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1.
Funct Integr Genomics ; 24(3): 77, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38632140

RESUMO

BACKGROUND: Gastric cancer (GC) remains a leading cause of cancer mortality globally. Synaptotagmin-4 (SYT4), a calcium-sensing synaptic vesicle protein, has been implicated in the oncogenesis of diverse malignancies. PURPOSE: This study delineates the role of SYT4 in modulating clinical outcomes and biological behaviors in GC. METHODS: We evaluated SYT4 expression in GC specimens using bioinformatics analyses and immunohistochemistry. Functional assays included CCK8 proliferation tests, apoptosis assays via flow cytometry, confocal calcium imaging, and xenograft models. Western blotting elucidated MAPK pathway involvement. Additionally, we investigated the impact of the calcium channel blocker amlodipine on cellular dynamics and MAPK pathway activity. RESULTS: SYT4 was higher in GC tissues, and the elevated SYT4 was significantly correlated with adverse prognosis. Both univariate and multivariate analyses confirmed SYT4 as an independent prognostic indicator for GC. Functionally, SYT4 promoted tumorigenesis by fostering cellular proliferation, inhibiting apoptosis, and enhancing intracellular Ca2+ influx, predominantly via MAPK pathway activation. Amlodipine pre-treatment attenuated SYT4-driven cell growth and potentiated apoptosis, corroborated by in vivo xenograft assessments. These effects were attributed to MAPK pathway suppression by amlodipine. CONCLUSION: SYT4 emerges as a potential prognostic biomarker and a pro-oncogenic mediator in GC through a Ca2+-dependent MAPK mechanism. Amlodipine demonstrates significant antitumor effects against SYT4-driven GC, positing its therapeutic promise. This study underscores the imperative of targeting calcium signaling in GC treatment strategies.


Assuntos
Anlodipino , Sinalização do Cálcio , Neoplasias Gástricas , Sinaptotagminas , Humanos , Anlodipino/farmacologia , Anlodipino/uso terapêutico , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Sinaptotagminas/antagonistas & inibidores , Sinaptotagminas/genética , Sinaptotagminas/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia
2.
Proc Natl Acad Sci U S A ; 121(14): e2321611121, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38547058

RESUMO

Malignant glioma exhibits immune evasion characterized by highly expressing the immune checkpoint CD47. RNA 5-methylcytosine(m5C) modification plays a pivotal role in tumor pathogenesis. However, the mechanism underlying m5C-modified RNA metabolism remains unclear, as does the contribution of m5C-modified RNA to the glioma immune microenvironment. In this study, we demonstrate that the canonical 28SrRNA methyltransferase NSUN5 down-regulates ß-catenin by promoting the degradation of its mRNA, leading to enhanced phagocytosis of tumor-associated macrophages (TAMs). Specifically, the NSUN5-induced suppression of ß-catenin relies on its methyltransferase activity mediated by cysteine 359 (C359) and is not influenced by its localization in the nucleolus. Intriguingly, NSUN5 directly interacts with and deposits m5C on CTNNB1 caRNA (chromatin-associated RNA). NSUN5-induced recruitment of TET2 to chromatin is independent of its methyltransferase activity. The m5C modification on caRNA is subsequently oxidized into 5-hydroxymethylcytosine (5hmC) by TET2, which is dependent on its binding affinity for Fe2+ and α-KG. Furthermore, NSUN5 enhances the chromatin recruitment of RBFOX2 which acts as a 5hmC-specific reader to recognize and facilitate the degradation of 5hmC caRNA. Notably, hmeRIP-seq analysis reveals numerous mRNA substrates of NSUN5 that potentially undergo this mode of metabolism. In addition, NSUN5 is epigenetically suppressed by DNA methylation and is negatively correlated with IDH1-R132H mutation in glioma patients. Importantly, pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. Our findings unveil a general mechanism by which NSUN5/TET2/RBFOX2 signaling regulates RNA metabolism and highlight NSUN5 targeting as a potential strategy for glioma immune therapy.


