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The prognosis of primary plasma cell leukemia (pPCL) is poor, and the relevant prognostic factors are incompletely understood. We aimed to explore the prognostic factors and develop a validated prognostic prediction model for pPCL patients in the new era. This multicenter retrospective study was conducted across 16 hospitals in China. Cox proportional hazards regression analysis was used to develop a prediction model. The predictive performance of the model was assessed using multiple metrics. Internal validation was conducted using bootstrap resampling. A total of 102 pPCL patients were included in this study, and 57 (55.9%) were male. The 12-month, 24-month, and 36-month OS rates for pPCL patients were 75.4%, 58.3%, and 47.6%, respectively. An overall survival prognostic nomogram for pPCL patients was established by integrating independent prognostic factors, including age, B2MG, and del17p. The nomogram exhibited good performance, with a C-index of 0.720 (95% CI 0.642-0.797) and an AUC of 0.653. Bootstrap validation yielded a C-index of 0.721 (95% CI 0.629-0.787) and an AUC of 0.653 (95% CI 0.546-0.759), indicating a relatively good fit of the calibration curve. A nomogram incorporating age, B2MG grade, and del17p were developed and validated to accurately and consistently predict the prognosis of pPCL patients.
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In this prospective, multicenter, Phase 2 clinical trial (NCT02987244), patients with peripheral T-cell lymphomas (PTCLs) who had responded to first-line chemotherapy with cyclophosphamide, doxorubicin or epirubicin, vincristine or vindesine, etoposide, and prednisone (Chi-CHOEP) were treated by autologous stem cell transplantation (ASCT) or with chidamide maintenance or observation. A total of 85 patients received one of the following interventions: ASCT (n = 15), chidamide maintenance (n = 44), and observation (n = 26). estimated 3 PFS and OS rates were 85.6%, 80.8%, and 49.4% (P = 0.001). The two-year OS rates were 85.6%, 80.8%, and 69.0% (P = 0.075).The ASCT and chidamide maintenance groups had significantly better progression-free survival (PFS) than the observation group (P = 0.001, and P = 0.01, respectively). The overall survival (OS) differed significantly between the chidamide maintenance group and the observation group ( P = 0.041). The multivariate and propensity score matching analyses for PFS revealed better outcomes in the subjects in the chidamide maintenance than observation groups (P = 0.02). The ASCT and chidamide maintenance groups had significant survival advantages over the observation group. In the post-remission stage of the untreated PTCL patients, single-agent chidamide maintenance demonstrated superior PFS and better OS than observation. Our findings highlight the potential benefit of chidamide in this patient subset, warranting further investigation through larger prospective trials. Clinical trial registration: clinicaltrial.gov, NCT02987244. Registered 8 December 2016, http://www.clinicaltrials.gov/ct2/show/NCT02987244 .
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Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Trasplante de Células Madre Hematopoyéticas , Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/terapia , Linfoma de Células T Periférico/mortalidad , Linfoma de Células T Periférico/tratamiento farmacológico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Aminopiridinas/uso terapéutico , Benzamidas/uso terapéutico , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , China/epidemiología , Trasplante Autólogo , Anciano , Tasa de Supervivencia , Adulto Joven , Quimioterapia de Mantención , Autoinjertos , Inducción de Remisión , AdolescenteRESUMEN
This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus dexamethasone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Total 79 eligible RRMM patients were planned to be included. Patients were treated with generic pomalidomide (4 mg daily on days 1-21, orally) and low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally; 20 mg for patients aged > 75 years) in 28-day cycles until disease progression with a maximum treatment duration of 2 years. The primary endpoint is the overall response rate (ORR) assessed by the independent review committee per the 2016 International Myeloma Working Group guidelines. A total of 85 eligible patients were included in this study from 32 centers in China, with a median age of 62.0 (range, 39-76) years, a median prior line of therapy of 4 (range, 1-16), and 41.2% patients with high-risk cytogenetics. The ORR was 38.8% (95% confidence interval (CI), 28.44-50.01). The disease control rate was 67.1% (95% CI, 56.02-76.87), meanwhile, the median progression-free survival was 5.55 months (95% CI, 3.68-7.52). Among the treatment-related adverse events (TRAEs), infective pneumonia (17.6%) was the most frequent non-hematologic adverse event, while a decrease in neutrophil count (52.9%) was the most common grade ≥ 3 TRAE. The study results indicated that the generic pomalidomide demonstrated consistent efficacy and a safety profile similar to the branded pomalidomide when combined with low-dose dexamethasone in Chinese RRMM patients.Registration number ClinicalTrials.gov NCT05236621, retrospectively registered on February 11, 2022.
