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Neovaginas are surgically constructed to correct uterovaginal agenesis in women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome or as part of gender-affirming surgery for transfeminine individuals. Understanding the assembly of the neovaginal microbiota is crucial for guiding its management. To address this, we conducted a longitudinal study on MRKH patients following laparoscopic peritoneal vaginoplasty. Our findings reveal that the early microbial assemblage exhibited stochastic characteristics, accompanied with a notable bloom of Enterococcus faecalis and genital Mycoplasmas. While both the pre-surgery dimple microbiota and the fecal microbiota constituted the primary species pool, the neovaginal microbiota developed into a microbiota that resembled that of a normal vagina at 6-12 months post-surgery, albeit with a bacterial vaginosis (BV)-like structure. By 2-4 years post-surgery, the neovaginal microbiota had further evolved into a structure closely resembling with the homeostatic pre-surgery dimple microbiota. This concords with the development of the squamous epithelium in the neovagina and highlights the pivotal roles of progressive selective forces imposed by the evolving neovaginal environment and the colonization tropism of vaginal species. Notably, we observed that strains of Lactobacillus crispatus colonizing the neovagina primarily originated from the dimple. Since L. crispatus is generally associated with vaginal health, this finding suggests potential avenues for future research to promote its colonization.
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Trastornos del Desarrollo Sexual 46, XX , Anomalías Congénitas , Microbiota , Conductos Paramesonéfricos , Vagina , Vagina/microbiología , Humanos , Femenino , Trastornos del Desarrollo Sexual 46, XX/microbiología , Trastornos del Desarrollo Sexual 46, XX/cirugía , Conductos Paramesonéfricos/anomalías , Adulto , Anomalías Congénitas/microbiología , Estudios Longitudinales , Adulto Joven , Vaginosis Bacteriana/microbiología , Adolescente , Útero/microbiología , Heces/microbiología , Enterococcus faecalis/aislamiento & purificación , LaparoscopíaRESUMEN
This study aimed to identify possible pathogenic genes in a 90-member family with a rare combination of multiple neurodegenerative disease phenotypes, which has not been depicted by the known neurodegenerative disease. We performed physical and neurological examinations with International Rating Scales to assess signs of ataxia, Parkinsonism, and cognitive function, as well as brain magnetic resonance imaging scans with seven sequences. We searched for co-segregations of abnormal repeat-expansion loci, pathogenic variants in known spinocerebellar ataxia-related genes, and novel rare mutations via whole-genome sequencing and linkage analysis. A rare co-segregating missense mutation in the CARS gene was validated by Sanger sequencing and the aminoacylation activity of mutant CARS was measured by spectrophotometric assay. This pedigree presented novel late-onset core characteristics including cerebellar ataxia, Parkinsonism, and pyramidal signs in all nine affected members. Brain magnetic resonance imaging showed cerebellar/pons atrophy, pontine-midline linear hyperintensity, decreased rCBF in the bilateral basal ganglia and cerebellar dentate nucleus, and hypo-intensities of the cerebellar dentate nuclei, basal ganglia, mesencephalic red nuclei, and substantia nigra, all of which suggested neurodegeneration. Whole-genome sequencing identified a novel pathogenic heterozygous mutation (E795V) in the CARS gene, meanwhile, exhibited none of the known repeat-expansions or point mutations in pathogenic genes. Remarkably, this CARS mutation causes a 20% decrease in aminoacylation activity to charge tRNACys with L-cysteine in protein synthesis compared with that of the wild type. All family members carrying a heterozygous mutation CARS (E795V) had the same clinical manifestations and neuropathological changes of Parkinsonism and spinocerebellar-ataxia. These findings identify novel pathogenesis of Parkinsonism-spinocerebellar ataxia and provide insights into its genetic architecture.
