bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of acupuncture for postpartum hypogalactia: protocol for a systematic review and meta-analysis
Authors: Bao Qiong-Nan , Zhou Yuan-Fang , Yin Zi-Han , Bi Qiu , Zhao Hong-Bin , Zhang Zhen-Yong , Liang Fan-Rong
Published: March 2023

Introduction

Breast milk is recognised as the best natural food for neonates, but many women experience postpartum hypogalactia (PH). Randomised trials have found that acupuncture exert therapeutic effect on women with PH. However, systematic reviews on the efficacy and safety of acupuncture are still lacking; therefore, this systematic review aims to evaluate the efficacy and safety of acupuncture for PH.

Methods and analysis

Six English databases (PubMed, Cochrane Library, EMBASE, EBSCO, Scopus, and Web of Science) and four Chinese databases (China National Knowledge Infrastructure, Wan-Fang, Chinese Biomedical Literature and Chinese Scientific Journal) will be systematically searched from their establishment to 1 September 2022. Randomised controlled trials of the efficacy of acupuncture for PH will be reviewed. The study selection, data extraction and research quality evaluation will be conducted independently by two reviewers. The primary outcome is the change in serum prolactin level from baseline to the end of treatment. Secondary results include milk secretion volume, total effectiveness rate, degree of mammary fullness, rate of exclusive breast feeding, and adverse events. A meta-analysis will be performed using RevMan V.5.4 statistical software. Otherwise, a descriptive analysis will be conducted. The risk of bias will be assessed using the revised Cochrane risk-of-bias tool.

Ethics and dissemination

This systematic review protocol does not require ethical approval because it does not include private information/data of the participants. This article will be published in peer-reviewed journals.

PROSPERO registration number

CRD42022351849.
A prospective, comparative study of clinical outcomes following clinic-based versus self-use of medical abortion
Authors: Kapp Nathalie , Mao Bunsoth , Menzel Jamie , Eckersberger Elisabeth , Saphonn Vonthanak , Rathavy Tung , Pearson Erin
Published: March 2023

Background

To determine whether clinical outcomes differ among women accessing a combined medical abortion regimen from a health clinic when compared with those accessing it from a pharmacy.

Methods

We conducted a multicentre, prospective, comparative, non-inferiority study of participants aged ≥15 years seeking medical abortion from five clinics and five adjacent pharmacy clusters in three provinces of Cambodia. Participants were recruited in-person at the point of purchase (clinic or pharmacy). Follow-up for self-reported pill use, acceptability, and clinical outcomes occurred by telephone at days 10 and 30 after mifepristone administration.

Results

Over 10 months, we enrolled 2083 women with 1847 providing outcome data: 937 from clinics and 910 from pharmacies. Most were early in their pregnancy (mean gestational age of 6.3 and 6.1 weeks, respectively) and almost all took the pills correctly (98% and 96%,). Additional treatment needed to complete the abortion was non-inferior for the pharmacy group (9.3%) compared with the clinic group (12.7%). More from the clinic group received additional care from a provider, such as antibiotics or diagnostics tests, than those from the pharmacy group (11.5% and 3.2%,), and one ectopic pregnancy (pharmacy group) was successfully treated. Most said they felt prepared for what happened after taking the pills (90.9% and 81.3%, respectively, p=0.273).

Conclusions

Self-use of a combined medical abortion product resulted in comparable clinical outcomes as use following a clinical visit, consistent with existing literature on its safety and efficacy. Registration and availability of medical abortion as an over-the-counter product would likely increase women’s access to safe abortion.
Dihydroartemisinin Affects STAT3/DDA1 Signaling Pathway and Reverses Breast Cancer Resistance to Cisplatin
Authors: Zhang Jing , Li Yang , Wang Ji-Guo , Feng Jing-Yu , Huang Guo-Dong , Luo Chang-Guo
Published: March 2023

Dihydroartemisinin (DHA) has anticancer effects on multiple tumors, including those associated with breast cancer. This study aimed to investigate the mechanism causing DHA-reversing cisplatin (DDP) resistance in breast cancer. Relative mRNA and protein levels were tested using a qRT-PCR and western blot assay. Cell proliferation, viability, and apoptosis were evaluated using colony formation, MTT, and flow cytometry assays, respectively. Interaction of STAT3 and DDA1 was measured via a dual-luciferase reporter assay. The results showed that DDA1 and p-STAT3 levels were dramatically elevated in DDP-resistant cells. DHA treatment repressed proliferation and induced apoptosis of DDP-resistant cells by suppressing STAT3 phosphorylation; the inhibition ability was positively proportional to the DHA concentration. DDA1 knockdown inhibited cyclin expression, promoted G0/G1 phase arrest, restrained cell proliferation, and induced apoptosis of DDP-resistant cells. Furthermore, knockdown of STAT3 restrained proliferation and induced apoptosis and G0/G1 cell cycle arrest of DDP-resistant cells by targeting DDA1. DHA could restrain tumor proliferation of breast cancer via enhancing drug sensitivity of DDP-resistant cells through the STAT3/DDA1 signaling pathway.
Effects of Resveratrol on Pulmonary Fibrosis via TGF-β/Smad/ERK Signaling Pathway
Authors: Liu Lei , Liu Bin , Li Liang , Zhou Xiangdong , Li Qi
Published: March 2023

