bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mammary Tumor–Derived Transplants as Breast Cancer Models to Evaluate Tumor–Immune Interactions and Therapeutic Responses
Authors: Moore Jade , Ma Lin , Lazar Ann A. , Barcellos-Hoff Mary Helen 
Published: December 2021

Abstract

In breast cancer, the type and distribution of infiltrating immune cells are associated with clinical outcome. Moreover, cancers with abundant tumor-infiltrating lymphocytes (TIL) are more likely to respond to immunotherapy, whereas those in which CD8+ T cells are completely absent (deserts) or excluded are less likely to respond. Detailed understanding of this biology is limited by a lack of preclinical breast cancer models that recapitulate TIL distributions and their associated biology. Here we established mammary tumor–derived transplants (mTDT) from 12 Trp53-null mammary tumors in syngeneic BALB/cJ mice and examined the stability of their growth rate, TIL distribution, and transcriptomic profiles. All mTDTs were estrogen receptor negative. Half of the parental tumors were classified as infiltrated, and the rest were divided between excluded and desert phenotypes. After two orthotopic passages, most (70%) mTDT from infiltrated parents recapitulated this pattern, whereas the desert or excluded parental patterns were maintained in about half of daughter mTDT. Approximately 30% of mTDT gave rise to lung or liver metastases, although metastasis was not associated with a TIL phenotype. Unsupervised transcriptomic analysis clustered mTDT according to their TIL spatial patterns. Infiltrated mTDT transplanted subcutaneously or orthotopically were resistant to anti–PD-L1. Profiling implicated prolonged antigen stimulation and loss of effector function of lymphocytes rather than T-cell exhaustion in the lack of response of infiltrated mTDT to checkpoint blockade. In summary, the molecular diversity and immune complexity of mTDT should facilitate the dissection of mechanisms of breast cancer response to immunotherapies.

Significance:
A set of diverse preclinical models of breast cancer is characterized to enable mechanistic dissection of tumor–immune interactions and to improve the efficacy of immunotherapies.
Targeting Chemotherapy to Decondensed H3K27me3-Marked Chromatin of AML Cells Enhances Leukemia Suppression
Authors: Porazzi Patrizia , Petruk Svetlana , Pagliaroli Luca , De Dominici Marco , Deming David , Puccetti Matthew V. , Kushinsky Saul , Kumar Gaurav , Minieri Valentina , Barbieri Elisa , Deliard Sandra , Grande Alexis , Trizzino Marco , Gardini Alessandro , Canaani Eli , Palmisiano Neil , Porcu Pierluigi , Ertel Adam , Fortina Paolo , Eischen Christine M. , Mazo Alexander , Calabretta Bruno 
Published: December 2021

Abstract

Despite treatment with intensive chemotherapy, acute myelogenous leukemia (AML) remains an aggressive malignancy with a dismal outcome in most patients. We found that AML cells exhibit an unusually rapid accumulation of the repressive histone mark H3K27me3 on nascent DNA. In cell lines, primary cells and xenograft mouse models, inhibition of the H3K27 histone methyltransferase EZH2 to decondense the H3K27me3-marked chromatin of AML cells enhanced chromatin accessibility and chemotherapy-induced DNA damage, apoptosis, and leukemia suppression. These effects were further promoted when chromatin decondensation of AML cells was induced upon S-phase entry after release from a transient G1 arrest mediated by CDK4/6 inhibition. In the p53-null KG-1 and THP-1 AML cell lines, EZH2 inhibitor and doxorubicin cotreatment induced transcriptional reprogramming that was, in part, dependent on derepression of H3K27me3-marked gene promoters and led to increased expression of cell death–promoting and growth-inhibitory genes.

In conclusion, decondensing H3K27me3-marked chromatin by EZH2 inhibition represents a promising approach to improve the efficacy of DNA-damaging cytotoxic agents in patients with AML. This strategy might allow for a lowering of chemotherapy doses, with a consequent reduction of treatment-related side effects in elderly patients with AML or those with significant comorbidities.

