bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel tumour enhancer function of Insulin-like growth factor II mRNA-binding protein 3 in colorectal cancer
Authors: Di Fusco Davide , Di Grazia Antonio , Di Maggio Giulia , Segreto Maria Teresa , Iannucci Andrea , Maresca Claudia , De Stefano Alessandro , Sica Giuseppe , Stolfi Carmine , Monteleone Giovanni , Monteleone Ivan 
Published: April 2023

AbstractCRC cells evolve a variety of strategies to limit or circumvent apoptosis cell death. RNA binding proteins (RBPs) regulate many of the molecular mechanisms that underlie the development of cancer. The insulin-like growth factor II mRNA-binding proteins (IMP) family are oncofoetal RBPs, consisting of IMP1, IMP2 and IMP3, which have an important role in RNA metabolism. IMP3 is highly expressed in colorectal cancer (CRC) tissue, where its expression often correlates with poor prognosis. However, the role of IMP3 in CRC is not fully understood. IMP3 expression was analysed using a public database and by Western blotting and immunohistochemistry in human colon samples derived from patients with sporadic CRC and healthy subjects. To address whether IMP3 controls cancer cell survival, we analysed cell death pathways in in vitro and in vivo experiments after IMP3 downregulation by siRNA or an antisense oligonucleotide. IMP3 was highly expressed in CRC samples compared to normal control tissues. The knockdown of IMP3 enhanced a caspase-independent cell death in CRC cell lines. Furthermore, the treatment of CRC cells with IMP3 siRNA did not alter the expression of GSDMD, GPX-4 and the activated form of RIP3, three key molecules that govern pyroptosis, ferroptosis and necroptosis, respectively. Abrogation of IMP3 in CRC significantly reduced Bcl-2 and Bcl-xL mRNA and was associated with an altered mitochondrial membrane potential that allowed the nuclear migration of the apoptosis-inducing factor (AIF). Moreover, specific immunoprecipitation experiments on CRC human cell lines indicated that IMP3 binds Bcl-2 and Bcl-xL mRNA, suggesting that IMP3 acts as a regulator of the intrinsic apoptotic pathway through the surveillance of anti-apoptotic Bcl mRNA metabolism. Finally, we showed that IMP3 block inhibited the growth of CRC cell lines in vivo after transplantation into immunodeficient mice. Altogether, these data support a novel role for IMP3 in controlling the intrinsic caspase-independent apoptotic pathway in CRC.
TIPE3 represses head and neck squamous cell carcinoma progression via triggering PGAM5 mediated mitochondria dysfunction
Authors: Chen Wei , Chen Xijuan , Wang Lixuan , Yang Rongchun , Zhang Weilin , Zhang Siyuan , Xia Juan , Cheng Bin , Wu Tong , Ren Xianyue 
Published: April 2023

AbstractMitochondria are essential organelles in balancing oxidative stress and cell death during cancer cell proliferation. Rapid tumor growth induces tremendous stress on mitochondria. The mammalian tumor necrosis factor-α-induced protein 8-likes (TIPEs) family plays critical roles in balancing cancer cell death and survival. Yet, the roles of TIPEs in HNSCC tumorigenesis and mitochondria stress maintenance is unclear. Based on an integrative analysis of public HNSCC datasets, we identified that the downregulation of TIPE3 via its promoter hypermethylation modification is the major event of TIPEs alterations during HNSCC tumorigenesis. Low expression levels of TIPE3 were correlated with high malignancy and poor clinical outcomes of HNSCC patients. Restoring TIPE3 represses HNSCC proliferation, migration, and invasion in vitro and in vivo, while silencing TIPE3 acted on an opposite way. Mechanistically, TIPE3 band to the PGAM5 and electron transport chain (ETC) complex. Restoring TIPE3 promoted PGAM5 recruiting BAX and dephosphorylating p-DRP1(Ser637), which triggered mitochondrial outer membrane permeabilization and fragmentation. Ultimately, TIPE3 induced ETC damage and oxygen consumption rate decrease, ROS accumulation, mitochondrial membrane potential depolarization, and cell apoptosis. Collectively, our work reveals that TIPE3 plays critical role in maintaining mitochondrial stress and cancer cell progression in HNSCC, which might be a potential therapeutic target for HNSCC patients.
Combination treatment with FAAH inhibitors/URB597 and ferroptosis inducers significantly decreases the growth and metastasis of renal cell carcinoma cells via the PI3K-AKT signaling pathway
Authors: Hao Junfeng , Chen Qiguang , Feng Yongmin , Jiang Qiyu , Sun Huiwei , Deng Botian , Huang Xin , Guan Jibin , Chen Qiuping , Liu Xincheng , Wang Yanjin , Cao Peng , Feng Fan , Li Xiaoyu 
Published: April 2023

