bluuebunny/crossref_metadata_2025 huggingface dataset:
CRIP1 fosters MDSC trafficking and resets tumour microenvironment via facilitating NF-κB/p65 nuclear translocation in pancreatic ductal adenocarcinoma
Authors: Liu Xiaomeng , Tang Rong , Xu Jin , Tan Zhen , Liang Chen , Meng Qingcai , Lei Yubin , Hua Jie , Zhang Yiyin , Liu Jiang , Zhang Bo , Wang Wei , Yu Xianjun , Shi Si
Published: August 2023

Objective

Pancreatic ductal adenocarcinoma (PDAC) is among the most immunosuppressive tumour types. The tumour immune microenvironment (TIME) is largely driven by interactions between immune cells and heterogeneous tumour cells. Here, we aimed to investigate the mechanism of tumour cells in TIME formation and provide potential combination treatment strategies for PDAC patients based on genotypic heterogeneity.

Design

Highly multiplexed imaging mass cytometry, RNA sequencing, mass cytometry by time of flight and multiplex immunofluorescence staining were performed to identify the pro-oncogenic proteins associated with low immune activation in PDAC. An in vitro coculture system, an orthotopic PDAC allograft tumour model, flow cytometry and immunohistochemistry were used to explore the biological functions of cysteine-rich intestinal protein 1 (CRIP1) in tumour progression and TIME formation. RNA sequencing, mass spectrometry and chromatin immunoprecipitation were subsequently conducted to investigate the underlying mechanisms of CRIP1.

Results

Our results showed that CRIP1 was frequently upregulated in PDAC tissues with low immune activation. Elevated CRIP1 expression induced high levels of myeloid-derived suppressor cell (MDSC) infiltration and fostered an immunosuppressive tumour microenvironment. Mechanistically, we primarily showed that CRIP1 bound to nuclear factor kappa-B (NF-κB)/p65 and facilitated its nuclear translocation in an importin-dependent manner, leading to the transcriptional activation of CXCL1/5. PDAC-derived CXCL1/5 facilitated the chemotactic migration of MDSCs to drive immunosuppression. SX-682, an inhibitor of CXCR1/2, blocked tumour MDSC recruitment and enhanced T-cell activation. The combination of anti-PD-L1 therapy with SX-682 elicited increased CD8+T cell infiltration and potent antitumor activity in tumour-bearing mice with high CRIP1 expression.

Conclusions

The CRIP1/NF-κB/CXCL axis is critical for triggering immune evasion and TIME formation in PDAC. Blockade of this signalling pathway prevents MDSC trafficking and thereby sensitises PDAC to immunotherapy.
IL-3 receptor signalling suppresses chronic intestinal inflammation by controlling mechanobiology and tissue egress of regulatory T cells
Authors: Ullrich Karen Anne-Marie , Derdau Julia , Baltes Carsten , Battistella Alice , Rosso Gonzalo , Uderhardt Stefan , Schulze Lisa Lou , Liu Li-Juan , Dedden Mark , Spocinska Marta , Kainka Lucina , Kubánková Markéta , Müller Tanja Martina , Schmidt Nina-Maria , Becker Emily , Ben Brahim Oumaima , Atreya Imke , Finotto Susetta , Prots Iryna , Wirtz Stefan , Weigmann Benno , López-Posadas Rocío , Atreya Raja , Ekici Arif Bülent , Lautenschläger Franziska , Guck Jochen , Neurath Markus F , Zundler Sebastian
Published: August 2023

IL-3 has been reported to be involved in various inflammatory disorders, but its role in inflammatory bowel disease (IBD) has not been addressed so far. Here, we determined IL-3 expression in samples from patients with IBD and studied the impact ofIl3orIl3rdeficiency on T cell-dependent experimental colitis. We explored the mechanical, cytoskeletal and migratory properties ofIl3r−/−andIl3r+/+T cells using real-time deformability cytometry, atomic force microscopy, scanning electron microscopy, fluorescence recovery after photobleaching andin vitroandin vivocell trafficking assays. We observed that, in patients with IBD, the levels of IL-3 in the inflamed mucosa were increased.In vivo, experimental chronic colitis on T cell transfer was exacerbated in the absence of Il-3 or Il-3r signalling. This was attributable to Il-3r signalling-induced changes in kinase phosphorylation and actin cytoskeleton structure, resulting in increased mechanical deformability and enhanced egress of Tregs from the inflamed colon mucosa. Similarly, IL-3 controlled mechanobiology in human Tregs and was associated with increased mucosal Treg abundance in patients with IBD. Collectively, our data reveal that IL-3 signaling exerts an important regulatory role at the interface of biophysical and migratory T cell features in intestinal inflammation and suggest that this might be an interesting target for future intervention.
Oncolytic viruses and antibodies: are they more successful when delivered separately or when engineered as a single agent?
Authors: Wan Peter Kok-Ting , Fernandes Ricardo A , Seymour Leonard W
Published: August 2023

Oncolytic viruses (OVs) provide the promise of tumor-selective cytotoxicity coupled with amplification of the therapeutic agent (the virus)in situwithin the tumor improving its therapeutic index. Despite this promise, however, single agent-treatments have not been as successful as combination therapies, particularly combining with checkpoint inhibitor antibodies. The antibodies may be delivered by two approaches, either encoded within the OV genome to restrict antibody production to sites of active virus infection or alternatively given alongside OVs as separate treatments. Both approaches have shown promising therapeutic outcomes, and this leads to an interesting question of whether one approach is potentially better than the other. In this review, we provide a brief summary of the combination OV-antibody therapies that target tumor cells, tumor microenvironment and immune cells to help define key parameters influencing which approach is superior, thereby improving insight into the rational design of OV treatment strategies.
Best practices in phase III clinical trials on DMTs for multiple sclerosis: a systematic analysis and appraisal of published trials
Authors: Mascarenas-Garcia Marta , Rivero-de-Aguilar Alejandro , Pérez-Ríos Mónica , Ruano-Raviña Alberto , Llaneza-Gonzalez Miguel Angel , Candal-Pedreira Cristina , Rey-Brandariz Julia , Varela-Lema Leonor
Published: August 2023

Background

Great advances have been made in the field of multiple sclerosis (MS) therapy due to the publication of numerous randomised clinical trials (RCTs). In this study, we carried out a critical appraisal of phase III RCTs of disease-modifying therapies (DMTs) for MS published after 2010, intending to identify critical areas of improvement.

