bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic characterization and pathogenicity of H7N9 highly pathogenic avian influenza viruses isolated from South China in 2017
Authors: Zhao Bingbing , Wang Wenqing , Song Yating , Wen Xiangyang , Feng Siyu , Li Weiqiang , Ding Yangbao , Chen Zuxian , He Zhuoliang , Wang Shao , Jiao Peirong
Published: March 2023

Since 2017, the new H7N9 highly pathogenic avian influenza viruses (HPAIVs) have been responsible for more than 200,000 cases of chicken infection and more than 120,000 chicken deaths in China. Our previous study found that the Q26 was chicken-origin H7N9 HPAIV. In this study, we analyzed the genetic characterization of Q24, Q65, Q66, Q85, and Q102 H7N9 avian influenza viruses isolated from Guangdong, China in 2017. Our results showed that these viruses were highly pathogenic and belonged to two different genotypes, which suggested they occurred genetic reassortant. To investigate the pathogenicity, transmission, and host immune responses of H7N9 virus in chickens, we selected Q24 and Q26 viruses to inoculate chickens. The Q24 and Q26 viruses killed all inoculated chickens within 3 days and replicated effectively in all tested tissues. They were efficiently transmitted to contact chickens and killed them within 4 days through direct contact. Furthermore, we found that the expressions of several immune-related genes (e.g., TLR3, TLR7, MDA5, MAVS, IFN-β, IL-6, IL-8, OAS, Mx1, MHC I, and MHC II) were upregulated obviously in the lungs and spleen of chickens inoculated with the two H7N9 viruses at 24 h post-inoculation (HPI). Among these, IL-6 and IFN-β in lungs were the most upregulated (by 341.02–381.48-fold and 472.50–500.56-fold, respectively). These results suggest that the new H7N9 viruses isolated in 2017, can replicate and transmit effectively and trigger strong immune responses in chickens, which helps us understand the genetic and pathogenic variations of H7N9 HPAIVs in China.
Mycobacterial IHF is a highly dynamic nucleoid-associated protein that assists HupB in organizing chromatin
Authors: Hołówka Joanna , Łebkowski Tomasz , Feddersen Helge , Giacomelli Giacomo , Drużka Karolina , Makowski Łukasz , Trojanowski Damian , Broda Natalia , Bramkamp Marc , Zakrzewska-Czerwińska Jolanta
Published: March 2023

Nucleoid-associated proteins (NAPs) crucially contribute to organizing bacterial chromatin and regulating gene expression. Among the most highly expressed NAPs are the HU and integration host factor (IHF) proteins, whose functional homologues, HupB and mycobacterial integration host factor (mIHF), are found in mycobacteria. Despite their importance for the pathogenicity and/or survival of tubercle bacilli, the role of these proteins in mycobacterial chromosome organization remains unknown. Here, we used various approaches, including super-resolution microscopy, to perform a comprehensive analysis of the roles of HupB and mIHF in chromosome organization. We report that HupB is a structural agent that maintains chromosome integrity on a local scale, and that the lack of this protein alters chromosome morphology. In contrast, mIHF is a highly dynamic protein that binds DNA only transiently, exhibits susceptibility to the chromosomal DNA topology changes and whose depletion leads to the growth arrest of tubercle bacilli. Additionally, we have shown that depletion of Mycobacterium smegmatis integration host factor (msIHF) leads to chromosome shrinkage and replication inhibition.
Learning robotic manipulation skills with multiple semantic goals by conservative curiosity-motivated exploration
Authors: Han Changlin , Peng Zhiyong , Liu Yadong , Tang Jingsheng , Yu Yang , Zhou Zongtan
Published: March 2023

Reinforcement learning (RL) empowers the agent to learn robotic manipulation skills autonomously. Compared with traditional single-goal RL, semantic-goal-conditioned RL expands the agent capacity to accomplish multiple semantic manipulation instructions. However, due to sparsely distributed semantic goals and sparse-reward agent-environment interactions, the hard exploration problem arises and impedes the agent training process. In traditional RL, curiosity-motivated exploration shows effectiveness in solving the hard exploration problem. However, in semantic-goal-conditioned RL, the performance of previous curiosity-motivated methods deteriorates, which we propose is because of their two defects: uncontrollability and distraction. To solve these defects, we propose a conservative curiosity-motivated method named mutual information motivation with hybrid policy mechanism (MIHM). MIHM mainly contributes two innovations: the decoupled-mutual-information-based intrinsic motivation, which prevents the agent from being motivated to explore dangerous states by uncontrollable curiosity; the precisely trained and automatically switched hybrid policy mechanism, which eliminates the distraction from the curiosity-motivated policy and achieves the optimal utilization of exploration and exploitation. Compared with four state-of-the-art curiosity-motivated methods in the sparse-reward robotic manipulation task with 35 valid semantic goals, including stacks of 2 or 3 objects and pyramids, our MIHM shows the fastest learning speed. Moreover, MIHM achieves the highest 0.9 total success rate, which is up to 0.6 in other methods. Throughout all the baseline methods, our MIHM is the only one that achieves to stack three objects.
Treatment of multiple sclerosis with rituximab: A Spanish multicenter experience
Authors: Gascón-Giménez Francisco , Alcalá Carmen , Ramió-Torrentà Lluís , Montero Paloma , Matías-Guiu Jorge , Gómez-Estevez Irene , Oreja-Guevara Celia , Gil-Perotín Sara , Blanco Yolanda , Carcelén María , Quintanilla-Bordás Carlos , Costa Lucienne , Villar Luisa Maria , Martínez-Rodriguez Jose Enrique , Domínguez José Andrés , Calles Carmen , González Inés , Sotoca Javier , Oterino Agustin , Lucas-Jimenez Celia , Pérez-Miralles Francisco , Casanova Bonaventura
Published: March 2023

Introduction

Rituximab (RTX) is considered a potential therapeutic option for relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS). The main objective of this work was to investigate the effectiveness and safety of rituximab in MS.