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Mieloma Múltiple , Talidomida/análogos & derivados , Humanos , Adulto , Persona de Mediana Edad , Anciano , Mieloma Múltiple/tratamiento farmacológico , Dexametasona , Recurrencia Local de Neoplasia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Marfan syndrome (MFS) is associated with TGF (transforming growth factor) ß-stimulated ERK (extracellular signal-regulated kinase) activity in vascular smooth muscle cells (VSMCs), which adopt a mixed synthetic/contractile phenotype. In VSMCs, TGFß induces IL (interleukin) 11) that stimulates ERK-dependent secretion of collagens and MMPs (matrix metalloproteinases). Here, we examined the role of IL11 in the MFS aorta. METHODS: We used echocardiography, histology, immunostaining, and biochemical methods to study aortic anatomy, physiology, and molecular endophenotypes in Fbn1C1041G/+ mice, an established murine model of MFS (mMFS). mMFS mice were crossed to an IL11-tagged EGFP (enhanced green fluorescent protein; Il11EGFP/+) reporter strain or to a strain deleted for the IL11 receptor (Il11ra1-/-). In therapeutic studies, mMFS were administered an X209 (neutralizing antibody against IL11RA [IL11 receptor subunit alpha]) or IgG for 20 weeks and imaged longitudinally. RESULTS: IL11 mRNA and protein were elevated in the aortas of mMFS mice, as compared to controls. mMFS mice crossed to Il11EGFP/+ mice had increased IL11 expression in VSMCs, notably in the aortic root and ascending aorta. As compared to the mMFS parental strain, double mutant mMFS:Il11ra1-/- mice had reduced aortic dilatation and exhibited lesser fibrosis, inflammation, elastin breaks, and VSMC loss, which was associated with reduced aortic COL1A1 (collagen type I alpha 1 chain), IL11, MMP2/9, and phospho-ERK expression. To explore therapeutic targeting of IL11 signaling in MFS, we administered either a neutralizing antibody against IL11RA (X209) or an IgG control. After 20 weeks of antibody administration, as compared to IgG, mMFS mice receiving X209 had reduced thoracic and abdominal aortic dilation as well as lesser fibrosis, inflammation, elastin breaks, and VSMC loss. By immunoblotting, X209 was shown to reduce aortic COL1A1, IL11, MMP2/9, and phospho-ERK expression. CONCLUSIONS: In MFS, IL11 is upregulated in aortic VSMCs to cause ERK-related thoracic aortic dilatation, inflammation, and fibrosis. Therapeutic inhibition of IL11, imminent in clinical trials, might be considered as a new approach in MFS.
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Enfermedades de la Aorta , Síndrome de Marfan , Animales , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Neutralizantes/farmacología , Aorta/metabolismo , Enfermedades de la Aorta/patología , Modelos Animales de Enfermedad , Elastina/metabolismo , Fibrosis , Inmunoglobulina G/metabolismo , Inflamación/metabolismo , Interleucina-11/metabolismo , Subunidad alfa del Receptor de Interleucina-11 , Síndrome de Marfan/complicaciones , Síndrome de Marfan/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Ratones , Músculo Liso Vascular/metabolismo , Receptores de Interleucina-11/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Marfan Syndrome (MFS) is an inherited connective tissue disorder caused by mutations in the FBN1 (fibrillin-1) gene. Lung abnormalities are common in MFS, but their pathogenesis is poorly understood. IL11 (interleukin-11) causes aortic disease in a mouse model of MFS and was studied here in the lung. METHODS: We examined histological and molecular phenotypes in the lungs of Fbn1C1041G/+ mice (mouse model of Marfan Syndrome [mMFS]), an established mouse model of MFS. To identify IL11-expressing cells, we used immunohistochemistry on lungs of 4- and 16-week-old Fbn1C1041G/+:Il11EGFP/+ reporter mice. We studied the effects of IL11 inhibition by RT-qPCR, immunoblots and histopathology in lungs from genetic or pharmacologic models: (1) 16-week-old IL11 receptor (IL11RA) knockout mMFS mice (Fbn1C1041G/+:Il11ra1-/- mice) and (2) in mMFS mice administered IgG control or interleukin-11 receptor antibodies twice weekly from 4 to 24 weeks of age. RESULTS: mMFS lungs showed progressive loss and enlargement of distal airspaces associated with increased proinflammatory and profibrotic gene expression as well as matrix metalloproteinases 2, 9, and 12. IL11 was increased in mMFS lungs and localized to smooth muscle and endothelial cells in young mMFS mice in the Fbn1C1041G/+:Il11EGFP/+ reporter strain and in fibroblasts, in older mice. In mMFS mice, genetic (Fbn1C1041G/+:Il11ra1-/-) or pharmacologic (anti-interleukin-11 receptor) inhibition of IL11 signaling reduced lung emphysema, fibrosis, and inflammation. This protective effect was associated with reduced pathogenic ERK1/2 signaling and lower metalloproteinase 2, 9, and 12 expression. CONCLUSIONS: IL11 causes lung disease in mMFS. This reveals a shared IL11-driven disease mechanism in lung and aorta in MFS and suggests inhibition of IL11 signaling as a holistic approach for treating multiorgan morbidity in MFS.
