bluuebunny/crossref_metadata_2025 huggingface dataset:
Overall Survival Prediction of Glioma Patients With Multiregional Radiomics
Authors: Shaheen Asma , Bukhari Syed Talha , Nadeem Maria , Burigat Stefano , Bagci Ulas , Mohy-ud-Din Hassan
Published: July 2022

Radiomics-guided prediction of overall survival (OS) in brain gliomas is seen as a significant problem in Neuro-oncology. The ultimate goal is to develop a robust MRI-based approach (i.e., a radiomics model) that can accurately classify a novel subject as a short-term survivor, a medium-term survivor, or a long-term survivor. The BraTS 2020 challenge provides radiological imaging and clinical data (178 subjects) to develop and validate radiomics-based methods for OS classification in brain gliomas. In this study, we empirically evaluated the efficacy of four multiregional radiomic models, for OS classification, and quantified the robustness of predictions to variations in automatic segmentation of brain tumor volume. More specifically, we evaluated four radiomic models, namely, the Whole Tumor (WT) radiomics model, the 3-subregions radiomics model, the 6-subregions radiomics model, and the 21-subregions radiomics model. The 3-subregions radiomics model is based on a physiological segmentation of whole tumor volume (WT) into three non-overlapping subregions. The 6-subregions and 21-subregions radiomic models are based on an anatomical segmentation of the brain tumor into 6 and 21 anatomical regions, respectively. Moreover, we employed six segmentation schemes – five CNNs and one STAPLE-fusion method – to quantify the robustness of radiomic models. Our experiments revealed that the 3-subregions radiomics model had the best predictive performance (mean AUC = 0.73) but poor robustness (RSD = 1.99) and the 6-subregions and 21-subregions radiomics models were more robust (RSD  1.39) with lower predictive performance (mean AUC  0.71). The poor robustness of the 3-subregions radiomics model was associated with highly variable and inferior segmentation of tumor core and active tumor subregions as quantified by the Hausdorff distance metric (4.4−6.5mm) across six segmentation schemes. Failure analysis revealed that the WT radiomics model, the 6-subregions radiomics model, and the 21-subregions radiomics model failed for the same subjects which is attributed to the common requirement of accurate segmentation of the WT volume. Moreover, short-term survivors were largely misclassified by the radiomic models and had large segmentation errors (average Hausdorff distance of 7.09mm). Lastly, we concluded that while STAPLE-fusion can reduce segmentation errors, it is not a solution to learning accurate and robust radiomic models.
Activin A Secreted From Peripheral Nerve Fibroblasts Promotes Proliferation and Migration of Schwann Cells
Authors: Li Yan , Cheng Zhenghang , Yu Fanhui , Zhang Qi , Yu Shu , Ding Fei , He Qianru
Published: July 2022

The peripheral nervous system has remarkable regenerative capabilities. Schwann cells and fibroblasts are known to play crucial roles in these processes. In this study, we delineated the differential effects of peripheral nerve fibroblasts and cardiac fibroblasts on Schwann cells. We found that peripheral nerve fibroblasts significantly promoted Schwann cell proliferation and migration compared with cardiac fibroblasts. The cytokine array results identified 32 of 67 proteins that were considered differentially expressed in peripheral nerve fibroblasts versus cardiac fibroblasts. Among them, 25 were significantly upregulated in peripheral nerve fibroblasts compared with cardiac fibroblasts. Activin A, the protein with the greatest differential expression, clearly co-localized with fibroblasts in the in vivo sciatic never injury rat model. In vitro experiments proved that activin A secreted from nerve fibroblasts is the key factor responsible for boosting proliferation and migration of Schwann cells through ALK4, ALK5, and ALK7. Overall, these findings suggest that peripheral nerve fibroblasts and cardiac fibroblasts exhibit different patterns of cytokine secretion and activin A secreted from peripheral nerve fibroblasts can promote the proliferation and migration of Schwann cells.
Fruit and Vegetable Consumption Interacts With HNF1A Variants on the C-Reactive Protein
Authors: Shin Dayeon , Lee Kyung Won
Published: July 2022

Epidemiological studies have demonstrated the inverse association between the intake of fruits and vegetables and inflammation. However, the mechanisms by which inflammation-related genes interact with fruit and vegetable intake and the role of these combinations in inflammation remain unclear. Therefore, we assessed the effect of interactions between fruit and vegetable intake and the hepatic nuclear factor 1 alpha (HNF1A) genetic variants on the C-reactive protein (CRP) levels. Baseline data from the Ansan and Ansung Cohort Study of the Korean Genome and Epidemiology Study (KoGES) were used. A total of 7,634 participants (3,700 men and 3,934 women) were included in the analyses. Fruit and vegetable intake was assessed using semi-quantitative food frequency questionnaire data. Genotyping information for HNF1A was extracted from the Affymetrix Genome-Wide Human SNP array 5.0. Inflammation was determined after overnight fasting by measuring CRP levels using automated analyzers. Multivariable logistic regression was used to estimate the adjusted odds ratio (AOR) with a 95% confidence interval (CI). In the fully adjusted model, men and women with the GG genotype of HNF1A rs2393791 and high fruit intake had lower odds of elevated CRP levels compared to those with the AA genotype and low fruit intake (AOR 0.50, 95% CI 0.38–0.67; AOR 0.73, 95% CI 0.55–0.97, respectively). Men and women with the rs2393791 GG genotype and high vegetable intake had lower odds of having elevated CRP levels compared to those with the AA genotype and low fruit intake (AOR 0.57, 95% CI 0.43–0.75; AOR 0.65, 95% CI 0.49–0.86, respectively). Men and women with the GG genotype and high total fruit and vegetable intake had lower odds of having elevated CRP levels. These findings indicate that fruit and vegetable intake interacts with HNF1A genetic polymorphisms, consequently influencing the inflammation levels.
The Hepatoprotective Effect of Leonurine Hydrochloride Against Alcoholic Liver Disease Based on Transcriptomic and Metabolomic Analysis
Authors: Wu Ke-Jia , Liu Pin-Pin , Chen Meng-Yuan , Zhou Meng-Xin , Liu Xin , Yang Qing , Xu Lin , Gong Zhiyong
Published: July 2022

