bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Impact of the Histopathological Index and Neuroimaging Features Status in Primary Central Nervous System Diffuse Large B-Cell Lymphoma: A Single-Center Retrospective Analysis of 51 Cases
Authors: Qi Zhou , Duan Lei , Yuan Guoqiang , Liu Jianli , Li Jian , Li Guoqiang , Yu Yue , Xu Yanlong , Ma Shangxian , Pan Yawen , Zhang Yinian
Published: July 2022

Primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is an uncommon non-Hodgkin lymphoma subtype, and its clinical and pathological characteristics remain unclear. PCNS-DLBCL patient data were retrospectively evaluated to determine clinical and pathological characteristics and prognostic factors. Furthermore, prognoses were calculated by Kaplan–Meier and Cox regression models based on clinical observations. In total, 51 immunocompetent patients were enrolled. The median age was 55 (range, 16–82) years, and the male-to-female ratio was 3:2. Headache (n = 19; 37%) and the frontal lobe (n = 16; 31%) were the most common presenting symptom and location, respectively. The median follow-up was 33 (range, 3–86) months, and the median overall survival (OS) and progression-free survival (PFS) were 18 months [95% confidence interval (CI), 21.2–34.2] and 15 months (95% CI, 16.9–28.7), respectively. Ki-67, cluster of differentiation-3, and deep brain involvement were independent prognostic markers. Moreover, multifocal lesions and deep brain involvement were unfavorable independent prognostic markers for PFS. This study indicates that targeted drug development for adverse prognostic factors is possible and provides guidance for clinical treatment decision-making.
Role of the Glyoxalase System in Breast Cancer and Gynecological Cancer-Implications for Therapeutic Intervention: a Review
Authors: Wang Jingyuan , Yang Xiao , Wang Zhiqi , Wang Jianliu
Published: July 2022

Methyglyoxal (MGO), an essential endogenous dicarbonyl metabolite, can lead to multiple physiological problems including hyperglycemia, kidney diseases, malignant tumors, beyond its normal concentration range. The glyoxalase system, making MGO maintained at a low level, links glycation to carcinogenesis, growth, metastasis, and cancer chemotherapy. The glyoxalase system comprises glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2), which is often overexpressed in various tumor tissues. However, very little is known about the glyoxalase system in breast cancer and gynecological cancer. In this review, we introduce the role of the glyoxalase system in breast cancer, endometrial cancer, ovarian cancer and cervical cancer, and highlight the potential of the glyoxalase system to be both as a marker for diagnosis and a novel target for antitumor therapy. However, the intrinsic molecular biology and mechanisms of the glyoxalase system in breast cancer and gynecological cancer need further exploration.
Clonal Evolution at First Sight: A Combined Visualization of Diverse Diagnostic Methods Improves Understanding of Leukemic Progression
Authors: Sandmann Sarah , Behrens Yvonne Lisa , Davenport Claudia , Thol Felicitas , Heuser Michael , Dörfel Daniela , Löhr Friederike , Castrup Agnes , Steinemann Doris , Varghese Julian , Schlegelberger Brigitte , Dugas Martin , Göhring Gudrun
Published: July 2022

Patients with myeloid neoplasia are classified by the WHO classification systems. Besides clinical and hematological criteria, cytogenetic and molecular genetic alterations highly impact treatment stratification. In routine diagnostics, a combination of methods is used to decipher different types of genetic variants. Eight patients were comprehensively analyzed using karyotyping, fluorescence in situ hybridization, array-CGH and a custom NGS panel. Clonal evolution was reconstructed manually, integrating all mutational information on single nucleotide variants (SNVs), insertions and deletions (indels), structural variants and copy number variants (CNVs). To allow a correct integration, we differentiate between three scenarios: 1) CNV occurring prior to the SNV/indel, but in the same cells. 2) SNV/indel occurring prior to the CNV, but in the same cells. 3) SNV/indel and CNV existing in parallel, independent of each other. Applying this bioinformatics approach, we reconstructed clonal evolution for all patients. This generalizable approach offers the possibility to integrate various data to analyze identification of driver and passenger mutations as well as possible targets for personalized medicine approaches. Furthermore, this model can be used to identify markers to assess the minimal residual disease.
FOXS1 Promotes Tumor Progression by Upregulating CXCL8 in Colorectal Cancer
Authors: Qiu Junfeng , Li Mingzhou , Su Cailin , Liang Yihao , Ou Ruizhang , Chen Xiaoning , Huang Chengmei , Zhang Yaxin , Ye Yaping , Liao Wenting , Zhang Chao
Published: July 2022

Background

Forkhead box S1 (FOXS1) is a member of the forkhead box (FOX) transcriptional factor superfamily. The biological roles and underlying regulatory mechanism of FOXS1 in CRC remain unclear.

Methods

Bioinformatics analysis, Western blotting, real-time PCR, and immunohistochemistry (IHC) were used to detect the expression FOXS1 in CRC. MTT assay, transwell assay, human umbilical vein endothelial cell tube formation assay, and chicken chorioallantoic membrane assay were performed to investigate the effects of FOXS1 on proliferation, invasion, and angiogenesis. Additionally, tumor formation assay and orthotopic implantation assay were used to investigate the effects of FOXS1 on tumor growth and metastasis in vivo. Furthermore, gene set enrichment analysis (GSEA) was used to analyze the correlation between FOXS1 and EMT or angiogenesis. The correlation between FOXS1 and CXCL8 expression was analyzed in clinical CRC samples using IHC.

