bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transmembrane and coiled-coil domain family 3 (TMCC3) regulates breast cancer stem cell and AKT activation
Authors: Wang Ya-Hui , Chan Yu-Tzu , Hung Tsai-Hsien , Hung Jung-Tung , Kuo Ming-Wei , Wang Sheng-Hung , Huang Yenlin , Lin Yu-Ju , Chen Shin-Cheh , Yu Jyh-Cherng , Wu Jen-Chine , Yu John , Yu Alice L. 
Published: March 2021

AbstractCancer stem cells (CSC) play a pivotal role in cancer metastasis and resistance to therapy. Previously, we compared the phosphoproteomes of breast cancer stem cells (BCSCs) enriched subpopulation and non-BCSCs sorted from breast cancer patient-derived xenograft (PDX), and identified a function unknown protein, transmembrane and coiled-coil domain family 3 (TMCC3) to be a potential enrichment marker for BCSCs. We demonstrated greater expression of TMCC3 in BCSCs than non-BCSCs and higher expression of TMCC3 in metastatic lymph nodes and lungs than in primary tumor of breast cancer PDXs. TMCC3 silencing suppressed mammosphere formation, ALDH activity and cell migration in vitro, along with reduced tumorigenicity and metastasis in vivo. Mechanistically, we found that AKT activation was reduced by TMCC3 silencing, but enhanced by TMCC3 overexpression. We further demonstrated that TMCC3 interacted directly with AKT through its 1-153 a.a. domain by cell-free biochemical assay in vitro and co-immunoprecipitation and interaction domain mapping assays in vivo. Based on domain truncation studies, we showed that the AKT-interacting domain of TMCC3 was essential for TMCC3-induced AKT activation, self-renewal, and metastasis. Clinically, TMCC3 mRNA expression in 202 breast cancer specimens as determined by qRT-PCR assay showed that higher TMCC3 expression correlated with poorer clinical outcome of breast cancer, including early-stage breast cancer. Multivariable analysis identified TMCC3 expression as an independent risk factor for survival. These findings suggest that TMCC3 is crucial for maintenance of BCSCs features through AKT regulation, and TMCC3 expression has independent prognostic significance in breast cancer. Thus, TMCC3 may serve as a new target for therapy directed against CSCs.
Olaparib increases the therapeutic index of hemithoracic irradiation compared with hemithoracic irradiation alone in a mouse lung cancer model
Authors: Jiang Yanyan , Martin Jennifer , Alkadhimi Maryam , Shigemori Kay , Kinchesh Paul , Gilchrist Stuart , Kersemans Veerle , Smart Sean , Thompson James M. , Hill Mark A. , O’Connor Mark J. , Davies Barry R. , Ryan Anderson J. 
Published: March 2021

Abstract
Background
The radiosensitising effect of the poly(ADP-ribose) polymerase inhibitor olaparib on tumours has been reported. However, its effect on normal tissues in combination with radiation has not been well studied. Herein, we investigated the therapeutic index of olaparib combined with hemithoracic radiation in a urethane-induced mouse lung cancer model.

Methods
To assess tolerability, A/J mice were treated with olaparib plus whole thorax radiation (13 Gy), body weight changes were monitored and normal tissue effects were assessed by histology. In anti-tumour (intervention) studies, A/J mice were injected with urethane to induce lung tumours, and were then treated with olaparib alone, left thorax radiation alone or the combination of olaparib plus left thorax radiation at 8 weeks (early intervention) or 18 weeks (late intervention) after urethane injection. Anti-tumour efficacy and normal tissue effects were assessed by visual inspection, magnetic resonance imaging and histology.

Results
Enhanced body weight loss and oesophageal toxicity were observed when olaparib was combined with whole thorax but not hemithorax radiation. In both the early and late intervention studies, olaparib increased the anti-tumour effects of hemithoracic irradiation without increasing lung toxicity.

