bluuebunny/crossref_metadata_2025 huggingface dataset:
Prediction of response to systemic treatment by kinetics of circulating tumor DNA in metastatic pancreatic cancer
Authors: Kirchweger Patrick , Kupferthaler Alexander , Burghofer Jonathan , Webersinke Gerald , Jukic Emina , Schwendinger Simon , Wundsam Helwig , Biebl Matthias , Petzer Andreas , Rumpold Holger
Published: August 2022

Introduction

Pretherapeutic detectable circulating tumor DNA (ctDNA) represents a promising prognostic biomarker for predicting relapse and overall survival in patients with metastatic pancreatic cancer. However, the prognostic value of ctDNA dynamics during treatment has not been studied thus far. We aimed to investigate the correlation between the change of ctDNA levels and response to treatment in patients treated by systemic therapy.

Material and methods

CtDNA detection using liquid biopsy (droplet digital PCR (ddPCR) utilizing KRAS G12/13 and, if negative, Q61 commercial test kits) was prospectively performed on patients with stage IV pancreatic cancer i) prior to initiation of systemic chemotherapy and ii) serially every 2 weeks until restaging. Detection rates, levels of ctDNA, and the course of the relative ctDNA change (ctDNA kinetics) were correlated to treatment response and clinical outcome.

Results

The detection rate at baseline was 64.3% (45/70), and complete serial measurement records were available for 32 ctDNA-positive patients. Reduction of ctDNA levels below 57.9% of its baseline value at week 2 after treatment initiation was significantly predictive of response to treatment (area under the curve (AUC) = 0.918, sensitivity 91.67%, and specificity 100%) and was associated with prolonged overall survival (OS) (5.7 vs. 11.4 months, p = 0.006) and progression-free survival (PFS) (2.5 vs. 7.7 months, p < 0.000) regardless of treatment line. Pretherapeutic ctDNA detection was independently associated with worse OS in patients receiving a first-line regimen (7 vs. 11.3 months, p = 0.046) and regardless of treatment line (11.4 vs. 15.9 months, p = 0.045) as well as worse PFS (3.4 vs. 10.8 months, p = 0.018).

Conclusion

The change in magnitude of ctDNA during systemic treatment allows the prediction of treatment response and is associated with both OS and PFS. This finding adds significant clinical potential to the already established prognostic value of ctDNA positivity in metastatic pancreatic cancer.
Identification of cuprotosis-mediated subtypes, the development of a prognosis model, and influence immune microenvironment in hepatocellular carcinoma
Authors: Xiao Jingjing , Liu Zhenhua , Wang Jinlong , Zhang Shuaimin , Zhang Yi
Published: August 2022

Purpose

Cuprotosis is a newly discovered form of non-apoptotic regulated cell death and is characterized by copper-dependent and associated with mitochondrial respiration. However, the prognostic significance and function of cuprotosis-related genes (CRGs) in hepatocellular carcinoma (HCC) are unknown. This study aims to develop cuprotosis-mediated patterns-related gene (CMPRG) prediction models for the prognosis of patients with HCC, exploring the functional underlying the CRGs on the influence of tumor microenvironment (TME) features.

Experimental design

This study obtained transcriptome profiling and the corresponding clinical information from the TCGA and GEO databases. Besides, the Cox regression model with LASSO was implemented to build a multi-gene signature, which was then validated in an internal validation set and two external validation sets through Kaplan-Meier, DCA, and ROC analyses.

Results

According to the LASSO analysis, we screened out a cuprotosis-mediated pattern 5-gene combination (including PBK; MMP1; GNAZ; GPC1 and AKR1D1). A nomogram was constructed for the presentation of the final model. The ROC curve assessed the model’s predictive ability, which resulted in an area under the curve (AUC) values ranging from 0.604 to 0.787 underwent internal and two external validation sets. Meanwhile, the risk score divided the patients into two groups of high and low risk, and the survival rate of high-risk patients was significantly lower than that of low-risk patients (P<0.01). The risk score could be an independent prognostic factor in the multifactorial Cox regression analysis (P<0.01). Functional analysis revealed that immune status, mutational loads, and drug sensitivity differed between the two risk groups.

Conclusions

In summary, we identified three cuprotosis-mediated patterns in HCC. And CMPRGs are a promising candidate biomarker for HCC early detection, owing to their strong performance in predicting HCC prognosis and therapy. Quantifying cuprotosis-mediated patterns in individual samples may help improve the understanding of multiomic characteristics and guide the development of targeted therapy for HCC.
Neoadjuvant tislelizumab and tegafur/gimeracil/octeracil (S-1) plus oxaliplatin in patients with locally advanced gastric or gastroesophageal junction cancer: Early results of a phase 2, single-arm trial
Authors: Yin Yuping , Lin Yao , Yang Ming , Lv Jianbo , Liu Jiaying , Wu Ke , Liu Ke , Li Anshu , Shuai Xiaoming , Cai Kailin , Wang Zheng , Wang Guobin , Shen Jianfeng , Zhang Peng , Tao Kaixiong
Published: August 2022

Background

Recently, the combination of immunotherapy with chemotherapy has been recommended as first-line treatment of metastatic gastric/gastroesophageal junction (G/GEJ) in the clinical guidelines of many countries; the therapeutic potential of this application needs to be further investigated for neoadjuvant therapy of advanced G/GEJ cancer patients.