Results

The results showed that FOXS1 expression was upregulated in CRC tissues compared with adjacent normal intestine tissues. A high FOXS1 expression is positively correlated with poor survival. FOXS1 promoted the malignant behavior of CRC cancer cells in vitro, including proliferation, invasion, and angiogenesis. In addition, FOXS1 promoted tumor growth and metastasis in nude mice. Mechanistically, FOXS1 upregulated the expression of C–X–C motif chemokine ligand 8 (CXCL8) at the transcriptional level. Knockdown of CXCL8 blocked FOXS1 induced the enhancement of the EMT and angiogenesis. GSEAs in public CRC datasets revealed strong correlations between FOXS1 expression and EMT marker and angiogenesis markers. IHC showed that FOXS1 expression was positively correlated with CXCL8 expression and CD31 expression in clinical CRC samples.

Conclusion

The results suggest that FOXS1 promotes angiogenesis and metastasis by upregulating CXCL8 in CRC. Interference with the FOXS1/CXCL8 axis may serve as a potential therapeutic target for the treatment of metastatic CRC.
Feasibility and Short-Term Toxicity of a Consecutively Delivered Five Fraction Stereotactic Body Radiation Therapy Regimen in Early-Stage Breast Cancer Patients Receiving Partial Breast Irradiation
Authors: Liu Yilan , Veale Christopher , Hablitz Diana , Krontiras Helen , Dalton Allison , Meyers Korie , Dobelbower Michael , Lancaster Rachael , Bredel Markus , Parker Catherine , Keene Kimberly , Thomas Evan , Boggs Drexell
Published: July 2022

Background

For appropriately selected patients with early-stage breast cancer (ESBC), accelerated partial breast irradiation (APBI) yields equivalent rates of ipsilateral breast tumor recurrence with mixed results in patient-rated cosmesis compared with whole-breast radiotherapy depending on the technique utilized. When utilizing external beam radiotherapy for APBI, techniques to reduce target margins and overall treatment volume are potentially important to decrease rates of long-term adverse cosmesis. Stereotactic body radiotherapy (SBRT) is a promising technique to deliver APBI because of its increased accuracy and sparing of uninvolved breast tissue. We report the initial results of a prospective clinical trial investigating feasibility, safety, and cosmetic outcomes of a daily five-fraction SBRT regimen for APBI.

Methods

Twenty-three patients with ESBC after lumpectomy who met APBI suitability were enrolled. During lumpectomy, a bioabsorbable three-dimensional fixed array tissue marker (BioZorb™, Hologic, Marlborough, MA) was placed for enhanced visualization of the cavity boundaries. Clinical target volume (CTV) was defined as the delineable cavity plus a 1-cm isotropic expansion followed by a 3-mm isotropic planning target volume (PTV) expansion. Patients received 30 Gy delivered in five planned consecutive daily fractions in either prone or supine positioning depending on individual anatomy. Two patients completed the five-fraction treatments in 9-day interval and 11-day interval due to external circumstances. A maximum PTV of 124cc was allowed to minimize incidence of fat necrosis. Plans utilized 10-MV flattening filter–free beams delivered on a Varian Edge linear accelerator. Local control, toxicity, and nurse/patient-scored cosmesis at pre-treatment baseline, 1 month post-treatment, and at subsequent 6-month intervals were recorded.

Results

Twenty-three patients were accrued at the time of submission with median follow-up of 6 months. No patients experienced grade ≥3 acute toxicity. Of the 10 events reported probably related to SBRT, nine were grade 1 (n = 9/10, 90%). There was no evidence of difference, deterioration, or change in patient or nurse-scored cosmesis from baseline to 1 and 6 months post-treatment. One patient developed nodal failure shortly after APBI.

Conclusions

Although longer follow-up is needed to assess long-term toxicity and local control, this study demonstrated a five-fraction SBRT regimen delivered over consecutive days is a safe, efficient, well-tolerated, and cosmetically favorable means of delivering APBI in suitable women.

Clinical Trial Registration

https://www.clinicaltrials.gov/ct2/show/NCT03643861, NCT03643861.
Somatic DNA Damage Response and Homologous Repair Gene Alterations and Its Association With Tumor Variant Burden in Breast Cancer Patients With Occupational Exposure to Pesticides
Authors: Scandolara Thalita Basso , Valle Sara Ferreira , Esteves Cristiane , Scherer Nicole de Miranda , de Armas Elvismary Molina , Furtado Carolina , Gomes Renan , Boroni Mariana , Jaques Hellen dos Santos , Alves Fernanda Mara , Rech Daniel , Panis Carolina , Bonvicino Cibele Rodrigues
Published: July 2022

Homologous recombination is a crucial pathway that is specialized in repairing double-strand breaks; thus, alterations in genes of this pathway may lead to loss of genomic stability and cell growth suppression. Pesticide exposure potentially increases cancer risk through several mechanisms, such as the genotoxicity caused by chronic exposure, leading to gene alteration. To analyze this hypothesis, we investigated if breast cancer patients exposed to pesticides present a different mutational pattern in genes related to homologous recombination (BRCA1, BRCA2, PALB2, and RAD51D) and damage-response (TP53) concerning unexposed patients. We performed multiplex PCR-based assays and next-generation sequencing (NGS) of all coding regions and flanking splicing sites of BRCA1, BRCA2, PALB2, TP53, and RAD51D in 158 unpaired tumor samples from breast cancer patients on MiSeq (Illumina) platform. We found that exposed patients had tumors with more pathogenic and likely pathogenic variants than unexposed patients (p = 0.017). In general, tumors that harbored a pathogenic or likely pathogenic variant had a higher mutational burden (p < 0.001). We also observed that breast cancer patients exposed to pesticides had a higher mutational burden when diagnosed before 50 years old (p = 0.00978) and/or when carrying BRCA1 (p = 0.0138), BRCA2 (p = 0.0366), and/or PALB2 (p = 0.00058) variants, a result not found in the unexposed group. Our results show that pesticide exposure impacts the tumor mutational landscape and could be associated with the carcinogenesis process, therapy response, and disease progression. Further studies should increase the observation period in exposed patients to better evaluate the impact of these findings.
Association Between ABO Blood Group and Venous Thromboembolism Risk in Patients With Peripherally Inserted Central Catheters: A Meta-analysis and Systematic Review
Authors: Zhang Qiang , Peng Hong , Hu Lu , Ren Ran , Peng Xingqiao , Song Jifang
Published: July 2022

