neural rough differential equation (STG-NRDE). Neural rough differential equations (NRDEs) are a breakthrough concept for processing time-series data. Their main concept is to use the log-signature transform to convert a time-series sample into a relatively shorter series of feature vectors. We extend the concept and design two NRDEs: one for the temporal processing and the other for the spatial processing. After that, we combine them into a single framework. We conduct experiments with 6 benchmark datasets and 27 baselines. STG-NRDE shows the best accuracy in all cases, outperforming all those 27 baselines by non-trivial margins.
Gender and International Relations
Authors: Sjoberg Laura , Thies Cameron G.
Published: June 2023

This is both an exciting and fraught time in the study of gender and sexuality in global politics. On the one hand, feminist scholars build on more than 30 years of research in the field, with increasingly diverse scholars doing increasingly interdisciplinary research. On the other hand, crises like the COVID-19 pandemic, the war in Ukraine, and global inflation have shown that there are many sites of sharp, continuing gender inequities. In response to this combined excitement and challenge, this article addresses four areas of gender and IR research that are both enduring and growing: gender and political economy, gender and security, queer approaches, and feminist foreign policy. As we discuss each of these areas, we begin with a recent exemplar of scholarship and then discuss other scholarship in that area to give a sense of contours of each subfield of inquiry.
Ionic Liquids Containing the Sulfonyl Fluoride Moiety: Integrating Chemical Biology with Materials Design
Authors: Adu Clinton , Boucher Mairead , Hillesheim Patrick C. , Mirjafari Arsalan
Published: June 2023

The persistent achievements of ionic liquids in various fields, including medicine and energy necessitate the efficient development of novel functional ionic liquids that exhibit favorable characteristics, alongside the development of practical and scalable synthetic methodologies. Ionic liquids are fundamentally understood as materials in which structure begets function, and the function and applicability of ILs is of utmost concern. It was recently reported that “full fluorosulfonyl” electrolyte is compatible with both the Li metal anode and the metal-oxide cathode that is crucial for the development of high-voltage rechargeable lithium-metal batteries. Inspired by these results, for the first time, we reported the synthesis of a series of ionic liquids with a sulfonyl fluoride motif using an highly effective and modular fluorosulfonylethylation procedure. Herein, we present a detailed analysis of novel sulfonyl fluoride-based ionic liquids paired with the hexafluorophosphate anion. We employed a combination of computational modeling and X-ray crystallographic studies to gain an in-depth understanding of their structure-property correlations.
The Influence of Optically Active Impurities on the Performance of Phosphors and Scintillators
Authors: Srivastava A. M. , Ronda C. R. , Beers W. W. , Cohen W. E.
Published: June 2023

This paper provides examples of a strategy employed to improve specific properties of phosphors and scintillators which would otherwise have limited their performance in lighting, cathode-ray tubes, and medical imaging technologies. When electron-hole pairs are produced by the exposure to high-energy radiation, the activator ion in the lattice preferentially captures one of the charge carriers. The subsequent capture of the carrier of opposite charge yields the activator ion luminescence. The carrier of the opposite charge can also be diverted to defects in the lattice. The trapping by defects reduces the brightness of phosphors and is responsible for the unwanted afterglow in scintillators. The strategy that is adopted to suppress the trapping by defects is to deliberately introduce an impurity ion that can compete successfully with the defects for the charge carrier. Since the impurity ion traps charge of the opposite sign to the activator ion, we label them as “anti-activators.” While the use of anti-activators gained importance in the field of scintillators in the 1990’s, results on their use for improving brightness of lamp and cathode-ray phosphors were available in the literature of the 1960’s and 1970’s.
Association between the Triglyceride Glucose Index and Hyperuricemia in Patients with Primary Hypertension: A Cross-Sectional Study
Authors: Liu Shanshan , Zhou Zhixian , Wu Miao , Zhang Hao , Xiao Yao
Published: June 2023

