bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole Exome Sequencing in South Africa: Stakeholder Views on Return of Individual Research Results and Incidental Findings
Authors: Van Der Merwe Nicole , Ramesar Raj , De Vries Jantina
Published: June 2022

The use of whole exome sequencing (WES) in medical research is increasing in South Africa (SA), raising important questions about whether and which individual genetic research results, particularly incidental findings, should be returned to patients. Whilst some commentaries and opinions related to the topic have been published in SA, there is no qualitative data on the views of professional stakeholders on this topic. Seventeen participants including clinicians, genomics researchers, and genetic counsellors (GCs) were recruited from the Western Cape in SA. Semi-structured interviews were conducted, and the transcripts analysed using the framework approach for data analysis. Current roadblocks for the clinical adoption of WES in SA include a lack of standardised guidelines; complexities relating to variant interpretation due to lack of functional studies and underrepresentation of people of African ancestry in the reference genome, population and variant databases; lack of resources and skilled personnel for variant confirmation and follow-up. Suggestions to overcome these barriers include obtaining funding and buy-in from the private and public sectors and medical insurance companies; the generation of a locally relevant reference genome; training of health professionals in the field of genomics and bioinformatics; and multidisciplinary collaboration. Participants emphasised the importance of upscaling the accessibility to and training of GCs, as well as upskilling of clinicians and genetic nurses for return of genetic data in collaboration with GCs and medical geneticists. Future research could focus on exploring the development of stakeholder partnerships for increased access to trained specialists as well as community engagement and education, alongside the development of guidelines for result disclosure.
Response to Different Oxygen Partial Pressures and Evolution Analysis of Apoptosis-Related Genes in Plateau Zokor (Myospalax baileyi)
Authors: An Zhifang , Chen Xiaoqi , Li Jimei
Published: June 2022

The plateau zokor (Myospalax baileyi) is a native species of the Qinghai–Tibet Plateau that spends its entire life underground in sealed burrows with hypoxic conditions. The present study aimed to assess the sequence characteristics of apoptosis-related genes and the response to different oxygen partial pressures (pO2) in plateau zokor and Sprague-Dawley rats. The sequences of the p53-induced protein with a death domain (Pidd), p53-upregulated modulator of apoptosis (Puma), insulin-like growth factor binding protein 3 (Igfbp3), and apoptosis protease-activating factor 1 (Apaf1) were evaluated concerning homology and convergent evolution sites, and their mRNA levels were evaluated in different tissues under 14.13 (3,300 m) and 16.12 kPa (2,260 m) pO2conditions. Our results showed that, (1) the sequences of the apoptosis-related genes in plateau zokor were highly similar to those ofNannospalax galili, followed byRattus norvegicus; (2). Pidd, Puma, Igfbp3, and Apaf1 of plateau zokor were found to have five, one, two, and five convergent sites in functional domains withN. galili, respectively. Lastly (3), under low pO2, the expression ofPiddandPumawas downregulated in the lung of plateau zokors. In turn,Igfbp3andApaf1were upregulated in the liver and lung, andPumawas upregulated in the skeletal muscle of plateau zokor under low pO2. In Sprague-Dawley rats, low pO2downregulatedPumaandApaf1expression in the liver and downregulatedIgfbp3andPumain the lung and skeletal muscle separately. In contrast, low pO2upregulatedPiddexpression in the liver and skeletal muscle of Sprague-Dawley rats. Overall, the expression patterns ofApaf1,Igfbp3, andPumashowed the opposite pattern in the liver, lung, and skeletal muscle, respectively, of plateau zokor as compared with Sprague-Dawley rats. In conclusion, for the long-time adaptation to hypoxic environments,Pidd,Puma,Igfbp3, andApaf1of plateau zokor underwent convergent evolution, which we believe may have led to upregulation of their levels under low oxygen partial pressures to induce apoptosis, so as to suppress tumorigenesis under hypoxic environments in plateau zokor.
Signal Recognition Particle in Human Diseases
Authors: Kellogg Morgana K. , Tikhonova Elena B. , Karamyshev Andrey L.
Published: June 2022

The signal recognition particle (SRP) is a ribonucleoprotein complex with dual functions. It co-translationally targets proteins with a signal sequence to the endoplasmic reticulum (ER) and protects their mRNA from degradation. If SRP is depleted or cannot recognize the signal sequence, then the Regulation of Aberrant Protein Production (RAPP) is activated, which results in the loss of secretory protein mRNA. If SRP recognizes the substrates but is unable to target them to ER, they may mislocalize or degrade. All these events lead to dramatic consequence for protein biogenesis, activating protein quality control pathways, and creating pressure on cell physiology, and might lead to the pathogenesis of disease. Indeed, SRP dysfunction is involved in many different human diseases, including: congenital neutropenia; idiopathic inflammatory myopathy; viral, protozoal, and prion infections; and cancer. In this work, we analyze diseases caused by SRP failure and discuss their possible molecular mechanisms.
A Novel Necroptosis-Associated IncRNAs Signature for Prognosis of Head and Neck Squamous Cell Carcinoma
Authors: Huang Jing , Lu Rong , Zhong Dongta , Weng Youliang , Liao Lianming
Published: June 2022

Purpose: The prognosis of head and neck squamous cell carcinoma (HNSCC) is poor. Necroptosis is a novel programmed form of necrotic cell death. The prognostic value of necroptosis-associated lncRNAs expression in HNSCC has not been explored.

