bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low Glucose–Induced Overexpression of HOXC-AS3 Promotes Metabolic Reprogramming of Breast Cancer
Authors: Zhu Wenjie , Chen Xu , Guo Xiangyu , Liu Haiting , Ma Ranran , Wang Yawen , Liang Yahang , Sun Ying , Wang Mengqi , Zhao Ruinan , Gao Peng 
Published: January 2022

Abstract

Breast cancer is the most common malignancy in women worldwide. However, the mechanisms underlying breast cancer energy metabolism and progression remain obscure. Cancer cells rapidly adapt to microenvironments with fluctuating nutrient levels. Here, we characterized a long noncoding RNA (lncRNA), HOXC-AS3, which is activated upon glucose deprivation to trigger a nutrient-stress response and a switch in glucose metabolism. Upregulation of HOXC-AS3 in breast cancer was identified by in published microarray and RNA-sequencing datasets, and then confirmed by qRT-PCR in fresh breast cancer tissues. Glucose deprivation induced HOXC-AS3 overexpression in a dose- and time-dependent manner in breast cancer cells. Gain- and loss-of-function experiments in vitro and in vivo showed that HOXC-AS3 triggers energy metabolism reprogramming. ChIRP-mass spectrometry and unique molecular identifier RNA immunoprecipitation and high-throughput sequencing (UMI RIP-seq) identified binding motifs of HOXC-AS3 with SIRT6. HOXC-AS3 selectively antagonized SIRT6-mediated H3K9ac deacetylation of glycolysis-related genes. Moreover, HOXC-AS3 binding to SIRT6 prevented contact inhibition of HIF1α, leading to reprogramming of metabolic pathways. In addition, HOXC-AS3, SP1, and miR-1224–5p formed a positive feedback loop to maintain cancer-promoting signals. Furthermore, administration of anti-HOXC-AS3-motif-RNAs effectively blocked the function of HOXC-AS3, ultimately suppressing breast cancer progression. These results reveal a critical role for HOXC-AS3 in regulating the metabolic reprogramming of breast cancer cells under metabolic stress. Use of an anti-HOXC-AS3-motif RNA mixture may be a promising strategy to suppress breast cancer progression.

Significance:
HOXC-AS3 is a low glucose–activated long noncoding RNA that triggers metabolic reprogramming in breast cancer cells to adapt to nutrient stress, identifying HOXC-AS3 as a potential therapeutic target for breast cancer treatment.
Genetic, Pharmacogenomic, and Immune Landscapes of Enhancer RNAs Across Human Cancers
Authors: Zhang Zhao , Luo Mei , Li Qiang , Liu Yuan , Lussier Charles , Zhang Jian , Ye Youqiong , Guo An-Yuan , Han Leng 
Published: January 2022

Abstract

Enhancer RNAs (eRNA) regulate gene expression and play critical roles in cancer. Using large-scale omics data from The Cancer Genome Atlas (TCGA), we systematically investigated the impact of genetic variants on eRNA expression and identified approximately 1 million eRNA quantitative trait loci (eRNA-QTL) as cis- and trans-acting. Over 16,000 eRNA-QTLs were associated with patient overall survival. Assessing the impact of eRNAs on more than 1,000 imputed anticancer drug responses across approximately 10,000 patients with cancer revealed more than 7 million significant associations. Furthermore, approximately 240,000 significant associations were identified between eRNA expression and immune cell abundance deconvoluted by TIMER, CIBERSORT, ImmuCellAI, and ImmuneCellGSVA. Finally, a user-friendly data portal was generated: Genetic, Pharmacogenomic, and Immune Landscapes of eRNAs (GPIeR; https://hanlab.tamhsc.edu/GPIeR/). GPIeR is a large-scale multidimensional data portal that can be used to explore eRNA-associated genetic variants, drug responses, and immune infiltration, with the purpose of facilitating functional and clinical investigations of eRNAs in cancer.

Significance:
This study provides insights into the impact of the enhancer RNA (eRNA) landscape on patient outcome, the immune microenvironment, and drug response across cancers and develops a multidimensional data portal to facilitate eRNA research.
Glucosamine Use and Risk of Colorectal Cancer: Results from UK Biobank
Authors: Kantor Elizabeth D. , O'Connell Kelli , Liang Peter S. , Navarro Sandi L. , Giovannucci Edward L. , Du Mengmeng 
Published: January 2022

Abstract

Background:
Use of the dietary supplement glucosamine has been associated with reduced risk of colorectal cancer; however, it remains unclear if the association varies by screening status, time, and other factors.