Pulmonary fibrosis (PF) is a progressive pulmonary disease with no effective treatment and high mortality. Resveratrol has shown promising benefits in the treatment of PF. However, the probable efficacy and underlying mechanism of resveratrol in PF treatment remain unclear. This study investigates the intervention effects and potential mechanisms underpinning the treatment of PF with resveratrol. The histopathological analysis of lung tissues in PF rats showed that resveratrol improved collagen deposition and reduced inflammation. Resveratrol decreased the levels of collagen, glutathione, superoxide dismutase, myeloperoxidase, and hydroxyproline, lowered total anti-oxidant capacity, and suppressed the migration of TGF-[Formula: see text]1 and LPS-induced 3T6 fibroblasts. With resveratrol intervention, the protein and RNA expressions of TGF-[Formula: see text]1, a-SMA, Smad3/4, p-Smad3/4, CTGF, and p-ERK1/2 were markedly downregulated. Similarly, the protein and RNA expression levels of Col-1 and Col-3 were significantly downregulated. However, Smad7 and ERK1/2 were evidently upregulated. The protein and mRNA expression levels of TGF-[Formula: see text], Smad, and p-ERK correlated positively with the lung index, while the protein and mRNA expression levels of ERK correlated negatively with the lung index. These results reveal that resveratrol may have therapeutic effects on PF by reducing collagen deposition, oxidation, and inflammation. The mechanism is associated with the regulation of the TGF-[Formula: see text]/Smad/ERK signaling pathway.
Split Casimir operator for simple Lie algebras in the cube of ad-representation and Vogel parameters
Authors: Isaev A. P. , Krivonos S. O. , Provorov A. A.
Published: March 2023

In this paper, we constructed characteristic identities for the 3-split (polarized) Casimir operators of simple Lie algebras in the adjoint representations [Formula: see text] and deduced a certain class of subrepresentations in [Formula: see text]. The projectors onto invariant subspaces for these subrepresentations were directly constructed from the characteristic identities for the 3-split Casimir operators. For all simple Lie algebras, universal expressions for the traces of higher powers of the 3-split Casimir operators were found and dimensions of the subrepresentations in [Formula: see text] were calculated. All our formulas are in agreement with the universal description of (irreducible) subrepresentations in [Formula: see text] for simple Lie algebras in terms of the Vogel parameters.
EXISTENCE AND STABILITY RESULTS FOR COUPLED SYSTEM OF FRACTIONAL DIFFERENTIAL EQUATIONS INVOLVING AB-CAPUTO DERIVATIVE
Authors: MEHMOOD NAYYAR , ABBAS AHSAN , AKGÜL ALI , ABDELJAWAD THABET , ALQUDAH MANAR A.
Published: March 2023

In this paper, we use Krasnoselskii’s fixed point theorem to find existence results for the solution of the following nonlinear fractional differential equations (FDEs) for a coupled system involving AB-Caputo fractional derivative [Formula: see text] with boundary conditions [Formula: see text] We discuss uniqueness with the help of the Banach contraction principle. The criteria for Hyers–Ulam stability of given AB-Caputo fractional-coupled boundary value problem (BVP) is also discussed. Some examples are provided to validate our results. In Example 1, we find a unique and stable solution of AB-Caputo fractional-coupled BVP. In Example 2, the analysis of approximate and exact solutions with errors of nonlinear integral equations is elaborated with graphs.
Internal and External Cancellation Conditions for Free Vibration of Damped Simple Beams Traversed by Successive Moving Loads
Authors: Wang Z. L. , Tan Z. X. , Chen L. , Yang D. S. , Xu H. , Shi K. , Yang Y. B.
Published: March 2023

In this paper, the internal and external cancellation phenomena for damped beams subjected to multi-moving loads are investigated in detail. To start, the theory for the vibration of a simply supported beam is revisited by including the effect of damping. For the first time, a simple expression is derived for the free vibration of the damped beam under multi-moving loads. Based on the concept of local minimum, two cancellation conditions are identified. One is the internal cancellation, which relates to the inherent property of the beam and is conventionally known. The other is the newly formulated external cancellation that relates to the number and spacing of moving loads. For comparison, both the resonant condition and the optimal criterion for span length of the bridge are also briefed. By comparing with the classical solution, the present simple expression for the free vibration of the beam is firstly validated. Then the factors affecting the cancellation are investigated against various load cases and damping levels. The results show that external cancellation occurs more frequently due to the increase in the number and spacing of the moving loads. The damping of the beam has a leaking effect on cancellation, in that nonzero vibration may occur, but it is also quickly damped out by damping itself.
Historical Review on Resonance and Cancellation of Simply Supported Beams Subjected to Moving Train Loads: From Theory to Practice
Authors: Yang Y. B. , Yau J. D. , Urushdaze S. , Lee T. Y.
Published: March 2023

The advent of railways and especially highspeed railways marks great strides in human transportation history. To guarantee exclusive right-of-way, highspeed railways are often built on equal simply supported beams resting on piers. In this paper, a historical review will be given of the resonance and cancellation phenomena observed for simply supported beams traveled by a set of moving loads, as they are typical of highspeed railways. The phenomenon of resonance was observed by early investigators including Timoshenko, Bolotin, Frýba, Matsuura, etc. However, the phenomenon of cancellation was noted lately in 1997 by Yang et al. By letting the conditions of resonance and cancellation coincident, they proposed the optimal span length for suppressing the resonance of simple beams, which is equal to 1.5 times the car length. This 1.5 times rule has been verified and adopted in the design of some highspeed railways. In this article, the theoretical solution for the problem will be revisited for unveiling the key parameters such as the resonance speed (in temporal domain) and resonance wavelength (in spatial domain). Then a rather in-depth review will be given of existing works on the resonance and cancellation of railway bridges from the waves perspective. Some new developments along these lines will also be identified.
Iron Oxide Nanoparticle Biosynthesis, Characterization, and Antimicrobial Activity Using Nigella sativa Seeds Extract
Authors: Mezher Thaer A. , Ali Abdullah M. , Abd Ahmed N.
Published: March 2023

