bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatozelluläres Karzinom
Authors: Mertens Joachim , Petrowsky Henrik , Heim Markus H.
Published: July 2021

Das hepatozelluläre Karzinom (HCC) entsteht in der Regel im Rahmen einer chronischen Lebererkrankung im fortgeschrittenen Stadium. Meist liegt schon eine Zirrhose vor. Patienten mit einer Zirrhose haben ein deutlich erhöhtes Risiko für ein HCC und sollten mittels 6‑monatlichen Ultraschalluntersuchungen überwacht werden. Patienten mit neu entdecktem HCC sollten in einem spezialisierten Zentrum abgeklärt und behandelt werden. Die Wahl der Therapie hängt dabei vom Stadium der Erkrankung ab. Dieses wiederum wird nicht nur von der Tumorgrösse, sondern auch von der Leberfunktion bestimmt. Bei Frühstadien des HCC kommen Therapien mit kurativer Intention zum Einsatz: chirurgische Resektion, Transplantation und perkutane Ablationstherapien. Das intermediäre Stadium wird primär mit transarterieller Chemoembolisation behandelt. Im fortgeschrittenen Stadium kommen die systemischen Therapien und in ausgewählten Patienten die transarterielle Radiotherapie zum Einsatz. Bei den systemischen Therapien hat mit der Zulassung der Kombination eines Immuncheckpointinhibitors mit einem Angiogenesehemmer ein Paradigmenwechsel stattgefunden.
The accuracy versus interpretability trade-off in fraud detection model
Authors: Nesvijevskaia Anna , Ouillade Sophie , Guilmin Pauline , Zucker Jean-Daniel
Published: July 2021

Like a hydra, fraudsters adapt and circumvent increasingly sophisticated barriers erected by public or private institutions. Among these institutions, banks must quickly take measures to avoid losses while guaranteeing the satisfaction of law-abiding customers. Facing an expanding flow of operations, effective banking relies on data analytics to support established risk control processes, but also on a better understanding of the underlying fraud mechanism. In addition, fraud being a criminal offence, the evidential aspect of the process must also be considered. These legal, operational, and strategic constraints lead to compromises on the means to be implemented for fraud management. This paper first focuses on the translation of practical questions raised in the banking industry at each step of the fraud management process into performance evaluation required to design a fraud detection model. Secondly, it considers a range of machine learning approaches that address these specificities: the imbalance between fraudulent and nonfraudulent operations, the lack of fully trusted labels, the concept-drift phenomenon, and the unavoidable trade-off between accuracy and interpretability of detection. This state-of-the-art review sheds some light on a technology race between black box machine learning models improved by post-hoc interpretation and intrinsic interpretable models boosted to gain accuracy. Finally, it discusses how concrete and promising hybrid approaches can provide pragmatic, short-term answers to banks and policy makers without swallowing up stakeholders with economical and ethical stakes in this technological race.
Optimizing noise characteristics of mode-locked Yb-doped fiber laser using gain-induced RIN-transfer dynamics
Authors: Han Jiangshuoxue , Liu Yang , Deng Zejiang , Xie Gehui , Luo Daping , Gu Chenglin , Zhou Lian , Li Wenxue
Published: July 2021

Gain-parameter-dependent transfer functions and phase-noise performances in a mode-locked Yb-doped fiber laser are measured in this study. It is discovered that the corner frequency in the amplitude and phase domains is determined by the absorption coefficient of the gain fiber, when the total absorption and other cavity parameters are fixed. This shows that an oscillator using gain fiber with higher dopant concentration accumulates more phase noise. Furthermore, we present net cavity dispersion-dependent transfer functions to verify the effect of dispersion management on the frequency response. We derive a guideline for optimizing mode-locked fiber laser design to achieve low phase noise and timing jitter.
MWA and ASKAP observations of atypical radio-halo-hosting galaxy clusters: Abell 141 and Abell 3404
Authors: Duchesne S. W. , Johnston-Hollitt M. , Wilber A. G.
Published: July 2021