Patients and methods

Observational multicenter study of clinical and radiological effectiveness and safety of rituximab in RRMS and PMS.

Results

A total of 479 rituximab-treated patients were included in 12 Spanish centers, 188 RRMS (39.3%) and 291 (60.7%) PMS. Despite standard treatment, the annualized relapse rate (ARR) the year before RTX was 0.63 (SD: 0.8) and 156 patients (41%) had at least one gadolinium-enhanced lesion (GEL) on baseline MRI. Mean EDSS had increased from 4.3 (SD: 1.9) to 4.8 (SD: 1.7) and almost half of the patients (41%) had worsened at least one point. After a median follow-up of 14.2 months (IQR: 6.5–27.2), ARR decreased by 85.7% (p < 0.001) and GEL by 82.9%, from 0.41 to 0.07 (p < 0.001). A significant decrease in EDSS to 4.7 (p = 0.046) was observed after 1 year of treatment and this variable remained stable during the second year of therapy. There was no evidence of disease activity in 68% of patients. Infusion-related symptoms were the most frequent side effect (19.6%) and most were mild. Relevant infections were reported only in 18 patients (including one case of probable progressive multifocal leukoencephalopathy).

Conclusion

Rituximab could be an effective and safe treatment in RRMS, including aggressive forms of the disease. Some selected PMS patients could also benefit from this treatment.
Case report: Cerebrotendinous xanthomatosis with a novel mutation in the CYP27A1 gene mimicking behavioral variant frontotemporal dementia
Authors: Chun Min Young , Heo Nam Jin , Seo Sang Won , Jang Hyemin , Suh Yeon-Lim , Jang Ja-Hyun , Kim Young-Eun , Kim Eun-Joo , Moon So Young , Jung Na-Yeon , Lee Sun Min , Kim Hee Jin
Published: March 2023

Background

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease caused by a mutation in the CYP27A1 gene. Due to the disruption of bile acid synthesis leading to cholesterol and cholestanol accumulation, CTX manifests as premature cataracts, chronic diarrhea, and intellectual disability in childhood and adolescence. This report presents a case of CTX with an unusual phenotype of behavioral variant frontotemporal dementia (bvFTD) in middle age.

Case presentation

A 60-year-old woman presented with behavioral and personality changes. She showed disinhibition, such as hoarding and becoming aggressive over trifles; compulsive behavior, such as closing doors; apathy; and dietary change. The patient showed a progressive cognitive decline and relatively sparing memory and visuospatial function. She had hyperlipidemia but no family history of neurodegenerative disorders. Initial fluid-attenuated inversion recovery (FLAIR) images showed a high signal in the periventricular area, and brain spectroscopy showed hypoperfusion in the frontal and temporal lobes, mimicking bvFTD. However, on physical examination, xanthomas were found on both the dorsum of the hands and the Achilles tendons. Hyperactive deep tendon reflexes in the bilateral biceps, brachioradialis, and knee and positive Chaddock signs on both sides were observed. Four years later, FLAIR images showed symmetrical high signals in the bilateral dentate nuclei of the cerebellum. Her serum cholestanol (12.4 mg/L; normal value ≤6.0) and 7α,12α-dihydroxycholest-4-en-3-one (0.485 nmol/mL; normal value ≤0.100) levels were elevated. A novel likely pathogenic variant (c.1001T>A, p.Met334Lys) and a known pathogenic variant (c.1420C>T, p.Arg474Trp) of the CYP27A1 gene were found in trans-location. The patient was diagnosed with CTX and prescribed chenodeoxycholic acid (750 mg/day).

Conclusions

This report discusses the case of a middle-aged CTX patient with an unusual phenotype of bvFTD. A novel likely pathogenic variant (c.1001T>A, p.Met334Lys) was identified in the CYP27A1 gene. Early diagnosis is important because supplying chenodeoxycholic acid can prevent CTX progression.
Active monitoring improves radiopharmaceutical administration quality
Authors: Crowley James R. , Barvi Iryna , Kiser Jackson W.
Published: March 2023

Introduction

In 2016, our center adopted technology to routinely monitor 18F-FDG radiopharmaceutical administrations. Within six months of following basic quality improvement methodology, our technologists reduced extravasation rates from 13.3% to 2.9% (p < 0.0001). These same technologists administer other radiopharmaceuticals (without monitoring technology) for general nuclear medicine procedures in a separate facility at the clinic. Our hypothesis was that they would apply 18F-FDG lessons-learned to 99mTc-MDP administrations and that 99mTc-MDP manual injection extravasation rate would be consistent with the ongoing 18F-FDG manual injection extravasation rate (3.4%). We tested our hypothesis by following the same quality improvement methodology and added monitoring equipment to measure extravasation rates for 99mTc-MDP administrations.

Results

816 99mTc-MDP administrations were monitored during 16-month period (four 4-month periods: A, B, C, D). Period A (first four months of active monitoring) extravasation rate was not statistically different from the Measure Phase extravasation rate of the previously completed PET/CT QI Project: 12.75% compared to 13.3% (p-0.7925). Period A extravasation rate was statistically different from Period C (months 9–12) extravasation rate and Period D (months 13–16) extravasation rate: 12.75% compared to 2.94% and to 3.43% (p < 0.0001). During Period C and D technologists achieved extravasation rates comparable to the longstanding manual 18F-FDG injection extravasation rate (3.4%).