Assuntos
5-Metilcitosina , 5-Metilcitosina/análogos & derivados , Proteínas de Ligação a DNA , Dioxigenases , Glioma , Proteínas Musculares , Humanos , 5-Metilcitosina/metabolismo , beta Catenina/metabolismo , Cromatina , Antígeno CD47/genética , RNA , Evasão da Resposta Imune , Glioma/patologia , RNA Mensageiro/metabolismo , Metiltransferases/metabolismo , RNA Nuclear Pequeno , Microambiente Tumoral , Fatores de Processamento de RNA/genética , Proteínas Repressoras/metabolismo
3.
Int J Surg Pathol ; : 10668969241226707, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321754

RESUMO

Ciliated muconodular papillary tumor (CMPT) is a rare pulmonary tumor, typically occurring in middle-aged and elderly individuals. The molecular mutation spectrum of CMPT remains insufficiently explored. Commonly known driver gene alterations include KRAS, BRAF, EGFR, and ALK rearrangement. This report details the clinicopathological features of 2 patients presenting with CMPT as pulmonary nodules during clinical examinations. Microscopic analysis revealed tumors with glandular or papillary structures, consisting of mucinous cells, ciliated columnar cells, and basal cells. Notably, both patients exhibited STRN::ALK fusion, a finding not previously associated with CMPT. STRN::ALK fusion serves as a target for therapy in various tumors, including non-small cell lung cancer, thyroid cancer, and colon cancer. Consequently, we conducted a review of relevant literature, summarizing the clinicopathological and molecular characteristics of CMPT to facilitate further research. Our insights enhance the understanding of this uncommon tumor and contribute to the expansion of its molecular alteration spectrum.

4.
Endocrine ; 2024 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-38306009

RESUMO

PURPOSE: Adrenal and extra-adrenal paragangliomas (PGLs) are a group of neuroendocrine tumors (NETs) with strong heterogeneity, which often express somatostatin receptor subtype 2 A (SSTR2A). However, the association between SSTR2A expression and genetic status of PGLs remains unclear. The purpose of the study was to identify whether various pathogenic variants (PVs) had an impact on SSTR2A expression in PGLs. METHODS: This retrospective study included 184 patients with pathologically confirmed PGLs. The immunohistochemical expression of SSTR2A were studied in 184 tumors and PVs were tested in 159 tumor samples. Clinical and genetic data were compared in SSTR2A positive and negative PGLs. RESULTS: SSTR2A was positive in 63.6% (117/184) of all tumors. PGLs with negative SSTR2A were more likely to be extra-adrenal (37.0% vs 18.0%; P = 0.005) and exhibited a considerably greater proportion of PVs (75.4% vs. 49.0%; P = 0.001) than those with positive SSTR2A. Compared to those without PVs, a higher proportion of PGLs with PVs in cluster 1B (P = 0.004) and cluster 2 (P = 0.004) genes, especially VHL (P = 0.009), FGFR1 (P = 0.010) and HRAS (P = 0.007), were SSTR2A negative. SSTR2A was positive in all tumors (4/4) with SDHx PVs and in 87.5% (7/8) of metastatic PGLs. CONCLUSIONS: SSTR2A negativity was correlated with extra-adrenal tumor location and PVs in cluster 1B and cluster 2 genes such as VHL, FGFR1 and HRAS. Immunohistochemistry of SSTR2A should be taken into consideration in the personalized management of PGLs.

5.
Nat Commun ; 15(1): 1381, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360860

RESUMO

Soft tissue sarcoma is a broad family of mesenchymal malignancies exhibiting remarkable histological diversity. We portray the proteomic landscape of 272 soft tissue sarcomas representing 12 major subtypes. Hierarchical classification finds the similarity of proteomic features between angiosarcoma and epithelial sarcoma, and elevated expression of SHC1 in AS and ES is correlated with poor prognosis. Moreover, proteomic clustering classifies patients of soft tissue sarcoma into 3 proteomic clusters with diverse driven pathways and clinical outcomes. In the proteomic cluster featured with the high cell proliferation rate, APEX1 and NPM1 are found to promote cell proliferation and drive the progression of cancer cells. The classification based on immune signatures defines three immune subtypes with distinctive tumor microenvironments. Further analysis illustrates the potential association between immune evasion markers (PD-L1 and CD80) and tumor metastasis in soft tissue sarcoma. Overall, this analysis uncovers sarcoma-type-specific changes in proteins, providing insights about relationships of soft tissue sarcoma.