Background

Previous studies have evaluated the association between ABO blood group and venous thromboembolism (VTE) risk in patients with peripherally inserted central catheters (PICCs). However, it remains unclear whether ABO blood groups are associated with PICC-associated VTE risk. Therefore, we conducted a meta-analysis of related studies to elucidate the potential role of ABO blood group as a risk factor for PICC-associated VTE.

Methods

All detectable case–control and cohort studies comparing the role of ABO blood group as a risk factor for PICC-associated VTE were collected for this analysis by searching PubMed, Embase, CNKI, Web of Science, and Wanfang. We conducted a meta-analysis of the eligible studies and computed the summary risk estimates with random or fixed effects models.

Results

A total of four studies involving 7,804 patients were included. Meta-analysis of the studies showed that the risk of PICC-associated VTE was significantly higher in blood types A [odds ratio (OR)=1.54, 95% CI=1.17–2.03), p=0.002], B (OR=2.35, 95% CI=1.71–3.23, p<0.0001), and AB (OR=2.55, 95% CI=1.68–3.88, p<0.0001) and lower in blood types O (OR=0.58, 95% CI=0.45–0.74, p<0.0001). Subgroup analysis based on ethnicity demonstrated that blood type O may be a genetic protective factor for PICC-associated VTE in Asians. Among Caucasians, individuals with blood types B and AB have a higher risk of PICC-associated VTE. Blood types A, B, and AB are risk factors for PICC-associated VTE in Asians.

Conclusions

Blood type O is associated with a decreased risk of PICC-associated VTE, especially in Asian populations. Moreover, blood types A, B, and AB are risk factors for PICC-associated VTE.
Pseudogenes and Liquid Phase Separation in Epigenetic Expression
Authors: Nsengimana Bernard , Khan Faiz Ali , Awan Usman Ayub , Wang Dandan , Fang Na , Wei Wenqiang , Zhang Weijuan , Ji Shaoping
Published: July 2022

Pseudogenes have been considered as non-functional genes. However, peptides and long non-coding RNAs produced by pseudogenes are expressed in different tumors. Moreover, the dysregulation of pseudogenes is associated with cancer, and their expressions are higher in tumors compared to normal tissues. Recent studies show that pseudogenes can influence the liquid phase condensates formation. Liquid phase separation involves regulating different epigenetic stages, including transcription, chromatin organization, 3D DNA structure, splicing, and post-transcription modifications like m6A. Several membrane-less organelles, formed through the liquid phase separate, are also involved in the epigenetic regulation, and their defects are associated with cancer development. However, the association between pseudogenes and liquid phase separation remains unrevealed. The current study sought to investigate the relationship between pseudogenes and liquid phase separation in cancer development, as well as their therapeutic implications.
Dual Function of Par3 in Tumorigenesis
Authors: Lv Tao , Xu Jiashun , Yuan Hemei , Wang Jianling , Jiang Xinni
Published: July 2022

Cell maintenance and the establishment of cell polarity involve complicated interactions among multiple protein complexes as well as the regulation of different signaling pathways. As an important cell polarity protein, Par3 is evolutionarily conserved and involved in tight junction formation as well as tumorigenesis. In this review, we aimed to explore the function of Par3 in tumorigenesis. Research has shown that Par3 exhibits dual functions in human cancers, both tumor-promoting and tumor-suppressive. Here, we focus on the activities of Par3 in different stages and types of tumors, aiming to offer a new perspective on the molecular mechanisms that regulate the functions of Par3 in tumor development. Tumor origin, tumor microenvironment, tumor type, cell density, cell–cell contact, and the synergistic effect of Par3 and other tumor-associated signaling pathways may be important reasons for the dual function of Par3. The important role of Par3 in mammalian tumorigenesis and potential signaling pathways is context dependent.
Exploration of the Immunotyping Landscape and Immune Infiltration-Related Prognostic Markers in Ovarian Cancer Patients
Authors: Zhao Na , Xing Yujuan , Hu Yanfang , Chang Hao
Published: July 2022

Background

Increasing evidence indicates that immune cell infiltration (ICI) affects the prognosis of multiple cancers. This study aims to explore the immunotypes and ICI-related biomarkers in ovarian cancer.

Methods

The ICI levels were quantified with the CIBERSORT and ESTIMATE algorithms. The unsupervised consensus clustering method determined immunotypes based on the ICI profiles. Characteristic genes were identified with the Boruta algorithm. Then, the ICI score, a novel prognostic marker, was generated with the principal component analysis of the characteristic genes. The relationships between the ICI scores and clinical features were revealed. Further, an ICI signature was integrated after the univariate Cox, lasso, and stepwise regression analyses. The accuracy and robustness of the model were tested by three independent cohorts. The roles of the model in the immunophenoscores (IPS), tumor immune dysfunction and exclusion (TIDE) scores, and immunotherapy responses were also explored. Finally, risk genes (GBP1P1, TGFBI, PLA2G2D) and immune cell marker genes (CD11B, NOS2, CD206, CD8A) were tested by qRT-PCR in clinical tissues.