Methods

We performed a systematic search of published RCTs on MS from January 2010 until December 2021. RCTs were assessed using an ad-hoc tool. This tool was developed based on existing generic methodological instruments and MS-specific guidelines and methodological papers. It included 14 items grouped in 5 domains: methodological quality, adequacy and measurement of outcomes, adverse event reporting, applicability and relevance of results, and transparency and conflict of interest.

Results

We identified 31 phase III RCTs. Most of them were fully compliant in terms of sample size (87%), randomisation (68%), blinding (61%), participant selection (68%), adverse event reporting (84%) and clinical relevance (52%). Only a few were compliant in terms of participant description (6%), comparison (42%), attrition bias (26%), adequacy of outcome measures (26%), applicability (23%), transparency (36%) and conflict of interest (6%). None were compliant in terms of analysis and reporting of outcomes. The most common limitations related to the absence of comorbidity data, unjustified use of placebo, inadequacy of outcomes design and absence of protocol and/or prospective registration.

Conclusions

RCTs for DMTs in MS have relevant and frequent limitations. These should be addressed to enhance their quality, transparency and external validity.
Characterising symptom clusters in patients with atrial fibrillation undergoing catheter ablation
Authors: Hobensack Mollie , Zhao Yihong , Scharp Danielle , Volodarskiy Alexander , Slotwiner David , Reading Turchioe Meghan
Published: August 2023

Objective

This study aims to leverage natural language processing (NLP) and machine learning clustering analyses to (1) identify co-occurring symptoms of patients undergoing catheter ablation for atrial fibrillation (AF) and (2) describe clinical and sociodemographic correlates of symptom clusters.

Methods

We conducted a cross-sectional retrospective analysis using electronic health records data. Adults who underwent AF ablation between 2010 and 2020 were included. Demographic, comorbidity and medication information was extracted using structured queries. Ten AF symptoms were extracted from unstructured clinical notes (n=13 416) using a validated NLP pipeline (F-score=0.81). We used the unsupervised machine learning approach known as Ward’s hierarchical agglomerative clustering to characterise and identify subgroups of patients representing different clusters. Fisher’s exact tests were used to investigate subgroup differences based on age, gender, race and heart failure (HF) status.

Results

A total of 1293 patients were included in our analysis (mean age 65.5 years, 35.2% female, 58% white). The most frequently documented symptoms were dyspnoea (64%), oedema (62%) and palpitations (57%). We identified six symptom clusters: generally symptomatic, dyspnoea and oedema, chest pain, anxiety, fatigue and palpitations, and asymptomatic (reference). The asymptomatic cluster had a significantly higher prevalence of male, white and comorbid HF patients.

Conclusions

We applied NLP and machine learning to a large dataset to identify symptom clusters, which may signify latent biological underpinnings of symptom experiences and generate implications for clinical care. AF patients’ symptom experiences vary widely. Given prior work showing that AF symptoms predict adverse outcomes, future work should investigate associations between symptom clusters and postablation outcomes.
The MIDORA trial: a phase II, randomised, double-blind, placebo-controlled, mechanistic insight and dosage optimisation study of the efficacy and safety of dazodalibep in patients with rheumatoid arthritis
Authors: Kivitz Alan , Wang Liangwei , Alevizos Ilias , Gunsior Michele , Falloon Judith , Illei Gabor , St Clair E William
Published: August 2023

Objectives

To evaluate the safety, efficacy and response duration of four different dosing regimens of dazodalibep (DAZ), a non-antibody biological antagonist of CD40L, in patients with rheumatoid arthritis (RA).

Methods

This double-blind study included adult patients with moderate-to-severe active RA with a positive test for serum rheumatoid factor and/or anticitrullinated protein antibodies, an inadequate response to methotrexate, other conventional disease-modifying antirheumatic drugs or tumour necrosis factor-α inhibitors, and no prior treatment with B-cell depleting agents. Eligible participants were randomised equally to five groups receiving intravenous infusions of DAZ or placebo. The primary endpoint was the change from baseline in the Disease Activity Score-28 with C reactive protein (DAS28-CRP) at day 113. Participants were followed through day 309.

Results

The study randomised 78 eligible participants. The change from baseline in DAS28-CRP (least squares means±SE) at day 113 was significantly greater for all DAZ groups (−1.83±0.28 to −1.90±0.27; p<0.05) relative to PBO (−1.06±0.26); significant reductions in DAS28-CRP were also observed for all DAZ groups at day 309. The distribution of adverse events was generally balanced among DAZ and PBO groups (74% and 63%, respectively). There were four serious adverse events deemed by investigators to be unrelated to study medication.

Conclusions

DAZ treatment for all dosage regimens significantly reduced DAS28-CRP at day 113 relative to PBO. The safety data suggest an acceptable safety and tolerability profile. Treatment effects at day 113 and the prolonged duration of responses after DAZ cessation support the use of longer dosing intervals.

