PhenoApt leverages clinical expertise to prioritize candidate genes via machine learning.

In recent years, exome sequencing (ES) has shown great utility in the diagnoses of Mendelian disorders. However, after rigorous filtering, a typical ES analysis still involves the interpretation of hundreds of variants, which greatly hinders the rapid identification of causative genes. Since the interpretations of ES data require comprehensive clinical analyses, taking clinical expertise into consideration can speed the molecular diagnoses of Mendelian disorders. To leverage clinical expertise to prioritize candidate genes, we developed PhenoApt, a phenotype-driven gene prioritization tool that allows users to assign a customized weight to each phenotype, via a machine-learning algorithm. Using the ability to rank causative genes in top-10 lists as an evaluation metric, baseline analysis demonstrated that PhenoApt outperformed previous phenotype-driven gene prioritization tools by a relative increase of 22.7%-140.0% in three independent, real-world, multi-center cohorts (cohort 1, n = 185; cohort 2, n = 784; and cohort 3, n = 208). Additional trials showed that, by adding weights to clinical indications, which should be explained by the causative gene, PhenoApt performance was improved by a relative increase of 37.3% in cohort 2 (n = 471) and 21.4% in cohort 3 (n = 208). Moreover, PhenoApt could assign an intrinsic weight to each phenotype based on the likelihood of its being a Mendelian trait using term frequency-inverse document frequency techniques. When clinical indications were assigned with intrinsic weights, PhenoApt performance was improved by a relative increase of 23.7% in cohort 2 and 15.5% in cohort 3. For the integration of PhenoApt into clinical practice, we developed a user-friendly website and a command-line tool.

Hypomethylation-associated LINC00987 downregulation induced lung adenocarcinoma progression by inhibiting the phosphorylation-mediated degradation of SND1.

DNA methylation, an epigenetic regulatory mechanism dictating gene transcription, plays a critical role in the occurrence and development of cancer. However, the molecular underpinnings of LINC00987 methylation in the regulation of lung adenocarcinoma (LUAD) remain elusive. This study investigated LINC00987 expression in LUAD patients through analysis of The Cancer Genome Atlas data sets. Quantitative real-time polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization assays were used to assess LINC00987 expression in LUAD. The bisulfite genomic sequence PCR (BSP) assay was used to determine the methylation levels of the LINC00987 promoter. The interaction between LINC00987 and SND1 was elucidated via immunoprecipitation and RNA pull-down assays. The functional significance of LINC00987 and SND1 in Calu-3 and NCI-H1688 cells was evaluated in vitro through CCK-8, EdU, Transwell, flow cytometry, and vasculogenic mimicry (VM) tube formation assays. LINC00987 expression decreased in LUAD concomitant with hypermethylation of the promoter region, while hypomethylation of the LINC00987 promoter in LUAD tissues correlated with tumor progression. Treatment with 5-Aza-CdR augmented LINC00987 expression and inhibited tumor growth. Mechanistically, LINC00987 overexpression impeded LUAD progression and VM through direct binding with SND1, thereby facilitating its phosphorylation and subsequent degradation. Additionally, overexpression of SND1 counteracted the adverse effects of LINC00987 downregulation on cell proliferation, apoptosis, cell migration, invasion, and VM in LUAD in vitro. In conclusion, this pioneering study focuses on the expression and function of LINC00987 and reveals that hypermethylation of the LINC00987 gene may contribute to LUAD progression. LINC00987 has emerged as a potential tumor suppressor gene in tumorigenesis through its binding with SND1 to facilitate its phosphorylation and subsequent degradation.

Dissection of mendelian predisposition and complex genetic architecture of craniovertebral junction malformation.