Results

Three immunotypes were identified, and ICI scores were generated based on the 75 characteristic genes. CD8 TCR pathways, chemokine-related pathways, and lymphocyte activation were critical to immunophenotyping. Higher ICI scores contributed to better prognoses. An independent prognostic factor, a three-gene signature, was integrated to calculate patients’ risk scores. Higher TIDE scores, lower ICI scores, lower IPS, lower immunotherapy responses, and worse prognoses were revealed in high-risk patients. Macrophage polarization and CD8 T cell infiltration were indicated to play potentially important roles in the development of ovarian cancer in the clinical validation cohort.

Conclusions

Our study characterized the immunotyping landscape and provided novel immune infiltration-related prognostic markers in ovarian cancer.
NCAPG2 Is a Novel Prognostic Biomarker and Promotes Cancer Stem Cell Maintenance in Low-Grade Glioma
Authors: Ren Wenjun , Yang Shu , Chen Xi , Guo Jishu , Zhao Heng , Yang Ruihan , Nie Zhi , Ding Li , Zhang Lei
Published: July 2022

Gliomas account for 75% of all primary malignant brain tumors in adults and are associated with high mortality. Mounting evidence has shown that NCAPG2 is differentially expressed in various cancers. However, the prognostic value and immune functions of NCAPG2 in low-grade glioma (LGG) remain unresolved. In the present study, we revealed that NCAPG2 was up-regulated in LGG, and its higher expression was associated with adverse clinical outcomes and poor clinical characteristics, including WHO grade, IDH mutation, 1p/19q codeletion, and primary therapy outcome. The results of the Cox regression analysis revealed that NCAPG2 was an independent factor for the prognosis of low-grade glioma. Meanwhile, we also established a nomogram based on NCAPG2 to predict the 1-, 3-, or 5-year survival in LGG patients. Furthermore, we found that Copy number variation (CNV) and DNA hypomethylation results in its overexpression in LGG. In addition, functional annotation confirmed that NCAPG2 was mainly involved in the immune regulation and WNT signaling pathways. Finally, we determined that increased expression of NCAPG2 was correlated with infiltration levels of various immune cells and immune checkpoint in LGG. Importantly, we found that NCAPG2 was highly expressed in glioma stem cells lines and knockdown of NCAPG2 significantly inhibited the self-renewal ability of GSC. This is the first study to identify NCAPG2 as a new potential prognostic biomarker and characterize the functional roles of NCAPG2 in the progression of LGG, and provides a novel potential diagnostic and therapeutic biomarker for LGG in the future.
Targeting AKT-Dependent Regulation of Antioxidant Defense Sensitizes AKT-E17K Expressing Cancer Cells to Ionizing Radiation
Authors: Goetting Isabell , Larafa Safa , Eul Katharina , Kunin Mikhail , Jakob Burkhard , Matschke Johann , Jendrossek Verena
Published: July 2022

Aberrant activation of the phosphatidyl-inositol-3-kinase/protein kinase B (AKT) pathway has clinical relevance to radiation resistance, but the underlying mechanisms are incompletely understood. Protection against reactive oxygen species (ROS) plays an emerging role in the regulation of cell survival upon irradiation. AKT-dependent signaling participates in the regulation of cellular antioxidant defense. Here, we were interested to explore a yet unknown role of aberrant activation of AKT in regulating antioxidant defense in response to IR and associated radiation resistance.

We combined genetic and pharmacologic approaches to study how aberrant activation of AKT impacts cell metabolism, antioxidant defense, and radiosensitivity. Therefore, we used TRAMPC1 (TrC1) prostate cancer cells overexpressing the clinically relevant AKT-variant AKT-E17K with increased AKT activity or wildtype AKT (AKT-WT) and analyzed the consequences of direct AKT inhibition (MK2206) and inhibition of AKT-dependent metabolic enzymes on the levels of cellular ROS, antioxidant capacity, metabolic state, short-term and long-term survival without and with irradiation.

TrC1 cells expressing the clinically relevant AKT1-E17K variant were characterized by improved antioxidant defense compared to TrC1 AKT-WT cells and this was associated with increased radiation resistance. The underlying mechanisms involved AKT-dependent direct and indirect regulation of cellular levels of reduced glutathione (GSH). Pharmacologic inhibition of specific AKT-dependent metabolic enzymes supporting defense against oxidative stress, e.g., inhibition of glutathione synthase and glutathione reductase, improved eradication of clonogenic tumor cells, particularly of TrC1 cells overexpressing AKT-E17K.

