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1.
Mol Cell ; 81(4): 708-723.e5, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33606974

RESUMO

The PI3K pathway regulates cell metabolism, proliferation, and migration, and its dysregulation is common in cancer. We now show that both physiologic and oncogenic activation of PI3K signaling increase the expression of its negative regulator PTEN. This limits the duration of the signal and output of the pathway. Physiologic and pharmacologic inhibition of the pathway reduces PTEN and contributes to the rebound in pathway activity in tumors treated with PI3K inhibitors and limits their efficacy. Regulation of PTEN is due to mTOR/4E-BP1-dependent control of its translation and is lost when 4E-BP1 is deleted. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in reducing the pathway activation by oncogenic PIK3CA mutants and the antitumor activity of PI3K pathway inhibitors. However, pathway output is hyperactivated in tumor cells with coexistent PI3K mutation and loss of PTEN function.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Homeostase , Neoplasias/enzimologia , PTEN Fosfo-Hidrolase/biossíntese , Biossíntese de Proteínas , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células CHO , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/genética , Cricetulus , Humanos , Mutação , Neoplasias/genética , PTEN Fosfo-Hidrolase/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
2.
Zhonghua Yi Xue Za Zhi ; 101(6): 400-404, 2021 Feb 09.
Artigo em Chinês | MEDLINE | ID: mdl-33611888

RESUMO

Objective: To analyze the consistency of plasma circulating tumor DNA (ctDNA) and tumor tissue DNA in detecting KRAS/NRAS/BRAF/PIK3CA gene mutations in patients with advanced colorectal cancer, and to explore the factors affecting the consistency. Methods: Patients with advanced colorectal cancer who were treated in Zhongshan Hospital Fudan University from December 2018 to May 2020 were enrolled. The results of plasma and tissue gene detection, clinicopathological information and treatment were collected. The consistency and influencing factors of plasma and tissue KRAS/NRAS/BRAF/PIK3CA status were analyzed. Results: The patients enrolled in this study all received plasma gene detection. The mutation rates of KRAS, NRAS, BRAF and PIK3CA in plasma were 27.30%, 2.42%, 6.06% and 9.70%, respectively. Among them, 128 patients underwent tissue gene testing, and the mutation rates of KRAS, NRAS, BRAF and PIK3CA were 30.47%, 2.34%, 7.03% and 3.13%, respectively. The overall coincidence rate of KRAS/NRAS/BRAF/PIK3CA status by plasma and tissue was 62.50% (Kappa=0.200, P=0.023). Univariate analysis showed that the consistency of gene detection was higher in newly diagnosed untreated group and liver metastasis group, but lower in lung metastasis group. Conclusion: Our real-world study found that there are some differences in KRAS/NRAS/BRAF/PIK3CA status between plasma and tissue. Anti-tumor therapy and metastatic sites may be important factors affecting the inconsistency.


Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Colorretais/genética , GTP Fosfo-Hidrolases/genética , Humanos , Proteínas de Membrana/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
4.
Nat Commun ; 11(1): 5488, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33127913

RESUMO

The 17q23 amplicon is associated with poor outcome in ER+ breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. Here, we interrogate transcriptome data from primary breast tumors and find that among genes in 17q23, PRR11 is a key gene associated with a poor response to therapeutic estrogen suppression. PRR11 promotes estrogen-independent proliferation and confers endocrine resistance in ER+ breast cancers. Mechanistically, the proline-rich motif-mediated interaction of PRR11 with the p85α regulatory subunit of PI3K suppresses p85 homodimerization, thus enhancing insulin-stimulated binding of p110-p85α heterodimers to IRS1 and activation of PI3K. PRR11-amplified breast cancer cells rely on PIK3CA and are highly sensitive to PI3K inhibitors, suggesting that PRR11 amplification confers PI3K dependence. Finally, genetic and pharmacological inhibition of PI3K suppresses PRR11-mediated, estrogen-independent growth. These data suggest ER+/PRR11-amplified breast cancers as a novel subgroup of tumors that may benefit from treatment with PI3K inhibitors and antiestrogens.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Moduladores de Receptor Estrogênico/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas/genética , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Antagonistas de Estrogênios/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Estrogênios , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Insulina , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1578-1584, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067957

