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1.
Theor Appl Genet ; 137(3): 69, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38441650

RESUMO

KEY MESSAGE: Twenty-eight QTLs for LLS disease resistance were identified using an amphidiploid constructed mapping population, a favorable 530-kb chromosome segment derived from wild species contributes to the LLS resistance. Late leaf spot (LLS) is one of the major foliar diseases of peanut, causing serious yield loss and affecting the quality of kernel and forage. Some wild Arachis species possess higher resistance to LLS as compared with cultivated peanut; however, ploidy level differences restrict utilization of wild species. In this study, a synthetic amphidiploid (Ipadur) of wild peanuts with high LLS resistance was used to cross with Tifrunner to construct TI population. In total, 200 recombinant inbred lines were collected for whole-genome resequencing. A high-density bin-based genetic linkage map was constructed, which includes 4,809 bin markers with an average inter-bin distance of 0.43 cM. The recombination across cultivated and wild species was unevenly distributed, providing a novel recombination landscape for cultivated-wild Arachis species. Using phenotyping data collected across three environments, 28 QTLs for LLS disease resistance were identified, explaining 4.35-20.42% of phenotypic variation. The major QTL located on chromosome 14, qLLS14.1, could be consistently detected in 2021 Jiyang and 2022 Henan with 20.42% and 12.12% PVE, respectively. A favorable 530-kb chromosome segment derived from Ipadur was identified in the region of qLLS14.1, in which 23 disease resistance proteins were located and six of them showed significant sequence variations between Tifrunner and Ipadur. Allelic variation analysis indicating the 530-kb segment of wild species might contribute to the disease resistance of LLS. These associate genomic regions and candidate resistance genes are of great significance for peanut breeding programs for bringing durable resistance through pyramiding such multiple LLS resistance loci into peanut cultivars.


Assuntos
Arachis , Resistência à Doença , Arachis/genética , Resistência à Doença/genética , Melhoramento Vegetal , Locos de Características Quantitativas , Cromossomos
2.
Mol Ther Nucleic Acids ; 35(1): 102127, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38352860

RESUMO

RNA editing plays an extensive role in the initiation and progression of cancer. However, the overall profile and molecular functions of RNA editing in different ovarian cancer subtypes have not been fully characterized and elucidated. Here, we conducted a study on RNA editing in four cohorts of ovarian cancer subtypes through large-scale parallel reporting and bioinformatics analysis. Our findings revealed that RNA editing patterns exhibit subtype-specific characteristics within cancer subtypes. The expression pattern of ADAR and the number of differential editing sites varied under different conditions. CCOC and EOC exhibited significant editing deficiency, whereas HGSC and MOC displayed significant editing excess. The sites within the turquoise module of the coedited network also revealed their correlation with ovarian cancer. In addition, we identified an average of over 40,000 cis-edQTLs in the four subtypes. Finally, we explored the association between RNA editing and drug response, uncovering several potentially effective editing-drug pairs (EDP) and suggesting the conceivable utility of RNA editing sites as therapeutic targets for cancer treatment. Overall, our comprehensive study has identified and characterized RNA editing events in various subtypes of ovarian cancer, providing a new perspective for ovarian cancer research and facilitating the development of medical interventions and treatments.

3.
Front Oncol ; 14: 1353818, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38384813

RESUMO

Background: Atypical chronic myeloid leukemia (aCML) is a BCR::ABL1 negative myelodysplastic/myeloproliferative neoplasm with poor overall survival. Some patients can be treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) from suitable donors. The effectiveness of decitabine or azacitidine (AZA) has recently been reported; however, their combined efficacy with selinexor has not yet been reported. Case description: In this study, we report the case of a patient with aCML who was successfully treated with selinexor combined with AZA. A 67-year-old man with a history of gastric mucosa-associated lymphoid tissue (MALT) lymphoma was admitted to the hospital with fatigue and emaciation. He was diagnosed with aCML and no longer responded to decitabine treatment after undergoing seven cycles. The patient was subsequently administered hydroxyurea (HU), selinexor, and AZA. After four courses of combination therapy, his blood cell counts improved; he no longer required transfusions and was able to discontinue HU. The patient continued receiving selinexor and AZA without severe complications. This case is the first to show that combinatorial selinexor and AZA therapy can effectively treat aCML. Conclusion: Our case sheds light on the importance of selinexor and AZA combined therapy in the exploration of new treatment strategies for aCML. Moreover, this treatment approach offers the possibility of bridging with allo-HSCT.