Significance:
Pharmacological inhibition of EZH2 renders DNA of AML cells more accessible to cytotoxic agents, facilitating leukemia suppression with reduced doses of chemotherapy.
See related commentary by Adema and Colla, p. 359
Polypharmacologic Reprogramming of Tumor-Associated Macrophages toward an Inflammatory Phenotype
Authors: Nishida-Aoki Nao , Gujral Taranjit S. 
Published: December 2021

Abstract

Tumor-associated macrophages (TAM) are an important component of the tumor microenvironment (TME) that can promote tumor progression, metastasis, and resistance to therapies. Although TAMs represent a promising target for therapeutic intervention, the complexity of the TME has made the study of TAMs challenging. Here, we established a physiologically relevant in vitro TAM polarization system that recapitulates TAM protumoral activities. This system was used to characterize dynamic changes in gene expression and protein phosphorylation during TAM polarization and to screen phenotypic kinase inhibitors that impact TAM programming. BMS-794833, a multitargeted compound, was identified as a potent inhibitor of TAM polarization. BMS-794833 decreased protumoral properties of TAMs in vitro and suppressed tumor growth in mouse triple-negative breast cancer models. The effect of BMS-794833 was independent of its primary targets (MET and VEGFR2) but was dependent on its effect on multiple signaling pathways, including focal adhesion kinases, SRC family kinases, STAT3, and p38 MAPKs. Collectively, these findings underline the efficacy of polypharmacologic strategies in reprogramming complex signaling cascades activated during TAM polarization.

Significance:
A physiologically relevant in vitro system of TAM polarization uncovers signaling pathways that regulate polarization and identifies strategies to target macrophage reprogramming to suppress cancer growth.
Comprehensive Analysis of Alternative Splicing in Gastric Cancer Identifies Epithelial–Mesenchymal Transition Subtypes Associated with Survival
Authors: Jun Yukyung , Suh Yun-Suhk , Park SungHee , Lee Jieun , Kim Jong-Il , Lee Sanghyuk , Lee Wan-Ping , Anczuków Olga , Yang Han-Kwang , Lee Charles 
Published: December 2021

Abstract

Alternatively spliced RNA isoforms are a hallmark of tumors, but their nature, prevalence, and clinical implications in gastric cancer have not been comprehensively characterized. We systematically profiled the splicing landscape of 83 gastric tumors and matched normal mucosa, identifying and experimentally validating eight splicing events that can classify all gastric cancers into three subtypes: epithelial-splicing (EpiS), mesenchymal-splicing (MesS), and hybrid-splicing. These subtypes were associated with distinct molecular signatures and epithelial–mesenchymal transition markers. Subtype-specific splicing events were enriched in motifs for splicing factors RBM24 and ESRP1, which were upregulated in MesS and EpiS tumors, respectively. A simple classifier based only on RNA levels of RBM24 and ESRP1, which can be readily implemented in the clinic, was sufficient to distinguish gastric cancer subtypes and predict patient survival in multiple independent patient cohorts. Overall, this study provides insights into alternative splicing in gastric cancer and the potential clinical utility of splicing-based patient classification.

Significance:
This study presents a comprehensive analysis of alternative splicing in the context of patient classification, molecular mechanisms, and prognosis in gastric cancer.
Fluoride Formed on Enamel by Fluoride Varnish or Gel Application: A Randomized Controlled Clinical Trial
Authors: Dall Agnol Mauro Antonio , Battiston Carla , Tenuta Livia Maria Andalo , Cury Jaime Aparecido 
Published: December 2021

