bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of p38 MAP kinase in cancer stem cells and metastasis
Authors: Kudaravalli Sriya , den Hollander Petra , Mani Sendurai A. 
Published: May 2022

AbstractTherapeutic resistance and metastatic progression are responsible for the majority of cancer mortalities. In particular, the development of resistance is a significant barrier to the efficacy of cancer treatments such as chemotherapy, radiotherapy, targeted therapies, and immunotherapies. Cancer stem cells (CSCs) underlie treatment resistance and metastasis. p38 mitogen-activated protein kinase (p38 MAPK) is downstream of several CSC-specific signaling pathways, and it plays an important role in CSC development and maintenance and contributes to metastasis and chemoresistance. Therefore, the development of therapeutic approaches targeting p38 can sensitize tumors to chemotherapy and prevent metastatic progression.
BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors
Authors: Cremona Mattia , Vandenberg Cassandra J. , Farrelly Angela M. , Madden Stephen F. , Morgan Clare , Kalachand Roshni , McAlpine Jessica N. , Toomey Sinead , Huntsman David G. , Grogan Liam , Breathnach Oscar , Morris Patrick , Carey Mark S. , Scott Clare L. , Hennessy Bryan T. 
Published: May 2022

AbstractBackgroundWe tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered inBRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors.MethodsThe levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vivo effects of treatments were evaluated in PDX mouse models.ResultsExpression of X-linked inhibitor of apoptosis (XIAP) is increased inBRCA1-mutated cancers and high levels are associated with improved patient outcomes after platinum chemotherapy. XIAP overexpression is mediated by NF-kB activation and is associated with an optimisation of PARP.BRCA1-mutated cell lines are particularly sensitive to IAP inhibitors due to an inhibitory effect on PARP. Both aBRCA1-mutated cell line with acquired resistance to PARP inhibitors and one with restoredBRCA1remain sensitive to IAP inhibitors. Treatment with IAP inhibitors restores the efficacy of PARP inhibition in these cell lines. The IAP inhibitor LCL161 alone and in combination with a PARP inhibitor, exhibited antitumour effects in PDX mouse models of resistant BRCA2 and 1-mutated ovarian cancer, respectively.ConclusionA clinical trial may be justified to further investigate the utility of IAP inhibitors.
Mxi1 participates in the progression of lung cancer via the microRNA-300/KLF9/GADD34 Axis
Authors: Lei Yujie , Huang Yunchao , Lin Jianbin , Sun Shihui , Che Keda , Shen Junting , Liao Jun , Chen Yangming , Chen Kai , Lin Zhaoxian , Lin Xing 
Published: May 2022

AbstractThe purpose of the current study was to define the role of MAX interactor 1 (Mxi1) in the pathogenesis of lung cancer and its underlying molecular mechanism. Bioinformatics analysis was performed to identify important regulatory pathway related to lung cancer. Dual luciferase reporter and ChIP assays were adopted to validate the interaction among Mxi1, miR-300 and KLF9. Loss- and gain-of-function studies were conducted to determine the roles of Mxi1, miR-300, and KLF9 in cell proliferation, migration, and invasion in vitro and their effects on myeloid-derived suppressor cell (MDSC) recruitment in vivo. Mxi1 was poorly expressed in lung cancer tissues and cells and its poor expression was associated with poor prognosis. Mxi1 inhibited miR-300 by suppressing its transcription. miR-300 suppressed the expression of KLF9, and KLF9 negatively regulated GADD34 expression in lung cancer cells. Mxi1 or KLF9 elevation or miR-300 repression inhibited lung cancer cell proliferation, as evidenced by reduced Ki67 and PCNA expression, and lowered invasion and migration. In vivo findings revealed that silencing KLF9 induced tumor growth by enhancing MDSC-mediated immunosuppression through upregulation of GADD34. Collectively, these findings suggest that Mxi1 can inhibit lung cancer progression by regulating the miR-300/KLF9 axis and GADD34-mediated immunosuppression.
UHMK1 aids colorectal cancer cell proliferation and chemoresistance through augmenting IL-6/STAT3 signaling
Authors: Gao Xuedi , Bao Wenfang , Bai Jin , Fan Kailing , Li Li , Li Yandong 
Published: May 2022