Trial registration number

NCT04163991
Pain and sleep after open-heart surgery-inhalation peppermint essence: double-blind randomized clinical trial
Authors: Maghami Mahla , Pour‑Abbasi Mohammad-Sadegh , Yadollahi Safoura , Maghami Mahboobeh , Azizi-fini Ismail , Afazel Mohammad-Reza
Published: August 2023

Objective

The aim of this study was to determine the effect of inhaling peppermint essence on pain relief and sleep quality after open-heart surgery.

Methods

In a double-blind randomised clinical trial carried out in Iran in 2020, 64 cardiac patients were selected by convenience sampling and randomly allocated to aromatherapy (n=32) and placebo (n=32) groups. The aromatherapy and control groups received inhaled aromatherapy using peppermint essence and distilled water, respectively. Data gathering tools were the Numeric Pain Rating Scale and St Mary’s Hospital Sleep Questionnaire. Data were analysed using an independent t-test, χ2test, Mann–Whitney U test and generalised estimating equation analysis.

Results

The mean severity of pain in the aromatherapy and placebo groups was 3.22±0.88 and 4.56±0.90, respectively, which was a statistically significant difference (p=0.0001). The mean sleep scores after the intervention on day 1 were 20.10±4.90 and 25.76±6.36 in the aromatherapy and placebo groups, respectively, and 18.63±5.56 and 22.62±5.69, respectively, on day 2. The difference between the two groups was statistically significantly different after the intervention in terms of sleep quality (p<0.05).

Conclusion

Aromatherapy attenuated pain and improved sleep quality after open-heart surgery. Peppermint essence aromatherapy is therefore recommended after surgery.
Magnetic-field-driven rise and fall of a bipartite entanglement in a spin-liquid phase of a spin-1/2 Heisenberg branched chain
Authors: Ghannadan Azadeh , Karl’ová Katarína , Strečka Jozef
Published: August 2023

The spin-1/2 Heisenberg branched chain with the unit cell composed of three spins in the main backbone and one spin at a side branching of one-dimensional chain is investigated with the help of density-matrix renormalization group (DMRG) and quantum Monte Carlo (QMC) methods. The DMRG simulations were employed to calculate zero-temperature magnetization curves and to construct the ground-state phase diagram, which is composed from four different ground states classified as gapped zero-plateau and one-half plateau phase, a gapless spin-liquid phase and a fully saturated phase. It is shown that the one-half magnetization plateau vanishes at the Kosterlitz–Thouless quantum critical point, which is wedged into a parameter space of the gapless quantum spin-liquid phase. The bipartite quantum entanglement between four distinct nearest-neighbor pairs of the spin-1/2 Heisenberg branched chain is quantified through the concurrence. It is found that the concurrence varies continuously within the quantum spin-liquid phase, where it may display a continuous rise, a continuous fall or eventually an intriguing rise-and-fall behavior. On the contrary, the concurrence is kept constant within two gapful zero- and one-half plateau phases. Temperature and magnetic-field dependencies of the magnetization and magnetic susceptibility computed within the QMC method uncover clear signatures of the quantum critical point at finite temperatures.
Organic geochemistry of
in situ
thermal-based analyses on Mars: the importance and influence of minerals
Authors: Sephton Mark A. , Tan Jonathan S. W. , Watson Jonathan S. , Hickman-Lewis Keyron , Madariaga Juan M.
Published: August 2023

A high-priority goal for past, present and future missions to Mars is the search for evidence of past or present life. Some of the most information-rich signals are those represented by organic biomarkers. Thermal extraction has historically been the most popular
in situ
analysis technique employed on Mars owing to its elegance and ability to liberate both smallounds and large macromolecular networks. The geological record of Mars contains a variety of minerals, some of which can interact with organic matter when subjected to thermal extraction. We discuss the organic records that may be associated with these mineral hosts and the problems encountered when mineral–organic mixtures are analysed by thermal-based methods. We also suggest potential mitigations for future experiments of a similar nature and note that these mitigating steps can be applied not only
in situ
on Mars, but also after samples are returned to Earth as part of the Mars Sample Return mission, where more resources and time for sample preparation are available.

Thematic collection:
This article is part of the Astrobiology: Perspectives from the Geology of Earth and the Solar System collection available at:
https://www.lyellcollection.org/topic/collections/astrobiology
Towards Efficient Coarse-grained Dialogue Response Selection
Authors: Lan Tian , Mao Xian-Ling , Wei Wei , Gao Xiaoyan , Huang Heyan
Published: August 2023

Coarse-grained response selection is a fundamental and essential subsystem for the widely used retrieval-based chatbots, aiming to recall a coarse-grained candidate set from a large-scale dataset. The dense retrieval technique has recently been proven very effective in building such a subsystem. However, dialogue dense retrieval models face two problems in real scenarios: (1) the multi-turn dialogue history is re-computed in each turn, leading to inefficient inference; (2) the index storage of the offline index is enormous, significantly increasing the deployment cost. To address these problems, we propose an efficient coarse-grained response selection subsystem consisting of two novel methods. Specifically, to address the first problem, we propose the
H
ierarchical
D
ense
R
etrieval. It caches rich multi-vector representations of the dialogue history and only encodes the latest user’s utterance, leading to better inference efficiency. Then, to address the second problem, we design the
D
eep
S
emantic
H
ashing to reduce the index storage while effectively saving its recall accuracy notably. Extensive experimental results prove the advantages of the two proposed methods over previous works. Specifically, with the limited performance loss, our proposed coarse-grained response selection model achieves over 5x FLOPs speedup and over 192x storage compression ratio. Moreover, our source codes have been publicly released.