Methods: We downloaded mRNA expression data of HNSCC patients from TCGA databases. Prognostic lncRNAs were identified by univariate Cox regression. LASSO was used to establish a model with necroptosis-related lncRNAs. Kaplan-Meier analysis and ROC were applied to verify the model. Finally, functional studies including gene set enrichment analyses, immune microenvironment analysis, and anti-tumor compound IC50 prediction were performed.

Results: We identified 1,117 necroptosis-related lncRNAs. The Cox regression showed 55 lncRNAs were associated with patient survival (p < 0.05). The risk model of 24- lncRNAs signature categorized patients into high and low risk groups. The patients in the low-risk group survived longer than the high-risk group (p < 0.001). Validation assays including ROC curve, nomogram and correction curves confirmed the prediction capability of the 24-lncRNA risk mode. Functional studies showed the two patient groups had distinct immunity conditions and IC50.

Conclusion: The 24-lncRNA model has potential to guide treatment of HNSCC. Future clinical studies are needed to verify the model.
A Systematic Analysis Reveals the Prognostic and Immunological Role of Reptin/RUVBL2 in Human Tumors
Authors: Su Xiaoru , Zheng Gaoming , Gui Zhifang , Yang Xiao , Zhang Lahong , Pan Feng
Published: June 2022

Reptin/RUVBL2 is involved in the remodeling of chromatin, DNA damage repair, and regulation of the cell cycle, all of which help to play essential roles in cancer. However, relevant pan-cancer analysis of Reptin is lacking. This study first investigated the potential oncogenic roles of Reptin and revealed a relationship between Reptin with clinicopathological characteristics and immune infiltration based on big data. Here, we showed that Reptin is overexpressed in many cancers. A significant association exists between the expression of Reptin and the prognosis of cancer cases. Reptin had a meaningful interaction with the immune infiltration of CD4+ Th1 cells and immune modulator genes in multiple cancer types. And negative correlation exists between Reptin and cancer-associated fibroblasts in BRCA, PRAD, TGCT, and THYM. A significant negative association exists between Reptin and regulatory T cells in TGCT and THCA. Moreover, Reptin is significantly associated with genomic heterogeneity, DNA mismatch repair genes, methyltransferase, and RNA modification genes in specific cancer types. Spliceosome, Hippo signaling pathway, DNA replication pathway, and acetyltransferase activity-associated functions were observed in the effect of Reptin on the tumor. This systematic analysis highlights Reptin as a vital cancer regulator among numerous genes and proved its potential prognosticator value and therapeutic target role for specific tumor types.
Optimizing the Construction and Update Strategies for the Genomic Selection of Pig Reference and Candidate Populations in China
Authors: Wei Xia , Zhang Tian , Wang Ligang , Zhang Longchao , Hou Xinhua , Yan Hua , Wang Lixian
Published: June 2022

Optimizing the construction and update strategies for reference and candidate populations is the basis of the application of genomic selection (GS). In this study, we first simulated1200-purebred-pigs population that have been popular in China for 20 generations to study the effects of different population sizes and the relationship between individuals of the reference and candidate populations. The results showed that the accuracy was positively correlated with the size of the reference population within the same generation (r = 0.9366, p < 0.05), while was negatively correlated with the number of generation intervals between the reference and candidate populations (r = −0.9267, p < 0.01). When the reference population accumulated more than seven generations, the accuracy began to decline. We then simulated the population structure of 1200 purebred pigs for five generations and studied the effects of different heritabilities (0.1, 0.3, and 0.5), genotyping proportions (20, 30, and 50%), and sex ratios on the accuracy of the genomic estimate breeding value (GEBV) and genetic progress. The results showed that if the proportion of genotyping individuals accounts for 20% of the candidate population, the traits with different heritabilities can be genotyped according to the sex ratio of 1:1male to female. If the proportion is 30% and the traits are of low heritability (0.1), the sex ratio of 1:1 male to female is the best. If the traits are of medium or high heritability, the male-to-female ratio is 1:1, 1:2, or 2:1, which may achieve higher genetic progress. If the genotyping proportion is up to 50%, for low heritability traits (0.1), the proportion of sows from all genotyping individuals should not be less than 25%, and for the medium and high heritability traits, the optimal choice for the male-to-female ratio is 1:1, which may obtain the greatest genetic progress. This study provides a reference for determining a construction and update plan for the reference population of breeding pigs.
Soil Depth Significantly Shifted Microbial Community Structures and Functions in a Semiarid Prairie Agroecosystem
Authors: Rchiad Zineb , Dai Mulan , Hamel Chantal , Bainard Luke D. , Cade-Menun Barbara J. , Terrat Yves , St-Arnaud Marc , Hijri Mohamed
Published: June 2022