The craniovertebral junction (CVJ) is an anatomically complex region of the axial skeleton that provides protection of the brainstem and the upper cervical spinal cord. Structural malformation of the CVJ gives rise to life-threatening neurological deficits, such as quadriplegia and dyspnea. Unfortunately, genetic studies on human subjects with CVJ malformation are limited and the pathogenesis remains largely elusive. In this study, we recruited 93 individuals with CVJ malformation and performed exome sequencing. Manual interpretation of the data identified three pathogenic variants in genes associated with Mendelian diseases, including CSNK2A1, MSX2, and DDX3X. In addition, the contribution of copy number variations (CNVs) to CVJ malformation was investigated and three pathogenic CNVs were identified in three affected individuals. To further dissect the complex mutational architecture of CVJ malformation, we performed a gene-based rare variant association analysis utilizing 4371 in-house exomes as control. Rare variants in LGI4 (carrier rate = 3.26%, p = 3.3 × 10-5) and BEST1 (carrier rate = 5.43%, p = 5.77 × 10-6) were identified to be associated with CVJ malformation. Furthermore, gene set analyses revealed that extracellular matrix- and RHO GTPase-associated biological pathways were found to be involved in the etiology of CVJ malformation. Overall, we comprehensively dissected the genetic underpinnings of CVJ malformation and identified several novel disease-associated genes and biological pathways.

Activating PIK3CA postzygotic mutations in segmental overgrowth of muscles with bone involvement in the body extremities.

Segmental overgrowth of the skeletal muscles with bone involvement in body extremities, predominantly affecting the upper limb, is an extremely rare condition with only 40-50 affected children described clinically. The molecular pathogenesis of this disorder remains largely unclear except for the identification of a somatic PIK3CA mutation in each of the six patients genetically tested, all restricted to upper limbs in the literature. This study aimed to further characterize the molecular defects for patients affected with segmental overgrowth of the skeletal muscles by analyzing a 9-gene panel selected from the PI3K/AKT/mTOR pathway and genes associated with other related conditions. Nineteen unrelated patients were chosen for this study, comprising ten upper limb (nine unilateral and one bilateral) and nine lower limb (eight unilateral and one bilateral) cases with variable bone involvement. In each case, an activating PIK3CA mutation (p.E110del, p.N345K, p.E542K, p.E545K, p.H1047R, or p.H1047L) was identified in the affected muscle tissue with variant allele frequencies ranging from 13.88 to 30.43%, while no mutation was detected in the paired peripheral blood sample, indicating somatic mosaicism. All detected mutations were limited to PIK3CA and were previously reported in other overgrowth syndromes currently categorized under the PIK3CA-Related Overgrowth Spectrum (PROS). Our study provides strong molecular evidence that isolated segmental overgrowth of the skeletal muscle with bone involvement is a subtype of PROS. Our findings expand the PROS clinical presentations with a newly molecularly classified condition and can provide guidance in clinical and molecular diagnosis and treatment for patients with this condition.

Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS).

BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited. RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis. CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

Identification of novel FBN1 variations implicated in congenital scoliosis.

Congenital scoliosis (CS) is a form of scoliosis caused by congenital vertebral malformations. Genetic predisposition has been demonstrated in CS. We previously reported that TBX6 loss-of-function causes CS in a compound heterozygous model; however, this model can explain only 10% of CS. Many monogenic and polygenic CS genes remain to be elucidated. In this study, we analyzed exome sequencing (ES) data of 615 Chinese CS from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) project. Cosegregation studies for 103 familial CS identified a novel heterozygous nonsense variant, c.2649G>A (p.Trp883Ter) in FBN1. The association between FBN1 and CS was then analyzed by extracting FBN1 variants from ES data of 574 sporadic CS and 828 controls; 30 novel variants were identified and prioritized for further analyses. A mutational burden test showed that the deleterious FBN1 variants were significantly enriched in CS subjects (OR = 3.9, P = 0.03 by Fisher's exact test). One missense variant, c.2613A>C (p.Leu871Phe) was recurrent in two unrelated CS subjects, and in vitro functional experiments for the variant suggest that FBN1 may contribute to CS by upregulating the transforming growth factor beta (TGF-ß) signaling. Our study expanded the phenotypic spectrum of FBN1, and provided nove insights into the genetic etiology of CS.

