bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective
Authors: Yang Yang , Li Shuo , Wang Yujiao , Zhao Yi , Li Qiu 
Published: September 2022

AbstractProtein tyrosine kinases (PTKs) are a class of proteins with tyrosine kinase activity that phosphorylate tyrosine residues of critical molecules in signaling pathways. Their basal function is essential for maintaining normal cell growth and differentiation. However, aberrant activation of PTKs caused by various factors can deviate cell function from the expected trajectory to an abnormal growth state, leading to carcinogenesis. Inhibiting the aberrant PTK function could inhibit tumor growth. Therefore, tyrosine kinase inhibitors (TKIs), target-specific inhibitors of PTKs, have been used in treating malignant tumors and play a significant role in targeted therapy of cancer. Currently, drug resistance is the main reason for limiting TKIs efficacy of cancer. The increasing studies indicated that tumor microenvironment, cell death resistance, tumor metabolism, epigenetic modification and abnormal metabolism of TKIs were deeply involved in tumor development and TKI resistance, besides the abnormal activation of PTK-related signaling pathways involved in gene mutations. Accordingly, it is of great significance to study the underlying mechanisms of TKIs resistance and find solutions to reverse TKIs resistance for improving TKIs efficacy of cancer. Herein, we reviewed the drug resistance mechanisms of TKIs and the potential approaches to overcome TKI resistance, aiming to provide a theoretical basis for improving the efficacy of TKIs.
Risk of developing a second primary cancer in male breast cancer survivors: a systematic review and meta-analysis
Authors: Allen Isaac , Hassan Hend , Sofianopoulou Eleni , Eccles Diana , Turnbull Clare , Tischkowitz Marc , Pharoah Paul , Antoniou Antonis C. 
Published: September 2022

AbstractBackgroundWith increasing survival after cancer diagnoses, second primary cancers (SPCs) are becoming more prevalent. We investigated the incidence and site of non-breast SPC risks following male breast cancer (BC).MethodsPubMed, Embase and Web of Science were systematically searched for studies reporting standardised incidence ratios (SIRs) for SPCs published by March 2022. Meta-analyses used the generic inverse-variance method, assuming a random-effects model. We evaluated SIRs for overall SPCs, site-specific risks, by age at BC onset, time since BC onset and geographic region. We assessed study quality using routine techniques.ResultsEight population-based retrospective cohort studies were identified. SIRs ranged from 1.05 to 2.17. The summary SIR estimate was 1.27 (95% CI: 1.03–1.56,I2: 86%), and there were increased colorectal (SIR: 1.29, 95% CI: 1.03–1.61), pancreatic (SIR: 1.64, 95% CI: 1.05–2.55) and thyroid (SIR: 5.58, 95% CI: 1.04–30.05) SPC risks. When an outlying study was excluded, the summary SIR for men diagnosed with BC before age 50 was 1.50 (95% CI: 1.21–1.85), significantly higher than men diagnosed at older ages (SIR: 1.14, 95% CI: 0.98–1.33).ConclusionsMale BC survivors are at elevated risks of developing second primary colorectal, pancreatic and thyroid cancers. The estimates may assist their clinical management and guide decisions on genetic testing.
Sensitisation of cancer cells to radiotherapy by serine and glycine starvation
Authors: Falcone Mattia , Uribe Alejandro Huerta , Papalazarou Vasileios , Newman Alice C. , Athineos Dimitris , Stevenson Katrina , Sauvé Charles-Etienne Gabriel , Gao Yajing , Kim Jin K. , Del Latto Michael , Kierstead Maria , Wu Chao , Smith J. Joshua , Romesser Paul B. , Chalmers Anthony J. , Blyth Karen , Maddocks Oliver D. K. 
Published: September 2022

Abstract
Background
Cellular metabolism is an integral component of cellular adaptation to stress, playing a pivotal role in the resistance of cancer cells to various treatment modalities, including radiotherapy. In response to radiotherapy, cancer cells engage antioxidant and DNA repair mechanisms which mitigate and remove DNA damage, facilitating cancer cell survival. Given the reliance of these resistance mechanisms on amino acid metabolism, we hypothesised that controlling the exogenous availability of the non-essential amino acids serine and glycine would radiosensitise cancer cells.