The North American Great Plains cover a large area of the Nearctic ecozone, and an important part of this biome is semiarid. The sustainable intensification of agriculture that is necessary to produce food for an ever-increasing world population requires knowledge of the taxonomic and functional structure of the soil microbial community. In this study, we investigated the influence of soil depth on the composition and functions of the microbial communities hosted in agricultural soils of a semiarid agroecosystem, using metagenomic profiling, and compared them to changes in soil chemical and physical properties. Shotgun sequencing was used to determine the composition and functions of the soil microbial community of 45 soil samples from three soil depths (0–15 cm, 15–30 cm, and 30–60 cm) under different agricultural land use types (native prairie, seeded prairie, and cropland) in southwest Saskatchewan. Analysis of community composition revealed the declining abundance of phyla Verrucomicrobia, Bacteroidetes, Chlorophyta, Bacillariophyta, and Acidobacteria with soil depth, whereas the abundance of phyla Ascomycota, Nitrospirae, Planctomycetes, and Cyanobacteria increased with soil depth. Soil functional genes related to nucleosides and nucleotides, phosphorus (P) metabolism, cell division and cell cycle, amino acids and derivatives, membrane transport, and fatty acids were particularly abundant at 30–60 cm. In contrast, functional genes related to DNA and RNA metabolism, metabolism of nitrogen, sulfur and carbohydrates, and stress response were more abundant in the top soil depth. The RDA analysis of functional genes and soil physico-chemical properties revealed a positive correlation between phages and soil organic P concentrations. In the rooting zone of this semiarid agroecosystem, soil microbes express variable structural patterns of taxonomic and functional diversity at different soil depths. This study shows that the soil microbial community is structured by soil depth and physicochemical properties, with the middle soil depth being an intermediate transition zone with a higher taxonomic diversity. Our results suggest the co-existence of various microbial phyla adapted to upper and lower soil depths in an intermediate-depth transition zone.
Isolation and Nitrogen Removal Efficiency of the Heterotrophic Nitrifying-Aerobic Denitrifying Strain K17 From a Rare Earth Element Leaching Site
Authors: Hu Jingang , Yang Xinyu , Deng Xiangyi , Liu Xuemei , Yu Junxia , Chi Ruan , Xiao Chunqiao
Published: June 2022

K17, an indigenous and heterotrophic nitrifying-aerobic denitrifying bacterium, was isolated from the soil of a weathered crust elution-deposited rare earth ore leaching site in Longnan County, China. Strain K17 was identified as Pseudomonas mosselii. In this study, the morphological characteristics of strain K17 were observed and the optimal ammonia nitrogen removal conditions for the strain were studied using a single-factor experiment. Key enzyme activities were determined, and we also explored the ammonia nitrogen removal process of strain K17 on simulated leaching liquor of the rare earth element leaching site. Based on the determination of ammonia nitrogen removal and enzyme activity, it was found that strain K17 has both heterotrophic nitrifying and aerobic denitrifying activities. In addition, single-factor experiments revealed that the most appropriate carbon source for strain K17 was sodium citrate with a C/N ratio of 10 and an initial NH4+-N concentration of 100 mg/l. Furthermore, the optimal initial pH and rotation speed were 7 and 165 r/min, respectively. Under optimal conditions, the ammonia nitrogen removal efficiency of strain K17 was greater than 95%. As an indigenous bacterium, strain K17 has great potential for treating residual ammonium leaching solutions from rare earth element leaching sites.
An Inflammatory Response-Related Gene Signature Reveals Distinct Survival Outcome and Tumor Microenvironment Characterization in Pancreatic Cancer
Authors: Xie Fengxiao , Huang Xin , He Chaobin , Wang Ruiqi , Li Shengping
Published: June 2022

Background: Desmoplasia or rich fibrotic stroma is a typical property of pancreatic cancer (PC), with a significant impact on tumor progression, metastasis, and chemotherapy response. Unusual inflammatory responses are considered to induce fibrosis of tissue, but the expression and clinical significance of inflammatory response-related genes in PC have not been clearly elucidated.

Methods: Prognosis-related differentially expressed genes (DEGs) between tumor and normal tissues were identified by comparing the transcriptome data of PC samples based on The Cancer Genome Atlas (TCGA) portal and the Genotype Tissue Expression (GTEx) databases. Samples from the ArrayExpress database were used as an external validation cohort.

Results: A total of 27 inflammatory response-related DEGs in PC were identified. Least absolute shrinkage and selection operator (LASSO) analysis revealed three core genes that served as an inflammatory response gene signature (IRGS), and a risk score was calculated. The diagnostic accuracy of the IRGS was validated in the training (n = 176) and validation (n = 288) cohorts, which reliably predicted the overall survival (OS) and disease-free survival (DFS) of patients with PC. Furthermore, multivariate analysis identified the risk score as an independent risk factor for OS and DFS. The comprehensive results suggested that a high IRGS score was correlated with decreased CD8+ T-cell infiltration, increased M2 macrophage infiltration, increased occurrence of stroma-activated molecular subtype and hypoxia, enriched myofibroblast-related signaling pathways, and greater benefit from gemcitabine.

Conclusion: The IRGS was able to promisingly distinguish the prognosis, the tumor microenvironment characteristics, and the benefit from chemotherapy for PC.
Investigating Intrinsically Disordered Proteins With Brownian Dynamics
Authors: Ahn Surl-Hee , Huber Gary A. , McCammon J. Andrew
Published: June 2022

Intrinsically disordered proteins (IDPs) have recently become systems of great interest due to their involvement in modulating many biological processes and their aggregation being implicated in many diseases. Since IDPs do not have a stable, folded structure, however, they cannot be easily studied with experimental techniques. Hence, conducting a computational study of these systems can be helpful and be complementary with experimental work to elucidate their mechanisms. Thus, we have implemented the coarse-grained force field for proteins (COFFDROP) in Browndye 2.0 to study IDPs using Brownian dynamics (BD) simulations, which are often used to study large-scale motions with longer time scales and diffusion-limited molecular associations. Specifically, we have checked our COFFDROP implementation with eight naturally occurring IDPs and have investigated five (Glu-Lys)25 IDP sequence variants. From measuring the hydrodynamic radii of eight naturally occurring IDPs, we found the ideal scaling factor of 0.786 for non-bonded interactions. We have also measured the entanglement indices (average Cα distances to the other chain) between two (Glu-Lys)25 IDP sequence variants, a property related to molecular association. We found that entanglement indices decrease for all possible pairs at excess salt concentration, which is consistent with long-range interactions of these IDP sequence variants getting weaker at increasing salt concentration.
Therapeutic Targeting of Tumor Cells and Tumor Immune Microenvironment Vulnerabilities
Authors: Kalyanaraman Balaraman , Cheng Gang , Hardy Micael
Published: June 2022