Excessive alcohol consumption can eventually progress to alcoholic liver disease (ALD). The underlying mechanism of ALD toxicity is primarily associated with oxidative damage. Many alkaloids have been reported to possess potential antioxidative efficacy, while the mechanism of their hepatoprotective activity against ALD is still not clear. In this study, eight alkaloids were selected from a monomer library of Traditional Chinese Medicine and evaluated for their antioxidant activity against ALD by the evaluation of Glutathione (GSH) and Malondialdehyde (MDA). The result suggested that Leonurine hydrochloride (LH) was a potent antioxidant that could reduce alcoholic liver damage. To further investigate the underlying mechanism of LH against ALD, the molecular pathway induced by LH was identified by RNA-seq analyses. Transcriptome data revealed the principal mechanism for the protective effect of LH against ALD might be attributed to the differentially expressed genes (DEGs) of PI3K-AKT, AMPK, and HIF-1 signaling pathways involved in the lipid metabolism. Given the hepatoprotective mechanism of LH is involved in lipid metabolism, the lipid metabolism induced by LH was further analyzed by UHPLC-MS/MS. Metabolome analysis indicated that LH significantly regulated glycerophospholipid metabolism including phosphatidylcholine, 1-acyl-sn-glycero-3-phosphocholine, phosphatidylethanolamine and 1-acyl-sn-glycero-3-phosphoethanolamine in the liver. Overall, this study revealed that the hepatoprotective mechanism of LH against alcoholic liver damage might be associated with the genes involved in glycerophospholipid metabolism.
Starch and Fiber Contents of Purified Control Diets Differentially Affect Hepatic Lipid Homeostasis and Gut Microbiota Composition
Authors: Schipke Julia , Brandenberger Christina , Vital Marius , Mühlfeld Christian
Published: July 2022

Background

Interpretation of results from diet-induced-obesity (DIO) studies critically depends on control conditions. Grain-based chows are optimized for rodent nutrition but do not match the defined composition of purified diets used for DIO, severely limiting the comparability. Purified control diets are recommended but often contain high starch and only minor fiber amounts. It is unknown whether this composition leads to metabolic alterations compared with chow and whether the addition of refined fibers at the expense of starch affects these changes.

Methods

In this experiment, 6-week-old C57BL/6N mice were fed (i) a conventional purified control diet (high-starch, low-fiber; Puri-starch), (ii) an alternative, custom-made purified control diet containing pectin and inulin (medium-starch, higher-fiber; Puri-fiber), or (iii) grain-based chow for 30 weeks (N = 8–10).

Results

Puri-starch feeding resulted in significantly elevated levels of plasma insulin (p = 0.004), cholesterol (p < 0.001), and transaminases (AST p = 0.002, ALT p = 0.001), hepatic de novo lipogenesis and liver steatosis, and an altered gut microbiota composition compared with chow-fed mice. In contrast, Puri-fiber exerted only minor effects on systemic parameters and liver lipid homeostasis, and promoted a distinct gut microbiota composition.

Conclusion

Carbohydrate-rich purified diets trigger a metabolic status possibly masking pathological effects of nutrients under study, restricting its use as control condition. The addition of refined fibers is suited to create purified, yet physiological control diets for DIO research.
Bioinformatic Prediction and Characterization of Proteins in Porphyra dentata by Shotgun Proteomics
Authors: Yang Mingchang , Ma Lizhen , Yang Xianqing , Li Laihao , Chen Shengjun , Qi Bo , Wang Yueqi , Li Chunsheng , Yang Shaoling , Zhao Yongqiang
Published: July 2022

Porphyra dentata is an edible red seaweed with high nutritional value. It is widely cultivated and consumed in East Asia and has vast economic benefits. Studies have found that P. dentata is rich in bioactive substances and is a potential natural resource. In this study, label-free shotgun proteomics was first applied to identify and characterize different harvest proteins in P. dentata. A total of 13,046 different peptides were identified and 419 co-expression target proteins were characterized. Bioinformatics was used to study protein characteristics, functional expression, and interaction of two important functional annotations, amino acid, and carbohydrate metabolism. Potential bioactive peptides, protein structure, and potential ligand conformations were predicted, and the results suggest that bioactive peptides may be utilized as high-quality active fermentation substances and potential targets for drug production. Our research integrated the global protein database, the first time bioinformatic analysis of the P. dentata proteome during different harvest periods, improves the information database construction and provides a framework for future research based on a comprehensive understanding.
Citrate Synthase Insufficiency Leads to Specific Metabolic Adaptations in the Heart and Skeletal Muscles Upon Low-Carbohydrate Diet Feeding in Mice
Authors: Sumi Kanako , Hatanaka Yuiko , Takahashi Reina , Wada Naoko , Ono Chihiro , Sakamoto Yuri , Sone Hirohito , Iida Kaoruko
Published: July 2022