Assuntos
Hemangiossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Proteômica , Sarcoma/metabolismo , Biomarcadores , Análise por Conglomerados , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Microambiente Tumoral
6.
Liver Int ; 44(4): 894-906, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38263714

RESUMO

BACKGROUND & AIMS: We aimed to develop a Transformer-based deep learning (DL) network for prognostic stratification in hepatocellular carcinoma (HCC) patients undergoing RFA. METHODS: A Swin Transformer DL network was trained to establish associations between magnetic resonance imaging (MRI) datasets and the ground truth of microvascular invasion (MVI) based on 696 surgical resection (SR) patients with solitary HCC ≤3 cm, and was validated in an external cohort (n = 180). The multiphase MRI-based DL risk outputs using an optimal threshold of .5 was employed as a MVI classifier for prognosis stratification in the RFA cohort (n = 180). RESULTS: Over 90% of all enrolled patients exhibited hepatitis B virus infection. Liver cirrhosis was significantly more prevalent in the RFA cohort compared to the SR cohort (72.2% vs. 44.1%, p < .001). The MVI risk outputs exhibited good performance (area under the curve values = .938 and .883) for predicting MVI in the training and validation cohort, respectively. The RFA patients at high risk of MVI classified by the MVI classifier demonstrated significantly lower recurrence-free survival (RFS) and overall survival rates at 1, 3 and 5 years compared to those classified as low risk (p < .001). Multivariate cox regression modelling of a-fetoprotein > 20 ng/mL [hazard ratio (HR) = 1.53; 95% confidence interval (95% CI): 1.02-2.33, p = .047], high risk of MVI (HR = 3.76; 95% CI: 2.40-5.88, p < .001) and unfavourable tumour location (HR = 2.15; 95% CI: 1.40-3.29, p = .001) yielded a c-index of .731 (bootstrapped 95% CI: .667-.778) for evaluating RFS after RFA. Among the three risk factors, MVI was the most powerful predictor for intrahepatic distance recurrence. CONCLUSIONS: The proposed MVI classifier can serve as a valuable imaging biomarker for prognostic stratification in early-stage HCC patients undergoing RFA.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ablação por Radiofrequência , Humanos , Prognóstico , Neoplasias Hepáticas/patologia , Estudos Retrospectivos , Invasividade Neoplásica
7.
Gastroenterology ; 166(3): 450-465.e33, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37995868

RESUMO

BACKGROUND & AIMS: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, and it has high metastatic and recurrence rates. We aimed to characterize the proteomic features of GIST to understand biological processes and treatment vulnerabilities. METHODS: Quantitative proteomics and phosphoproteomics analyses were performed on 193 patients with GIST to reveal the biological characteristics of GIST. Data-driven hypotheses were tested by performing functional experiments using both GIST cell lines and xenograft mouse models. RESULTS: Proteomic analysis revealed differences in the molecular features of GISTs from different locations or with different histological grades. MAPK7 was identified and functionally proved to be associated with tumor cell proliferation in GIST. Integrative analysis revealed that increased SQSTM1 expression inhibited the patient response to imatinib mesylate. Proteomics subtyping identified 4 clusters of tumors with different clinical and molecular attributes. Functional experiments confirmed the role of SRSF3 in promoting tumor cell proliferation and leading to poor prognosis. CONCLUSIONS: Our study provides a valuable data resource and highlights potential therapeutic approaches for GIST.