Therapeutic targeting of tumor vulnerabilities is emerging as a key area of research. This review is focused on exploiting the vulnerabilities of tumor cells and the immune cells in the tumor immune microenvironment (TIME), including tumor hypoxia, tumor acidity, the bidirectional proton-coupled monocarboxylate transporters (MCTs) of lactate, mitochondrial oxidative phosphorylation (OXPHOS), and redox enzymes in the tricarboxylic acid cycle. Cancer cells use glucose for energy even under normoxic conditions. Although cancer cells predominantly rely on glycolysis, many have fully functional mitochondria, suggesting that mitochondria are a vulnerable target organelle in cancer cells. Thus, one key distinction between cancer and normal cell metabolism is metabolic reprogramming. Mitochondria-targeted small molecule inhibitors of OXPHOS inhibit tumor proliferation and growth. Another hallmark of cancer is extracellular acidification due lactate accumulation. Emerging results show that lactate acts as a fuel for mitochondrial metabolism and supports tumor proliferation and growth. Metabolic reprogramming occurs in glycolysis-deficient tumor phenotypes and in kinase-targeted, drug-resistant cancers overexpressing OXPHOS genes. Glycolytic cancer cells located away from the vasculature overexpress MCT4 transporter to prevent overacidification by exporting lactate, and the oxidative cancer cells located near the vasculature express MCT1 transporter to provide energy through incorporation of lactate into the tricarboxylic acid cycle. MCTs are, therefore, a vulnerable target in cancer metabolism. MCT inhibitors exert synthetic lethality in combination with metformin, a weak inhibitor of OXPHOS, in cancer cells. Simultaneously targeting multiple vulnerabilities within mitochondria shows synergistic antiproliferative and antitumor effects. Developing tumor-selective, small molecule inhibitors of OXPHOS with a high therapeutic index is critical to fully exploiting the mitochondrial vulnerabilities. We and others developed small-molecule inhibitors containing triphenylphosphonium cation that potently inhibit OXPHOS in tumor cells and tissues. Factors affecting tumor cell vulnerabilities also impact immune cells in the TIME. Glycolytic tumor cells supply lactate to the tumor-suppressing regulatory T cells overexpressing MCTs. Therapeutic opportunities for targeting vulnerabilities in tumor cells and the TIME, as well as the implications on cancer health disparities and cancer treatment, are addressed.
A Comprehensive Understanding of the Genomic Bone Tumor Landscape: A Multicenter Prospective Study
Authors: Xie Xianbiao , Bian Yiying , Li Haomiao , Yin Junqiang , Tian Lantian , Jiang Renbing , Zeng Ziliang , Shi Xiaoliang , Lei Zixiong , Hou Changhe , Qu Yueting , Wang Liwei , Shen Jingnan
Published: June 2022

Complexity and heterogeneity increases the difficulty of diagnosis and treatment of bone tumors. We aimed to identify the mutational characterization and potential biomarkers of bone tumors. In this study, a total of 357 bone tumor patients were recruited and the next generation sequencing (NGS)-based YuanSu450 panel, that includes both DNA and RNA sequencing, was performed for genomic alteration identification. The most common mutated genes in bone tumors included TP53, NCOR1, VEGFA, RB1, CCND3, CDKN2A, GID4, CCNE1, TERT, and MAP2K4. The amplification of genes such as NCOR1, VEGFA, and CCND3 mainly occurred in osteosarcoma. Germline mutation analysis reveal a high frequency of HRD related mutations (46.4%, 13/28) in this cohort. With the assistance of RNA sequencing, 16.8% (19/113) gene fusions were independently detected in 20% (16/79) of patients. Nearly 34.2% of patients harbored actionable targeted mutations, of which the most common mutation is CDKN2A deletion. The different mutational characterizations between juvenile patients and adult patients indicated the potential effect of age in bone tumor treatment. According to the genomic alterations, the diagnosis of 26 (7.28%) bone tumors were corrected. The most easily misdiagnosed bone tumor included malignant giant cell tumors of bone (2.8%, 10/357) and fibrous dysplasia of bone (1.7%, 6/357). Meanwhile, we found that the mutations of MUC16 may be a potential biomarker for the diagnosis of mesenchymal chondrosarcomas. Our results indicated that RNA sequencing effectively complements DNA sequencing and increased the detection rate of gene fusions, supporting that NGS technology can effectively assist the diagnosis of bone tumors.
Ethanol Exposure Up-Regulates PD-L1/PD-1 Immune Checkpoint Pathway and Promotes Mammary Tumor Development
Authors: Xu Wenhua , Wu Linqing , Xu Mei , Luo Jia , Chen Gang
Published: June 2022