Objective. The aim of this study was to investigate the association between the triglyceride glucose (TyG) index and hyperuricemia (HUA) in patients with grades 1–3 hypertension. Study Design. This is a cross-sectional study. A total of 1,707 patients from the cardiovascular department of Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine were studied. In this study, 899 patients with grades 1-2 hypertension were included, of which 151 had HUA; additionally, 808 patients with grade 3 hypertension were included, of which 162 patients had HUA. This study obtained all patient data from the electronic medical record system of the Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine. The TyG index was calculated as Ln (triglycerides × fasting glucose/2). Hyperuricemia was defined as uric acid ≥420 μmol/L (7 mg/dL). Multivariate logistic regression, penalized spline regression, and generalized additive models were used to evaluate the association between the TyG index and HUA. Stratified analyses were performed to assess the association in populations with different grades of hypertension. Results. The average TyG index was 8.71 ± 0.58. After adjusting for correlated variables, the logistic regression analysis revealed a positive correlation between the TyG index and HUA (OR = 1.83; 95% CI: 1.40–2.39). Smooth curve fitting showed that this correlation was linear in the whole range of the TyG index. In the subgroup analysis, the TyG index more strongly associated with HUA in the grades 1-2 hypertension group (OR = 2.22; 95% CI: 1.44–3.42) compared to that in the grade 3 hypertension group (OR = 1.58; 95% CI: 1.11–2.24;

P

for interaction = 0.03). In addition, this association was consistent in all models. Conclusion. The TyG index was positively associated with HUA in patients with hypertension, and the association was more strongly confirmed in those with grades 1-2 hypertension rather than in those with grade 3 hypertension.
Ectopic Cecal Varices as a Cause of Lower Gastrointestinal Bleeding
Authors: Qatomah Abdulrahman , Almushir Sulaiman , Aljohani Faisal
Published: June 2023

Ectopic varices account for 1%–5% of all variceal bleeding episodes in patients with portal hypertension. They can be found at any part of gastrointestinal tract including the small intestines, colon, or rectum. We report a case of a 59-year-old man who presented with bleeding per rectum 2 days after a routine colonoscopy, in which 2 lesions were biopsied. Gastroscopy was negative for bleeding, and he was not stable enough to undergo colonoscopy. CT angiography showed a large portosystemic shunt with multiple collaterals in the right lower quadrant. These findings were clues for a diagnosis of ectopic cecal varices.
Respiratory Event-Induced Blood Pressure Oscillations Vary by Sleep Stage in Sleep Apnea Patients
Authors: Chaung Yao Shun , Alex Raichel M. , Jani Mahrshi , Watenpaugh Donald E. , Vilimkova Kahankova Radana , Sands Scott A. , Behbehani Khosrow
Published: June 2023

Obstructive sleep apnea (OSA) pathologically stresses the cardiovascular system. Apneic events cause significant oscillatory surges in nocturnal blood pressure (BP). Trajectories of these surges vary widely. This variability challenges the quantification, characterization, and mathematical modeling of BP surge dynamics. We present a method of aggregating trajectories of apnea-induced BP surges using a sample-by-sample averaging of continuously recorded BP. We applied the method to recordings of overnight BP (average total sleep time:

4.77
±
1.64

 h) for 10 OSA patients (mean AHI: 63.5 events/h; range: 18.3-105.4). We studied surges in blood pressure due to obstructive respiratory events separated from other such events by at least 30 s (274 total events). These events increased systolic (SBP) and diastolic (DBP) BP by

19
±
7.1

 mmHg (14.8%) and

11
±
5.6

 mmHg (15.5%), respectively, relative to mean values during wakefulness. Further, aggregated SBP and DBP peaks occurred on average 9 s and 9.5 s after apnea events, respectively. Interestingly, the amplitude of the SBP and DBP peaks varied across sleep stages, with mean peak ranging from

128.8
±
12.4

to

166.1
±
15.5

 mmHg for SBP and from

63.1
±
8.2

to

84.2
±
9.4

 mmHg for DBP. The aggregation method provides a high level of granularity in quantifying BP oscillations from OSA events and may be useful in modeling autonomic nervous system responses to OSA-induced stresses.
Salario mínimo y política redistributiva
Authors: García Carlos
Published: June 2023

El salario mínimo presenta un rompecabezas para los economistas. Desde una mirada económica simple, el salario mínimo no debería tener propiedades sociales sustancialmente beneficiosas. Intuitivamente, un precio mínimo legal representa una restricción en los mercados que impide que se produzcan intercambios mutuamente beneficiosos. Continuar leyendo...
Data from Chi3l1 Is a Modulator of Glioma Stem Cell States and a Therapeutic Target in Glioblastoma
Authors: Guetta-Terrier Charlotte , Karambizi David , Akosman Bedia , Zepecki John P. , Chen Jia-Shu , Kamle Suchitra , Fajardo J. Eduardo , Fiser Andras , Singh Ritambhara , Toms Steven A. , Lee Chun Geun , Elias Jack A. , Tapinos Nikos
Published: June 2023