1
An Approach to the Systematic Characterization of Multitask Accelerated CNN Inference in Edge MPSoCs
Authors: Cilardo Alessandro , Maisto Vincenzo , Mazzocca Nicola , Rocco Di Torrepadula Franca
Published: August 2023

Deep Learning is ubiquitous today and is increasingly moving from the cloud down to the edge of networked infrastructures, where it enables embedded applications to perform complex inference tasks close to the data sources, reducing long-distance data movement and alleviating the need for a powerful cloud infrastructure. Edge-class multi-processor system on chip (MPSoC) devices featuring an on-chip FPGA fabric offer key advantages for Deep Learning inference tasks, especially for complex applications where multiple models may be run concurrently in the same platform. In this work, we propose an approach and a practical framework for the systematic characterization of multithreaded Deep Learning inference on edge FPGA MPSoCs. We instantiate the framework into a real-world MPSoC platform, targeting Xilinx Vitis-AI as a representative example of a commercial Deep Learning acceleration toolkit for edge environments. We design a comprehensive experimental campaign and apply it to the platform for several convolutional neural networks, each trained on three different datasets. We show that our approach can be used for both hardware- and software-level analysis of a target system. Among other findings, the analysis revealed a suboptimal behavior of the underlying toolkit runtime, involving the utilization of the accelerator cores and the uneven software latency of the support library, influenced by the shapes of the input tensors.
Sky Islands Are a Global Tool for Predicting the Ecological and Evolutionary Consequences of Climate Change
Authors: Love Sarah J. , Schweitzer Jennifer A. , Woolbright Scott A. , Bailey Joseph K.
Published: August 2023

Sky islands are unique geologic formations, home to populations of organisms that have weathered climate change since the Pleistocene. Long-term isolation and climatic differences between sky islands and adjacent mountain chains result in natural laboratories well suited for examining the direct effects of climate change. Here, we review the global sky island literature to examine how taxa have responded to climate change. Results show lineage formation, reduced genetic variation, and trait evolution across taxa driven by genetic drift and natural selection. These effects continue today due to ongoing habitat reduction and steep selective gradients on sky islands relative to mountain chains. Comparative studies and experimental manipulations are needed to build broad inference into how past climate change has shaped the structure and function of whole ecosystems. The next era of sky island research is poised to create a model for climate change responses and eco-evolutionary dynamics, with profound conservation implications.
Novel Disturbance Regimes and Ecological Responses
Authors: Turner Monica G. , Seidl Rupert
Published: August 2023

Many natural disturbances have a strong climate forcing, and concern is rising about how ecosystems will respond to disturbance regimes to which they are not adapted. Novelty can arise either as attributes of the disturbance regime (e.g., frequency, severity, duration) shift beyond their historical ranges of variation or as new disturbance agents not present historically emerge. How much novelty ecological systems can absorb and whether changing disturbance regimes will lead to novel outcomes is determined by the ecological responses of communities, which are also subject to change. Powerful conceptual frameworks exist for anticipating consequences of novel disturbance regimes, but these remain challenging to apply in real-world settings. Nonlinear relationships (e.g., tipping points, feedbacks) are of particular concern because of their disproportionate effects. Future research should quantify the rise of novelty in disturbance regimes and assess the capacity of ecosystems to respond to these changes. Novel disturbance regimes will be potent catalysts for ecological change.
Hidden Threat: The Influence of Sea-Level Rise on Coastal Groundwater and the Convergence of Impacts on Municipal Infrastructure
Authors: Habel Shellie , Fletcher Charles H. , Barbee Matthew M. , Fornace Kyrstin L.
Published: August 2023

Sea-level rise (SLR) is influencing coastal groundwater by both elevating the water table and shifting salinity profiles landward, making the subsurface increasingly corrosive. Low-lying coastal municipalities worldwide (potentially 1,546, according to preliminary analysis) are vulnerable to an array of impacts spurred by these phenomena, which can occur decades before SLR-induced surface inundation. Damage is accumulating across a variety of infrastructure networks that extend partially and fully beneath the ground surface. Because the resulting damage is largely concealed and imperceptible, it is largely overlooked as part of infrastructure management and planning. Here, we provide an overview of SLR-influenced coastal groundwater and related processes that have the potential to damage societally critical infrastructure and mobilize urban contamination. In an effort to promote research efforts that can inform effective adaptation and management, we discuss various impacts to critical infrastructure and propose actions based on literature focused specifically on SLR-influenced coastal groundwater.
miR-4780 Derived from N2-Like Neutrophil Exosome Aggravates Epithelial-Mesenchymal Transition and Angiogenesis in Colorectal Cancer
Authors: Wang Liang , Shan Yuqiang , Zheng Sixin , Li Jiangtao , Cui Peng
Published: August 2023