RESUMO

OBJECTIVE: To investigate the potential mechanisms of miR-224 affecting the proliferation and invasion of diffuse large B-cell lymphoma (DLBCL) cells. METHODS: The blood samples of 76 DLBCL patients(DLBCL group) diagnosed at the First Affiliated Hospital of Kunming Medical University from June 2011 to December 2017, and 41 healthy persons of physical examination (normal control group) as well as human lymphatic endothelial cells (HELC) and DLBCL cell lines HBL1, OCI-LY10, OCI-LY8, OCI-LY19 were collected. The expression of miR-224 and PIK3CD mRNA was measured by RT-qPCR. The proliferation of HBL1 cells was detected by CCK-8 method and colony formation test. The invasion ability of HBL1 cells was detected by Transwell test. Dual-luciferase reporter gene assay was used to verify the relationship between miR-224 and PIK3CD. The expression of PIK3CD protein was measured by Western blot. RESULTS: The expression of miR-224 in blood of DLBCL patients was very significantly lower than that in normal control group (P<0.01). The overexpression of miR-224 significantly decreased proliferation and invasion of HBL1 cells (all P<0.01). PIK3CD was a target gene of miR-224. Knockdown of PIK3CD significantly suppressed the proliferation and invasion of HBL1 cells (all P<0.01). CONCLUSION: MiR-224 plays a key role in the progression of DLBCL, and the proliferation and invasion of HBL1 cells can be suppressed by targeted inhibition of PIK3CD.


Assuntos
Linfoma Difuso de Grandes Células B , MicroRNAs , Linhagem Celular Tumoral , Proliferação de Células , Classe I de Fosfatidilinositol 3-Quinases/genética , Células Endoteliais , Humanos , Linfoma Difuso de Grandes Células B/genética , MicroRNAs/genética
6.
Nat Commun ; 11(1): 4977, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020483

RESUMO

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.


Assuntos
Interleucina-6/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Medula Óssea/patologia , Mama/citologia , Neoplasias da Mama/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Receptor gp130 de Citocina/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Interleucina-6/genética , Mutação , Metástase Neoplásica/genética , Receptores de Interleucina-6/deficiência , Receptores de Interleucina-6/metabolismo , Células Estromais/metabolismo , Microambiente Tumoral
7.
Science ; 370(6512): 82-89, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004515

RESUMO

Knowledge of somatic mutation accumulation in normal cells, which is essential for understanding cancer development and evolution, remains largely lacking. In this study, we investigated somatic clonal events in morphologically normal human urothelium (MNU; epithelium lining the bladder and ureter) and identified macroscopic clonal expansions. Aristolochic acid (AA), a natural herb-derived compound, was a major mutagenic driving factor in MNU. AA drastically accelerates mutation accumulation and enhances clonal expansion. Mutations in MNU were widely observed in chromatin remodeling genes such as KMT2D and KDM6A but rarely in TP53, PIK3CA, and FGFR3 KMT2D mutations were found to be common in urothelial cells, regardless of whether the cells experience exogenous mutagen exposure. Copy number alterations were rare and largely confined to small-scale regions, along with copy-neutral loss of heterozygosity. Single AA-associated clones in MNU expanded to a scale of several square centimeters in size.


Assuntos
Ácidos Aristolóquicos/toxicidade , Montagem e Desmontagem da Cromatina/genética , Mutagênicos/toxicidade , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/genética , Urotélio/efeitos dos fármacos , Urotélio/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Histona Desmetilases/genética , Humanos , Mutagênese , Mutação , Proteínas de Neoplasias/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Proteína Supressora de Tumor p53/genética
8.
PLoS One ; 15(9): e0238477, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32877461