Conclusion

Our initial hypothesis, that awareness of a problem and the steps need to correct it would result in process improvement, was not accurate. While those factors are important, they are not sufficient. Our findings suggest that active monitoring and the associated display of results are critical to quality improvement efforts to reduce and sustain radiopharmaceutical extravasation rates.
Ketogenic therapies for glioblastoma: Understanding the limitations in transitioning from mice to patients
Authors: Clontz Angela D.
Published: March 2023

Glioblastoma Multiforme is an aggressive brain cancer affecting children and adults frequently resulting in a short life expectancy. Current cancer therapies include surgery and radiation followed by chemotherapy, which due to their ineffectiveness, requires repeated exposure to the same therapies. Since the 1990s, researchers and doctors have explored other therapies, such as diet therapies, to aid in combating gliomas. The ketogenic diet has gained popularity due to Otto Warburg’s theory that tumor cells prefer “aerobic glycolysis” and cannot metabolize ketones. The inability of gliomas to use ketones provides an excellent opportunity to weaken the tumor while protecting healthy cells during cancer treatments. This review will examine some of the current research using the ketogenic diet as a form of cancer therapy to determine if this intervention is manageable and effective in patients with glioblastoma. Peer-reviewed articles from 2009 to 2019 were used. The primary objective is to distinguish differences between pre-clinical and clinical research to determine if the ketogenic diet is reproducible from mouse models into humans to determine its effectiveness. The analysis revealed several limitations of the ketogenic diet as an intervention. The effectiveness is more robust in mice than in human studies. Furthermore, tolerability is marginally supported in human studies requiring more reproducible research to validate that the intervention is manageable and effective in patients with glioblastoma.
Decreased transthyretin predicts a poor prognosis in primary myelodysplastic syndrome
Authors: Chen Ying , Niu Tingting , Chen Ting , Wu Yue , Zou Duobing , Shi Cong , Wu Ying , Zhang Zhaoyi , Wu Ningning , Zhang Yi , Yan Xiao , Sheng Lixia , Lv Dingfeng , Ouyang Guifang , Chen Xueqin , Mu Qitian
Published: March 2023

Background

This study aims to investigate the prognostic significance of transthyretin in newly diagnosed myelodysplastic syndromes (MDS).

Methods

The clinical, laboratory, and follow-up data of 280 newly diagnosed patients with MDS were collected. The relationship between serum transthyretin levels and overall survival (OS) and leukemia-free survival (LFS) were analyzed by Kaplan–Meier analysis and Cox Regression Model.

Result

In the MDS cohort, there were 121 cases in the low transthyretin group and 159 cases in the normal transthyretin group. MDS patients with decreased transthyretin had a higher risk score on the Revised International Prognostic Scoring System (IPSS-R) (p = 0.004) and on the molecular IPSS (IPSS-M) (p = 0.005), a higher frequency of TP53 mutation (p < 0.0001), a shorter OS (p < 0.0001) and LFS (p < 0.0001). Multivariate analyses showed that higher IPSS-R and IPSS-M score were adverse factors for OS (p = 0.008 and p = 0.015, respectively) and LFS (p = 0.024 and p = 0.005, respectively). Mutations of TP53 and NRAS were also poor factors for LFS (p = 0.034 and p = 0.018, respectively). Notably, decreased transthyretin was an independent adverse predictor for OS (p = 0.009, HR = 0.097, 95%CI, 0.017–0.561) but not for LFS (p = 0.167) when IPSS-R was included in the Cox regression model and an independent poor one for OS (p = 0.033, HR = 0.267, 95%CI, 0.080–0.898) and LFS (p = 0.024, HR = 0.290, 95%CI, 0.099–0.848) while IPSS-M involved.

Conclusion

The results indicate that decreased transthyretin could be an independent adverse prognostic factor in patients with MDS and may provide a supplement to IPSS-R and IPSS-M.
Plasma-only circulating tumor DNA analysis detects minimal residual disease and predicts early relapse in hepatocellular carcinoma patients undergoing curative resection
Authors: Xu Yuyan , Cai Jianpeng , Zhong Kaihang , Wen Yaohong , Cai Lei , He Guolin , Liao Hangyu , Zhang Cheng , Fu Shunjun , Chen Tingting , Cai Jinping , Zhong Xuefeng , Chen Chunzhu , Huang Mengli , Cheng Yuan , Pan Mingxin
Published: March 2023

Background

Minimal residual disease (MRD) is considered an essential factor leading to relapse within 2 years (early relapse) after radical surgery, which is challenging to be detected by conventional imaging. Circulating tumor DNA (ctDNA) provides a novel approach for detecting MRD and predicting clinical outcomes. Here, we tried to construct a fixed panel for plasma-only ctDNA NGS to enable tumor-uninformed MRD detection in hepatocellular carcinoma (HCC).

Methods

Here, we performed the followings: (i) profiling genomic alteration spectrum of ctDNA from the Chinese HCC cohort consisting of 493 individuals by NGS; (ii) screening of MRD monitoring genes; and (iii) performance evaluation of MRD monitoring genes in predicting early relapse in the ZJZS2020 cohort comprising 20 HCC patients who underwent curative resection.