Conclusions
The addition of olaparib increased the therapeutic index of hemithoracic radiation in a mouse model of lung cancer.
PKA compartmentalization links cAMP signaling and autophagy
Authors: Grisan Francesca , Iannucci Liliana F. , Surdo Nicoletta C. , Gerbino Andrea , Zanin Sofia , Di Benedetto Giulietta , Pozzan Tullio , Lefkimmiatis Konstantinos 
Published: March 2021

AbstractAutophagy is a highly regulated degradative process crucial for maintaining cell homeostasis. This important catabolic mechanism can be nonspecific, but usually occurs with fine spatial selectivity (compartmentalization), engaging only specific subcellular sites. While the molecular machines driving autophagy are well understood, the involvement of localized signaling events in this process is not well defined. Among the pathways that regulate autophagy, the cyclic AMP (cAMP)/protein kinase A (PKA) cascade can be compartmentalized in distinct functional units called microdomains. However, while it is well established that, depending on the cell type, cAMP can inhibit or promote autophagy, the role of cAMP/PKA microdomains has not been tested. Here we show not only that the effects on autophagy of the same cAMP elevation differ in different cell types, but that they depend on a highly complex sub-compartmentalization of the signaling cascade. We show in addition that, in HT-29 cells, in which autophagy is modulated by cAMP rising treatments, PKA activity is strictly regulated in space and time by phosphatases, which largely prevent the phosphorylation of soluble substrates, while membrane-bound targets are less sensitive to the action of these enzymes. Interestingly, we also found that the subcellular distribution of PKA type-II regulatory PKA subunits hinders the effect of PKA on autophagy, while displacement of type-I regulatory PKA subunits has no effect. Our data demonstrate that local PKA activity can occur independently of local cAMP concentrations and provide strong evidence for a link between localized PKA signaling events and autophagy.
The noncoding RNAs SNORD50A and SNORD50B-mediated TRIM21-GMPS interaction promotes the growth of p53 wild-type breast cancers by degrading p53
Authors: Su Xi , Feng Chao , Wang Simeng , Shi Liang , Gu Qingqing , Zhang Haihong , Lan Xinhui , Zhao Yuelei , Qiang Wei , Ji Meiju , Hou Peng 
Published: March 2021

AbstractSmall nucleolar RNA SNORD50A and SNORD50B (SNORD50A/B) has been reported to be recurrently deleted and function as a putative tumor suppressor in different types of cancer by binding to and suppressing the activity of the KRAS oncoproteins. Its deletion correlates with poorer patient survival. However, in this study, we surprisingly found that SNORD50A/B loss predicted a better survival in breast cancer patients carrying wild-type p53. Functional studies showed that SNORD50A/B deletion strongly inhibited the proliferation, migration, invasion and tumorigenic potential, and induced cell cycle arrest and apoptosis in p53 wild-type breast cancer cells, while exerted the opposite effects in p53 mutated breast cancer cells. This was also supported by ectopically expressing SNORD50A/B in both p53 wild-type and mutated breast cancer cells. Mechanistically, SNORD50A/B clearly enhances the interaction between E3 ubiquitin ligase TRIM21 and its substrate GMPS by forming a complex among them, thereby promoting GMPS ubiquitination and its subsequent cytoplasmic sequestration. SNORD50A/B deletion in p53 wild-type breast cancer cells will release GMPS and induce the translocation of GMPS into the nucleus, where GMPS can recruit USP7 and form a complex with p53, thereby decreasing p53 ubiquitination, stabilizing p53 proteins, and inhibiting malignant phenotypes of cancer cells. Altogether, the present study first reports that SNORD50A/B plays an oncogenic role in p53 wild-type breast cancers by mediating TRIM21-GMPS interaction.
Immunotherapy for recurrent glioblastoma: practical insights and challenging prospects
Authors: Wang Xin , Lu Jie , Guo Gaochao , Yu Jinming 
Published: March 2021