RESUMO

Somatic copy number alterations (CNA) are common in endometrial serous carcinoma (ESC). We used the Tumor Cancer Genome Atlas Pan Cancer dataset (TCGA Pan Can) to explore the impact of somatic CNA and gene expression levels (mRNA) of cancer-related genes in ESC. Results were correlated with clinico-pathologic parameters such as age of onset, disease stage, progression-free survival (PFS) and overall survival (OS) (n = 108). 1,449 genes with recurrent somatic CNA were identified, observed in 10% or more tumor samples. Somatic CNA and mRNA expression levels were highly correlated (r> = 0.6) for 383 genes. Among these, 45 genes were classified in the Tier 1 category of Cancer Genome Census-Catalogue of Somatic Mutations in Cancer. Eighteen of 45 Tier 1 genes had highly correlated somatic CNA and mRNA expression levels including ARNT, PIK3CA, TBLXR1, ASXL1, EIF4A2, HOOK3, IKBKB, KAT6A, TCEA1, KAT6B, ERBB2, BRD4, KEAP1, PRKACA, DNM2, SMARCA4, AKT2, SS18L1. Our results are in agreement with previously reported somatic CNA for ERBB2, BRD4 and PIK3C in ESC. In addition, AKT2 (p = 0.002) and KAT6A (p = 0.015) amplifications were more frequent in tumor samples from younger patients (<60), and CEBPA (p = 0.028) and MYC (p = 0.023) amplifications were more common with advanced (stage III and IV) disease stage. Patients with tumors carrying KAT6A and MYC amplifications had shorter PFS and OS. The hazard ratio (HR) of KAT6A was 2.82 [95 CI 1.12-7.07] for PFS and 3.87 [95 CI 1.28-11.68] for OS. The HR of MYC was 2.25 [95 CI 1.05-4.81] and 2.62[95 CI 1.07-6.41] for PFS and OS, respectively.


Assuntos
Neoplasias do Endométrio/genética , Histona Acetiltransferases/genética , Biomarcadores Tumorais/genética , Classe I de Fosfatidilinositol 3-Quinases , Cistadenocarcinoma Seroso/genética , Variações do Número de Cópias de DNA/genética , DNA Helicases , Bases de Dados Genéticas , Intervalo Livre de Doença , Neoplasias do Endométrio/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Histona Acetiltransferases/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch , Mutação , Fator 2 Relacionado a NF-E2 , Proteínas Nucleares/genética , Oncogenes , Neoplasias Ovarianas/patologia , Prognóstico , Intervalo Livre de Progressão , Fatores de Transcrição , Transcriptoma/genética
9.
Anticancer Res ; 40(10): 5417-5421, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988862

RESUMO

BACKGROUND: Type II diabetes agents have anticancer effects on head and neck squamous cell carcinoma (HNSCC). The mechanistic target of rapamycin (MTOR) pathway represents a putative target. MATERIALS AND METHODS: We interrogated an Affymetrix HNSCC dataset for MTOR-related gene expression. RESULTS: MTOR expression itself was unchanged, but various related genes demonstrated differential expression. Pathway promoters ras homolog (RHEB), MTOR-associated protein (MLST8), and ribosomal protein S6 kinase B1 (RPS6KB1) were up-regulated. Expression of growth suppressors tuberous sclerosis complex 2 (TSC2), programmed cell death 4 (PDCD4), and BCL2 apoptosis regulator-associated agonist of cell death (BAD) were reduced in HNSCC. Upstream, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), AKT serine/threonine kinase 1 (AKT1), and phosphatase and tensin homolog (PTEN) were up-regulated in cancer. CONCLUSION: Several MTOR pathway promoters and tumor suppressors were found to be differentially expressed, favoring MTOR pathway up-regulation in HNSCC. Genomic databases can be interrogated to identify intervention targets and endpoints in HNSCC trials.


Assuntos
Bases de Dados Genéticas , Neoplasias de Cabeça e Pescoço/genética , Proteínas de Neoplasias/genética , Serina-Treonina Quinases TOR/genética , Proteínas Reguladoras de Apoptose/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias de Cabeça e Pescoço/classificação , Neoplasias de Cabeça e Pescoço/patologia , Humanos , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas de Ligação a RNA/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Transdução de Sinais/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína de Morte Celular Associada a bcl/genética , Homólogo LST8 da Proteína Associada a mTOR/genética
10.
Anticancer Res ; 40(10): 5883-5893, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988919