Results

A total of 493 plasma samples from the Chinese HCC cohort were detected using a 381/733-gene NGS panel to characterize the mutational spectrum of ctDNA. Most patients (94.1%, 464/493) had at least one mutation in ctDNA. The variants fell most frequently in TP53 (45.1%), LRP1B (20.2%), TERT (20.2%), FAT1 (16.2%), and CTNNB1 (13.4%). By customized filtering strategy, 13 MRD monitoring genes were identified, and any plasma sample with one or more MRD monitoring gene mutations was considered MRD-positive. In the ZJZS2020 cohort, MRD positivity presented a sensitivity of 75% (6/8) and a specificity of 100% (6/6) in identifying early postoperative relapse. The Kaplan-Meier analysis revealed a significantly short relapse-free survival (RFS; median RFS, 4.2 months vs. NR, P=0.002) in the MRD-positive patients versus those with MRD negativity. Cox regression analyses revealed MRD positivity as an independent predictor of poor RFS (HR 13.00, 95% CI 2.60-69.00, P=0.002).

Conclusions

We successfully developed a 13-gene panel for plasma-only MRD detection, which was effective and convenient for predicting the risk of early postoperative relapse in HCC.
Identification and verification of the temozolomide resistance feature gene DACH1 in gliomas
Authors: Gu Qiang , Li Lang , Yao Jiahao , Dong Fa-yan , Gan Yifan , Zhou Shuhuai , Wang Xinyu , Wang Xue-feng
Published: March 2023

Introduction

The most important chemotherapy treatment for glioma patients is temozolomide. However, the development of drug resistance severely restricts the use of temozolomide. Therefore, elucidating the mechanism of temozolomide resistance, enhancing temozolomide sensitivity, and extending patient survival are urgent tasks for researchers.

Methods

Temozolomide resistance hub differential genes were identified using differential analysis and protein interaction analysis from the GEO datasets (GSE100736 and GSE113510). These genes were further studied in glioma patients treated with temozolomide in the TCGA and CGGA databases. Patients from the mRNAseq_325 dataset (CGGA) were considered as the training set to construct a risk model for predicting glioma sensitivity to temozolomide, while patients from the mRNAseq_693 dataset (CGGA) and TCGA-GBM dataset were considered as the validation set to evaluate the performance of models. PCR and western blot were performed to determine the difference in expression of the feature gene DACH1 between glioma cells and temozolomide-resistant glioma cells. The alterations in the sensitivity of tumor cells to temozolomide were also observed after DACH1 was silenced. The patients were then divided into two groups based on the expression of DACH1, and the differences in patient survival rates, molecular pathway activation, and level of immune infiltration were compared.

Results

Based on four signature genes (AHR, DACH1, MGMT, and YAP1), a risk model for predicting glioma sensitivity to temozolomide was constructed, and the results of timeROC in both the training and validation sets showed that the model had good predictive performance. The expression of the signature gene DACH1 was significantly downregulated in temozolomide-resistant cells, according to the results of the PCR and western blot experiments. The sensitivity of tumor cells to temozolomide was significantly reduced after DACH1 was silenced. DACH1 probably regulates temozolomide resistance in glioblastoma through the transcriptional dysregulation in cancer and ECM.

Discussion

This study constructs a risk model that can predict glioma susceptibility to temozolomide and validates the function of the feature gene DACH1, which provides a promising target for the research of temozolomide resistance.
JNJ-64619178 radiosensitizes and suppresses fractionated ionizing radiation-induced neuroendocrine differentiation (NED) in prostate cancer
Authors: Pawar Jogendra Singh , Al-Amin Md. Yusuf , Hu Chang-Deng
Published: March 2023

Background

Radiation therapy (RT) is a standard treatment regimen for locally advanced prostate cancer; however, its failure results in tumor recurrence, metastasis, and cancer-related death. The recurrence of cancer after radiotherapy is one of the major challenges in prostate cancer treatment. Despite overall cure rate of 93.3% initially, prostate cancer relapse in 20-30% patients after radiation therapy. Cancer cells acquire radioresistance upon fractionated ionizing radiation (FIR) treatment, eventually undergo neuroendocrine differentiation (NED) and transform into neuroendocrine-like cells, a mechanism involved in acquiring resistance to radiation therapy. Radiosensitizers are agents that inhibit the repair of radiation-induced DNA damage. Protein arginine methyltransferase 5 (PRMT5) gets upregulated upon ionizing radiation treatment and epigenetically activates DNA damage repair genes in prostate cancer cells. In this study, we targeted PRMT5 with JNJ-64619178 and assessed its effect on DNA damage repair gene activation, radiosensitization, and FIR-induced NED in prostate cancer.

Methods

γH2AX foci analysis was performed to evaluate the DNA damage repair after radiation therapy. RT-qPCR and western blot were carried out to analyze the expression of DNA damage repair genes. Clonogenic assay was conducted to find out the surviving fraction after radiation therapy. NED was targeted with JNJ-64619178 in androgen receptor (AR) positive and negative prostate cancer cells undergoing FIR treatment.

Results

JNJ-64619178 inhibits DNA damage repair in prostate cancer cells independent of their AR status. JNJ-64619178 impairs the repair of ionizing radiation-induced damaged DNA by transcriptionally inhibiting the DNA damage repair gene expression and radiosensitizes prostate, glioblastoma and lung cancer cell line. It targets NED induced by FIR in prostate cancer cells.