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The incidence of young-onset colorectal cancer (yCRC) has been increasing in recent decades, but little is known about the gut microbiome of these patients. Most studies have focused on old-onset CRC (oCRC), and it remains unclear whether CRC signatures derived from old patients are valid in young patients. To address this, we assembled the largest yCRC gut metagenomes to date from two independent cohorts and found that the CRC microbiome had limited association with age across adulthood. Differential analysis revealed that well-known CRC-associated taxa, such as Clostridium symbiosum, Peptostreptococcus stomatis, Parvimonas micra and Hungatella hathewayi were significantly enriched (false discovery rate <0.05) in both old- and young-onset patients. Similar strain-level patterns of Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli were observed for oCRC and yCRC. Almost all oCRC-associated metagenomic pathways had directionally concordant changes in young patients. Importantly, CRC-associated virulence factors (fadA, bft) were enriched in both oCRC and yCRC compared to their respective controls. Moreover, the microbiome-based classification model had similar predication accuracy for CRC status in old- and young-onset patients, underscoring the consistency of microbial signatures across different age groups.
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Edad de Inicio , Neoplasias Colorrectales , Microbioma Gastrointestinal , Humanos , Neoplasias Colorrectales/microbiología , Adulto , Masculino , Femenino , Persona de Mediana Edad , Anciano , Metagenoma , Metagenómica/métodos , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , Adulto Joven , Heces/microbiología , Estudios de CohortesRESUMEN
The nasal cavity harbors diverse microbiota that contributes to human health and respiratory diseases. However, whether and to what extent the host genome shapes the nasal microbiome remains largely unknown. Here, by dissecting the human genome and nasal metagenome data from 1401 healthy individuals, we demonstrated that the top three host genetic principal components strongly correlated with the nasal microbiota diversity and composition. The genetic association analyses identified 63 genome-wide significant loci affecting the nasal microbial taxa and functions, of which 2 loci reached study-wide significance (p < 1.7 × 10-10): rs73268759 within CAMK2A associated with genus Actinomyces and family Actinomycetaceae; and rs35211877 near POM121L12 with Gemella asaccharolytica. In addition to respiratory-related diseases, the associated loci are mainly implicated in cardiometabolic or neuropsychiatric diseases. Functional analysis showed the associated genes were most significantly expressed in the nasal airway epithelium tissue and enriched in the calcium signaling and hippo signaling pathway. Further observational correlation and Mendelian randomization analyses consistently suggested the causal effects of Serratia grimesii and Yokenella regensburgei on cardiometabolic biomarkers (cystine, glutamic acid, and creatine). This study suggested that the host genome plays an important role in shaping the nasal microbiome.
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Enfermedades Cardiovasculares , Microbiota , Humanos , Estudio de Asociación del Genoma Completo , Nariz , Microbiota/genética , Variación GenéticaRESUMEN
Analyses of inequalities related to prevention and cancer therapeutics/care show disparities between countries with different economic standing, and within countries with high Gross Domestic Product. The development of basic technological and biological research provides clinical and prevention opportunities that make their implementation into healthcare systems more complex, mainly due to the growth of Personalized/Precision Cancer Medicine (PCM). Initiatives like the USA-Cancer Moonshot and the EU-Mission on Cancer and Europe's Beating Cancer Plan are initiated to boost cancer prevention and therapeutics/care innovation and to mitigate present inequalities. The conference organized by the Pontifical Academy of Sciences in collaboration with the European Academy of Cancer Sciences discussed the inequality problem, dependent on the economic status of a country, the increasing demands for infrastructure supportive of innovative research and its implementation in healthcare and prevention programs. Establishing translational research defined as a coherent cancer research continuum is still a challenge. Research has to cover the entire continuum from basic to outcomes research for clinical and prevention modalities. Comprehensive Cancer Centres (CCCs) are of critical importance for integrating research innovations to preclinical and clinical research, as for ensuring state-of-the-art patient care within healthcare systems. International collaborative networks between CCCs are necessary to reach the critical mass of infrastructures and patients for PCM research, and for introducing prevention modalities and new treatments effectively. Outcomes and health economics research are required to assess the cost-effectiveness of new interventions, currently a missing element in the research portfolio. Data sharing and critical mass are essential for innovative research to develop PCM. Despite advances in cancer research, cancer incidence and prevalence is growing. Making cancer research infrastructures accessible for all patients, considering the increasing inequalities, requires science policy actions incentivizing research aimed at prevention and cancer therapeutics/care with an increased focus on patients' needs and cost-effective healthcare.