5.
J Thromb Haemost ; 22(4): 1202-1214, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38184203

RESUMO

BACKGROUND: The E3 ubiquitin ligase casitas B-lineage lymphoma-b (CBLB) is a newly identified component of the ubiquitin-dependent protein degradation system and is considered an important negative regulator of immune cells. CBLB is essential for establishing a threshold of T-cell activation and regulating peripheral T-cell tolerance through various mechanisms. However, the involvement of CBLB in the pathogenesis of immune thrombocytopenia (ITP) is unknown. OBJECTIVES: We aimed to investigate the expression and role of CBLB in CD4+ T cells obtained from patients with ITP through quantitative proteomics analyses. METHODS: CD4+ T cells were transfected with adenoviral vectors overexpressing CBLB to clarify the effect of CBLB on anergic induction of T cells in patients with ITP. DNA methylation levels of the CBLB promoter and 5' untranslated region (UTR) in patient-derived CD4+ T cells were detected via MassARRAY EpiTYPER assay (Agena Bioscience). RESULTS: CD4+ T cells from patients with ITP showed resistance to anergic induction, highly activated phosphoinositide 3-kinase-protein kinase B (AKT) signaling, decreased CBLB expression, and 5' UTR hypermethylation of CBLB. CBLB overexpression in T cells effectively attenuated the elevated phosphorylated protein kinase B level and resistance to anergy. Low-dose decitabine treatment led to significantly elevated levels of CBLB expression in CD4+ T cells from 7 patients showing a partial or complete response. CONCLUSION: These results indicate that the 5' UTR hypermethylation of CBLB in CD4+ T cells induces resistance to T-cell anergy in ITP. Thus, the upregulation of CBLB expression by low-dose decitabine treatment may represent a potential therapeutic approach to ITP.


Assuntos
Linfoma , Púrpura Trombocitopênica Idiopática , Humanos , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/genética , Regiões 5' não Traduzidas , Decitabina , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Proto-Oncogênicas c-cbl/genética , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Linfoma/genética
6.
J Proteome Res ; 23(1): 175-184, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37909265

RESUMO

Understanding the pathogenesis and finding diagnostic markers for colorectal cancer (CRC) are the key to its diagnosis and treatment. Integrated transcriptomics and proteomics analysis can be used to characterize alterations of molecular phenotypes and reveal the hidden pathogenesis of CRC. This study employed a novel strategy integrating transcriptomics and proteomics to identify pathological molecular pathways and diagnostic biomarkers of CRC. First, differentially expressed proteins and coexpressed genes generated from weighted gene coexpression network analysis (WGCNA) were intersected to obtain key genes of the CRC phenotype. In total, 63 key genes were identified, and pathway enrichment analysis showed that the process of coagulation and peptidase regulator activity could both play important roles in the development of CRC. Second, protein-protein interaction analysis was then conducted on these key genes to find the central genes involved in the metabolic pathways underpinning CRC. Finally, Itih3 and Lrg1 were further screened out as diagnostic biomarkers of CRC by applying statistical analysis on central genes combining transcriptomics and proteomics data. The deep involvement of central genes in tumorigenesis demonstrates the accuracy and reliability of this novel transcriptomics-proteomics integration strategy in biomarker discovery. The identified candidate biomarkers and enriched metabolic pathways provide insights for CRC diagnosis and treatment.