Conclusion

JNJ-64619178 can radiosensitize and suppress NED induced by FIR in prostate cancer cells and can be a potential radiosensitizer for prostate cancer treatment.
Thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): Real world data of a Greek nationwide multicenter retrospective study
Authors: Chatzileontiadou S. , Hatjiharissi E. , Angelopoulou M. , Asimakopoulos J. V. , Loutsidi N. E. , Chatzikonstantinou T. , Zikos P. , Bouchla A. , Bezirgiannidou Z. , Kouvata E. , Frouzaki C. , Chaloudis P. , Sotiropoulos D. , Douka V. , Sirigou A. , Mandala E. , Psyllaki M. , Papadaki H. A. , Marinakis T. , Viniou N. A. , Kokkori S. , Kontopidou F. , Skepetari A. , Vassilopoulos G. , Kotsianidis I. , Pappa V. , Lalayanni C. , Baltadakis I. , Delimpassi S. , Pagoni M. , Papaioannou M.
Published: March 2023

Thrombosis is the most common and a life-threatening complication in patients with Paroxysmal Nocturnal Hemoglobinuria. One-third of patients with PNH experience at least one thromboembolic event during the course of the disease, with thrombosis being the most common cause of death in these patients. The mechanism of thrombosis in PNH is complex and continues to be of great research interest. Since the introduction of C5 complement inhibitors in the treatment of PNH, the incidence of thromboembolic events has decreased substantially. We retrospectively analyzed data concerning the thrombotic episodes of 41 patients with PNH from 14 different national hematology centers in Greece. Sixteen patients (39%) experienced at least one episode of thrombosis, including, seven (43.8%) at diagnosis, seven (43.8%) during the course of the disease and two (12.5%) patients prior to PNH diagnosis. Nearly half of these individuals (n=7, 43.8%) had multiple episodes of thrombosis during the course of their disease. The most common sites of thrombosis were intra-abdominal veins. Three out of 26 patients developed thrombosis while on eculizumab. In none of the 16 patients, the thrombotic event was fatal. Our findings, despite the small number of patients, confirmed that thrombosis continues to be a significant complication of PNH affecting more than one third of the patients.
Development and validation of survival prediction model for gastric adenocarcinoma patients using deep learning: A SEER-based study
Authors: Zeng Junjie , Li Kai , Cao Fengyu , Zheng Yongbin
Published: March 2023

Background

The currently available prediction models, such as the Cox model, were too simplistic to correctly predict the outcome of gastric adenocarcinoma patients. This study aimed to develop and validate survival prediction models for gastric adenocarcinoma patients using the deep learning survival neural network.

Methods

A total of 14,177 patients with gastric adenocarcinoma from the Surveillance, Epidemiology, and End Results (SEER) database were included in the study and randomly divided into the training and testing group with a 7:3 ratio. Two algorithms were chosen to build the prediction models, and both algorithms include random survival forest (RSF) and a deep learning based-survival prediction algorithm (DeepSurv). Also, a traditional Cox proportional hazard (CoxPH) model was constructed for comparison. The consistency index (C-index), Brier score, and integrated Brier score (IBS) were used to evaluate the model’s predictive performance. The accuracy of predicting survival at 1, 3, 5, and 10 years was also assessed using receiver operating characteristic curves (ROC), calibration curves, and area under the ROC curve (AUC).

Results

Gastric adenocarcinoma patients were randomized into a training group (n = 9923) and a testing group (n = 4254). DeepSurv showed the best performance among the three models (c-index: 0.772, IBS: 0.1421), which was superior to that of the traditional CoxPH model (c-index: 0.755, IBS: 0.1506) and the RSF with 3-year survival prediction model (c-index: 0.766, IBS: 0.1502). The DeepSurv model produced superior accuracy and calibrated survival estimates predicting 1-, 3- 5- and 10-year survival (AUC: 0.825-0.871).

Conclusions

A deep learning algorithm was developed to predict more accurate prognostic information for gastric cancer patients. The DeepSurv model has advantages over the CoxPH and RSF models and performs well in discriminative performance and calibration.
The role of artificial intelligence based on PET/CT radiomics in NSCLC: Disease management, opportunities, and challenges
Authors: Hu Qiuyuan , Li Ke , Yang Conghui , Wang Yue , Huang Rong , Gu Mingqiu , Xiao Yuqiang , Huang Yunchao , Chen Long
Published: March 2023

Objectives

Lung cancer has been widely characterized through radiomics and artificial intelligence (AI). This review aims to summarize the published studies of AI based on positron emission tomography/computed tomography (PET/CT) radiomics in non-small-cell lung cancer (NSCLC).

Materials and methods

A comprehensive search of literature published between 2012 and 2022 was conducted on the PubMed database. There were no language or publication status restrictions on the search. About 127 articles in the search results were screened and gradually excluded according to the exclusion criteria. Finally, this review included 39 articles for analysis.

Results

Classification is conducted according to purposes and several studies were identified at each stage of disease:1) Cancer detection (n=8), 2) histology and stage of cancer (n=11), 3) metastases (n=6), 4) genotype (n=6), 5) treatment outcome and survival (n=8). There is a wide range of heterogeneity among studies due to differences in patient sources, evaluation criteria and workflow of radiomics. On the whole, most models show diagnostic performance comparable to or even better than experts, and the common problems are repeatability and clinical transformability.

Conclusion

AI-based PET/CT Radiomics play potential roles in NSCLC clinical management. However, there is still a long way to go before being translated into clinical application. Large-scale, multi-center, prospective research is the direction of future efforts, while we need to face the risk of repeatability of radiomics features and the limitation of access to large databases.
Clinical characteristics of meconium aspiration syndrome in neonates with different gestational ages and the risk factors for neurological injury and death: A 9-year cohort study
Authors: Luo Lei , Zhang Meng , Tang Jun , Li Wenxing , He Yang , Qu Yi , Mu Dezhi
Published: March 2023

Background

The presence of meconium is associated with gestational age, and the incidence of meconium aspiration syndrome (MAS) increases with gestational age. Our study compared the differences in the clinical characteristics of patients with MAS at different gestational ages and discussed the risk factors for neurological injury and death from MAS.