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Interleucina-11 , Síndrome de Marfan , Enfisema Pulmonar , Animales , Ratones , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Fibrilina-1/genética , Interleucina-11/genética , Subunidad alfa del Receptor de Interleucina-11 , Síndrome de Marfan/complicaciones , Síndrome de Marfan/genética , Síndrome de Marfan/patología , Metaloproteinasa 2 de la Matriz/genética , Ratones Noqueados , Enfisema Pulmonar/complicaciones , Enfisema Pulmonar/genéticaRESUMEN
Posterior capsule opacification (PCO) is a serious complication after cataract surgery. Diabetes could increase the occurrence of PCO, but the mechanism is still unclear. The purpose of this study is to investigate the role of small extracellular vesicles (sEVs) derived from diabetic aqueous humor in PCO process. Intraoperatively-derived aqueous humor sEVs from patients with diabetic related cataract (DRC) promoted the epithelial-mesenchymal transition (EMT) and metastasis of human lens epithelial cells (LECs). Via mouse PCO surgical model and DiI labeled fluorescence detection of sEVs, the sEVs derived from vascular endothelium were discovered directly contacting with LECs. Furthermore, we demonstrated that high-glucose-cultured human umbilical vein endothelial cells (HUVEC) -derived sEVs facilitated EMT process of HLE-B3 using co-culture model in vitro. miRNA-seq data and GEO datasets analysis revealed that miR-1246 was essential in EMT process with diabetes. The miR-1246 was highly expressed in diabetic aqueous humor sEVs and high-glucose-treated vascular-endothelial-cell-derived sEVs. Moreover, miR-1246 promoted the metastasis and EMT process of HLE-B3 cells by directly targeting GSK-3ß. Inhibiting miR-1246 could negatively regulated EMT. This finding might serve as a potential therapy for diabetic PCO.
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Opacificación Capsular , Diabetes Mellitus , Cristalino , MicroARNs , Humanos , Ratones , Animales , Opacificación Capsular/genética , Opacificación Capsular/patología , Glucógeno Sintasa Quinasa 3 beta , Células Endoteliales/patología , MicroARNs/genética , Células Epiteliales/patología , Diabetes Mellitus/patología , Glucosa , Transición Epitelial-MesenquimalRESUMEN
This meta-analysis was to evaluate the outcome of haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) for aplastic anemia (AA) compared with matched related donor (MRD)-HSCT, matched unrelated donor (MUD)-HSCT, and immunosuppressive therapy (IST). Pubmed, Embase, Cochrane Library, Web of Science, CNKI, WanFang, and VIP databases were searched for relevant studies from inception to 22 June 2022. Relative risk (RR) was used to indicate the effect indicator, with a 95% confidence interval (CI) being applied to express the effect size. A subgroup analysis based on the literature quality (low, fair, and high) was applied. Totally, 25 studies were included in this study, comprising 2252 patients. Our findings demonstrated no difference between Haplo-HSCT and MRD-HSCT in 1-, 2-, and 3-year overall survival (OS), failure-free survival (FFS), and engraftment. However, Haplo-HSCT had higher incidences of II-IV acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), and cytomegalovirus infection. There were no differences in 3- and 5-year OS, 3-year FFS, platelet engraftment, graft failure (GF), II-IV grade of aGVHD, and complication between Haplo-HSCT and MUD-HSCT; however, Haplo-HSCT had a lower incidence of cGVHD. Compared with IST, Haplo-HSCT had a higher 3-year FFS and 3- and 6-month response rate. However, there were no differences in 3- and 5-year OS, and 12-month response rate between Haplo-HSCT and IST. This study suggests that Haplo-HSCT may be a realistic therapeutic option for AA, which may provide a reference for decision-making.