Alcohol consumption in women enhances breast cancer incidence and ethanol is the main causal factor. Compromised host immunity through immunosuppression facilitates the development of many types of cancer, including breast cancer. Immune cells in breast tissues, particularly tumor-infiltrating CD8 cytotoxic T cells, play a critical role in the host anti-tumor immunity against breast tumorigenesis. These cytotoxic T cells are the major immune cells to carry out anti-tumor immunity through their cytotoxic effector function, which can be regulated by immune checkpoint pathways. The PD-1/PD-L1 pathway (the interaction between programmed death-1, PD-1, and its ligand, programmed death-ligand 1, PD-L1) is the best characterized one. However, the effects of ethanol exposure on T cell anti-tumor immunity and how that may contribute to ethanol-enhanced mammary tumorigenicity remain unknown. FVB.Cg-Tg(Wnt1)1Hev/J transgenic mice develop spontaneous mammary tumors starting around the age of 2-3 months and have been a widely-used mouse model for breast cancer research. Using this mouse model, the current study determined the effects of ethanol on the PD-L1/PD-1 pathway and how that may contribute to mammary tumorigenesis. The results indicated that ethanol exposure enhanced mammary tumor formation accompanied with an up-regulation of PD-1/PD-L1 pathway (increased PD-L1 levels in tumor tissue cells and the amount of PD-1-expressing tumor-infiltrating CD8 T cells) and inhibited T cell anti-tumor function, while inhibition of PD-1/PD-L1 restored T cell anti-tumor effector function and mitigated ethanol-enhanced tumorigenesis.
A New Methodology to Estimate Drug Cost Avoidance in Clinical Trials: Development and Application
Authors: García-Sánchez Sebastián , Collado-Borrell Roberto , González-Haba Eva , Revuelta-Herrero José Luis , Escudero-Vilaplana Vicente , Marzal-Alfaro María Belén , Sánchez-Fresneda María Norberta , Mur-Mur Ana , Herranz Ana , Martín Miguel , Sanjurjo María
Published: June 2022

Background

Oncology clinical trials can lead to relevant financial savings in drug acquisition for healthcare providers. Considerable methodological heterogeneity is observed among previous studies estimating these savings.

Methods

We developed a methodology to estimate the economic benefit obtained from the enrollment of patients into clinical trials through the analysis of drug cost avoidance. We designed a decision algorithm to determine if a clinical trial is associated with drug cost avoidance. This algorithm is based on five scenarios according to the availability or not of standard treatment, the presence or absence of a control arm (placebo or active treatment), and the provider of the medication. We considered as reference the cost of the standard treatment that the patient would have received in routine clinical practice. We standardized drug doses and treatment durations according to the literature. Costs were considered from a National Health System perspective. We applied this methodology at a single, research-active University Hospital in 2019. A cost avoidance analysis per trial and patient was carried out on cancer patients.

Results

We analyzed 140 trials in which 198 patients were recruited. Drug cost avoidance was found in 120 trials (85.7%). The estimated total drug cost avoidance amounted to over €3,200,000. Melanoma and genitourinary tumors were the tumor types associated with the highest cost avoidance. The average drug cost avoidance per patient was €16,245.

Conclusion

We describe a standardized method to estimate drug cost avoidance in clinical trials. We have applied it to all ongoing oncology clinical trials in our center. This methodology could be valuable for other centers to analyze the potential saving of clinical trials.
Integration of Inflammation-Immune Factors to Build Prognostic Model Predictive of Prognosis and Minimal Residual Disease for Hepatocellular Carcinoma
Authors: Xu Xin , Huang Ao , Guo De-Zhen , Wang Yu-Peng , Zhang Shi-Yu , Yan Jia-Yan , Wang Xin-Yu , Cao Ya , Fan Jia , Zhou Jian , Fu Xiu-Tao , Shi Ying-Hong
Published: June 2022

Background

Tumor recurrence after hepatectomy is high for hepatocellular carcinoma (HCC), and minimal residual disease (MRD) could be the underlying mechanism. A predictive model for recurrence and presence of MRD is needed.

Methods

Common inflammation-immune factors were reviewed and selected to construct novel models. The model consisting of preoperative aspartate aminotransferase, C-reactive protein, and lymphocyte count, named ACLR, was selected and evaluated for clinical significance.

Results

Among the nine novel inflammation-immune models, ACLR showed the highest accuracy for overall survival (OS) and time to recurrence (TTR). At the optimal cutoff value of 80, patients with high ACLR (> 80) had larger tumor size, higher Edmondson’s grade, more vascular invasion, advanced tumor stage, and poorer survival than those with low ACLR (≤ 80) in the training cohort (5-year OS: 43.3% vs. 80.1%, P < 0.0001; 5-year TTR: 74.9% vs. 45.3%, P < 0.0001). Multivariate Cox analysis identified ACLR as an independent risk factor for OS [hazard ratio (HR) = 2.22, P < 0.001] and TTR (HR = 2.36, P < 0.001). Such clinical significance and prognostic value were verified in validation cohort. ACLR outperformed extant models, showing the highest area under receiver operating characteristics curve for 1-, 3-, and 5-year OS (0.737, 0.719, and 0.708) and 1-, 3-, and 5-year TTR (0.696, 0.650, and 0.629). High ACLR correlated with early recurrence (P < 0.001) and extremely early recurrence (P < 0.001). In patients with high ACLR, wide resection margin might confer survival benefit by decreasing recurrence (median TTR, 25.5 vs. 11.4 months; P = 0.037).

Conclusions

The novel inflammation-immune model, ACLR, could effectively predict prognosis, and the presence of MRD before hepatectomy and might guide the decision on resection margin for patients with HCC.
Metachronous Multiple Primary Carcinoma With Acute Promyelocytic Leukemia: 2 Cases Report and Literature Review
Authors: Wang Cong , Shen Yamei , Zhang Yuxia , Guo Fahui , Li Qian , Zhang Huahua , Han Xueping , Zhao Haitao , Yang Zilong
Published: June 2022