Methods:
We therefore evaluated these questions in UK Biobank. Multivariable-adjusted HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards regression.

Results:
No association was observed between use of glucosamine and risk of colorectal cancer overall (HR = 0.94; 95% CI, 0.85–1.04). However, the association varied by screening status (Pinteraction = 0.05), with an inverse association observed only among never-screened individuals (HR = 0.86; 95% CI, 0.76–0.98). When stratified by study time, an inverse association was observed in early follow-up among those entering the cohort in early years (2006–2008; HR = 0.80; 95% CI, 0.67–0.95). No heterogeneity was observed by age, sex, body mass index, smoking status, or use of nonsteroidal anti-inflammatory drugs.

Conclusions:
While there was no association between glucosamine use and colorectal cancer overall, the inverse association among never-screened individuals mirrors our observations in prior exploratory analyses of U.S. cohorts. The National Health Service Bowel Cancer Screening Program started in 2006 in England and was more widely implemented across the UK by 2009/2010. In line with this, we observed an inverse association limited to early follow-up in those surveyed from 2006 to 2008, before screening was widely implemented.

Impact:
These data suggest that unscreened individuals may benefit from use of glucosamine; however, further studies are needed to confirm the interplay of screening and timing.
Metabolic Alterations and WNT Signaling Impact Immune Response in HGSOC
Authors: Arend Rebecca C. , Scalise Carly B. , Gordon Emily R. , Davis Allison M. , Foxall McKenzie E. , Johnston Bobbi E. , Crossman David K. , Cooper Sara J. 
Published: January 2022

AbstractPurpose:Our study used transcriptomic and metabolomic strategies to determine the molecular profiles of HGSOC patient samples derived from primary tumor and ascites cells. These data identified clinically relevant heterogeneity among and within patients and highlighted global and patient-specific cellular responses to neoadjuvant chemotherapy (NACT).Experimental Design:Tissue from 61 treatment-naïve patients with HGSOC were collected. In addition, 11 benign, 32 ascites, and 18 post-NACT samples (matched to the individual patient's pre-NACT sample) were collected. RNA sequencing (RNA-seq) was performed on all samples collected. Two-dimensional spatial proteomic data was collected for two pairs of pre- and post-NACT. Untargeted metabolomics data using GCxGC-MS was generated for 30 treatment-naive tissues. Consensus clustering, analysis of differential expression, pathway enrichment, and survival analyses were performed.Results:Treatment-naïve HGSOC tissues had distinct transcriptomic and metabolomic profiles. The mesenchymal subtype harbored a metabolomic profile distinct from the other subtypes. Compared with primary tumor tissue, ascites showed significant changes in immune response and signaling pathways. NACT caused significant alterations in gene expression and WNT activity, and this corresponded to altered immune response. Overall, WNT signaling levels were inversely correlated with immune cell infiltration in HGSOC tissues and WNT signaling post-NACT was inversely correlated with progression-free survival.Conclusions:Our study concluded that HGSOC is a heterogenous disease at baseline and growing molecular differences can be observed between primary tumor and ascites cells or within tumors in response to treatment. Our data reveal potential exploratory biomarkers relevant for treatment selection and predicting patient outcomes that warrant further research.
Phase II Study of ONC201 in Neuroendocrine Tumors including Pheochromocytoma-Paraganglioma and Desmoplastic Small Round Cell Tumor
Authors: Anderson Peter M. , Trucco Matteo M. , Tarapore Rohinton S. , Zahler Stacey , Thomas Stefanie , Gortz Janette , Mian Omar , Stoignew Martin , Prabhu Varun , Morrow Sara , Allen Joshua E. 
Published: January 2022