Although fluoride varnish (FV) and acidulated phosphate fluoride gel (APF-gel) are considered clinically effective to reduce caries, in vitro studies have shown that FV reacts slowly with enamel because most NaF present in the formulation is not solubilized in the FV. Therefore, we conducted a clinical study to evaluate if the time that FV remains on dental surfaces could overcome its slower chemical reactivity when compared with APF-gel. Sixty-eight volunteers were randomly allocated into 4 groups: negative control (Control, no treatment), APF-gel application (1.23% F applied for 4 min), and FV application (Duraphat®, 2.26% F) for 4 h (FV-4h) or 24 h (FV-24 h). To evaluate fluoride formed and retained on enamel, acid biopsies were made on the buccal surfaces of the maxillary central incisors before, at the end of the application of fluoride products (immediately after gel application, or after 4 or 24 h of varnish application), and after 7 and 28 days. Fluoride concentration in dental biofilm was also analyzed before and up to 28 days after initial application. The data were analyzed by 2-way ANOVA, considering treatment and time as factors. The APF-gel and FV-24h groups formed greater fluoride concentration on enamel than the FV-4h and the control group at the end of application (p = 0.0001), with no difference from each other (p = 0.99). The groups did not differ regarding fluoride in biofilm fluid (p = 0.73) and solids (p = 0.40). In conclusion, FV needs to remain in contact with the teeth for prolonged times (>4 h) to reach the same reactivity obtained by a 4-min application of APF-gel.
Ruptures and Wrong-Footings: Destabilizing Disciplinary Cultures
Authors: Crisp Fiona , Dorsett Chris , Mackenzie Louise 
Published: December 2021

Abstract
In this transcribed conversation, three artists from the U.K. research group The Cultural Negotiation of Science (CNoS) share the generational perspectives they bring to the contested field of arts-science research. Traversing territories between art-practice, physics, genetics and critical theory, their practice-based strategies actively destabilize the binary nature of cross-disciplinary dialogue in productive ways, allowing the spaces between artistic and scientific modes of inquiry to become sites of learning, both within and beyond academic institutions.
Does the Rotating Convection Paradigm Describe Secondary Eyewall Formation in Idealized Three-Dimensional Simulations?
Authors: Persing John , Montgomery Michael T. 
Published: December 2021

AbstractThe formation of a plausible secondary eyewall is examined with two principal simulation experiments that differ only in the fixed value of rain fall speed, one with a value of 70 m s−1(approaching the pseudo-adiabatic limit) that simulates a secondary eyewall, and one with a value of 7 m s−1that does not simulate a secondary eyewall. Key differences are sought between these idealized three-dimensional simulations. A notable expansion of the lower-tropospheric tangential wind field to approximately 400-km radius is found associated with the precursor period of the secondary eyewall. The wind field expansion is traced to an enhanced vertical mass flux across the 5.25-km height level, which leads, in turn, to enhanced radial inflow in the lower troposphere and above the boundary layer. The inflow spins up the tangential wind outside the primary eyewall via the conventional spinup mechanism. This amplified tangential wind field is linked to a broad region of outwardly directed agradient force in the upper boundary layer. Whereas scattered convection is found outside the primary eyewall in both simulations, the agradient force is shown to promote a ring-like organization of this convection when boundary layer convergence occurs in a persistent, localized region of supergradient winds. The results support prior work highlighting a new model of secondary eyewall formation emphasizing a boundary layer control pathway for initiating the outer eyewall as part of the rotating convection paradigm of tropical cyclone evolution.
Roles of Meridional Overturning in Subpolar Southern Ocean SST Trends: Insights from Ensemble Simulations
Authors: Zhang Liping , Delworth Thomas L. , Kapnick Sarah , He Jie , Cooke William , Wittenberg Andrew T. , Johnson Nathaniel C. , Rosati Anthony , Yang Xiaosong , Lu Feiyu , Bushuk Mitchell , McHugh Colleen , Murakami Hiroyuki , Zeng Fanrong , Jia Liwei , Tseng Kai-Chih , Morioka Yushi 
Published: December 2021