AbstractGlioblastoma (GB) is the most common high-grade intracranial malignant tumor with highly malignant biological behavior and a high recurrence rate. Although anti-PD-1/PD-L1 antibodies have achieved significant survival benefits in several kinds of solid tumors, the phase III clinical trial Checkmate 143 demonstrated that nivolumab, which targets PD-1, did not achieve survival benefits compared with bevacizumab in recurrent glioblastoma (rGB) patients. Nevertheless, neoadjuvant anti-PD-1 therapy followed by surgery and adjuvant anti-PD-1 therapy could effectively activate local and systemic immune responses and significantly improve the OS of rGB patients. Furthermore, several studies have also confirmed the progress made in applying tumor-specific peptide vaccination or chimeric antigen receptor-T (CAR-T) cell therapy to treat rGB patients, and successes with antibodies targeting other inhibitory checkpoints or costimulatory molecules have also been reported. These successes inspired us to explore candidate combination treatments based on anti-PD-1/PD-L1 antibodies. However, effective predictive biomarkers for clinical efficacy are urgently needed to avoid economic waste and treatment delay. Attempts to prolong the CAR-T cell lifespan and increase T cell infiltration through engineering techniques are addressing the challenge of strengthening T cell function. In this review, we describe the immunosuppressive molecular characteristics of rGB; clinical trials exploring anti-PD-1/PD-L1 therapy, tumor-specific peptide vaccination, and CAR-T cell therapy; candidate combination strategies; and issues related to strengthening T cell function.
Cost function dependent barren plateaus in shallow parametrized quantum circuits
Authors: Cerezo M. , Sone Akira , Volkoff Tyler , Cincio Lukasz , Coles Patrick J. 
Published: March 2021

AbstractVariational quantum algorithms (VQAs) optimize the parameters θ of a parametrized quantum circuit V(θ) to minimize a cost function C. While VQAs may enable practical applications of noisy quantum computers, they are nevertheless heuristic methods with unproven scaling. Here, we rigorously prove two results, assuming V(θ) is an alternating layered ansatz composed of blocks forming local 2-designs. Our first result states that defining C in terms of global observables leads to exponentially vanishing gradients (i.e., barren plateaus) even when V(θ) is shallow. Hence, several VQAs in the literature must revise their proposed costs. On the other hand, our second result states that defining C with local observables leads to at worst a polynomially vanishing gradient, so long as the depth of V(θ) is $${\mathcal{O}}(\mathrm{log}\,n)$$
O

(

log

n

)

. Our results establish a connection between locality and trainability. We illustrate these ideas with large-scale simulations, up to 100 qubits, of a quantum autoencoder implementation.
FTO-mediated cytoplasmic m6Am demethylation adjusts stem-like properties in colorectal cancer cell
Authors: Relier Sébastien , Ripoll Julie , Guillorit Hélène , Amalric Amandine , Achour Cyrinne , Boissière Florence , Vialaret Jérôme , Attina Aurore , Debart Françoise , Choquet Armelle , Macari Françoise , Marchand Virginie , Motorin Yuri , Samalin Emmanuelle , Vasseur Jean-Jacques , Pannequin Julie , Aguilo Francesca , Lopez-Crapez Evelyne , Hirtz Christophe , Rivals Eric , Bastide Amandine , David Alexandre 
Published: March 2021

AbstractCancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its N6,2’-O-dimethyladenosine (m6Am) demethylase activity. While m6Am is strategically located next to the m7G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m6Am level in mRNA which results in enhanced in vivo tumorigenicity and chemoresistance. Inhibition of the nuclear m6Am methyltransferase, PCIF1/CAPAM, fully reverses this phenotype, stressing the role of m6Am modification in stem-like properties acquisition. FTO-mediated regulation of m6Am marking constitutes a reversible pathway controlling CSC abilities. Altogether, our findings bring to light the first biological function of the m6Am modification and its potential adverse consequences for colorectal cancer management.
Identification of disease treatment mechanisms through the multiscale interactome
Authors: Ruiz Camilo , Zitnik Marinka , Leskovec Jure 
Published: March 2021

