bluuebunny/crossref_metadata_2025 huggingface dataset:
Ascitic Senescent T Cells Are Linked to Chemoresistance in Patients With Advanced High-Grade Serous Ovarian Cancer
Authors: Zhang Jie , He Tianhui , Yin Zhongnan , Shang Chunliang , Xue Lixiang , Guo Hongyan
Published: July 2022

Senescent T cells are reported to be increased in patients with cancer and are poor prognostic indicators. However, the distribution of senescent T cells and their correlation with clinical features in high-grade serous ovarian cancer (HGSOC) is unknown. We detected the percentage of senescent T cells in the peripheral blood and ascites of patients with advanced HGSOC (n = 86) at diagnosis by flow cytometry. Compared with healthy donors, patients with HGSOC exhibited an accumulation of CD28−CD57+ (Tsen) CD8+ T cells in the peripheral blood and ascites. The frequency of Tsen CD8+ T cells in the peripheral blood was positively correlated with age and pretreatment serum CA125 and increased in patients with large volume ascites, whereas the frequency of Tsen CD8+ T cells in ascites was elevated in patients with lymph node metastasis. Patients with Tsen-high in ascites (>19.92%), but not in the peripheral blood, were more likely to be resistant to chemotherapy and had shorter progression-free survival. Tsen CD8+ T cells exhibited common senescence features including increased SA-β-gal activity, declines in proliferation, loss of CD27 and gain of KLRG-1, and the production of cytokines. In ascites, the percentage of Tsen CD8+ T cells was positively correlated with levels of interleukin-10 and granzyme B. This study suggests the potential of ascitic Tsen CD8+ T cells at diagnosis as a prognostic biomarker in HGSOC.
A Comparative Study of Multiple Deep Learning Models Based on Multi-Input Resolution for Breast Ultrasound Images
Authors: Wu Huaiyu , Ye Xiuqin , Jiang Yitao , Tian Hongtian , Yang Keen , Cui Chen , Shi Siyuan , Liu Yan , Huang Sijing , Chen Jing , Xu Jinfeng , Dong Fajin
Published: July 2022

Purpose

The purpose of this study was to explore the performance of different parameter combinations of deep learning (DL) models (Xception, DenseNet121, MobileNet, ResNet50 and EfficientNetB0) and input image resolutions (REZs) (224 × 224, 320 × 320 and 488 × 488 pixels) for breast cancer diagnosis.

Methods

This multicenter study retrospectively studied gray-scale ultrasound breast images enrolled from two Chinese hospitals. The data are divided into training, validation, internal testing and external testing set. Three-hundreds images were randomly selected for the physician-AI comparison. The Wilcoxon test was used to compare the diagnose error of physicians and models under P=0.05 and 0.10 significance level. The specificity, sensitivity, accuracy, area under the curve (AUC) were used as primary evaluation metrics.

Results

A total of 13,684 images of 3447 female patients are finally included. In external test the 224 and 320 REZ achieve the best performance in MobileNet and EfficientNetB0 respectively (AUC: 0.893 and 0.907). Meanwhile, 448 REZ achieve the best performance in Xception, DenseNet121 and ResNet50 (AUC: 0.900, 0.883 and 0.871 respectively). In physician-AI test set, the 320 REZ for EfficientNetB0 (AUC: 0.896, P < 0.1) is better than senior physicians. Besides, the 224 REZ for MobileNet (AUC: 0.878, P < 0.1), 448 REZ for Xception (AUC: 0.895, P < 0.1) are better than junior physicians. While the 448 REZ for DenseNet121 (AUC: 0.880, P < 0.05) and ResNet50 (AUC: 0.838, P < 0.05) are only better than entry physicians.

Conclusion

Based on the gray-scale ultrasound breast images, we obtained the best DL combination which was better than the physicians.
Circulating Carnitine Levels and Breast Cancer: A Matched Retrospective Case-Control Study
Authors: Zhang Jiayi , Wu Gang , Zhu Hailong , Yang Fengyuan , Yang Shuman , Vuong Ann M. , Li Jincheng , Zhu Demiao , Sun Yiyan , Tao Wei
Published: July 2022

Introduction

Epidemiological studies investigating the association between carnitine and breast cancer are scarce.

Materials and Methods

This 1:1 age-matched retrospective case-control study identified 991 female breast cancer cases and 991 female controls without breast cancer using pathological testing. We used targeted metabolomics technology to measure 16 types of whole blood carnitine compounds, such as free carnitine (C0) and octadecanoylcarnitine (C18).

Results

The average age for cases and controls was approximately 50 ± 8.7 years. After adjusting for covariates, each standard deviation (SD) increase in malonylcarnitine (C3DC; OR 0.91; 95% CI 0.83-1.00), decenoylcarnitine (C10:1; OR 0.87; 95% CI 0.79-0.96), and decadienoylcarnitine (C10:2; OR 0.90; 95% CI 0.82-0.99) level was associated with decreased odds of breast cancer. However, higher butyrylcarnitine (C4) levels were associated with increased odds of breast cancer (OR 1.12; 95% CI 1.02-1.23). No statistically significant relationship was noted between other carnitine compounds and breast cancer. The false discovery rates for C3DC, C4, C10:1 and C10:2 were 0.172, 0.120, 0.064 and 0.139, respectively.