Methods
We exposed colorectal, breast and pancreatic cancer cell lines/organoids to radiation in vitro and in vivo in the presence and absence of exogenous serine and glycine. We performed phenotypic assays for DNA damage, cell cycle, ROS levels and cell death, combined with a high-resolution untargeted LCMS metabolomics and RNA-Seq.

Results
Serine and glycine restriction sensitised a range of cancer cell lines, patient-derived organoids and syngeneic mouse tumour models to radiotherapy. Comprehensive metabolomic and transcriptomic analysis of central carbon metabolism revealed that amino acid restriction impacted not only antioxidant response and nucleotide synthesis but had a marked inhibitory effect on the TCA cycle.

Conclusion
Dietary restriction of serine and glycine is a viable radio-sensitisation strategy in cancer.
CircSEMA4B inhibits the progression of breast cancer by encoding a novel protein SEMA4B-211aa and regulating AKT phosphorylation
Authors: Wang Xuehui , Jian Wei , Luo Qifeng , Fang Lin 
Published: September 2022

AbstractPI3K/AKT signaling pathway plays an important role in regulating the tumorigenesis, recurrence, and metastasis of breast cancer (BC). In this study, we discovered a circRNA with protein-coding potential, which we named circSEMA4B. CircSEMA4B could encode a novel protein, SEMA4B-211aa. Both circSEMA4B and SEMA4B-211aa were remarkably downregulated in BC tissues and cell lines. Low expression of circSEMA4B was positively associated with TNM stage, tumor size, lymph node metastasis, and distant metastasis of BC patients. The functional investigation showed that circSEMA4B and SEMA4B-211aa could significantly inhibit the proliferation and migration of BC in vivo and in vitro. Of note, SEMA4B-211aa inhibited the generation of PIP3 by binding to p85, thereby inhibiting the phosphorylation of AKT (Thr308). CircSEMA4B inhibited the phosphorylation of AKT (Ser473) through miR-330-3p/PDCD4 axis. Taken together, circSEMA4B is a novel negative regulator of PI3K/AKT signaling pathway, providing novel mechanistic insights into the underlying mechanisms of BC.
The speckle-type POZ protein (SPOP) inhibits breast cancer malignancy by destabilizing TWIST1
Authors: Wei Chunli , Liu Yun , Liu Xiaoyan , Cheng Jingliang , Fu Jiewen , Xiao Xiuli , Moses Robb E. , Li Xiaotao , Fu Junjiang 
Published: September 2022

AbstractEpithelial-mesenchymal transition (EMT) inducing transcription factor TWIST1 plays a vital role in cancer metastasis. How the tumor-suppressive E3 ligase, speckle-type POZ protein (SPOP), regulates TWIST1 in breast cancer remains unknown. In this study, we report that SPOP physically interacts with, ubiquitinates, and destabilizes TWIST1. SPOP promotes K63-and K48-linked ubiquitination of TWIST1, predominantly at K73, thereby suppressing cancer cell migration and invasion. Silencing SPOP significantly enhances EMT, which accelerates breast cancer cell migration and invasiveness in vitro and lung metastasis in vivo. Clinically, SPOP is negatively correlated with the levels of TWIST1 in highly invasive breast carcinomas. Reduced SPOP expression, along with elevated TWIST1 levels, is associated with poor prognosis in advanced breast cancer patients, particularly those with metastatic triple-negative breast cancer (TNBC). Taken together, we have disclosed a new mechanism linking SPOP to TWIST1 degradation. Thus SPOP may serve as a prognostic marker and a potential therapeutic target for advanced TNBC patients.
Oocyte Casein kinase 1α deletion causes defects in primordial follicle formation and oocyte loss by impairing oocyte meiosis and enhancing autophagy in developing mouse ovary
Authors: Zhang Di , Jiang Ying , Luo Xuan , Liu Hui , Zhou Yewen , Cui Sheng 
Published: September 2022