Methods

We performed a prospective, single-arm, open-label, phase 2 trial of the PD-1 inhibitor tislelizumab combined with S-1 plus oxaliplatin (SOX) in patients with advanced LAG/GEJ cancer. All patients underwent the three-cycle (21 days/cycle) treatment except for one patient who underwent two cycles. The primary endpoints were tumor major pathology response (MPR) and other events of tumor response assessed by the RECIST 1.1 and Becker criteria. Moreover, we constructed a few-shot learning model to predict the probability of MPR, which could screen those patients who might benefit from the neoadjuvant immunotherapy–chemotherapy scheme. This study was registered at https://clinicaltrials.gov/ct2/show/NCT0-4890392.

Results

Thirty-two patients were enrolled; 17 patients (53.1%) achieved MPR (≤10% viable tumor cells) after treatment, and among them, 8 (25.0%) had a pathological complete response (pCR). The 1-year overall survival (OS) rate was 91.4% and the 1-year recurrence-free survival (RFS) rate was 90.0%. Adverse events occurred in 24 patients (65.6%) and grade III–IV adverse events were observed in 4 patients (12.5%) during the neoadjuvant period. Furthermore, we found commonly used preoperative assessment tools such as CT and EUS, which presented limited accuracy of tumor therapeutic response in this study; thus, we developed a therapeutic response predictive model that consisted of TNFα, IFNγ, IL-10, CD4, and age of patient, and the AUC of this FSL model was 0.856 (95% CI: 0.823–0.884).

Discussion

Our study showed that the neoadjuvant PD-1 inhibitor tislelizumab combined with SOX had promising application potential and presented no increasing treatment-related adverse events in patients with advanced G/GEJ cancer. Moreover, the predictive model could help therapists to evaluate the therapeutic response of this scheme accurately.

Clinical Trial Registration

https://clinicaltrials.gov/ct2/show/NCT0-4890392, identifier [NCT04890392].
Auto-segmentation for total marrow irradiation
Authors: Watkins William Tyler , Qing Kun , Han Chunhui , Hui Susanta , Liu An
Published: August 2022

Purpose

To evaluate the accuracy and efficiency of Artificial-Intelligence (AI) segmentation in Total Marrow Irradiation (TMI) including contours throughout the head and neck (H&N), thorax, abdomen, and pelvis.

Methods

An AI segmentation software was clinically introduced for total body contouring in TMI including 27 organs at risk (OARs) and 4 planning target volumes (PTVs). This work compares the clinically utilized contours to the AI-TMI contours for 21 patients. Structure and image dicom data was used to generate comparisons including volumetric, spatial, and dosimetric variations between the AI- and human-edited contour sets. Conventional volume and surface measures including the Sørensen–Dice coefficient (Dice) and the 95th% Hausdorff Distance (HD95) were used, and novel efficiency metrics were introduced. The clinical efficiency gains were estimated by the percentage of the AI-contour-surface within 1mm of the clinical contour surface. An unedited AI-contour has an efficiency gain=100%, an AI-contour with 70% of its surface<1mm from a clinical contour has an efficiency gain of 70%. The dosimetric deviations were estimated from the clinical dose distribution to compute the dose volume histogram (DVH) for all structures.

Results

A total of 467 contours were compared in the 21 patients. In PTVs, contour surfaces deviated by >1mm in 38.6% ± 23.1% of structures, an average efficiency gain of 61.4%. Deviations >5mm were detected in 12.0% ± 21.3% of the PTV contours. In OARs, deviations >1mm were detected in 24.4% ± 27.1% of the structure surfaces and >5mm in 7.2% ± 18.0%; an average clinical efficiency gain of 75.6%. In H&N OARs, efficiency gains ranged from 42% in optic chiasm to 100% in eyes (unedited in all cases). In thorax, average efficiency gains were >80% in spinal cord, heart, and both lungs. Efficiency gains ranged from 60-70% in spleen, stomach, rectum, and bowel and 75-84% in liver, kidney, and bladder. DVH differences exceeded 0.05 in 109/467 curves at any dose level. The most common 5%-DVH variations were in esophagus (86%), rectum (48%), and PTVs (22%).

Conclusions

AI auto-segmentation software offers a powerful solution for enhanced efficiency in TMI treatment planning. Whole body segmentation including PTVs and normal organs was successful based on spatial and dosimetric comparison.
Dissecting a hypoxia-related angiogenic gene signature for predicting prognosis and immune status in hepatocellular carcinoma
Authors: Zhang Guixiong , Xiao Yitai , Zhang Xiaokai , Fan Wenzhe , Zhao Yue , Wu Yanqin , Wang Hongyu , Li Jiaping
Published: August 2022

Background

Hypoxia and angiogenesis, as prominent characteristics of malignant tumors, are implicated in the progression of hepatocellular carcinoma (HCC). However, the role of hypoxia in the angiogenesis of liver cancer is unclear. Therefore, we explored the regulatory mechanisms of hypoxia-related angiogenic genes (HRAGs) and the relationship between these genes and the prognosis of HCC.

Methods

The transcriptomic and clinical data of HCC samples were downloaded from public datasets, followed by identification of hypoxia- and angiogenesis-related genes in the database. A gene signature model was constructed based on univariate and multivariate Cox regression analyses, and validated in independent cohorts. Kaplan-Meier survival and time-dependent receiver operating characteristic (ROC) curves were generated to evaluate the model’s predictive capability. Gene set enrichment analysis (GSEA) was performed to explore signaling pathways regulated by the gene signature. Furthermore, the relationships among gene signature, immune status, and response to anti-angiogenesis agents and immune checkpoint blockade (ICB) were analyzed.