AbstractPurpose:Tumor dopamine-like DRD2 receptor expression is higher in pheochromocytoma-paraganglioma (PC-PG) compared with other cancers. ONC201 is a bitopic DRD2 antagonist with preclinical ONC201 activity in desmoplastic small round cell tumor (DSRCT).Patients and Methods:Patients (N = 30) with neuroendocrine tumors were treated on this investigator-initiated trial (NCT03034200). ONC201 dose and schedule were 625 mg orally weekly in cohorts A (PC-PG) + B (other neuroendocrine tumors) and 625 mg orally on 2 consecutive days each week in cohort C, which included 5 responding patients. The primary endpoint was radiographic response measured using RECIST. Secondary endpoints included progression-free survival, overall survival, and safety.Results:In arm A (n = 10; all PC-PG), 50% (5/10) exhibited a partial response (PR) and 2 additional patients had stable disease (SD) &gt;3 months. Median duration of therapy for arm A patients was 9 months (range: 1.5–33 months) with 5 patients treated &gt;1 year. In arm B (n = 12), there were 1 PR (DSRCT) and 2 SD (DSRCT; neuroblastoma) &gt;3 months. Median duration of therapy in arm A was 18 months (range: 1–33 months) and arm B was 3 months (range: 1.5–33 months). Arm C PC-PG (N = 8) showed 1 PR and 7 SD at 3 months, with median duration of therapy &gt;10 months. There was no decline in Karnofsky performance status at week 12 for 28 of 30 patients and no dose modification due to treatment-related adverse events.Conclusions:Oral ONC201 was well tolerated in patients with metastatic neuroendocrine tumors and associated with clinical benefit, including tumor responses, particularly in some patients with DSRCT and the majority of patients with PC-PG.See related commentary by Owen and Trikalinos, p. 1748
Integrated Proteomics-Based Physical and Functional Mapping of AXL Kinase Signaling Pathways and Inhibitors Define Its Role in Cell Migration
Authors: Majumder Anurima , Hosseinian Sina , Stroud Mia , Adhikari Emma , Saller James J. , Smith Matthew A. , Zhang Guolin , Agarwal Shruti , Creixell Marc , Meyer Benjamin S. , Kinose Fumi , Bowers Kiah , Fang Bin , Stewart Paul A. , Welsh Eric A. , Boyle Theresa A. , Meyer Aaron S. , Koomen John M. , Haura Eric B. 
Published: January 2022

Abstract

To better understand the signaling complexity of AXL, a member of the tumor-associated macrophage (TAM) receptor tyrosine kinase family, we created a physical and functional map of AXL signaling interactions, phosphorylation events, and target-engagement of three AXL tyrosine kinase inhibitors (TKI). We assessed AXL protein complexes using proximity-dependent biotinylation (BioID), effects of AXL TKI on global phosphoproteins using mass spectrometry, and target engagement of AXL TKI using activity-based protein profiling. BioID identifies AXL-interacting proteins that are mostly involved in cell adhesion/migration. Global phosphoproteomics show that AXL inhibition decreases phosphorylation of peptides involved in phosphatidylinositol-mediated signaling and cell adhesion/migration. Comparison of three AXL inhibitors reveals that TKI RXDX-106 inhibits pAXL, pAKT, and migration/invasion of these cells without reducing their viability, while bemcentinib exerts AXL-independent phenotypic effects on viability. Proteomic characterization of these TKIs demonstrates that they inhibit diverse targets in addition to AXL, with bemcentinib having the most off-targets. AXL and EGFR TKI cotreatment did not reverse resistance in cell line models of erlotinib resistance. However, a unique vulnerability was identified in one resistant clone, wherein combination of bemcentinib and erlotinib inhibited cell viability and signaling. We also show that AXL is overexpressed in approximately 30% to 40% of nonsmall but rarely in small cell lung cancer. Cell lines have a wide range of AXL expression, with basal activation detected rarely.

Implications:
Our study defines mechanisms of action of AXL in lung cancers which can be used to establish assays to measure drug targetable active AXL complexes in patient tissues and inform the strategy for targeting it's signaling as an anticancer therapy.
A Natural Polyphenol Exerts Antitumor Activity and Circumvents Anti–PD-1 Resistance through Effects on the Gut Microbiota
Authors: Messaoudene Meriem , Pidgeon Reilly , Richard Corentin , Ponce Mayra , Diop Khoudia , Benlaifaoui Myriam , Nolin-Lapalme Alexis , Cauchois Florent , Malo Julie , Belkaid Wiam , Isnard Stephane , Fradet Yves , Dridi Lharbi , Velin Dominique , Oster Paul , Raoult Didier , Ghiringhelli François , Boidot Romain , Chevrier Sandy , Kysela David T. , Brun Yves V. , Falcone Emilia Liana , Pilon Geneviève , Oñate Florian Plaza , Gitton-Quent Oscar , Le Chatelier Emmanuelle , Durand Sylvere , Kroemer Guido , Elkrief Arielle , Marette André , Castagner Bastien , Routy Bertrand 
Published: January 2022