Assuntos
Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Humanos , Animais , Camundongos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteômica , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Fatores de Processamento de Serina-Arginina
8.
Nat Commun ; 14(1): 8119, 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38065972

RESUMO

Acral melanoma (AM) is a rare subtype of melanoma characterized by a high incidence of lymph node (LN) metastasis, a critical factor in tumor dissemination and therapeutic decision-making. Here, we employ single-cell and spatial transcriptomic analyses to investigate the dynamic evolution of early AM dissemination. Our findings reveal substantial inter- and intra-tumor heterogeneity in AM, alongside a highly immunosuppressive tumor microenvironment and complex intercellular communication networks, particularly in patients with LN metastasis. Notably, we identify a strong association between MYC+ Melanoma (MYC+MEL) and FGFBP2+NKT cells with LN metastasis. Furthermore, we demonstrate that LN metastasis requires a metabolic shift towards fatty acid oxidation (FAO) induced by MITF in MYC+MEL cells. Etomoxir, a clinically approved FAO inhibitor, can effectively suppress MITF-mediated LN metastasis. This comprehensive dataset enhances our understanding of LN metastasis in AM, and provides insights into the potential therapeutic targeting for the management of early AM dissemination.


Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/patologia , Neoplasias Cutâneas/patologia , Metástase Linfática , Perfilação da Expressão Gênica , Transcriptoma , Microambiente Tumoral/genética
9.
J Clin Pathol ; 76(11): 757-762, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37852629

RESUMO

AIMS: Accurate histopathological evaluation of the endoscopic submucosal dissection (ESD) specimens is essential for clinicians to guide further triage and management. This study aimed to report a novel processing technique for large ESD (≥4 cm) specimens. METHODS: 92 patients with colorectal neoplasms who had undergone ESD were included. 46 ESD specimens were treated with conventional handling process, while the rest 46 cases were given the optimised method. Macrobiocassettes and L-shaped embedding moulds were applied in the optimised method. We evaluated the efficacy of this improved procedure in terms of the number of paraffin blocks, storage space and time consumption of pathological assessment. RESULTS: The average diameter of ESD specimens was 4.5±0.4 cm and 4.7±0.5 cm in the control and test group (p=0.023), respectively. In control group, 398 paraffin blocks of 46 cases were obtained. With the same cases number and larger lesion size, only 276 blocks were achieved in test group (p<0.001). As for the storage space, the total volume of paraffin blocks and slides (4554.0 cm3 and 1207.5 cm3) of optimised method was significantly reduced compared with the control group (6208.8 cm3 and 1741.3 cm3) (p=0.001, p<0.001). In addition, the optimised method was superior to the conventional one in shortening time consumption of pathological assessment (164.5 min and 269.0 min, p<0.001). CONCLUSIONS: The optimised technique not only reduced the workload and storage space, but also facilitated accurate pathological assessment.


Assuntos
Neoplasias Colorretais , Ressecção Endoscópica de Mucosa , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Ressecção Endoscópica de Mucosa/métodos , Parafina , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia
10.
Cell Res ; 33(8): 585-603, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37337030

RESUMO

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.


Assuntos
Ecossistema , Neoplasias Hepáticas , Camundongos , Animais , Humanos , Neoplasias Hepáticas/patologia , Hepatócitos/metabolismo , Terapia de Imunossupressão , Linhagem Celular Tumoral
11.
Diagnostics (Basel) ; 13(7)2023 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-37046555