Results

The prognostic model was based on three HRAGs (ANGPT2, SERPINE1 and SPP1). The model accurately predicted that low-risk patients would have longer overall survival than high-risk patients, consistent with findings in other cohorts. GSEA indicated that high-risk group membership was significantly associated with hypoxia, angiogenesis, the epithelial-mesenchymal transition, and activity in immune-related pathways. The high-risk group also had more immunosuppressive cells and higher expression of immune checkpoints such as PD-1 and PD-L1. Conversely, the low-risk group had a better response to anti-angiogenesis and ICB therapy.

Conclusions

The gene signature based on HRAGs was predictive of prognosis and provided an immunological perspective that will facilitate the development of personalized therapies.
Risk factors associated with severe disease in respiratory syncytial virus infected children under 5 years of age
Authors: Havdal Lise Beier , Bøås Håkon , Bekkevold Terese , Bakken Kran Anne-Marte , Rojahn Astrid Elisabeth , Størdal Ketil , Debes Sara , Døllner Henrik , Nordbø Svein Arne , Barstad Bjørn , Haarr Elisebet , Fernández Liliana Vázquez , Nakstad Britt , Inchley Christopher , Flem Elmira
Published: August 2022

Objective

To evaluate risk factors for severe disease in children under 59 months of age hospitalized with respiratory syncytial virus (RSV) infection.

Study design

We prospectively enrolled 1,096 cases of laboratory confirmed RSV infection during three consecutive RSV seasons in 2015–2018. Potential risk factors for severe disease were retrieved through patient questionnaires and linkage to national health registries. Need for respiratory support (invasive ventilation, bi-level positive airway pressure, or continuous positive airway pressure), and length of stay exceeding 72 h were used as measures of disease severity. Associations were investigated using multivariable logistic regression analyses. Multiple imputation was used to avoid bias and inference induced by missing data.

Results

Risk factors associated with a need for respiratory support included age younger than 3 months of age [aOR: 6.73 (95% CI 2.71–16.7)], having siblings [aOR: 1.65 (95% CI 1.05–2.59)] and comorbidity [aOR: 2.40 (95% CI 1.35–4.24)]. The length of hospital stay >72 h was significantly associated with being younger than 3 months of age [aOR: 3.52 (95% CI 1.65–7.54)], having siblings [aOR: 1.45 (95% CI 1.01–2.08)], and comorbidity [aOR: 2.18 (95% CI 1.31–3.61)]. Sub-group analysis of children younger than 6 months of age confirmed the association between both young age and having siblings and the need for respiratory support.

Conclusion

In a large cohort of children <59 months hospitalized with RSV infection, young age, comorbidity, and having siblings were associated with more severe disease.
Multi-lingual “Asthma APP” improves health knowledge of asthma among Australian First Nations carers of children with asthma
Authors: Versteegh Lesley A. , Chang Anne B. , Chirgwin Sharon , Tenorio Fransisca P. , Wilson Catherine A. , McCallum Gabrielle B.
Published: August 2022

Background

Among Australian First Nations people, asthma is associated with worse morbidity and mortality than non-First Nations people. Improving the delivery of health education that is innovative and culturally relevant to linguistically diverse populations is needed. Digital platforms, such as mobile applications (APP), have the potential to improve evidence-based health education, particularly in settings where access to specialist services is limited and turnover of staff is high, such as in remote Australia. In response to consumer needs, we developed a multi-lingual Asthma APP from our existing asthma flipchart, with a “voice-over” in seven local First Nations languages and English, using a mixture of static and interactive formats. In this study, we evaluated (a) the functionality and usability of the APP with First Nations health professionals with and without asthma and (b) whether the APP improves health knowledge and understanding of asthma among First Nations carers of children with asthma.

Methods

In total, 7 First Nations health professionals participated in semi-structured interviews prior to the evaluation with 80 First Nations carers of children with asthma from the Northern Territory and Queensland, Australia. Carers underwent pre- and post-education questionnaires (maximum score = 25), where the post-questionnaire was administered immediately post the APP education session.

Results

Health professionals found that APP was easy to navigate and culturally appropriate. Among the 80 carers, most were mothers (86%), aged between 26 and 50 years (75%) and 61% lived in remote settings (>100 km from a tertiary hospital). Most carers chose English audio (76%) with the remainder choosing one of the First Nations languages. Overall, asthma knowledge significantly improved post-education (median scores pre = 21 [interquartile range (IQR), 19–22; post = 24 (IQR 22–24), p = 0.05].

Conclusion

The First Nations-specific multi-lingual Asthma APP was easy to use and acceptable for the use by health professionals that also significantly improved short-term asthma knowledge among First Nations carers of children with asthma. The Asthma APP is an innovative and culturally acceptable method of delivering evidence-based, health education to culturally and linguistically diverse populations among Australian First Nations people.
Determinants of potentially harmful traditional cord care practices among mothers in Ethiopia
Authors: Merga Bedasa Taye , Fekadu Gelana , Raru Temam Beshir , Ayana Galana Mamo , Hassen Fila Ahmed , Bekana Miressa , Negash Belay , Eshetu Bajrond , Birhanu Abdi , Mulatu Gutema , Balis Bikila
Published: August 2022

Background

Globally, newborn deaths have declined from 5 million in 1990 to 2.4 million in 2019; however, the risk of death in the first 28 days is high. Harmful umbilical cord care contributes to neonatal infection, which accounts for millions of neonatal deaths. This study assessed determinants of potentially harmful traditional cord care practices in Ethiopia using data from a nationally representative survey.

Materials and methods

Secondary data analyses were employed using data from the 2016 Ethiopian Demographic and Health Survey. Weighted samples of 4,402 mothers who gave birth in the last 3 years prior to the survey were included in the analysis. Binary logistic regression was fitted to identify associations of outcome variables with explanatory variable analysis, and the results were presented with an adjusted odds ratio (AOR) at a 95% confidence interval (CI), declaring statistical significance at a p-value < 0.05 in all analyses.