We report on the detection of a giant radio halo in the cluster Abell 3404 as well as confirmation of the radio halo observed in Abell 141 (with linear extents$\sim\!770$and$\sim\!850$kpc, respectively). We use the Murchison Widefield Array, the Australian Square Kilometre Array Pathfinder, and the Australia Telescope Compact Array to characterise the emission and intervening radio sources from$\sim100$to 1 000 MHz; power law models are fit to the spectral energy distributions with spectral indices$\alpha_{88}^{1\,110} = -1.66 \pm 0.07$and$\alpha_{88}^{943} = -1.06 \pm 0.09$for the radio halos in Abell 3404 and Abell 141, respectively. We find strong correlation between radio and X-ray surface brightness for Abell 3404 but little correlation for Abell 141. We note that each cluster has an atypical morphology for a radio-halo-hosting cluster, with Abell 141 having been previously reported to be in a pre-merging state, and Abell 3404 is largely relaxed with only minor evidence for a disturbed morphology. We find that the radio halo powers are consistent with the current radio halo sample and$P_\nu$–Mscaling relations, but note that the radio halo in Abell 3404 is an ultra-steep–spectrum radio halo (USSRH) and, as with other USSRHs lies slightly below the best-fit$P_{1.4}$–Mrelation. We find that an updated scaling relation is consistent with previous results and shifting the frequency to 150 MHz does not significantly alter the best-fit relations with a sample of 86 radio halos. We suggest that the USSRH halo in Abell 3404 represents the faint class of radio halos that will be found in clusters undergoing weak mergers.
Fat mass assessment using the triceps skinfold thickness enhances the prognostic value of the Global Leadership Initiative on Malnutrition criteria in patients with lung cancer
Authors: Yin Liangyu , Fan Yang , Lin Xin , Zhang Ling , Li Na , Liu Jie , Guo Jing , Zhang Mengyuan , He Xiumei , Liu Lijuan , Zhang Hongmei , Shi Muli , Chong Feifei , Chen Xiao , Wang Chang , Wang Xu , Liang Tingting , Liu Xiangliang , Deng Li , Li Wei , Song Chunhua , Cui Jiuwei , Shi Hanping , Xu Hongxia ,   The Investigation on Nutrition Status and Clinical Outcome of Common Cancers (INSCOC) Group
Published: July 2021

The present study evaluated whether fat mass assessment using the triceps skinfold (TSF) thickness provides additional prognostic value to the Global Leadership Initiative on Malnutrition (GLIM) framework in patients with lung cancer (LC). We performed an observational cohort study including 2672 LC patients in China. Comprehensive demographic, disease and nutritional characteristics were collected. Malnutrition was retrospectively defined using the GLIM criteria, and optimal stratification was used to determine the best thresholds for the TSF. The associations of malnutrition and TSF categories with survival were estimated independently and jointly by calculating multivariable-adjusted hazard ratios (HR). Malnutrition was identified in 808 (30·2 %) patients, and the best TSF thresholds were 9·5 mm in men and 12 mm in women. Accordingly, 496 (18·6 %) patients were identified as having a low TSF. Patients with concurrent malnutrition and a low TSF had a 54 % (HR = 1·54, 95 % CI = 1·25, 1·88) greater death hazard compared with well-nourished individuals, which was also greater compared with malnourished patients with a normal TSF (HR = 1·23, 95 % CI = 1·06, 1·43) or malnourished patients without TSF assessment (HR = 1·31, 95 % CI = 1·14, 1·50). These associations were concentrated among those patients with adequate muscle mass (as indicated by the calf circumference). Additional fat mass assessment using the TSF enhances the prognostic value of the GLIM criteria. Using the population-derived thresholds for the TSF may provide significant prognostic value when used in combination with the GLIM criteria to guide strategies to optimise the long-term outcomes in patients with LC.
Do Alpha Males Deliver Alpha? Facial Width-to-Height Ratio and Hedge Funds
Authors: Lu Yan , Teo Melvyn
Published: July 2021

An abundance of evidence relates facial width-to-height ratio (fWHR) to masculine behaviors in males. We show that hedge funds operated by high-fWHR managers underperform those operated by low-fWHR managers, bear greater downside risk, are more susceptible to fire sales, and fail more often. High-fWHR managers compensate for their underperformance by marketing their funds more aggressively, thereby garnering higher flows and fee revenues. By exploiting major personal events that shape testosterone, namely marriage and fatherhood, we trace the biological mechanism underlying the relation between fWHR and investment performance to circulating testosterone. Our findings are robust and extend to equity mutual funds.
Highlighting the interplay of microRNAs from Leishmania parasites and infected-host cells
Authors: Rashidi Sajad , Mansouri Reza , Ali-Hassanzadeh Mohammad , Ghani Esmaeel , Barazesh Afshin , Karimazar Mohammadreza , Nguewa Paul , Carrera Silva Eugenio Antonio
Published: July 2021

Leishmania parasites, the causative agents of leishmaniasis, are protozoan parasites with the ability to modify the signalling pathway and cell responses of their infected host cells. These parasite strategies alter the host cell environment and conditions favouring their replication, survival and pathogenesis. Since microRNAs (miRNAs) are able to post-transcriptionally regulate gene expression processes, these biomolecules can exert critical roles in controlling Leishmania-host cell interplay. Therefore, the identification of relevant miRNAs differentially expressed in Leishmania parasites as well as in infected cells, which affect the host fitness, could be critical to understand the infection biology, pathogenicity and immune response against these parasites. Accordingly, the current review aims to address the differentially expressed miRNAs in both, the parasite and infected host cells and how these biomolecules change cell signalling and host immune responses during infection. A deep understanding of these processes could provide novel guidelines and therapeutic strategies for managing and treating leishmaniasis.
Ogilvie's syndrome presented with delirium in an older lady with corticobasal syndrome
Authors: Mutlay Feyza , Kaya Derya , Isik Ahmet Turan
Published: July 2021

Objective

Corticobasal syndrome (CBS) is one of an atypical parkinsonian syndromes characterized by extrapyramidal features as well as cortical involvement signs. A variety of factors may lead to delirium in older adults with chronic progressive life-limiting neurological illnesses like CBS. Ogilvie's syndrome (OS) is an acute colonic pseudo-obstruction in which abdominal distension, nausea, vomiting, and constipation can be seen. We report a case of OS identified as the underlying possible cause of delirium in an 80-year-old woman with CBS. We also discuss the importance of holistic approach which is essential to manage the underlying cause and to preserve the quality of life in particular for the frail geriatric population who potentially needs palliative care or already benefits from palliative care.