Conclusions

Higher levels of C3DC, C10:1, and C10:2 were protective factors for breast cancer, whereas increased C4 levels were a risk factor for the disease.
High-Accuracy Oral Squamous Cell Carcinoma Auxiliary Diagnosis System Based on EfficientNet
Authors: Xu Ziang , Peng Jiakuan , Zeng Xin , Xu Hao , Chen Qianming
Published: July 2022

It is important to diagnose the grade of oral squamous cell carcinoma (OSCC), but the current evaluation of the biopsy slide still mainly depends on the manual operation of pathologists. The workload of manual evaluation is large, and the results are greatly affected by the subjectivity of the pathologists. In recent years, with the development and application of deep learning, automatic evaluation of biopsy slides is gradually being applied to medical diagnoses, and it has shown good results. Therefore, a new OSCC auxiliary diagnostic system was proposed to automatically and accurately evaluate the patients’ tissue slides. This is the first study that compared the effects of different resolutions on the results. The OSCC tissue slides from The Cancer Genome Atlas (TCGA, n=697) and our independent datasets (n=337) were used for model training and verification. In the test dataset of tiles, the accuracy was 93.1% at 20x resolution (n=306,134), which was higher than that at 10x (n=154,148, accuracy=90.9%) and at 40x (n=890,681, accuracy=89.3%). The accuracy of the new system based on EfficientNet, which was used to evaluate the tumor grade of the biopsy slide, reached 98.1% [95% confidence interval (CI): 97.1% to 99.1%], and the area under the receiver operating characteristic curve (AUROC) reached 0.998 (95%CI: 0.995 to 1.000) in the TCGA dataset. When verifying the model on the independent image dataset, the accuracy still reached 91.4% (95% CI: 88.4% to 94.4%, at 20x) and the AUROC reached 0.992 (95%CI: 0.982 to 1.000). It may benefit oral pathologists by reducing certain repetitive and time-consuming tasks, improving the efficiency of diagnosis, and facilitating the further development of computational histopathology.
CT-Based Radiomics Nomogram Improves Risk Stratification and Prediction of Early Recurrence in Hepatocellular Carcinoma After Partial Hepatectomy
Authors: Wu Cuiyun , Yu Shufeng , Zhang Yang , Zhu Li , Chen Shuangxi , Liu Yang
Published: July 2022

Objectives

To develop and validate an intuitive computed tomography (CT)-based radiomics nomogram for the prediction and risk stratification of early recurrence (ER) in hepatocellular carcinoma (HCC) patients after partial hepatectomy.

Methods

A total of 132 HCC patients treated with partial hepatectomy were retrospectively enrolled and assigned to training and test sets. Least absolute shrinkage and selection operator and gradient boosting decision tree were used to extract quantitative radiomics features from preoperative contrast-enhanced CT images of the HCC patients. The radiomics features with predictive value for ER were used, either alone or in combination with other predictive features, to construct predictive models. The best performing model was then selected to develop an intuitive, simple-to-use nomogram, and its performance in the prediction and risk stratification of ER was evaluated using the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA).

Results

The radiomics model based on the radiomics score (Rad-score) achieved AUCs of 0.870 and 0.890 in the training and test sets, respectively. Among the six predictive models, the combined model based on the Rad-score, Edmondson grade, and tumor size had the highest AUCs of 0.907 in the training set and 0.948 in the test set and was used to develop an intuitive nomogram. Notably, the calibration curve and DCA for the nomogram showed good calibration and clinical application. Moreover, the risk of ER was significantly different between the high- and low-risk groups stratified by the nomogram (p <0.001).

Conclusions

The CT-based radiomics nomogram developed in this study exhibits outstanding performance for ER prediction and risk stratification. As such, this intuitive nomogram holds promise as a more effective and user-friendly tool in predicting ER for HCC patients after partial hepatectomy.
Hepatocellular Carcinoma Intrinsic Cell Death Regulates Immune Response and Prognosis
Authors: De Re Valli , Rossetto Anna , Rosignoli Alessandro , Muraro Elena , Racanelli Vito , Tornesello Maria Lina , Zompicchiatti Aron , Uzzau Alessandro
Published: July 2022

Ablative and locoregional treatment options, such as radiofrequency, ethanol injection, microwave, and cryoablation, as well as irreversible electroporation, are effective therapies for early-stage hepatocellular carcinoma (HCC). Hepatocyte death caused by ablative procedures is known to increase the release of tumor-associated antigen, thus enhancing tumor immunogenicity. In addition, the heat ablative resection induces pyroptotic cell death accompanied by the release of several inflammatory factors and immune-related proteins, including damage-associated molecular patterns (DAMPs), heat shock proteins (HSPs), ficolin 3, ATP, and DNA/RNA, which potentiate the antitumoral immune response. Surgical approaches that enhance tumor necrosis and reduce hypoxia in the residual liver parenchyma have been shown to increase the disease-free survival rate by reducing the host’s immunosuppressive response. Scalpel devices and targeted surgical approach combined with immune-modulating drugs are an interesting and promising area to maximize therapeutic outcomes after HCC ablation.
HPV16 E6-Activated OCT4 Promotes Cervical Cancer Progression by Suppressing p53 Expression via Co-Repressor NCOR1
Authors: Shu Shujuan , Li Zhi , Liu Liu , Ying Xia , Zhang Yina , Wang Ting , Zhou Xiaoye , Jiang Peiyue , Lv Weiguo
Published: July 2022