Lactylome analyses suggest systematic lysine-lactylated substrates in oral squamous cell carcinoma under normoxia and hypoxia.

Cancer cells tend to live in hypoxic environment characterized by enhanced glycolysis and accumulation of lactate. Intracellular lactate is shown to drive a novel type of post-translational modification (PTM), lysine lactylation (Kla). Kla has been confirmed to affect the malignant progression of tumors such as hepatocellular carcinoma (HCC) and colon cancer, whereas the global lactylomic profiling of oral squamous cell carcinoma (OSCC) is unclear. Here, the integrative lactylome and proteome analyses by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 1011 Kla sites within 532 proteins and 1197 Kla sites within 608 proteins in SCC25 cells under normoxic and hypoxic environments, respectively. Among these lactylated proteins, histones accounted for only a small fraction, suggesting the presence of Kla modification of OSCC in a large number of non-histone proteins. Notably, Kla preferred to enrich in spliceosome, ribosome and glycolysis/gluconeogenesis pathway in both normoxic and hypoxic cultures. Compared with normoxia, 589 differential proteins with 898 differentially lactylated sites were detected under hypoxia, which were mainly associated with the glycolysis/gluconeogenesis pathway by KEGG analysis. Importantly, we verified the presence of lactylation modification in the spliceosomal proteins hnRNPA1, SF3A1, hnRNPU and SLU7, as well as in glycolytic enzyme PFKP. In addition, the differential alternative splicing analysis described the divergence of pre-mRNA splicing patterns in the presence or absence of sodium lactate and at different oxygen concentrations. Finally, a negative correlation between tissue Kla levels and the prognosis of OSCC patients was revealed by immunohistochemistry. Our study is the first report to elucidate the lactylome and its biological function in OSCC, which deepens our understanding of the mechanisms underlying OSCC progression and provides a novel strategy for targeted therapy for OSCC.

A comprehensive overview of psoriatic research over the past 20 years: machine learning-based bibliometric analysis.

Background: The surge in the number of publications on psoriasis has posed significant challenges for researchers in effectively managing the vast amount of information. However, due to the lack of tools to process metadata, no comprehensive bibliometric analysis has been conducted. Objectives: This study is to evaluate the trends and current hotspots of psoriatic research from a macroscopic perspective through a bibliometric analysis assisted by machine learning based semantic analysis. Methods: Publications indexed under the Medical Subject Headings (MeSH) term "Psoriasis" from 2003 to 2022 were extracted from PubMed. The generative statistical algorithm latent Dirichlet allocation (LDA) was applied to identify specific topics and trends based on abstracts. The unsupervised Louvain algorithm was used to establish a network identifying relationships between topics. Results: A total of 28,178 publications were identified. The publications were derived from 176 countries, with United States, China, and Italy being the top three countries. For the term "psoriasis", 9,183 MeSH terms appeared 337,545 times. Among them, MeSH term "Severity of illness index", "Treatment outcome", "Dermatologic agents" occur most frequently. A total of 21,928 publications were included in LDA algorithm, which identified three main areas and 50 branched topics, with "Molecular pathogenesis", "Clinical trials", and "Skin inflammation" being the most increased topics. LDA networks identified "Skin inflammation" was tightly associated with "Molecular pathogenesis" and "Biological agents". "Nail psoriasis" and "Epidemiological study" have presented as new research hotspots, and attention on topics of comorbidities, including "Cardiovascular comorbidities", "Psoriatic arthritis", "Obesity" and "Psychological disorders" have increased gradually. Conclusions: Research on psoriasis is flourishing, with molecular pathogenesis, skin inflammation, and clinical trials being the current hotspots. The strong association between skin inflammation and biologic agents indicated the effective translation between basic research and clinical application in psoriasis. Besides, nail psoriasis, epidemiological study and comorbidities of psoriasis also draw increased attention.

NUDT5-Determines the fate of head and neck squamous cell carcinoma cells under endoplasmic reticulum stress by catalyzing nuclear ATP production to promote DNA repair.