Methods

A total of 294 neonates diagnosed with MAS between 2013 and 2021 were included. Patients were divided into preterm, early-term, full-term, and late-term groups according to gestational age. We compared the patients’ basic demographic, treatment, complications, and clinical outcomes in the different groups. We also analyzed the risk factors of neurological injury and death in patients with MAS.

Results

The mean age at admission (0.55 ± 0.9 h) was lower and the proportion of cesarean deliveries (90.00%, 27/30) was higher in the preterm group than in the other three groups. There was no statistically significant difference among the four groups regarding 1- and 5-min Apgar scores and the need for delivery room resuscitation. In terms of complications, early-term infants had the highest incidence of neurological injury (52.9%, 27/51), and late-term infants had the highest incidence of pneumothorax (37.8%, 17/45). The overall mortality rate of children with MAS was 7.80% (23/294), and the difference in mortality rates among the four groups was not significant. Low 1-min Apgar score and gestational age, metabolic acidosis, and respiratory failure were independent risk factors for neurological injury; metabolic acidosis, respiratory failure, and sepsis were independent risk factors for death in neonates with MAS.

Conclusion

The clinical characteristics of MAS neonates of different gestational age are different mainly in complications. Early-term infants are more likely to complicate with neurological injury, and late-term infants are more likely to complicate with pneumothorax. Low 1-min Apgar score and gestational age, metabolic acidosis, and respiratory failure were established as risk factors for neurological injury; metabolic acidosis, respiratory failure, and sepsis were independent risk factors for death in neonates with MAS.
UBA1 inhibition contributes radiosensitization of glioblastoma cells via blocking DNA damage repair
Authors: Wu Changyong , Shen Yang , Shi Lin , Zhang Junhao , Guo Tongxuan , Zhou Lingni , Wang Wanzhou , Zhang Xu , Yu Rutong , Liu Xuejiao
Published: March 2023

Glioblastoma multiforme (GBM) is a brain tumor with high mortality and recurrence rate. Radiotherapy and chemotherapy after surgery are the main treatment options available for GBM. However, patients with glioblastoma have a grave prognosis. The major reason is that most GBM patients are resistant to radiotherapy. UBA1 is considered an attractive potential anti-tumor therapeutic target and a key regulator of DNA double-strand break repair and genome replication in human cells. Therefore, we hypothesized that TAK-243, the first-in-class UBA1 inhibitor, might increase GBM sensitivity to radiation. The combined effect of TAK-243 and ionizing radiation on GBM cell proliferation, and colony formation ability was detected using CCK-8, colony formation, and EdU assays. The efficacy of TAK-243 combined with ionizing radiation for GBM was further evaluated in vivo, and the mechanism of TAK-243 sensitizing radiotherapy was preliminarily discussed. The results showed that TAK-243, in combination with ionizing radiation, significantly inhibited GBM cell proliferation, colony formation, cell cycle arrest in the G2/M phase, and increased the proportion of apoptosis. In addition, UBA1 inhibition by TAK-243 substantially increased the radiation-induced γ-H2AX expression and impaired the recruitment of the downstream effector molecule 53BP1. Therefore, TAK-243 inhibited the radiation-induced DNA double-strand break repair and thus inhibited the growth of GBM cells. Our results provided a new therapeutic strategy for improving the radiation sensitivity of GBM and laid a theoretical foundation and experimental basis for further clinical trials.
Aqueous extract of Salvia miltiorrhiza Bunge reduces blood pressure through inhibiting oxidative stress, inflammation and fibrosis of adventitia in primary hypertension
Authors: Wu Ruoyu , Zhou Yongjie , Xu Hongjun , Zhao Wei , Zhou Luyang , Zhao Yilin , Cui Qingzhuo , Ning Junda , Chen Hongxu , An Shengjun
Published: March 2023

Graphical Abstract

SABP, an optimized compatibility of four hydrophilic metabolites (DSS, Sal-A, Sal-B and PAL) from Salvia miltiorrhiza Bunge, can reduce the systolic blood pressure in SHR through its antioxidant, anti-inflammatory, anti-vascular remodeling and anti-fibrosis effects.
Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damage
Authors: Zeng Jianhua , Huang Hao , Zhang Yan , Lv Xin , Cheng Jiawei , Zou Si Jue , Han Yuanyuan , Wang Songkai , Gong Li , Peng Zhangzhe
Published: March 2023

Renal fibrosis is a common pathological outcome of various chronic kidney diseases, and as yet, there is no specific treatment. Dapagliflozin has shown renal protection in some clinical trials as a glucose-lowering drug, but its role and mechanism on renal fibrosis remain unclear. In this study, we used a 0.2% adenine diet-induced renal fibrosis mouse model to investigate whether dapagliflozin could protect renal function and alleviate renal fibrosis in this animal model. In vivo, we found that dapagliflozin’s protective effect on renal fibrosis was associated with 1) sustaining mitochondrial integrity and respiratory chain complex expression, maintained the amount of mitochondria; 2) improving fatty acid oxidation level with increased expression of CPT1-α, PPAR-α, ACOX1, and ACOX2; 3) reducing inflammation and oxidative stress, likely via regulation of IL-1β, IL-6, TNF-α, MCP-1, cxcl-1 expression, and glutathione (GSH) activity, superoxide dismutase (SOD) and malondialdehyde (MDA) levels; and 4) inhibiting the activation of the TGF-β1/MAPK pathway. In HK2 cells treated with TGF-β1, dapagliflozin reduced the expression of FN and α-SMA, improved mitochondrial respiratory chain complex expression, and inhibited activation of the TGF-β1/MAPK pathway.
Physics informed neural networks for phase field fracture modeling enhanced by length-scale decoupling degradation functions
Authors: Lian Haojie , Zhao Peiyun , Zhang Mengxi , Wang Peng , Li Yongsong
Published: March 2023