Human papillomaviruses (HPV), mainly HPV16 and HPV18, of high-risk classification are involved in cervical cancer carcinogenesis and progression. Octamer-binding transcription factor 4 (OCT4) is a key transcription factor that is increased in various cancer types. Cervical cancer patients with higher levels of OCT4 had worse survival rates. However, the definite mechanisms underlying its function in the development of cervical cancer still remain to be explicated. Here, our study demonstrated that OCT4 expression was slightly increased in cervical cancer tissues than in precancerous ones. However, OCT4 was significantly upregulated in HPV16-positive tissues, in contrast to the expression profiling for p53. Moreover, knockdown of HPV16 E6 in SiHa cells suppressed the expression of OCT4 with impaired activities of cell proliferation, migration, and invasion, while it recovered the expression of p53. Overexpression of OCT4 and p53 exerted opposite roles on cell proliferation, migration, invasion, and colony formation of cervical cancer cells. More importantly, the enforced expression of OCT4 augmented p53-inhibited cell migration, invasion, and colony formation in human cervical cancer by promoting EMT. Finally, we identified that OCT4 could bind to the p53 promoter region to repress p53 expression by recruiting co-repressor NCOR1 using luciferase, ChIP, and co-IP experiments. We further illustrated that OCT4 not only increased the lung metastasis of cervical cancer but also effectively reversed p53-inhibited lung metastasis. In conclusion, our results suggested that HPV16 E6 activated the expression of OCT4 and subsequently crippled the transcription of p53 via co-repressor NCOR1, which contributed to cervical cancer progression.
Preclinical Assessment of MEK Inhibitors for Malignant Peripheral Nerve Sheath Tumors Reveals Differences in Efficacy and Adaptive Response
Authors: Gu Yihui , Wang Wei , Li Yuehua , Li Haibo , Guo Zizhen , Wei Chengjiang , Long Manmei , Chung Manhon , Aimaier Rehanguli , Li Qingfeng , Wang Zhichao
Published: July 2022

Malignant peripheral nerve sheath tumors (MPNSTs) are rare soft-tissue sarcomas refractory to standard therapies. Inactivation of NF1 and subsequent upregulation of RAS/RAF/MEK/ERK signaling exist in the majority of MPNSTs. However, the lack of preclinical assessment of MEK inhibitors in MPNSTs hinders the clinical application as well as the development of combination therapy. To guide further clinical studies, we evaluated different MEK inhibitors in terms of efficacy, safety, and mechanism of adaptive response in treating MPNSTs. Using a MPNST tissue microarray, we found that p-ERK could serve as a biomarker for predicting the prognosis of MPNST patients as well as an effective therapeutic target. Through in vitro and in vivo experiments, we identified trametinib as the most potent MEK inhibitor for the treatment of MPNSTs. Mechanistically, reduced reactivation of the MAPK pathway and compensatory activation of the parallel pathways contributed to better efficacy. Our results provide a basis for the further clinical application of MEK inhibitors as single agents or combinational therapies.
Adenoid Cystic Carcinoma of the Breast in a Male Patient: A Case Report and Literature Review
Authors: Wan Dan , Zhou Hongyuan , Zhang Yutao
Published: July 2022

Adenoid cystic carcinoma (ACC) of the breast (breast ACC) is a rare tumor, especially in men, with only 17 cases reported in the literature. Owing to this rarity, male breast ACC is susceptible to missed or incorrect diagnoses, and data on treatment options and prognosis is also scarce. Herein, we report a case of a male patient with primary breast ACC and performed a detailed clinicopathological analysis of the 17 cases reported in the literature. A 38-year-old Chinese man patient developed right-sided breast nipple retraction in 2013 and presented to our hospital in 2015 with a palpable mass in the right breast for four days. B-scan ultrasound indicated the presence of a solid space-occupying lesion in the right breast. Breast Imaging Reporting and Data System (BI-RADS) classified the lesion as category 4B, and mammography showed a right breast nodule classified as BI-RADS 4C. Modified radical mastectomy for breast cancer was performed on the right breast. Microscopic examination of the excised tissue revealed diffuse tumor invasion of the subcutaneous fibers and adipose tissue, with tumor cells arranged in cribriform, tubular, and microcystic patterns. Immunohistochemical staining indicated that the glandular epithelial cells were positive for CD117, CK7, and Ki67 (approximately 30%) and negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, while the myoepithelial/basal cells were positive for P63, CK5/6 and S-100. Moreover, basement membrane materials were positive for collagen type IV. Molecular pathology analysis by fluorescence in situ hybridization revealed that the tumor was negative for MYB rearrangements. The patient was followed up for 82 months with no tumor recurrence or metastasis. According to the current literature, mastectomies have a better prognosis than lumpectomy. Accurately identifying the diagnosis of male breast ACC and considering the surgery of mastectomy may be the key factors for patients to obtain a good prognosis based on the microscopic characteristics of the tumor.
Chinese Medicine Syndrome Differentiation for Early Breast Cancer: A Multicenter Prospective Clinical Study
Authors: Guo Qianqian , Coyle Meaghan E. , Zhang Anthony Lin , Xue Xiaohong , Bian Weihe , Song Aili , Xie Xiaohong , Hong Ri , Lyu Gang , Liu Lifang , Chen Qianjun , Xue Charlie Changli
Published: July 2022

Background

Chinese medicine (CM) syndrome differentiation is one of the fundamental principles that guide the practice of Chinese herbal medicine (CHM). CHM has been widely used among breast cancer patients. Contemporary literature varies in syndrome diagnosis, and there is a need to standardize syndrome differentiation according to the different stages of breast cancer treatment. This multicenter clinical study aims to identify the CM syndromes and the clinical signs and symptoms in women with early breast cancer.