Results

About 13.70% (95% CI: 12.7%, 14.7%) of mothers practice harmful traditional umbilical cord care. Maternal age (25–34 years, AOR = 1.77, 95% CI: 1.36, 2.31, 35–49 years, AOR = 1.53, 95% CI: 1.07, 2.19), maternal education (primary: AOR = 0.54, 95% CI: 0.41, 0.70 and secondary and above: AOR = 0.61, 95% CI: 0.40, 0.94), parity (para two, AOR = 0.71, 95% CI: 0.55, 0.92), and place of delivery (home delivery, AOR = 1.96, 95% CI: 1.51, 2.56) were factors associated with potentially harmful traditional umbilical cord care practices.

Conclusion

Maternal educational status, parity, maternal age, and place of delivery were associated with harmful traditional cord care practices. Thus, improving mothers’ education, strengthening antenatal and postnatal care (PNC), and utilization of institutional delivery would help to reduce harmful traditional cord care practices.
Parents’ experiences and perceptions of the acceptability of a whole-hospital, pro-active electronic pediatric early warning system (the DETECT study): A qualitative interview study
Authors: Saron Holly , Carter Bernie , Siner Sarah , Preston Jennifer , Peak Matthew , Mehta Fulya , Lane Steven , Lambert Caroline , Jones Dawn , Hughes Hannah , Harris Jane , Evans Leah , Dee Sarah , Eyton-Chong Chin-Kien , Carrol Enitan D. , Sefton Gerri
Published: August 2022

Background

Failure to recognize and respond to clinical deterioration in a timely and effective manner is an urgent safety concern, driving the need for early identification systems to be embedded in the care of children in hospital. Pediatric early warning systems (PEWS) or PEW scores alert health professionals (HPs) to signs of deterioration, trigger a review and escalate care as needed. PEW scoring allows HPs to record a child’s vital signs and other key data including parent concern.

Aim

This study aimed to explore the experiences and perceptions of parents about the acceptability of a newly implemented electronic surveillance system (the DETECT surveillance system), and factors that influenced acceptability and their awareness around signs of clinical deterioration and raising concern.

Methods

Descriptive, qualitative semi-structured telephone interviews were undertaken with parents of children who had experienced a critical deterioration event (CDE) (n = 19) and parents of those who had not experienced a CDE (non-CDE parents) (n = 17). Data were collected between February 2020 and February 2021.

Results

Qualitative data were analyzed using generic thematic analysis. Analysis revealed an overarching theme of trust as a key factor that underpinned all aspects of children’s vital signs being recorded and monitored. The main themes reflect three domains of parents’ trust: trust in themselves, trust in the HPs, and trust in the technology.

Conclusion

Parents’ experiences and perceptions of the acceptability of a whole-hospital, pro-active electronic pediatric early warning system (The DETECT system) were positive; they found it acceptable and welcomed the use of new technology to support the care of their child.
Systematic characterization of Puerariae Flos metabolites in vivo and assessment of its protective mechanisms against alcoholic liver injury in a rat model
Authors: Qu Jialin , Chen Qiuyue , Wei Tianfu , Dou Ning , Shang Dong , Yuan Dan
Published: August 2022

Puerariae Flos, a representative homology plant of medicine and food for alcoholism, has a long history of clinical experience and remarkable curative effect in the treatment of alcoholic liver disease (ALD). However, its effective forms and hepatoprotective mechanisms remain unknown. In the present study, a strategy based on UPLC-QTOF MS combined with mass defect filtering technique was established for comprehensive mapping of the metabolic profile of PF in rat plasma, urine, bile, and feces after oral administration. Furthermore, the absorbed constituents into plasma and bile with a relatively high level were subjected to the network analysis, functional enrichment analysis, and molecular docking to clarify the potential mechanism. Finally, the therapeutic effect of PF on ALD and predicted mechanisms were further evaluated using a rat model of alcohol-induced liver injury and Western blot analysis. In total, 25 prototype components and 82 metabolites, including 93 flavonoids, 13 saponins, and one phenolic acid, were identified or tentatively characterized in vivo. In addition, glucuronidation, sulfation, methylation, hydroxylation, and reduction were observed as the major metabolic pathways of PF. The constructed compound–target–pathway network revealed that 11 absorbed constituents associated with the 16 relevant targets could be responsible for the protective activity of PF against ALD by regulating nine pathways attributable to glycolysis/gluconeogenesis, amino acid metabolism, and lipid regulation as well as inflammation and immune regulation. In addition, four active ingredients (6″-O-xylosyltectoridin, genistein-7-glucuronide-4′-sulfate, tectoridin-4′-sulfate, and 6″-O-xylosyltectoridin-4′-sulfate) as well as two target genes (MAO-A and PPAR-α) were screened and validated to play a crucial role with a good molecular docking score. The present results not only increase the understanding on the effective form and molecular mechanisms of PF-mediated protection against ALD but also promote better application of PF as a supplement food and herbal medicine for the treatment of ALD.
Akebia saponin D protects hippocampal neurogenesis from microglia-mediated inflammation and ameliorates depressive-like behaviors and cognitive impairment in mice through the PI3K-Akt pathway
Authors: Liu Qin , Zhang Jinqiang , Xiao Chenghong , Su Dapeng , Li Liangyuan , Yang Changgui , Zhao Zhihuang , Jiang Weike , You Zili , Zhou Tao
Published: August 2022