In the most recent few years, there has been a significant uptick in curiosity regarding the process of manufacturing metal oxide nanoparticles by making use of the extract of various plant components. The generated iron oxide nanoparticles demonstrate validity for use in biomedical applications. In the work that we are presenting here, we use the extract of Nigella sativa seeds to carry out an environmentally friendly iron oxide nanoparticle synthesis (Fe2O3 NPs). Advanced diagnostic tools such as scanning electron microscopy (SEM), Fourier transform infrared (FTIR) analysis, X-ray diffraction (XRD) investigation, and others were utilized in order to perform structural characterization on the generated Fe2O3 NPs. According to the preliminary findings, the particles have a semispherical form with an average particle size that falls between 15[Formula: see text]nm and 20[Formula: see text]nm. Phytochemicals, particularly polyphenols, are extremely important contributors to the production of iron oxide nanoparticles. Since the findings of the antimicrobial investigation were highly encouraging, the antimicrobial activity of the iron oxide particles that were created was investigated to see if they might inhibit the growth of specific bacterial and fungal pathogens.
Shear-wave velocity estimation based on rock physics modelling of a limestone gas reservoir in the Pannonian Basin
Authors: Vukadin Domagoj
Published: March 2023

In the Pannonian Basin, especially in Croatia, there are a small number of wells for which acquired shear-wave (S-wave) velocities have been obtained. Often, quantitative interpretation relies only on compressional-wave (P-wave) velocity data, and S-wave velocity must be modelled. S-wave velocity estimation in combination with other petrophysical data is essential for detailed reservoir characterization. P- and S-wave velocities enable seismic modelling of different saturation states in a reservoir. This paper demonstrates a workflow for S-wave velocity estimation where S-wave velocity data are absent in the gas field and neighbouring fields with the same lithology, based on the Kuster–Toksöz and Xu–Payne models applied to the Pannonian Basin limestone reservoir. The results are calibrated with the P-wave velocity obtained from borehole data and the vertical seismic profile (VSP) S-wave interval velocity. Although rock physics models are idealized analogues of real rocks, a very good correlation was obtained between the modelled and measured P-wave velocity, as well as between the modelled S-wave velocity and the VSP interval velocity. The study also illustrates the problem of defining the pore aspect ratio in zones of increasing shale content. Due to the limited research on the limestones of the Pannonian Basin, these results enable a better understanding of the seismic parameters of the Pannonian Basin limestones. The results indicate that the proposed workflow gives an adequate estimation of S-wave velocities.
A Next Basket Recommendation Reality Check
Authors: Li Ming , Jullien Sami , Ariannezhad Mozhdeh , de Rijke Maarten
Published: March 2023

The goal of a next basket recommendation (NBR) system is to recommend items for the next basket for a user, based on the sequence of their prior baskets. We examine whether the performance gains of the NBR methods reported in the literature hold up under a fair and comprehensive comparison. To clarify the mixed picture that emerges from our comparison, we provide a novel angle on the evaluation of next basket recommendation (NBR) methods, centered on the distinction between repetition and exploration: the next basket is typically composed of previously consumed items (i.e., repeat items) and new items (i.e., explore items). We propose a set of metrics that measure the repetition/exploration ratio and performance of NBR models. Using these new metrics, we provide a second analysis of state-of-the-art NBR models. The results help to clarify the extent of the actual progress achieved by existing NBR methods as well as the underlying reasons for any improvements that we observe. Overall, our work sheds light on the evaluation problem of NBR, provides a new evaluation protocol, and yields useful insights for the design of models for this task.
Video Captioning by Learning from Global Sentence and Looking Ahead
Authors: Niu Tian-Zi , Chen Zhen-Duo , Luo Xin , Zhang Peng-Fei , Huang Zi , Xu Xin-Shun
Published: March 2023

Video captioning aims to automatically generate natural language sentences describing the content of a video. Although encoder-decoder-based models have achieved promising progress, it is still very challenging to effectively model the linguistic behavior of humans in generating video captions. In this paper, we propose a novel video captioning model by learning from
gLobal sEntence and looking AheaD, LEAD
for short. Specifically, LEAD consists of two modules: a
Vision Module (VM)
and a
Language Module (LM)
. Thereinto, VM is a novel attention network, which can map visual features to high-level language space and model entire sentences explicitly. LM can not only effectively make use of the information of the previous sequence when generating the current word, but also have a look at the future word. Therefore, based on VM and LM, LEAD can obtain global sentence information and future word information to make video captioning more like a fill-in-the-blank task than a word-by-word sentence generation. In addition, we also propose an autonomous strategy and a multi-stage training scheme to optimize the model, which can mitigate the problem of information leakage. Extensive experiments show that LEAD outperforms some state-of-the-art methods on MSR-VTT, MSVD, and VATEX, demonstrating the effectiveness of the proposed approach in video captioning. In addition, we release the code of our proposed model to be publicly available.