Methods

Participants who met the inclusion and exclusion criteria were interviewed during the five treatment stages: preoperative, postoperative, chemotherapy, radiation therapy, and endocrine therapy. Patient demographic data and CM syndrome (as recorded by the treating CM clinicians in medical records) were gathered. Signs and symptoms were analyzed using descriptive statistics to derive the standardized CM syndromes using hierarchical cluster analysis.

Results

The analysis included 964 interviews with 620 participants enrolled between April 29, 2020 and May 30, 2021 from eight participating hospitals in China. The two most frequent syndromes recorded in medical records were dual deficiency of qi and blood, and dual deficiency of qi and yin during all but the preoperative stage. The symptoms of lassitude, lack of strength, and insomnia were common in all but the preoperative stage. Cluster analysis identified two clusters in the preoperative stage that most closely resembled the syndrome diagnoses of liver stagnation with congealing phlegm, and dual deficiency of the liver and kidney. Two clusters—dual deficiency of qi and blood, and dual deficiency of qi and yin—were common to multiple treatment stages. The syndrome cluster of spleen and stomach disharmony existed in both the postoperative and chemotherapy stages. Cluster analysis of the radiation therapy stage identified the unique syndrome of yin deficiency with fire toxin, while the endocrine therapy included the syndromes of liver depression and kidney deficiency.

Conclusions

This multicenter clinical study showed consistency between results from cluster analysis and the most common syndromes recorded in the medical records. Findings from this clinical study will be further validated in a Delphi study to standardize CM syndromes for various stages of breast cancer treatment.

Clinical Trial Registration

www.chictr.org.cn/index.aspx, identifier ChiCTR2000032497.
3D Ultrasound-Guided Photoacoustic Imaging to Monitor the Effects of Suboptimal Tyrosine Kinase Inhibitor Therapy in Pancreatic Tumors
Authors: Claus Abigail , Sweeney Allison , Sankepalle Deeksha M. , Li Brian , Wong Daniel , Xavierselvan Marvin , Mallidi Srivalleesha
Published: July 2022

Pancreatic cancer is a disease with an incredibly poor survival rate. As only about 20% of patients are eligible for surgical resection, neoadjuvant treatments that can relieve symptoms and shrink tumors for surgical resection become critical. Many forms of treatments rely on increased vulnerability of cancerous cells, but tumors or regions within the tumors that may be hypoxic could be drug resistant. Particularly for neoadjuvant therapies such as the tyrosine kinase inhibitors utilized to shrink tumors, it is critical to monitor changes in vascular function and hypoxia to predict treatment efficacy. Current clinical imaging modalities used to obtain structural and functional information regarding hypoxia or oxygen saturation (StO2) do not provide sufficient depth penetration or require the use of exogenous contrast agents. Recently, ultrasound-guided photoacoustic imaging (US-PAI) has garnered significant popularity, as it can noninvasively provide multiparametric information on tumor vasculature and function without the need for contrast agents. Here, we built upon existing literature on US-PAI and demonstrate the importance of changes in StO2 values to predict treatment response, particularly tumor growth rate, when the outcomes are suboptimal. Specifically, we image xenograft mouse models of pancreatic adenocarcinoma treated with suboptimal doses of a tyrosine kinase inhibitor cabozantinib. We utilize the US-PAI data to develop a multivariate regression model that demonstrates that a therapy-induced reduction in tumor growth rate can be predicted with 100% positive predictive power and a moderate (58.33%) negative predictive power when a combination of pretreatment tumor volume and changes in StO2 values pretreatment and immediately posttreatment was employed. Overall, our study indicates that US-PAI has the potential to provide label-free surrogate imaging biomarkers that can predict tumor growth rate in suboptimal therapy.
Penpulimab for Relapsed or Refractory Classical Hodgkin Lymphoma: A Multicenter, Single-Arm, Pivotal Phase I/II Trial (AK105-201)
Authors: Song Yuqin , Zhou Keshu , Jin Chuan , Qian Zhengzi , Hou Ming , Fan Lei , Li Fei , Ding Kaiyang , Zhou Hui , Li Xiaoling , Chen Bing , Sun Xiuhua , Song Xianmin , Jiang Ming , Zhang Qingyuan , Liu Lihong , Yu Guohua , Hu Yu , Zhao Zheng , Liu Ligen , Xue Hongwei , Luo Jun , He Bai , Jin Xiaoping , Zhao Min , Li Baiyong , Xia Yu , Zhu Jun
Published: July 2022

Background

Nearly all anti-PD-1 antibodies are of the IgG4 isotype, and thus possess residual FcR effector functions. Such anti-PD-1 antibodies are also associated with immune tolerance and escape due to instability of the CH3 domain and Fc-Fc interaction. In this trial, we examined the efficacy and safety of penpulimab, a novel IgG1 anti-PD-1 antibody that does not bind to the Fc receptor, in patients with refractory or relapsed classical Hodgkin lymphoma (R/R cHL).

Methods

Adult patients (≥18 years of age) with R/R cHL received 200 mg penpulimab once biweekly until disease progression or unacceptable toxicities for a maximum of 24 months. The primary endpoint was objective response rate (ORR) based on the Independent Radiology Review Committee per Lugano 2014 criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs).