Given the ability of akebia saponin D (ASD) to protect various types of stem cells, in the present study, we hypothesized that ASD could promote the proliferation, differentiation, and survival of neural stem/precursor cells (NSPCs), even in a microglia-mediated inflammatory environment, thereby mitigating inflammation-related neuropsychopathology. We established a mouse model of chronic neuroinflammation by exposing animals to low-dose lipopolysaccharide (LPS, 0.25 mg/kg/d) for 14 days. The results showed that chronic exposure to LPS strikingly reduced hippocampal levels of PI3K and pAkt and neurogenesis in mice. In the presen of a microglia-mediated inflammatory niche, the PI3K-Akt signaling in cultured NSPCs was inhibited, promoting their apoptosis and differentiation into astrocytes, while decreasing neurogenesis. Conversely, ASD strongly increased the levels of PI3K and pAkt and stimulated NSPC proliferation, survival and neuronal differentiation in the microglia-mediated inflammatory niche in vitro and in vivo. ASD also restored the synaptic function of hippocampal neurons and ameliorated depressive- and anxiety-like behaviors and cognitive impairment in mice chronically exposed to LPS. The results from network pharmacology analysis showed that the PI3K-AKT pathway is one of the targets of ASD to against major depressive disorder (MDD), anxiety and Alzheimer’s disease (AD). And the results from molecular docking based on computer modeling showed that ASD is bound to the interaction interface of the PI3K and AKT. The PI3K-Akt inhibitor LY294002 blocked the therapeutic effects of ASD in vitro and in vivo. These results suggested that ASD protects NSPCs from the microglia-mediated inflammatory niche, promoting their proliferation, survival and neuronal differentiation, as well as ameliorating depressive- and anxiety-like behaviors and cognitive impairment by activating the PI3K-AKT pathway. Our work suggests the potential of ASD for treating Alzheimer’s disease, depression and other cognitive disorders involving impaired neurogenesis by microglia-mediated inflammation.
Using real-world data for supporting regulatory decision making: Comparison of cardiovascular and safety outcomes of an empagliflozin randomized clinical trial versus real-world data
Authors: Jang Ha Young , Kim In-Wha , Oh Jung Mi
Published: August 2022

Aims: In countries where a randomized clinical trial (RCT) is difficult to perform, a real-world evidence (RWE) study with a design similar to an RCT may be an option for drug regulatory decision-making. In this study, the objective was to find out to what extent the safety of empagliflozin from the RWE study in Korea is different from the one in RCT by emulating the design of foreign RCT. The outcome covers various safety outcomes including cardiovascular safety.

Methods: The EMPA-REG OUTCOME trial (NCT01131676) was selected for comparison. The inclusion/exclusion criteria and follow-up method for the RWE were matched to the comparison RCT. Major adverse cardiovascular events (MACEs) were used as a primary outcome and 15 other outcomes were also included for analysis.

Result: We followed 23,126 matched patients with type 2 diabetes mellitus (11,563 empagliflozin users and 11,563 sitagliptin users) for 2.7 years (median). Empagliflozin use was associated with a significantly decreased risk of MACEs [EMPA-REG DUPLICATE RWE: adjusted HR 0.87, 95% confidence interval (CI) 0.79–0.96]. The predefined estimate agreement, regulatory agreement, and standardized difference for RCT duplication were achieved [EMPA-REG OUTCOME RCT: adjusted HR 0.86, 95% (CI) 0.74–0.99]. According to the predefined criteria for 15 outcomes, 10 outcomes were evaluated as good, and three as moderate.

Conclusion: Our study results suggest that RWE in one country in comparison with an RCT has the potential for providing evidence for future regulatory decision-making in an environment where RCT could not be performed.
Yang-xin-xue keli exerts therapeutic effects via regulating mitochondrial homeostasis and function in doxorubicin-induced rat heart failure
Authors: Long Kunlan , Zhao Ziyi , Chen Jun , Zhi Lijia , Wang Chunxia , Liao Dan , Wang Meng , Gao Peiyang
Published: August 2022

Background: Heart failure, especially chronic heart failure, is generally induced by the accumulation of reactive oxygen species (ROS), as well as the subsequent loss of mitochondrial permeability transition pore (mPTP) openings and pathological mitochondrial dysfunction. Herein, we explored the therapeutic effects of the Chinese medicine Yangxin Keli (YXXKL) on chronic heart failure and its underlying working mechanism.

Methods: To mimic oxidative stress-induced chronic heart failure, a rat heart failure model was induced by the administration of DOX. Transthoracic echocardiography was performed to confirm the successful establishment of the heart failure model by observing significantly decreased cardiac function in the rats. Mitochondrial membrane potential, function, and ATP synthesis activity were measured after YXXKL was employed.

Results The administration of YXXKL not only significantly improved cardiac function but also reversed the myocardium loss and fibrosis induced via DOX. Moreover, the administration of YXXKL also increased ATP synthesis and mitochondrial DNA mass in left ventricular tissues, which indicated that mitochondria may be a key target of YXXKL. Thus, we employed rat cardiomyocyte H9c2 and primary rat cardiac myocytes (RCMs) to induce oxidative stress-induced myocardial injury via DOX treatment. YXXKL-medicated serum promoted cell proliferation, which was inhibited by the addition of IC30 DOX, and the serum also inhibited cell apoptosis, which was promoted by the addition of IC50 DOX. YXKL-medicated serum was able to scavenge ROS and maintain the mitochondrial membrane potential as well as promote mitochondrial function, including the promotion of ATP synthesis, mitochondrial DNA mass, and transcriptional activity. Furthermore, we also observed that YXXKL-medicated serum inhibited DOX-induced autophagy/mitophagy by scavenging ROS.