We conclude that improved capacity of TrC1 AKT-E17K cells to balance antioxidant defense with provision of energy and other metabolites upon irradiation compared to TrC1 AKT-WT cells contributes to their increased radiation resistance. Our findings on the importance of glutathione de novo synthesis and glutathione regeneration for radiation resistance of TrC1 AKT-E17K cells offer novel perspectives for improving radiosensitivity in cancer cells with aberrant AKT activity by combining IR with inhibitors targeting AKT-dependent regulation of GSH provision.
The Role of Adipokines in Pancreatic Cancer
Authors: Wang Qi , Wang Huizhi , Ding Yuntao , Wan Mengtian , Xu Min
Published: July 2022

In modern society, inappropriate diets and other lifestyle habits have made obesity an increasingly prominent health problem. Pancreatic cancer (PC), a kind of highly aggressive malignant tumor, is known as a silent assassin and is the seventh leading cause of cancer death worldwide, pushing modern medicine beyond help. Adipokines are coming into notice because of the role of the intermediate regulatory junctions between obesity and malignancy. This review summarizes the current evidence for the relationship between highly concerning adipokines and the pathogenesis of PC. Not only are classical adipokines such as leptin and adiponectin included, but they also cover the recognized chemerin and osteopontin. Through a summary of the biological functions of these adipokines as well as their receptors, it was discovered that in addition to their basic function of stimulating the biological activity of tumors, more studies confirm that adipokines intervene in the progression of PC from the viewpoint of tumor metabolism, immune escape, and reprogramming of the tumor microenvironment (TME). Besides endocrine function, the impact of white adipose tissue (WAT)-induced chronic inflammation on PC is briefly discussed. Furthermore, the potential implication of the acknowledged endocrine behavior of brown adipose tissue (BAT) in relation to carcinogenesis is also explored. No matter the broad spectrum of obesity and the poor prognosis of PC, supplemental research is needed to unravel the detailed network of adipokines associated with PC. Exploiting profound therapeutic strategies that target adipokines and their receptors may go some way to improving the current worrying prognosis of PC patients.
Development and External Validation of a Preoperative Nomogram for Predicting Lateral Pelvic Lymph Node Metastasis in Patients With Advanced Lower Rectal Cancer
Authors: Zhang Lei , Shi Feiyu , Hu Chenhao , Zhang Zhe , Liu Junguang , Liu Ruihan , She Junjun , Tang Jianqiang
Published: July 2022

Background

The preoperative prediction of lateral pelvic lymph node (LPLN) metastasis is crucial in determining further treatment strategies for advanced lower rectal cancer patients. In this study, we established a nomogram model to preoperatively predict LPLN metastasis and then externally validated the accuracy of this model.

Methods

A total of 287 rectal cancer patients who underwent LPLN dissection were included in this study. Among them, 200 patients from the Peking University First Hospital were included in the development set, and 87 patients from the First Affiliated Hospital of Xi’an Jiaotong University were included in the independent external validation set. Multivariate logistic regression analysis was used to develop the nomogram. The performance of the nomogram was assessed based on its calibration, discrimination, and clinical utility.

Results

Five factors (differentiation grade, extramural vascular invasion, distance of the tumor from the anal verge, perirectal lymph node status, and largest short-axis diameter of LPLN) were identified and included in the nomogram. The nomogram developed based on the analysis showed robust discrimination with an area under the receiver operating characteristic curve (AUC) of 0.878 (95% CI, 0.824–0.932). The validation set showed good discrimination with an AUC of 0.863 (95% CI, 0.779–0.948). Decision curve analysis showed that the nomogram was clinically useful.

Conclusions

The present study proposed a clinical-imaging nomogram with a combination of clinicopathological risk factors and imaging features. After external verification, the predictive power of the nomogram model was satisfactory, and it is expected to be a convenient, visual, and personalized clinical tool for assessing the risk of LPLN metastasis in advanced lower rectal cancer patients.
Application of Multi-Omics Approach in Sarcomas: A Tool for Studying Mechanism, Biomarkers, and Therapeutic Targets
Authors: Zou Zijian , Sun Wei , Xu Yu , Liu Wanlin , Zhong Jingqin , Lin Xinyi , Chen Yong
Published: July 2022

Sarcomas are rare, heterogeneous mesenchymal neoplasms with various subtypes, each exhibiting unique genetic characteristics. Although studies have been conducted to improve the treatment for sarcomas, the specific development from normal somatic cells to sarcoma cells is still unclear and needs further research. The diagnosis of sarcomas depends heavily on the pathological examination, which is yet a difficult work and requires expert analysis. Advanced treatment like precise medicine optimizes the efficacy of treatment and the prognosis of sarcoma patients, yet, in sarcomas, more studies should be done to put such methods in clinical practice. The revolution of advanced technology has pushed the multi-omics approach to the front, and more could be learnt in sarcomas with such methods. Multi-omics combines the character of each omics techniques, analyzes the mechanism of tumor cells from different levels, which makes up for the shortage of single-omics, and gives us an integrated picture of bioactivities inside tumor cells. Multi-omics research of sarcomas has reached appreciable progress in recent years, leading to a better understanding of the mutation, proliferation, and metastasis of sarcomas. With the help of multi-omics approach, novel biomarkers were found, with promising effects in improving the process of diagnosis, prognosis anticipation, and treatment decision. By analyzing large amounts of biological features, subtype clustering could be done in a better precision, which may be useful in the clinical procedure. In this review, we summarized recent discoveries using multi-omics approach in sarcomas, discussed their merits and challenges, and concluded with future perspectives of the sarcoma research.
The Majority of United States Citizens With Cancer do not Have Access to Carbon Ion Radiotherapy
Authors: Foote Robert L. , Tsujii Hirohiko , Imai Reiko , Tsuji Hiroshi , Hug Eugen B. , Kanai Tatsuaki , Lu Jiade J. , Debus Juergen , Engenhart-Cabillic Rita , Mahajan Anita
Published: July 2022