Abstract
One of the most puzzling observed features of recent climate has been a multidecadal surface cooling trend over the subpolar Southern Ocean (SO). In this study we use large ensembles of simulations with multiple climate models to study the role of the SO meridional overturning circulation (MOC) in these sea surface temperature (SST) trends. We find that multiple competing processes play prominent roles, consistent with multiple mechanisms proposed in the literature for the observed cooling. Early in the simulations (twentieth century and early twenty-first century) internal variability of the MOC can have a large impact, in part due to substantial simulated multidecadal variability of the MOC. Ensemble members with initially strong convection (and related surface warming due to convective mixing of subsurface warmth to the surface) tend to subsequently cool at the surface as convection associated with internal variability weakens. A second process occurs in the late-twentieth and twenty-first centuries, as weakening of oceanic convection associated with global warming and high-latitude freshening can contribute to the surface cooling trend by suppressing convection and associated vertical mixing of subsurface heat. As the simulations progress, the multidecadal SO variability is suppressed due to forced changes in the mean state and increased oceanic stratification. As a third process, the shallower mixed layers can then rapidly warm due to increasing forcing from greenhouse gas warming. Also, during this period the ensemble spread of SO SST trend partly arises from the spread of the wind-driven Deacon cell strength. Thus, different processes could conceivably have led to the observed cooling trend, consistent with the range of possibilities presented in the literature. To better understand the causes of the observed trend, it is important to better understand the characteristics of internal low-frequency variability in the SO and the response of that variability to global warming.
Double Diffusion, Shear Instabilities, and Heat Impacts of a Pacific Summer Water Intrusion in the Beaufort Sea
Authors: Fine Elizabeth C. , MacKinnon Jennifer A. , Alford Matthew H. , Middleton Leo , Taylor John , Mickett John B. , Cole Sylvia T. , Couto Nicole , Boyer Arnaud Le , Peacock Thomas 
Published: December 2021

AbstractPacific Summer Water eddies and intrusions transport heat and salt from boundary regions into the western Arctic basin. Here we examine concurrent effects of lateral stirring and vertical mixing using microstructure data collected within a Pacific Summer Water intrusion with a length scale of ∼20 km. This intrusion was characterized by complex thermohaline structure in which warm Pacific Summer Water interleaved in alternating layers ofm thickness with cooler water, due to lateral stirring and intrusive processes. Along interfaces between warm/salty and cold/freshwater masses, the density ratio was favorable to double-diffusive processes. The rate of dissipation of turbulent kinetic energy (ε) was elevated along the interleaving surfaces, with values up to 3 × 10−8W kg−1compared to backgroundεof less than 10−9W kg−1. Based on the distribution ofεas a function of density ratioRρ, we conclude that double-diffusive convection is largely responsible for the elevatedεobserved over the survey. The lateral processes that created the layered thermohaline structure resulted in vertical thermohaline gradients susceptible to double-diffusive convection, resulting in upward vertical heat fluxes. Bulk vertical heat fluxes above the intrusion are estimated in the range of 0.2–1 W m−2, with the localized flux above the uppermost warm layer elevated to 2–10 W m−2. Lateral fluxes are much larger, estimated between 1000 and 5000 W m−2, and set an overall decay rate for the intrusion of 1–5 years.
A Hybrid Multivariate Deep Learning Network for Multistep Ahead Sea Level Anomaly Forecasting
Authors: Wang Guosong , Wang Xidong , Wu Xinrong , Liu Kexiu , Qi Yiquan , Sun Chunjian , Fu Hongli 
Published: December 2021

Abstract
The accumulated remote sensing data of altimeters and scatterometers have provided new opportunities for ocean state forecasting and have improved our knowledge of ocean–atmosphere exchanges. Studies on multivariate, multistep, spatiotemporal sequence forecasts of sea level anomalies (SLA) for different modalities, however, remain problematic. In this paper, we present a novel hybrid and multivariate deep neural network, named HMnet3, which can be used for SLA forecasting in the South China Sea (SCS). First, a spatiotemporal sequence forecasting network is trained by an improved convolutional long short-term memory (ConvLSTM) network using a channelwise attention mechanism and multivariate data from 1993 to 2015. Then a time series forecasting network is trained by an improved long short-term memory (LSTM) network, which is realized by ensemble empirical mode decomposition (EEMD). Finally, the two networks are combined by a successive correction method to produce SLA forecasts for lead times of up to 15 days, with a special focus on the open sea and coastal regions of the SCS. During the testing period of 2016–18, the performance of HMnet3 with sea surface temperature anomaly (SSTA), wind speed anomaly (SPDA), and SLA data is much better than those of state-of-the-art dynamic and statistical (ConvLSTM, persistence, and climatology) forecast models. Stricter testbeds for trial simulation experiments with real-time datasets are investigated, where the eddy classification metrics of HMnet3 are favorable for all properties, especially for those of small-scale eddies.
Anesthesia Health System Capacities in Public Hospitals of Punjab, Pakistan
Authors: Shahbaz Sumbal , Zakar Rubeena , Fischer Florian 
Published: December 2021