AbstractMost diseases disrupt multiple proteins, and drugs treat such diseases by restoring the functions of the disrupted proteins. How drugs restore these functions, however, is often unknown as a drug’s therapeutic effects are not limited to the proteins that the drug directly targets. Here, we develop the multiscale interactome, a powerful approach to explain disease treatment. We integrate disease-perturbed proteins, drug targets, and biological functions into a multiscale interactome network. We then develop a random walk-based method that captures how drug effects propagate through a hierarchy of biological functions and physical protein-protein interactions. On three key pharmacological tasks, the multiscale interactome predicts drug-disease treatment, identifies proteins and biological functions related to treatment, and predicts genes that alter a treatment’s efficacy and adverse reactions. Our results indicate that physical interactions between proteins alone cannot explain treatment since many drugs treat diseases by affecting the biological functions disrupted by the disease rather than directly targeting disease proteins or their regulators. We provide a general framework for explaining treatment, even when drugs seem unrelated to the diseases they are recommended for.
Recruited macrophages that colonize the post-inflammatory peritoneal niche convert into functionally divergent resident cells
Authors: Louwe P. A. , Badiola Gomez L. , Webster H. , Perona-Wright G. , Bain C. C. , Forbes S. J. , Jenkins S. J. 
Published: March 2021

AbstractInflammation generally leads to recruitment of monocyte-derived macrophages. What regulates the fate of these cells and to what extent they can assume the identity and function of resident macrophages is unclear. Here, we show that macrophages elicited into the peritoneal cavity during mild inflammation persist long-term but are retained in an immature transitory state of differentiation due to the presence of enduring resident macrophages. By contrast, severe inflammation results in ablation of resident macrophages and a protracted phase wherein the cavity is incapable of sustaining a resident phenotype, yet ultimately elicited cells acquire a mature resident identity. These macrophages also have transcriptionally and functionally divergent features that result from inflammation-driven alterations to the peritoneal cavity micro-environment and, to a lesser extent, effects of origin and time-of-residency. Hence, rather than being predetermined, the fate of inflammation-elicited peritoneal macrophages seems to be regulated by the environment.
Synchronous RNA conformational changes trigger ordered phase transitions in crystals
Authors: Ramakrishnan Saminathan , Stagno Jason R. , Conrad Chelsie E. , Ding Jienyu , Yu Ping , Bhandari Yuba R. , Lee Yun-Tzai , Pauly Gary , Yefanov Oleksandr , Wiedorn Max O. , Knoska Juraj , Oberthür Dominik , White Thomas A. , Barty Anton , Mariani Valerio , Li Chufeng , Brehm Wolfgang , Heinz William F. , Magidson Valentin , Lockett Stephen , Hunter Mark S. , Boutet Sébastien , Zatsepin Nadia A. , Zuo Xiaobing , Grant Thomas D. , Pandey Suraj , Schmidt Marius , Spence John C. H. , Chapman Henry N. , Wang Yun-Xing 
Published: March 2021

AbstractTime-resolved studies of biomacromolecular crystals have been limited to systems involving only minute conformational changes within the same lattice. Ligand-induced changes greater than several angstroms, however, are likely to result in solid-solid phase transitions, which require a detailed understanding of the mechanistic interplay between conformational and lattice transitions. Here we report the synchronous behavior of the adenine riboswitch aptamer RNA in crystal during ligand-triggered isothermal phase transitions. Direct visualization using polarized video microscopy and atomic force microscopy shows that the RNA molecules undergo cooperative rearrangements that maintain lattice order, whose cell parameters change distinctly as a function of time. The bulk lattice order throughout the transition is further supported by time-resolved diffraction data from crystals using an X-ray free electron laser. The synchronous molecular rearrangements in crystal provide the physical basis for studying large conformational changes using time-resolved crystallography and micro/nanocrystals.
CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer
Authors: Ahmed Musaddeque , Soares Fraser , Xia Ji-Han , Yang Yue , Li Jing , Guo Haiyang , Su Peiran , Tian Yijun , Lee Hyung Joo , Wang Miranda , Akhtar Nayeema , Houlahan Kathleen E. , Bosch Almudena , Zhou Stanley , Mazrooei Parisa , Hua Junjie T. , Chen Sujun , Petricca Jessica , Zeng Yong , Davies Alastair , Fraser Michael , Quigley David A. , Feng Felix Y. , Boutros Paul C. , Lupien Mathieu , Zoubeidi Amina , Wang Liang , Walsh Martin J. , Wang Ting , Ren Shancheng , Wei Gong-Hong , He Housheng Hansen 
Published: March 2021