AbstractFerroptosis, a nonapoptotic form of programmed cell death characterized by significant iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various cancer-related signaling pathways. Recently, considerable progress has been made in demonstrating the critical role of lipid metabolism in regulating ferroptosis, indicating the potential of combinational strategies for treating cancer in the future. In this study, we explored the combinational effects of lipid metabolism compounds and ferroptosis inducers on renal cell carcinoma (RCC) cells. We found potent synergy of the fatty acid amide hydrolase (FAAH) inhibitor URB597 with ferroptosis inducer (1S, 3R)-RSL3 (RSL3) in inhibiting the growth and metastasis of RCC cells both in vitro and in vivo via induction of G1 cell cycle arrest and promotion of the production of lipid peroxides, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and cytosolic reactive oxygen species (ROS). In addition, inhibition of FAAH increased the sensitivity of RCC cells to ferroptosis. Genome-wide RNA sequencing indicated that the combination of URB597 and RSL3 has more significant effects on regulation of the expression of genes related to cell proliferation, the cell cycle, cell migration and invasion, and ferroptosis than either single agent alone. Moreover, we found that combinational treatment modulated the sensitivity of RCC cells to ferroptosis via the phosphatidylinositol 3 kinase (PI3K)-AKT signaling pathway. These data demonstrate that dual targeting of FAAH and ferroptosis could be a promising strategy for treating RCC.
Sphingomyelin 16:0 is a therapeutic target for neuronal death in acid sphingomyelinase deficiency
Authors: Gaudioso Ángel , Jiang Xuntian , Casas Josefina , Schuchman Edward H. , Ledesma María Dolores 
Published: April 2023

AbstractAcid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the SMPD1 gene encoding for the acid sphingomyelinase (ASM). While intravenous infusion of recombinant ASM is an effective treatment for the peripheral disease, the neurological complications of ASMD remain unaddressed. It has been shown that aberrantly high level of total brain sphingomyelin (SM) is a key pathological event leading to neurodegeneration. Using mice lacking ASM (ASMko), which mimic the disease, we here demonstrate that among the SM species, SM16:0 shows the highest accumulation and toxicity in ASMko neurons. By targeting lysosomes, SM16:0 causes permeabilization and exocytosis of these organelles and induces oxidative stress and cell death. We also show that genetic silencing of Ceramide Synthase 5, which is involved in SM16:0 synthesis and overexpressed in the ASMko brain, prevents disease phenotypes in ASMko cultured neurons and mice. The levels of SM16:0 in plasma also show a strong correlation with those in brain that is higher than in liver, even at early stages of the disease. These results identify SM16:0 both as a novel therapeutic target and potential biomarker of brain pathology in ASMD.
Factor Xa cleaves SARS-CoV-2 spike protein to block viral entry and infection
Authors: Dong Wenjuan , Wang Jing , Tian Lei , Zhang Jianying , Settles Erik W. , Qin Chao , Steinken-Kollath Daniel R. , Itogawa Ashley N. , Celona Kimberly R. , Yi Jinhee , Bryant Mitchell , Mead Heather , Jaramillo Sierra A. , Lu Hongjia , Li Aimin , Zumwalt Ross E. , Dadwal Sanjeet , Feng Pinghui , Yuan Weiming , Whelan Sean P. J. , Keim Paul S. , Barker Bridget Marie , Caligiuri Michael A. , Yu Jianhua 
Published: April 2023

AbstractSerine proteases (SP), including furin, trypsin, and TMPRSS2 cleave the SARS-CoV-2 spike (S) protein, enabling the virus to enter cells. Here, we show that factor (F) Xa, an SP involved in blood coagulation, is upregulated in COVID-19 patients. In contrast to other SPs, FXa exerts antiviral activity. Mechanistically, FXa cleaves S protein, preventing its binding to ACE2, and thus blocking viral entry and infection. However, FXa is less effective against variants carrying the D614G mutation common in all pandemic variants. The anticoagulant rivaroxaban, a direct FXa inhibitor, inhibits FXa-mediated S protein cleavage and facilitates viral entry, whereas the indirect FXa inhibitor fondaparinux does not. In the lethal SARS-CoV-2 K18-hACE2 model, FXa prolongs survival yet its combination with rivaroxaban but not fondaparinux abrogates that protection. These results identify both a previously unknown function for FXa and an associated antiviral host defense mechanism against SARS-CoV-2 and suggest caution in considering direct FXa inhibitors for preventing or treating thrombotic complications in COVID-19 patients.
MEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ
Authors: Schrenk Sandra , Bischoff Lindsay J. , Goines Jillian , Cai Yuqi , Vemaraju Shruti , Odaka Yoshinobu , Good Samantha R. , Palumbo Joseph S. , Szabo Sara , Reynaud Damien , Van Raamsdonk Catherine D. , Lang Richard A. , Boscolo Elisa 
Published: April 2023