Assuntos
Neoplasias Colorretais , Proteômica , Humanos , Reprodutibilidade dos Testes , Biomarcadores Tumorais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Perfilação da Expressão Gênica , Fenótipo , Regulação Neoplásica da Expressão Gênica
7.
Int J Biol Macromol ; 259(Pt 1): 128788, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38154706

RESUMO

Polyurethane (PU) and poly(l-lactide) (PLLA) have attracted increasing attention in the development of shape memory polymers (SMPs) due to their good biocompatibility and degradability. Although Pluronic P123 can be used to tune polymeric surface hydrophilicity, its effect on SM performance is a mystery. In this study, a soluble cross-linked PU is synthesized as the switching phase and combined with PLLA and P123 to construct a hydrothermally responsive SM composite. The water contact angle of PU/PLLA/P123 decreases from 22.7° to 5.1° within 2 min. PU and P123 form the switching group, which enhances the SM behavior of the composite. The shape fixity (Rf) and shape recovery (Rr) of PU/PLLA/P123 are 94.4 % and 98 % in 55 °C water, respectively, and the shape recovery time is only 10 s. P123 plays the role of "turbine" in the SM process. PU/PLLA/P123 exhibits a balance between stiffness and elasticity, and good degradability. Furthermore, PU/PLLA/P123 is also biocompatible and beneficial to cell proliferation and growth. Therefore, it offers an alternative approach to developing hydrothermally responsive SM biocomposites based on P123, PU and PLLA for biomedical applications.


Assuntos
Poloxaleno , Poliuretanos , Poliésteres , Água , Materiais Biocompatíveis
8.
Langmuir ; 39(41): 14811-14821, 2023 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-37791913

RESUMO

The self-healable polymers that can repair physical damage autonomously to extend their lifetime and reduce maintenance costs are promising intelligent materials. However, utilizing shape memory to facilitate self-repair is unusual at present. In this work, a series of poly(acrylic acid)-polytetrahydrofuran-poly(acrylic acid) polymers (PAA-PTMG-PAA, diPAA-PTMG) are synthesized as a switching phase and healing accelerator to blend into poly(vinyl alcohol) (PVA). The water swelling rate of the blend is up to 400.0% at 1/1 molecular weight ratio of PTMG/PAA and 20.0 wt % blend ratio of diPAA-PTMG to PVA, and its crystallization is changed significantly under wet conditions. The blend membrane exhibits not only a good hydrothermal-response shape memory effect but also a favorable self-healing behavior. The tensile strength and elongation at break are 12.4 MPa and 320.0% after healing at 25 °C, respectively. In particular, the wound membrane can achieve a better self-healing effect with the assistance of shape memory at 37 °C, and the elongation at the break increased to 515.9% after healing. The membrane is not cytotoxic, so it will be a promising biomedical material.

9.
Comput Biol Med ; 166: 107546, 2023 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-37826952

RESUMO

Cervical cancer, the second most common female malignant tumor, seriously threatens women's health and lives. Despite the availability of the HPV vaccine, effective treatment options for cervical cancer are still lacking. New research perspectives now clarify that RNA editing dysregulation and changes in circRNA expression are jointly involved in disease pathogenesis, so molecular changes associated with circRNA and RNA editing may provide clues for the development of new therapeutic strategies for cervical cancer. In this study, we designed a series of pipelines to identify and analyze dysregulated RNA editing events in circRNAs. Our findings indicate a decrease in A-to-I RNA editing levels in cervical cancer compared to normal tissues, and editing may influence the back-splicing process of circRNAs through structural modifications of Alu elements. Moreover, our research reveals that RNA editing could modulate circRNA biogenesis by influencing RNA binding protein (RBP) binding on a transcriptome-wide scale, as well as influence the expression and coding potential of circRNAs. Importantly, we identified three RNA editing sites that could serve as potential biomarkers. In summary, our study presents a comprehensive landscape of RNA editing perturbations in circRNAs, providing new insights into the complex relationship between RNA editing and circRNA dysregulation in cervical cancer.