RESUMO

BACKGROUND/AIM: Somatic mutations were investigated in 21 patients with postmenopausal estrogen receptor (ER)-positive and human epidermal growth factor receptor-2 (HER-2)-positive (ER+HER2+) breast cancer (BC) treated with neoadjuvant letrozole and lapatinib, to identify their distinct molecular landscape. PATIENTS AND METHODS: We used tissue samples of 21 patients from phase II Neo ALL-IN cohort, and somatic alterations were examined using targeted exome sequencing performed in Foundation Medicine, Inc. (FMI). RESULTS: TP53 (61.9%) and PIK3CA (57.1%) were the two most frequently mutated genes that were inter-correlated (p=0.026). They were associated with unfavorable clinical outcomes, particularly when accompanying PIK3CA mutations at exon 9 in helical domains. Meanwhile, MLL2 alteration was negatively associated with mutations of TP53 or PIK3CA, and it tended to be present in patients with low KI-67 levels and no initial nodal involvement. Moreover, patients with MLL2 mutations numerically showed more favorable overall response rates (ORR) (80% vs. 56.2%) and better 5-year event-free survival (EFS) rates (100% vs. 87.5%) compared to the wild-type. CONCLUSION: Mutations in TP53 and PIK3CA hotspot at exon 9 may be potential negative predictors of ER+HER2+ BC treated with neoadjuvant letrozole and lapatinib, while MLL2 inactivating mutation might confer therapeutic benefit in these patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Proteínas de Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Idoso , Biomarcadores Tumorais/genética , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib/administração & dosagem , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Mutação/genética , Intervalo Livre de Progressão , Receptor ErbB-2/genética
11.
Front Immunol ; 11: 2094, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973818

RESUMO

The spread of the novel human respiratory coronavirus (SARS-CoV-2) is a global public health emergency. There is no known successful treatment as of this time, and there is a need for medical options to mitigate this current epidemic. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and is primarily trophic for the lower and upper respiratory tract. A number of current studies on COVID-19 have demonstrated the substantial increase in pro-inflammatory factors in the lungs during infection. The virus is also documented in the central nervous system and, particularly in the brainstem, which plays a key role in respiratory and cardiovascular function. Currently, there are few antiviral approaches, and several alternative drugs are under investigation. Two of these are Idelalisib and Ebastine, already proposed as preventive strategies in airways and allergic diseases. The interesting and evolving potential of phosphoinositide 3-kinase δ (PI3Kδ) inhibitors, together with Ebastine, lies in their ability to suppress the release of pro-inflammatory cytokines, such as IL-1ß, IL-8, IL-6, and TNF-α, by T cells. This may represent an optional therapeutic choice for COVID-19 to reduce inflammatory reactions and mortality, enabling patients to recover faster. This concise communication aims to provide new potential therapeutic targets capable of mitigating and alleviating SARS-CoV-2 pandemic infection.


Assuntos
Betacoronavirus , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Terapia de Alvo Molecular/métodos , Pneumonia Viral/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/uso terapêutico , Antivirais/uso terapêutico , Butirofenonas/farmacologia , Butirofenonas/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Infecções por Coronavirus/virologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Pandemias , Peptidil Dipeptidase A/metabolismo , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pneumonia Viral/virologia , Purinas/farmacologia , Purinas/uso terapêutico , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico
12.
PLoS One ; 15(9): e0237802, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976510

RESUMO

As availability of precision therapies expands, a well-validated circulating cell-free DNA (cfDNA)-based comprehensive genomic profiling assay has the potential to provide considerable value as a complement to tissue-based testing to ensure potentially life-extending therapies are administered to patients most likely to benefit. Additional data supporting the clinical validity of cfDNA-based testing is necessary to inform optimal use of these assays in the clinic. The FoundationOne®Liquid CDx assay is a pan-cancer cfDNA-based comprehensive genomic profiling assay that was recently approved by FDA. Validation studies included >7,500 tests and >30,000 unique variants across >300 genes and >30 cancer types. Clinical validity results across multiple tumor types are presented. Additionally, results demonstrated a 95% limit of detection of 0.40% variant allele fraction for select substitutions and insertions/deletions, 0.37% variant allele fraction for select rearrangements, 21.7% tumor fraction for copy number amplifications, and 30.4% TF for copy number losses. The limit of detection for microsatellite instability and blood tumor mutational burden were also determined. The false positive variant rate was 0.013% (approximately 1 in 8,000). Reproducibility of variant calling was 99.59%. In comparison with an orthogonal method, an overall positive percent agreement of 96.3% and negative percent agreement of >99.9% was observed. These study results demonstrate that FoundationOne Liquid CDx accurately and reproducibly detects the major types of genomic alterations in addition to complex biomarkers such as microsatellite instability, blood tumor mutational burden, and tumor fraction. Critically, clinical validity data is presented across multiple cancer types.