Abstract

Several approaches to manipulate the gut microbiome for improving the activity of cancer immune-checkpoint inhibitors (ICI) are currently under evaluation. Here, we show that oral supplementation with the polyphenol-rich berry camu-camu (CC; Myrciaria dubia) in mice shifted gut microbial composition, which translated into antitumor activity and a stronger anti–PD-1 response. We identified castalagin, an ellagitannin, as the active compound in CC. Oral administration of castalagin enriched for bacteria associated with efficient immunotherapeutic responses (Ruminococcaceae and Alistipes) and improved the CD8+/FOXP3+CD4+ ratio within the tumor microenvironment. Moreover, castalagin induced metabolic changes, resulting in an increase in taurine-conjugated bile acids. Oral supplementation of castalagin following fecal microbiota transplantation from ICI-refractory patients into mice supported anti–PD-1 activity. Finally, we found that castalagin binds to Ruminococcus bromii and promoted an anticancer response. Altogether, our results identify castalagin as a polyphenol that acts as a prebiotic to circumvent anti–PD-1 resistance.

Significance:
The polyphenol castalagin isolated from a berry has an antitumor effect through direct interactions with commensal bacteria, thus reprogramming the tumor microenvironment. In addition, in preclinical ICI-resistant models, castalagin reestablishes the efficacy of anti–PD-1. Together, these results provide a strong biological rationale to test castalagin as part of a clinical trial.
This article is highlighted in the In This Issue feature, p. 873
Um olhar sobre a proteção social na América Latina frente à pandemia
Authors: Aranha Adriana , Bronzo Carla 
Published: January 2022

O artigo parte da perspectiva de que a proteção social é um dispositivo central para o enfrentamento das desigualdades e riscos sociais, mas sua importância se amplia no contexto pós-pandemia do COVID-19, demandando uma mudança de paradigma e de novas representações e sentidos para o papel do Estado na proteção da população mais pobre e vulnerável. Partindo da descrição de tipologias de sistemas de proteção social, se analisam as respostas dadas pelos países latinoamericanos no campo da proteção não contributiva, para o enfrentamento da crise sanitária e suas implicações sociais. A partir de fontes secundárias – documentos nacionais, relatórios de agências internacionais e artigos sobre o tema - o artigo propõe um balanço das iniciativas regionais de modo geral, mas com foco em oito países com alta, média e baixas brechas de proteção: Brasil, Argentina, Chile, Uruguai, Peru, Equador, Bolívia e Paraguai. Em base às informações coletadas, o artigo problematiza alguns desafios contemporâneos, no contexto da proteção social da América Latina. A conquista da cidadania, estabelecida como um desiderato nas sociedades modernas, encontra barreiras estruturais para ser efetivada na região, a mais desigual do mundo.
Ratio of Mixed Venous Oxygen Saturation-to-Pulmonary Capillary Wedge Pressure: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program
Authors: Hillerson Dustin , Charnigo Richard , Moon Kim Sun , Iyengar Amrita , Lane Matthew , Misumida Naoki , Kolodziej Andrew R. , Ogunbayo Gbolahan O. , Abdel-Latif Ahmed , Gurley John C. , Booth David C. 
Published: January 2022

Background:
Hemodynamic values from right heart catheterization aid diagnosis and clinical decision-making but may not predict outcomes. Mixed venous oxygen saturation percentage and pulmonary capillary wedge pressure relate to cardiac output and congestion, respectively. We theorized that a novel, simple ratio of these measurements could estimate cardiovascular prognosis.

Methods:
We queried Veterans Affairs’ databases for clinical, hemodynamic, and outcome data. Using the index right heart catheterization between 2010 and 2016, we calculated the ratio of mixed venous oxygen saturation-to-pulmonary capillary wedge pressure, termed ratio of saturation-to-wedge (RSW). The primary outcome was time to all-cause mortality; secondary outcome was 1-year urgent heart failure presentation. Patients were stratified into quartiles of RSW, Fick cardiac index (CI), thermodilution CI, and pulmonary capillary wedge pressure alone. Kaplan-Meier curves and Cox proportional hazards models related comparators with outcomes.

Results:

Of 12 019 patients meeting inclusion criteria, 9826 had values to calculate RSW (median 4.00, interquartile range, 2.67–6.05). Kaplan-Meier curves showed early, sustained separation by RSW strata. Cox modeling estimated that increasing RSW by 50% decreases mortality hazard by 19% (estimated hazard ratio, 0.81 [95% CI, 0.79–0.83],
P
<0.001) and secondary outcome hazard by 28% (hazard ratio, 0.72 [95% CI, 0.70–0.74],
P
<0.001). Among the 3793 patients with data for all comparators, Cox models showed RSW best associated with outcomes (by both C statistics and Bayes factors). Furthermore, pulmonary capillary wedge pressure was superior to thermodilution CI and Fick CI. Multivariable adjustment attenuated without eliminating the association of RSW with outcomes.