Results

A total of 94 patients were enrolled. The median follow-up was 15.8 months. The ORR was 89.4% (95% CI 80.8%, 95.0%) in the full analysis set (85 patients). Forty (47.1%) patients achieved complete remission, 36 (42.4%) patients achieved partial remission. The 12-month PFS rate was 72.1% (95% CI 60.5%, 80.8%) and the 18-month OS rate was 100%. Totally 97.9% (92/94) of patients experienced at least one TRAE. The rate of grade 3 and above TRAEs was 26.6% (25/94). In addition, 51 (54.3%) patients experienced an irAE, and 4 (4.3%) patients developed grade 3 or above irAEs. No irAE-related death occurred.

Conclusions

Penpulimab was effective and safe in patients with R/R cHL.
Co-occurrence of VHL and SDHA Pathogenic Variants: A Case Report
Authors: Tung Moon Ley , Chandra Bharatendu , Dillahunt Kyle , Gosse Matthew D. , Sato T. Shawn , Sidhu Alpa
Published: July 2022

Von Hippel Lindau(VHL)syndrome presents with cerebellar and spinal hemangioblastomas, renal cell cancer, neuroendocrine pancreatic tumor, and pheochromocytoma and it is caused by germline mutations in the VHL gene. Pathogenic germline variants in the succinate dehydrogenase A (SDHA) gene are associated with paraganglioma and pheochromocytoma. Here we report co-occurrence of germline pathogenic variants in both VHL and SDHA genes in a patient who presented with pancreatic neuroendocrine tumor. As these genes converge on the pseudo-hypoxia signaling pathway, further studies are warranted to determine the significance of co-occurrence of these variants in relation to tumor penetrance, disease severity, treatment response and clinical outcomes in this selected group of patients.
Computational Characterizing Necroptosis Reveals Implications for Immune Infiltration and Immunotherapy of Hepatocellular Carcinoma
Authors: Zhu Jun , Han Tenghui , Zhao Shoujie , Zhu Yejing , Ma Shouzheng , Xu Fenghua , Bai Tingting , Tang Yuxin , Xu Yungang , Liu Lei
Published: July 2022

Necroptosis is a programmed form of necrotic cell death in regulating cancer ontogenesis, progression, and tumor microenvironment (TME) and could drive tumor-infiltrating cells to release pro-inflammatory cytokines, incurring strong immune responses. Nowadays, there are few identified biomarkers applied in clinical immunotherapy, and it is increasingly recognized that high levels of tumor necroptosis could enhance the response to immunotherapy. However, comprehensive characterization of necroptosis associated with TME and immunotherapy in Hepatocellular carcinoma (HCC) remains unexplored. Here, we computationally characterized necroptosis landscape in HCC samples from TCGA and ICGA cohorts and stratified them into two necroptosis clusters (A or B) with significantly different characteristics in clinical prognosis, immune cell function, and TME-landscapes. Additionally, to further evaluate the necroptosis levels of each sample, we established a novel necroptosis-related gene score (NRGscore). We further investigated the TME, tumor mutational burden (TMB), clinical response to immunotherapy, and chemotherapeutic drug sensitivity of HCC subgroups stratified by the necroptosis landscapes. The NRGscore is robust and highly predictive of HCC clinical outcomes. Further analysis indicated that the high NRGscore group resembles the immune-inflamed phenotype while the low score group is analogous to the immune-exclusion or metabolism phenotype. Additionally, the high NRGscore group is more sensitive to immune checkpoint blockade-based immunotherapy, which was further validated using an external HCC cohort, metastatic melanoma cohort, and advanced urothelial cancer cohort. Besides, the NRGscore was demonstrated as a potential biomarker for chemotherapy, wherein the high NRGscore patients with more tumor stem cell composition could be more sensitive to Cisplatin, Doxorubicin, Paclitaxel-based chemotherapy, and Sorafenib therapy. Collectively, a comprehensive characterization of the necroptosis in HCC suggested its implications for predicting immune infiltration and response to immunotherapy of HCC, providing promising strategies for treatment.
The Pain Outcomes Comparing Yoga vs. Structured Exercise (POYSE) Trial in Veterans With Fibromyalgia: Study Design and Methods
Authors: Allsop Vivianne L. , Schmid Arlene A. , Miller Kristine K. , Slaven James E. , Daggy Joanne K. , Froman Amanda , Kline Matthew , Sargent Christy , French Dustin D. , Ang Dennis , Van Puymbroeck Marieke , Schalk Nancy L. , Bair Matthew J.
Published: July 2022

Background

Fibromyalgia is a common pain condition that often leads to significant disability. Unfortunately, the effectiveness of most medications for fibromyalgia is limited, and there is a need for alternative, non-pharmacological therapies. Yoga and aerobic exercise are both evidence-based non-pharmacological treatments for fibromyalgia. However, no prior studies have directly compared the effectiveness of yoga vs. exercise.

Objective

This article describes the study design and recruitment outcomes of the Pain Outcomes comparing Yoga vs. Structured Exercise (POYSE) Trial, a two-arm randomized comparative effectiveness trial.

Methods

Veterans with fibromyalgia, defined by the 2010 American College of Rheumatology diagnostic criteria, who also experienced at least moderate pain severity were enrolled. The participants were randomized to a 12-week yoga-based or a structured exercise program (SEP) and will undergo comprehensive outcome assessments at baseline, 1, 3, 6, and 9 months by interviewers blinded to treatment assignment. The primary outcome will be the overall severity of fibromyalgia as measured by the total Fibromyalgia Impact Questionnaire-Revised. Secondary outcomes included depression, anxiety, health-related quality of life, pain beliefs, fatigue, sleep, and self-efficacy.