AbstractProstate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of 260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.
The transcriptional landscape of Shh medulloblastoma
Authors: Skowron Patryk , Farooq Hamza , Cavalli Florence M. G. , Morrissy A. Sorana , Ly Michelle , Hendrikse Liam D. , Wang Evan Y. , Djambazian Haig , Zhu Helen , Mungall Karen L. , Trinh Quang M. , Zheng Tina , Dai Shizhong , Stucklin Ana S. Guerreiro , Vladoiu Maria C. , Fong Vernon , Holgado Borja L. , Nor Carolina , Wu Xiaochong , Abd-Rabbo Diala , Bérubé Pierre , Wang Yu Chang , Luu Betty , Suarez Raul A. , Rastan Avesta , Gillmor Aaron H. , Lee John J. Y. , Zhang Xiao Yun , Daniels Craig , Dirks Peter , Malkin David , Bouffet Eric , Tabori Uri , Loukides James , Doz François P. , Bourdeaut Franck , Delattre Olivier O. , Masliah-Planchon Julien , Ayrault Olivier , Kim Seung-Ki , Meyronet David , Grajkowska Wieslawa A. , Carlotti Carlos G. , de Torres Carmen , Mora Jaume , Eberhart Charles G. , Van Meir Erwin G. , Kumabe Toshihiro , French Pim J. , Kros Johan M. , Jabado Nada , Lach Boleslaw , Pollack Ian F. , Hamilton Ronald L. , Rao Amulya A. Nageswara , Giannini Caterina , Olson James M. , Bognár László , Klekner Almos , Zitterbart Karel , Phillips Joanna J. , Thompson Reid C. , Cooper Michael K. , Rubin Joshua B. , Liau Linda M. , Garami Miklós , Hauser Peter , Li Kay Ka Wai , Ng Ho-Keung , Poon Wai Sang , Yancey Gillespie G. , Chan Jennifer A. , Jung Shin , McLendon Roger E. , Thompson Eric M. , Zagzag David , Vibhakar Rajeev , Ra Young Shin , Garre Maria Luisa , Schüller Ulrich , Shofuda Tomoko , Faria Claudia C. , López-Aguilar Enrique , Zadeh Gelareh , Hui Chi-Chung , Ramaswamy Vijay , Bailey Swneke D. , Jones Steven J. , Mungall Andrew J. , Moore Richard A. , Calarco John A. , Stein Lincoln D. , Bader Gary D. , Reimand Jüri , Ragoussis Jiannis , Weiss William A. , Marra Marco A. , Suzuki Hiromichi , Taylor Michael D. 
Published: March 2021

AbstractSonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.
Chemical feedbacks during magma degassing control chlorine partitioning and metal extraction in volcanic arcs
Authors: Tattitch B. , Chelle-Michou C. , Blundy J. , Loucks R. R. 
Published: March 2021

AbstractHydrous fluids released from subducting oceanic lithosphere fuel arc magmatism and associated hydrothermal mineralization, including formation of porphyry copper deposits. Critical magma degassing parameters are the depth, chemistry and style of fluid release during magma ascent, notably the behaviour of chlorine, a key metal-transporting ligand. Currently, understanding is limited by restricted data on fluid-melt partitioning of chlorine as a function of pressure and magma chemistry, and the complex interplay between the two that occurs in polybaric magmatic systems. Here we present experimental determinations of chlorine partitioning as a function of fluid and melt composition at pressures from 50 to 800 MPa. We provide, for the first time, a quantitative understanding of chlorine and copper evolution that is valid for shallow, deep or transcrustal differentiation and degassing. Monte Carlo simulations using our new data reproduce the chemical evolution of melt inclusions from arc volcanoes and fluid inclusions from upper crustal intrusions and porphyry copper deposits. Our results not only provide a novel chemical framework for understanding magma degassing, but quantify the primacy of magmatic chlorine concentration at the point of fluid saturation in promoting efficient copper extraction from magmas.