The co-occurrence of multiple primary cancers with hematological malignancies is uncommon, and acute promyelocytic leukemia (APL) with MPC is even rarer, with only a few cases reported in the literature. Herein, we introduce the diagnosis and treatment of 2 cases of MPC complicated with APL in our hospital and review the relevant literature. Both patients were primary solid tumor patients and were treated with surgery and chemotherapy, and had stable disease (SD). However, more than 1 year after the primary tumor was diagnosed, clinical symptoms were found and APL was diagnosed. Both patients received standard remission-induction therapy, but unfortunately died in the short term due to hemorrhagic complications. In conclusion, treatment of hematological neoplasms, especially acute leukemia combined with multiple primary cancers, is challenging. The prognostic factors and survival analysis of MPC patients with combined APL still need further clinical research and analysis.
Case Report: Exceptional Response to Poziotinib in Patient with Metastatic Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutation
Authors: Prelaj Arsela , Bottiglieri Achille , Bhat Gajanan , Washington Rocky , Calareso Giuseppina , Greco Gabriella Francesca , Ferrara Roberto , Brambilla Marta , De Toma Alessandro , Occhipinti Mario , Manglaviti Sara , Soro Alberto , Ganzinelli Monica , Lo Russo Giuseppe , Proto Claudia
Published: June 2022

Among the several next-generation tyrosine kinase inhibitors (TKIs) tested against uncommon EFGR alterations, poziotinib has been demonstrated to be a powerful agent for metastatic non-small-cell lung cancer (mNSCLC) with aberrations in HER2 exon 20, and FDA approval is being sought in the previously-treated population. Poziotinib has also shown activity in mNSCLC with aberrations in EGFR exon 20. Herein, we report the first published case of a patient affected by mNSCLC harbouring an EGFR exon 20 insertion (EGFRex20ins) mutation who achieved a complete response (CR) under treatment with poziotinib as part of the ZENITH20 trial. In January 2021, a former smoker 62-year-old female patient was diagnosed with relapse, after two surgeries and post-operative chemotherapy of mNSCLC, at liver and retroperitoneal nodes. Given the identification by Next Generation Sequencing (NGS) of EGFRex20ins mutation, she was enrolled in ZENITH20-cohort 5 trial, a phase 2 multicentre study aimed to assess the efficacy and safety of poziotinib in patients with EGFR or HER2 exon 20 insertion mutations. Poziotinib as first-line systemic therapy for metastatic disease was initiated at the end of January 2021 and administrated at the initial dosage of 8 mg orally twice daily (BID). The most common side effects from the beginning of the treatment included alopecia, macular skin rash, diarrhoea, xerostomia, and conjunctivitis. Due to these adverse events, poziotinib was discontinued during the first 3 months and then reduced to 6 mg orally BID in April 2021. After the dose de-escalation, the adverse events ameliorated, and the patient better tolerated the treatment without further interruption. Since the first reevaluation (after 4 weeks of therapy), the treatment with poziotinib resulted to be remarkably effective, with a partial response (PR) subsequently confirmed in May and July 2021. Then, in October 2021, a CT scan confirmed a CR, maintained with good tolerance at the last reevaluation in February 2022. Treatment is still ongoing at the same dosage. In this case, poziotinib has represented a successful and well-tolerated first-line treatment alternative to chemotherapy in this patient with EGFR exon 20 insertion mutated mNSCLC.
Increased Circulating Levels of CRP and IL-6 and Decreased Frequencies of T and B Lymphocyte Subsets Are Associated With Immune-Related Adverse Events During Combination Therapy With PD-1 Inhibitors for Liver Cancer
Authors: Yu Yingying , Wang Siyu , Su Nan , Pan Shida , Tu Bo , Zhao Jinfang , Shen Yingjuan , Qiu Qin , Liu Xiaomeng , Luan Junqing , Wang Fu-Sheng , Meng Fanping , Shi Ming
Published: June 2022

Background

Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune-related adverse events (irAEs) are inevitable in patients with liver cancer. Although the incidence of severe irAEs is low, but can result in fatal consequences. To date, only a few commonly used clinical biomarkers have been reported.

Aim

To assess commonly used clinical biomarkers associated with the occurrence of irAEs to enable better management of irAEs by clinicians.

Methods

We retrospectively reviewed patients with liver cancer treated with at least one cycle of PD-1 immune checkpoint inhibitors (ICIs) combined with tyrosine kinase inhibitors (TKIs). IrAEs were documented according to the common terminology criteria for adverse events version 5. Clinical and laboratory parameters were also evaluated.

Results

A total of 67 patients were included, 36 with irAEs and 31 without irAEs. A total of 104 adverse events occurred; 83 of these events were grade 1/2 (G1/G2), 21 were grade 3/4 (G3/G4), and one died of G4 hepatitis. Patients with irAEs had higher levels of C-reactive protein (CRP) and interleukin-6 (IL-6) and lower levels of lymphocyte subsets, except natural killer (NK) cell counts, than those without irAEs (P <0.05). Patients who experienced G3/G4 irAEs had higher levels of CRP and IL-6 and lower levels of CD4+ T lymphocytes and B lymphocytes than those who experienced G1/G2 irAEs (P <0.05). Of note, impairments in liver function and routine blood tests were also observed (P <0.05). The results of univariate and multivariate analyses for any grade of irAEs revealed that the combination of sintilimab and lenvatinib (P= 0.004, odds ratio [OR]: 7.414, 95% confidence interval [95% CI]: 1.925–28.560) and CRP ≥8.2 mg/L (P= 0.024, OR: 3.727, CI: 1.185–11.726) were independent risk factors. Univariate and multivariate analyses of the risk factors of G3/G4 irAEs suggested that the combination of sintilimab and lenvatinib was a potential risk factor (P = 0.049, OR: 8.242, CI: 1.006–67.532).