1
Identification and Fast Measurement Method of Open-circuit Voltage
Authors: Lin Peng , Jin Peng , Zhang Hongyin
Published: March 2023

Accurate measurement of the open-circuit voltage (OCV) promotes state of charge (SOC) accuracy. In this study, three transformation methods are employed to make the OCV identifiable, and factors affecting the accuracy of OCV identification are investigated. Furthermore, a fast OCV measurement method is proposed. The results show that the forward difference transformation and the adaptive differential evolution algorithm are more suitable for OCV identification. The accuracy of OCV identification is affected by pulse characteristics, sampling frequency, C-rate, and resting time between pulses. Positive-negative (PN) pulses of equal amplitude are more suitable for OCV identification than hybrid pulse power characteristics. A method for fast OCV measurement is developed based on the relationship between the identification error of the OCV and the number of PN pulses. A total of 57 PN pulses with an amplitude of 2 C are used to realize accurate OCV identification at various charge/discharge states, C-rate, and SOC, with an average error of −0.03% (about 1 mV). The proposed method only needs to obtain the battery voltage and current to achieve a fast measurement of OCV, which also serves as a foundation for an accurate estimation of the battery state.
Application of problem-based self-designed experiments in physiology laboratory teaching
Authors: Ding Yue-Min , Shen Wei-Da , Yang Jing , He Yan , Wang Lin-Lin , Zhang Xiong
Published: March 2023

This study involved a teaching reform based on problem-based self-designed experiments in a physiology laboratory course. Students in the test group were required to conduct self-designed experiments based on questions for each experimental theme, in addition to completing the specified experimental items. The results showed that the teaching reform promoted the students’ self-directed learning and problem-solving ability, stimulated their enthusiasm for scientific research, and was conducive to cultivating innovative medical talents.
A novel mouse model for an inducible gene modification in the renal thick ascending limb
Authors: Bourqui Laurent , Winter Denise V. , Odermatt Alex , Loffing-Cueni Dominique , Loffing Johannes
Published: March 2023

The renal thick ascending limb (TAL) is critical for renal control of fluid and ion homeostasis. However, the underlying molecular mechanisms that regulate TAL function are incompletely understood. This study describes a novel transgenic mouse model (Slc12a1-creERT2) for inducible and highly efficient gene targeting in the TAL that promises to ease physiological studies on the functional role of candidate regulatory genes.
Assessment of Knowledge about Obstetric Danger Signs and Associated Factors among Pregnant Women in Debre Tabor Town, Northwest Ethiopia
Authors: Mihret Mestawut , Wondimu Hailegebriel
Published: March 2023

Background. World Health Organization estimates that 800 women die from pregnancy or childbirth-related complications around the world every day. With the assumption that “every pregnancy faces risk” women should be aware of the danger signs of obstetric complications during pregnancy, delivery, and postpartum. Indications on the prevalence of obstetric danger signs and risk factors were crucial in designing programs at different levels in reducing maternal morbidity and mortality. Objective. To assess the knowledge about obstetric danger signs and associated factors among pregnant women in Debre Tabor town, Northwest Ethiopia, 2021. Methods. A community-based cross-sectional study was conducted with 295 respondents to assess knowledge about obstetrical danger signs among pregnant women in Debre Tabor town from July to September 2021. Data were collected through self-administered questionnaires. Proportional followed by simple random sampling was used to select the study participants among the pregnant women in each of the six kebeles of the town. Adjusted odds ratios at 95% confidence interval and a value of

p
<
0.05

were used to identify the predictors. Results. From a total of 295 interviewed, 61% of them were poorly knowledgeable about obstetric danger signs, but 39% of them were knowledgeable. According to our study, maternal age less than or equal to 30 years (adjusted odds

ratio
=
5.44

; 95% confidence interval: 3.26,9.10), no formal education (adjusted odds

ratio
=
9.488

; 95% confidence interval: 4.73, 13.14), one-time gravidity (adjusted odds

ratio
=
7.81

; 95% confidence interval: 4.79, 9.19), and frequency of antenatal follow-up less than 4 times (adjusted odds

ratio
=
4.10

; 95% confidence interval: 1.88, 8.96) were factors which significantly associated with the poor knowledge of obstetric danger signs. Conclusion. As the knowledge of pregnant women towards obstetric danger signs was low, maternal age less than or equal to 30 years, no formal education, one-time gravidity, and less than 4 times the frequency of antenatal follow-up are associated factors for poor knowledge on obstetric danger signs.
Enhancing Distribution System Performance via Distributed Generation Placement and Reconfiguration Based on Improved Symbiotic Organisms Search
Authors: Huy Truong Hoang Bao
Published: March 2023

Minimal power loss is highly desired for an efficient and economical operation in distributed systems. This paper presents an improved symbiotic organisms search (ISOS) for system reconfiguration (SR) and distributed generation placement (SR-DGP) simultaneously. The proposed ISOS combined the simple quadratic interpolation (SQI) strategy into SOS to improve the search process. The ISOS was adopted to define the optimal system topology, location, and capacity of distributed generators (DGs) to minimize power losses. The proposed ISOS was evaluated on the 33-node and 69-node systems. The proposed ISOS successfully reduced the power losses by 73.1206% and 84.2861% for the 33-bus and 69-bus. Moreover, ISOS was also compared with other approaches, where ISOS obtained better results than other approaches for all test systems. Hence, ISOS showed its effectiveness in dealing with the SR-DGP problem.
Prognosis and Characterization of Microenvironment in Cervical Cancer Influenced by Fatty Acid Metabolism-Related Genes
Authors: Zhou Yanjun , Zhu Jiahao , Gu Mengxuan , Gu Ke
Published: March 2023