AbstractActivating non-inherited mutations in the guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) gene family have been identified in childhood vascular tumors. Patients experience extensive disfigurement, chronic pain and severe complications including a potentially lethal coagulopathy termed Kasabach-Merritt phenomenon. Animal models for this class of vascular tumors do not exist. This has severely hindered the discovery of the molecular consequences ofGNAQmutations in the vasculature and, in turn, the preclinical development of effective targeted therapies. Here we report a mouse model expressing hyperactive mutantGNAQin endothelial cells. Mutant mice develop vascular and coagulopathy phenotypes similar to those seen in patients. Mechanistically, by transcriptomic analysis we demonstrate increased mitogen activated protein kinase signaling in the mutant endothelial cells. Targeting of this pathway with Trametinib suppresses the tumor growth by reducing vascular cell proliferation and permeability. Trametinib also prevents the development of coagulopathy and improves mouse survival.
PRMT3-mediated arginine methylation of IGF2BP1 promotes oxaliplatin resistance in liver cancer
Authors: Shi Yunxing , Niu Yi , Yuan Yichuan , Li Kai , Zhong Chengrui , Qiu Zhiyu , Li Keren , Lin Zhu , Yang Zhiwen , Zuo Dinglan , Qiu Jiliang , He Wei , Wang Chenwei , Liao Yadi , Wang Guocan , Yuan Yunfei , Li Binkui 
Published: April 2023

AbstractAlthough oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge in the clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling of clinical samples, and functional validation in vitro and in vivo, we identify PRMT3 as a key driver of oxaliplatin resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is in part dependent on the methylation of IGF2BP1 at R452, which is critical for the function of IGF2BP1 in stabilizing the mRNA of HEG1, an effector of PRMT3-IGF2BP1 axis. Also, PRMT3 overexpression may serve as a biomarker for oxaliplatin resistance in HCC patients. Collectively, our study defines the PRTM3-IGF2BP1-HEG1 axis as important regulators and therapeutic targets in oxaliplatin-resistance and suggests the potential to use PRMT3 expression level in pretreatment biopsy as a biomarker for oxaliplatin-resistance in HCC patients.
Nasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction
Authors: Gong Lanqi , Luo Jie , Zhang Yu , Yang Yuma , Li Shanshan , Fang Xiaona , Zhang Baifeng , Huang Jiao , Chow Larry Ka-Yue , Chung Dittman , Huang Jinlin , Huang Cuicui , Liu Qin , Bai Lu , Tiu Yuen Chak , Wu Pingan , Wang Yan , Tsao George Sai-Wah , Kwong Dora Lai-wan , Lee Anne Wing-Mui , Dai Wei , Guan Xin-Yuan 
Published: April 2023

AbstractDespite the intense CD8+ T-cell infiltration in the tumor microenvironment of nasopharyngeal carcinoma, anti-PD-1 immunotherapy shows an unsatisfactory response rate in clinical trials, hindered by immunosuppressive signals. To understand how microenvironmental characteristics alter immune homeostasis and limit immunotherapy efficacy in nasopharyngeal carcinoma, here we establish a multi-center single-cell cohort based on public data, containing 357,206 cells from 50 patient samples. We reveal that nasopharyngeal carcinoma cells enhance development and suppressive activity of regulatory T cells via CD70-CD27 interaction. CD70 blocking reverts Treg-mediated suppression and thus reinvigorate CD8+ T-cell immunity. Anti-CD70+ anti-PD-1 therapy is evaluated in xenograft-derived organoids and humanized mice, exhibiting an improved tumor-killing efficacy. Mechanistically, CD70 knockout inhibits a collective lipid signaling network in CD4+ naïve and regulatory T cells involving mitochondrial integrity, cholesterol homeostasis, and fatty acid metabolism. Furthermore, ATAC-Seq delineates that CD70 is transcriptionally upregulated by NFKB2 via an Epstein-Barr virus-dependent epigenetic modification. Our findings identify CD70+ nasopharyngeal carcinoma cells as a metabolic switch that enforces the lipid-driven development, functional specialization and homeostasis of Tregs, leading to immune evasion. This study also demonstrates that CD70 blockade can act synergistically with anti-PD-1 treatment to reinvigorate T-cell immunity against nasopharyngeal carcinoma.
Targeting USP2 regulation of VPRBP-mediated degradation of p53 and PD-L1 for cancer therapy
Authors: Yi Jingjie , Tavana Omid , Li Huan , Wang Donglai , Baer Richard J. , Gu Wei 
Published: April 2023