Conclusion

Changes in patient CRP, IL-6, and lymphocyte subsets were associated with irAE onset and may act as potential biomarkers of irAEs. Impairments in liver function and routine blood tests owing to the occurrence of irAEs may become new concerns for clinicians.
Spine Stereotactic Body Radiotherapy to Three or More Contiguous Vertebral Levels
Authors: Dibs Khaled , Blakaj Dukagjin M. , Prasad Rahul N. , Olausson Alexander , Bourekas Eric C. , Boulter Daniel , Ayan Ahmet S. , Cochran Eric , Marras William S. , Mageswaran Prasath , Thomas Evan , Lee Hyeri , Grecula John , Raval Raju R. , Mendel Ehud , Scharschmidt Thomas , Lonser Russell , Chakravarti Arnab , Elder James B. , Palmer Joshua D.
Published: June 2022

Background

With survival improving in many metastatic malignancies, spine metastases have increasingly become a source of significant morbidity; achieving durable local control (LC) is critical. Stereotactic body radiotherapy (SBRT) may offer improved LC and/or symptom palliation. However, due to setup concerns, SBRT is infrequently offered to patients with ≥3 contiguous involved levels. Because data are limited, we sought to evaluate the feasibility, toxicity, and cancer control outcomes of spine SBRT delivered to ≥3 contiguous levels.

Methods

We retrospectively identified all SBRT courses delivered between 2013 and 2019 at a tertiary care institution for postoperative or intact spine metastases. Radiotherapy was delivered to 14–35 Gy in 1–5 fractions. Patients were stratified by whether they received SBRT to 1–2 or ≥3 contiguous levels. The primary endpoint was 1-year LC and was compared between groups. Factors associated with increased likelihood of local failure (LF) were explored. Acute and chronic toxicity was assessed. In-depth dosimetric data were collected.

Results

Overall, 165 patients with 194 SBRT courses were identified [54% were men, median age was 61 years, 93% had Karnofsky Performance Status (KPS) ≥70, and median follow-up was 15 months]. One hundred thirteen patients (68%) received treatment to 1–2 and 52 to 3–7 (32%) levels. The 1-year LC was 88% (89% for 1–2 levels vs. 84% for ≥3 levels, p = 0.747). On multivariate analysis, uncontrolled systemic disease was associated with inferior LC for patients with ≥3 treated levels. No other demographic, disease, treatment, or dosimetric variables achieved significance. Rates of new/progressive fracture were equivalent (8% vs. 9.5%, p = 0.839). There were no radiation-induced myelopathy or grade 3+ acute or late toxicities in either group. Coverage of ≥95% of the planning target volume with ≥95% prescription dose was similar between groups (96% 1–2 levels vs. 89% ≥3 levels, p = 0.078).

Conclusions

For patients with ≥3 contiguous involved levels, spine SBRT is feasible and may offer excellent LC without significant toxicity. Prospective evaluation is warranted.
Efficacy and Safety of Mitoxantrone Hydrochloride Injection for Tracing Axillary Sentinel Nodes in Breast Cancer: A Self-Controlled Clinical Trial
Authors: Jiao Dechuang , Yang Benlong , Chen Jiajian , Wang Chunjian , Jin Lidan , Zhao Wenhe , Gao Xueqiang , Wang Haibo , Li Jun , Zhao Haidong , Wu Di , Fan Zhimin , Wang Shujun , Liu Zhenzhen , Wang Yongsheng , Wu Jiong
Published: June 2022

Background

Mitoxantrone hydrochloride injection for tracing (MHI), a new strategy to identify lymph nodes, has not been tested for axillary node staging in breast cancer. This multicenter, self-controlled, non-inferiority trial aimed to evaluate MHI’s efficacy and safety in sentinel lymph node biopsy (SLNB).

Methods

The trial was conducted across seven hospitals from December 2019 to December 2020. Patients with early-stage breast cancer received MHI and technetium-99m (99mTc) during the surgery. Sentinel node detection rates were compared between MHI and 99mTc to evaluate non-inferiority and concordance. Non-inferiority was valid if the lower limit of the 95% CI of sentinel node relative detection rate difference was ≥−5%.

Results

SLN relative detection rate of MHI was 97.31% (362/372). Of the SLNs, 79.69% (871/1093) were co-detected by both tracers. Of the patients, 4.13% (16/387) had adverse events and recovered during the follow-up.

Conclusions

MHI is a lymphatic tracer with comparable efficacy to radionuclides and can be used alone or in combination with radioactive substances for SLNB.

Clinical Trial Registration

http://www.chinadrugtrials.org.cn, CTR20192435.
Transcriptomics and Network Pharmacology Reveal the Protective Effect of Chaiqin Chengqi Decoction on Obesity-Related Alcohol-Induced Acute Pancreatitis via Oxidative Stress and PI3K/Akt Signaling Pathway
Authors: Yang Xinmin , Yao Linbo , Yuan Mei , Zhang Xiaoying , Jakubowska Monika A. , Ferdek Pawel E. , Dai Lei , Yang Jingyu , Jin Tao , Deng Lihui , Fu Xianghui , Du Dan , Liu Tingting , Criddle David N. , Sutton Robert , Huang Wei , Xia Qing
Published: June 2022