Method

An older patient with CBS presented with symptoms similar to that of acute colonic obstruction and subsequently developed delirium. The patient was found to have colonic pseudo-obstruction (OS).

Result

Neostigmin infusion was therefore given to treat it and delirium was resolved.

Significance of results

To the best of our knowledge, clinical manifestation of delirium as OS in a patient with CBS has not been previously reported. OS may be superimposed to CBS in older patients, and OS in such patients may play a role as a precipitating factor for the development of delirium. Given the fact that CBS is progressive and rare neurodegenerative disease and almost all of these patients need palliative care, eventually, health-care professionals, especially in palliative care, should be aware of distinctive challenges of life-limiting chronic neurological illnesses, such as conditions that may lead to the development of acute colonic pseudo-obstruction because the rapid treatment of them prevents the use of potentially harmful drugs, surgical procedures, or inappropriate interventions.
Attention-based deep learning networks for identification of human gait using radar micro-Doppler spectrograms
Authors: Doherty Hannah Garcia , Burgueño Roberto Arnaiz , Trommel Roeland P. , Papanastasiou Vasileios , Harmanny Ronny I. A.
Published: July 2021

Identification of human individuals within a group of 39 persons using micro-Doppler (μ-D) features has been investigated. Deep convolutional neural networks with two different training procedures have been used to perform classification. Visualization of the inner network layers revealed the sections of the input image most relevant when determining the class label of the target. A convolutional block attention module is added to provide a weighted feature vector in the channel and feature dimension, highlighting the relevant μ-D feature-filled areas in the image and improving classification performance.
Dielectric-loaded L-band filters for high-power space applications
Authors: Vallerotonda Paolo , Cacciamani Fabrizio , Pelliccia Luca , Cazzorla Alessandro , Tiradossi Davide , Steffè Walter , Vitulli Francesco , Picchione Elio , Galdeano Jaione , Martìn-Iglesias Petronilo , Tomassoni Cristiano
Published: July 2021

The design and first experimental results of Tx and Rx L-band bandpass filters for a high-power satellite diplexer are presented in this paper. Designed in the framework of an ESA ARTES AT project, the filters are based on TM010 mode dielectric resonators. These resonators allow for better results in terms of volume occupation with respect to other dielectric resonators still maintaining high Q-factor values (>2000). Volume saving above 30% is achieved with respect to standard coaxial filters. The filter geometries and materials have been chosen in order to improve the power-handling and to cope with related critical issues for space applications (i.e. avoid any multipactor discharge in the operating RF power range and low-PIM response). Measurements of Tx filter show good correlation with the design in terms of central frequency, BW, and unloaded Q-factor (almost 3000). Measurements of Rx filter show a worse correlation with the design in terms of filter response shape. This is ascribed to size tolerances of one of the filter resonators. Multiple analyses are ongoing to remove this degradation in the final engineering model.
How to support German cities in implementing the SDGs: learning from and about co-design
Authors: Krellenberg Kerstin , Koch Florian
Published: July 2021

Non-technical summary

Scientists often argue that today's efforts towards sustainability in cities call for a strong exchange on knowledge with non-scientific actors. But do urban practitioners think the same way? Do they see the need for scientific support in their work? In our research, we directly asked these questions to urban practitioners. This article evolves around their answers and describes the activities we conducted in order to start the necessary discussion with them.

Technical summary

Given the challenges cities are facing in their efforts towards sustainability, we scrutinize if urban practitioners believe that scientific knowledge can support them in implementing the Sustainable Development Goals (SDGs), and if, how. To find evidence, we conducted a ‘co-design’ approach in Future Earth in terms of knowledge production, targeting at German cities. In consequence, the aims of this article are twofold. First, we aim at describing the implementation of the co-design process itself as a potentially useful tool for the interaction with urban practitioners and the evaluation of their specific needs. Second, we present the main results of the co-design process and its contribution for SDG implementation in cities. Combining the two aims, we argue for novel research approaches that allow for more collaborative activities as well as for adequate funding opportunities in the light of urban sustainability transformations.