AbstractUHMK1, a serine/threonine kinase with a U2AF homology motif, is implicated in RNA processing and protein phosphorylation. Increasing evidence has indicated its involvement in tumorigenesis. However, it remains to be elucidated whether UHMK1 plays a role in the development of colorectal cancer (CRC). Here, we demonstrated that UHMK1 was frequently upregulated in CRC samples compared with adjacent normal tissue and high expression of UHMK1 predicted poor outcomes. Knockdown of UHMK1 by siRNAs restrained CRC cell proliferation and increased oxaliplatin sensitivity, whereas overexpression of UHMK1 promoted CRC cell growth and oxaliplatin resistance, suggesting that UHMK1 plays important oncogenic roles in CRC. Mechanistically, we showed that UHMK1 had a significant effect on IL6/STAT3 signaling by interacting with STAT3. The interaction of UHMK1 with STAT3 enhanced STAT3 activity in regulating gene transcription. Furthermore, we found that STAT3 could in turn transcriptionally activate UHMK1 expression in CRC cells. The complementary experiments for cell growth and oxaliplatin resistance indicated the interdependent relationship between UHMK1 and STAT3. Thus, these collective findings uncovered a new UHMK1/STAT3 positive feedback regulatory loop contributing to CRC development and chemoresistance.
The pathological role of damaged organelles in renal tubular epithelial cells in the progression of acute kidney injury
Authors: Li Zixian , Liu Zejian , Luo Mianna , Li Xingyu , Chen Huixia , Gong Siqiao , Zhang Minjie , Zhang Yaozhi , Liu Huafeng , Li Xiaoyu 
Published: May 2022

AbstractAcute kidney injury (AKI) is a common clinical condition associated with high morbidity and mortality. The pathogenesis of AKI has not been fully elucidated, with a lack of effective treatment. Renal tubular epithelial cells (TECs) play an important role in AKI, and their damage and repair largely determine the progression and prognosis of AKI. In recent decades, it has been found that the mitochondria, endoplasmic reticulum (ER), lysosomes, and other organelles in TECs are damaged to varying degrees in AKI, and that they can influence each other through various signaling mechanisms that affect the recovery of TECs. However, the association between these multifaceted signaling platforms, particularly between mitochondria and lysosomes during AKI remains unclear. This review summarizes the specific pathophysiological mechanisms of the main TECs organelles in the context of AKI, particularly the potential interactions among them, in order to provide insights into possible novel treatment strategies.
A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies
Authors: Scott Jamie I. , Mendive-Tapia Lorena , Gordon Doireann , Barth Nicole D. , Thompson Emily J. , Cheng Zhiming , Taggart David , Kitamura Takanori , Bravo-Blas Alberto , Roberts Edward W. , Juarez-Jimenez Jordi , Michel Julien , Piet Berber , de Vries I. Jolanda , Verdoes Martijn , Dawson John , Carragher Neil O. , Connor Richard A. O’ , Akram Ahsan R. , Frame Margaret , Serrels Alan , Vendrell Marc 
Published: May 2022

AbstractImmunotherapy promotes the attack of cancer cells by the immune system; however, it is difficult to detect early responses before changes in tumor size occur. Here, we report the rational design of a fluorogenic peptide able to detect picomolar concentrations of active granzyme B as a biomarker of immune-mediated anticancer action. Through a series of chemical iterations and molecular dynamics simulations, we synthesize a library of FRET peptides and identify probeH5with an optimal fit into granzyme B. We demonstrate that probeH5enables the real-time detection of T cell-mediated anticancer activity in mouse tumors and in tumors from lung cancer patients. Furthermore, we show image-based phenotypic screens, which reveal that the AKT kinase inhibitor AZD5363 shows immune-mediated anticancer activity. The reactivity of probeH5may enable the monitoring of early responses to anticancer treatments using tissue biopsies.
Vertically optimized phase separation with improved exciton diffusion enables efficient organic solar cells with thick active layers
Authors: Cai Yunhao , Li Qian , Lu Guanyu , Ryu Hwa Sook , Li Yun , Jin Hui , Chen Zhihao , Tang Zheng , Lu Guanghao , Hao Xiaotao , Woo Han Young , Zhang Chunfeng , Sun Yanming 
Published: May 2022