Conclusions:
In a large national database, RSW was superior to conventional right heart catheterization indices at assessing risk of mortality and urgent heart failure presentation. This simple calculation with routine data may contribute to clinical decision-making in this population.
A multilayer network model of neuron-astrocyte populations in vitro reveals mGluR5 inhibition is protective following traumatic injury
Authors: Schroeder Margaret E. , Bassett Danielle S. , Meaney David F. 
Published: January 2022

Abstract
Astrocytes communicate bidirectionally with neurons, enhancing synaptic plasticity and promoting the synchronization of neuronal microcircuits. Despite recent advances in understanding neuron-astrocyte signaling, little is known about astrocytic modulation of neuronal activity at the population level, particularly in disease or following injury. We used high-speed calcium imaging of mixed cortical cultures in vitro to determine how population activity changes after disruption of glutamatergic signaling and mechanical injury. We constructed a multilayer network model of neuron-astrocyte connectivity, which captured distinct topology and response behavior from single-cell-type networks. mGluR5 inhibition decreased neuronal activity, but did not on its own disrupt functional connectivity or network topology. In contrast, injury increased the strength, clustering, and efficiency of neuronal but not astrocytic networks, an effect that was not observed in networks pretreated with mGluR5 inhibition. Comparison of spatial and functional connectivity revealed that functional connectivity is largely independent of spatial proximity at the microscale, but mechanical injury increased the spatial-functional correlation. Finally, we found that astrocyte segments of the same cell often belong to separate functional communities based on neuronal connectivity, suggesting that astrocyte segments function as independent entities. Our findings demonstrate the utility of multilayer network models for characterizing the multiscale connectivity of two distinct but functionally dependent cell populations.
Individual Differences in Indirect Speech Act Processing Found Outside the Language Network
Authors: Bendtz Katarina , Ericsson Sarah , Schneider Josephine , Borg Julia , Bašnáková Jana , Uddén Julia 
Published: January 2022

Abstract
Face-to-face communication requires skills that go beyond core language abilities. In dialogue, we routinely make inferences beyond the literal meaning of utterances and distinguish between different speech acts based on, e.g., contextual cues. It is, however, not known whether such communicative skills potentially overlap with core language skills or other capacities, such as theory of mind (ToM). In this functional magnetic resonance imaging (fMRI) study we investigate these questions by capitalizing on individual variation in pragmatic skills in the general population. Based on behavioral data from 199 participants, we selected participants with higher vs. lower pragmatic skills for the fMRI study (N = 57). In the scanner, participants listened to dialogues including a direct or an indirect target utterance. The paradigm allowed participants at the whole group level to (passively) distinguish indirect from direct speech acts, as evidenced by a robust activity difference between these speech acts in an extended language network including ToM areas. Individual differences in pragmatic skills modulated activation in two additional regions outside the core language regions (one cluster in the left lateral parietal cortex and intraparietal sulcus and one in the precuneus). The behavioral results indicate segregation of pragmatic skill from core language and ToM. In conclusion, contextualized and multimodal communication requires a set of interrelated pragmatic processes that are neurocognitively segregated: (1) from core language and (2) partly from ToM.
Description of Cryptaphelenchus recticaudatus n. sp. (Aphelenchoidea: Ektaphelenchinae) in Pinus elliottii from the USA
Authors: Gu Jianfeng , Fang Yiwu , Ma Xinxin 
Published: January 2022

Summary
Cryptaphelenchus recticaudatus n. sp. is described and illustrated in Pinus elliottii from the USA. The new species is characterised by the female body 310-431 μm long with distinctly annulated cuticle, lateral fields with four lines, lip region separated from the body by a shallow depression, delicate stylet with small knobs, post-vulval uterine sac short, and rectum and anus invisible. Males are 228-314 μm long, spicules 9.8-12.4 μm long with a well-developed and broad condylus, and seven caudal papillae arranged as a single (P1) and pair (P2) of precloacal papillae plus two pairs of postcloacal papillae. Based upon the general female morphology, the new species most closely resembles C. baujardi and C. iranicus. The morphological differences with the aforementioned species and other species of the genus are discussed. The phylogenetic analyses based on small (SSU) and large subunit (LSU) D2-D3 expansion segments of ribosomal DNA of different individuals of the new species revealed that the new species fell into the Cryptaphelenchus clade in both SSU and LSU trees. The monophyly of the genus was retained after adding newly generated sequences of the new species.