OBJECTIVES: NUDT5 is the only discovered enzyme that catalyses ATP production in cell nuclei. In this study, we investigate the character of NUDT5 in head and neck squamous cell carcinoma (HNSCC) cells under endoplasmic reticulum (ER) stress. METHODS: The formation of ER stress was confirmed in HNSCC cells using Real-time PCR and Western blot techniques. The expression of NUDT5 was modified by transfecting HNSCC cells with siRNA and plasmids, respectively. The effects of NUDT5 manipulation were assessed using various methods including cell counting kit-8 assay, western blotting, RNA sequencing, Immunofluorescence Microscopy analysis, cell cycle analysis and nucleic ATP measurement, and a xenograft mouse model. RESULTS: In this study, we found that the expression of NUDT5 proteins was upregulated under ER stress conditions in HNSCC cells. Knocking down NUDT5 under ER stress could hinder nuclear ATP generation and thus induce more DNA damage and apoptosis of HNSCC cells. Only the wild-type NUDT5 or ATP catalysis active mutant T45A-NUDT5, rather than the ATP catalysis null mutant T45D-NUDT5, could directly rescue nuclear ATP depletion caused by NUDT5 inhibition and protect HNSCC cells from DNA damage and cell apoptosis. Finally, in vivo studies showed that knocking down NUDT5 in ER-stressed conditions could significantly inhibit tumour growth. CONCLUSION: Our study demonstrated for the first time that NUDT5 guaranteed the integrity of DNA under ER stress-triggered DNA damage by catalysing nuclear ATP production. Our findings offer new insights into how the energy supply in cell nuclei fuels cancer cell survival in stressful microenvironment.

Oral cancer cells affect pancreatic ß-cell function through transmissible endoplasmic reticulum stress.

OBJECTIVES: In this study, we aimed to investigate whether oral cancer cells affect pancreatic ß-cells function through transmissible endoplasmic reticulum stress (TERS). METHODS: Tunicamycin (TM) was selected as the endoplasmic reticulum stress (ERS) inducer. The human oral cancer cell lines CAl-27 and SCC-25 were selected as the donor cells, and mouse insulinoma 6 (MIN6) cell lines were chosen as the recipient cells. Quantitative real-time polymerase chain reaction (qPCR) and Western blot (WB) analysis were used to detect ERS markers and insulin expression. The TdT-mediated dUTP nick-end labeling (TUNEL) method was applied to detect apoptosis levels. The clone formation method was utilized to detect cell proliferation capability. The secretory function of pancreatic ß-cells was detected with an enzyme linked immunosorbent assay (ELISA) kit and a bicinchoninic acid (BCA) kit. RESULTS: The MIN6 cells were subjected to TM stimulation. qPCR and WB analysis revealed that ERS markers were upregulated. This result implied that the MIN6 cells can induce ERS. The supernatant of oral cancer cells under ERS was added to the MIN6 cells. qPCR and WB analysis showed that the oral cancer cells that had been subjected to ERS could induce ERS in the MIN6 cells, that is, the phenomenon of TERS occurred. The TUNEL assay indicated that the apoptosis of the MIN6 cells increased under TERS. The clone formation assay demonstrated that the proliferation capability of the MIN6 cells decreased under TERS. qPCR and WB analysis revealed that under TERS, insulin synthesis by the MIN6 cells decreased and insulin synthesis was inhibited at the translation level. The ELISA and BCA kits demonstrated that insulin secretion by the MIN6 cells was reduced under TERS. CONCLUSIONS: Oral cancer cells can affect pancreatic ß-cells through TERS, resulting in increased apoptosis, decreased viability, and reduced insulin secretion and synthesis capability.

Trends and Hotspots in Nanoparticles for the Targeted Delivery of Nucleic Acids: A Ten-Year Bibliometric Study.