AbstractThe development of organic solar cells (OSCs) with thick active layers is of crucial importance for the roll-to-roll printing of large-area solar panels. Unfortunately, increasing the active layer thickness usually results in a significant reduction in efficiency. Herein, we fabricated efficient thick-film OSCs with an active layer consisting of one polymer donor and two non-fullerene acceptors. The two acceptors were found to possess enlarged exciton diffusion length in the mixed phase, which is beneficial to exciton generation and dissociation. Additionally, layer by layer approach was employed to optimize the vertical phase separation. Benefiting from the synergetic effects of enlarged exciton diffusion length and graded vertical phase separation, an efficiency of 17.31% (certified value of 16.9%) is obtained for the 300 nm-thick OSC, with a short-circuit current density of 28.36 mA cm−2, and a high fill factor of 73.0%. Moreover, the device with an active layer thickness of 500 nm also shows an efficiency of 15.21%. This work provides valuable insights into the fabrication of OSCs with thick active layers.
Mre11-Rad50 oligomerization promotes DNA double-strand break repair
Authors: Kissling Vera M. , Reginato Giordano , Bianco Eliana , Kasaciunaite Kristina , Tilma Janny , Cereghetti Gea , Schindler Natalie , Lee Sung Sik , Guérois Raphaël , Luke Brian , Seidel Ralf , Cejka Petr , Peter Matthias 
Published: May 2022

AbstractThe conserved Mre11-Rad50 complex is crucial for the detection, signaling, end tethering and processing of DNA double-strand breaks. While it is known that Mre11-Rad50 foci formation at DNA lesions accompanies repair, the underlying molecular assembly mechanisms and functional implications remained unclear. Combining pathway reconstitution in electron microscopy, biochemical assays and genetic studies, we show that S. cerevisiae Mre11-Rad50 with or without Xrs2 forms higher-order assemblies in solution and on DNA. Rad50 mediates such oligomerization, and mutations in a conserved Rad50 beta-sheet enhance or disrupt oligomerization. We demonstrate that Mre11-Rad50-Xrs2 oligomerization facilitates foci formation, DNA damage signaling, repair, and telomere maintenance in vivo. Mre11-Rad50 oligomerization does not affect its exonuclease activity but drives endonucleolytic cleavage at multiple sites on the 5′-DNA strand near double-strand breaks. Interestingly, mutations in the human RAD50 beta-sheet are linked to hereditary cancer predisposition and our findings might provide insights into their potential role in chemoresistance.
Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content
Authors: Papes Fabio , Camargo Antonio P. , de Souza Janaina S. , Carvalho Vinicius M. A. , Szeto Ryan A. , LaMontagne Erin , Teixeira José R. , Avansini Simoni H. , Sánchez-Sánchez Sandra M. , Nakahara Thiago S. , Santo Carolina N. , Wu Wei , Yao Hang , Araújo Barbara M. P. , Velho Paulo E. N. F. , Haddad Gabriel G. , Muotri Alysson R. 
Published: May 2022

Abstract
Transcription Factor 4 (TCF4) has been associated with autism, schizophrenia, and other neuropsychiatric disorders. However, how pathological TCF4 mutations affect the human neural tissue is poorly understood. Here, we derive neural progenitor cells, neurons, and brain organoids from skin fibroblasts obtained from children with Pitt-Hopkins Syndrome carrying clinically relevant mutations in TCF4. We show that neural progenitors bearing these mutations have reduced proliferation and impaired capacity to differentiate into neurons. We identify a mechanism through which TCF4 loss-of-function leads to decreased Wnt signaling and then to diminished expression of SOX genes, culminating in reduced progenitor proliferation in vitro. Moreover, we show reduced cortical neuron content and impaired electrical activity in the patient-derived organoids, phenotypes that were rescued after correction of TCF4 expression or by pharmacological modulation of Wnt signaling. This work delineates pathological mechanisms in neural cells harboring TCF4 mutations and provides a potential target for therapeutic strategies for genetic disorders associated with this gene.
Pathophysiological pathway differences in children who present with COVID-19 ARDS compared to COVID -19 induced MIS-C
Authors: McCafferty Conor , Cai Tengyi , Borgel Delphine , Lasne Dominique , Renolleau Sylvain , Vedrenne-Cloquet Meryl , Bonnet Damien , Wu Jemma , Zaw Thiri , Bhatnagar Atul , Song Xiaomin , Van Den Helm Suelyn , Letunica Natasha , Attard Chantal , Karlaftis Vasiliki , Praporski Slavica , Ignjatovic Vera , Monagle Paul 
Published: May 2022