RESUMO

Steatohepatitic hepatocellular carcinoma (SH-HCC) is a distinctive histologic variant of HCC for the presence of steatohepatitis. This study intended to evaluate the contrast-enhanced imaging features and clinicopathological characteristics of 26 SH-HCCs in comparison with 26 age-and-sex-matched non-SH-HCCs. The frequency of obesity (34.6%, p = 0.048) and type 2 diabetes mellitus (23.1%, p = 0.042) were significantly higher in SH-HCC patients. As seen via B-mode ultrasound (BMUS), SH-HCCs were predominantly hyperechoic (65.4%, p = 0.002) lesions, while non-SH-HCCs were mainly hypo-echoic. As seen via contrast-enhanced ultrasound (CEUS), 96.2% of SH-HCCs exhibited hyperenhancement in the arterial phase. During the portal venous and late phase, 88.5% of SH-HCCs showed late and mild washout. Consequently, most SH-HCCs and all non-SH-HCCs were categorized as LR-4 or LR-5. As seen via magnetic resonance imaging (MRI), a signal drop in the T1WI opposed-phase was observed in 84.6% of SH-HCCs (p = 0.000). Notably, diffuse fat in mass was detected in 57.7% (15/26) SH-HCCs (p < 0.001). As seen via contrast-enhanced MRI (CEMRI), most of the SH-HCCs and non-SH-HCCs exhibited heterogeneous hyperenhancement in the arterial phase (80.8% versus 69.2%, p = 0.337). During the delayed phase, 76.9% SH-HCCs and 88.5% non-SH-HCCs exhibited hypo-enhancement. Histopathologically, the rate of microvascular invasion (MVI) was significantly lower in SH-HCCs than non-SH-HCCs (42.3% versus 73.1%, p = 0.025). The frequency of hepatic steatosis >5% in non-tumoral liver parenchyma of SH-HCCs was significantly higher than in non-SH-HCCs (88.5% versus 26.9%, p = 0.000). Additionally, the fibrotic stages of S0, S1 and S2 in SH-HCCs were significantly higher than in non-SH-HCCs (p = 0.044). During follow-up, although the PFS of SH-HCC patients was significantly longer than non-SH-HCC patients (p = 0.046), for the overall survival rate of SH-HCC and non-SH-HCC patients there was no significant difference (p = 0.162). In conclusion, the frequency of metabolism-related diseases in SH-HCC patients was significantly higher than in non-SH-HCC patients. The imaging features of SH-HCCs combined the fatty change and typical enhancement performance of standard HCC as seen via CEUS/CEMRI.

12.
Cell Rep Med ; 4(2): 100931, 2023 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-36724786

RESUMO

Responses toward preoperative chemotherapy are heterogeneous in patients with gastric adenocarcinoma. Existing studies in the field focus heavily on the tumor microenvironment (TME), whereas little is known about the relationship between systemic immunity and chemotherapy response. In this study, we collect serum samples from patients with gastric adenocarcinoma before, on, and after preoperative chemotherapy and study their immune proteomics using an antibody-based proteomics panel. We also collect surgically resected tumor samples and incorporate multiple methods to assess their TME. We find that both local and systemic immune features are associated with treatment response. Preoperative chemotherapy induces a sophisticated systemic immune response indicated by dynamic serum immune proteomics. A pretreatment serum protein scoring system is established for response prediction. Together, these findings highlight the fundamental but largely underestimated role of systemic immunity in the treatment of gastric cancer, suggesting a patient stratification strategy based on pretreatment serum immune proteomics.


Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Proteômica , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Microambiente Tumoral
13.
Clin Hemorheol Microcirc ; 85(3): 211-221, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36846993

RESUMO

OBJECTIVE: To evaluate the contrast enhanced ultrasound (CEUS) and contrast enhanced magnetic resonance imaging (CEMRI) features of intrahepatic splenosis (IHS). METHODS & MATERIALS: Five patients (three males and two females, median age, 44 years; range,32-73 years) with seven IHSs were retrieved from the database of our hospital from March 2012 to October 2021. All IHSs were confirmed histologically by surgery. The CEUS and CEMRI characteristics of individual lesion were fully analyzed. RESULTS: All IHS patients were asymptomatic and four out of five patients had history of splenectomy. On CEUS, all IHSs were hyperenhancement in arterial phase. 71.4% (5/7) of IHSs manifested overall filling within few seconds, the other two lesions showed centripetal filling. Subcapsular vascular hyperenhancement and feeding artery was seen in 28.6% (2/7) and 42.9% (3/7) of IHSs, respectively. During portal venous phase, IHSs presented hyperenhancement (2/7) or isoenhancement (5/7). Moreover, rim-like hypoenhanced area was uniquely observed surrounding 85.7% (6/7) of IHSs. In late phase, seven IHSs remained continuous hyper- or isoenhancement. On CEMRI, five IHSs showed mosaic hyperintense in early arterial phase, the other two lesions showed homogeneous hyperintense. In portal venous phase, all IHSs revealed continuous hyper- (71.4%, 5/7) or iso-intense (28.6%, 2/7). During late phase, one IHS (14.3%, 1/7) became hypointense, the other lesions remained hyper- or isointense. CONCLUSION: Diagnosis of IHS can be based on typical CEUS and CEMRI features in patients with history of splenectomy.