Despite significant advances in diagnostic methods and treatment strategies, the prognosis for patients with advanced colon cancer remains poor, and mortality rates are often high due to metastasis. Increasing evidence showed that it is of significant importance to investigate how the tumor microenvironment participates in the development of colorectal cancer (CRC). In this manuscript, neutrophils were sequentially stimulated with all-trans retinoic acid and transforming growth factor-β in turn to induce the neutrophil polarization. Differentially expressed miRNA in neutrophil exosomes have been sequenced by microarray profile, and the effect of N2-like neutrophil-derived exosomal miR-4780 on epithelial-mesenchymal transition (EMT) and angiogenesis was investigated. In our results, we found that neutrophils were enriched in CRC tumor tissue and that CD11b expression correlated with tumor site and serous membrane invasion. At the same time, we demonstrated that internalization of N2 exosomes exacerbated the viability, migration, and invasion of CRC cell lines and inhibited apoptosis. To further investigate the molecular mechanism, we analyzed the miRNA expression profile in the N2-like neutrophils, which led to the selection of hsa-miR-4780 for the subsequent experiment. The overexpression of miR-4780 from N2-like neutrophil-derived exosomes exacerbated EMT and angiogenesis. Moreover, miR-4780 can regulate its target gene SOX11 to effect EMT and angiogenesis in CRC cell lines. CRC with liver metastasis model also validated that aberrant expression of miR-4780 in N2-like neutrophil exosomes exacerbated tumor metastasis and development of tumor via EMT and angiogenesis. In conclusion, our current findings reveal an important mechanism by which mR-4780 from N2-like neutrophil exosomes exacerbates tumor metastasis and progression via EMT and angiogenesis.
Identification and Determination of Impurities in a New Therapeutic Agent for Fatty Liver Disease
Authors: Shao Huihui , Feng Jing , Zhang Hanyilan , Zhang Yuanyuan , Qin Tong , Hu Yuhua , Zhang Wenxuan , Wang Tiesong , Wu Song , Yang Qingyun
Published: August 2023

Methyl 7,7′-dimethoxy-5′-(morpholinomethyl)-[4,4′-bibenzo[d][1,3] dioxole]-5-carboxylate methanesulfonate (IMM) is an innovative drug for the treatment of nonalcoholic fatty liver disease (NAFLD) owing to its high efficacy and low toxicity. In this study, five minor impurities (I, II, III, IV, and V) were identified and analyzed using spectroscopic evidence, chemical synthetic methods, and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The impurities included hydrolysates and oxidation by-products extracted from both the drug in its final formulation and during synthesis. Toxicity prediction revealed potential carcinogenicity of impurity V containing an N-oxygen fragment. A reliable and selective HPLC method for the quantitative analysis of impurities I–IV and a sensitive HPLC-MS/MS method for potential genotoxic impurity V were developed and optimized. The methods were validated based on the International Council for Harmonization guidelines. Satisfactory linearity was obtained for the analytes over the range of 0.1–2.0 μg/mL for impurities I–IV and 0.3–30.0 ng/mL for impurity V, and in all cases, the fitting correlation coefficients exceeded 0.999. The obtained limits of detection values were 0.05 ng/mL and 0.005 μg/mL for impurity V and impurities I–IV, respectively. The precision and repeatability of the methods were less than 1.08% and 8.72% for each impurity. The recovery percentages of all impurities were in the range of 91.18%–111.27%, with the relative standard deviation of less than 3.69%. The greenness assessment of the HPLC method and the HPLC-MS/MS method were evaluated by using AGREE software with a score value of 0.72 and 0.68, respectively. The recommended procedures that were accurate, specific, and ecofriendly were applied to the existing active pharmaceutical ingredients of IMM, and they generated satisfactory results.
A Novel Activation Function of Deep Neural Network
Authors: Xiangyang Lin , Xing Qinghua , Han Zhang , Feng Chen
Published: August 2023

In deep neural networks, the activation function is an important component. The most popular activation functions at the moment are Sigmoid, Sin, rectified linear unit (ReLU), and some variants of ReLU. However, each of them has its own weakness. To improve the network fitting and generalization ability, a new activation function, TSin, is designed. The basic design idea for TSin function is to rotate the Sin function 45° counterclockwise and then finetune it to give it multiple better properties needed as an activation function, such as nonlinearity, global differentiability, unsaturated property, zero-centered property, monotonicity, quasi identity transformation property, and so on. The first is a theoretical derivation of TSin function by formulas. Then three experiments are designed for performance test. The results show that compared with some popular activation functions, TSin has advantages in terms of training stability, convergence speed, and convergence precision. The study of TSin not only provides a new choice of activation function in deep learning but also provides a new idea for activation function design in the future.
MicroRNA‐17‐5p and MicroRNA‐130b‐3p Promote Radioresistance of Glioma Stem Cells by Targeting PTEN/AKT/HIF‐1α Pathway‐Controlled Phosphopentose Metabolism
Authors: Xie Tao , Ding Yu-Hao , Dong Jun , Fu Xi-An
Published: August 2023

Background. The radioresistance of glioma stem cells (GSCs) is related to some microRNAs (miRs) generated by radiation. This study aimed to investigate the effects of miR‐17‐5p and miR‐130b‐3p on the radiosensitivity of GSCs. Methods. miR‐17‐5p and miR‐130b‐3p expressions in SU3 and SU3‐5R cells were determined. SU3 cells transfected with miR‐17‐5p or miR‐130b‐3p mimics or inhibitors were used to determine cell viability after irradiation as well as to examine changes of supernatant glucose, intracellular glucose 6‐phosphate dehydrogenase (G6PDH), 6‐phosphogluconate dehydrogenase (6‐PGDH), reduced nicotinamide adenine dinucleotide phosphate (NADPH), reduced glutathione (GSH), glutathione peroxidase (GSH‐Px), phosphatase and tensin homolog (PTEN), hypoxia‐inducible factor‐1α (HIF‐1α), glucose transporter (GLUT)‐1/3, protein kinase B (AKT), and p‐AKT levels. The target gene of the two miRs was verified by luciferase reporter gene assay. Results. miR‐17‐5p and miR‐130b‐3p expressions in the radiation‐resistant SU3‐5R cells or 8 Gy irradiation‐treated SU3 cells were high. After transfection of SU3 cells with miR‐17‐5p or miR‐130b‐3p mimics, cell viability, intracellular HIF‐1α, GLUT‐1/3, AKT, and p‐AKT protein expressions, and intracellular G6PDH, 6‐PGDH, NADPH, GSH‐Px, and GSH levels were high, whereas intracellular PTEN expression and supernatant glucose were low. The opposite effects were also observed in the two miR inhibitors‐transfected SU3 cells. Further study confirmed that miR‐17‐5p or miR‐130b‐3p could directly bind with the PTEN. Conclusion. Radiation‐induced miR‐17‐5p and miR‐130b‐3p might cause the radioresistance of GSCs, and the mechanisms were associated with the enhancement of antioxidant production, which was from the increments of AKT/HIF‐1α signaling pathway‐controlled glucose transmembrane transport and phosphopentose metabolism by targeting PTEN.
Adverse Maternal and Perinatal Outcomes of Meconium‐Stained Amniotic Fluid in Term Labor at Hospitals in South Gondar Zone, Northwest Ethiopia: A Prospective Cohort Study
Authors: Addisu Dagne , Mekie Maru
Published: August 2023