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Neoplasias , Humanos , Ciudad del Vaticano , Neoplasias/prevención & control , Investigación Biomédica Traslacional , Atención a la Salud , Medicina de PrecisiónRESUMEN
Aneuploidy compromises genomic stability, often leading to embryo inviability, and is frequently associated with tumorigenesis and aging. Different aneuploid chromosome stoichiometries lead to distinct transcriptomic and phenotypic changes, making it helpful to study aneuploidy in tightly controlled genetic backgrounds. By deploying the engineered SCRaMbLE (synthetic chromosome rearrangement and modification by loxP-mediated evolution) system to the newly synthesized megabase Sc2.0 chromosome VII (synVII), we constructed a synthetic disomic yeast and screened hundreds of SCRaMbLEd derivatives with diverse chromosomal rearrangements. Phenotypic characterization and multi-omics analysis revealed that fitness defects associated with aneuploidy could be restored by (1) removing most of the chromosome content or (2) modifying specific regions in the duplicated chromosome. These findings indicate that both chromosome copy number and specific chromosomal regions contribute to the aneuploidy-related phenotypes, and the synthetic chromosome resource opens new paradigms in studying aneuploidy.
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Dissecting and understanding the cancer ecosystem, especially that around the tumor margins, which have strong implications for tumor cell infiltration and invasion, are essential for exploring the mechanisms of tumor metastasis and developing effective new treatments. Using a novel tumor border scanning and digitization model enabled by nanoscale resolution-SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we identified a 500 µm-wide zone centered around the tumor border in patients with liver cancer, referred to as "the invasive zone". We detected strong immunosuppression, metabolic reprogramming, and severely damaged hepatocytes in this zone. We also identified a subpopulation of damaged hepatocytes with increased expression of serum amyloid A1 and A2 (referred to collectively as SAAs) located close to the border on the paratumor side. Overexpression of CXCL6 in adjacent malignant cells could induce activation of the JAK-STAT3 pathway in nearby hepatocytes, which subsequently caused SAAs' overexpression in these hepatocytes. Furthermore, overexpression and secretion of SAAs by hepatocytes in the invasive zone could lead to the recruitment of macrophages and M2 polarization, further promoting local immunosuppression, potentially resulting in tumor progression. Clinical association analysis in additional five independent cohorts of patients with primary and secondary liver cancer (n = 423) showed that patients with overexpression of SAAs in the invasive zone had a worse prognosis. Further in vivo experiments using mouse liver tumor models in situ confirmed that the knockdown of genes encoding SAAs in hepatocytes decreased macrophage accumulation around the tumor border and delayed tumor growth. The identification and characterization of a novel invasive zone in human cancer patients not only add an important layer of understanding regarding the mechanisms of tumor invasion and metastasis, but may also pave the way for developing novel therapeutic strategies for advanced liver cancer and other solid tumors.
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Ecosistema , Neoplasias Hepáticas , Ratones , Animales , Humanos , Neoplasias Hepáticas/patología , Hepatocitos/metabolismo , Terapia de Inmunosupresión , Línea Celular TumoralRESUMEN
Coronavirus 2019 (COVID-19) is a complex disease that affects billions of people worldwide. Currently, effective etiological treatment of COVID-19 is still lacking; COVID-19 also causes damages to various organs that affects therapeutics and mortality of the patients. Surveillance of the treatment responses and organ injury assessment of COVID-19 patients are of high clinical value. In this study, we investigated the characteristic fragmentation patterns and explored the potential in tissue injury assessment of plasma cell-free DNA in COVID-19 patients. Through recruitment of 37 COVID-19 patients, 32 controls and analysis of 208 blood samples upon diagnosis and during treatment, we report gross abnormalities in cfDNA of COVID-19 patients, including elevated GC content, altered molecule size and end motif patterns. More importantly, such cfDNA fragmentation characteristics reflect patient-specific physiological changes during treatment. Further analysis on cfDNA tissue-of-origin tracing reveals frequent tissue injuries in COVID-19 patients, which is supported by clinical diagnoses. Hence, our work demonstrates and extends the translational merit of cfDNA fragmentation pattern as valuable analyte for effective treatment monitoring, as well as tissue injury assessment in COVID-19.