10.
JMIR Res Protoc ; 12: e48247, 2023 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-37728978

RESUMO

BACKGROUND: Commonly used noninvasive serological indicators serve as a step before endoscope diagnosis and help identify the high-risk gastric cancer (GC) population. However, they are associated with high false positives and high false negatives. Alternative noninvasive approaches, such as cancer-related features in cell-free DNA (cfDNA) fragments, have been gradually identified and play essential roles in early cancer detection. The integrated analysis of multiple cfDNA features has enhanced detection sensitivity compared to individual features. OBJECTIVE: This study aimed to develop and validate an assay based on assessing genomic-scale methylation and fragmentation profiles of plasma cfDNA for early cancer detection, thereby facilitating the early diagnosis of GC. The primary objective is to evaluate the overall specificity and sensitivity of the assay in predicting GC within the entire cohort, and subsequently within each clinical stage of GC. The secondary objective involved investigating the specificity and sensitivity of the assay in combination with possible serological indicators. METHODS: This is an observational case-control study. Blood samples will be prospectively collected before gastroscopy from 180 patients with GC and 180 nonmalignant control subjects (healthy or with benign gastric diseases). Cases and controls will be randomly divided into a training and a testing data set at a ratio of 2:1. Plasma cfDNA will be isolated and extracted, followed by bisulfite-free low-depth whole methylome sequencing. A multidimensional model named Thorough Epigenetic Marker Integration Solution (THEMIS) will be constructed in the training data set. The model includes features such as the methylated fragment ratio, chromosomal aneuploidy of featured fragments, fragment size index, and fragment end motif. The performance of the model in distinguishing between patients with cancer and noncancer controls will then be evaluated in the testing data set. Furthermore, GC-related biomarkers, such as pepsinogen, gastrin-17, and Helicobacter pylori, will be measured for each patient, and their predictive accuracy will be assessed both independently and in combination with the THEMIS model. RESULTS: Recruitment began in November 2022 and will be ended in April 2024. As of August 2022,250 patients have been enrolled. The final data analysis is anticipated to be completed by September 2024. CONCLUSIONS: This is the first registered case-control study designed to investigate a stacked ensemble model integrating several cfDNA features generated from a bisulfite-free whole methylome sequencing assay. These features include methylation patterns, fragmentation profiles, and chromosomal copy number changes, with the aim of identifying the GC population. This study will determine whether multidimensional analysis of cfDNA will prove to be an effective strategy for distinguishing patients with GC from nonmalignant individuals within the Chinese population. We anticipate the THEMIS model will complement the standard-of-care screening and aid in identifying high-risk patients for further diagnosis. TRIAL REGISTRATION: ClinicalTrial.gov NCT05668910; https://www.clinicaltrials.gov/study/NCT05668910. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48247.

11.
Colloids Surf B Biointerfaces ; 230: 113510, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37574614

RESUMO

Many tissue engineering constructs have been investigated for repairing the calcified cartilage layer in the recent years, but engineering a consistent and stable interface to facilitate a graft-to-bone fixation remains a concern. In the work, hydroxyapatite (HA) is modified by diisocyanate (HDI) and integrated with polyvinyl alcohol (PVA) to prepare the hydrogel. The IR shows that HDI is grafted onto HA and helps HA to cross-link in situ in the PVA gel network. When the mass ratio of HA/PVA is 3.5 wt%, the swelling rate in the PBS of different pH reduced with time prolong, and the hydrogel takes on good swelling resistance. The tensile strength and toughness are 1890 KPa and 264 KJ/m-3, respectively, while the compression strength reaches 1125 KPa at compressive strain of 60%. The hydrogel not only is well durable via continuous 100 rounds of compression-recovery, but also has excellent bioactivity. The work will provide a platform for developing multifunctional soft tissue scaffold.