Obesity-related acute pancreatitis (AP) is characterized by increasing prevalence worldwide and worse clinical outcomes compared to AP of other etiologies. Chaiqin chengqi decoction (CQCQD), a Chinese herbal formula, has long been used for the clinical management of AP but its therapeutic actions and the underlying mechanisms have not been fully elucidated. This study has investigated the pharmacological mechanisms of CQCQD in a novel mouse model of obesity-related alcohol-induced AP (OA-AP). The mouse OA-AP model was induced by a high-fat diet for 12 weeks and subsequently two intraperitoneal injections of ethanol, CQCQD was administered 2 h after the first injection of ethanol. The severity of OA-AP was assessed and correlated with changes in transcriptomic profiles and network pharmacology in the pancreatic and adipose tissues, and further docking analysis modeled the interactions between compounds of CQCQD and their key targets. The results showed that CQCQD significantly reduced pancreatic necrosis, alleviated systemic inflammation, and decreased the parameters associated with multi-organ dysfunction. Transcriptomics and network pharmacology analysis, as well as further experimental validation, have shown that CQCQD induced Nrf2/HO-1 antioxidant protein response and decreased Akt phosphorylation in the pancreatic and adipose tissues. In vitro, CQCQD protected freshly isolated pancreatic acinar cells from H2O2-elicited oxidative stress and necrotic cell death. The docking results of AKT1 and the active compounds related to AKT1 in CQCQD showed high binding affinity. In conclusion, CQCQD ameliorates the severity of OA-AP by activating of the antioxidant protein response and down-regulating of the PI3K/Akt signaling pathway in the pancreas and visceral adipose tissue.
Shema Oral Liquid Ameliorates the Severity of LPS-Induced COPD via Regulating DNMT1
Authors: Zhang Fangbo , Guo Feifei , Liu Yang , Zhang Yi , Li Defeng , Yang Hongjun
Published: June 2022

Background: Chronic obstructive pulmonary disease (COPD) is the most common respiratory disease with high morbidity and mortality. Shema oral liquid (Shema) is a traditional Chinese medicine (TCM) approved for the treatment of respiratory diseases. Clinical applications have shown that Shema has antitussive, expectorant, and anti-asthmatic effects, but its definite efficacy to COPD is still unclear. This study aimed to explore the therapeutic capacity and potential mechanism of Shema in treatment of COPD.

Methods: Network pharmacology was used to investigated the possible pharmacological mechanism of Shema against COPD. A rat model of lipopolysaccharide (LPS)-induced COPD was established to determine pulmonary ventilatory function, serum inflammatory cytokines, and pulmonary pathological change. Subsequently, tandem mass tag (TMT)-based quantitative proteomics was used to further reveal the therapeutic targets related with Shema against COPD. Western blot was finally performed to validate the expression of targeted proteins screened by proteomics research.

Results: Network pharmacology analysis indicated that Shema against COPD mainly inhibited the inflammation and affected the immune system. The animal experiment demonstrated that Shema treatment protected the lung tissue from LPS induced injury, inhibited the levels of serum inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, and improved the respiratory ventilatory function by upregulating forced expiratory volume in 0.1 s (FEV0.1), FEV0.3, forced vital capacity (FVC), and the ratios of FEV0.1 (0.3)/FVC. Proteomic analysis and western blot both proved that Shema inhibited the expression of DNA methyltransferase 1 (DNMT1) in the lung tissue.

Conclusion: The therapeutic mechanism of Shema in treatment of COPD may involve inhibiting inflammatory response, improving pulmonary ventilatory function, and alleviating LPS-induced lung injury through regulating the expression of DNMT1. This study also shed light on the development of therapeutic strategies in treating COPD by intervening DNMT-related pathways.
Valuing the “Burden” and Impact of Rare Diseases: A Scoping Review
Authors: Delaye Julien , Cacciatore Pasquale , Kole Anna
Published: June 2022

Introduction: Rare diseases (RDs) are a severe, chronic, degenerative and often life-threatening group of conditions affecting more than 30 million people in Europe. Their impact is often underreported and ranges from psychological and physical symptoms seriously compromising quality of life. There is then a need to consolidate knowledge on the economic, social, and quality of life impacts of rare diseases.

Methods: This scoping review is the result of 9 qualitative interviews with experts and a literature search on Cost-of-Illness (COI) studies and quality of life (QoL) studies following the PRISMA methodology. Grey literature was also included to complement findings. Results. 63 COI studies were retrieved, covering 42 diseases and a vast majority of them using a prevalence-based approach (94%). All studies included medical costs, while 60% included non-medical costs, 68% productivity losses and 43% informal care costs. 56 studies on QoL were retrieved, mostly from Europe, with 30 different measurement tools. Grey literature included surveys from the pharmaceutical industry and patient organisations.

Discussion: The majority of studies evaluating the impact of RDs on the individual and society use the COI approach, mostly from a societal perspective. Studies often vary in scope, making them difficult to consolidate or compare results. While medical costs and productivity losses are consistently included, QoL aspects are rarely considered in COI and are usually measured through generic tools.

Conclusion: A comprehensive study on impact of rare disease across countries in Europe is lacking. Existing studies are heterogeneous in their scope and methodology and often lack a holistic picture of the impact of rare. Consensus on standards and methodology across countries and diseases is then needed. Studies that consider a holistic approach are often conducted by pharmaceutical companies and patient organisations exploring a specific disease area but are not necessarily visible in the literature and could benefit from the sharing of standards and best practices.
Using the FA-NAR Dynamic Neural Network Model and Big Data to Monitor Dam Safety
Authors: Pan Bin , Quan Zhitong , Huang Xueli , Sun Guang
Published: June 2022

In view of the dynamics of the dam safety monitoring data, the sensitivity to time and space, and the nonlinearity, it has been proposed to use the firefly algorithm to search to determine the delay order and the number of hidden layer units and combine them with nonlinear autoregressive algorithms. The algorithms are combined to obtain the FA-NAR algorithm dam deformation prediction model, which is compared with the traditional BP algorithm prediction results, combined with the Xiaolangdi dam deformation monitoring data for prediction, and the dam deformation data predicted by the dynamic neural network have a better convergence effect and a more accurate prediction result. It provides a certain reference basis for perfecting dam safety monitoring.