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COVID-19 , Ácidos Nucleicos Libres de Células , Humanos , COVID-19/diagnóstico , Ácidos Nucleicos Libres de Células/genéticaRESUMEN
Although recent studies have revealed the association between the human microbiome especially gut microbiota and longevity, their causality remains unclear. Here, we assess the causal relationships between the human microbiome (gut and oral microbiota) and longevity, by leveraging bidirectional two-sample Mendelian randomization (MR) analyses based on genome-wide association studies (GWAS) summary statistics of the gut and oral microbiome from the 4D-SZ cohort and longevity from the CLHLS cohort. We found that some disease-protected gut microbiota such as Coriobacteriaceae and Oxalobacter as well as the probiotic Lactobacillus amylovorus were related to increased odds of longevity, whereas the other gut microbiota such as colorectal cancer pathogen Fusobacterium nucleatum, Coprococcus, Streptococcus, Lactobacillus, and Neisseria were negatively associated with longevity. The reverse MR analysis further revealed genetically longevous individuals tended to have higher abundances of Prevotella and Paraprevotella but lower abundances of Bacteroides and Fusobacterium species. Few overlaps of gut microbiota-longevity interactions were identified across different populations. We also identified abundant links between the oral microbiome and longevity. The additional analysis suggested that centenarians genetically had a lower gut microbial diversity, but no difference in oral microbiota. Our findings strongly implicate these bacteria to play a role in human longevity and underscore the relocation of commensal microbes among different body sites that would need to be monitored for long and healthy life.
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Longevidad , Microbiota , Anciano de 80 o más Años , Humanos , Longevidad/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Lactobacillus acidophilusRESUMEN
Purpose: The purpose of this study was to describe genotype-phenotype associations and novel insights into genetic characteristics in a trio-based cohort of inherited eye diseases (IEDs). Methods: To determine the etiological role of de novo mutations (DNMs) and genetic profile in IEDs, we retrospectively reviewed a large cohort of proband-parent trios of Chinese origin. The patients underwent a detailed examination and was clinically diagnosed by an ophthalmologist. Panel-based targeted exome sequencing was performed on DNA extracted from blood samples, containing coding regions of 792 IED-causative genes and their flanking exons. All participants underwent genetic testing. Results: All proband-parent trios were divided into 22 subgroups, the overall diagnostic yield was 48.67% (605/1243), ranging from 4% to 94.44% for each of the subgroups. A total of 108 IED-causative genes were identified, with the top 24 genes explaining 67% of the 605 genetically solved trios. The genetic etiology of 6.76% (84/1243) of the trio was attributed to disease-causative DNMs, and the top 3 subgroups with the highest incidence of DNM were aniridia (n = 40%), Marfan syndrome/ectopia lentis (n = 38.78%), and retinoblastoma (n = 37.04%). The top 10 genes have a diagnostic yield of DNM greater than 3.5% in their subgroups, including PAX6 (40.00%), FBN1 (38.78%), RB1 (37.04%), CRX (10.34%), CHM (9.09%), WFS1 (8.00%), RP1L1 (5.88%), RS1 (5.26%), PCDH15 (4.00%), and ABCA4 (3.51%). Additionally, the incidence of DNM in offspring showed a trend of correlation with paternal age at reproduction, but not statistically significant with paternal (P = 0.154) and maternal (P = 0.959) age at reproduction. Conclusions: Trios-based genetic analysis has high accuracy and validity. Our study helps to quantify the burden of the full spectrum IED caused by each gene, offers novel potential for elucidating etiology, and plays a crucial role in genetic counseling and patient management.