Results

A total of 2,671 recruitment letters were sent to potential participants with fibromyalgia. Of the potential participants, 623 (23.3%) were able to be contacted by telephone and had their eligibility assessed. Three hundred seventy-one of those interviewed were found to be eligible (59.6%) and 256 (69.0%) agreed to participate and were randomized to the YOGA (n= 129) or the SEP (n= 127) arm of the trial.

Conclusions

Clinicians are faced with numerous challenges in treating patients with fibromyalgia. The interventions being tested in the POYSE trial have the potential to provide primary care and other care settings with new treatment options for clinicians while simultaneously providing a much needed relief for patients suffering from fibromyalgia.

Trial Registration

Funded by VA Rehabilitation Research and Development (D1100-R); Trial registration:ClinicalTrials.gov, NCT01797263.
Risk Factors of Very Severe RSV Infections in a Multicenter Cohort of Very Preterm and Extreme Preterm Babies Receiving or Not Palivizumab
Authors: Mulot Gwenaelle , Benchaib Mehdi , Plaisant Frank , Ploin Dominique , Gillet Yves , Javouhey Etienne , Claris Olivier , Picaud Jean-Charles , Casalegno Jean-Sebastien , Butin Marine
Published: July 2022

Introduction

Preterm infants are at risk of lower respiratory tract infections (LRTI), including Respiratory Syncytial Virus (RSV) associated bronchiolitis, for which palivizumab prophylaxis can be proposed. Our aim was to determine risk factors of very severe RSV disease in children born before 34 weeks of gestation.

Methods

Among 2,101 infants born before 34 weeks of gestation in 3 maternity wards between 2012 and 2017, the laboratory confirmed RSV-infected patients requiring hospitalization before 12 months of corrected age were retrospectively included. We collected data about the neonatal period, the palivizumab prophylaxis and the hospitalization for a RSV-related LRTI. LRTI was considered as very severe (VS-LRTI) when patients required invasive or non-invasive positive pressure ventilation.

Results

Among 86 included patients, 31 met the criteria of VS-LRTI. The VS-LRTI patients had a higher birth gestational age and weight but less heart disease and bronchopulmonary dysplasia. They received palivizumab prophylaxis less frequently than the other patients but the difference was not significant. At the onset of infection, VS-LRTI patients had a younger corrected age for prematurity and presented more frequently with apnea, bradycardia, life-threatening event, hemodynamic failure, hypercapnia. Using logistic regression, the main factor associated with VS-LRTI was a younger corrected age for prematurity at the onset of infection [Odd ratio for each month of corrected age = 0.77 (0.62; 0.93), p = 0.012].

Conclusion

Infants at the highest risk of VS-LRTI were infants with a younger corrected age for prematurity. Therefore, a better targeting of infants requiring palivizumab prophylaxis and early interventions at hospital discharge could limit VS-LRTI in these infants.
Beneficial Effects of Limosilactobacillus fermentum CECT 5716 Administration to Infants Delivered by Cesarean Section
Authors: Blanco-Rojo Ruth , Maldonado José , Schaubeck Monika , Özen Metehan , López-Huertas Eduardo , Olivares Mónica
Published: July 2022

Cesarean section (CS) disrupts the natural microbiota colonization process in infants, which might compromise immune system maturation, leading to a higher risk of infections. We evaluated the effect of the probiotic Limosilactobacillus (L.) fermentum CECT 5716 on the incidence of gastrointestinal and respiratory infections in the CS infant subgroups (n = 173) of three randomized clinical trials in which this probiotic strain was demonstrated to be safe and effective for preventing infections. Therefore, the data for the CS infants were extracted to obtain the incidence rate ratio (IRR) and 95% CI for gastrointestinal and respiratory infections for each study and were then combined to obtain a pooled IRR and 95% CI using the generic inverse variance method. There was a significant reduction of 73% in the incidence of gastrointestinal infections in CS infants receiving L. fermentum CECT 5716 compared with those receiving the control formula [n = 173, IRR: 0.27 (0.13, 0.53), p = 0.0002]. Regarding respiratory infections, although pooled results showed a reduction of 14% in the probiotic group, the difference was not statistically significant [n = 173, IRR (95% CI): 0.86 (0.67, 1.11), p = 0.25]. In conclusion, the administration of L. fermentum CECT 5716 to CS-born infants protects them from gastrointestinal infections by reducing the risk by up to 73% in this population.
Learning Curve of Closed Reduction and Internal Fixation for Supracondylar Fractures of the Humerus in Children
Authors: Qian Chuang , Zheng Yiming , Meng Junrong , Mo Yueqiang , Sun Jinhua , Li Hao , Wang Dahui
Published: July 2022

Background

This study aimed to identify the threshold for success in supracondylar humeral fracture surgery by describing the learning curve for beginners and exploring the relationship between the learning curve and the prognosis of supracondylar fractures of the humerus.

Methods

Surgical information was collected of the first 100 humeral fractures treated by four pediatric orthopedic surgeons. The relationship between operation time, wire placement success rate, and surgical experience was determined using the restricted cubic strip (RCS). The inflection point in the curve and other risk factors that may affect fracture prognosis were collected and subjected to multiple logistic regression to clarify the relationship between the learning curve and prognosis of supracondylar fractures of the humerus. After the training, the four fresh surgeons were interviewed in the form of questionnaires to get feedback from the trainees.