A decrease in TCA cycle activity may lead to impaired nutrition metabolism and cellular energy shortage. Herein, we aimed to characterize the detailed metabolic changes that compensate for energy shortages in energy-consuming organs (heart and skeletal muscles) in mice with knockout of citrate synthase (CS), an important enzyme in the TCA cycle. CS hetero knockout (CS +/−) mice and wild-type mice were fed a low-carbohydrate ketogenic diet (LCKD) or high-fat, high-carbohydrate diet (HFHCD) to induce metabolic changes. Body weight, blood serum parameters, metabolic gene expression, and adenosine triphosphate (ATP) levels were measured in the heart and skeletal muscles. Glycogen content, anabolic and catabolic biomarkers, and morphological changes were also assessed in the skeletal muscles. After diet feeding, there were no differences observed in the body weight and blood serum parameters between wild-type and CS +/− mice. The cardiac expression of genes related to the utilization of fatty acids, monocarboxylates, and branched amino acids increased in LCKD-fed CS +/− mice. In contrast, no significant differences in gene expression were observed in the muscles of LCKD-fed mice or the heart and muscles of HFHCD-fed mice. ATP levels decreased only in the skeletal muscles of LCKD-fed CS +/− mice. Additionally, the decrease in glycogen content, suppression of p70 S6 kinase, and presence of type I fiber atrophy were observed in the muscles of LCKD-fed CS +/− mice. These results suggest that the energy-consuming organs with CS insufficiency may undergo tissue-specific adaption to compensate for energy shortages when the carbohydrate supply is limited.
Construction of a lncRNA–mRNA Co-Expression Network for Nasopharyngeal Carcinoma
Authors: Fan Chunmei , Xiong Fang , Tang Yanyan , Li Panchun , Zhu Kunjie , Mo Yongzhen , Wang Yumin , Zhang Shanshan , Gong Zhaojiang , Liao Qianjin , Li Guiyuan , Zeng Zhaoyang , Guo Can , Xiong Wei , Huang He
Published: July 2022

Long non-coding RNAs (lncRNAs) widely regulate gene expression and play important roles in the pathogenesis of human diseases, including malignant tumors. However, the functions of most lncRNAs remain to be elucidated. In order to study and screen novel lncRNAs with important functions in the carcinogenesis of nasopharyngeal carcinoma (NPC), we constructed a lncRNA expression profile of 10 NPC tissues and 6 controls through a gene microarray. We identified 1,276 lncRNAs, of which most are unknown, with different expression levels in the healthy and NPC tissues. In order to shed light on the functions of these unknown lncRNAs, we first constructed a co-expression network of lncRNAs and mRNAs using bioinformatics and systematic biological approach. Moreover, mRNAs were clustered and enriched by their biological functions, and those lncRNAs have similar expression trends with mRNAs were defined as functional molecules with potential biological significance. The module may help identify key lncRNAs in the carcinogenesis of NPC and provide clues for in-depth study of their functions and associated signaling pathways. We suggest the newly identified lncRNAs may have clinic value as biomarkers and therapeutic targets for NPC diagnosis and treatment.
Fruquintinib in Combination With PD-1 Inhibitors in Patients With Refractory Non-MSI-H/pMMR Metastatic Colorectal Cancer: A Real-World Study in China
Authors: Gou Miaomiao , Qian Niansong , Zhang Yong , Yan Huan , Si Haiyan , Wang Zhikuan , Dai Guanghai
Published: July 2022

Background

Fruquintinib, a vascular endothelial growth factor receptor inhibitor, is a new anticancer drug independently developed in China to treat refractory metastatic colorectal cancer (mCRC). In Japan, regorafenib combined with nivolumab has been demonstrated to be promising in patients with refractory mCRC. Here, in a real-world study, we were aimed to evaluate the efficacy of fruquintinib with various programmed death-1 (PD-1) inhibitors after standard treatment in Chinese non-microsatellite instability-high (MSI-H)/mismatch repair proficient mCRC patients.

Methods

A total of 45 patients with refractory mCRC were involved in the study. They received fruquintinib (3 or 5 mg, orally administered once a day for 3 weeks followed by 1 week off in 4-week cycles) and a PD-1 inhibitor(200 mg pembrolizumab, 3 mg/kg nivolumab, 200 mg sintilimab or camrelizumab, intravenously administered on D1 once every 3 weeks). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and objective response rate (ORR) were reviewed and evaluated.

Results

Among the 45 patients, the median age was 54 years (29-85). The ORR was 11.1% (5/45), DCR 62.2% (28/45), median PFS equal 3.8 months, and median OS was 14.9 months. The response duration was 3.4 months. PFS between left and right primary tumors and PFS with or without lung metastases were both not significantly different (p > 0.05), which was inconsistent with the result of REGONIVO study. The multivariate analysis indicated no association of OS benefit in the specified subgroups. No adverse-effect-related deaths were reported.

Conclusions

Fruquintinib, in combination with anti-PD-1, was observed to have clinical activity in a small population of patients with heavily pretreated mCRC in our center. Further studies are needed to verify this outcome in a large population.
A Cancer Health Needs Assessment Reveals Important Differences Between US-Born and Foreign-Born Latinos in California
Authors: Quino Juanita Elizabeth , Perez Fabian , Perez Angelica , Vang April Pangia , Avendano Leonie , Dang Julie , Chen Moon S. , Arana Alexa Morales , Rocha Sienna , Nuno Miriam , Lara Primo N. , Fejerman Laura , Carvajal-Carmona Luis G.
Published: July 2022

Background

Cancer is the leading cause of death among Latinos, the largest minority population in the United States (US). To address cancer challenges experienced by Latinos, we conducted a catchment area population assessment (CAPA) using validated questions from the National Cancer Institute (NCI) population health assessment supplement at our NCI-designated cancer center in California.

Methods

A mixed-methods CAPA was administered by bilingual-bicultural staff, with a focus on understanding the differences between foreign-born and US-born Latinos.