AbstractCOVID-19 has infected more than 275 million worldwide (at the beginning of 2022). Children appear less susceptible to COVID-19 and present with milder symptoms. Cases of children with COVID-19 developing clinical features of Kawasaki-disease have been described. Here we utilise Mass Spectrometry proteomics to determine the plasma proteins expressed in healthy children pre-pandemic, children with multisystem inflammatory syndrome (MIS-C) and children with COVID-19 induced ARDS. Pathway analyses were performed to determine the affected pathways. 76 proteins are differentially expressed across the groups, with 85 and 52 proteins specific to MIS-C and COVID-19 ARDS, respectively. Complement and coagulation activation are implicated in these clinical phenotypes, however there was significant contribution of FcGR and BCR activation in MIS-C and scavenging of haem and retinoid metabolism in COVID-19 ARDS. We show global proteomic differences in MIS-C and COVID-ARDS, although both show complement and coagulation dysregulation. The results contribute to our understanding of MIS-C and COVID-19 ARDS in children.
The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy
Authors: Graca Flavia A. , Rai Mamta , Hunt Liam C. , Stephan Anna , Wang Yong-Dong , Gordon Brittney , Wang Ruishan , Quarato Giovanni , Xu Beisi , Fan Yiping , Labelle Myriam , Demontis Fabio 
Published: May 2022

AbstractDecline in skeletal muscle cell size (myofiber atrophy) is a key feature of cancer-induced wasting (cachexia). In particular, atrophy of the diaphragm, the major muscle responsible for breathing, is an important determinant of cancer-associated mortality. However, therapeutic options are limited. Here, we have used Drosophila transgenic screening to identify muscle-secreted factors (myokines) that act as paracrine regulators of myofiber growth. Subsequent testing in mouse myotubes revealed that mouse Fibcd1 is an evolutionary-conserved myokine that preserves myofiber size via ERK signaling. Local administration of recombinant Fibcd1 (rFibcd1) ameliorates cachexia-induced myofiber atrophy in the diaphragm of mice bearing patient-derived melanoma xenografts and LLC carcinomas. Moreover, rFibcd1 impedes cachexia-associated transcriptional changes in the diaphragm. Fibcd1-induced signaling appears to be muscle selective because rFibcd1 increases ERK activity in myotubes but not in several cancer cell lines tested. We propose that rFibcd1 may help reinstate myofiber size in the diaphragm of patients with cancer cachexia.
Genetic associations with healthy ageing among Chinese adults
Authors: Chang Xuling , Zhou Yan-Feng , Wang Ling , Liu Jianjun , Yuan Jian-Min , Khor Chiea-Chuen , Heng Chew-Kiat , Pan An , Koh Woon-Puay , Dorajoo Rajkumar 
Published: May 2022

AbstractThe genetic basis of overall healthy ageing, especially among the East-Asian population is understudied. We conducted a genome-wide association study among 1618 Singapore Chinese elderly participants (65 years or older) ascertained to have aged healthily and compared their genome-wide genotypes to 6221 participants who did not age healthily, after a 20-year follow-up. Two genetic variants were identified (PMeta < 2.59 × 10−8) to be associated with healthy aging, including theLRP1Blocus previously associated in long-lived individuals without cognitive decline. Our study sheds additional insights on the genetic basis of healthy ageing.
GGDEF domain as spatial on-switch for a phosphodiesterase by interaction with landmark protein HubP
Authors: Rick Tim , Kreiling Vanessa , Höing Alexander , Fiedler Svenja , Glatter Timo , Steinchen Wieland , Hochberg Georg , Bähre Heike , Seifert Roland , Bange Gert , Knauer Shirley K. , Graumann Peter L. , Thormann Kai M. 
Published: May 2022

AbstractIn bacteria, the monopolar localization of enzymes and protein complexes can result in a bimodal distribution of enzyme activity between the dividing cells and heterogeneity of cellular behaviors. In Shewanella putrefaciens, the multidomain hybrid diguanylate cyclase/phosphodiesterase PdeB, which degrades the secondary messenger c-di-GMP, is located at the flagellated cell pole. Here, we show that direct interaction between the inactive diguanylate cyclase (GGDEF) domain of PdeB and the FimV domain of the polar landmark protein HubP is crucial for full function of PdeB as a phosphodiesterase. Thus, the GGDEF domain serves as a spatially controlled on-switch that effectively restricts PdeBs activity to the flagellated cell pole. PdeB regulates abundance and activity of at least two crucial surface-interaction factors, the BpfA surface-adhesion protein and the MSHA type IV pilus. The heterogeneity in c-di-GMP concentrations, generated by differences in abundance and timing of polar appearance of PdeB, orchestrates the population behavior with respect to cell-surface interaction and environmental spreading.
Emergence of instability-driven domains in soft stratified materials
Authors: Li Jian , Slesarenko Viacheslav , Rudykh Stephan 
Published: May 2022