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Oftalmopatías , Pruebas Genéticas , Humanos , Virulencia , Estudios Retrospectivos , Mutación , Linaje , Transportadoras de Casetes de Unión a ATP/genética , Proteínas del Ojo/genéticaRESUMEN
Subsequently to the publication of the above article, the authors have realized that a couple of clerical errors were made when writing the article, and wish to correct these errors in a corrigendum statement. First, in the Materials and methods section on p. 2216, the final sentence of the 'Immunohistochemistry and tissue microarray' subsection, the authors wish to add a further definition, so that the text reads as follows (changes highlighted in bold): 'The positive expression of RET was defined as ≥5% staining of a tumor section; high expression was defined as ≥40% staining of a tumor section, and low expression as <40%'. Secondly, in the Results section, 'Mutation frequency of each gene distributed in 4 biological categories' subsection, p. 2220, righthand column, second paragraph, line 17, the sentence written here should have read as follows: 'The group with the positive expression of RET included 28.9% (26/90) of the patients, and 4 of these patients were defined as high expression'. The authors are grateful to the Editor of Oncology Reports for allowing them this opportunity to publish a corrigendum, and apologize to the readership of the journal for any inconvenience caused. [Oncology Reports 37: 22152226, 2017; DOI: 10.3892/or.2017.5494].
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The effective treatment of advanced cervical cancer remains challenging. Herein, single-nucleus RNA sequencing (snRNA-seq) and SpaTial enhanced resolution omics-sequencing (Stereo-seq) are used to investigate the immunological microenvironment of cervical squamous cell carcinoma (CSCC). The expression levels of most immune suppressive genes in the tumor and inflammation areas of CSCC are not significantly higher than those in the non-cancer samples, except for LGALS9 and IDO1. Stronger signals of CD56+ NK cells and immature dendritic cells are found in the hypermetabolic tumor areas, whereas more eosinophils, immature B cells, and Treg cells are found in the hypometabolic tumor areas. Moreover, a cluster of pro-tumorigenic cancer-associated myofibroblasts (myCAFs) are identified. The myCAFs may support the growth and metastasis of tumors by inhibiting lymphocyte infiltration and remodeling of the tumor extracellular matrix. Furthermore, these myCAFs are associated with poorer survival probability in patients with CSCC, predict resistance to immunotherapy, and might be present in a small fraction (< 30%) of patients with advanced cancer. Immunohistochemistry and multiplex immunofluorescence staining are conducted to validate the spatial distribution and potential function of myCAFs. Collectively, these findings enhance the understanding of the immunological microenvironment of CSCC and shed light on the treatment of advanced CSCC.
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Carcinoma de Células Escamosas , Neoplasias de Tejido Conjuntivo , Neoplasias del Cuello Uterino , Femenino , Humanos , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , ARN Nuclear Pequeño , Análisis de Secuencia de ARN , Transcriptoma/genética , Microambiente Tumoral/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: Cell-free messenger RNA (cf-mRNA) and long non-coding RNA (cf-lncRNA) are becoming increasingly important in liquid biopsy by providing biomarkers for disease prediction, diagnosis and prognosis, but the simultaneous characterization of coding and non-coding RNAs in human biofluids remains challenging. METHODS: Here, we developed polyadenylation ligation-mediated sequencing (PALM-Seq), an RNA sequencing strategy employing treatment of RNA with T4 polynucleotide kinase to generate cell-free RNA (cfRNA) fragments with 5' phosphate and 3' hydroxyl and RNase H to deplete abundant RNAs, achieving simultaneous quantification and characterization of cfRNAs. RESULTS: Using PALM-Seq, we successfully identified well-known differentially abundant mRNA, lncRNA and microRNA in the blood plasma of pregnant women. We further characterized cfRNAs in blood plasma, saliva, urine, seminal plasma and amniotic fluid and found that the detected numbers of different RNA biotypes varied with body fluids. The profiles of cf-mRNA reflected the function of originated tissues, and immune cells significantly contributed RNA to blood plasma and saliva. Short fragments (<50 nt) of mRNA and lncRNA were major in biofluids, whereas seminal plasma and amniotic fluid tended to retain long RNA. Body fluids showed distinct preferences of pyrimidine at the 3' end and adenine at the 5' end of cf-mRNA and cf-lncRNA, which were correlated with the proportions of short fragments. CONCLUSION: Together, PALM-Seq enables a simultaneous characterization of cf-mRNA and cf-lncRNA, contributing to elucidating the biology and promoting the application of cfRNAs.