Results

255 Latinos responded to the survey conducted between August 2019 and May 2020. Most respondents were foreign-born (63.9%), female (78.2%), and monolingual Spanish speakers (63.2%). Results showed that compared to US-born Latinos, foreign-born individuals were older, had lower educational attainment, were most likely to be monolingual Spanish speakers, were low-income, and were more likely to be uninsured. Foreign-born Latinos had lower levels of alcohol consumption and higher consumption of fruits and vegetables. The rate of preventive cancer screenings for breast, cervical and colorectal cancer did not differ by birthplace, although a low fraction (35.3%) of foreign-born Latinas who were up-to-date compared to US-born Latinas (83.3%) with colorectal cancer screening was observed. Time since the last routine check-up for all preventable cancers (cervical p=0.0002, breast p=0.0039, and colorectal p=0.0196) is significantly associated with being up to date with cancer screening. Individuals who had a check-up of two or more years ago are 84% less likely to be up to date with pap smears than those who had a check-up within the year (p=0.0060). Individuals without health insurance are 94% less likely to be up to date with mammograms and colonoscopy/FIT tests (p=0.0016 and p=0.0133, respectively) than those who are insured. There is no significant association between screening and nativity.

Conclusions

Considerable differences in socio-economic and environmental determinants of health and colorectal cancer screening rates were observed between US-born and foreign-born Latinos. The present study represents the foundation for future targeted intervention among immigrant populations at our cancer center’s catchment area.
Multisite Radiotherapy Combined With Tislelizumab for Metastatic Castration-Resistant Prostate Cancer With Second-Line and Above Therapy Failure: Study Protocol for an Open-Label, Single-Arm, Phase Ib/II Study
Authors: Cheng Ke , Wang Yuqing , Chen Ye , Zhu Jingjie , Qi Xiaohui , Wang Yachen , Zou Yanqiu , Lu Qiuhan , Li Zhiping
Published: July 2022

Background

Tislelizumab combined with radiotherapy as a salvage treatment for patients with end-stage metastatic castration-resistant prostate cancer (mCRPC) is not reported. This study aimed to describe a protocol to evaluate the safety and efficacy of multisite radiotherapy combined with tislelizumab as a salvage therapy for mCRPC in patients who had at least one second-line treatment failure.

Methods

The study included patients with mCRPC who had at least one lesion suitable for radiotherapy and failed androgen deprivation therapy (ADT), followed by at least one novel second-line endocrine therapy. All patients received tislelizumab monotherapy induction therapy for two cycles, then combined with multisite radiotherapy for one cycle, followed by tislelizumab maintenance therapy, until either disease progressed or the patient developed unacceptable toxicity. Radiation methods and lesions were individually selected according to the specified protocol. Primary endpoints included safety and objective response rate. Secondary endpoints included prostate-specific antigen (PSA) response rate, disease control rate, overall survival, radiographic progression-free survival (rPFS), and biochemical progression-free survival (bPFS). Furthermore, the exploratory endpoints included the identification of the predictive biomarkers and exploration of the correlation between biomarkers and the tumor response to the combined regimen.

Discussion

This study included three treatment stages to evaluate the efficacy of immunotherapy and the combination of immunotherapy and radiotherapy for patients with mCRPC who have had at least second-line treatment failure. Additionally, radiation-related and immune-related early and late toxicities were determined, respectively. Furthermore, the study also aimed to identify the predictive biomarkers associated with immunotherapy for treating mCRPC.

Trial Registration

https://www.chictr.org.cn/showproj.aspx?proj=126359, identifier ChiCTR2100046212.
Deep Learning Analysis Using 18F-FDG PET/CT to Predict Occult Lymph Node Metastasis in Patients With Clinical N0 Lung Adenocarcinoma
Authors: Ouyang Ming-li , Zheng Rui-xuan , Wang Yi-ran , Zuo Zi-yi , Gu Liu-dan , Tian Yu-qian , Wei Yu-guo , Huang Xiao-ying , Tang Kun , Wang Liang-xing
Published: July 2022

Introduction

The aim of this work was to determine the feasibility of using a deep learning approach to predict occult lymph node metastasis (OLM) based on preoperative FDG-PET/CT images in patients with clinical node-negative (cN0) lung adenocarcinoma.

Materials and Methods

Dataset 1 (for training and internal validation) included 376 consecutive patients with cN0 lung adenocarcinoma from our hospital between May 2012 and May 2021. Dataset 2 (for prospective test) used 58 consecutive patients with cN0 lung adenocarcinoma from June 2021 to February 2022 at the same center. Three deep learning models: PET alone, CT alone, and combined model, were developed for the prediction of OLM. The performance of the models was evaluated on internal validation and prospective test in terms of accuracy, sensitivity, specificity, and areas under the receiver operating characteristic curve (AUCs).

Results

The combined model incorporating PET and CT showed the best performance, achieved an AUC of 0.81 [95% confidence interval (CI): 0.61, 1.00] in the prediction of OLM in internal validation set (n = 60) and an AUC of 0.87 (95% CI: 0.75, 0.99) in the prospective test set (n = 58). The model achieved 87.50% sensitivity, 80.00% specificity, and 81.00% accuracy in the internal validation set and achieved 75.00% sensitivity, 88.46% specificity, and 86.60% accuracy in the prospective test set.