Media summary

Co-design to support SDG implementation in cities towards sustainability transformations.
Proactivity at Work
Authors: Vogt Catharina , van Gils Suzanne , Van Quaquebeke Niels , L. Grover Steven , Eckloff Tilman
Published: July 2021

Abstract. We propose that two aspects of leadership, perceived respectful leadership and the degree of leaders’ prototypicality, positively affect employee proactivity. A multisource and multilevel field study of 234 employees supervised by 62 leaders shows that respectful leadership relates positively to employee proactivity in terms of personal initiative and that leader group prototypicality diminishes this effect. Moreover, perceived respectful leadership and prototypicality substitute for one another in their relation to follower proactivity. This study contributes to previous research that shows leader–follower relationships enhance proactivity by showing the impact of perceived respectful leadership and leader group prototypicality.
Coeval Drying Across the Central Tropical Pacific Over the Last Millennium
Authors: Wyman D. A. , Conroy J. L. , Osburn M. R. , Atwood A. R.
Published: July 2021

Hydroclimatic variability in the tropical Pacific reflects large‐scale ocean‐atmosphere processes that imprint on global climate, but tropical Pacific hydroclimate variability over the last millennium remains uncertain. Here we present a multi‐proxy reconstruction from a lacustrine sediment record on Kiritimati Atoll that spans the last millennium. A lake salinity reconstruction from the δ2H values of total lipid extracts, combined with changes in sediment mineralogy and the stable isotopic composition of inorganic carbonates, indicate the presence of several distinct hydrologic regimes on Kiritimati, including a period of persistent aridity from 960–1030 CE, shorter episodes of aridity from 1030–1370 CE, and extreme aridity throughout the latter half of the last millennium, from 1370–1970 CE, that drove complete evaporation of the lake. A period of wetter, variable conditions defines recent decades. Compound‐specific lipid biomarker δ2H values indicate that shifts in microbial community structure occurred in the past, from a community dominated by photoautotrophic and chemoautotrophic organisms in more arid periods to a more metabolically diverse community in the recent period. Comparison of this record with nearby sediment records from Washington Island reveals a similar pattern of aridity through the last millennium, followed by wetter conditions in the modern period. These coherent changes in hydroclimate in the central Pacific are inconsistent with a migration of the Pacific Intertropical Convergence Zone within these latitudes. Rather, past aridity was caused by reduced El Niño‐Southern Oscillation variability, observed through the low‐pass filter of lacustrine records, or by multidecadal to multi‐century strengthening of the Pacific Walker Circulation.
Using the World Wide Lightning Location Network (WWLLN) to Study Very Low Frequency Transmission in the Earth‐Ionosphere Waveguide: 1. Comparison With a Full‐Wave Model
Authors: Jacobson Abram R. , Holzworth Robert H. , Brundell James B.
Published: July 2021

We investigate a novel way to quantify Very Low Frequency transmission in the Earth‐Ionosphere Waveguide, using data from the World Wide Lightning Location Network (WWLLN). The lightning signals from intense and long‐duration storm clusters are recorded at several stations. Any individual stroke amplitude is in principle unknown, so that the recorded electric field from that stroke varies semi‐randomly from the recorded field due to other strokes from that storm cluster. Thus, it is not possible to straightforwardly infer the channel characteristics from a stroke recorded at a single station. However, if two stations record the signal from the same stroke, then the inter‐station ratio of the recorded amplitude on the two fixed propagation paths is (in the absence of noise) independent of source power. We develop a procedure to provide information on time‐variations in the waveguide transmission, using an approach based on ratios of amplitudes from pair of stations which record the same strokes. These amplitude‐ratio data are then compared to an existing model of full‐wave Very Low Frequency reflection from the underside of the ionosphere.
Kinectin 1 promotes the growth of triple-negative breast cancer via directly co-activating NF-kappaB/p65 and enhancing its transcriptional activity
Authors: Gao Lin , Chen Shanze , Hong Malin , Zhou Wenbin , Wang Bilan , Qiu Junying , Xia Jinquan , Zhao Pan , Fu Li , Wang Jigang , Dai Yong , Xie Ni , Yang Qinhe , Huang Hsien-Da , Gao Xiang , Zou Chang
Published: July 2021

Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer. Various endeavor has been made to explore the molecular biology basis of TNBC. Herein, we reported a novel function of factor Kinectin 1 (KTN1) as a carcinogenic promoter in TNBC. KTN1 expression in TNBC was increased compared with adjacent tissues or luminal or Her2 subtypes of breast cancer, and TNBC patients with high KTN1 expression have poor prognosis. In functional studies, knockdown of KTN1 inhibited the proliferation and invasiveness of TNBC both in vitro and in vivo, while overexpression of KTN1 promoted cancer cell proliferation and invasiveness. RNA-seq analysis revealed that the interaction of cytokine-cytokine receptor, particularly CXCL8 gene, was upregulated by KTN1, which was supported by the further experiments. CXCL8 depletion inhibited the tumorigenesis and progression of TNBC. Additionally, rescue experiments validated that KTN1-mediated cell growth acceleration in TNBC was dependent on CXCL8 both in vitro and in vivo. Furthermore, it was found that KTN1 enhanced the phosphorylation of NF-κB/p65 protein at Ser536 site, and specifically bound to NF-κB/p65 protein in the nucleus and cytoplasm of cells. Moreover, the transcription of CXCL8 gene was directly upregulated by the complex of KTN1 and NF-κB/p65 protein. Taken together, our results elucidated a novel mechanism of KTN1 gene in TNBC tumorigenesis and progression. KTN1 may be a potential molecular target for the development of TNBC treatment.
Translational evidence for lithium-induced brain plasticity and neuroprotection in the treatment of neuropsychiatric disorders
Authors: Puglisi-Allegra Stefano , Ruggieri Stefano , Fornai Francesco
Published: July 2021