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Ácidos Nucleicos Libres de Células , MicroARNs , ARN Largo no Codificante , Ácidos Nucleicos Libres de Células/genética , Femenino , Humanos , MicroARNs/genética , Poliadenilación/genética , Embarazo , ARN Largo no Codificante/genética , ARN Mensajero/genética , Análisis de Secuencia de ARNRESUMEN
Triploids are rare in nature because of difficulties in meiotic and gametogenic processes, especially in vertebrates. The Carassius complex of cyprinid teleosts contains sexual tetraploid crucian carp/goldfish (C. auratus) and unisexual hexaploid gibel carp/Prussian carp (C. gibelio) lineages, providing a valuable model for studying the evolution and maintenance mechanism of unisexual polyploids in vertebrates. Here we sequence the genomes of the two species and assemble their haplotypes, which contain two subgenomes (A and B), to the chromosome level. Sequencing coverage analysis reveals that C. gibelio is an amphitriploid (AAABBB) with two triploid sets of chromosomes; each set is derived from a different ancestor. Resequencing data from different strains of C. gibelio show that unisexual reproduction has been maintained for over 0.82 million years. Comparative genomics show intensive expansion and alterations of meiotic cell cycle-related genes and an oocyte-specific histone variant. Cytological assays indicate that C. gibelio produces unreduced oocytes by an alternative ameiotic pathway; however, sporadic homologous recombination and a high rate of gene conversion also exist in C. gibelio. These genomic changes might have facilitated purging deleterious mutations and maintaining genome stability in this unisexual amphitriploid fish. Overall, the current results provide novel insights into the evolutionary mechanisms of the reproductive success in unisexual polyploid vertebrates.
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Carpas , Poliploidía , Animales , Genoma , Carpa Dorada/genética , Reproducción/genéticaRESUMEN
Methods for sensitive and high-throughput evaluation of CRISPR RNA-guided nucleases (RGNs) off-targets (OTs) are essential for advancing RGN-based gene therapies. Here we report SURRO-seq for simultaneously evaluating thousands of therapeutic RGN OTs in cells. SURRO-seq captures RGN-induced indels in cells by pooled lentiviral OTs libraries and deep sequencing, an approach comparable and complementary to OTs detection by T7 endonuclease 1, GUIDE-seq, and CIRCLE-seq. Application of SURRO-seq to 8150 OTs from 110 therapeutic RGNs identifies significantly detectable indels in 783 OTs, of which 37 OTs are found in cancer genes and 23 OTs are further validated in five human cell lines by targeted amplicon sequencing. Finally, SURRO-seq reveals that thermodynamically stable wobble base pair (rGâ¢dT) and free binding energy strongly affect RGN specificity. Our study emphasizes the necessity of thoroughly evaluating therapeutic RGN OTs to minimize inevitable off-target effects.