Assuntos
Bioensaio/métodos , Ácidos Nucleicos Livres/genética , Genômica , Neoplasias/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Receptores ErbB/genética , Éxons/genética , Humanos , Limite de Detecção , Mutação/genética , Intervalo Livre de Progressão , Reprodutibilidade dos Testes
14.
Oncology ; 98(11): 817-826, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32892196

RESUMO

BACKGROUND: Developing personalized strategies for cancer has shown good efficacies. METHODS: We assessed the molecular targets programmed death ligand 1 (PD-L1), microsatellite instability (MSI), and PIK3CA. Seventy-four patients with liposarcomas who underwent curative resection were assessed for PD-L1 expression in the tumor and tumor-infiltrating lymphocytes (TILs), mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) by immunohistochemistry, MSI using polymerase chain reaction, and PIK3CA mutation/amplification using pyrosequencing and fluorescence in situ hybridization. RESULTS: Seventeen (23%) cases were TIL+ (≥1 + expression) and associated with longer 5-year overall survival than those with TIL- tumors (84.4 vs. 60.8%, p = 0.007). Six (35.3%) PD-L1+ tumors were detected only in TIL+ cases, with none detected in tumor cells. Two well-differentiated liposarcomas showed MSI, one low and one high with concurrent loss of MLH1, MSH6, and PMS2. PIK3CA mutation was detected in 7 (9.5%) [exon 9 (n = 4) and exon 20 (n = 3)] and only 1 Q546K mutation was a PD-L1+ tumor. PIK3CA copy number gain was detected in 18 (24.4%) and was associated with TIL+ tumors (p = 0.045). CONCLUSIONS: Our comprehensive immuno-molecular panel suggests that liposarcoma should be categorized based on the molecular genomic subtype for precision medicine.


Assuntos
Antígeno B7-H1/biossíntese , Classe I de Fosfatidilinositol 3-Quinases/genética , Lipossarcoma/genética , Lipossarcoma/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Estudos de Coortes , Feminino , Amplificação de Genes , Humanos , Imuno-Histoquímica , Lipossarcoma/patologia , Lipossarcoma/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Adulto Jovem
15.
PLoS One ; 15(8): e0236580, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756609

RESUMO

Lung cancer is generally treated with conventional therapies, including chemotherapy and radiation. These methods, however, are not specific to cancer cells and instead attack every cell present, including normal cells. Personalized therapies provide more efficient treatment options as they target the individual's genetic makeup. The goal of this study was to identify the frequency of causal genetic mutations across a variety of lung cancer subtypes in the earlier stages. 833 samples of non-small cell lung cancer from 799 patients who received resection of their lung cancer, were selected for molecular analysis of six known mutations, including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK. A SNaPshot assay was used for point mutations and fragment analysis searched for insertions and deletions. ALK was evaluated by IHC +/- FISH. Statistical analysis was performed to determine correlations between molecular and clinical/pathological patient data. None of the tested variants were identified in most (66.15%) of cases. The observed frequencies among the total samples vs. only the adenocarcinoma cases were notable different, with the highest frequency being the KRAS mutation (24.49% vs. 35.55%), followed by EGFR (6.96% vs. 10.23%), PIK3CA (1.20% vs. 0.9%), BRAF (1.08% vs. 1.62%), ALK (0.12% vs. 0.18%), while the lowest was the HER2 mutation (0% for both). The statistical analysis yielded correlations between presence of a mutation with gender, cancer type, vascular invasion and smoking history. The outcome of this study will provide data that helps stratify patient prognosis and supports development of more precise treatments, resulting in improved outcomes for future lung cancer patients.


Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Predisposição Genética para Doença , Prognóstico , Adenocarcinoma/classificação , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética
17.
Nat Commun ; 11(1): 3377, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632100

RESUMO

The mammary gland is a highly vascularized tissue capable of expansion and regression during development and disease. To enable mechanistic insight into the coordinated morphogenic crosstalk between the epithelium and vasculature, we introduce a 3D microfluidic platform that juxtaposes a human mammary duct in proximity to a perfused endothelial vessel. Both compartments recapitulate stable architectural features of native tissue and the ability to undergo distinct forms of branching morphogenesis. Modeling HER2/ERBB2 amplification or activating PIK3CA(H1047R) mutation each produces ductal changes observed in invasive progression, yet with striking morphogenic and behavioral differences. Interestingly, PI3KαH1047R ducts also elicit increased permeability and structural disorganization of the endothelium, and we identify the distinct secretion of IL-6 as the paracrine cause of PI3KαH1047R-associated vascular dysfunction. These results demonstrate the functionality of a model system that facilitates the dissection of 3D morphogenic behaviors and bidirectional signaling between mammary epithelium and endothelium during homeostasis and pathogenesis.