Increasing evidence indicates lithium (Li+) efficacy in neuropsychiatry, pointing to overlapping mechanisms that occur within distinct neuronal populations. In fact, the same pathway depending on which circuitry operates may fall in the psychiatric and/or neurological domains. Li+ restores both neurotransmission and brain structure unveiling that psychiatric and neurological disorders share common dysfunctional molecular and morphological mechanisms, which may involve distinct brain circuitries. Here an overview is provided concerning the therapeutic/neuroprotective effects of Li+ in different neuropsychiatric disorders to highlight common molecular mechanisms through which Li+ produces its mood-stabilizing effects and to what extent these overlap with plasticity in distinct brain circuitries. Li+ mood-stabilizing effects are evident in typical bipolar disorder (BD) characterized by a cyclic course of mania or hypomania followed by depressive episodes, while its efficacy is weaker in the opposite pattern. We focus here on neural adaptations that may underlie psychostimulant-induced psychotic development and to dissect, through the sensitization process, which features are shared in BD and other psychiatric disorders, including schizophrenia. The multiple functions of Li+ highlighted here prove its exceptional pharmacology, which may help to elucidate its mechanisms of action. These may serve as a guide toward a multi-drug strategy. We propose that the onset of sensitization in a specific BD subtype may predict the therapeutic efficacy of Li+. This model may help to infer in BD which molecular mechanisms are relevant to the therapeutic efficacy of Li+.
MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer
Authors: Lampis Andrea , Hahne Jens C. , Gasparini Pierluigi , Cascione Luciano , Hedayat Somaieh , Vlachogiannis Georgios , Murgia Claudio , Fontana Elisa , Edwards Joanne , Horgan Paul G. , Terracciano Luigi , Sansom Owen J. , Martins Carlos D. , Kramer-Marek Gabriela , Croce Carlo M. , Braconi Chiara , Fassan Matteo , Valeri Nicola
Published: July 2021

Junctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer; however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) (n = 947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC (n = 1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC.
SKP-SCs transplantation alleviates 6-OHDA-induced dopaminergic neuronal injury by modulating autophagy
Authors: Ma Chengxiao , Zhang Wen , Wang Wengcong , Shen Jiabing , Cai Kefu , Liu Mei , Cao Maohong
Published: July 2021

Parkinson’s disease is a common neurodegenerative disease. Cell transplantation is a promising therapeutic option for improving the survival and function of dopaminergic neurons, but the mechanisms underlying the interaction between the transplanted cells and the recipient neurons remain to be studied. In this study, we investigated the effects of skin precursor cell-derived Schwann cells (SKP-SCs) directly cocultured with 6-OHDA-injured dopaminergic neurons in vitro and of SKP-SCs transplanted into the brains of 6-OHDA-induced PD mice in vivo. In vitro and in vivo studies revealed that SKP-SCs could reduce the damage to dopaminergic neurons by enhancing self-autophagy and modulating neuronal autophagy. Thus, the present study provides the first evidence that cell transplantation mitigates 6-OHDA-induced damage to dopaminergic neurons by enhancing self-autophagy, suggesting that earlier transplantation of Schwann cells might help alleviate the loss of dopaminergic neurons.
The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression
Authors: Gao Long , Liu Yuan , Du Xiaohong , Ma Sai , Ge Minmin , Tang Haijun , Han Chenfeng , Zhao Xin , Liu Yanbin , Shao Yun , Wu Zhao , Zhang Lianjun , Meng Fang , Xiao-Feng Qin F.
Published: July 2021

It has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+ T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+ and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.
The proteolytic landscape of cells exposed to non-lethal stresses is shaped by executioner caspases
Authors: Conde-Rubio María del Carmen , Mylonas Roman , Widmann Christian
Published: July 2021

Cells are in constant adaptation to environmental changes to insure their proper functioning. When exposed to stresses, cells activate specific pathways to elicit adaptive modifications. Those changes can be mediated by selective modulation of gene and protein expression as well as by post-translational modifications, such as phosphorylation and proteolytic processing. Protein cleavage, as a controlled and limited post-translational modification, is involved in diverse physiological processes such as the maintenance of protein homeostasis, activation of repair pathways, apoptosis and the regulation of proliferation. Here we assessed by quantitative proteomics the proteolytic landscape in two cell lines subjected to low cisplatin concentrations used as a mild non-lethal stress paradigm. This landscape was compared to the one obtained in the same cells stimulated with cisplatin concentrations inducing apoptosis. These analyses were performed in wild-type cells and in cells lacking the two main executioner caspases: caspase-3 and caspase-7. Ninety-two proteins were found to be cleaved at one or a few sites (discrete cleavage) in low stress conditions compared to four hundred and fifty-three in apoptotic cells. Many of the cleaved proteins in stressed cells were also found to be cleaved in apoptotic conditions. As expected, ~90% of the cleavage events were dependent on caspase-3/caspase-7 in apoptotic cells. Strikingly, upon exposure to non-lethal stresses, no discrete cleavage was detected in cells lacking caspase-3 and caspase-7. This indicates that the proteolytic landscape in stressed viable cells fully depends on the activity of executioner caspases. These results suggest that the so-called executioner caspases fulfill important stress adaptive responses distinct from their role in apoptosis. Mass spectrometry data are available via ProteomeXchange with identifier PXD023488.
OASIS/CREB3L1 is a factor that responds to nuclear envelope stress
Authors: Kamikawa Yasunao , Saito Atsushi , Matsuhisa Koji , Kaneko Masayuki , Asada Rie , Horikoshi Yasunori , Tashiro Satoshi , Imaizumi Kazunori
Published: July 2021