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Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , ARN Guía de Kinetoplastida , Sistemas CRISPR-Cas/genética , Línea Celular , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Endonucleasas/genética , Endonucleasas/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , ARN Guía de Kinetoplastida/genética , Ribonucleasas/metabolismoRESUMEN
Targeted therapy for lung squamous cell carcinoma (LUSC) remains a challenge due to the lack of robust targets. Here, we identified MECOM as a candidate of therapeutic target for LUSC by screening 38 genes that were commonly amplified in three pairs of primary tumors and patient-derived xenografts (PDXs) using a clustered regularly interspaced short palindromic repeats (CRISPR)-mediated approach. High MECOM expression levels were associated with poor prognosis. Forced expression of MECOM in LUSC cell lines promoted cancer stem cell (CSC) properties, and its knockout inhibited CSC phenotypes. Furthermore, systemic delivery of CRISPR-mediated MECOM depletion cassette using adenovirus with an adaptor, which is composed of a single-chain fragment variable (scFv) against epithelial cell adhesion molecules (EpCAM) fused to the ectodomain of coxsackievirus and adenovirus receptor, and a protector, which consists of the scFv connected to the hexon symmetry of the adenovirus, could specifically target subcutaneous and orthotopic LUSC and retard tumor growth. This study could provide a novel therapeutic strategy for LUSC with high efficacy and specificity.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Proteína del Locus del Complejo MDS1 y EV11 , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Línea Celular Tumoral , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/tratamiento farmacológico , Proteína del Locus del Complejo MDS1 y EV11/genética , Células Madre Neoplásicas/metabolismo , Factores de Transcripción/genética , AnimalesRESUMEN
Background: Programmed death 1 (PD-1) and the ligand of PD-1 (PD-L1) are central targets for immune-checkpoint therapy (ICT) blocking immune evasion-related pathways elicited by tumor cells. A number of PD-1 inhibitors have been developed, but the efficacy of these inhibitors varies considerably and is typically below 50%. The efficacy of ICT has been shown to be dependent on the gut microbiota, and experiments using mouse models have even demonstrated that modulation of the gut microbiota may improve efficacy of ICT. Methods: We followed a Han Chinese cohort of 85 advanced non-small cell lung cancer (NSCLC) patients, who received anti-PD-1 antibodies. Tumor biopsies were collected before treatment initiation for whole exon sequencing and variant detection. Fecal samples collected biweekly during the period of anti-PD-1 antibody administration were used for metagenomic sequencing. We established gut microbiome abundance profiles for identification of significant associations between specific microbial taxa, potential functionality, and treatment responses. A prediction model based on random forest was trained using selected markers discriminating between the different response groups. Results: NSCLC patients treated with antibiotics exhibited the shortest survival time. Low level of tumor-mutation burden and high expression level of HLA-E significantly reduced progression-free survival. We identified metagenomic species and functional pathways that differed in abundance in relation to responses to ICT. Data on differential enrichment of taxa and predicted microbial functions in NSCLC patients responding or non-responding to ICT allowed the establishment of random forest algorithm-adopted models robustly predicting the probability of whether or not a given patient would benefit from ICT. Conclusions: Overall, our results identified links between gut microbial composition and immunotherapy efficacy in Chinese NSCLC patients indicating the potential for such analyses to predict outcome prior to ICT.
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Several studies have demonstrated that the T-cell receptor (TCR) repertoire is associated with prognosis and immune therapy response in several types of cancer. However, the comprehensive features of TCR repertoire in tumor-infiltrating and circulating T cells, as well as its clinical significance of diagnosis in hepatocellular carcinoma (HCC) patients, are still unknown. In this study, we perform paired tumor/peritumoral tissues and peripheral blood samples from 58 patients with HCC and sequenced them with high-throughput TCR to comprehensively analyze the characteristics of TCR and the clinical significance of peripheral TCR sequence. By exploring the abundance and diversity of TCR repertoires, we observe that there was a significantly higher TCR diversity in peripheral blood than in tumoral and peritumoral tissues, while tumoral and peritumoral tissues showed similar TCR diversity. A substantial difference in the usage frequencies of several Vß, Jß genes, and TCRß VJ pairings was found among three types of tissues. Moreover, we reveal that HCC patients have a unique profile of TCR repertoire in peripheral blood in contrast to healthy individuals. We further establish an HCC diagnostic model based on TCRß VJ pairing usage in peripheral blood, which yields a best-fit area under the curve (AUC) of 0.9746 ± 0.0481 (sensitivity = 0.9675 ± 0.0603, specificity = 0.9998 ± 0.0007, average of 100 repeats) in the test set. Our study describes the characteristics of tissue infiltration and circulating T-cell bank in patients with HCC and shows the potential of using circulating TCR sequence as a biomarker for the non-invasive diagnosis of patients with HCC.