Assuntos
Materiais Biocompatíveis , Durapatita , Materiais Biocompatíveis/farmacologia , Hidrogéis , Álcool de Polivinil , Biônica , Cartilagem
12.
Plant Sci ; 336: 111850, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37648117

RESUMO

Theanine is a unique secondary metabolite in tea plants and contributes to the umami taste and health benefits of tea. However, theanine biosynthesis in tea plants is not fully understood, and its mechanism of transcriptional regulation remains poorly reported. Theanine content was significantly correlated with the expression of theanine biosynthesis-related gene CsGS1c and transcription factor CsMYB42 in different leaf positions and picking times, but there was no significant correlation in different tissues of albino tea plant 'Anjibaicha'. This suggests that CsMYB42 may regulate CsGS1c to synthesize theanine in albino tea leaves, and the regulation is tissue specific. CsMYB42 is a nuclear-localized R2R3-MYB transcription factor gene with transcriptional activation activity. Yeast one-hybrid assay and electrophoretic mobility shift assay confirmed the direct binding of CsMYB42 to the promoter of CsGS1c. Luciferase assay showed that CsMYB42 activates the CsGS1c expression. Furthermore, the inhibition of CsMYB42 using an antisense oligonucleotide in tea leaves decreased CsGS1c expression and theanine content. These results indicate that CsMYB42 plays a crucial role in activating the expression of CsGS1c and may be involved in the biosynthesis of theanine in albino tea leaves. This study provides fresh insights into the tissue-specific regulation of theanine biosynthesis, which laid a foundation for breeding high-theanine tea plants.

13.
Int J Biol Macromol ; 253(Pt 1): 126567, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-37643671

RESUMO

Organic-inorganic composites as an efficient strategy to upgrade the structural and functional properties of synthetic polymers are attracting extensive attentions. However, there are few studies on the shape memory (SM) behavior of organic-inorganic composites. In the work, poly(ε-caprolactone) hybridized TiO2 nanomaterial (PCL-TiO2) is made as the switching phase and integrated into poly (l-lactide) (PLLA) to construct an SM composite. PCL-TiO2/PLLA shows "sea-island" structure and better interfacial adhesion than PCL/PLLA, which facilitates the transmission of elastic power between the switching phase and the fixing phase. PCL-TiO2 as switching phase exhibits lower enthalpy at 57 °C than PCL, and PCL-TiO2 also acts as "heat dispersion pump station", which builds a dynamically responsive system and initiates shape change. The shape fixing and recovery ratio of PCL-TiO2/PLLA are 93.9 % and 94.4 %, respectively, and go back to the original shape within 15 s at 57 °C. At the same time, PCL-TiO2 endows SMP with good antibacterial properties. Then this work provides a well-placed way for developing SM materials with structure-function integration.


Assuntos
Antibacterianos , Poliésteres , Poliésteres/química , Antibacterianos/química
14.
BMC Infect Dis ; 23(1): 559, 2023 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-37641023

RESUMO

BACKGROUND: Intestinal tuberculosis is a chronic and specific infection caused by Mycobacterium tuberculosis invading the intestine. Due to the nonspecific clinical presentation, it is stressed that intestinal perforation complicates umbilical intestinal fistula and bladder ileal fistula is very rare and extremely difficult to be diagnosed. It is significant to identify the disease and take urgent intervene in the early stage. CASE PRESENTATION: An 18-month-old boy patient presented with abdominal pain. Abdominal CT suggested abscess formation in the right lower abdomen and pelvis. The patient underwent resection of necrotic and stenotic intestinal segments with the creation of an ileostomy, cystostomy and vesicoureteral fistula repair for the presence of intestinal perforation complicated by vesicoureteral fistula and umbilical enterocutaneous fistula. Histopathology confirmed the intestinal tuberculosis. The patient was discharged successfully after 11 days post anti-tuberculosis treatment. CONCLUSION: Our case report here is a rare case of umbilical intestinal fistula with bladder ileal fistula secondary to intestinal perforation from intestinal tuberculosis. The purpose of this report is to make the surgical community aware of atypical presentations of intestinal tuberculosis. If our peers encounter the similar situation, they can be prepared for corresponding diagnosis and treatment.