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Anemia Aplásica , Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Resultado del Tratamiento , Trasplante Haploidéntico/efectos adversos , Estudios Retrospectivos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Donante no Emparentado , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Acondicionamiento Pretrasplante/métodosRESUMEN
BACKGROUND: Echinococcosis, also known as hydatid disease, is a zoonotic parasitic disease prevalent in pastoral areas, mainly involving the liver and lungs, and less frequently the bones and surrounding soft tissues. Diagnosis and treatment of bone hydatid disease is a challenge, and because of the insidious course of the disease, the lesions are often widely disseminated by the time patients seek medical attention. CASE PRESENTATION: A 29-year-old woman presented with a painless mass that was gradually increasing in size in the cervical thorax. Imaging revealed an enlarged clavicle with multiple bone cortical defects and the existence of cysts in the soft tissues surrounding the clavicle, for which complete excision of the clavicle and the attached cysts was performed. There was no recurrence of the cyst within one year after the operation, and the patient felt well and had normal shoulder joint movement. CONCLUSIONS: Bone hydatid may appear in bones throughout the body, and cysts that leak from the bone into the surrounding soft tissues may spread at a relatively rapid rate. Prompt surgical removal of the affected bone and surrounding cysts is necessary for treatment.
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Quistes , Equinococosis , Echinococcus , Animales , Femenino , Humanos , Adulto , Clavícula/diagnóstico por imagen , Clavícula/cirugía , Clavícula/patología , Equinococosis/diagnóstico por imagen , Equinococosis/cirugía , ZoonosisRESUMEN
INTRODUCTION: Inflammatory bowel disease (IBD), which mainly leads to diarrhea, fatigue, stool blood, abdominal pain, and cramping, is threatening public health. Tripartite motif-containing 52 (TRIM52) has been reported to play an important role in inflammatory responses via activating the toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway. However, the causes of IBD need to be elucidated, and the function of TRIM52 in IBD remains unclear. Here, we demonstrated that TRIM52 aggravated inflammation and pyroptosis in dextran sulfate sodium (DSS)-induced IBD by activating TLR4/NF-κBs pathway. METHODS: The colitis model was established on mice through DSS induction. For the TRIM52 knockdown, the mice were infected with a recombinant adenoviral vector expressing sgRNAs targeting TRIM52. RT-qPCR, western blot, and immunohistochemistry were performed to verify TRIM52 expression in DSS-induced IBD. The body weight, disease activity index, colon length, and H&E staining were used to assess the IBD symptoms in mice with TRIM52 knockdown. The inflammatory responses were examined by RT-qPCR and ELISA measuring tumor necrosis factor-α (TNF-α), inter-leukin 6 (IL-6), and interleukin 1ß (IL-1ß). Furthermore, the pyroptosis in colon tissue was detected by western blot. Finally, the TLR4/NF-κBs pathway activity was also examined by western blot. RESULTS: TRIM52 expression was up-regulated in DSS-induced IBD, and knockdown of TRIM52 could alleviate the symptoms of IBD. TRIM52 knockdown retarded DSS-induced inflammatory response and inhibited DSS-induced pyroptosis in colon tissue. In addition, TRIM52 played a role in activating TLR4/NF-κBs pathway. CONCLUSION: Knockdown of TRIM52 alleviated inflammation and pyroptosis in IBD by regulating TLR4/NF-κBs pathway. TRIM52 is expected to be a novel diagnostic indicator for IBD and a target of therapeutic treatment.
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Colitis , Enfermedades Inflamatorias del Intestino , Piroptosis , Proteínas de Motivos Tripartitos , Animales , Ratones , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , Inflamación , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Transducción de Señal , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Proteínas de Motivos Tripartitos/metabolismoRESUMEN
Next-generation sequencing (NGS) of mitochondrial DNA (mtDNA) has widespread applications in aging and cancer studies. However, cross-contamination of mtDNA constitutes a major concern. Previous methods for the detection of mtDNA contamination mainly focus on haplogroup-level phylogeny, but neglect haplotype-level differences, leading to limited sensitivity and accuracy. In our study, we present mitoDataclean, a random-forest-based machine learning package for accurate identification of cross-contamination, evaluation of contamination levels and detection of contamination-derived variants in mtDNA NGS data. Comprehensive optimization of mitoDataclean revealed that training simulation with mixtures of small haplogroup distance and low polymorphic difference was critical for optimal modeling. Compared to existing methods, mitoDataclean exhibited significantly improved sensitivity and accuracy for the detection of sample contamination in simulated data. In addition, mitoDataclean achieved area under the curve values of 0.91 and 0.97 for discerning genuine and contamination-derived mtDNA variants in a simulated Western dataset and private sequencing contamination data, respectively, suggesting that this tool may be applicable for different populations and samples with different sources of contamination. Finally, mitoDataclean was further evaluated in several private and public datasets and showed a robust ability for contamination detection. Altogether, our study demonstrates that mitoDataclean may be used for accurate detection of contaminated samples and contamination-derived variants in mtDNA NGS data.