Assuntos
Neoplasias Hepáticas , Esplenose , Masculino , Feminino , Humanos , Adulto , Meios de Contraste , Esplenose/diagnóstico por imagem , Ultrassonografia/métodos , Veia Porta/patologia , Imageamento por Ressonância Magnética , Neoplasias Hepáticas/patologia , Estudos Retrospectivos
14.
BMC Pulm Med ; 23(1): 18, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36647116

RESUMO

BACKGROUND: This study evaluated programmed cell death-ligand 1 (PD-L1) expression from pre-invasive adenocarcinoma to invasive lung adenocarcinoma, aimed to investigate the potential association of PD-L1 pathway with lung adenocarcinoma early evolution. METHODS: We evaluated PD-L1 expression in 1123 resected lung specimens of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) of stage IA1-IA3. PD-L1 expression was defined based on the proportion of stained tumor cells using the tumor proportion score: < 1% (negative), ≥ 1% (positive) and ≥ 50% (strongly positive). Correlations between PD-L1 expression and T stage, pathological subtype, adenocarcinoma grade, spread through air space (STAS), vascular invasion, lymphatic invasion and driven genes were analyzed. RESULTS: There was almost no PD-L1 expression in AIS or MIA. However, PD-L1 expression was correlated with invasiveness of lung adenocarcinoma. The percentages of PD-L1 positive in IA1-IA3 were 7.22%, 11.29%, and 14.20%, respectively. The strongly positive rates of PD-L1 were 0.38%, 1.64%, and 3.70% in IA1-IA3, respectively. PD-L1 expression and positive rate were also associated with poor pathological subtype and poor biological behavior, such as adenocarcinoma Grade 3, micropapillary or solid dominant subtype, STAS and vascular invasion. Finally, PD-L1 positive rate seems also corrected with driven gene ALK, ROS-1 and KRAS. CONCLUSIONS: PD-L1 expression was positively correlated with the emergence of invasiveness and poor pathological subtype or biological behavior of early-stage lung adenocarcinoma. PD-L1 pathway may be involved in the early evolution of lung adenocarcinoma from AIS to IAC.


Assuntos
Adenocarcinoma in Situ , Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Adenocarcinoma in Situ/patologia , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/genética , Neoplasias Pulmonares/patologia , Prognóstico
15.
Nat Commun ; 14(1): 505, 2023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36720864

RESUMO

Diffuse gliomas are devastating brain tumors. Here, we perform a proteogenomic profiling of 213 retrospectively collected glioma tumors. Proteogenomic analysis reveals the downstream biological events leading by EGFR-, IDH1-, TP53-mutations. The comparative analysis illustrates the distinctive features of GBMs and LGGs, indicating CDK2 inhibitor might serve as a promising drug target for GBMs. Further proteogenomic integrative analysis combined with functional experiments highlight the cis-effect of EGFR alterations might lead to glioma tumor cell proliferation through ERK5 medicates nucleotide synthesis process. Proteome-based stratification of gliomas defines 3 proteomic subgroups (S-Ne, S-Pf, S-Im), which could serve as a complement to WHO subtypes, and would provide the essential framework for the utilization of specific targeted therapies for particular glioma subtypes. Immune clustering identifies three immune subtypes with distinctive immune cell types. Further analysis reveals higher EGFR alteration frequencies accounts for elevation of immune check point protein: PD-L1 and CD70 in T-cell infiltrated tumors.