Conclusion: Taken together, we conclude that YXXKLI may exert therapeutic effects on oxidative stress-related heart failure via the regulation of mitochondria.
Co-Treatment With Resveratrol and FGF1 Protects Against Acute Liver Toxicity After Doxorubicin Treatment via the AMPK/NRF2 Pathway
Authors: Xu Xianchou , Liu Qingbo , Li Jiahao , Xiao Mengjie , Gao Ting , Zhang Xiaohui , Lu Guangping , Wang Jie , Guo Yuanfang , Wen Peinan , Gu Junlian
Published: August 2022

Doxorubicin (DOX), an anthracycline type of chemotherapy, is an effective therapy for several types of cancer, but serious side effects, such as severe hepatotoxicity, limit its use currently. Accordingly, an effective therapeutic strategy to prevent DOX-related hepatotoxicity is urgently needed. Through the inhibition of oxidative stress, fibroblast growth factor 1 (FGF1) is an effect therapy for a variety of liver diseases, but its use is limited by an increased risk of tumorigenesis due to hyperproliferation. Resveratrol (RES), a natural product, inhibits the growth of many cancer cell lines, including liver, breast, and prostate cancer cells. Therefore, this study explored whether and how RES in combination with FGF1 can alleviate DOX-induced hepatotoxicity. The results showed that RES or FGF1 alone improved DOX-induced hepatic inflammation, apoptosis and oxidative stress, and these adverse effects were further attenuated after treatment with both RES and FGF1. Mechanistically, both in vivo and in vitro results showed that RES/FGF1 reduced oxidative stress and thereby alleviated liver injury by promoting nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and subsequently upregulating expression of antioxidant proteins in an adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. Together, our results not only demonstrate that co-treatment with RES and FGF1 significantly inhibited DOX-induced hepatic inflammation and apoptosis, but also that co-treatment with RES and FGF1 markedly suppressed DOX-induced hepatic oxidative stress, via targeting the AMPK/NRF2 pathway and subsequently ameliorating hepatic dysfunction. Thus, the combination of RES and FGF1 may provide a new therapeutic strategy for limiting DOX-induced hepatotoxicity.
Expression of oxytocin in hypothalamus and reduction of nociceptive stress following administration of Kamikihi-to in female rats
Authors: Maruyama Takashi , Shimizu Makiko , Ikeda Naofumi , Baba Kazuhiko , Yoshimura Mitsuhiro , Ueta Yoichi
Published: August 2022

Hypothalamo-neurohypophysial oxytocin (OXT) plays an essential role in reproduction and in several socio-physiological functions, including stress reduction, anxiety relief, feeding suppression, social recognition, and trust building. Recent studies suggest that the central OXT system is also involved in antinociceptive and anti-inflammatory functions. Kamikihi-to (KKT), a Japanese traditional herbal (Kampo) medicine composed of 14 herbal ingredients, is clinically prescribed for patients with psychological symptoms, including anxiety, depression, and insomnia, and it has been associated with OXT expression. We investigated the antinociceptive response and OXT expression according to sex and the effects of KKT pre administration in a rat model. We found that nociceptive responses measured via the hot plate and formalin tests were attenuated following the administration of KKT-enriched feed for 4 weeks. The observation of mRFP1 fluorescence in OXT-mRFP1 transgenic rats revealed that KKT-administered rats showed increased expression of OXT in the magnocellular and parvocellular paraventricular nucleus of the hypothalamus. Food intake in the KKT-pre-administered group significantly decreased after cholecystokinin (CCK)-8 administration. Our results suggest that KKT is involved in the attenuation of nociceptive stress in female rats by enhancing the expression of OXT in the hypothalamus.
Cardiotoxicity associated with immune checkpoint inhibitors: Current status and future challenges
Authors: Gan Lu , Liu Demin , Ma Yanan , Chen Xuening , Dai Aihui , Zhao Sihan , Jin Xiaoxue , Gu Guoqiang
Published: August 2022

Immune checkpoint inhibitors (ICIs) are the most notable breakthrough in tumor treatment. ICIs has been widely used in tumor patients, but its wide range of immune-related adverse events (irAEs) should not be ignored. irAEs can be involved in any organ system, including immune-related cardiotoxicity. Although the cardiotoxicity induced by immune checkpoint inhibitors is rare, it is extremely lethal and has attracted increasing attention. PD-1 and PD-L1 are expressed in human cardiomyocytes, so the application of PD-1/PDL-1 inhibitors can cause many adverse reactions to the cardiovascular system. This review summarizes the latest epidemiological evidence on the cardiovascular toxicity of programmed cell death protein-1(PD-1)/programmed cell death ligand-1(PD-L1) inhibitors and the clinical manifestations, as well as the potential pathological mechanisms. These updates may provide a novel perspective for monitoring early toxicity and establishing appropriate treatment for patients with ICI-related cardiotoxicity.
Comparative pharmacokinetics and urinary excretion of arsenic and mercury after oral administration of realgar, cinnabar and AnGongNiuHuang Pill to rats
Authors: Wu Xiao , Zhong Zeling , Lin Kuangmin , Liu Xinhe , Wu Zhichao , Liu Zitian , Li Yongming
Published: August 2022