Conclusion

This study presented a deep learning approach to enable the prediction of occult nodal involvement based on the PET/CT images before surgery in cN0 lung adenocarcinoma, which would help clinicians select patients who would be suitable for sublobar resection.
Effectiveness of Trastuzumab Combined With Capecitabine Treatment in a Patient With Hilar Cholangiocarcinoma Complicated by Liver Metastases With an ERBB2-Activating Mutation: A Case Report
Authors: Zeng Daobing , Zhao Xiaofei , Di Liang , Lou Luyan , Song Yanfang , Zhang Yanrui , Liu Huanhuan , Li Guangming
Published: July 2022

The identification of ERBB2 (HER2) alteration in some solid tumors has become critically important due to the actionable events predictive of response to anti-HER2 therapy. However, the efficacy of ERBB2 mutated hilar cholangiocarcinoma (hCCA) against ERBB2 is rarely reported. Here we report a 76-year-old female diagnosed with hCCA complicated by liver metastases after radical resection. The next-generation sequencing assay showed that the tumor had an ERBB2 mutation. Then, the patient was treated with trastuzumab plus capecitabine. After 2 months of treatment, she had a partial response. Until now, the patient is still alive. This study has shown the potential of trastuzumab combined with capecitabine as an effective treatment for hilar cholangiocarcinoma complicated by liver metastases harboring ERBB2 alterations.
P-Rex1 Signaling Hub in Lower Grade Glioma Patients, Found by In Silico Data Mining, Correlates With Reduced Survival and Augmented Immune Tumor Microenvironment
Authors: Beltrán-Navarro Yarely Mabell , Reyes-Cruz Guadalupe , Vázquez-Prado José
Published: July 2022

Systematic analysis of tumor transcriptomes, combined with deep genome sequencing and detailed clinical assessment of hundreds of patients, constitutes a powerful strategy aimed to identify potential biomarkers and therapeutic targets to guide personalized treatments. Oncogenic signaling cascades are integrated by multidomain effector proteins such as P-Rex1, a guanine nucleotide exchange factor for the Rac GTPase (RacGEF), known to promote metastatic dissemination of cancer cells. We hypothesized that patients with high P-Rex1 expression and reduced survival might be characterized by a particular set of signaling proteins co-expressed with this effector of cell migration as a central component of a putative signaling hub indicative of poor prognosis. High P-Rex1 expression correlated with reduced survival of TCGA Lower Grade Glioma (LGG) patients. Thus, guided by PREX1 expression, we searched for signaling partners of this RacGEF by applying a systematic unbiased in silico data mining strategy. We identified 30 putative signaling partners that also correlated with reduced patient survival. These included GPCRs such as CXCR3, GPR82, FZD6, as well as MAP3K1, MAP2K3, NEK8, DYRK3 and RPS6KA3 kinases, and PTPN2 and PTPN22 phosphatases, among other transcripts of signaling proteins and phospho-substrates. This PREX1 signaling hub signature correlated with increased risk of shorter survival of LGG patients from independent datasets and coincided with immune and endothelial transcriptomic signatures, indicating that myeloid infiltration and tumor angiogenesis might contribute to worsen brain tumor pathology. In conclusion, P-Rex1 and its putative signaling partners in LGG are indicative of a signaling landscape of the tumor microenvironment that correlates with poor prognosis and might guide the characterization of signaling targets leading the eventual development of immunotherapeutic strategies.
Low expression and Hypermethylation of ATP2B1 in Intrahepatic Cholangiocarcinoma Correlated With Cold Tumor Microenvironment
Authors: Zhang Xiehua , He Yuchao , Ren Peiqi , Chen Lu , Han Zhiqiang , Qi Lisha , Chen Liwei , Luo Yi , Zhang Ning , Lu Wei , Guo Hua
Published: July 2022

Background

The efficacy of current therapeutic schedule is limited owing to fibroproliferative tumor microenvironment (TME) of cholangiocarcinoma, compelling a search for new therapeutic targets.

Methods

Gene expression profiles and methylation profiles were obtained from UCSC Xena. Consensus clustering was performed on the transcriptome data of cholangiocarcinoma to determine the different immune subtypes. The differentially expressed genes (DEGs) between hot tumor and cold tumors were identified. ESTIMATE was used to assess immune score, and the cases were separated into relatively superior and inferior immune score groups. Single-sample gene set enrichment analysis was applied to assess 28 immune cells in the cholangiocarcinoma microenvironment. Unsupervised consensus was applied for methylation profiling to distribute the high and low methylation groups. The correlation between DNA methylation and mRNA expression was investigated, and the relationship between the ATP2B1 gene and the immune microenvironment was explored. Finally, 77 cases of intrahepatic cholangiocarcinoma (ICC) were collected for verification.

Results

Seven subtypes were related to patient outcomes (P=0.005). The proportions of CD8+ T cells in the “hot” immune type was significantly greater than that in the “cold” immune type (P<0.05). Next, DEGs and DNA methylation-governed genes were intersected, and ATP2B1 was identified as a prognosis factor in ICC (P=0.035). ATP2B1 expression was positively correlated with immune scores (P=0.005, r=0.458), the levels of infiltrating CD8+ T cells (P=0.004, r=0.47), and CD4+ T cells (P=0.027, r=0.37). Immunohistochemistry confirmed that the amounts of CD8+ and CD4+ T cells were significantly higher in ICC tissue samples than in tissues with ATP2B1 overexpression (P<0.05).

Conclusions

ATP2B1 overexpression can activate immune signals and prompt cold tumor response.
Risk Factors of Microscopically Tumor-Free Surgical Margins for Recurrence and Survival of Oral Squamous Cell Carcinoma Patients
Authors: Pei Meiling , Han Dawool , Kim Ki-Yeol , Kim Dong Wook , Nam Woong , Kim Hyung Jun , Cho Eunae Sandra , Kim Hyun Sil , Cha In-Ho , Zhang Xianglan
Published: July 2022

Objectives

The concept of adequate surgical margins remains controversial in oral squamous cell carcinoma (OSCC) surgery. This study aimed to identify surgical margin-related indicators that might impact recurrence and survival of OSCC patients.

Materials and Methods

Histopathological examination was performed using hematoxylin-eosin-stained surgical margin tissue sections in 235 OSCC patients. Axin2 and Snail expression at the surgical margin was detected by immunohistochemistry. The impact of the Axin2-Snail cascade on tumorigenesis of the immortalized human oral keratinocyte (IHOK) line was investigated in vivo.