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ADN Mitocondrial , Neoplasias , ADN Mitocondrial/genética , ADN de Neoplasias , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Aprendizaje Automático , Mutación , Neoplasias/genética , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: The mechanisms of Gastric cancer (GC) initiation and progression are complicated, at least partly owing to the dynamic changes of gene regulation during carcinogenesis. Thus, investigations on the changes in regulatory networks can improve the understanding of cancer development and provide novel insights into the molecular mechanisms of cancer. METHODS: Differential co-expression analysis (DCEA), differential gene regulation network (GRN) modeling and differential regulation analysis (DRA) were integrated to detect differential transcriptional regulation events between gastric normal mucosa and cancer samples based on GSE54129 dataset. Cytological experiments and IHC staining assays were used to validate the dynamic changes of CREB1 regulated targets in different stages. RESULTS: A total of 1955 differentially regulated genes (DRGs) were identified and prioritized in a quantitative way. Among the top 1% DRGs, 14 out of 19 genes have been reported to be GC relevant. The four transcription factors (TFs) among the top 1% DRGs, including CREB1, BPTF, GATA6 and CEBPA, were regarded as crucial TFs relevant to GC progression. The differentially regulated links (DRLs) around the four crucial TFs were then prioritized to generate testable hypotheses on the differential regulation mechanisms of gastric carcinogenesis. To validate the dynamic alterations of gene regulation patterns of crucial TFs during GC progression, we took CREB1 as an example to screen its differentially regulated targets by using cytological and IHC staining assays. Eventually, TCEAL2 and MBNL1 were proved to be differentially regulated by CREB1 during tumorigenesis of gastric cancer. CONCLUSIONS: By combining differential networking information and molecular cell experiments verification, testable hypotheses on the regulation mechanisms of GC around the core TFs and their top ranked DRLs were generated. Since TCEAL2 and MBNL1 have been reported to be potential therapeutic targets in SCLC and breast cancer respectively, their translation values in GC are worthy of further investigation.
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Neoplasias Gástricas , Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Neoplasias Gástricas/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
OBJECTIVE: The effects of Otubain-2 (OTUB2) on the proliferation, invasion, and migration of esophageal squamous cell carcinoma (ESCC) were investigated by interfering with OTUB2 expression. METHODS: Bioinformatics analysis was used to analyze OTUB2 expression in esophageal carcinoma and interactions between OTUB2 and YAP1/TAZ. Paraffin-embedded ESCC tissues (n = 183) were selected for immunohistochemical staining to detect OTUB2, YAP1, TAZ, CTGF and their relationship with clinicopathological parameters, then the survival prognosis of ESCC patients was analyzed. Immunofluorescence, western blotting, and qRT-PCR were used to evaluate OTUB2 in ESCC cell lines. Cell lines with the highest expression of OTUB2 were transfected with lentivirus to knockdown OTUB2 levels. Changes in KYSE150 cell proliferation, migration, and invasion were measured using CCK-8, wound healing, and clone formation assays. The Transwell test and flow cytometry identified OTUB2 targets and explored roles and mechanisms involved in ESCC. Effects of OTUB2 on YAP1/TAZ signaling were also observed. RESULTS: Bioinformatics analysis revealed OTUB2 was highly expressed in esophageal cancer and was associated with YAP1/TAZ. Immunohistochemistry showed that OTUB2 expression was increased in ESCC samples compared to parcancerous tissue. YAP1 and TAZ were higher expression in ESCC tissues, mainly localized in the nucleus. Compared with controls, the proliferation, migration, and invasion ability of KYSE150 cells after OTUB2 knockdown were significantly reduced (P < 0.05). The protein expression levels of YAP1, TAZ and CTGF decreased after knocking down the expression of OTUB2 (P < 0.05). OTUB2 knockdown in ESCC cell lines suppressed YAP1/TAZ signaling. CONCLUSIONS: OTUB2 regulated the protein expression of YAP1/TAZ to promote cell proliferation, migration, invasion, and tumor development. Therefore, OTUB2 may represent a biomarker for ESCC and a potential target for ESCC treatment.