AbstractCasein kinase 1α is a member of CK1 family, which is ubiquitously expressed and plays multiple functions, including its potential roles in regulating cell division. But the functions of CK1α in mammalian oogenesis and folliculogenesis remain elusive. In this study, we assayed the cell type of CK1α expression in the developing mouse ovary and confirmed that CK1α was highly expressed in ovaries after birth. The oocyte-specific CK1α knockout (cKO) mouse model was then established by crossing Ddx4-Cre mice with Csnk1a1-floxp mice, and the effects of CK1α deletion on oogenesis and folliculogenesis were identified. The results showed that oocyte CK1α deletion impaired the progression of oocyte meiosis and primordial follicle formation during meiotic prophase I, which subsequently caused oocyte loss and mouse infertility. Further, the in vivo CK1α deletion and in vitro inhibition of CK1 activity resulted in the defects of DNA double-strand break (DSB) repair, whereas apoptosis and autophagy were enhanced in the developing ovary. These may contribute to oocyte loss and infertility in cKO mice. It is thus concluded that CK1α is essential for mouse oogenesis and folliculogenesis by involving in regulating the processes of oocyte meiosis and DNA DSB repair during meiotic prophase I of mouse oocytes. However, the related signaling pathway and molecular mechanisms need to be elucidated further.
Quantitative fragmentomics allow affinity mapping of interactomes
Authors: Gogl Gergo , Zambo Boglarka , Kostmann Camille , Cousido-Siah Alexandra , Morlet Bastien , Durbesson Fabien , Negroni Luc , Eberling Pascal , Jané Pau , Nominé Yves , Zeke Andras , Østergaard Søren , Monsellier Élodie , Vincentelli Renaud , Travé Gilles 
Published: September 2022

AbstractHuman protein networks have been widely explored but most binding affinities remain unknown, hindering quantitative interactome-function studies. Yet interactomes rely on minimal interacting fragments displaying quantifiable affinities. Here, we measure the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer. We calculate interactomic distances, identify hot spots for viral interference, generate binding profiles and specificity logos, and explain selected cases by crystallographic studies. Mass spectrometry experiments on cell extracts and literature surveys show that quantitative fragmentomics effectively complements protein interactomics by providing affinities and completeness of coverage, putting a full human interactome affinity survey within reach. Finally, we show that interactome hijacking by the viral PBM of human papillomavirus E6 oncoprotein substantially impacts the host cell proteome beyond immediate E6 binders, illustrating the complex system-wide relationship between interactome and function.
Scaling behavior of electron decoherence in a graphene Mach-Zehnder interferometer
Authors: Jo M. , Lee June-Young M. , Assouline A. , Brasseur P. , Watanabe K. , Taniguchi T. , Roche P. , Glattli D. C. , Kumada N. , Parmentier F. D. , Sim H. -S. , Roulleau P. 
Published: September 2022

AbstractOver the past 20 years, many efforts have been made to understand and control decoherence in 2D electron systems. In particular, several types of electronic interferometers have been considered in GaAs heterostructures, in order to protect the interfering electrons from decoherence. Nevertheless, it is now understood that several intrinsic decoherence sources fundamentally limit more advanced quantum manipulations. Here, we show that graphene offers a unique possibility to reach a regime where the decoherence is frozen and to study unexplored regimes of electron interferometry. We probe the decoherence of electron channels in a graphene quantum Hall PN junction, forming a Mach-Zehnder interferometer1,2, and unveil a scaling behavior of decay of the interference visibility with the temperature scaled by the interferometer length. It exhibits a remarkable crossover from an exponential decay at higher temperature to an algebraic decay at lower temperature where almost no decoherence occurs, a regime previously unobserved in GaAs interferometers.
Mechanistic understanding of human SLFN11
Authors: Metzner Felix J. , Wenzl Simon J. , Kugler Michael , Krebs Stefan , Hopfner Karl-Peter , Lammens Katja 
Published: September 2022