Results

The width and dysplasia of surgical margins were not significantly associated with the outcome of OSCC patients. In a multivariate analysis using variable clinicopathologic factors and with Axin2 and Snail expression as cofactors, higher age (hazard ratio [HR]:1.050; P=0.047), Axin2 (HR:6.883; P=0.014), and Snail abundance (HR:5.663; P=0.009) had independent impacts on worsened overall survival. Similarly, lesion site in retromolar trigone (HR:4.077; P=0.010), upper (HR:4.332; P=0.005) and lower gingiva (HR:3.545; P=0.012), presence of extranodal extension (HR:9.967; P<0.001), perineural invasion (HR:3.627; P=0.024), and Snail abundance (HR:3.587; P<0.001) had independent impacts on worsened recurrence-free survival. Furthermore, Axin2 knockdown induced decreased Snail expression and attenuated tumorigenesis in the IHOK line.

Conclusion

Histopathological examination of surgical margins may not be reliable to predict OSCC patient outcome. Molecular analysis may provide a more accurate risk assessment of surgical margins in OSCC. In particular, Axin2 and Snail are potential predictive biomarkers for the risk assessment of surgical margins in OSCC.
High Expression of PARP1 in Tumor and Stroma Cells Predicts Different Prognosis and Platinum Resistance in Patients With Advanced Epithelial Ovarian Cancer
Authors: Zuo Wei-Wei , Zhao Chun-Fang , Li Yan , Sun Hai-Yan , Ma Guo-Ming , Liu Yue-Ping , Kang Shan
Published: July 2022

Objective

This study aimed to explore the roles of PARP1 mRNA and protein expression in platinum resistance and prognosis of EOC patients, and reveal the different roles of PARP1 protein in epithelial tumor and stroma cells.

Methods

The PARP1 mRNA expression of the EOC tissues was examined by RT-qPCR. The impacts of PARP1 expression on prognosis were measured by Kaplan-Meier and Cox regression. Receiver operating characteristic (ROC) curve analysis was employed for calculating the diagnostic value of PARP1 on platinum resistance. The microarray of formalin-fixed, paraffin-embedded (FFPE) tissues was processed for multiplex immunofluorescence to detect the protein levels of PARP1 and cytokeratin (CK).

Results

The PARP1mRNA expression of EOC patients was higher in the platinum-resistant group compared with the sensitive group (P<0.01). Kaplan-Meier analysis demonstrated that high PARP1 mRNA expression was associated with poor survival of EOC patients. In Cox regression analyses, high PARP1 mRNA expression independently predicted poor prognosis (P=0.001, HR=2.076, 95%CI=1.373-3.140). The area under the ROC curve of PARP1 mRNA for predicting the platinum resistance in EOC patients was 0.649, with a sensitivity of 0.607 and specificity of 0.668. Furthermore, the protein expression of PARP1 was higher in the platinum-resistant group than in the sensitive group (P<0.01) and associated with a worse prognosis. Additionally, according to CK labeling, we observed that enhanced expression of PARP1 in the CK+ region was associated with platinum resistance and lower survival, but in CK- region, it predicted a good prognosis and platinum sensitivity.

Conclusion

PARP1 may be a potential biomarker to predict platinum resistance and prognosis for EOC patients, exerting different roles on epithelial tumor and stromal cells.
Nanotech Probes: A Revolution in Cancer Diagnosis
Authors: Zhang Qi , Hou Kai , Chen Hongbo , Zeng Ning , Wu Yiping
Published: July 2022

Recent advances in nanotechnologies for cancer diagnosis and treatment have received considerable attention worldwide. Nanoparticles are being used to create nanodrugs and probes to diagnose and treat a variety of diseases, including cancer. Nanomedicines have unique advantages, such as increased surface-to-volume ratios, which enable them to interact with, absorb, and deliver small biomolecules to a very specific target, thereby improving the effectiveness of both probes and drugs. Nanoprobe biotechnology also plays an important role in the discovery of novel cancer biomarkers, and nanoprobes have become an important part of early clinical diagnosis of cancer. Various organic and inorganic nanomaterials have been developed as biomolecular carriers for the detection of disease biomarkers. Thus, we designed this review to evaluate the advances in nanoprobe technology in tumor diagnosis.
Role and Mechanisms of Tumor-Associated Macrophages in Hematological Malignancies
Authors: Xie Yutong , Yang Huan , Yang Chao , He Liren , Zhang Xi , Peng Li , Zhu Hongbin , Gao Lei
Published: July 2022

Mounting evidence has revealed that many nontumor cells in the tumor microenvironment, such as fibroblasts, endothelial cells, mesenchymal stem cells, and leukocytes, are strongly involved in tumor progression. In hematological malignancies, tumor-associated macrophages (TAMs) are considered to be an important component that promotes tumor growth and can be polarized into different phenotypes with protumor or antitumor roles. This Review emphasizes research related to the role and mechanisms of TAMs in hematological malignancies. TAMs lead to poor prognosis by influencing tumor progression at the molecular level, including nurturing cancer stem cells and laying the foundation for metastasis. Although detailed molecular mechanisms have not been clarified, TAMs may be a new therapeutic target in hematological disease treatment.
Identification and Validation of a Four-Gene Ferroptosis Signature for Predicting Overall Survival of Lung Squamous Cell Carcinoma
Authors: Wang Qi , Chen Yaokun , Gao Wen , Feng Hui , Zhang Biyuan , Wang Haiji , Lu Haijun , Tan Ye , Dong Yinying , Xu Mingjin
Published: July 2022

Background

Lung squamous cell carcinoma (LUSC) represents 30% of all non-small cell lung carcinoma. Targeted therapy is not sufficient for LUSC patients because of the low frequency of targeted-effective mutation in LUSC whereas immunotherapy offers more options for patients with LUSC. We explored a ferroptosis-related prognostic signature that can potentially assess the prognosis and immunotherapy efficacy of LUSC patients.