Increasing evidence suggests that diverse activation patterns of metabolic signalling pathways may lead to molecular diversity of cervical cancer (CC). But rare research focuses on the alternation of fatty acid metabolism (FAM) in CC. Therefore, we constructed and compared models based on the expression of FAM-related genes from the Cancer Genome Atlas by different machine learning algorithms. The most reliable model was built with 14 significant genes by LASSO-Cox regression, and the CC cohort was divided into low-/high-risk groups by the median of risk score. Then, a feasible nomogram was established and validated by C-index, calibration curve, net benefit, and decision curve analysis. Furthermore, the hub genes among differential expression genes were identified and the post-transcriptional and translational regulation networks were characterized. Moreover, the somatic mutation and copy number variation landscapes were depicted. Importantly, the specific mutation drivers and signatures of the FAM phenotypes were excavated. As a result, the high-risk samples were featured by activated de novo fatty acid synthesis, epithelial to mesenchymal transition, angiogenesis, and chronic inflammation response, which might be caused by mutations of oncogenic driver genes in RTK/RAS, PI3K, and NOTCH signalling pathways. Besides the hyperactivity of cytidine deaminase and deficiency of mismatch repair, the mutations of POLE might be partially responsible for the mutations in the high-risk group. Next, the antigenome including the neoantigen and cancer germline antigens was estimated. The decreasing expression of a series of cancer germline antigens was identified to be related to reduction of CD8 T cell infiltration in the high-risk group. Then, the comprehensive evaluation of connotations between the tumour microenvironment and FAM phenotypes demonstrated that the increasing risk score was related to the suppressive immune microenvironment. Finally, the prediction of therapy targets revealed that the patients with high risk might be sensitive to the RAF inhibitor AZ628. Our findings provide a novel insight for personalized treatment in CC.
Correlation between SMADs and Colorectal Cancer Expression, Prognosis, and Immune Infiltrates
Authors: Ding Ning , Luo Hongbiao , Zhang Tao , Peng Tianshu , Yao Yanru , He Yongheng
Published: March 2023

Background. In recent years, the incidence and mortality of colorectal cancer (CRC) are increasing, and the 5-year survival rate of advanced metastatic CRC is poor. Small mothers against decapentaplegic (SMAD) superfamily are intracellular signal transduction proteins associated with the development and prognosis of a variety of tumors. At present, no study has systematically analysed the relationship between SMADs and CRC. Methods. Here, R3.6.3 was used to analyse the expression of SMADs in pan-cancer and CRC. Protein expression of SMADs were analysed by Human Protein Atlas (HPA). Gene expression profiling interactive analysis (GEPIA) was used to evaluate the correlation between SMADs and tumor stage in CRC. The effect of R language and GEPIA on prognosis was analysed. Mutation rates of SMADs in CRC were determined by cBioPortal, and potentially related genes were predicted using GeneMANIA. R analysis was used to correlate immune cell infiltration in CRC. Results. Both SMAD1 and SMAD2 were found to be weakly expressed in CRC and correlated with the immune invasion level. SMAD1 was correlated with patient prognosis, and SMAD2 was correlated with tumor stage. SMAD3, SMAD4, and SMAD7 were all expressed at low levels in CRC and associated with a variety of immune cells. SMAD3 and SMAD4 proteins were also expressed at low levels, and SMAD4 had the highest mutation rate. SMAD5 and SMAD6 were overexpressed in CRC, and SMAD6 was also associated with patient overall survival (OS) and CD8+ T cells, macrophages, and neutrophils. Conclusions. Our results reveal innovative and strong evidence that SMADs can be used as biomarkers for the treatment and prognosis of CRC.
Identification and Validation of a m5C RNA Modification-Related Gene Signature for Predicting Prognosis and Immunotherapeutic Efficiency of Gastric Cancer
Authors: Song Li , Wang Shouguo , Li Qiankun , Lu Yao , Yang Rungong , Feng Xianqi
Published: March 2023

Background. 5-methylcytosine (m5C) is a major site of RNA methylation modification, and its abnormal modification is associated with the development of gastric cancer (GC). This study aimed to explore the value of m5C-related genes on the prognosis of GC patients through bioinformatics. Methods. First, m5C-related genes were obtained by nonnegative matrix factorization (NMF) analysis and differentially expressed analysis. The m5C-related model was established and validated in distinct datasets. Moreover, a differential analysis of risk scores according to clinical characteristics was performed. The enrichment analysis was carried out to elucidate the underlying molecular mechanisms. Furthermore, we calculated the differences in immunotherapy and chemotherapy sensitivity between the high- and low-risk groups. Finally, we validated the expression levels of identified model genes by quantitative real-time polymerase chain reaction (qRT-PCR). Results. A total of five m5C-related subtypes of GC patients in the TCGA database were identified. The m5C-related model was constructed based on APOD, ASCL2, MFAP2, and CREB3L3. Functional enrichment revealed that the m5C-related model might involve in the cell cycle and cell adhesion. Moreover, the high-risk group had a higher abundance of stromal and immune cells in malignant tumor tissues and a lower tumor purity than the low-risk group. The patients in the high-risk group were more sensitive to chemotherapy and had better sensitivity to CTLA4 inhibitors. Furthermore, qRT-PCR results from our specimens verified an over-expression of ASCL2, CREB3L3, and MFAP2 in the cancer cells compared with the normal cells. Conclusion. A total of five GC subtypes were identified, and a risk model was constructed based on m5C modification.
ASS1-Mediated Reductive Carboxylation of Cytosolic Glutamine Confers Ferroptosis Resistance in Cancer Cells
Authors: Hu Qiangsheng , Dai Jie , Zhang Zheng , Yu Huansha , Zhang Jing , Zhu Xinsheng , Qin Yi , Zhang Lele , Zhang Peng
Published: March 2023