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BACKGROUND: Many studies have demonstrated the high efficacy of cell-free nuclear DNA in cancer diagnostics. Compared to nuclear DNA, mitochondrial DNA (mtDNA) exhibits distinct characteristics, including multiple copies per cell and higher mutation frequency. However, the potential applicability of cell-free mtDNA (cf-mtDNA) in plasma and urine remains poorly investigated. METHODS: Here, we comprehensively analyzed the fragmentomic and mutational characteristics of cf-mtDNA in urine and plasma samples from controls and cancer patients using next-generation sequencing. RESULTS: Compared to plasma cf-mtDNA, urine cf-mtDNA exhibited increased copy numbers and wider spread in fragment size distributions. Based on 2 independent animal models, urine cf-mtDNA originated predominantly from local shedding and transrenal excretion. Further analysis indicated an enhanced fragmentation of urine cf-mtDNA in renal cell carcinoma (RCC) and colorectal cancer (CRC) patients. Using the mtDNA sequence of peripheral blood mononuclear cells for reference, the mutant fragments were shorter than wild-type fragments in urine cf-mtDNA. Size selection of short urine cf-mtDNA fragments (<150 bp) significantly enhanced the somatic mutation detection. Our data revealed remarkably different base proportions of fragment ends between urine and plasma cf-mtDNA that also were associated with fragment size. Moreover, both RCC and CRC patients exhibited significantly higher T-end and lower A-end proportions in urine cf-mtDNA than controls. By integrating the fragmentomic and mutational features of urine cf-mtDNA, our nomogram model exhibited a robust efficacy for cancer diagnosis. CONCLUSIONS: Our proof-of-concept findings revealed aberrant fragmentation and mutation profiles of urine cf-mtDNA in cancer patients that have diagnostic potential.
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ADN Mitocondrial , Neoplasias , Animales , ADN Mitocondrial/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucocitos Mononucleares , MutaciónRESUMEN
Adenosine triphosphate (ATP) in the tumor microenvironment serves a vital role during tumor progression. ATP synthase F1 ß subunit (ATP5B) is one of the most important subunits of ATP synthase and increases cellular ATP levels. ATP5B reportedly participates in carcinogenesis in several tumors. However, the regulatory mechanisms of ATP5B remain poorly understood in gastric cancer (GC). Here, we determined that high ATP5B expression in tumor tissues of GC is positively correlated with age, the tumor size, the TNM stage, lymph node metastasis, and patients' poor prognosis. The overexpression of ATP5B in GC cells elevated the cellular ATP content and promoted migration, invasion and proliferation. The levels of MMP2 expression, phosphorylated FAK, and phosphorylated AKT were increased after ATP5B overexpression in GC cells. Additionally, ATP5B overexpression increased the extracellular ATP level through the secretion of intracellular ATP and activated the FAK/AKT/MMP2 signaling pathway. ATP5B-induced downstream pathway activation was induced through the plasma membrane P2X7 receptor. Inhibitors of P2X7, FAK, AKT, and MMP2 suppressed the proliferative, migratory, and invasive capabilities of GC cells. In conclusion, our experiments indicate that ATP5B contributes to tumor progression of GC via FAK/AKT/MMP2 pathway. ATP5B, therefore, may be a biomarker of poor prognosis and a potential therapeutic target for GC.
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Quinasa 1 de Adhesión Focal/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias Gástricas/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Quinasa 1 de Adhesión Focal/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/genética , Ratones , Persona de Mediana Edad , ATPasas de Translocación de Protón Mitocondriales/genética , Neoplasias Experimentales , Neoplasias Peritoneales/secundario , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal , Neoplasias Gástricas/patología , Análisis de Matrices Tisulares , Regulación hacia ArribaRESUMEN
Mitochondria are central eukaryotic organelles in cellular metabolism and ATP production. Mitochondrial DNA (mtDNA) alterations have been implicated in the development of colorectal cancer (CRC). However, there are few reports on the association between mtDNA haplogroups or single nucleotide polymorphisms (SNPs) and the risk of CRC. The mtDNA of 286 Northern Han Chinese CRC patients were sequenced by next-generation sequencing technology. MtDNA data from 811 Han Chinese population controls were collected from two public data sets. Then, logistic regression analysis was used to determine the effect of mtDNA haplogroup or SNP on the risk of CRC. We found that patients with haplogroup M7 exhibited a reduced risk of CRC when compared to patients with other haplogroups (odds ratio [OR] = 0.532, 95% confidence interval [CI] = 0.285-0.937, p = 0.036) or haplogroup B (OR = 0.477, 95% CI = 0.238-0.916, p = 0.030). Furthermore, haplogroup M7 was still associated with the risk of CRC when the validation and combined control cohort were used. In addition, several haplogroup M7 specific SNPs, including 199T>C, 4071C>T and 6455C>T, were significantly associated with the risk of CRC. Our results indicate the risk potential of mtDNA haplogroup M7 and SNPs in CRC in Northern China.