Methods

A total of 502 LUSC patients were downloaded from The Cancer Genome Atlas (TCGA). The external validation data were obtained from the Gene Expression Omnibus (GEO): GSE73403. Then, we identified the candidate genes and constructed the prognostic signature through the Cox survival regression analyses and least absolute shrinkage and selection operator (LASSO). Risk score plot, Kaplan–Meier curve, and ROC curve were used to assess the prognostic power and performance of the model. The CIBERSORT algorithm estimated the fraction of immune cell types. TIDE was utilized to predict the response to immunotherapy. IMvigor210 was used to explore the association between the risk scores and immunotherapy outcomes. A nomogram combined selected clinical characteristics, and the risk scores were constructed.

Results

We screened 132 differentially expressed ferroptosis-related genes. According to KEGG and GO pathway analyses, these genes were mainly engaged in the positive regulation of cytokine production, cytokine metabolic process, and oxidoreductase activity. We then constructed a prognostic model via LASSO regression. The proportions of CD8+ T cells, CD4+ activated T cells, and follicular helper T cells were significantly different between low-risk and high-risk groups. TIDE algorithm indicated that low-risk LUSC patients might profit more from immune checkpoint inhibitors. The predictive value of the ferroptosis gene model in immunotherapy response was further confirmed in IMvigor210. Finally, we combined the clinical characteristics with a LASSO regression model to construct a nomogram that could be easily applied in clinical practice.

Conclusion

We identified a prognostic model that provides an accurate and objective basis for guiding individualized treatment decisions for LUSC.
Cervical Motor and Nociceptive Dysfunction After an Acute Whiplash Injury and the Association With Long-Term Non-Recovery: Revisiting a One-Year Prospective Cohort With Ankle Injured Controls
Authors: Kasch Helge , Carstensen Tina , Ravn Sophie Lykkegaard , Andersen Tonny Elmose , Frostholm Lisbeth
Published: July 2022

Aims

To explore the development of cervical motor and nociceptive dysfunction in patients with whiplash (WPs) and non-recovery based on injury-related work disability 1-year after injury when compared with ankle-injured controls (ACs).

Methods

A 1-year observational prospective study examining consecutive WPs and age- and sex-matched ACs at 1 week,3 months, 6 months, and 1 year post-injury using semi-structured interviews; global pain rating (VAS0-10) and the pain rating index (PRI-T) and number-of-words-chosen (NWC) from the McGill Pain Questionnaire; examining nociceptive functioning using the cold pressor test (CPT), pressure algometry, and methodic palpation, and central pain processing using counter-stimulation; and examining motor functioning by active cervical range-of-motion (CROM), and neck strength [maximal voluntary contraction flexion/extension (MVC)]. One-year work disability/non-recovery was determined using a semi-structured interview.

Results

A total of 141 WPs and 40 ACs were included. Total pain rating index (PRI-T) NWC were higher in ACs after 1 week but higher in WPs after 3 months, 6 months, and 1 year. Ongoing global pain was higher in WPs after 1 week and after 3 and 6 months but not after 1 year. Pressure pain thresholds were reduced, and palpation was higher in the neck and jaw in WPs after 1 week but was not consistently different afterward from ACs. Cervical mobility was reduced in WPs after 1 week, 3 months, and 6 months but not after 1 year, and MVC was significantly reduced in WPs when compared with ACs after 1 week and 1 year but not after 3 and 6 months. One-year non-recovery was only encountered in 11 WPs and not in the AC group. Non-recovered WPs (N-WPs) had consistently significantly higher VAS0−10, PRI-T, NWC, reduced pressure pain thresholds, raised muscle-tenderness, reduced active cervical range-of-motion, reduced active-neck-flexion/extension, and reported higher neck disability scores than recovered WPs. Of special interest, there was increasing tenderness in trigeminal-derived muscles based on palpation scores, and marked reduction of PPDT was most pronounced in N-WPs when compared with recovered WPs and ACs.

Conclusion

Cervical motor dysfunction and segmental nociceptive sensitization were present from early after injury in WPs and prolonged in N-WPs. Differences in trigeminal and cervical motor and sensory function in N-WPs could be of interest for future treatment studies.
The Prevalence of Social Withdrawal in Infants With Cleft Lip and Palate: The Feasibility of the Full and the Modified Versions of the Alarm Distress Baby Scale
Authors: Pérez Martínez Carla , Grollemund Bruno , Gavelle Pascale , Viaux-Savelon Sylvie , Guedeney Antoine
Published: July 2022

Background

Social withdrawal is a risk indicator for infant development with both organic and non-organic causes. Cleft lip and palate (CLP) impose a higher risk of physical and emotional distress in infants and alters parent-infant relationships. The ADBB scale is a screening tool to identify social withdrawal as a sign of distress in infants. The aim of this study is to evaluate the prevalence of social withdrawal behavior in infants with CLP using the full 8-item ADBB scale and the modified 5-item ADBB scale, and to examine the feasibility of both scales.

Methods

145 infants with Cleft Lip and Palate were enrolled and video recorded during a pediatric consultation. All infants were scored by two expert raters trained in ADBB scale, and subsequently scored with the m-ADBB by an independent expert. We measured the interrater agreement for the full ADBB scale and psychometric properties of both scales.