As of December 31, 2020, there were 12 facilities located in Asia and Europe which were treating cancer patients with carbon ion radiotherapy (CIRT). Between June 1994 and December 2020, 37,548 patients were treated with CIRT worldwide. Fifteen of these patients were United States (U.S.) citizens. Using the Surveillance, Epidemiology, and End Results cancer statistics database, the Mayo Clinic in Rochester, MN has conservatively estimated that there are approximately 44,340 people diagnosed each year in the U.S. with malignancies that would benefit from treatment with CIRT. The absence of CIRT facilities in the U.S. not only limits access to CIRT for cancer care but also prevents inclusion of U.S. citizens in phase III clinical trials that will determine the comparative effectiveness and cost effectiveness of CIRT for a variety of malignancies for FDA approval and insurance coverage. Past and present phase III clinical trials have not been able to enroll U.S. citizens due to their unwillingness or inability to travel abroad for CIRT for an extended period. These barriers could be overcome with a limited number of CIRT facilities in the U.S.
Effect of Oropharyngeal Administration of Colostrum in Premature Newborns ≤32 Weeks of Gestation on the Immune Response and Neonatal Morbidity: A Double-Blind Randomized Clinical Trial
Authors: Romero-Maldonado Silvia , Soriano-Becerril Diana Mercedes , García-May Perla Karina , Reyes-Muñoz Enrique , Muñoz-Ortíz Eudoxia Georgina , Carrera-Muiños Sandra , Granados-Cepeda Martha Lucía , Cardona-Pérez Jorge Arturo , Castro-Millán Elsa , Segura-Cervantes Enrique , Ceballos Guillermo , Montoya-Estrada Araceli
Published: July 2022

Introduction

The mother's colostrum carries immunological components, such as cytokines and immunoglobulins (Igs), derived from the maternal circulation with bacteriostatic properties.

Objective

The objective of this study was to evaluate the effect of oropharyngeal administration of colostrum (OPAC) vs. placebo in the first 4 days of life in premature newborns ≤32 weeks of gestation on serum Ig concentration, neonatal morbidity, and total days of hospitalization.

Hypothesis

The OPAC increases serum Igs and decreases morbidity and total days of hospitalization.

Materials and Methods

A double-blind randomized controlled trial was carried out. Participants were randomly assigned to one of the two groups, namely, group 1: placebo (P) (n = 50) and group 2: colostrum (C) (n = 46). A blood sample was obtained at baseline and 7 and 28 days of life to quantify immunoglobulin G (IgG), immunoglobulin A (IgA), and IgM. Results: The C group showed an increase in serum IgA on day 28 expressed as median and [interquartile range]; C: 25 [12–35] vs. P: 11 [8–18], p < 0.001. There were no significant differences in neonatal morbidity. Newborns in the colostrum group showed the completed enteral feeding earlier (days), C: 13.9 ± 7 vs. P: 17.4 ± 8.4, p < 0.04; they reached the birth weight earlier, C: 10.9 ± 2.8 vs. P: 12.9 ± 4, p < 0.01, and had less days of hospitalization, C: 60.2 ± 33.8 vs. P: 77.2 ± 47.3, p < 0.04. Neonatal mortality was lower in the colostrum group than the placebo group 0% vs. 12%, respectively, without a statistical difference (p = 0.06).

Conclusion

In premature newborns ≤32 weeks of gestation, the OPAC within 4 days after birth increases serum IgA concentration at day 28 compared to placebo. Similarly, OPAC decreased the days to complete enteral feeding and reach the birth weight and total days of hospitalization.

Clinical Trial Registration

[https://clinicaltrials.gov/ct2/show/NCT03578341], identifier: [NCT03578341].
Undernutrition and Associated Factors Among Children Aged 6–23 Months in Dessie Town, Northeastern Ethiopia, 2021: A Community Based Cross-Sectional Study
Authors: Sewenet Tesfamaryam , W/Selassie Mulugeta , Zenebe Yosef , Yimam Wondwossen , Woretaw Lebasie
Published: July 2022

Background

Globally about 159, 101, and 52 million children are stunted, underweight, and wasted, respectively. According to the 2016 Ethiopian Demographic and Health Survey, about 38% of Ethiopian children are stunted and 46, 28.4, and 9.8% of children in Amhara Region are stunted, underweight and wasted, respectively. This study aimed to assess undernutrition and associated factors among children aged 6-23 months old at Dessie town, 2021.

Method

A community-based cross-sectional study was conducted from October – November 2021 in Dessie Town. A total of 421 Mothers/caregivers with children aged 6-23 months old were selected by a systematic sampling method from the health extension registration book. Epi-data 3.01 was used for data entry, SPSS version 20 for statistical analysis, and WHO Anthro version 3.2.2 software for calculating the z scores. Binary logistic regression and multivariate logistic regression were used to analyze the data. AOR with 95% CI and P-values less than 0.05 were considered to see the statistical significance.

Results

A total of 421 mothers or care givers paired with 6-23 months old children participated in the study. The prevalence of stunting, underweight, wasting were 36.8% (95% CI: 32%, 41.6%), 27.6% (95% CI: 23.6%, 32.2%), and 11.5% (95% CI: 8.4%, 14.7%) respectively. Sex of the child (AOR = 1.55; 95% CI: 1.02, 2.34), handwashing practice (AOR = 2.32; 95% CI: 1.05, 5.11) and maternal family planning use (AOR = 0.39; 95% CI: 0.19, 0.77) were significantly associated with stunting. Age of child 12-17 months (AOR = 4.62; 95% CI: 2.65, 8.06) and sex of the child (AOR = 1.93; 95% CI: 1.21, 3.07) were associated with underweight. Age of child 12-17 months (AOR = 2.25; 95% CI: 1.06, 4.78) and treatment of drinking water (AOR = 0.21; 95% CI: 0.07, 0.59) were associated with wasting.