Abstract
Chitinase 3–like 1 (Chi3l1) is a secreted protein that is highly expressed in glioblastoma. Here, we show that Chi3l1 alters the state of glioma stem cells (GSC) to support tumor growth. Exposure of patient-derived GSCs to Chi3l1 reduced the frequency of CD133+SOX2+ cells and increased the CD44+Chi3l1+ cells. Chi3l1 bound to CD44 and induced phosphorylation and nuclear translocation of β-catenin, Akt, and STAT3. Single-cell RNA sequencing and RNA velocity following incubation of GSCs with Chi3l1 showed significant changes in GSC state dynamics driving GSCs towards a mesenchymal expression profile and reducing transition probabilities towards terminal cellular states. ATAC-seq revealed that Chi3l1 increases accessibility of promoters containing a Myc-associated zinc finger protein (MAZ) transcription factor footprint. Inhibition of MAZ downregulated a set of genes with high expression in cellular clusters that exhibit significant cell state transitions after treatment with Chi3l1, and MAZ deficiency rescued the Chi3L-induced increase of GSC self-renewal. Finally, targeting Chi3l1 in vivo with a blocking antibody inhibited tumor growth and increased the probability of survival. Overall, this work suggests that Chi3l1 interacts with CD44 on the surface of GSCs to induce Akt/β-catenin signaling and MAZ transcriptional activity, which in turn upregulates CD44 expression in a pro-mesenchymal feed-forward loop. The role of Chi3l1 in regulating cellular plasticity confers a targetable vulnerability to glioblastoma.
Significance:
Chi3l1 is a modulator of glioma stem cell states that can be targeted to promote differentiation and suppress growth of glioblastoma.
Data from Ubiquitin Ligases Siah1a/2 Control Alveolar Macrophage Functions to Limit Carcinogen-Induced Lung Adenocarcinoma
Authors: Scortegagna Marzia , Du Yuanning , Bradley Linda M. , Wang Kun , Molinolo Alfredo , Ruppin Eytan , Murad Rabi , Ronai Ze'ev A.
Published: June 2023

Abstract
Cellular components of the tumor microenvironment, including myeloid cells, play important roles in the progression of lung adenocarcinoma (LUAD) and its response to therapy. Here, we characterize the function of the ubiquitin ligases Siah1a/2 in regulating the differentiation and activity of alveolar macrophages (AM) and assess the implication of Siah1a/2 control of AMs for carcinogen-induced LUAD. Macrophage-specific genetic ablation of Siah1a/2 promoted accumulation of AMs with an immature phenotype and increased expression of protumorigenic and pro-inflammatory Stat3 and β-catenin gene signatures. Administration of urethane to wild-type mice promoted enrichment of immature-like AMs and lung tumor development, which was enhanced by macrophage-specific Siah1a/2 ablation. The profibrotic gene signature seen in Siah1a/2-ablated immature-like macrophages was associated with increased tumor infiltration of CD14+ myeloid cells and poorer survival of patients with LUAD. Single-cell RNA-seq confirmed the presence of a cluster of immature-like AMs expressing a profibrotic signature in lungs of patients with LUAD, a signature enhanced in smokers. These findings identify Siah1a/2 in AMs as gatekeepers of lung cancer development.
Significance:
The ubiquitin ligases Siah1a/2 control proinflammatory signaling, differentiation, and profibrotic phenotypes of alveolar macrophages to suppress lung carcinogenesis.
TABLE 1 from Desmoplastic Reaction Associates with Prognosis and Adjuvant Chemotherapy Response in Colorectal Cancer: A Multicenter Retrospective Study
Authors: Hu Qingru , Wang Yiting , Yao Su , Mao Yun , Liu Liu , Li Zhenhui , Chen Yonghe , Zhang Shenyan , Li Qian , Zhao Yingnan , Fan Xinjuan , Cui Yanfen , Zhao Ke , Liu Zaiyi
Published: June 2023