Assuntos
Enterite , Fístula Intestinal , Perfuração Intestinal , Peritonite Tuberculosa , Tuberculose Gastrointestinal , Tuberculose dos Linfonodos , Masculino , Humanos , Lactente , Bexiga Urinária , Perfuração Intestinal/diagnóstico , Perfuração Intestinal/etiologia , Perfuração Intestinal/cirurgia , Fístula Intestinal/complicações , Fístula Intestinal/diagnóstico , Fístula Intestinal/cirurgia , Intestinos , Tuberculose Gastrointestinal/complicações , Tuberculose Gastrointestinal/diagnóstico , Tuberculose Gastrointestinal/cirurgia
15.
Comput Biol Med ; 164: 107243, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37453378

RESUMO

Long non-coding RNAs (LncRNAs) are non-protein coding transcripts more than 200 nucleotides in length. Deep sequencing technologies have unveiled lncRNAs can harbor translatable short open reading frames (sORFs). Yet the regulatory mechanisms governing lncRNA translation events remain poorly understood. Here, we exhaustively detected the sequence, functional element, and structure features relevant to lncRNA translation in human. Extensive identification and analysis reveal that translatable lncRNAs contain richer protein-coding related sequence features, cap-dependent and cap-independent translation initiation mechanisms, and more stable secondary structures, as compared to untranslatable lncRNAs. These findings strongly support lncRNAs serve as a repository for the production of new small peptides. Based on the feature fusion affecting translation and the extreme gradient boosting (XGBoost) algorithm, we developed the first computational tool that dedicated for predicting translatable lncRNAs, named TransLncPred. Benchmark experimental results show that our method outperforms several state-of-the-art RNA coding potential prediction tools on the same training and testing datasets. The 100-time 10-fold cross-validation tests also demonstrate that regulatory element-derived features, especially N7-methylguanosine (m7G) and internal ribosome entry site (IRES), contribute to the improvement in predictive performance.


Assuntos
RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Algoritmos , Fases de Leitura Aberta
16.
Yi Chuan ; 45(6): 472-487, 2023 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-37340962

RESUMO

In recent years, the rate of female infertility in China has been increasing, posing an urgent challenge to improve fertility. A healthy reproductive system is essential for successful reproduction, and N6-methyladenosine (m6A) is the most abundant chemical modification in eukaryotes and plays a critical role in cellular processes. Recent studies have shown that m6A modifications also have a keying effect in various physiological and pathological processes in the female reproductive system, although their regulatory mechanisms and biological functions remain unclear. In this review, we first introduce the reversible regulatory mechanisms of m6A and its functions, discuss the role of m6A in female reproductive function and disorders of the reproductive system, and present recent advances in m6A detection technologies and methods. Our review provides new insights into the biological role of m6A and its potential application in the treatment of female reproductive disorders.


Assuntos
Adenosina , Eucariotos , Feminino , Humanos , China , Genitália Feminina
17.
Front Immunol ; 14: 1151755, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37234148

RESUMO

A high tumor mutation burden (TMB) is known to drive the response to immune checkpoint inhibitors (ICI) and is associated with favorable prognoses. However, because it is a one-dimensional numerical representation of non-synonymous genetic alterations, TMB suffers from clinical challenges due to its equal quantification. Since not all mutations elicit the same antitumor rejection, the effect on immunity of neoantigens encoded by different types or locations of somatic mutations may vary. In addition, other typical genomic features, including complex structural variants, are not captured by the conventional TMB metric. Given the diversity of cancer subtypes and the complexity of treatment regimens, this paper proposes that tumor mutations capable of causing various degrees of immunogenicity should be calculated separately. TMB should therefore, be segmented into more exact, higher dimensional feature vectors to exhaustively measure the foreignness of tumors. We systematically reviewed patients' multifaceted efficacy based on a refined TMB metric, investigated the association between multidimensional mutations and integrative immunotherapy outcomes, and developed a convergent categorical decision-making framework, TMBserval (Statistical Explainable machine learning with Regression-based VALidation). TMBserval integrates a multiple-instance learning concept with statistics to create a statistically interpretable model that addresses the broad interdependencies between multidimensional mutation burdens and decision endpoints. TMBserval is a pan-cancer-oriented many-to-many nonlinear regression model with discrimination and calibration power. Simulations and experimental analyses using data from 137 actual patients both demonstrated that our method could discriminate between patient groups in a high-dimensional feature space, thereby rationally expanding the beneficiary population of immunotherapy.