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Neoplasias Colorrectales/genética , ADN Mitocondrial/genética , Haplotipos , China , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Copy number variations (CNVs) in cell-free DNA (cfDNA) are emerging as noninvasive biomarkers for various cancers. However, multiple-level analysis of cfDNA CNVs for hepatocellular carcinoma (HCC) patients with radical treatments remains uninvestigated. Here, CNVs at genome-wide, chromosomal-arm, and bin levels were analyzed in cfDNA from 117 HCC patients receiving radical treatments. Then, the relationship between cfDNA CNVs and clinical outcomes was explored. Our results showed that a concordant profile of CNVs was observed between cfDNA and tumor tissue DNA. Three genome-wide CNV indicators including tumor fraction (TFx), prediction score (P-score), and stability score (S-score) were calculated and demonstrated to exhibit significant correlation with poorer overall survival (OS) and recurrence-free survival (RFS). Furthermore, the high-frequency cfDNA CNVs at chromosomal-arm level including the loss of 4q, 17p, and 19p and the gain of 8q and 1q clearly predicted HCC prognosis. Finally, a bin-level risk score was constructed to improve the ability of CNVs in predicting prognosis. Altogether, our study indicates that the multiple-level cfDNA CNVs are significantly associated with OS and RFS in HCC patients with radical treatments, suggesting that cfDNA CNVs detected by low-coverage whole-genome sequencing (WGS) may be used as potential prognostic biomarkers of HCC patients.
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Carcinoma Hepatocelular/genética , Ácidos Nucleicos Libres de Células/genética , Variaciones en el Número de Copia de ADN , Neoplasias Hepáticas/genética , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/mortalidad , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 4 , Cromosomas Humanos Par 6 , Cromosomas Humanos Par 8 , ADN de Neoplasias , Supervivencia sin Enfermedad , Femenino , Marcadores Genéticos , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Resultado del Tratamiento , Secuenciación Completa del GenomaRESUMEN
Interleukin-11 (IL11) is important for fibroblast-to-myofibroblast transformations. Here, we examined the signalling and phenotypic effects of inhibiting IL11 signalling using neutralizing antibodies against IL11 or its cognate receptor (IL11RA) in a mouse model of acute and severe pressure overload. C57BL/6J mice underwent ascending aortic constriction (AAC) surgery and were randomized to anti-IL11, anti-IL11RA, or isotype control antibodies (20 mg/kg, bi-weekly for 2 weeks). AAC surgery induced the expression of IL11, IL11RA and extracellular matrix (ECM) genes that was associated with cardiac hypertrophy and aortic remodelling. Inhibition of IL11 signalling reduced AAC-induced cardiac fibrosis and ECM gene expression as well as ERK1/2 phosphorylation but had no effect on cardiac hypertrophy. STAT3 was phosphorylated in the hearts of AAC-treated mice but this was unrelated to IL11 activity, which we confirmed in mouse cardiac fibroblasts in vitro. These data highlight that blocking IL11 signalling reduces cardiac fibrosis due to severe pressure overload and suggests ERK, but not STAT3, activity as the relevant underlying signalling pathway.
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Cardiomegalia , Interleucina-11 , Animales , Fibrosis , Ratones , Transducción de Señal/efectos de los fármacosRESUMEN
AIMS: Recently, we demonstrated that the hearts of neonatal pigs (2-day old) have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after postnatal day 3. However, it is unknown if corticosteroid, a broad anti-inflammatory agent, will abrogate the regenerative capacity in the hearts of neonatal pigs. The aim of the current study is to evaluate the effect Dexamethasone (Dex), a broad anti-inflammatory agent, on heart regeneration, structure, and function of the neonatal pigs' post-myocardial infarction (MI). METHODS AND RESULTS: Dex (0.2 mg/kg/day) was injected intramuscularly into the neonatal pig (age: 2 days postnatal) during the first week post-MI. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance (CMR) imaging. Bromodeoxyuridine (BrdU) pulse-chase labeling, histology, immunohistochemistry, and flow cytometry were performed to determine inflammatory cell infiltration, CM cytokinesis, and myocardial fibrosis. Dex injection during the first-week suppressed acute inflammation post-MI in the pig hearts. It inhibited BrdU incorporation to pig CMs and CM cytokinesis via inhibiting aurora-B protein expression which was associated with mature scar formation and thinned walls at the infarct site. CMR imaging showed Dex caused left ventricular aneurysm and poor ejection fraction. CONCLUSIONS: Dex inhibited CM cytokinesis and functional recovery and caused ventricular aneurysm in the hearts of 2-day old pigs post-MI.