Nanoparticles for the gene therapy field have seen remarkable progress over the last 10 years; however, low delivery efficiency and other reasons impede the clinical translation of nanocarriers. Therefore, a summary of hotspots and trends in this field is needed to promote further research development. In this research, from 2011 to 2021, 1,221 full records and cited references of Web of Science-indexed manuscripts regarding nanoparticle-targeted delivery systems have been analyzed by CiteSpace, VOSviewer, and MapEquation. In these software, keywords co-occurrence networks, alluvial diagram, co-citation networks, and structural variation analysis were carried out to emphasize the scientific community's focus on nanomedicine of targeted delivering of nucleic acids. Keywords such as transfection efficiency, tumor cell, membrane antigen, and siRNA delivery were highlighted in the density map from VOSviewer. In addition, an alluvial flow diagram was constructed to detect changes in concepts. In the co-citation network, cluster 1 (exosomes) and cluster 17 (genome editing) were new research fields, and the efforts in modifying nanoparticles were revealed in the structural variation analysis. Aptamer and SELEX (systematic evolution of ligands by exponential enrichment) represented a helpful system in targeted delivery. These results indicated that the transfection efficiency of nanocarriers required continuous improvements. With the approval of several nucleic acid drugs, a new content of nanoparticle carriers is to introduce gene-editing technology, especially CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9). In addition, exosomes have great potential as targeted nanoparticles. By mapping the knowledge domains of nanomedicine in targeted delivering of nucleic acids, this study analyzed the intellectual structure of this domain in the recent 10 years, highlighting classical modifications on nanoparticles and estimating future trends for researchers and decision-makers interested in this field.

Emerging trends in photodynamic therapy for head and neck cancer: A 10-year bibliometric analysis based on CiteSpace.

BACKGROUND: Head and neck cancer (HNC) was the seventh most common cancer worldwide. Photodynamic therapy (PDT) is a clinically approved, minimally invasive treatment, which was shown to be effective in the treatment of head and neck cancer and potentially malignant disorders. We used a bibliometric analysis to analyze the publications of radiomics in oncology to clearly illustrate the current situation and future trends and encourage more researchers to participate in radiomics research in oncology. METHODS: Publications for Photodynamic therapy in for head and neck cancer and potentially malignant disorders were downloaded from the Web of Science Core Collection (WoSCC). CiteSpace was used for a bibliometric analysis of countries, institutions, journals, authors, keywords, and references pertaining to this field. The state of research and areas of focus were analyzed through burst detection. RESULTS: A total of 1002 studies were used for analysis on CiteSpace. The USA is in first place by number of publications. Hopper C, was the most prolific author, and the author with the most citations was Chen XY. Among the journals and the co-cited journals, "Photodiagnosis and Photodynamic Therapy" was the first. "Nanoparticle" showed the highest burst strength level and materials research is major area of focus in this field. CONCLUSIONS: This bibliometric analysis of photodynamic therapy in head and neck cancer, provides a visual analysis of publications in this field. The conclusion of the current research in this field was that it focused on the research of photosensitizers, particularly nanomaterials and targeted therapies.

Landscape of Secondary Findings in Chinese Population: A Practice of ACMG SF v3.0 List.

Clinical exome sequencing (CES) has shown great utility in the diagnosis of Mendelian disorders. CES can unravel secondary findings (SFs) unrelated to the primary diagnosis but with potential health implications. The American College of Medical Genetics and Genomics (ACMG) has published a guideline for reporting secondary findings and recently updated an ACMG SF v3.0 list comprising 73 genes. Several studies have been performed to explore the prevalence of SFs. However, the data were limited in the Chinese population. In this study, we evaluated the genetic data of 2987 individuals from the Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study group in accordance with the ACMG SF v3.0 list. The detected variants were evaluated using the ACMG classification guidelines, HGMD, and ClinVar database. Totally, 157 (157/2987, 5.3%) individuals had reportable variants within genes associated with cancer, cardiovascular, metabolic, and miscellaneous phenotypes. We identified 63 known pathogenic (KP) variants in 72 individuals (72/2987, 2.4%) and 96 expected pathogenic (EP) variants in 105 individuals (3.5%). Forty-five individuals carried SFs in v3.0 newly added genes, which accounted for 1.5% of our cohort. Our findings could contribute to existing knowledge of secondary findings in different ethnicities and indicate the necessity for clinicians to update the SFs gene list.