Induction of ferroptosis, a recently defined form of nonapoptotic cell death caused by iron-dependent lipid peroxidation, has emerged as an anticancer strategy. Erastin is a ferroptosis activator that promotes cell death that not only depends on the depletion of cellular cysteine but also relies on mitochondrial oxidative metabolism of glutamine. Here, we demonstrate that ASS1, a key enzyme involved in the urea cycle, plays a crucial role in ferroptosis resistance. Loss of ASS1 increased the sensitivity of non–small cell lung cancer (NSCLC) cells to erastin in vitro and decreased tumor growth in vivo. Metabolomics analysis with stable isotope-labeled glutamine showed that ASS1 promotes reductive carboxylation of cytosolic glutamine and compromises the oxidative tricarboxylic acid cycle from glutamine anaplerosis, reducing mitochondrial-derived lipid reactive oxygen species. Moreover, transcriptome sequencing showed that ASS1 activates the mTORC1–SREBP1–SCD5 axis to promote de novo monounsaturated fatty acid synthesis by using acetyl-CoA derived from the glutamine reductive pathway. Treating ASS1-deficient NSCLC cells with erastin combined with arginine deprivation significantly enhanced cell death compared with either treatment alone. Collectively, these results reveal a previously unknown regulatory role of ASS1 in ferroptosis resistance and provide a potential therapeutic target for ASS1-deficient NSCLC.

Significance:

ASS1 promotes reductive carboxylation of glutamine and confers ferroptosis resistance, providing multiple treatment options for ASS1-deficient non–small cell lung cancer.
The Oncolytic Adenovirus XVir-N-31 Joins Forces with CDK4/6 Inhibition Augmenting Innate and Adaptive Antitumor Immunity in Ewing Sarcoma
Authors: Schober Sebastian Johannes , Schoening Caroline , Eck Jennifer , Middendorf Charlotte , Lutsch Julia , Knoch Pia , von Ofen Anna Josefine , Gassmann Hendrik , Thiede Melanie , Hauer Julia , Kolk Andreas , Mantwill Klaus , Gschwend Jürgen E. , Burdach Stefan E.G. , Nawroth Roman , Thiel Uwe , Holm Per Sonne
Published: March 2023

Purpose:

Ewing sarcoma (EwS) is a highly malignant pediatric tumor characterized by a non-T-cell-inflamed immune-evasive phenotype. When relapsed or metastasized, survival is poor, emphasizing the need for novel treatment strategies. Here, we analyze the novel combination approach using the YB-1-driven oncolytic adenovirus XVir-N-31 and CDK4/6 inhibition to augment EwS immunogenicity.

Experimental Design:

In vitro, viral toxicity, replication, and immunogenicity were studied in several EwS cell lines. In vivo tumor xenograft models with transient humanization were applied to evaluate tumor control, viral replication, immunogenicity, and dynamics of innate as well as human T cells after treatment with XVir-N-31 combined with CDK4/6 inhibition. Furthermore, immunologic features of dendritic cell maturation and T-cell-stimulating capacities were assessed.

Results:

The combination approach significantly increased viral replication and oncolysis in vitro, induced HLA-I upregulation, and IFNγ-induced protein 10 expression and enhanced maturation of monocytic dendritic cells with superior capacities to stimulate tumor antigen-specific T cells. These findings were confirmed in vivo showing tumor infiltration by (i) monocytes with antigen-presenting capacities and M1 macrophage marker genes, (ii) TReg suppression in spite of adenovirus infection, (iii) superior engraftment, and (iv) tumor infiltration by human T cells. Consequently, survival was improved over controls with signs of an abscopal effect after combination treatment.

Conclusions:

The joint forces of the YB-1-driven oncolytic adenovirus XVir-N-31 and CDK4/6 inhibition induce therapeutically relevant local and systemic antitumor effects. Innate as well as adaptive immunity against EwS is boosted in this preclinical setting, pointing toward high therapeutic potential in the clinic.
Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riyue , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J.
Published: March 2023

Purpose:

To assess whether MUC1 peptide vaccine produces an immune response and prevents subsequent colon adenoma formation.

Patients and Methods:

Multicenter, double-blind, placebo-controlled randomized trial in individuals age 40 to 70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0.

Results:

Fifty-three participants received the MUC1 vaccine and 50 placebo. Thirteen of 52 (25%) MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range, 2.9–17.3) at week 12 versus 0/50 placebo recipients (one-sided Fisher exact P < 0.0001). Of 13 responders at week 12, 11 (84.6%) responded to a booster injection at week 52 with a ≥2-fold increase in MUC1 IgG measured at week 55. Recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group versus 27 of 48 (56.3%) in the MUC1 group [adjusted relative risk (aRR), 0.83; 95% confidence interval (CI), 0.60–1.14; P = 0.25]. Adenoma recurrence occurred in 3/11 (27.3%) immune responders at week 12 and week 55 (aRR, 0.41; 95% CI, 0.15–1.11; P = 0.08 compared with placebo). There was no difference in serious adverse events.