Conclusion and Recommendation

In this study, the prevalence of undernutrition among children aged 6-23 months was higher for stunting (36.8%), underweight (27.6%) and wasting (11.5%) compared to WHO classification. Improved access to water, hygiene and sanitation, family planning services, avoiding gender discrimination during child feeding, and age-appropriate feeding practices are recommended. Moreover, implementation of public policies on food and nutrition is required for children 6-23 months of age.
Pregnancy Outcomes in Women With Mechanical Valve Prostheses Using Vitamin K Antagonist Therapy: The Experience of the Salam Centre for Cardiac Surgery in Sudan
Authors: Erba Nicoletta , Gatti Sofia , Hassan Suha Abdelwahab Abdalla , Langer Martin , Chatenoud Liliane , Portella Gina , Baiocchi Raffaela
Published: July 2022

Pregnancy and childbirth on anticoagulants after mechanical heart valve replacement present a high risk of complications for both mother and baby. On top of pregnancy worsening the mother's cardiac function, anticoagulant therapy itself is a crucial problem. A safe and effective anticoagulation regimen for both mother and fetus is not possible. The most effective drugs for preventing valve thrombosis are VKAs, whose dosage needs to be adjusted with frequent INR checks. Moreover, VKAs can have embryopathic and teratogenic action. Patients in follow-up and anticoagulant treatment at the Salam Centre for Cardiac Surgery in Sudan live spread out over a large area where transport to the Center is generally difficult; pregnancy treatment has, therefore, been adapted to the limitations of reality. Pregnancy is discouraged and contraception and therapeutic abortion are recommended, but this guidance frequently goes unheeded. Here we describe maternal and fetal outcomes in 307 consecutive pregnancies recorded by staff at the oral anticoagulant clinic (OAC) from April 2017 to November 2021. Out of 307 pregnancies, there were 15 maternal deaths (4.9%), 24 thrombotic events (7.8%) and 22 major bleedings (7.2%). Fifty pregnancies (16.3%) were terminated by therapeutic abortion. Only 47.6% of pregnancies had good maternal and neonatal outcomes. Data clearly show that, due to the complexity of pregnancy in women with mechanical heart valves and the scarcity of tertiary healthcare services in the area where patients live, maternal mortality is at an unacceptable level and requires a structured, multi-disciplinary intervention.
Network Pharmacology and Experimental Validation to Explore the Mechanism of Qing-Jin-Hua-Tan-Decoction Against Acute Lung Injury
Authors: Xiao Shunli , Liu Lu , Sun Zhengxiao , Liu Xiaoqian , Xu Jing , Guo Zhongyuan , Yin Xiaojie , Liao Fulong , Xu Jun , You Yun , Zhang Tiejun
Published: July 2022

Qing-Jin-Hua-Tan-Decoction (QJHTD), a classic famous Chinese ancient prescription, has been used for treatment of pulmonary diseases since Ming Dynasty. A total of 22 prototype compounds of QJHTD absorbed into rat blood were chosen as candidates for the pharmacological network analysis and molecular docking. The targets from the intersection of compound target and ALI disease targets were used for GO and KEGG enrichment analyses. Molecular docking was adopted to further verify the interactions between 22 components and the top 20 targets with higher degree values in the component–target–pathway network. In vitro experiments were performed to verify the results of network pharmacology using SPR experiments, Western blot experiments, and the PMA-induced neutrophils to produce neutrophil extracellular trap (NET) model. The compound–target–pathway network includes 176 targets and 20 signaling pathways in which the degree of MAPK14, CDK2, EGFR, F2, SRC, and AKT1 is higher than that of other targets and which may be potential disease targets. The biological processes in QJHTD for ALI mainly included protein phosphorylation, response to wounding, response to bacterium, regulation of inflammatory response, and so on. KEGG enrichment analyses revealed multiple signaling pathways, including lipid and atherosclerosis, HIF-1 signaling pathway, renin–angiotensin system, and neutrophil extracellular trap formation. The molecular docking results showed that baicalin, oroxylin A-7-glucuronide, hispidulin-7-O-β-D-glucuronide, wogonoside, baicalein, wogonin, tianshic acid, and mangiferin can be combined with most of the targets, which might be the core components of QJHTD in treatment of ALI. Direct binding ability of baicalein, wogonin, and baicalin to thrombin protein was all micromolar, and their KD values were 11.92 μM, 1.303 μM, and 1.146 μM, respectively, revealed by SPR experiments, and QJHTD could inhibit Src phosphorylation in LPS-activated neutrophils by Western blot experiments. The experimental results of PMA-induced neutrophils to produce NETs indicated that QJHTD could inhibit the production of NETs. This study revealed the active compounds, effective targets, and potential pharmacological mechanisms of QJHTD acting on ALI.
Association Between Serum Carnosinase Concentration and Activity and Renal Function Impairment in a Type-2 Diabetes Cohort
Authors: Qiu Jiedong , Yard Benito A. , Krämer Bernhard K. , van Goor Harry , van Dijk Peter , Kannt Aimo
Published: July 2022

Introduction: Genetic studies have identified associations of carnosinase 1 (CN1) polymorphisms with diabetic kidney disease (DKD). However, CN1 levels and activities have not been assessed as diagnostic or prognostic markers of DKD in cohorts of patients with type 2 diabetes (T2D).