Assuntos
Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/patologia , Biomarcadores Tumorais/genética , Prognóstico , Imunoterapia/métodos , Mutação
18.
Cancer ; 129(15): 2422-2430, 2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37096747

RESUMO

BACKGROUND: DNA-based next-generation sequencing has been widely used in the selection of target therapies for patients with nonsmall cell lung cancer (NSCLC). RNA-based next-generation sequencing has been proven to be valuable in detecting fusion and exon-skipping mutations and is recommended by National Comprehensive Cancer Network guidelines for these mutation types. METHODS: The authors developed an RNA-based hybridization panel targeting actionable driver oncogenes in solid tumors. Experimental and bioinformatics pipelines were optimized for the detection of fusions, single-nucleotide variants (SNVs), and insertion/deletion (indels). In total, 1253 formalin-fixed, paraffin-embedded samples from patients with NSCLC were analyzed by DNA and RNA panel sequencing in parallel to assess the performance of the RNA panel in detecting multiple types of mutations. RESULTS: In analytical validation, the RNA panel achieved a limit of detection of 1.45-3.15 copies per nanogram for SNVs and 0.21-6.48 copies per nanogram for fusions. In 1253 formalin-fixed, paraffin-embedded NSCLC samples, the RNA panel identified a total of 124 fusion events and 26 MET exon 14-skipping events, in which 14 fusions and six MET exon 14-skipping mutations were missed by DNA panel sequencing. By using the DNA panel as the reference, the positive percent agreement and the positive predictive value of the RNA panel were 98.08% and 98.62%, respectively, for detecting targetable SNVs and 98.15% and 99.38%, respectively, for detecting targetable indels. CONCLUSIONS: Parallel DNA and RNA sequencing analyses demonstrated the accuracy and robustness of the RNA sequencing panel in detecting multiple types of clinically actionable mutations. The simplified experimental workflow and low sample consumption will make RNA panel sequencing a potentially effective method in clinical testing.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Neoplasias Pulmonares/genética , Mutação , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de RNA , Formaldeído
19.
Langmuir ; 39(17): 6151-6159, 2023 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-37076449

RESUMO

Human-machine interactions, medical monitoring, and flexible robots stimulate interest in hydrogel sensing devices. However, developing hydrogel sensors with multifunctions such as good mechanics, electroconductivity, resistance to solvent volatility as well as freezing, self-adhesion, and independence on external power supply remains a challenge. In the work, a poly(acrylic acid-N-isopropylacrylamide) P(AA-NIPAm) organic hydrogel loading LiCl is prepared by ultraviolet cross-linking in ethylene glycol/H2O. The organic hydrogel exhibits favorable mechanical properties such as an elongation of break at 700% and a breaking strength of 20 KPa, can adhere to various substrates, and resists frost and solvent volatility. Especially, it possesses an excellent conductivity of 8.51 S/m. The organic hydrogel shows wide strain sensitivity based on resistance change, and the gauge factor reaches 5.84 in the range of 300-700%. It has short responsive and recuperative time and is still stable within 1000 rounds. Moreover, the organic hydrogel is also assembled into a self-powered device in which the open-circuit voltage is 0.74 V. The device can transform external stimuli such as stretching or compressing into the output current change, so it detects human motion effectively in real time. The work provides a perspective for electrical sensing engineering.

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