Background. The passage of meconium during labor increased the chance of undesirable birth outcomes. The adverse effects of meconium are worsening in resource‐limited countries. In Ethiopia, there is an argument concerning meconium’s negative effects and management on pregnant women and their babies. Therefore, this study was intended to assess the adverse maternal and perinatal outcomes of meconium in term labor in the South Gondar Zone, Ethiopia. Methods. A prospective cohort study was conducted using 580 laboring mothers (145 exposed and 435 nonexposed groups). A two‐stage sampling method was implemented to get study subjects. The data were collected using an interviewer‐administered structured questionnaire and a medical chart review. SPSS version 25 was used for data analysis. Chi‐squared and Fisher’s exact tests were used to compare the two groups’ differences. The strength of the association was measured using relative risk with a 95% CI. Result. There was more operative delivery (28.3% versus 5.3%), puerperal sepsis (79.54% versus 2.06%), nonreassuring fetal heart rate pattern (29.7% versus 2.1%), meconium aspiration syndrome (7.58% versus 0.68%), neonatal sepsis (9% versus 4.1%), perinatal asphyxia (13.8% versus 7.6%), admission to the neonatal intensive care unit (23.4% versus 3.2%), and early neonatal deaths (4.8% versus 1.4%) among meconium stained groups as compared to the clear amniotic fluid groups. Conclusion. Meconium‐stained amniotic fluid significantly increased adverse maternal and perinatal outcomes in Ethiopia. The risk of perinatal asphyxia, nonreassuring fetal heart rate pattern, neonatal sepsis, meconium aspiration syndrome, admission to the NICU, early neonatal death, operative delivery, and puerperal sepsis were significantly higher in meconium‐exposed groups. Special attention should be given to meconium‐exposed mothers during the intrapartum period and in postnatal follow‐up.
The Effect of Mesenchymal Stem Cell-Derived Exosomes and miR17-5p Inhibitor on Multicellular Liver Fibrosis Microtissues
Authors: Sani Farnaz , Soufi Zomorrod Mina , Azarpira Negar , Soleimani Masoud
Published: August 2023

Background. Although several studies have been conducted on modeling human liver disease, it is still challenging to mimic nonalcoholic fatty liver disease in vitro. Here, we aimed to develop a fibrotic liver microtissue composed of hepatocytes, hepatic stellate, and endothelial cells. In addition, the therapeutic effects of umbilical cord mesenchymal stem cell-derived exosomes (UC-MSC-EXO) and anti-miR17-5p as new antifibrotic drugs were investigated. Methods. To create an effective preclinical fibrosis model, multicellular liver microtissues (MLMs) consisting of HepG2, LX2, and HUVECs were cultured and supplemented with a mixture of palmitic acid and oleic acid for 96 hr. Then, MLMs were exposed to UC-MSC-EXO and anti-miR17-5p in different groups. The results of cell viability, reactive oxygen species (ROS) production, liver enzyme levels, inflammation, and histopathology were analyzed to assess the treatment efficacy. Furthermore, the expression of collagen I (COL I) and α-smooth muscle actin (α-SMA) as critical matrix components, transforming growth factor beta (TGF-β), and miR-17-5p were measured. Results. Free fatty acid supplementation causes fibrosis in MLMs. Our results demonstrated that UC-MSC-EXO and anti-miR17-5p attenuated TGF-β1, interleukin-1β, and interleukin-6 in all experimental groups. According to the suppression of the TGF-β1 pathway, LX2 activation was inhibited, reducing extracellular matrix proteins, including COL I and α-SMA. Also, miR-17-5p expression was elevated in fibrosis conditions. Furthermore, we showed that our treatments decreased alanine aminotransferase and aspartate aminotransferase, and increased albumin levels in the culture supernatant. We also found that both MSC-EXO and MSC-EXO + anti-miR17-5p treatments could reduce ROS production. Conclusion. Our findings indicated that anti-miR17-5p and MSC-EXO might be promising therapeutic options for treating liver fibrosis. Furthermore, EXO + anti-miR had the best effects on boosting the fibrotic markers. Therefore, we propose this novel MLM model to understand fibrosis mechanisms better and develop new drugs.
Brain Renin–Angiotensin System: From Physiology to Pathology in Neuronal Complications Induced by SARS‐CoV‐2
Authors: Ahmadi Shamseddin , Khaledi Shiler
Published: August 2023