Assuntos
Glioma , Proteogenômica , Humanos , Proteômica , Estudos Retrospectivos , Glioma/genética , Receptores ErbB/genética
17.
Cancer Med ; 12(4): 4110-4124, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36208025

RESUMO

PURPOSE: This study aimed to evaluate the clinical relevance of exosomal HER2 (Exo HER2) level in assessing the tissue HER2 status and predicting the efficacy of trastuzumab treatment. METHODS: In this prospective study, patients with advanced gastric cancer (AGC) from three hospitals between August 2016 to November 2020 were enrolled. The Exo HER2 level was detected by enzyme-linked immunosorbent assay. Receiver operating characteristic curve (ROC) was drawn referring to the HER2 tissue status to assess the diagnostic value of Exo HER2. Cox proportional hazards regression and logistic regression were used to evaluate the association between Exo HER2 and progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients who received trastuzumab-based first-line therapy. RESULTS: In this study, 242 patients with advanced or metastatic gastric adenocarcinoma were registered. Of these, 238 AGC patients were eligible for evaluating serum-derived exosome HER2 diagnostic value, including 114 HER2-positive. Finally, 64 were eligible for efficacy analysis. The area under the ROC curve was 0.746. The optimal cutoff value for diagnosing tissue HER2-positive status was 729.95 ng/ml, with a sensitivity of 66.7% and a specificity of 74.2%. In 64 patients treated with trastuzumab, higher baseline Exo HER2 level indicated better prognosis. 844 ng/ml and 723 ng/ml were the right cutoffs for distinguishing the population with superior PFS (hazard ratio [HR] = 0.41, P = 0.017) and OS (HR = 0.30, P < 0.001), respectively. CONCLUSION: Serum exosomal HER2 level might serve as an effective biomarker for assessing tissue HER2 status in AGC and screening the potential patients who might benefit from anti-HER2 therapy.


Assuntos
Exossomos , Neoplasias Gástricas , Humanos , Trastuzumab/uso terapêutico , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/etiologia , Estudos Prospectivos , Exossomos/patologia , Receptor ErbB-2 , Prognóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
18.
Pathol Oncol Res ; 29: 1611577, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38273860

RESUMO

Background: Malignant mesothelioma (MM) is a tumor originating from the pleura, peritoneum, or pericardial cavity. It is divided into diffuse and localized malignant mesothelioma, with four subtypes in diffuse MM: epithelioid, sarcomatoid, desmoplastic, and biphasic, with biphasic being less common. The onset of this tumor is insidious, and the prognosis is extremely poor in some cases, with a median survival of 6-18 months and no standard treatment options in the past. Aims: We report a case of peritoneal malignant mesothelioma that was successfully treated with transformative therapy. We also review the literature in the hope of providing reference for the treatment and pathological diagnosis of such patients. Methods: The case of the peritoneal malignant mesothelioma was processed and reported in the routine manner for biopsy specimens at different stages. Results and conclusion: We report a case of a malignant tumor originating in the hepatorenal recess, which was diagnosed as biphasic malignant mesothelioma through a biopsy. Immunohistochemical testing showed PD-L1 expression. After multidisciplinary discussion, the patient received transformative treatment, including a trial of combined immunotherapy. The tumor significantly shrank, and the patient obtained a chance for curative surgical resection. Microscopic examination showed significant collagenization in the lesion area, with almost no residual tumor. After 19 months of comprehensive treatment, the patient developed multiple fluffy opacities under the pleura of both lungs. Transthoracic core needle biopsy under CT guidance, the pathology showed organizing pneumonia, considering it as delayed interstitial pneumonitis due to immunotherapy based on previous treatment history. Successful comprehensive treatment was achieved for this case of peritoneal malignant mesothelioma, and the patient has been alive without evidence of disease for 33 months, with long-term follow-up. In this process, the pathologist had three opportunities for pathological diagnosis, which required understanding the patient's medical history, being attentive to the clinical purpose of the specimen, and providing accurate responses to morphological changes at different stages, along with corresponding descriptions and diagnoses to provide effective information for clinical treatment.


Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Peritoneais , Humanos , Mesotelioma/terapia , Prognóstico , Neoplasias Peritoneais/terapia , Neoplasias Peritoneais/patologia
19.
Front Immunol ; 14: 1290185, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38274825

RESUMO

Introduction: Heat ablation is one of the key modalities in treating liver cancer, yet the residual cancer tissues suffering sublethal heat treatment possess a potential for increased malignancy. This study conducts a comprehensive analysis of cellular dynamics, metabolic shifts, and macrophage polarization within the tumor microenvironment following sublethal heat treatment. Methods: We observed significant acidification in tumor cell supernatants, attributed to increased lactic acid production. The study focused on how this pH shift, crucial in tumor progression and resistance, influences macrophage polarization, especially towards the M2 phenotype known for tumor-promoting functions. We also examined the upregulation of MCT1 expression post sublethal heat treatment and its primary role in lactic acid transport. Results: Notably, the study found minimal disparity in MCT1 expression between hepatocellular carcinoma patients and healthy liver tissues, highlighting the complexity of cancer biology. The research further revealed an intricate relationship between lactic acid, MCT1, and the inhibition of macrophage pyroptosis, offering significant insights for therapeutic strategies targeting the tumor immune environment. Post sublethal heat treatment, a reduction in paraspeckle under lactic acid exposure was observed, indicating diverse cellular impacts. Additionally, PKM2 was identified as a key molecule in this context, with decreased levels after sublethal heat treatment in the presence of lactic acid. Discussion: Collectively, these findings illuminate the intertwined mechanisms of sublethal heat treatments, metabolic alterations, and immune modulation in the tumor milieu, providing a deeper understanding of the complex interplay in cancer biology and treatment.


Assuntos
Carcinoma Hepatocelular , Piroptose , Humanos , Linhagem Celular Tumoral , Ácido Láctico/metabolismo , Temperatura Alta , Paraspeckles , Carcinoma Hepatocelular/patologia , Macrófagos/metabolismo , Microambiente Tumoral
20.
Metabolites ; 12(12)2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36557266

RESUMO

Liposarcoma (LPS) is a rare and heterogeneous malignancy of adipocytic origin. Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are two of the most common subtypes, showing similar genetic characterizations but distinct biological behaviors and clinical prognosis. Compared to WDLPS, DDLPS is more aggressive and has the potential of metastasis, as the malignant adipocytic tumor's metabolic changes may have taken place during the tumorigenesis of LPSs. Therefore, to investigate the lipid alterations between the two subtypes, high-resolution liquid chromatography tandem mass spectrometry (LC-MS/MS) based untargeted lipidomic analysis was performed onto LPS tissues from 6 WDLPS and 7 DDLPS patients. The lipidomic analysis showed the upregulated phosphatidylcholines and phosphoethanolamines in DDLPS, and the upregulated triglycerides and diglycerides in WDLPS, which might be due to the uncompleted adipocytic dedifferentiation leading to such tumorigenesis. Such a finding was also confirmed by the similarity comparison of two LPS subtypes to the transcriptome of stromal vascular fraction at different differentiation stages. Transcriptomic analysis also demonstrated that metabolic pathways including the pentose phosphate pathway (PPP) were upregulated in WDLPS compared to DDLPS. Therefore, the cell line LPS853 was treated with the PPP inhibitor 6-aminonicotinamide ex vivo and the proliferation and invasion of LPS853 was significantly promoted by PPP inhibition, suggesting the potential role of PPP in the development and differentiation of LPS. In conclusion, this study described the altered lipid profiles of WDLPS and DDLPS for the first time, revealing the different differentiation stages of the two subtypes and providing a potential metabolic target for LPS treatment.

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