Realgar- and cinnabar-containing AnGongNiuHuang Pill (AGNHP) is widely used for treating encephalopathy syndrome. However, it raises great safety concerns due to the adverse effects reported by arsenic or mercury poisoning. Although AGNHP has been generally recognized, little is known about the metabolism of arsenic and mercury and their resulting potential health risk in vivo. Thus, comparative pharmacokinetics and urinary excretion of arsenic and mercury were conducted in rats after oral administration of realgar, cinnabar and AGNHP, respectively. The contents of arsenic and mercury in rat blood and urine were determined by hydride-generation atomic fluorescence spectrometry (HG-AFS) after wet digestion. AGNHP significantly reduced the absorption of arsenic in blood and promoted urinary arsenic excretion. Whereas, it increased the blood mercury absorption and reduced urinary mercury excretion. No significant toxicity was observed in the clinical dose range of AGNHP. However, excessive exposure to arsenic and mercury may still pose risks especially by long-term or excessive medication. The results are helpful for the rational clinical applications of realgar- and cinnabar-containing TCMs.
Exploring potential mechanism of ciwujia tablets for insomnia by UPLC-Q-TOF-MS/MS, network pharmacology, and experimental validation
Authors: Liu Hongda , Yang Le , Wan Chunlei , Li Zhineng , Yan Guangli , Han Ying , Sun Hui , Wang Xijun
Published: August 2022

Insomnia, whether chronic or intermittent, is a common central nervous system disease. Ciwujia Tablet (CWT) is a well-known traditional Chinese medicine (TCM) made from the extract of Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. This medication is commonly used for treating insomnia in China, but the lack of in-depth research focused on the chemical ingredients of CWT creates a gap in knowledge regarding its effective constituents against insomnia. Considering that the therapeutic material basis, targets, and pathways related to this drug have not been fully investigated by scholars in the field, the focus of this study is on identifying the chemical ingredients or structural characteristics of CWT by the UPLC-Q-TOF-MS/MS technique. Besides, concepts of network pharmacology were also used to investigate the targets and pathways of CWT. An insomnia rat model was established by intraperitoneal injection of p-chlorophenylalanine, and the results were verified through various experiments. A total of 46 ingredients were identified in CWT, such as eleutheroside B, eleutheroside E, isofraxidin, and chlorogenic acid. Among them, 17 ingredients with good solubility, favorable gastrointestinal absorption, and high bioavailability were selected for network pharmacological analysis. It was concluded that CWT participated in the regulation of neurotransmitter levels, modulation of ion transport, neurotransmitter receptor activity, synaptic transmission, dopaminergic transmission and other essential processes. Results from the animal experiments showed that CWT can increase the content of inhibitory neurotransmitters 5-HT and GABA in the brain, reduce the synthesis of excitatory escalating transmitters DA and NE, shorten the sleep latency and prolong the sleep duration of insomnia rats. Furthermore, CWT could significantly alleviate the symptoms of insomnia in model rats. Identifying the chemical ingredients of CWT in this experiment is of great significance for exploring its potential curative effects, which provides a solid basis for further understanding the therapeutic value of this medication.
Chemical identification of an active component and putative neural mechanism for repellent effect of a native ant’s odor on invasive species
Authors: Uebi Tatsuya , Sakita Tomoya , Ikeda Ryo , Sakanishi Keita , Tsutsumi Tomoaki , Zhang Zijian , Ma Huiying , Matsubara Ryosuke , Matsuyama Shigeru , Nakajima Satoko , Huang Rong-Nan , Habe Shunya , Hefetz Abraham , Ozaki Mamiko
Published: August 2022

The invasive Argentine ants (Linepithema humile) and the red imported fire ants (Solenopsis invicta) constitute a worldwide threat, causing severe disruption to ecological systems and harming human welfare. In view of the limited success of current pest control measures, we propose here to employ repellents as means to mitigate the effect of these species. We demonstrate that cuticular hydrocarbons (CHCs) used as nestmate-recognition pheromone in the Japanese carpenter ant (Camponotus japonicus), and particularly its (Z)-9-tricosene component, induced vigorous olfactory response and intense aversion in these invasive species. (Z)-9-Tricosene, when given to their antennae, caused indiscriminate glomerular activation of antennal lobe (AL) regions, creating neural disarray and leading to aversive behavior. Considering the putative massive central neural effect, we suggest that the appropriate use of certain CHCs of native ants can facilitate aversive withdrawal of invasive ants.
Lactate-induced lactylation in skeletal muscle is associated with insulin resistance in humans
Authors: Maschari Dominic , Saxena Gunjan , Law Timothy D. , Walsh Erin , Campbell Mason C. , Consitt Leslie A
Published: August 2022

Elevated circulating lactate has been associated with obesity and insulin resistance. The aim of the current study was to determine if lactate-induced lysine lactylation (kla), a post-translational modification, was present in human skeletal muscle and related to insulin resistance. Fifteen lean (Body Mass Index: 22.1 ± 0.5 kg/m2) and fourteen obese (40.6 ± 1.4 kg/m2) adults underwent a muscle biopsy and 2-h oral glucose tolerance test. Skeletal muscle lactylation was increased in obese compared to lean females (19%, p < 0.05) and associated with insulin resistance (r = 0.37, p < 0.05) in the whole group. Skeletal muscle lactylation levels were significantly associated with markers of anaerobic metabolism (plasma lactate and skeletal muscle lactate dehydrogenase [LDH], p < 0.05) and negatively associated with markers of oxidative metabolism (skeletal muscle cytochrome c oxidase subunit 4 and Complex I [pyruvate] OXPHOS capacity, p < 0.05). Treatment of primary human skeletal muscle cells (HSkMC) with sodium lactate for 24 h increased protein lactylation and IRS-1 serine 636 phosphorylation in a similar dose-dependent manner (p < 0.05). Inhibition of glycolysis (with 2-deoxy-d-glucose) or LDH-A (with sodium oxamate or LDH-A siRNA) for 24 h reduced HSkMC lactylation which paralleled reductions in culture media lactate accumulation. This study identified the existence of a lactate-derived post-translational modification in human skeletal muscle and suggests skeletal muscle lactylation could provide additional insight into the regulation of skeletal muscle metabolism, including insulin resistance.
Self-supervised learning for macromolecular structure classification based on cryo-electron tomograms
Authors: Gupta Tarun , He Xuehai , Uddin Mostofa Rafid , Zeng Xiangrui , Zhou Andrew , Zhang Jing , Freyberg Zachary , Xu Min
Published: August 2022