Angiotensin‐converting enzyme 2 (ACE2), a key enzyme in the renin–angiotensin system (RAS), is expressed in various tissues and organs, including the central nervous system (CNS). The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the virus responsible for coronavirus disease‐2019 (COVID‐19), binds to ACE2, which raises concerns about the potential for viral infection in the CNS. There are numerous reports suggesting a link between SARS‐CoV‐2 infection and neurological manifestations. This study aimed to present an updated review of the role of brain RAS components, especially ACE2, in neurological complications induced by SARS‐CoV‐2 infection. Several routes of SARS‐CoV‐2 entry into the brain have been proposed. Because an anosmia condition appeared broadly in COVID‐19 patients, the olfactory nerve route was suggested as an early pathway for SARS‐CoV‐2 entry into the brain. In addition, a hematogenous route via disintegrations in the blood–brain barrier following an increase in systemic cytokine and chemokine levels and retrograde axonal transport, especially via the vagus nerve innervating lungs, have been described. Common nonspecific neurological symptoms in COVID‐19 patients are myalgia, headache, anosmia, and dysgeusia. However, more severe outcomes include cerebrovascular diseases, cognitive impairment, anxiety, encephalopathy, and stroke. Alterations in brain RAS components such as angiotensin II (Ang II) and ACE2 mediate neurological manifestations of SARS‐CoV‐2 infection, at least in part. Downregulation of ACE2 due to SARS‐CoV‐2 infection, followed by an increase in Ang II levels, leads to hyperinflammation and oxidative stress, which in turn accelerates neurodegeneration in the brain. Furthermore, ACE2 downregulation in the hypothalamus induces stress and anxiety responses by increasing corticotropin‐releasing hormone. SARS‐CoV‐2 infection may also dysregulate the CNS neurotransmission, leading to neurological complications observed in severe cases of COVID‐19. It can be concluded that the neurological manifestations of COVID‐19 may be partially associated with changes in brain RAS components.
Identifying Neighborhoods with Cervical Cancer Disparities for Targeted Community Outreach and Engagement by an NCI-Designated Cancer Center: A Geospatial Approach
Authors: Lee Ming S. , Elliott Nancy S. , Bethel Valerie D. , Balise Raymond R. , Kobetz Erin N.
Published: August 2023

Background:

Cervical cancer disparities exist in the United States with the highest incidence in Hispanic women and the highest mortality in Black women. Effective control of cervical cancer in the population requires targeted interventions tailored to community composition in terms of race, ethnicity, and social determinants of health (SDOH).

Methods:

Using cancer registry and SDOH data, geospatial hot spot analyses were carried out to identify statistically significant neighborhood clusters with high numbers of cervical cancer cases within the catchment area of an NCI-Designated Cancer Center. The locations, racial and ethnic composition, and SDOH resources of these hot spots were used by the center's community outreach and engagement office to deploy mobile screening units (MSU) for intervention in communities with women facing heightened risk for cervical cancer.

Results:

Neighborhood hot spots with high numbers of cervical cancer cases in south Florida largely overlap with locations of poverty. Cervical cancer hot spots are associated with a high percentage of Hispanic cases and low SDOH status, including low income, housing tenure, and education attainment.

Conclusions:

A geospatially referenced cancer surveillance platform integrating cancer registry, SDOH, and cervical screening data can effectively identify targets for cervical cancer intervention in neighborhoods experiencing disparities.

Impact:

Guided with a data-driven surveillance system, MSUs proactively bringing prevention education and cervical screening to communities with more unscreened, at-risk women are an effective means for addressing disparities associated with cervical cancer control.
Data from The MDM2–p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced or Metastatic Solid Tumors: Results of a Phase Ia, First-in-Human, Dose-Escalation Study
Authors: LoRusso Patricia , Yamamoto Noboru , Patel Manish R. , Laurie Scott A. , Bauer Todd M. , Geng Junxian , Davenport Teffany , Teufel Michael , Li Jian , Lahmar Mehdi , Gounder Mrinal M.
Published: August 2023

Abstract
Brigimadlin (BI 907828) is an oral MDM2–p53 antagonist that has shown encouraging antitumor activity in vivo. We present phase Ia results from an open-label, first-in-human, phase Ia/Ib study investigating brigimadlin in patients with advanced solid tumors (NCT03449381). Fifty-four patients received escalating doses of brigimadlin on day 1 of 21-day cycles (D1q3w) or days 1 and 8 of 28-day cycles (D1D8q4w). Based on dose-limiting toxicities during cycle 1, the maximum tolerated dose was selected as 60 mg for D1q3w and 45 mg for D1D8q4w. The most common treatment-related adverse events (TRAE) were nausea (74.1%) and vomiting (51.9%); the most common grade ≥3 TRAEs were thrombocytopenia (25.9%) and neutropenia (24.1%). As evidence of target engagement, time- and dose-dependent increases in growth differentiation factor 15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in patients with well-differentiated or dedifferentiated liposarcoma (100% and 75% disease control rates, respectively).
Significance:
We report phase Ia data indicating that the oral MDM2–p53 antagonist brigimadlin has a manageable safety profile and shows encouraging signs of efficacy in patients with solid tumors, particularly those with MDM2-amplified advanced/metastatic well-differentiated or dedifferentiated liposarcoma. Further clinical investigation of brigimadlin is ongoing.

See related commentary by Italiano, p. 1765.