AbstractSchlafen 11 (SLFN11) is an interferon-inducible antiviral restriction factor with tRNA endoribonuclease and DNA binding functions. It is recruited to stalled replication forks in response to replication stress and inhibits replication of certain viruses such as the human immunodeficiency virus 1 (HIV-1) by modulating the tRNA pool. SLFN11 has been identified as a predictive biomarker in cancer, as its expression correlates with a beneficial response to DNA damage inducing anticancer drugs. However, the mechanism and interdependence of these two functions are largely unknown. Here, we present cryo-electron microscopy (cryo-EM) structures of human SLFN11 in its dimeric apoenzyme state, bound to tRNA and in complex with single-strand DNA. Full-length SLFN11 neither hydrolyses nor binds ATP and the helicase domain appears in an autoinhibited state. Together with biochemical and structure guided mutagenesis studies, our data give detailed insights into the mechanism of endoribonuclease activity as well as suggestions on how SLFN11 may block stressed replication forks.
A randomized controlled trial of heterologous ChAdOx1 nCoV-19 and recombinant subunit vaccine MVC-COV1901 against COVID-19
Authors: Chen Chih-Jung , Yang Lan-Yan , Chang Wei-Yang , Huang Yhu-Chering , Chiu Cheng-Hsun , Shih Shin-Ru , Huang Chung-Guei , Huang Kuan-Ying A. 
Published: September 2022

AbstractHeterologous prime-boost COVID-19 vaccine strategy may facilitate mass COVID-19 immunization. We reported early immunogenicity and safety outcomes of heterologous immunization with a viral vector vaccine (ChAdOx1) and a spike-2P subunit vaccine (MVC-COV1901) in a participant-blinded, randomized, non-inferiority trial (NCT05054621). A total of 100 healthy adults aged 20–70 years having the first dose of ChAdOx1 were 1:1 randomly assigned to receive a booster dose either with ChAdOx1 (n = 50) or MVC-COV1901 (n = 50) at an interval of 4–6 or 8–10 weeks. At day 28 post-boosting, the neutralizing antibody geometric mean titer against wild-type SARS-CoV-2 in MVC-COV1901 recipients (236 IU/mL) was superior to that in ChAdOx1 recipients (115 IU/mL), with a GMT ratio of 2.1 (95% CI, 1.4 to 2.9). Superiority in the neutralizing antibody titer against Delta variant was also found for heterologous MVC-COV1901 immunization with a GMT ratio of 2.6 (95% CI, 1.8 to 3.8). Both spike-specific antibody-secreting B and T cell responses were substantially enhanced by the heterologous schedule. Heterologous boosting was particularly prominent at a short prime-boost interval. No serious adverse events occurred across all groups. The findings support the use of heterologous prime-boost with ChAdOx1 and protein-based subunit vaccines.
Structural mechanism of tapasin-mediated MHC-I peptide loading in antigen presentation
Authors: Jiang Jiansheng , Taylor Daniel K. , Kim Ellen J. , Boyd Lisa F. , Ahmad Javeed , Mage Michael G. , Truong Hau V. , Woodward Claire H. , Sgourakis Nikolaos G. , Cresswell Peter , Margulies David H. , Natarajan Kannan 
Published: September 2022

AbstractLoading of MHC-I molecules with peptide by the catalytic chaperone tapasin in the peptide loading complex plays a critical role in antigen presentation and immune recognition. Mechanistic insight has been hampered by the lack of detailed structural information concerning tapasin–MHC-I. We present here crystal structures of human tapasin complexed with the MHC-I molecule HLA-B*44:05, and with each of two anti-tapasin antibodies. The tapasin-stabilized peptide-receptive state of HLA-B*44:05 is characterized by distortion of the peptide binding groove and destabilization of the β2-microglobulin interaction, leading to release of peptide. Movements of the membrane proximal Ig-like domains of tapasin, HLA-B*44:05, and β2-microglobulin accompany the transition to a peptide-receptive state. Together this ensemble of crystal structures provides insights into a distinct mechanism of tapasin-mediated peptide exchange.
The immune landscape of human thymic epithelial tumors
Authors: Xin Zhongwei , Lin Mingjie , Hao Zhixing , Chen Di , Chen Yongyuan , Chen Xiaoke , Xu Xia , Li Jinfan , Wu Dang , Chai Ying , Wu Pin 
Published: September 2022