Delineation of dual molecular diagnosis in patients with skeletal deformity.

BACKGROUND: Skeletal deformity is characterized by an abnormal anatomical structure of bone and cartilage. In our previous studies, we have found that a substantial proportion of patients with skeletal deformity could be explained by monogenic disorders. More recently, complex phenotypes caused by more than one genetic defect (i.e., dual molecular diagnosis) have also been reported in skeletal deformities and may complicate the diagnostic odyssey of patients. In this study, we report the molecular and phenotypic characteristics of patients with dual molecular diagnosis and variable skeletal deformities. RESULTS: From 1108 patients who underwent exome sequencing, we identified eight probands with dual molecular diagnosis and variable skeletal deformities. All eight patients had dual diagnosis consisting of two autosomal dominant diseases. A total of 16 variants in 12 genes were identified, 5 of which were of de novo origin. Patients with dual molecular diagnosis presented blended phenotypes of two genetic diseases. Mendelian disorders occurred more than once include Osteogenesis Imperfecta Type I (COL1A1, MIM:166200), Neurofibromatosis, Type I (NF1, MIM:162200) and Marfan Syndrome (FBN1, MIM:154700). CONCLUSIONS: This study demonstrated the complicated skeletal phenotypes associated with dual molecular diagnosis. Exome sequencing represents a powerful tool to detect such complex conditions.

Identification of Novel FBN2 Variants in a Cohort of Congenital Contractural Arachnodactyly.

Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant disorder of connective tissue characterized by crumpled ears, arachnodactyly, camptodactyly, large joint contracture, and kyphoscoliosis. The nature course of CCA has not been well-described. We aim to decipher the genetic and phenotypic spectrum of CCA. The cohort was enrolled in Beijing Jishuitan Hospital and Peking Union Medical College Hospital, Beijing, China, based on Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study (http://www.discostudy.org/). Exome sequencing was performed on patients' blood DNA. A recent published CCA scoring system was validated in our cohort. Seven novel variants and three previously reported FBN2 variants were identified through exome sequencing. Two variants outside of the neonatal region of FBN2 gene were found. The phenotypes were comparable between patients in our cohort and previous literature, with arachnodactyly, camptodactyly and large joints contractures found in almost all patients. All patients eligible for analysis were successfully classified into likely CCA based on the CCA scoring system. Furthermore, we found a double disease-causing heterozygous variant of FBN2 and ANKRD11 in a patient with blended phenotypes consisting of CCA and KBG syndrome. The identification of seven novel variants broadens the mutational and phenotypic spectrum of CCA and may provide implications for genetic counseling and clinical management.

Research on neck dissection for oral squamous-cell carcinoma: a bibliometric analysis.

Neck dissection for oral squamous-cell carcinoma (OSCC) is a clinically controversial issue and has therefore been the subject of abundant research. However, no one has performed a bibliometric study on this topic to date. The aim of this study was to assess the development of research on neck dissection for OSCC in terms of the historical evolution, current hotspots and future directions, particularly including research trends and frontiers from 2010 to 2019. Literature records related to research on neck dissection for OSCC were retrieved from the Web of Science Core Collection (WoSCC). CiteSpace was used as a tool to perform a bibliometric analysis of this topic. The survey included 2 096 papers. "Otorhinolaryngology" was the most popular research area. The most active institutions and countries were Memorial Sloan Kettering Cancer Center and the USA, respectively. Shah J.P. was the most cited author. Among the six identified "core journals", Head & Neck ranked first. The top three trending keywords were 'invasion', 'upper aerodigestive' and 'negative neck'. 'D'Cruz AK (2015)' was the most cited and the strongest burst reference in the last decade. The study evaluated the effect on survival of elective versus therapeutic neck dissection in patients with lateralized early-stage OSCC. The depth of invasion and the management of N0 OSCC were research frontiers in this field. The present study provides a comprehensive bibliometric analysis of research on neck dissection for OSCC, which will assist investigators in exploring potential research directions.