This article is highlighted in the In This Issue feature, p. 1749
Data from Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia
Authors: Kan Winnie L. , Dhagat Urmi , Kaufmann Kerstin B. , Hercus Timothy R. , Nero Tracy L. , Zeng Andy G.X. , Toubia John , Barry Emma F. , Broughton Sophie E. , Gomez Guillermo A. , Benard Brooks A. , Dottore Mara , Cheung Tung Shing Karen S. , Boutzen Héléna , Samaraweera Saumya E. , Simpson Kaylene J. , Jin Liqing , Goodall Gregory J. , Begley C. Glenn , Thomas Daniel , Ekert Paul G. , Tvorogov Denis , D'Andrea Richard J. , Dick John E. , Parker Michael W. , Lopez Angel F.
Published: August 2023

Abstract
Leukemia stem cells (LSC) possess distinct self-renewal and arrested differentiation properties that are responsible for disease emergence, therapy failure, and recurrence in acute myeloid leukemia (AML). Despite AML displaying extensive biological and clinical heterogeneity, LSC with high interleukin-3 receptor (IL3R) levels are a constant yet puzzling feature, as this receptor lacks tyrosine kinase activity. Here, we show that the heterodimeric IL3Rα/βc receptor assembles into hexamers and dodecamers through a unique interface in the 3D structure, where high IL3Rα/βc ratios bias hexamer formation. Importantly, receptor stoichiometry is clinically relevant as it varies across the individual cells in the AML hierarchy, in which high IL3Rα/βc ratios in LSCs drive hexamer-mediated stemness programs and poor patient survival, while low ratios mediate differentiation. Our study establishes a new paradigm in which alternative cytokine receptor stoichiometries differentially regulate cell fate, a signaling mechanism that may be generalizable to other transformed cellular hierarchies and of potential therapeutic significance.
Significance:
Stemness is a hallmark of many cancers and is largely responsible for disease emergence, progression, and relapse. Our finding that clinically significant stemness programs in AML are directly regulated by different stoichiometries of cytokine receptors represents a hitherto unexplained mechanism underlying cell-fate decisions in cancer stem cell hierarchies.

This article is highlighted in the In This Issue feature, p. 1749
Keeping IPMNs in Check: A Novel Role for the Transcription Factor NKX6-2 in Preserving an Indolent Cell Identity in Pancreatic Cystic Lesions
Authors: Ben-Shmuel Aviad , Scherz-Shouval Ruth
Published: August 2023

In this issue of Cancer Discovery, Sans and colleagues identify the transcription factor NKX6-2 as a principal element in maintaining the low-grade gastric cell phenotype of intraductal papillary mucinous neoplasms (IPMN) in the pancreas. Their discoveries in patient cohorts and dissection in animal models provide a novel molecular understanding underpinning IPMN differentiation, with implications for risk stratification and therapeutic intervention in pancreatic cancer.

See related article by Sans et al., p. 1844 (7).
Computational Quantification of Cancer Immunoediting
Authors: Liu Kun , He Shengyuan , Sun Shangqin , Zhang Xinxin , He Yanzhen , Quan Fei , Pang Bo , Xiao Yun
Published: August 2023

The remarkable success of cancer immunotherapy has revolutionized cancer treatment, emphasizing the importance of tumor–immune interactions in cancer evolution and treatment. Cancer immunoediting describes the dual effect of tumor–immune interactions: inhibiting tumor growth by destroying tumor cells and facilitating tumor escape by shaping tumor immunogenicity. To better understand tumor–immune interactions, it is critical to develop computational methods to measure the extent of cancer immunoediting. In this review, we provide a comprehensive overview of the computational methods for quantifying cancer immunoediting. We focus on describing the basic ideas, computational processes, advantages, limitations, and influential factors. We also summarize recent advances in quantifying cancer immunoediting studies and highlight future research directions. As the methods for quantifying cancer immunoediting are continuously improved, future research will further help define the role of immunity in tumorigenesis and hopefully provide a basis for the design of new personalized cancer immunotherapy strategies.
Ncoa2 Promotes CD8+ T cell–Mediated Antitumor Immunity by Stimulating T-cell Activation via Upregulation of PGC-1α Critical for Mitochondrial Function
Authors: Zhong Xiancai , Wu Hongmin , Ouyang Ching , Zhang Wencan , Shi Yun , Wang Yi-Chang , Ann David K. , Gwack Yousang , Shang Weirong , Sun Zuoming
Published: August 2023

Nuclear receptor coactivator 2 (Ncoa2) is a member of the Ncoa family of coactivators, and we previously showed that Ncoa2 regulates the differentiation of induced regulatory T cells. However, it remains unknown if Ncoa2 plays a role in CD8+ T-cell function. Here, we show that Ncoa2 promotes CD8+ T cell–mediated immune responses against tumors by stimulating T-cell activation via upregulating PGC-1α expression to enhance mitochondrial function. Mice deficient in Ncoa2 in T cells (Ncoa2fl/fl/CD4Cre) displayed defective immune responses against implanted MC38 tumors, which associated with significantly reduced tumor-infiltrating CD8+ T cells and decreased IFNγ production. Consistently, CD8+ T cells from Ncoa2fl/fl/CD4Cre mice failed to reject tumors after adoptive transfer into Rag1−/− mice. Further, in response to TCR stimulation, Ncoa2fl/fl/CD4Cre CD8+ T cells failed to increase mitochondrial mass, showed impaired oxidative phosphorylation, and had lower expression of PGC-1α, a master regulator of mitochondrial biogenesis and function. Mechanically, T-cell activation–induced phosphorylation of CREB triggered the recruitment of Ncoa2 to bind to enhancers, thus, stimulating PGC-1α expression. Forced expression of PGC-1α in Ncoa2fl/fl/CD4Cre CD8+ T cells restored mitochondrial function, T-cell activation, IFNγ production, and antitumor immunity. This work informs the development of Ncoa2-based therapies that modulate CD8+ T cell–mediated antitumor immune responses.