The nuclear envelope (NE) safeguards the genome and is pivotal for regulating genome activity as the structural scaffold of higher-order chromatin organization. NE had been thought as the stable during the interphase of cell cycle. However, recent studies have revealed that the NE can be damaged by various stresses such as mechanical stress and cellular senescence. These types of stresses are called NE stress. It has been proposed that NE stress is closely related to cellular dysfunctions such as genome instability and cell death. Here, we found that an endoplasmic reticulum (ER)-resident transmembrane transcription factor, OASIS, accumulates at damaged NE. Notably, the major components of nuclear lamina, Lamin proteins were depleted at the NE where OASIS accumulates. We previously demonstrated that OASIS is cleaved at the membrane domain in response to ER stress. In contrast, OASIS accumulates as the full-length form to damaged NE in response to NE stress. The accumulation to damaged NE is specific for OASIS among OASIS family members. Intriguingly, OASIS colocalizes with the components of linker of nucleoskeleton and cytoskeleton complexes, SUN2 and Nesprin-2 at the damaged NE. OASIS partially colocalizes with BAF, LEM domain proteins, and a component of ESCRT III, which are involved in the repair of ruptured NE. Furthermore, OASIS suppresses DNA damage induced by NE stress and restores nuclear deformation under NE stress conditions. Our findings reveal a novel NE stress response pathway mediated by OASIS.
Circ_0030998 promotes tumor proliferation and angiogenesis by sponging miR-567 to regulate VEGFA in colorectal cancer
Authors: Jin Longyang , Han Chao , Zhai Tianyu , Zhang Xiaoyu , Chen Chun , Lian Lei
Published: July 2021

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Circular RNAs (circRNAs) are involved in pathological processes, especially in the development of cancers, but the roles of circRNAs in CRC are largely unknown. In this study, we investigated the role and underlying mechanisms of Circ_0030998 in CRC cell proliferation and angiogenesis. We found that Circ_0030998 was upregulated in CRC tissues and cells, and its upregulation was related to poor prognosis in CRC patients. Circ_0030998 promoted CRC cell proliferation in vitro and in vivo, and facilitated the angiogenesis of HUVECs. Mechanistic studies demonstrated that Circ_0030998 acted as a miR-567 sponge to relieve its inhibitory effect on VEGFA. Rescue assays validated that Circ_0030998 functioned in CRC cell proliferation and angiogenesis relying on VEGFA. Our findings clarified the Circ_0030998/miR-567/VEGFA regulation axis and indicated that Circ_0030998 could be a potential therapeutic target for CRC.
Impairment of neuronal mitochondrial function by l-DOPA in the absence of oxygen-dependent auto-oxidation and oxidative cell damage
Authors: Hörmann Philipp , Delcambre Sylvie , Hanke Jasmin , Geffers Robert , Leist Marcel , Hiller Karsten
Published: July 2021

L-3,4-Dihydroxyphenylalanin (l-DOPA or levodopa) is currently the most used drug to treat symptoms of Parkinson’s disease (PD). After crossing the blood–brain barrier, it is enzymatically converted to dopamine by neuronal cells and restores depleted endogenous neurotransmitter levels. l-DOPA is prone to auto-oxidation and reactive intermediates of its degradation including reactive oxygen species (ROS) have been implicated in cellular damage. In this study, we investigated how oxygen tension effects l-DOPA stability. We applied oxygen tensions comparable to those in the mammalian brain and demonstrated that 2% oxygen almost completely stopped its auto-oxidation. l-DOPA even exerted a ROS scavenging function. Further mechanistic analysis indicated that l-DOPA reprogrammed mitochondrial metabolism and reduced oxidative phosphorylation, depolarized the mitochondrial membrane, induced reductive glutamine metabolism, and depleted the NADH pool. These results shed new light on the cellular effects of l-DOPA and its neuro-toxicity under physiological oxygen levels that are very distinct to normoxic in vitro conditions.
Current insights into the expression and functions of tumor-derived immunoglobulins
Authors: Zhao Jing , Peng Hui , Gao Jie , Nong Anna , Hua Haoming , Yang Shulin , Chen Liying , Wu Xiangsheng , Zhang Hao , Wang Juping
Published: July 2021