Patient demographics and clinicopathologic characteristics in two cohorts
Supplementary Figure S1 from Desmoplastic Reaction Associates with Prognosis and Adjuvant Chemotherapy Response in Colorectal Cancer: A Multicenter Retrospective Study
Authors: Hu Qingru , Wang Yiting , Yao Su , Mao Yun , Liu Liu , Li Zhenhui , Chen Yonghe , Zhang Shenyan , Li Qian , Zhao Yingnan , Fan Xinjuan , Cui Yanfen , Zhao Ke , Liu Zaiyi
Published: June 2023

Correlation between DR and T status, N status
Figure S1 from Systemic Treatments and Molecular Biomarkers for Perivascular Epithelioid Cell Tumors: A Single-Institution Retrospective Analysis
Authors: Testa Stefano , Bui Nam Q. , Ganjoo Kristen N.
Published: June 2023

Supplementary Figure S1 showing study flow diagram with details regarding the pathology cases review and patient selection process.
Data from Systemic Treatments and Molecular Biomarkers for Perivascular Epithelioid Cell Tumors: A Single-institution Retrospective Analysis
Authors: Testa Stefano , Bui Nam Q. , Ganjoo Kristen N.
Published: June 2023

Perivascular epithelioid cell tumors (PEComa) are a large family of mesenchymal neoplasms, with variable clinical course. Evidence regarding treatment of advanced PEComas is scarce, with only one FDA-approved treatment available. The goals of this study were to provide data regarding systemic treatments for advanced PEComas and to identify biomarkers of prognostic relevance. This is a single-institution retrospective study of patients with advanced PEComas requiring systemic treatment, including malignant PEComa, angiomyolipoma (including the epithelioid variant), and lymphangioleiomyomatosis. Outcomes measured were overall survival (OS), first-line and combined progression-free survival (PFS), and tumor response. Kaplan–Meier, univariable, and multivariable Cox proportional hazards analysis were performed. A total of 29 patients were included, most with malignant PEComa (n = 17). Median OS was 204.9 months, while median PFS was 92.4 months from first-line, and 15.8 months for all lines combined. TFE3 overexpression correlated with higher risk of death (HR: 11.8, P = 0.04), and shorter median OS (P = 0.001). Chemotherapy and mTOR inhibitors showed similar OS (P = 0.84), and first-line PFS (P = 0.67). Combined PFS was similar between individual mTOR inhibitors, chemotherapy, immune checkpoint inhibitors and other treatments (P = 0.19). Different mTOR inhibitors demonstrated similar efficacy, making cost and availability important considerations when choosing a specific agent. mTOR inhibitors showed similar outcomes as chemotherapy, suggesting that these should be preferred whenever possible for patients with PEComas given the morbidity associated with chemotherapy. TFE3 overexpression highlighted a subgroup of PEComas with worse prognosis and more aggressive behavior.
Significance:
This study examines systemic treatments for advanced PEComas, a rare group of sarcomas, and identifies molecular biomarkers of prognosis. Our results show that mTOR inhibitors have similar efficacy as chemotherapy, and that TFE3 overexpression, on IHC or FISH, correlates with a more aggressive disease course.
Data from Systemic Treatments and Molecular Biomarkers for Perivascular Epithelioid Cell Tumors: A Single-Institution Retrospective Analysis
Authors: Testa Stefano , Bui Nam Q. , Ganjoo Kristen N.
Published: June 2023