Results

The full ADBB scale identified 15.9% of infants as having social withdrawal behavior (score above cutoff ≥5). Among the infants evaluated with the m-ADBB scale, 44.9% had a score above the suggested cutoff (≥2). For both scales, the item “vocalization” showed the higher scores. We found a good internal consistency for the full ADBB (Cronbach's alpha = 0.82) and an acceptable internal consistency for the modified ADBB (Cronbach's alpha = 0.71). The interrater agreement for the full ADBB scale was excellent (kappa = 0.837). The Spearman correlation coefficient between the total scores of the two versions was 0.88 (P < 0.001).

Conclusion

Our results indicate a relatively high prevalence of social withdrawal in infants with Cleft Lip and Palate, especially evaluated with the modified 5-item ADBB scale. We found that the full ADBB and the modified ADBB scales are feasible to use as screening tools of social withdrawal in this population.

Clinical Trial Registration

This trial is registered on ClinicalTrials.gov, identifier: NCT00993993. The data is the property of Assistance Publique, Hôpitaux de Paris.
Clinical Feature, Treatment, and KCNH5 Mutations in Epilepsy
Authors: Hu Xiufu , Yang Junli , Zhang Man , Fang Tie , Gao Qin , Liu Xinjie
Published: July 2022

The voltage-gated Kv10.2 potassium channel, encoded by KCNH5, is broadly expressed in mammalian tissues, including the brain. Its potential mechanism remains unclear. According to previous studies, dysfunction of Kv10.2 may be associated with epileptic encephalopathies and autism spectrum disorder (ASD). To date, only one disease-causing mutation of KCNH5 has been reported, and it involves a case that presented with seizures and autism symptoms. In this study, we discovered and characterized three de novo mutations in KCNH5 that potentially caused severe conditions observed in three Chinese children. All of them experienced seizures, two of them presented with epileptic encephalopathy, one of them presented with ASD, and one did not relapse after drug withdrawal. Notably, treatment with antiepileptic drugs (AEDs) was effective in all patients whose epileptic seizures were controlled. The structures of the proteins resulting from the mutations were predicted in two of the three cases. This provides powerful insight into clinical heterogeneity and genotype-phenotype correlation in KCNH5-related diseases.
Holder Pasteurization: Comparison of Water-Bath and Dry-Tempering Devices
Authors: Müller Katharina , Toll Luisa J. , Manzardo Olimpia A. , Baumgartner Jana , Nickel Erika , Wenzel Folker , Klotz Daniel
Published: July 2022

Background

Human milk (HM) for premature infants is frequently Holder pasteurized (heated at 62.5 ± 0.5°C for 30 min) despite its detrimental effects on heat-sensitive milk components. This tolerated compromise ensures HM's microbial safety while less detrimental methods like short-time HM treatments (HTST) are still being evaluated. Dry-tempering devices (DT-HoP) were recently introduced in clinical practice due to hygienic concerns about water-based Holder pasteurizers (WB-HoP). Evidence on the impact of such dry-tempering devices on HM quality is lacking. The aim of this study was to compare protein retention rates after DT-HoP, WB-HoP and HTST.

Methods

We colorimetrically determined alkaline phosphatase activity (ALP), concentrations of secretory immunoglobulin A (sIgA), and lactoferrin (LF) before and after DT-HoP, WB-HoP and HTST.

Results

ALP was below the detection limit after HoP, but retained 52.8 ± 13% activity after HTST (p < 0.01). Secretory IgA (WB-HoP = 73.2 ± 13.5% vs. DT-HoP = 57 ± 14%, p = 0.0018) and LF retention (WB-HoP=47 ± 40% vs. DT-HoP=25 ± 8%, p = 0.07) differed between the two HoP modes. Again, retention was better maintained after HTST compared to HoP (80.4 ± 23% sIgA and 70 ± 42% LF concentration, all p < 0.01).

Conclusion

Dry-tempering milk lowers even further the quality of HM when performing HoP compared to water-bath pasteurization, while HTST warrants continued evaluation for clinical application.
Correlation of SARS-CoV-2 Viral Load and Clinical Evolution of Pediatric Patients in a General Hospital From Buenos Aires, Argentina
Authors: Brizuela Martín Eduardo , Goñi Sandra Elizabeth , Cardama Georgina Alexandra , Zinni María Alejandra , Castello Alejandro Andres , Sommese Leandro Matías , Farina Hernán Gabriel
Published: July 2022

Background

SARS-CoV-2 infection is associated with a wide range of clinical manifestations and severity. Pediatric cases represent <10% of total cases, with a mortality rate below 1%. Data of correlation between SARS-CoV-2 viral load in respiratory samples and severity of disease in pediatric patients is scarce. The cycle threshold (CT) value for the detection of SARS-CoV-2 could be used as an indirect indicator of viral load in analyzed respiratory samples.

Objective

The aim of this study was to describe CT values and their correlation with clinical manifestations, epidemiology and laboratory parameters in pediatric patients with confirmed COVID-19.

Methods

In this observational, retrospective, analytic and single-center study we included patients under 15 years with confirmed COVID-19 by RT-PCR SARS-CoV-2 admitted to the Isidoro Iriarte Hospital (Argentina) between March 1st 2020 and April 30th 2021.

Results

485 patients were included, the distribution according to disease severity was: 84% (408 patients) presented mild disease, 12% (59 patients) moderate disease and 4% (18 patients) severe disease. Patients with moderate and severe illness had an increased hospitalization rate, prolonged hospitalization, higher frequency of comorbidities and oxygen and antibiotics use. CT values, that could be used as an indirect measure of viral load, was associated with severity of clinical manifestations and age under 12 months. No patient required admission to PICU nor mechanical ventilation. No deaths were registered.

Conclusions

In this study, the viral load of SARS-CoV-2 in respiratory samples, determined by the cycle threshold, was significantly correlated with moderate to severe cases and with age.