Numerous studies have reported expressions of immunoglobulins (Igs) in many human tumor tissues and cells. Tumor-derived Igs have displayed multiple significant functions which are different from classical Igs produced by B lymphocytes and plasma cells. This review will concentrate on major progress in expressions, functions, and mechanisms of tumor-derived Igs, similarities and differences between tumor-derived Igs and B-cell-derived Igs. We also discuss the future research directions of tumor-derived Igs, including their structural characteristics, physicochemical properties, mechanisms for rearrangement and expression regulation, signaling pathways involved, and clinical applications.
Identification of the pyroptosis‑related prognostic gene signature and the associated regulation axis in lung adenocarcinoma
Authors: Lin Wanli , Chen Ying , Wu Bomeng , chen Ying , Li Zuwei
Published: July 2021

Lung adenocarcinoma (LUAD) remains the most common deadly disease and has a poor prognosis. Pyroptosis could regulate tumour cell proliferation, invasion, and metastasis, thereby affecting the prognosis of cancer patients. However, the role of pyroptosis-related genes (PRGs) in LUAD remains unclear. In our study, comprehensive bioinformatics analysis was performed to construct a prognostic gene model and ceRNA network. The correlations between PRGs and tumour-immune infiltration, tumour mutation burden, and microsatellite instability were evaluated using Pearson’s correlation analysis. A total of 23 PRGs were upregulated or downregulated in LUAD. The genetic mutation variation landscape of PRG in LUAD was also summarised. Functional enrichment analysis revealed that these 33 PRGs were mainly involved in pyroptosis, the NOD-like receptor signalling pathway, and the Toll-like receptor signalling pathway. Prognosis analysis indicated a poor survival rate in LUAD patients with low expression of NLRP7, NLRP1, NLRP2, and NOD1 and high CASP6 expression. A prognostic PRG model constructed using the above five prognostic genes could predict the overall survival of LUAD patients with medium-to-high accuracy. Significant correlation was observed between prognostic PRGs and immune-cell infiltration, tumour mutation burden, and microsatellite instability. A ceRNA network was constructed to identify a lncRNA KCNQ1OT1/miR-335-5p/NLRP1/NLRP7 regulatory axis in LUAD. In conclusion, we performed a comprehensive bioinformatics analysis and identified a prognostic PRG signature containing five genes (NLRP7, NLRP1, NLRP2, NOD1, and CASP6) for LUAD patients. Our results also identified a lncRNA KCNQ1OT1/miR-335-5p/NLRP1/NLRP7 regulatory axis, which may also play an important role in the progression of LUAD. Further study needs to be conducted to verify this result.
Structural basis of ethnic-specific variants of PAX4 associated with type 2 diabetes
Authors: Hosoe Jun , Suzuki Ken , Miya Fuyuki , Kato Takashi , Tsunoda Tatsuhiko , Okada Yukinori , Horikoshi Momoko , Shojima Nobuhiro , Yamauchi Toshimasa , Kadowaki Takashi
Published: July 2021

Recently, we conducted genome-wide association studies of type 2 diabetes (T2D) in a Japanese population, which identified 20 novel T2D loci that were not associated with T2D in Europeans. Moreover, nine novel missense risk variants, such as those of PAX4, were not rare in the Japanese population, but rare in Europeans. We report in silico structural analysis of ethnic-specific variants of PAX4, which suggests the pathogenic effect of these variants.
Predicting trends in the quality of state-of-the-art neural networks without access to training or testing data
Authors: Martin Charles H. , Peng Tongsu , Mahoney Michael W.
Published: July 2021

In many applications, one works with neural network models trained by someone else. For such pretrained models, one may not have access to training data or test data. Moreover, one may not know details about the model, e.g., the specifics of the training data, the loss function, the hyperparameter values, etc. Given one or many pretrained models, it is a challenge to say anything about the expected performance or quality of the models. Here, we address this challenge by providing a detailed meta-analysis of hundreds of publicly available pretrained models. We examine norm-based capacity control metrics as well as power law based metrics from the recently-developed Theory of Heavy-Tailed Self Regularization. We find that norm based metrics correlate well with reported test accuracies for well-trained models, but that they often cannot distinguish well-trained versus poorly trained models. We also find that power law based metrics can do much better—quantitatively better at discriminating among series of well-trained models with a given architecture; and qualitatively better at discriminating well-trained versus poorly trained models. These methods can be used to identify when a pretrained neural network has problems that cannot be detected simply by examining training/test accuracies.
Post-capillary venules are the key locus for transcytosis-mediated brain delivery of therapeutic nanoparticles
Authors: Kucharz Krzysztof , Kristensen Kasper , Johnsen Kasper Bendix , Lund Mette Aagaard , Lønstrup Micael , Moos Torben , Andresen Thomas Lars , Lauritzen Martin Johannes
Published: July 2021