Abstract
Perivascular epithelioid cell tumors (PEComas) are a large family of mesenchymal neoplasms, with variable clinical course. Evidence regarding treatment of advanced PEComas is scarce, with only one FDA-approved treatment available. The goals of this study were to provide data regarding systemic treatments for advanced PEComas and to identify biomarkers of prognostic relevance. This is a single-institution retrospective study of patients with advanced PEComas requiring systemic treatment, including malignant PEComa, angiomyolipoma (including the epithelioid variant), and lymphangioleiomyomatosis. Outcomes measured were overall survival (OS), first-line and combined progression-free survival (PFS), and tumor response. Kaplan-Meier, univariable and multivariable Cox proportional hazard analysis were performed. A total of 29 patients were included, most with malignant PEComa (n=17). Median OS was 204.9 months, while median PFS was 92.4 months from first-line, and 15.8 months for all lines combined. TFE3 overexpression correlated with higher risk of death (HR:11.8, P = 0.04), and shorter median OS (P = 0.001). Chemotherapy and mTOR inhibitors showed similar OS (P = 0.84), and first-line PFS (P = 0.67). Combined PFS was similar between individual mTOR inhibitors, chemotherapy, immune checkpoint inhibitors (ICIs) and other treatments (P = 0.19). Different mTOR inhibitors demonstrated similar efficacy, making cost and availability important considerations when choosing a specific agent. mTOR inhibitors showed similar outcomes as chemotherapy, suggesting that these should be preferred whenever possible for patients with PEComas given the morbidity associated with chemotherapy. TFE3 overexpression highlighted a subgroup of PEComas with worse prognosis and more aggressive behavior.
Phase Ib/II Study of a Liposomal Formulation of Eribulin (E7389-LF) plus Nivolumab in Patients with Advanced Solid Tumors: Results from Phase Ib
Authors: Ida Hanae , Shimizu Toshio , Nishino Makoto , Nakamura Yoshiaki , Yazaki Shu , Katsuya Yuki , Sato Jun , Koyama Takafumi , Iwasa Satoru , Sudo Kazuki , Kondo Shunsuke , Yonemori Kan , Shitara Kohei , Shiono Satoshi , Matsuoka Daiko , Yasuda Keisuke , Otake Yohei , Suzuki Takuya , Takase Takao , Takashima Shuya , Yamaguchi Kohei , Semba Taro , Yamamoto Noboru
Published: June 2023

Purpose:

To determine a recommended dose of liposomal eribulin (E7389-LF) in combination with nivolumab in patients with advanced solid tumors, and to evaluate the safety, efficacy, pharmacokinetics, and biomarker impact of this regimen.

Experimental Design:

Japanese patients with advanced, nonresectable, or recurrent solid tumors and no existing alternative standard/effective therapy (except nivolumab monotherapy) were assigned to either E7389-LF 1.7 mg/m2 plus nivolumab 360 mg every 3 weeks, E7389-LF 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks, E7389-LF 1.1 mg/m2 plus nivolumab 240 mg every 2 weeks, or E7389-LF 1.4 mg/m2 plus nivolumab 240 mg every 2 weeks. Primary objectives were to evaluate the safety/tolerability of each dose cohort and to determine the recommended phase II dose (RP2D). Secondary/exploratory objectives, including safety [dose-limiting toxicities (DLT) and adverse events (AE)], pharmacokinetics, efficacy [including objective response rate (ORR)], and biomarker results were used in determining the RP2D.

Results:

Twenty-five patients were enrolled to treatment [E7389-LF 1.7 mg/mg2 every 3 weeks (n = 6), E7389-LF 2.1 mg/m2 every 3 weeks (n = 6), E7389-LF 1.1 mg/m2 every 2 weeks (n = 7), E7389-LF 1.4 mg/m2 every 2 weeks (n = 6)]. Twenty-four patients were evaluated for DLTs, of whom 3 had DLTs (1 at E7389-LF 1.7 mg/m2 every 3 weeks, 1 at 1.1 mg/m2 every 2 weeks, and 1 at 1.4 mg/m2 every 2 weeks). All patients had ≥1 treatment-related treatment-emergent AE (TEAE); 68.0% had ≥1 grade 3–4 treatment-related TEAE. Changes in vasculature and IFN-related biomarkers were seen in each cohort. The overall ORR was 16%.

Conclusions:

E7389-LF plus nivolumab was tolerable overall; the recommended dose for future study was 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks.

Significance:

This phase Ib part of a phase Ib/II study assessed the tolerability and activity of a liposomal formulation of eribulin (E7389-LF) plus nivolumab in 25 patients with advanced solid tumors. The combination was tolerable overall; 4 patients had a partial response. Vasculature and immune-related biomarker levels increased, suggesting vascular remodeling.
Systemic Treatments and Molecular Biomarkers for Perivascular Epithelioid Cell Tumors: A Single-institution Retrospective Analysis
Authors: Testa Stefano , Bui Nam Q. , Ganjoo Kristen N.
Published: June 2023