AbstractSince Mdm2 (Mouse double minute 2) inhibitors show serious toxicity in clinic studies, different approaches to achieve therapeutic reactivation of p53-mediated tumor suppression in cancers need to be explored. Here, we identify the USP2 (ubiquitin specific peptidase 2)-VPRBP (viral protein R binding protein) axis as an important pathway for p53 regulation. Like Mdm2, VPRBP is a potent repressor of p53 but VPRBP stability is controlled by USP2. Interestingly, the USP2-VPRBP axis also regulates PD-L1 (programmed death-ligand 1) expression. Strikingly, the combination of a small-molecule USP2 inhibitor and anti-PD1 monoclonal antibody leads to complete regression of the tumors expressing wild-type p53. In contrast to Mdm2, knockout of Usp2 in mice has no obvious effect in normal tissues. Moreover, no obvious toxicity is observed upon the USP2 inhibitor treatment in vivo as Mdm2-mediated regulation of p53 remains intact. Our study reveals a promising strategy for p53-based therapy by circumventing the toxicity issue.
A two-dimensional mid-infrared optoelectronic retina enabling simultaneous perception and encoding
Authors: Wang Fakun , Hu Fangchen , Dai Mingjin , Zhu Song , Sun Fangyuan , Duan Ruihuan , Wang Chongwu , Han Jiayue , Deng Wenjie , Chen Wenduo , Ye Ming , Han Song , Qiang Bo , Jin Yuhao , Chua Yunda , Chi Nan , Yu Shaohua , Nam Donguk , Chae Sang Hoon , Liu Zheng , Wang Qi Jie 
Published: April 2023

AbstractInfrared machine vision system for object perception and recognition is becoming increasingly important in the Internet of Things era. However, the current system suffers from bulkiness and inefficiency as compared to the human retina with the intelligent and compact neural architecture. Here, we present a retina-inspired mid-infrared (MIR) optoelectronic device based on a two-dimensional (2D) heterostructure for simultaneous data perception and encoding. A single device can perceive the illumination intensity of a MIR stimulus signal, while encoding the intensity into a spike train based on a rate encoding algorithm for subsequent neuromorphic computing with the assistance of an all-optical excitation mechanism, a stochastic near-infrared (NIR) sampling terminal. The device features wide dynamic working range, high encoding precision, and flexible adaption ability to the MIR intensity. Moreover, an inference accuracy more than 96% to MIR MNIST data set encoded by the device is achieved using a trained spiking neural network (SNN).
Signalling inhibition by ponatinib disrupts productive alternative lengthening of telomeres (ALT)
Authors: Kusuma Frances Karla , Prabhu Aishvaryaa , Tieo Galen , Ahmed Syed Moiz , Dakle Pushkar , Yong Wai Khang , Pathak Elina , Madan Vikas , Jiang Yan Yi , Tam Wai Leong , Kappei Dennis , Dröge Peter , Koeffler H. Phillip , Jeitany Maya 
Published: April 2023

AbstractAlternative lengthening of telomeres (ALT) supports telomere maintenance in 10–15% of cancers, thus representing a compelling target for therapy. By performing anti-cancer compound library screen on isogenic cell lines and using extrachromosomal telomeric C-circles, as a bona fide marker of ALT activity, we identify a receptor tyrosine kinase inhibitor ponatinib that deregulates ALT mechanisms, induces telomeric dysfunction, reduced ALT-associated telomere synthesis, and targets, in vivo, ALT-positive cells. Using RNA-sequencing and quantitative phosphoproteomic analyses, combined with C-circle level assessment, we find an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing telomeric C-circles. Furthermore, transcriptome and interactome analyses suggest a role of JUN in DNA damage repair. These results are corroborated by synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors, such as triciribine. Taken together, we describe here a signalling pathway impacting ALT which can be targeted by a clinically approved drug.
Automated optimisation of solubility and conformational stability of antibodies and proteins
Authors: Rosace Angelo , Bennett Anja , Oeller Marc , Mortensen Mie M. , Sakhnini Laila , Lorenzen Nikolai , Poulsen Christian , Sormanni Pietro 
Published: April 2023