The paper proposed a novel framework for efficient simulation of crack propagation in brittle materials. In the present work, the phase field represents the sharp crack surface with a diffuse fracture zone and captures the crack path implicitly. The partial differential equations of the phase field models are solved with physics informed neural networks (PINN) by minimizing the variational energy. We introduce to the PINN-based phase field model the degradation function that decouples the phase-field and physical length scales, whereby reducing the mesh density for resolving diffuse fracture zones. The numerical results demonstrate the accuracy and efficiency of the proposed algorithm.
Early platelet level reduction as a prognostic factor in intensive care unit patients with severe aspiration pneumonia
Authors: Wang Li-Na , He Dai-Kun , Shao Yi-Ru , Lv Jiang , Wang Peng-Fei , Ge Ying , Yan Wei
Published: March 2023

Introduction: This study investigates risk factors underlying the prognosis of severe aspiration pneumonia (SAP) in intensive care unit (ICU) patients and attempts to provide early prognosis reference for clinical tasks.

Methods: Patients diagnosed with SAP and admitted to the ICU of Jinshan Hospital, Fudan University, Shanghai, China, between January 2021 and December 2021 were recruited in this retrospective cohort study. Clinical data on a patient’s general condition, underlying diseases, laboratory indicators, and 90-day outcomes (survival or death) were recorded.

Results: Multivariate logistic regression analysis showed that a low platelet count was an independent risk factor affecting the prognosis of death (OR = 6.68, 95% CI:1.10–40.78, β = 1.90, P = 0.040). Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of variables; cut-off values were calculated and the area under the curve was 0.7782 [(95% CI:0.686–0.871), p < 0.001] for the prediction of death at 90 days in all patients. The Kaplan-Meier curve used for survival analysis showed that, compared with the normal platelet group, the overall survival rate of patients with low platelet levels was significantly lower, and the difference was statistically significant [HR = 2.11, (95% CI:1.47–3.03), p = 0.0001, z = 4.05, X2 = 14.89]. Cox regression analysis, used to further verify the influence of prognostic risk factors, showed that a concurrent low platelet count was the most important independent risk factor affecting the prognosis of SAP (HR = 2.12 [95% CI:1.12–3.99], X2 = 50.95, p = 0.021).

Conclusion: These findings demonstrate an association between SAP mortality and platelet levels on admission. Thus, platelet level at admission may be used as a readily available marker for assessing the prognosis of patients with SAP.
Sex hormone-mediated change on muscle activation deactivation dynamics in young eumenorrheic women
Authors: Soedirdjo Subaryani D. H. , Rodriguez Luis A. , Chung Yu-Chen , Casey Ellen , Dhaher Yasin Y.
Published: March 2023

The goal of the study was to characterize muscle activation/deactivation dynamics across the menstrual cycle in healthy young women. Twenty-two healthy eumenorrheic women (age: 27.0 ± 4.4 years; mean ± SD) were tested every other day for one menstrual cycle. Serum estradiol and progesterone were quantified at the time of testing. Peak torque (PT), time to peak torque (TPT), and half relaxation time (HRT) of soleus muscle twitch were measured. Muscle twitch was elicited by delivering 1 ms width electrical pulses to the tibial nerve at an intensity that generated a maximum motor response (S-100) and at supramaximal intensity (S-120; 1.2 × S-100). The analyses were performed for each menstrual cycle phase: 1) the follicular phase to analyze the effect of estradiol while the progesterone concentrations remained at low concentrations; 2) the luteal phase to analyze the effect of progesterone with background estradiol concentrations. In the follicular phase, there was no association of estradiol for PT, TPT, and HRT. In the luteal phase, while estradiol had no association on PT, TPT, and HRT, progesterone expressed a significant association with HRT reduction but no association on PT or TPT. Also, there was a significant estradiol and progesterone interaction for HRT. However, the regression parameters are nearly zero, suggesting that the change in HRT may not have an impact on muscle performance across the menstrual cycle but implications on other women’s health conditions with elevated sex hormone concentrations, such as pregnancy, may prove critical.
Correlation between acylcarnitine/free carnitine ratio and cardiopulmonary exercise test parameters in patients with incident dialysis
Authors: Ito Wataru , Uchiyama Kiyotaka , Mitsuno Ryunosuke , Sugita Erina , Nakayama Takashin , Ryuzaki Toshinobu , Takahashi Rina , Katsumata Yoshinori , Hayashi Kaori , Kanda Takeshi , Washida Naoki , Sato Kazuki , Itoh Hiroshi
Published: March 2023

Objective: Diminished physical capacity is common and progressive in patients undergoing dialysis, who are also prone to deficiency in carnitine, which plays a pivotal role in maintaining skeletal muscle and cardiac function. The present study aimed to evaluate the association of carnitine profile with exercise parameters in patients with incident dialysis.