Radiomics in Oncology: A 10-Year Bibliometric Analysis.

OBJECTIVES: To date, radiomics has been applied in oncology for over a decade and has shown great progress. We used a bibliometric analysis to analyze the publications of radiomics in oncology to clearly illustrate the current situation and future trends and encourage more researchers to participate in radiomics research in oncology. METHODS: Publications for radiomics in oncology were downloaded from the Web of Science Core Collection (WoSCC). WoSCC data were collected, and CiteSpace was used for a bibliometric analysis of countries, institutions, journals, authors, keywords, and references pertaining to this field. The state of research and areas of focus were analyzed through burst detection. RESULTS: A total of 7,199 pieces of literature concerning radiomics in oncology were analyzed on CiteSpace. The number of publications has undergone rapid growth and continues to increase. The USA and Chinese Academy of Sciences are found to be the most prolific country and institution, respectively. In terms of journals and co-cited journals, Scientific Reports is ranked highest with respect to the number of publications, and Radiology is ranked highest among co-cited journals. Moreover, Jie Tian has published the most publications, and Phillipe Lambin is the most cited author. A paper published by Gillies et al. presents the highest citation counts. Artificial intelligence (AI), segmentation methods, and the use of radiomics for classification and diagnosis in oncology are major areas of focus in this field. Test-retest statistics, including reproducibility and statistical methods of radiomics research, the relation between genomics and radiomics, and applications of radiomics to sarcoma and intensity-modulated radiotherapy, are frontier areas of this field. CONCLUSION: To our knowledge, this is the first study to provide an overview of the literature related to radiomics in oncology and may inspire researchers from multiple disciplines to engage in radiomics-related research.

A Pretargeted Imaging Strategy for EGFR-Positive Colorectal Carcinoma via Modulation of Tz-Radioligand Pharmacokinetics.

PURPOSE: Previously, we successfully developed a pretargeted imaging strategy (atezolizumab-TCO/[99mTc]HYNIC-PEG11-Tz) for evaluating programmed cell death ligand-1 (PD-L1) expression in xenograft mice. However, the surplus unclicked [99mTc]HYNIC-PEG11-Tz is cleared somewhat sluggishly through the intestines, which is not ideal for colorectal cancer (CRC) imaging. To shift the excretion of the Tz-radioligand to the renal system, we developed a novel Tz-radioligand by adding a polypeptide linker between HYNIC and PEG11. PROCEDURES: Pretargeted molecular probes [99mTc]HYNIC-polypeptide-PEG11-Tz and cetuximab-TCO were synthesized. [99mTc]HYNIC-polypeptide-PEG11-Tz was evaluated for in vitro stability and in vivo blood pharmacokinetics. In vitro ligation reactivity of [99mTc]HYNIC-polypeptide-PEG11-Tz towards cetuximab-TCO was also tested. Biodistribution assay and imaging of [99mTc]HYNIC-polypeptide-PEG11-Tz were performed to observe its excretion pathway. Pretargeted biodistribution was measured at three different accumulation intervals to determine the optimal pretargeted interval time. Pretargeted (cetuximab-TCO 48 h/[99mTc]HYNIC-PEG11-Tz 6 h) and (cetuximab-TCO 48 h/[99mTc]HYNIC-Polypeptide-PEG11-Tz 6 h) imagings were compared to examine the effect of the excretion pathway on tumor imaging. RESULTS: [99mTc]HYNIC-polypeptide-PEG11-Tz showed favorable in vitro stability and rapid blood clearance in mice. SEC-HPLC revealed almost complete reaction between cetuximab-TCO and [99mTc]HYNIC-polypeptide-PEG11-Tz in vitro, with the 8:1 Tz-to-mAb reaction providing a conversion yield of 87.83 ± 3.27 %. Biodistribution and imaging analyses showed that the Tz-radioligand was cleared through the kidneys. After 24, 48, and 72 h of accumulation in HCT116 tumor, the tumor-to-blood ratio of cetuximab-TCO was 0.83 ± 0.13, 1.40 ± 0.31, and 1.15 ± 0.21, respectively. Both pretargeted (cetuximab-TCO 48 h/[99mTc]HYNIC-PEG11-Tz 6 h) and (cetuximab-TCO 48 h/[99mTc]HYNIC-polypeptide-PEG11-Tz 6 h) clearly delineated HCT116 tumor. Pretargeted imaging strategy using cetuximab-TCO/[99mTc]HYNIC-polypeptide-PEG11-Tz could be used for diagnosing CRC, as the surplus unclicked [99mTc]HYNIC-polypeptide-PEG11-Tz was cleared through the urinary system, leading to low abdominal uptake background. CONCLUSION: Our novel pretargeted imaging strategy (cetuximab-TCO/[99mTc]HYNIC-polypeptide-PEG11-Tz) was useful for imaging CRC, broadening the application scope of pretargeted imaging strategy. The pretargeted imaging strategy clearly delineated HCT116 tumor, showing that its use could be extended to selection of internalizing antibodies.