AbstractHuman thymic epithelial tumors (TET) are common malignancies in the anterior mediastinum with limited biological understanding. Here we show, by single cell analysis of the immune landscape, that the developmental pattern of intra-tumoral T-cells identify three types within TETs. We characterize the developmental alterations and TCR repertoires of tumor-infiltrating T cells in the context of the distinguishing epithelial tumor cell types. We demonstrate that a subset of tumor cells, featuring medullary thymic epithelial cell (TEC) phenotype and marked by KRT14/GNB3 expression, accumulate in type 1 TETs, while T-cell positive selection is inhibited. Type 2 TETs are dominated by CCL25+ cortical TEC-like cells that appear to promote T-cell positive selection. Interestingly, the CHI3L1+ medullary TEC-like cells that are the characteristic feature of type 3 TETs don’t seem to support T-cell development, however, they may induce a tissue-resident CD8+ T cell response. In summary, our work suggests that the molecular subtype of epithelial tumour cells in TETs determine their tumour immune microenvironment, thus GNB3 and CHI3L1 might predict the immunological behavior and hence prognosis of these tumours.
Growth of bilayer MoTe2 single crystals with strong non-linear Hall effect
Authors: Ma Teng , Chen Hao , Yananose Kunihiro , Zhou Xin , Wang Lin , Li Runlai , Zhu Ziyu , Wu Zhenyue , Xu Qing-Hua , Yu Jaejun , Qiu Cheng Wei , Stroppa Alessandro , Loh Kian Ping 
Published: September 2022

Abstract
The reduced symmetry in strong spin-orbit coupling materials such as transition metal ditellurides (TMDTs) gives rise to non-trivial topology, unique spin texture, and large charge-to-spin conversion efficiencies. Bilayer TMDTs are non-centrosymmetric and have unique topological properties compared to monolayer or trilayer, but a controllable way to prepare bilayer MoTe2 crystal has not been achieved to date. Herein, we achieve the layer-by-layer growth of large-area bilayer and trilayer 1T′ MoTe2 single crystals and centimetre-scale films by a two-stage chemical vapor deposition process. The as-grown bilayer MoTe2 shows out-of-plane ferroelectric polarization, whereas the monolayer and trilayer crystals are non-polar. In addition, we observed large in-plane nonlinear Hall (NLH) effect for the bilayer and trilayer Td phase MoTe2 under time reversal-symmetric conditions, while these vanish for thicker layers. For a fixed input current, bilayer Td MoTe2 produces the largest second harmonic output voltage among the thicker crystals tested. Our work therefore highlights the importance of thickness-dependent Berry curvature effects in TMDTs that are underscored by the ability to grow thickness-precise layers.
Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia
Authors: Lee Seung Hyun , Kim Nayoung , Kim Minkyu , Woo Sang-Ho , Han Inhee , Park Jisu , Kim Kyeongdae , Park Kyu Seong , Kim Kibyeong , Shim Dahee , Park Sang-eun , Zhang Jing Yu , Go Du-Min , Kim Dae-Yong , Yoon Won Kee , Lee Seung-Pyo , Chung Jongsuk , Kim Ki-Wook , Park Jung Hwan , Lee Seung Hyun , Lee Sak , Ann Soo-jin , Lee Sang-Hak , Ahn Hyo-Suk , Jeong Seong Cheol , Kim Tae Kyeong , Oh Goo Taeg , Park Woong-Yang , Lee Hae-Ock , Choi Jae-Hoon 
Published: September 2022

AbstractValvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-IIhi macrophages. Interestingly, we find activated PPARγ pathway in Cd36+ valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPARγ activation protects the aortic valve against inflammation.
Thermal coupling of the Indo-Pacific warm pool and Southern Ocean over the past 30,000 years
Authors: Zhang Shuai , Yu Zhoufei , Wang Yue , Gong Xun , Holbourn Ann , Chang Fengming , Liu Heng , Cheng Xuhua , Li Tiegang 
Published: September 2022

AbstractThe role of the tropical Pacific Ocean and its linkages to the southern hemisphere during the last deglacial warming remain highly controversial. Here we explore the evolution of Pacific horizontal and vertical thermal gradients over the past 30 kyr by compiling 340 sea surface and 7 subsurface temperature records, as well as one new ocean heat content record. Our records reveal that La Niña-like conditions dominated during the deglaciation as a result of the more intense warming in the western Pacific warm pool. Both the subsurface temperature and ocean heat content in the warm pool rose earlier than the sea surface temperature, and in phase with South Pacific subsurface temperature and orbital precession, implying that heat exchange between the tropical upper water column and the extratropical Southern Ocean facilitated faster warming in the western Pacific. Our study underscores the key role of the thermal coupling between the warm pool and the Southern Ocean and its relevance for future global warming.