Perivascular epithelioid cell tumors (PEComa) are a large family of mesenchymal neoplasms, with variable clinical course. Evidence regarding treatment of advanced PEComas is scarce, with only one FDA-approved treatment available. The goals of this study were to provide data regarding systemic treatments for advanced PEComas and to identify biomarkers of prognostic relevance. This is a single-institution retrospective study of patients with advanced PEComas requiring systemic treatment, including malignant PEComa, angiomyolipoma (including the epithelioid variant), and lymphangioleiomyomatosis. Outcomes measured were overall survival (OS), first-line and combined progression-free survival (PFS), and tumor response. Kaplan–Meier, univariable, and multivariable Cox proportional hazards analysis were performed. A total of 29 patients were included, most with malignant PEComa (n = 17). Median OS was 204.9 months, while median PFS was 92.4 months from first-line, and 15.8 months for all lines combined. TFE3 overexpression correlated with higher risk of death (HR: 11.8, P = 0.04), and shorter median OS (P = 0.001). Chemotherapy and mTOR inhibitors showed similar OS (P = 0.84), and first-line PFS (P = 0.67). Combined PFS was similar between individual mTOR inhibitors, chemotherapy, immune checkpoint inhibitors and other treatments (P = 0.19). Different mTOR inhibitors demonstrated similar efficacy, making cost and availability important considerations when choosing a specific agent. mTOR inhibitors showed similar outcomes as chemotherapy, suggesting that these should be preferred whenever possible for patients with PEComas given the morbidity associated with chemotherapy. TFE3 overexpression highlighted a subgroup of PEComas with worse prognosis and more aggressive behavior.

Significance:

This study examines systemic treatments for advanced PEComas, a rare group of sarcomas, and identifies molecular biomarkers of prognosis. Our results show that mTOR inhibitors have similar efficacy as chemotherapy, and that TFE3 overexpression, on IHC or FISH, correlates with a more aggressive disease course.
"Amanhã você estará aqui?" O trabalho com objetos em uma instituição para crianças com dificuldades no laço social
Authors: Bonilha Fernanda Cintra do Prado Pereira
Published: June 2023

Este artigo trata de uma experiência institucional de estágio no Institut Médico Pédagogique Notre Dame de la Sagesse, também conhecido como Le Courtil. O Courtil é uma instituição belga que acolhe crianças e jovens com dificuldades no laço social. A partir do caso clínico de uma garota de oito anos, discute-se a importância dos objetos para a invenção e o tratamento que o sujeito dá ao real. Demonstra-se que o tratamento é um trabalho singular realizado pelo sujeito em parceria com os interventores. A prática entre vários e a transferência são colocadas em evidência como dispositivos que favorecem esse trabalho.
O front na periferia: políticas de vida para a infância não sonhada
Authors: Perrone Cláudia Maria , Buechler Flavia Tridapalli , Silva Gabriela Gomes da , Rancich Juliana Martins Costa
Published: June 2023

A extensão do neoliberalismo para além do campo econômico resultou na consolidação da racionalidade do capital como lei social geral e o campo da educação tem servido como importante instrumento político de manutenção desse discurso. No Brasil, presenciamos a crescente exposição à condição de precariedade induzida, especialmente de crianças e jovens da periferia, sujeitos indesejáveis e não sonhados pela nação, expostos cotidianamente a uma lógica de guerra. Contudo, a união de corpos coletivos engajados em fomentar políticas de vida em territórios marginalizados tem se implicado performaticamente para fazer vingar o sonho de um futuro diferente para as próximas gerações. Através da articulação Psicanálise, Educação e Política, apresentamos caminhos possíveis para pensar a educação escolar a contrapelo da escola neoliberal.
Hydrogels to Recapture Extracellular Matrix Cues That Regulate Vascularization
Authors: Song Jiyeon , Gerecht Sharon
Published: June 2023

The ECM (extracellular matrix) is a 3-dimensional network that supports cellular responses and maintains structural tissue integrity in healthy and pathological conditions. The interactions between ECM and cells trigger signaling cascades that lead to phenotypic changes and structural and compositional turnover of the ECM, which in turn regulates vascular cell behavior. Hydrogel biomaterials are a powerful platform for basic and translational studies and clinical applications due to their high swelling capacity and exceptional versatility in compositions and properties. This review highlights recent developments and uses of engineered natural hydrogel platforms that mimic the ECM and present defined biochemical and mechanical cues for vascularization. Specifically, we focus on modulating vascular cell stimulation and cell-ECM/cell-cell interactions in the microvasculature that are the established biomimetic microenvironment.
Abstract 05: Hospital Variation In Epinephrine Administration Prior To Defibrillation For Cardiac Arrest Due To Shockable Rhythm
Authors: Stewart Colten , Chan Paul S , kennedy kevin , Swanson Morgan , Girotra Saket
Published: June 2023

Background:
Contrary to guidelines, we recently found that epinephrine administration before first defibrillation for in-hospital cardiac arrest (IHCA) due to a shockable rhythm is not uncommon. However, the extent to which the above practice varies across hospitals and its association with
hospital-level
survival is unknown.