Deciphering the mutational signature of congenital limb malformations.

Congenital limb malformations (CLMs) affect 1 in 500 live births. However, the value of exome sequencing (ES) for CLM is lacking. The purpose of this study was to decipher the mutational signature of CLM on an exome level. We enrolled a cohort of 66 unrelated probands (including 47 families) with CLM requiring surgical correction. ES was performed for all patients and available parental samples. A definite molecular diagnosis was achieved in 21 out of 66 (32%) patients. We identified 19 pathogenic or likely pathogenic single-nucleotide variants and three copy number variants, of which 11 variants were novel. We identified four variants of uncertain significance. Additionally, we identified RPL9 and UBA2 as novel candidate genes for CLM. By comparing the detailed phenotypic features, we expand the phenotypic spectrum of diastrophic dysplasia and chromosome 6q terminal deletion syndrome. We also found that the diagnostic rate was significantly higher in patients with a family history of CLM (p = 0.012) or more than one limb affected (p = 0.034). Our study expands our understanding of the mutational and phenotypic spectrum of CLM and provides novel insights into the genetic basis of these syndromes.

Phenotypic and genetic spectrum of isolated macrodactyly: somatic mosaicism of PIK3CA and AKT1 oncogenic variants.

BACKGROUND: Isolated macrodactyly is a severe congenital hand anomaly with functional and physiological impact. Known causative genes include PIK3CA, AKT1 and PTEN. The aim of this study is to gain insights into the genetics basis of isolated macrodactyly. RESULTS: We enrolled 24 patients with isolated macrodactyly. Four of them were diagnosed with Proteus syndrome based on skin presentations characteristic to this disease. Targeted next-generation sequencing was performed using patients' blood and affected tissues. Overall, 20 patients carry mosaic PIK3CA pathogenic variants, i.e. p.His1047Arg (N = 7), p.Glu542Lys (N = 6), p.Glu545Lys (N = 2), p.His1047Leu (N = 2), p.Glu453Lys (N = 1), p.Gln546Lys (N = 1) and p.His1047Tyr (N = 1). Four patients who met the diagnostic criteria of Proteus syndrome carry mosaic AKT1 p.Glu17Lys variant. Variant allele frequencies of these mosaic variants obtained through next-generation sequencing range from 10 to 33%. In genotype-phenotype correlation analysis of patients with PIK3CA variant, we found that patients with the macrodactyly of the lower limbs tend to carry PIK3CA variants located in the helical domain (P = 0.005). CONCLUSIONS: Mosaic PIK3CA and AKT1 variants can be found in all of our samples with isolated macrodactyly. Insights into phenotypic and genetic spectrum of isolated macrodactyly may be helpful in perusing a more precise and effective management of isolated macrodactyly.