Results

A total of 400 supracondylar fractures of the humerus from four pediatric orthopedists were included in the study. On an RCS analysis, 65 surgical experiences were the inflection point of the learning curve. Before and after these 65 surgical experiences, there were significant differences in the patients' anatomical reduction (186 vs. 122, P < 0.001), conversion to incision (33 vs. 6, P = 0.008), and supervising physician guidance (28 vs. 2, P < 0.001). In the multiple logistic regression analysis, functional recovery after supracondylar fractures of the humerus was significantly associated with surgical experience, intraoperative conversion to incision, and post-operative infection. Four surgeons and a supervisor were interviewed. They believed that self-confidence establishment requires the experience accumulation of about 30 operations. The most critical surgical technique is the reduction of fractures.

Conclusions

Although the accumulated experience of 30 operations can establish the self-confidence of trainers, fresh surgeons must accumulate experience with 65 operations to master closed reduction and internal fixation for supracondylar fractures. Surgical experience significantly impacts the post-operative recovery of patients with fractures.

Level of Evidence

Level III.
Uncovering the Underlying Mechanisms of Ketamine as a Novel Antidepressant
Authors: Xu Songbai , Yao Xiaoxiao , Li Bingjin , Cui Ranji , Zhu Cuilin , Wang Yao , Yang Wei
Published: July 2022

Major depressive disorder (MDD) is a devastating psychiatric disorder which exacts enormous personal and social-economic burdens. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been discovered to exert rapid and sustained antidepressant-like actions on MDD patients and animal models. However, the dissociation and psychotomimetic propensities of ketamine have limited its use for psychiatric indications. Here, we review recently proposed mechanistic hypotheses regarding how ketamine exerts antidepressant-like actions. Ketamine may potentiate α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR)-mediated transmission in pyramidal neurons by disinhibition and/or blockade of spontaneous NMDAR-mediated neurotransmission. Ketamine may also activate neuroplasticity- and synaptogenesis-relevant signaling pathways, which may converge on key components like brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) and mechanistic target of rapamycin (mTOR). These processes may subsequently rebalance the excitatory/inhibitory transmission and restore neural network integrity that is compromised in depression. Understanding the mechanisms underpinning ketamine’s antidepressant-like actions at cellular and neural circuit level will drive the development of safe and effective pharmacological interventions for the treatment of MDD.
Identifying an Immune-Related Gene ST8SIA1 as a Novel Target in Patients With Clear-Cell Renal Cell Carcinoma
Authors: Hu Xu , Yang Yanfei , Wang Yaohui , Ren Shangqing , Li Xiang
Published: July 2022

Clear-cell renal cell carcinoma (ccRCC) is one of the most common urological cancers. The tumor microenvironment plays an important role in tumor development. The present study was conducted to identify novel immune-related biomarkers. The differentially expressed genes were identified using the ESTIMATE algorithm base on GEO and TCGA databases. The Kaplan–Meier survival curve and univariate and multivariate analyses were performed. The association between ST8SIA1 and the immune system was explored. The gene set enrichment analysis (GSEA) and online databases were used for functional annotation. ST8SIA1 was identified as a potential prognostic gene. Elevated ST8SIA1 was observed in the tumor tissues compared with adjacent normal tissues and associated with higher T stage and advanced TNM stage (all p < 0.05). The mRNA and protein levels of ST8SIA1 in cancer tissues and cells are also upregulated. The Kaplan–Meier survival curve and univariate and multivariate analyses showed that higher expression of ST8SIA1 was associated with worse OS (all p < 0.05). ST8SIA1 expression levels were negatively correlated with tumor purity and positively associated with infiltrated immune cells and expression of immune checkpoint genes. Function analysis also revealed that ST8SIA1 was significantly associated with immune-related pathways. In conclusion, ST8SIA1 was identified as an immune-related gene and a potential target in ccRCC patients. Further relevant studies are required to validate our findings.
The Effect of Lithocholic Acid on the Gut-Liver Axis
Authors: Sheng Wei , Ji Guang , Zhang Li
Published: July 2022

Lithocholic acid (LCA) is a monohydroxy bile acid produced by intestinal flora, which has been found to be associated with a variety of hepatic and intestinal diseases. LCA is previously considered to be toxic, however, recent studies revealed that LCA and its derivatives may exert anti-inflammatory and anti-tumor effects under certain conditions. LCA goes through enterohepatic circulation along with other bile acids, here, we mainly discuss the effects of LCA on the gut-liver axis, including the regulation of gut microbiota, intestinal barrier, and relevant nuclear receptors (VDR, PXR) and G protein-coupled receptor five in related diseases. In addition, we also find that some natural ingredients are involved in regulating the detoxification and excretion of LCA, and the interaction with LCA also mediates its own biological activity.
The Pathogenesis of HCC Driven by NASH and the Preventive and Therapeutic Effects of Natural Products
Authors: Shao Gaoxuan , Liu Ying , Lu Lu , Zhang Guangtao , Zhou Wenjun , Wu Tao , Wang Lei , Xu Hanchen , Ji Guang
Published: July 2022