AbstractNature frequently employs the buckling phenomenon to facilitate the formation of complicated patterns across length-scales. Current knowledge, however, is limited to a small set of buckling-induced microstructure transformations in soft composites; and the pattern formation phenomenon remains largely unknown for a vast pool of material morphologies. Here, we investigate the unexplored rich domain of soft heterogeneous composites. We experimentally observe the formation of instability-driven domains in stratified composites with a non-dilute stiff phase. We illustrate that the discovered domain patterns are energetically favorable over wrinkling. Moreover, we introduce a closed-form analytical expression allowing us to predict the evolution of the patterns in the post-buckling regime. Finally, we show that various patterns can be pre-designed via altering material compositions. These findings can help advance our understanding of the mechanisms governing pattern formations in soft biological tissues, and potentially enable the platform for mechanical metamaterials.
Sabertooth carcass consumption behavior and the dynamics of Pleistocene large carnivoran guilds
Authors: Domínguez-Rodrigo Manuel , Egeland Charles P. , Cobo-Sánchez Lucía , Baquedano Enrique , Hulbert Richard C. 
Published: May 2022

AbstractApex predators play an important role in the top-down regulation of ecological communities. Their hunting and feeding behaviors influence, respectively, prey demography and the availability of resources to other consumers. Among the most iconic—and enigmatic—terrestrial predators of the late Cenozoic are the Machairodontinae, a diverse group of big cats whose hypertrophied upper canines have earned them the moniker “sabertooths.” Many aspects of these animals’ paleobiology, especially their prey preferences and carcass consumption behavior, remain unsettled. While skeletal anatomy, dental morphology and wear, and isotopic profiles provide important insights, the most direct way to resolve these issues is through the fossil remains of sabertooth prey. Here, we report on a taphonomic analysis of an early Pleistocene faunal assemblage from Haile 21A (Florida, USA) that preserves feeding damage from the lion-sized sabertoothXenosmilus hodsonae. Patterns of tooth-marking and bone damage indicate thatXenosmilusfully defleshed the carcasses of their prey and even engaged in some minor bone consumption. This has important implications for Pleistocene carnivoran guild dynamics, including the carcass foraging behavior of the first stone-tool-using hominins.
Discordant American Society of Anesthesiologists Physical Status Classification between anesthesiologists and surgeons and its correlation with adverse patient outcomes
Authors: Kwa Charlene Xian Wen , Cui Jiaqian , Lim Daniel Yan Zheng , Sim Yilin Eileen , Ke Yuhe , Abdullah Hairil Rizal 
Published: May 2022

AbstractThe American Society of Anesthesiologists Physical Status Classification (ASA) is used for communication of patient health status, risk scoring, benchmarking and financial claims. Prior studies using hypothetical scenarios have shown poor concordance of ASA classification among healthcare providers. There is a paucity of studies using clinical data, and of clinical factors or patient outcomes associated with discordant classification. The study aims to assess ASA classification concordance between surgeons and anesthesiologists, factors surrounding discordance and its impact on patient outcomes. This retrospective cohort study was conducted in a tertiary medical center on 46,284 consecutive patients undergoing elective surgery between January 2017 and December 2019. The ASA class showed moderate concordance (weighted Cohen’s κ 0.53) between surgeons and anesthesiologists. We found significant associations between discordant classification and patient comorbidities, age and race. Patients with discordant classification had a higher risk of 30-day mortality (odds ratio (OR) 2.00, 95% confidence interval (CI) = 1.52–2.62, p < 0.0001), 1-year mortality (OR 1.53, 95% CI = 1.38–1.69, p < 0.0001), and Intensive Care Unit admission > 24 h (OR 1.69, 95% CI = 1.47–1.94, p < 0.0001). Hence, there is a need for improved standardization of ASA scoring and cross-specialty review in ASA-discordant cases.