Conclusions:

An immune response was observed only in vaccine recipients. Adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence compared with placebo was observed in participants who had an immune response at week 12 and with the booster injection.
Combinatorial BCL2 Family Expression in Acute Myeloid Leukemia Stem Cells Predicts Clinical Response to Azacitidine/Venetoclax
Authors: Waclawiczek Alexander , Leppä Aino-Maija , Renders Simon , Stumpf Karolin , Reyneri Cecilia , Betz Barbara , Janssen Maike , Shahswar Rabia , Donato Elisa , Karpova Darja , Thiel Vera , Unglaub Julia M. , Grabowski Susanna , Gryzik Stefanie , Vierbaum Lisa , Schlenk Richard F. , Röllig Christoph , Hundemer Michael , Pabst Caroline , Heuser Michael , Raffel Simon , Müller-Tidow Carsten , Sauer Tim , Trumpp Andreas
Published: March 2023

The BCL2 inhibitor venetoclax (VEN) in combination with azacitidine (5-AZA) is currently transforming acute myeloid leukemia (AML) therapy. However, there is a lack of clinically relevant biomarkers that predict response to 5-AZA/VEN. Here, we integrated transcriptomic, proteomic, functional, and clinical data to identify predictors of 5-AZA/VEN response. Although cultured monocytic AML cells displayed upfront resistance, monocytic differentiation was not clinically predictive in our patient cohort. We identified leukemic stem cells (LSC) as primary targets of 5-AZA/VEN whose elimination determined the therapy outcome. LSCs of 5-AZA/VEN-refractory patients displayed perturbed apoptotic dependencies. We developed and validated a flow cytometry-based “Mediators of apoptosis combinatorial score” (MAC-Score) linking the ratio of protein expression of BCL2, BCL-xL, and MCL1 in LSCs. MAC scoring predicts initial response with a positive predictive value of more than 97% associated with increased event-free survival. In summary, combinatorial levels of BCL2 family members in AML-LSCs are a key denominator of response, and MAC scoring reliably predicts patient response to 5-AZA/VEN.

Significance:

Venetoclax/azacitidine treatment has become an alternative to standard chemotherapy for patients with AML. However, prediction of response to treatment is hampered by the lack of clinically useful biomarkers. Here, we present easy-to-implement MAC scoring in LSCs as a novel strategy to predict treatment response and facilitate clinical decision-making.

This article is highlighted in the In This Issue feature, p. 1275
Increased Two-Hour Post-Load Plasma Glucose Fluctuation Corresponds with Worse Clinical Prognoses among Acute Ischemic Stroke Patients without a History of Diabetes Mellitus
Authors: Wang Rui , Fu Jin , Wang Anxin , Zhang Xiaoli , Wei Ke , Fu Xuelian , Wang Yifei , Hong Xiangxiang , Zhou Yinglian , Liu Yue , Huang Shan , Yue Hui , Bi Qianqian , Wang Yongpeng , Pan Yuesong , Wang Feng
Published: March 2023

Introduction: This study aimed to evaluate the relationship between 2-h post-load minus fasting plasma glucose (2hPG-FPG) and 1-year clinical outcomes, such as death, stroke recurrence, and modified Rankin Scale (mRS) ≥2–3 among acute ischemic stroke (AIS) patients without diabetes mellitus (DM) history. Methods: 1,214 AIS patients without DM history, obtained from ACROSS-China, were divided into 4 quartiles, based on 2hPG-FPG measurements obtained 14 days post-admission. Four models were constructed using multivariate Cox and logistic regression analyses, based on the inclusion of age, gender, trial of ORG 10172 in acute stroke treatment, NIH Stroke Scale scores (model 1), plus 10 other clinical parameters (model 2), plus newly diagnosed DM (NDDM) post-admission (model 3), plus 2hPG and FPG (model 4). Associations found from those 4 models between 2hPG-FPG and 1-year clinical outcomes were confirmed via stratification, multiplicative interaction, sensitivity, and restricted cubic spline analyses. Results: The highest quartile of 2hPG-FPG, after adjusting for variables, such as stroke severity (model 2), was independently associated with death, stroke recurrence, and mRS ≥2–3 (odds ratio [OR] = 3.95, 2.96, 4.15, and 4.83, respectively, all p < 0.0001). Increased 2hPG-FPG remained independently associated with mRS ≥2–3 in models 3–4, as well as increased mRS ≥2 under stratification analyses among both non-NDDM and NDDM patients. Conclusion: 2hPG-FPG is a relatively specific indicator of poorer 1-year clinical prognoses among AIS patients, independent of NDDM, 2hPG, and FPG post-hospital admission. Therefore, the oral glucose tolerance test could be a useful approach for detecting a higher likelihood for developing poorer prognoses among patients without DM history.
COVID-19 Infection in Hidradenitis Suppurativa Patients: A Retrospective Study
Authors: De Devea R. , Rick Jonathan W. , Shih Terri , Hsiao Jennifer L. , Hamzavi Iltefat , Shi Vivian Y.
Published: March 2023