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Dexametasona/efectos adversos , Aneurisma Cardíaco/etiología , Aneurisma Cardíaco/patología , Infarto del Miocardio/complicaciones , Cicatrización de Heridas/efectos de los fármacos , Animales , Animales Recién Nacidos , Biomarcadores , Dexametasona/farmacología , Manejo de la Enfermedad , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Ecocardiografía , Técnica del Anticuerpo Fluorescente , Aneurisma Cardíaco/diagnóstico por imagen , Aneurisma Cardíaco/metabolismo , Inmunohistoquímica , Imagen por Resonancia Magnética , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Porcinos , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Increasing evidence indicates that angiogenesis plays an important role in tumor progression. The function of cathepsin L (CTSL), an endosomal proteolytic enzyme, in promoting tumor metastasis is well recognized. The mechanisms by which CTSL has promoted the angiogenesis of gastric cancer (GC), however, remains unclear. METHODS: The nuclear expression levels of CTSL were assessed in GC samples. The effects of CTSL on GC angiogenesis were determined by endothelial tube formation analysis, HUVEC migration assay, and chick embryo chorioallantoic membrane (CAM) assay. The involvement of the CDP/Cux/VEGF-D pathway was analyzed by angiogenesis antibody array, Western blot, co-immunoprecipitation (Co-IP) and dual-luciferase reporter assay. RESULTS: In this study, we found that the nuclear CTSL expression level in GC was significantly higher than that in adjacent nontumor gastric tissues and was a potential important clinical prognostic factor. Loss- and gain-of-function assays indicated that CTSL promotes the tubular formation and migration of HUVEC cells in vitro. The CAM assay also showed that CTSL promotes angiogenesis of GC in vivo. Mechanistic analysis demonstrated that CTSL can proteolytically process CDP/Cux and produce the physiologically relevant p110 isoform, which stably binds to VEGF-D and promotes the transcription of VEGF-D, thus contributing to the angiogenesis of GC. CONCLUSION: The findings of the present study suggested that CTSL plays a constructive role in the regulation of angiogenesis in human GC and could be a potential therapeutic target for GC.
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Inductores de la Angiogénesis/metabolismo , Catepsina L/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Transducción de Señal/genética , Neoplasias Gástricas/genética , Animales , Embrión de Pollo , Citidina Difosfato/metabolismo , Proteínas de Homeodominio/metabolismo , Humanos , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Factor D de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is a common malignant tumor in the immune system with high mortality. We investigated the functional effects of long non-coding RNA paternally expressed imprinted gene 10 (PEG10) on DLBCL progression. MATERIAL AND METHODS Real-time quantitative polymerase chain reaction was used to measure the level of PEG10, kinesin family member 2A (KIF2A) and microRNA-101-3p (miR-101-3p) in DLBCL tissues and cell lines. The relative protein level was detected by western blot analysis. The biological behaviors including cell proliferation, apoptosis, migration, and invasion were determined by MTT assay, flow cytometry analysis, and Transwell assays, respectively. Bioinformatics analysis and dual-luciferase reporter assay were performed to evaluate the interaction among PEG10, miR-101-3p, and KIF2A. RESULTS PEG10 and KIF2A level were significantly upregulated, while miR-101-3p was downregulated in DLBCL tissues and cells. PEG10 positively regulated KIF2A level in DLBCL. PEG10, or KIF2A deletion significantly inhibited the proliferative, migratory, and invasive abilities of DLBCL cells and elevated cell apoptosis in DLBCL cells. KIF2A upregulation partially reversed the effects of PEG10 downregulation on cell growth, metastasis, and apoptosis in DLBCL. Moreover, PEG10 negatively regulated miR-101-3p level and miR-101-3p upregulation exerted inhibition effects on the progression of DLBCL. Besides, miR-101-3p was a target of PEG10 and miR-101-3p could directly target KIF2A. PEG10 promoted KIF2A level by sponging miR-101-3p. CONCLUSIONS Our findings revealed that PEG10 played an oncogenic role in DLBCL progression, which might be a potential target for the treatment of DLBCL.