AbstractBiologics, such as antibodies and enzymes, are crucial in research, biotechnology, diagnostics, and therapeutics. Often, biologics with suitable functionality are discovered, but their development is impeded by developability issues. Stability and solubility are key biophysical traits underpinning developability potential, as they determine aggregation, correlate with production yield and poly-specificity, and are essential to access parenteral and oral delivery. While advances for the optimisation of individual traits have been made, the co-optimization of multiple traits remains highly problematic and time-consuming, as mutations that improve one property often negatively impact others. In this work, we introduce a fully automated computational strategy for the simultaneous optimisation of conformational stability and solubility, which we experimentally validate on six antibodies, including two approved therapeutics. Our results on 42 designs demonstrate that the computational procedure is highly effective at improving developability potential, while not affecting antigen-binding. We make the method available as a webserver at www-cohsoftware.ch.cam.ac.uk.
Bactericidal synergism between phage endolysin Ply2660 and cathelicidin LL-37 against vancomycin-resistant Enterococcus faecalis biofilms
Authors: Zhang Huihui , Zhang Xinyuan , Liang Siyu , Wang Jing , Zhu Yao , Zhang Wanjiang , Liu Siguo , Schwarz Stefan , Xie Fang 
Published: April 2023

AbstractAntibiotic resistance and the ability to form biofilms of Enterococcus faecalis have compromised the choice of therapeutic options, which triggered the search for new therapeutic strategies, such as the use of phage endolysins and antimicrobial peptides. However, few studies have addressed the synergistic relationship between these two promising options. Here, we investigated the combination of the phage endolysin Ply2660 and the antimicrobial peptide LL-37 to target drug-resistant biofilm-producing E. faecalis. In vitro bactericidal assays were used to demonstrate the efficacy of the Ply2660–LL-37 combination against E. faecalis. Larger reductions in viable cell counts were observed when Ply2660 and LL-37 were applied together than after individual treatment with either substance. Transmission electron microscopy revealed that the Ply2660–LL-37 combination could lead to severe cell lysis of E. faecalis. The mode of action of the Ply2660–LL-37 combination against E. faecalis was that Ply2660 degrades cell wall peptidoglycan, and subsequently, LL-37 destroys the cytoplasmic membrane. Furthermore, Ply2660 and LL-37 act synergistically to inhibit the biofilm formation of E. faecalis. The Ply2660–LL-37 combination also showed a synergistic effect for the treatment of established biofilm, as biofilm killing with this combination was superior to each substance alone. In a murine peritoneal septicemia model, the Ply2660–LL-37 combination distinctly suppressed the dissemination of E. faecalis isolates and attenuated organ injury, being more effective than each treatment alone. Altogether, our findings indicate that the combination of a phage endolysin and an antimicrobial peptide may be a potential antimicrobial strategy for combating E. faecalis.
Biological insights and novel biomarker discovery through deep learning approaches in breast cancer histopathology
Authors: Mandair Divneet , Reis-Filho Jorge S. , Ashworth Alan 
Published: April 2023

AbstractBreast cancer remains a highly prevalent disease with considerable inter- and intra-tumoral heterogeneity complicating prognostication and treatment decisions. The utilization and depth of genomic, transcriptomic and proteomic data for cancer has exploded over recent times and the addition of spatial context to this information, by understanding the correlating morphologic and spatial patterns of cells in tissue samples, has created an exciting frontier of research, histo-genomics. At the same time, deep learning (DL), a class of machine learning algorithms employing artificial neural networks, has rapidly progressed in the last decade with a confluence of technical developments - including the advent of modern graphic processing units (GPU), allowing efficient implementation of increasingly complex architectures at scale; advances in the theoretical and practical design of network architectures; and access to larger datasets for training - all leading to sweeping advances in image classification and object detection. In this review, we examine recent developments in the application of DL in breast cancer histology with particular emphasis of those producing biologic insights or novel biomarkers, spanning the extraction of genomic information to the use of stroma to predict cancer recurrence, with the aim of suggesting avenues for further advancing this exciting field.