Effective treatments of neurodegenerative diseases require drugs to be actively transported across the blood-brain barrier (BBB). However, nanoparticle drug carriers explored for this purpose show negligible brain uptake, and the lack of basic understanding of nanoparticle-BBB interactions underlies many translational failures. Here, using two-photon microscopy in mice, we characterize the receptor-mediated transcytosis of nanoparticles at all steps of delivery to the brain in vivo. We show that transferrin receptor-targeted liposome nanoparticles are sequestered by the endothelium at capillaries and venules, but not at arterioles. The nanoparticles move unobstructed within endothelium, but transcytosis-mediated brain entry occurs mainly at post-capillary venules, and is negligible in capillaries. The vascular location of nanoparticle brain entry corresponds to the presence of perivascular space, which facilitates nanoparticle movement after transcytosis. Thus, post-capillary venules are the point-of-least resistance at the BBB, and compared to capillaries, provide a more feasible route for nanoparticle drug carriers into the brain.
DHX9-dependent recruitment of BRCA1 to RNA promotes DNA end resection in homologous recombination
Authors: Chakraborty Prasun , Hiom Kevin
Published: July 2021

Double stranded DNA Breaks (DSB) that occur in highly transcribed regions of the genome are preferentially repaired by homologous recombination repair (HR). However, the mechanisms that link transcription with HR are unknown. Here we identify a critical role for DHX9, a RNA helicase involved in the processing of pre-mRNA during transcription, in the initiation of HR. Cells that are deficient in DHX9 are impaired in the recruitment of RPA and RAD51 to sites of DNA damage and fail to repair DSB by HR. Consequently, these cells are hypersensitive to treatment with agents such as camptothecin and Olaparib that block transcription and generate DSB that specifically require HR for their repair. We show that DHX9 plays a critical role in HR by promoting the recruitment of BRCA1 to RNA as part of the RNA Polymerase II transcription complex, where it facilitates the resection of DSB. Moreover, defects in DHX9 also lead to impaired ATR-mediated damage signalling and an inability to restart DNA replication at camptothecin-induced DSB. Together, our data reveal a previously unknown role for DHX9 in the DNA Damage Response that provides a critical link between RNA, RNA Pol II and the repair of DNA damage by homologous recombination.
Ultralow-threshold laser using super-bound states in the continuum
Authors: Hwang Min-Soo , Lee Hoo-Cheol , Kim Kyoung-Ho , Jeong Kwang-Yong , Kwon Soon-Hong , Koshelev Kirill , Kivshar Yuri , Park Hong-Gyu
Published: July 2021

Wavelength-scale lasers provide promising applications through low power consumption requiring for optical cavities with increased quality factors. Cavity radiative losses can be suppressed strongly in the regime of optical bound states in the continuum; however, a finite size of the resonator limits the performance of bound states in the continuum as cavity modes for active nanophotonic devices. Here, we employ the concept of a supercavity mode created by merging symmetry-protected and accidental bound states in the continuum in the momentum space, and realize an efficient laser based on a finite-size cavity with a small footprint. We trace the evolution of lasing properties before and after the merging point by varying the lattice spacing, and we reveal this laser demonstrates the significantly reduced threshold, substantially increased quality factor, and shrunken far-field images. Our results provide a route for nanolasers with reduced out-of-plane losses in finite-size active nanodevices and improved lasing characteristics.
High prevalence of APOA1/C3/A4/A5 alterations in luminal breast cancers among young women in East Asia
Authors: Lin Ching-Hung , Huang Ruby Yun-Ju , Lu Tzu-Pin , Kuo Kuan-Ting , Lo Ko-Yun , Chen Ching-Hsuan , Chen I-Chun , Lu Yen-Shen , Chuang Eric Y. , Thiery Jean Paul , Huang Chiun-Sheng , Cheng Ann-Lii
Published: July 2021

In East Asia, the breast cancer incidence rate among women aged <50 years has rapidly increased. Emerging tumors are distinctly characterized by a high prevalence of estrogen receptor (ER)–positive/human epidermal growth factor receptor (HER2)–negative cancer. In the present study, we identified unique genetic alterations in these emerging tumors. We analyzed gene copy number variations (CNVs) in breast tumors from 120 Taiwanese patients, and obtained public datasets of CNV and gene expression (GE). The data regarding CNV and GE were separately compared between East Asian and Western patients, and the overlapping genes identified in the comparisons were explored to identify the gene–gene interaction networks. In the age <50 years/ER + /HER2– subgroup, tumors of East Asian patients exhibited a higher frequency of copy number loss in APOA1/C3/A4/A5, a lipid-metabolizing gene cluster (33 vs. 10%, P < .001) and lower APOA1/C3/A4/A5 expressions than tumors of Western patients. These copy number loss related– and GE–related results were validated in another Taiwanese cohort and in two GE datasets, respectively. The copy number loss was significantly associated with poor survival among Western patients, but not among East Asian patients. Lower APOA1, APOC3, and APOA5 expressions were associated with higher ESTIMATE immune scores, indicating an abundance of tumor-infiltrating immune cells. In conclusion, APOA1/C3/A4/A5 copy number loss was more prevalent in luminal breast tumors among East Asian women aged <50 years, and its immunomodulatory effect on the tumor microenvironment possibly plays various roles in the tumor biology of East Asian patients.