Nonalcoholic steatohepatitis (NASH) is a clinical syndrome with pathological changes that are similar to those of alcoholic hepatitis without a history of excessive alcohol consumption. It is a specific form of nonalcoholic fatty liver disease (NAFLD) that is characterized by hepatocyte inflammation based on hepatocellular steatosis. Further exacerbation of NASH can lead to cirrhosis, which may then progress to hepatocellular carcinoma (HCC). There is a lack of specific and effective treatments for NASH and NASH-driven HCC, and the mechanisms of the progression of NASH to HCC are unclear. Therefore, there is a need to understand the pathogenesis and progression of these diseases to identify new therapeutic approaches. Currently, an increasing number of studies are focusing on the utility of natural products in NASH, which is likely to be a promising prospect for NASH. This paper reviews the possible mechanisms of the pathogenesis and progression of NASH and NASH-derived HCC, as well as the potential therapeutic role of natural products in NASH and NASH-derived HCC.
A Review of Neuroprotective Effects and Mechanisms of Ginsenosides From Panax Ginseng in Treating Ischemic Stroke
Authors: Zhao Aimei , Liu Nan , Yao Mingjiang , Zhang Yehao , Yao Zengyu , Feng Yujing , Liu Jianxun , Zhou Guoping
Published: July 2022

Ischemic stroke has been considered one of the leading causes of mortality and disability worldwide, associated with a series of complex pathophysiological processes. However, effective therapeutic methods for ischemic stroke are still limited. Panax ginseng, a valuable traditional Chinese medicine, has been long used in eastern countries for various diseases. Ginsenosides, the main active ingredient of Panax ginseng, has demonstrated neuroprotective effects on ischemic stroke injury during the last decade. In this article, we summarized the pathophysiology of ischemic stroke and reviewed the literature on ginsenosides studies in preclinical and clinical ischemic stroke. Available findings showed that both major ginsenosides and minor ginsenosides (such as Rg3, Rg5, and Rh2) has a potential neuroprotective effect, mainly through attenuating the excitotoxicity, Ca2+ overload, mitochondria dysfunction, blood-brain barrier (BBB) permeability, anti-inflammation, anti-oxidative, anti-apoptosis, anti-pyroptosis, anti-autophagy, improving angiogenesis, and neurogenesis. Therefore, this review brings a current understanding of the mechanisms of ginsenosides in the treatment of ischemic stroke. Further studies, especially in clinical trials, will be important to confirm the clinical value of ginseng and ginsenosides.
A Comparison of Different Tissues Identifies the Main Precursors of Volatile Substances in Chicken Meat
Authors: Luo Na , Liu Li , Yuan Xiaoya , Jin Yuxi , Zhao Guiping , Wen Jie , Cui Huanxian
Published: July 2022

Amino acids and fatty acids are the main precursors of volatile organic compounds (VOCs) in meat. The purpose of this study was to determine the main VOC components in chicken breast muscle (BM) and abdominal fat (AF) tissue, as well as the source of VOCs, to provide a basis for quality improvement of broilers. BM and AF served as experimental and control groups, and gas chromatography-mass spectrometry (GC-MS) and untargeted metabolomics were employed to identify the source of VOCs. The results revealed nine VOCs in BM and AF tissues, including hexanal, octanal, and nonanal. VOCs including 1-octen-3-ol, (E,E)-2, 4-nonadienal, and benzaldehyde were significantly elevated in BM compared with AF (p < 0.05), while heptane and diethyl disulphide showed the opposite trend (p < 0.05). Levels of hexanal, heptanal, and octanal were similar in the two tissues. Metabolites of VOCs in chicken BM were investigated by weighted co-expression network analysis. However, only blue module in BM tissue was positively correlated with hexanal (r = 0.66, p = 0.01), heptanal (r = 0.67, p = 0.008), and (E,E)-2,4-nonadienal (r = 0.88, p = 3E-05). L-tyrosine, L-asparagine, adenosine, and valine were the main precursors of (E,E)-2,4-nonadienal and heptanal in BM tissue. Amino acids are the main precursors of 1-octen-3-ol, (E,E)-2, 4-nonadienal, and heptanal in chicken meat, while fatty acids are the main precursors of diethyl disulfide. However, hexanal can be synthesized from amino acids and small amounts of fatty acids as precursors. These findings expand our understanding of VOCs in chicken.
Mutation in Mg-Protoporphyrin IX Monomethyl Ester (Oxidative) Cyclase Gene ZmCRD1 Causes Chlorophyll-Deficiency in Maize
Authors: Xue Yingjie , Dong Haixiao , Huang Hongru , Li Shipeng , Shan Xiaohui , Li He , Liu Hongkui , Xia Dong , Su Shengzhong , Yuan Yaping
Published: July 2022

Chlorophyll molecules are non-covalently associated with chlorophyll-binding proteins to harvest light and perform charge separation vital for energy conservation during photosynthetic electron transfer in photosynthesis for photosynthetic organisms. The present study characterized a pale-green leaf (pgl) maize mutant controlled by a single recessive gene causing chlorophyll reduction throughout the whole life cycle. Through positional mapping and complementation allelic test, Zm00001d008230 (ZmCRD1) with two missense mutations (p.A44T and p.T326M) was identified as the causal gene encoding magnesium-protoporphyrin IX monomethyl ester cyclase (MgPEC). Phylogenetic analysis of ZmCRD1 within and among species revealed that the p.T326M mutation was more likely to be causal. Subcellular localization showed that ZmCRD1 was targeted to chloroplasts. The pgl mutant showed a malformed chloroplast morphology and reduced number of starch grains in bundle sheath cells. The ZmCRD1 gene was mainly expressed in WT and mutant leaves, but the expression was reduced in the mutant. Most of the genes involved in chlorophyll biosynthesis, chlorophyll degradation, chloroplast development and photosynthesis were down-regulated in pgl. The photosynthetic capacity was limited along with developmental retardation and production reduction in pgl. These results confirmed the crucial role of ZmCRD1 in chlorophyll biosynthesis, chloroplast development and photosynthesis in maize.