Assuntos
Glândulas Mamárias Humanas/metabolismo , Morfogênese/genética , Mutação , Comunicação Parácrina/genética , Biomimética/métodos , Linhagem Celular , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Endotélio Vascular/crescimento & desenvolvimento , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Glândulas Mamárias Humanas/irrigação sanguínea , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Fenótipo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
18.
Nat Commun ; 11(1): 3412, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641742

RESUMO

Regulatory B cells restrict immune and inflammatory responses across a number of contexts. This capacity is mediated primarily through the production of IL-10. Here we demonstrate that the induction of a regulatory program in human B cells is dependent on a metabolic priming event driven by cholesterol metabolism. Synthesis of the metabolic intermediate geranylgeranyl pyrophosphate (GGPP) is required to specifically drive IL-10 production, and to attenuate Th1 responses. Furthermore, GGPP-dependent protein modifications control signaling through PI3Kδ-AKT-GSK3, which in turn promote BLIMP1-dependent IL-10 production. Inherited gene mutations in cholesterol metabolism result in a severe autoinflammatory syndrome termed mevalonate kinase deficiency (MKD). Consistent with our findings, B cells from MKD patients induce poor IL-10 responses and are functionally impaired. Moreover, metabolic supplementation with GGPP is able to reverse this defect. Collectively, our data define cholesterol metabolism as an integral metabolic pathway for the optimal functioning of human IL-10 producing regulatory B cells.


Assuntos
Linfócitos B Reguladores/metabolismo , Colesterol/metabolismo , Interleucina-10/metabolismo , Fosfatos de Poli-Isoprenil/metabolismo , Animais , Antígenos CD19/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Técnicas de Cocultura , Doenças Hereditárias Autoinflamatórias/metabolismo , Humanos , Macrófagos/metabolismo , Síndrome Metabólica/metabolismo , Deficiência de Mevalonato Quinase/metabolismo , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Análise de Componente Principal , Transdução de Sinais , Células Th1/metabolismo , Receptor Toll-Like 9/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Acta Cytol ; 64(6): 547-555, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32683364

RESUMO

INTRODUCTION: Several studies have implicated the PIK3/AKT pathway in the pathophysiology of cancer progression as its activation seems to be aberrant in several forms of cancer. The purpose of the present systematic review is to evaluate the impact of PIK3CA mutations on survival outcomes of patients with cervical cancer. METHODS: We used the Medline (1966-2020), Scopus (2004-2020), ClinicalTrials.gov (2008-2020), EMBASE (1980-2020), Cochrane Central Register of Controlled Trials (CENTRAL) (1999-2020), and Google Scholar (2004-2020) databases in our primary search along with the reference lists of electronically retrieved full-text papers. Statistical meta-analysis was performed with the RevMan 5.3 software. RESULTS: Overall, 12 articles were included in the present study that comprised 2,196 women with cervical cancer. Of those, 3 studies did not report significant differences in survival outcomes among patients with mutated versus wild-type PIK3CA tumors, 5 studies reported decreased survival outcomes, and 3 studies revealed increased survival rates. The meta-analysis revealed that patients with the mutated PIK3CA genotypes had worse overall survival compared to patients with wild-type PIK3CA (HR 2.31; 95% CI: 1.51, 3.55; 95% PI: 0.54, 9.96; data from 3 studies) and the same was observed in the case of DFS rates (HR 1.82; 95% CI: 1.47, 2.25; 95% PI: 1.29, 2.56; data from 4 studies). CONCLUSION: Current evidence concerning the impact of PIK3CA mutations on survival outcomes of patients with cervical cancer is inconclusive, although the majority of included studies support a potential negative effect, primarily among those with squamous cell carcinoma tumors.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/mortalidade , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/métodos , Gerenciamento de Dados , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias do Colo do Útero/patologia
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