Design and Methods: This was a single-center cross-sectional study including 87 consecutive patients aged 20–90 years who were initiated on dialysis in Keio University Hospital between December 2019 and December 2022 and fulfilled the eligibility criteria. Exercise parameters were evaluated via cardiopulmonary testing (CPX) using the electronically braked STRENGTH ERGO 8 ergometer, whereas the carnitine profile was assessed by determining serum free carnitine (FC), acylcarnitine (AC) levels and AC/FC ratio.

Results: The mean cohort age was 62.1 ± 15.2 years, with male and hemodialysis predominance (70% and 73%, respectively). AC/FC was 0.46 ± 0.15, and CPX revealed peak oxygen consumption (VO2) of 13.9 ± 3.7 (mL/kg/min) with percent-predicted peak VO2 of 53.6% ± 14.7% and minute ventilation (VE)/carbon dioxide output (VCO2) slope of 35.1 ± 8.0. Fully-adjusted multivariate linear regression analysis showed that AC/FC was significantly associated with decreased peak VO2 (β, −5.43 [95% confidence interval (CI), −10.15 to −0.70]) and percent-predicted peak VO2 (β, −19.98 [95% CI, −38.43 to −1.52]) and with increased VE/VCO2 slope (β, 13.76 [95% CI, 3.78–23.75]); FC and AC did not exhibit similar associations with these parameters. Moreover, only AC/FC was associated with a decreased peak work rate (WR), percent-predicted WR, anaerobic threshold, delta VO2/delta WR, and chronotropic index.

Conclusion: In patients on incident dialysis, exercise parameters, including those related to both skeletal muscle and cardiac function, were strongly associated with AC/FC, a marker of carnitine deficiency indicating altered fatty acid metabolism. Further studies are warranted to determine whether carnitine supplementation can improve exercise capacity in patients on incident dialysis.
Above and below-ground growth, accumulated dry matter and nitrogen remobilization of wheat (Triticum aestivum) genotypes grown in PVC tubes under well- and deficit-watered conditions
Authors: Zhiipao R. Rustum , Pooniya Vijay , Kumar Dinesh , Biswakarma Niraj , Shivay Yashbir Singh , Dass Anchal , Kumar Bainsla Naresh , Lakhena Kamlesh K. , Pandey Rakesh K. , Burman Anamika , Bhatia Arti , Jat Ram D. , Govindasamy Prabhu , Swarnalakshmi Karivaradharajan , Das Kajal , Choudhary Ram L. , Babu Subhash
Published: March 2023

The continuing decline in water resources under the ever-changing climate compels us to re-orient our focus to a more sustainable practice. This study investigates the performance of Triticum aestivum wheat genotypes viz. HD-2967, HD-3086, HD-3249, DBW-187, and HD-3226 under well- and deficit-watered conditions for their root-traits, biomass and nitrogen accumulation and remobilization, and water use efficiencies, grown in PVC-tubes. The genotypes HD-2967, HD-3086, HD-3249, DBW-187, and HD-3226 under well-watered (WW) resulted in 36, 35, 38, 33, and 42% more grain yield compared to deficit-watered (DW). Among the genotypes, HD-3249 had the highest grain yield under both well- and deficit-watered conditions. Compared to DW, the WW had 28%, 30%, and 28% greater root length, biomass, and root length density at flowering {102 days (d), Z61}, while among the genotypes, HD-3249 had relatively greater root-traits. At flowering (Z61) and maturity (132 d, Z89), genotypes under WW accumulated 30-46% and 30-53%, respectively greater shoot biomass over the DW. Furthermore, the shoot biomass remobilised for HD-2967, HD-3086, HD-3249, DBW-187, and HD-3226 under the WW was 32, 37, 39, 35, and 35% greater than the DW. The nitrogen partitioning to different plant parts at flowering (Z61) and maturity (Z89) was significantly greater with the WW than with DW. The total nitrogen- remobilized and contribution to grain-N under the WW was 55, 58, 52, 53, 58% and 9, 19, 15, 17, 17% greater than the DW for the genotypes HD-2967, HD-3086, HD-3249, DBW-187, and HD-3226. The irrigation water use efficiency (WUE) at flowering (Z61) was more under the deficit-watered, but the biomass and grain total WUE was improved with the well-watered condition. Hence, it is apparent that proper scheduling of irrigation and N applications, along with the adoption of a genotype suited to a particular environment, will result in better WUE and grain yields, along with better utilization of scarce resources.
A large-scale forward genetic screen for maize mutants with altered lignocellulosic properties
Authors: Wang Shaogan , Robertz Stefan , Seven Merve , Kraemer Florian , Kuhn Benjamin M. , Liu Lifeng , Lunde China , Pauly Markus , Ramírez Vicente
Published: March 2023

The development of efficient pipelines for the bioconversion of grass lignocellulosic feedstocks is challenging due to the limited understanding of the molecular mechanisms controlling the synthesis, deposition, and degradation of the varying polymers unique to grass cell walls. Here, we describe a large-scale forward genetic approach resulting in the identification of a collection of chemically mutagenized maize mutants with diverse alterations in their cell wall attributes such as crystalline cellulose content or hemicellulose composition. Saccharification yield, i.e. the amount of lignocellulosic glucose (Glc) released by means of enzymatic hydrolysis, is increased in two of the mutants and decreased in the remaining six. These mutants, termed candy-leaf (cal), show no obvious plant growth or developmental defects despite associated differences in their lignocellulosic composition. The identified cal mutants are a valuable tool not only to understand recalcitrance of grass lignocellulosics to enzymatic deconstruction but also to decipher grass-specific aspects of cell wall biology once the genetic basis, i.e. the location of the mutation, has been identified.