Introduction: Hidradenitis suppurativa (HS) is associated with comorbidities that are risk factors for severe COVID-19 infection. We evaluated demographics and COVID-19 outcomes in HS patients. Methods: HS patients with COVID-19 (HS+/COVID+) and a randomized age-, race-, and sex-matched control population of patients without HS with COVID-19 (HS−/COVID+) were selected through a retrospective chart review. Data were collected on demographics, medications, comorbidities, vaccination status, and COVID-19 treatment/outcomes. Fisher’s exact test was used to analyze the relationship between risk factors and COVID-19 outcomes. A p value of <0.05 was considered statistically significant. Results: There were 58 HS+/COVID+ patients, primarily African American (83%, n = 48) and female (88%, n = 51). Compared to HS+/COVID+ patients, HS−/COVID+ patients were significantly more likely to have cardiovascular disease (51% vs. 24%; p = 0.0029) and be pregnant (23% vs. 4%; p = 0.0093). HS+/COVID+ and HS−/COVID+ patients did not vary significantly in vaccination rate at time of COVID-19 diagnosis (6% vs. 5%; p = 0.78). HS−/COVID+ patients were significantly more likely to have COVID-19 complications (35% vs. 7%; p = 0.001) and receive COVID-19 treatment (37% vs. 7%; p = 0.0001) when compared to HS+/COVID+ patients. Conclusion: Our findings support the growing evidence that having HS itself may not be a risk factor for severe COVID-19 outcomes.
Platelet-Derived MicroRNAs Regulate Cardiac Remodeling After Myocardial Ischemia
Authors: Schütte Jan Philipp , Manke Mailin-Christin , Hemmen Katherina , Münzer Patrick , Schörg Barbara F. , Ramos Gustavo Campos , Pogoda Michaela , Dicenta Valerie , Hoffmann Sabrina H.L. , Pinnecker Jürgen , Kollotzek Ferdinand , Zdanyte Monika , Mueller Karin A.L. , Singh Yogesh , Mack Andreas F. , Pichler Bernd , Lang Florian , Nieswandt Bernhard , Gawaz Meinrad , Heinze Katrin G. , Casadei Nicolas , Borst Oliver
Published: March 2023

Background:

Platelets can infiltrate ischemic myocardium and are increasingly recognized as critical regulators of inflammatory processes during myocardial ischemia and reperfusion (I/R). Platelets contain a broad repertoire of microRNAs (miRNAs), which, under certain conditions such as myocardial ischemia, may be transferred to surrounding cells or released into the microenvironment. Recent studies could demonstrate that platelets contribute substantially to the circulating miRNA pool holding the potential for so far undiscovered regulatory functions. The present study aimed to determine the role of platelet-derived miRNAs in myocardial injury and repair following myocardial I/R.

Methods:

In vivo model of myocardial I/R, multimodal in vivo and ex vivo imaging approaches (light-sheet fluorescence microscopy, positron emission tomography and magnetic resonance imaging, speckle-tracking echocardiography) of myocardial inflammation and remodeling, and next-generation deep sequencing analysis of platelet miRNA expression.

Results:

In mice with a megakaryocyte/platelet-specific knockout of pre-miRNA processing ribonuclease
Dicer
, the present study discloses a key role of platelet-derived miRNAs in the tightly regulated cellular processes orchestrating left ventricular remodeling after myocardial I/R following transient left coronary artery ligation. Disruption of the miRNA processing machinery in platelets by deletion of
Dicer
resulted in increased myocardial inflammation, impaired angiogenesis, and accelerated development of cardiac fibrosis, culminating in an increased infarct size by d7 that persisted through d28 of myocardial I/R. Worsened cardiac remodeling after myocardial infarction in mice with a platelet-specific
Dicer
deletion resulted in an increased fibrotic scar formation and distinguishably increased perfusion defect of the apical and anterolateral wall at day 28 post-myocardial infarction. Altogether, these observations culminated in an impaired left ventricular function and hampered long-term cardiac recovery after experimental myocardial infarction and reperfusion therapy. Treatment with the P2Y
12
(P2Y purinoceptor 12) antagonist ticagrelor completely reversed increased myocardial damage and adverse cardiac remodeling observed in

Dicer
Pf4∆/Pf4∆

mice.

Conclusions:

The present study discloses a critical role of platelet-derived miRNA in myocardial inflammation and structural remodeling processes following myocardial I/R.
Arrhythmogenic Cardiotoxicity Associated With Contemporary Treatments of Lymphoproliferative Disorders
Authors: Sherazi Saadia , Schleede Susan , McNitt Scott , Casulo Carla , Moore Jeremiah E. , Storozynsky Eugene , Patel Arpan , Vidula Neelima , Aktas Mehmet K. , Zent Clive S. , Goldenberg Ilan
Published: March 2023

Background

There are limited data on risk of arrhythmias among patients with lymphoproliferative disorders. We designed this study to determine the risk of atrial and ventricular arrhythmia during treatment of lymphoma in a real‐world setting.

Methods and Results

The study population comprised 2064 patients included in the University of Rochester Medical Center Lymphoma Database from January 2013 to August 2019. Cardiac arrhythmias—atrial fibrillation/flutter, supraventricular tachycardia, ventricular arrhythmia, and bradyarrhythmia—were identified using
International Classification of Diseases, Tenth Revision
(
ICD‐10
) codes. Multivariate Cox regression analysis was used to assess the risk of arrhythmic events with treatments categorized as Bruton tyrosine kinase inhibitor (BTKi), mainly ibrutinib/non‐BTKi treatment versus no treatment. Median age was 64 (54–72) years, and 42% were women. The overall rate of any arrhythmia at 5 years following the initiation of BTKi was (61%) compared with (18%) without treatment. Atrial fibrillation/flutter was the most common type of arrhythmia accounting for 41%. Multivariate analysis showed that BTKi treatment was associated with a 4.3‐fold (
P
<0.001) increased risk for arrhythmic event (
P
<0.001) compared with no treatment, whereas non‐BTKi treatment was associated with a 2‐fold (
P
<0.001) risk increase. Among subgroups, patients without a history of prior arrhythmia exhibited a pronounced increase in the risk for the development of arrhythmogenic cardiotoxicity (3.2‐fold;
P
<0.001).

Conclusions

Our study identifies a high burden of arrhythmic events after initiation of treatment, which is most pronounced among patients treated with the BTKi ibrutinib. Patients undergoing treatments for lymphoma may benefit from prospective focused cardiovascular monitoring prior, during, and after treatment regardless of arrhythmia history.