Macromolecular structure classification from cryo-electron tomography (cryo-ET) data is important for understanding macro-molecular dynamics. It has a wide range of applications and is essential in enhancing our knowledge of the sub-cellular environment. However, a major limitation has been insufficient labelled cryo-ET data. In this work, we use Contrastive Self-supervised Learning (CSSL) to improve the previous approaches for macromolecular structure classification from cryo-ET data with limited labels. We first pretrain an encoder with unlabelled data using CSSL and then fine-tune the pretrained weights on the downstream classification task. To this end, we design a cryo-ET domain-specific data-augmentation pipeline. The benefit of augmenting cryo-ET datasets is most prominent when the original dataset is limited in size. Overall, extensive experiments performed on real and simulated cryo-ET data in the semi-supervised learning setting demonstrate the effectiveness of our approach in macromolecular labeling and classification.
Expression of long noncoding RNA uc.375 in bronchopulmonary dysplasia and its function in the proliferation and apoptosis of mouse alveolar epithelial cell line MLE 12
Authors: Bao Tianping , Zhu Haiyan , Zheng Yafei , Hu Jingjing , Wang Huifang , Cheng Huaiping , Zhang Yuan , Tian Zhaofang
Published: August 2022

Background: According to our previous gene ChIP results, long noncoding RNA uc.375 was down-regulated in lung tissue of bronchopulmonary dysplasia (BPD) mice induced by hyperoxia. FoxA1 gene showed higher levels in lung tissue of BPD mice and is reported to promote the apoptosis of alveolar epithelial cells. We aimed to clarify the expression pattern of uc.375 in BPD and explore the interaction between uc.375 and FoxA1.

Methods: Newborn mice were placed in a 95% high-oxygen environment for 7 days. Lung tissue samples from mice were used for lncRNA microarray to screen BPD related lncRNAs. Mouse alveolar epithelial cell line MLE 12 was stably transfected with uc.375 and FoxA1 silencing or overexpression lentiviral vectors. The proliferation activity of MLE 12 cells was detected by a cell counting kit 8 (CCK-8) assay. MLE 12 cell apoptosis was determined by Hoechst/PI staining and flow cytometry analysis. The protein levels of Cleaved Caspase-3, FoxA1, SP-C and UCP2 were investigated by western blot. The relative mRNA expression levels were detected by quantitative real-time PCR.

Results: uc.375 is mainly distributed in the nucleus of alveolar epithelial cells, as revealed by In Situ Hybridization assay results. uc.375 was lowly expressed in the lung tissues of BPD mice. According to the results of CCK-8 assay, analysis of Hoechst/PI staining and western blotting, uc.375 silencing inhibited cell proliferation, facilitated apoptosis of MLE 12 cells, promoted caspase 3 and FoxA1 expression, and inhibited the expression of SP-C and UCP2. On the contrary, after overexpressing uc.375, the opposite results were obtained. Silencing FoxA1 inhibited MLE 12 apoptosis, promoted proliferation, inhibited apoptosis-related factor caspase 3, and promoted the expression of SP-C and UCP2. FoxA1 silencing also reversed the effect induced by uc.375 knockdown on the proliferation and apoptosis of MLE 12 cells.

Conclusion: Based on the biomedical images-derived analysis results, uc.375 negatively regulates FoxA1 expression, affects alveolar development, and plays an important role in the initiation and progression of BPD, providing a new molecular target for the prevention and treatment of BPD.
Physiological and muscle tissue responses in Litopenaeus vannamei under hypoxic stress via iTRAQ
Authors: Chang Fengtong , Li Na , Shi Xiang , Olga Volovych , Wang Xiaobing , Diao Xiaoping , Zhou Hailong , Tang Xianming
Published: August 2022

White L. vannamei have become the most widely cultivated shrimp species worldwide. Cultivation of L. vannamei is one of the predominant sectors in China’s aquaculture industry. This study focused on the physiological and biochemical responses, differential protein expression, and expression characteristics of the related crucial functional protein genes under low oxygen conditions among different strains of L. vannamei. It was found that 6 h of hypoxic stress caused a significant reduction in the total hemocyte number in both strains, while the hypoxia-sensitive strain showed a stronger reduction. In contrast, the hemocyanin concentration showed only an overall upward trend. Proteomic analysis of L. vannamei muscle tissue revealed 3,417 differential proteins after 12 h of hypoxic stress. Among them, 29 differentially expressed proteins were downregulated and 244 were upregulated in the hypoxia-sensitive strain. In contrast, there were only 10 differentially expressed proteins with a downregulation pattern and 25 with an upregulation pattern in the hypoxia-tolerant strain. Five protein genes that responded significantly to hypoxic stress were selected for quantitative real-time PCR analysis, namely, hemocyanin, chitinase, heat shock protein 90 (HSP 90), programmed death protein, and glycogen phosphorylase. The results showed that the gene expression patterns were consistent with proteomic experimental data except for death protein and glycogen phosphorylase. These results can enrich the general knowledge of hypoxic stress in L. vannamei and the information provided differentially expressed proteins which may be used to assist breeding programs of L. vannamei of new strains with tolerance to hypoxia.