Methods:
Using 2000-19 data from the Get With The Guidelines
®
-Resuscitation (GWTG-R) registry, we identified 57,816 adult patients (521 sites) with an index IHCA due to an initial shockable rhythm who received at least 1 defibrillation prior to achieving return of spontaneous circulation. We constructed multivariable hierarchical regression models to examine site-level variation in epinephrine before first defibrillation and its association with hospital survival.

Results:
Overall, the median rate of epinephrine before defibrillation was 18.8% and varied markedly across hospitals (range: 0%-70.6%, median odds ratio [OR] 1.50; 95% C.I. 1.43 - 1.57). Compared to hospitals in the lowest quartile (Q1) for epinephrine before defibrillation, hospitals in the highest quartile (Q4) were more likely to be major teaching hospitals and have more hospital beds. After adjusting for baseline variables, the median risk-standardized survival was 42.5% (IQR: 39.2%-46.0%). Compared to Q1 hospitals (epinephrine first rate of 0-12.4%), there was a stepwise decline in risk-standardized survival at hospitals with higher rates of epinephrine before first defibrillation: Q2: RR 0.95 [0.90-0.99]; Q3: RR 0.91 [0.87-0.96]; Q4: RR 0.81 [0.77-0.86]; P value for trend <0.001.

Conclusions:
For patients with shockable IHCA, there is marked hospital variation in epinephrine administration prior to first defibrillation, and this practice is associated with lower rates of survival to discharge. Hospital efforts to prioritize immediate defibrillation for patients with shockable IHCA are urgently needed.
Abstract 09: Readmission Risk And The Role Of Racial Residential Segregation Following Out-of-hospital Cardiac Arrest Among Medicare Beneficiaries
Authors: Abbott Ethan , Buckler David , Hsu Jesse , Abella Benjamin , Carr Brendan G , zebrowski alexis
Published: June 2023

Introduction:
Among out-of-hospital cardiac arrest (OHCA) survivors, high rates of mortality and readmissions have been reported after discharge. Racial residential segregation, a result of longstanding US institutional racism, has been associated with worse health outcomes across multiple conditions, but its relationship to readmission risk for OHCA is unknown. We investigated if the index of concentration at the extremes (ICE) is associated with increased risk of readmission for Medicare beneficiaries after survival from index hospitalization for OHCA.

Methods:
Using age-eligible Medicare fee-for-service claims from 2013-2015, we identified beneficiaries with a primary OHCA diagnosis (using ICD-CM diagnosis codes) who survived to discharge. The primary predictors were three ICE measures (race, income, and racialized income) calculated at the ZIP code level and binned into quintiles. The primary outcome was all-cause readmission after discharge from inpatient OHCA hospitalization. Competing risks regression models were fitted with a frailty term with readmission as the event of interest and mortality prior to readmission as the competing event, while accounting for beneficiary demographics, comorbidities, length of stay, and cardiac procedures.

Results:
We identified 200,509 OHCA claims; 29,847 (14.8%) survived to discharge. Mean beneficiary age was 75 years (SD 8), 40% were female, 79% White, and 15% Black. Within 30 days of discharge 8839 (29.6%) had died and 12075 (40%) were readmitted; congestive heart failure was the leading cause of readmission (12.5 %). In univariate analysis, we found a decreased risk of readmission in the more racially and economically privileged quintiles (Q2-Q5) of ICE race (HR 0.87-0.99) and ICE racialized income measures (HR 0.91-0.96) as compared to reference (Q1) but this was not significant across all quintiles. In fully adjusted competing risk regression models, we did not find a significant association with risk of readmission and measures of residential segregation.

Conclusion:
Measures of racial residential segregation are associated with increased risk of readmission among Medicare beneficiaries residing in less privileged ZIP codes, but not present after adjusting for important covariates.