Purpose: This study intends to outline the capacity of anesthesia health system in public hospitals of Punjab, Pakistan. Methods: A cross-sectional survey among public hospitals of Punjab was carried out that provide emergency and elective surgical care. We measured capacity in terms of infrastructure; surgical, anesthetic, and obstetric (SAO) workforce; surgical interventions; information management; equipment; and medication which was accomplished between October 2020 and February 2021. Results: Out of 106 public hospitals in Punjab, almost 40% had only one anesthesia provider. Only 50% of the hospitals reported round the clock availability of anesthesia providers for surgical cases. While caesarean sections were carried out in more than 90% of health facilities, general surgery, pediatric surgery, and open fracture surgery were conducted only in 50% of the hospitals. Although local and general anesthetic agents were available in the majority of hospitals, essential medicines for safe anesthesia were not available in all hospitals. Conclusion: This first comprehensive assessment of anesthesia health system capacity exposed a crucial deficiency of critical supplies and workforce for providing safe anesthesia and, hence, safe surgery. The surveyed facilities had an uneven division of resources.
Pre-Algebra Students’ Performance Locating and Interpreting Data in Graphs and Maps
Authors: Rosenblum L. Penny , Zebehazy Kim T. , Gage Nicholas A. , Beal Carole R. 
Published: December 2021

Introduction Developing graphicacy skills is important for students with visual impairments if they are to succeed in science, technology, engineering, and mathematics (STEM) content. Teachers of students with visual impairments report that they lack resources to use in teaching students graphicacy skills. Methods Forty-one students with visual impairments in grades 5–10 completed a pretest, intervention, and posttest designed to evaluate their skills locating and interpreting graphical data. Videos of the pre- and posttests were scored using a researcher developed instrument. Results Following intervention, there was a significant difference in students’ ability to use descriptors and mathematical terms when exploring graphs and a map. Students answered significantly more questions correctly from pre- to posttest. Discussion Students who receive direct instruction in how to locate and interpret data in graphs and maps can improve their level of independence in STEM classes. Use of an intervention that targets the development of graphicacy skills has been found to be effective. Implications for practitioners More research is needed to determine effective hand strategies students should use when exploring different types of graphics.
Debunking the myth of ‘Blue Mondays’: No evidence of affect drop after taking clinical MDMA
Authors: Sessa Ben , Aday Jacob S , O’Brien Steve , Curran H Valerie , Measham Fiona , Higbed Laurie , Nutt David J 
Published: December 2021

Background: Incorporating 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct to psychotherapy has shown promise in recent years for treating various mental health conditions, particularly those involving trauma. However, concerns about declines in mood and cognition during the days following dosing, also known as ‘Blue Mondays’, have been raised as limitations to its clinical use. Although these changes have been well-documented among recreational users, there are critical confounds to these reports that limit generalizability to clinically administered MDMA. Aims: Here, we aimed to evaluate the evidence basis for the negative side effects associated with MDMA as well as inform our understanding of the drug’s post-acute effects in a clinical context with an open-label study. Methods: The current open-label study examined MDMA therapy for alcohol use disorder (AUD; N = 14) and measured mood, sleep quality, illicit MDMA consumption and anecdotal reports after the acute drug effects had worn off. Results: Participants maintained a positive mood during the week following drug administration in a clinical context. Relative to baseline, self-reported sleep quality improved at the 3- and 6-month follow-ups. Finally, no participants reported using or desiring to use illicit MDMA, and the anecdotal reports indicated that they perceived the treatment favourably. Conclusion: The results support the overall safety and tolerability of clinically administered MDMA and, importantly, suggest that the ‘come downs’ previously associated with the substance may be explained by confounds in research relating to the illicit sourcing of the drug and specific environmental setting for recreational consumption.