Methods: We established high-throughput, automated CN1 activity and concentration assays using robotic systems. Using these methods, we determined baseline serum CN1 levels and activity in a T2D cohort with 970 patients with no or only mild renal impairment. The patients were followed for a mean of 1.2 years. Baseline serum CN1 concentration and activity were assessed as predictors of renal function impairment and incident albuminuria during follow up.

Results: CN1 concentration was significantly associated with age, gender and estimated glomerular filtration rate (eGFR) at baseline. CN1 activity was significantly associated with glycated hemoglobin A1c (HbA1c) and eGFR. Serum CN1 at baseline was associated with eGFR decline and predicted renal function impairment and incident albuminuria during the follow-up.

Discussion: Baseline serum CN1 levels were associated with presence and progression of renal function decline in a cohort of T2D patients. Confirmation in larger cohorts with longer follow-up observation periods will be required to fully establish CN1 as a biomarker of DKD.
Sea Buckthorn Proanthocyanidins are the Protective Agent of Mitochondrial Function in Macrophages Under Oxidative Stress
Authors: Liu Keshan , Li Wenxia , Yuen Michael , Yuen Tina , Yuen Hywel , Wang Min , Peng Qiang
Published: July 2022

Sea buckthorn proanthocyanidins (SBP) are the most important antioxidant components of sea buckthorn, which are widely used in functional foods and cosmetics. Studies have shown that SBP have significant protective effects on macrophages against oxidative stress induced by hydrogen peroxide (H2O2). However, the mechanism remains uncertain. In the present study, we explored the effects of SBP on mitochondrial function and the mechanism of their protective effects against oxidative stress in cells. Our results showed that SBP could increase mitochondrial membrane potential, inhibit mPTP opening, reduce mitochondrial swelling, and enhance mitochondrial synthesis and metabolism. Thus, they alleviated oxidative damage and protected the cells against mitochondrial function. Western blot analysis showed that SBP had a protective effect on RAW264.7 cells by activating the AMPK-PGC1α-Nrf2 pathway. These results showed that SBP alleviated mitochondrial damage and dysfunction caused by oxidative stress. This study revealed the mechanism of SBP in reducing oxidative damage and provided a theoretical basis for further research on natural bioactive compounds to exert antioxidant activity and prevent arteriosclerosis and other diseases.
Pre-Clinical Development of a Potent Neutralizing Antibody MW3321 With Extensive SARS-CoV-2 Variants Coverage
Authors: Jiang Wen , Zhang Zherui , Zhu Yuhe , Chen Ben , Gu Chunying , Liu Zhiyan , Zhang Xukai , Xiong Hualong , Zhang Yanan , Zheng Bin , Wang Rongjuan , Jiao Shasha , Wang An , Zhang Tianying , Zhang Jinchao , Wang Shuang , Zhang Bo , Li Gang , Gui Xun
Published: July 2022

Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, several variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged and have consistently replaced the previous dominant variant. Therapeutics against variants of SARS-CoV-2 are urgently needed. Ideal SARS-CoV-2 therapeutic antibodies would have high potency in viral neutralization against several emerging variants. Neutralization antibodies targeting SARS-CoV-2 could provide immediate protection after SARS-CoV-2 infection, especially for the most vulnerable populations. In this work, we comprehensively characterize the breadth and efficacy of SARS-CoV-2 RBD-targeting fully human monoclonal antibody (mAb) MW3321. MW3321 retains full neutralization activity to all tested 12 variants that have arisen in the human population, which are assigned as VOC (Variants of Concern) and VOI (Variants of Interest) due to their impacts on public health. Escape mutation experiments using replicating SARS-CoV-2 pseudovirus show that escape mutants were not generated until passage 6 for MW3321, which is much more resistant to escape mutation compared with another clinical staged SARS-CoV-2 neutralizing mAb MW3311. MW3321 could effectively reduce viral burden in hACE2-transgenic mice challenged with either wild-type or Delta SARS-CoV-2 strains through viral neutralization and Fc-mediated effector functions. Moreover, MW3321 exhibits a typical hIgG1 pharmacokinetic and safety profile in cynomolgus monkeys. These data support the development of MW3321 as a monotherapy or cocktail against SARS-CoV-2-related diseases.
Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies
Authors: Pouliquen Daniel L. , Boissard Alice , Henry Cécile , Coqueret Olivier , Guette Catherine
Published: July 2022

Curcuminoids, which include natural acyclic diarylheptanoids and the synthetic analogs of curcumin, have considerable potential for fighting against all the characteristics of invasive cancers. The epithelial-to-mesenchymal transition (EMT) is a fundamental process for embryonic morphogenesis, however, the last decade has confirmed it orchestrates many features of cancer invasiveness, such as tumor cell stemness, metabolic rewiring, and drug resistance. A wealth of studies has revealed EMT in cancer is in fact driven by an increasing number of parameters, and thus understanding its complexity has now become a cornerstone for defining future therapeutic strategies dealing with cancer progression and metastasis. A specificity of curcuminoids is their ability to target multiple molecular targets, modulate several signaling pathways, modify tumor microenvironments and enhance the host’s immune response. Although the effects of curcumin on these various parameters have been the subject of many reviews, the role of curcuminoids against EMT in the context of cancer have never been reviewed so far. This review first provides an updated overview of all EMT drivers, including signaling pathways, transcription factors, non-coding RNAs (ncRNAs) and tumor microenvironment components, with a special focus on the most recent findings. Secondly, for each of these drivers the effects of curcumin/curcuminoids on specific molecular targets are analyzed. Finally, we address some common findings observed between data reported in the literature and the results of investigations we conducted on experimental malignant mesothelioma, a model of invasive cancer representing a useful tool for studies on EMT and cancer.