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1.
Phys Rev Lett ; 125(12): 128103, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-33016731

RESUMO

While many cellular mechanisms leading to chemotherapeutic resistance have been identified, there is an increasing realization that tumor-stroma interactions also play an important role. In particular, mechanical alterations are inherent to solid cancer progression and profoundly impact cell physiology. Here, we explore the influence of compressive stress on the efficacy of chemotherapeutics in pancreatic cancer spheroids. We find that increased compressive stress leads to decreased drug efficacy. Theoretical modeling and experiments suggest that mechanical stress decreases cell proliferation which in turn reduces the efficacy of chemotherapeutics that target proliferating cells. Our work highlights a mechanical form of drug resistance and suggests new strategies for therapy.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Modelos Biológicos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Estresse Mecânico
2.
Folia Biol (Praha) ; 66(3): 104-110, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33069189

RESUMO

Cancer development is a highly complicated process in which tumour growth depends on the development of its vascularization system. To support their own growth, tumour cells significantly modify their microenvironment. One of such modifications inflicted by tumours is stimulation of endothelial cell migration and proliferation. There is accumulating evidence that extracellular vesicles (EVs) secreted by tumour cells (tumour-derived EVs, TEVs) may be regarded as "messengers" with the potential for affecting the biological activities of target cells. Interaction of TEVs with different cell types occurs in an auto- and paracrine manner and may lead to changes in the function of the latter, e.g., promoting motility, proliferation, etc. This study analysed the proangiogenic activity of EVs derived from human pancreatic adenocarcinoma cell line (HPC-4, TEVHPC) in vitro and their effect in vivo on Matrigel matrix vascularization in severe combined immunodeficient (SCID) mice. TEVHPC enhanced proliferation of HPC-4 cells and induced their motility. Moreover, TEVHPC stimulated human umbilical vein endothelial cell (HUVEC) proliferation and migration in vitro. Additionally, TEVHPC influenced secretion of proangiogenic factors (IL-8, VEGF) by HUVEC cells and supported Matrigel matrix haemoglobinization in vivo. These data show that TEVs may support tumour propagation in an autocrine manner and may support vascularization of the tumour. The presented data are in line with the theory that tumour cells themselves are able to modulate the microenvironment via TEVs to maximize their growth potential.


Assuntos
Carcinoma Ductal Pancreático/patologia , Vesículas Extracelulares/patologia , Neoplasias Pancreáticas/patologia , Animais , Comunicação Autócrina , Divisão Celular , Linhagem Celular Tumoral , Quimiotaxia , Colágeno , Combinação de Medicamentos , Células Endoteliais da Veia Umbilical Humana , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Laminina , Camundongos , Camundongos SCID , Transplante de Neoplasias , Neovascularização Patológica/etiologia , Proteoglicanas , RNA Mensageiro/biossíntese , Microambiente Tumoral , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Nat Commun ; 11(1): 4301, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32879317

RESUMO

Copy-number aberrations (CNAs) and whole-genome duplications (WGDs) are frequent somatic mutations in cancer but their quantification from DNA sequencing of bulk tumor samples is challenging. Standard methods for CNA inference analyze tumor samples individually; however, DNA sequencing of multiple samples from a cancer patient has recently become more common. We introduce HATCHet (Holistic Allele-specific Tumor Copy-number Heterogeneity), an algorithm that infers allele- and clone-specific CNAs and WGDs jointly across multiple tumor samples from the same patient. We show that HATCHet outperforms current state-of-the-art methods on multi-sample DNA sequencing data that we simulate using MASCoTE (Multiple Allele-specific Simulation of Copy-number Tumor Evolution). Applying HATCHet to 84 tumor samples from 14 prostate and pancreas cancer patients, we identify subclonal CNAs and WGDs that are more plausible than previously published analyses and more consistent with somatic single-nucleotide variants (SNVs) and small indels in the same samples.


Assuntos
Neoplasias da Mama/genética , Variações do Número de Cópias de DNA , Duplicação Gênica , Neoplasias Pancreáticas/genética , Neoplasias da Próstata/genética , Neoplasias da Mama/patologia , Conjuntos de Dados como Assunto , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Masculino , Taxa de Mutação , Metástase Neoplásica/genética , Neoplasias Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Análise de Célula Única , Sequenciamento Completo do Exoma
4.
Lancet Oncol ; 21(9): e431-e443, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888472

RESUMO

Peptide receptor radionuclide therapy (PRRT) is a type of radiotherapy that targets peptide receptors and is typically used for neuroendocrine tumours (NETs). Some of the key challenges in its use are the prediction of efficacy and toxicity, patient selection, and response optimisation. In this Review, we assess current knowledge on the molecular profile of NETs and the strategies and tools used to predict, monitor, and assess the toxicity of PRRT. The few mutations in tumour genes that can be evaluated (eg, ATM and DAXX) are limited to pancreatic NETs and are most likely not informative. Assays that are transcriptomic or based on genes are effective in the prediction of radiotherapy response in other cancers. A blood-based assay for eight genes (the PRRT prediction quotient [PPQ]) has an overall accuracy of 95% for predicting responses to PRRT in NETs. No molecular markers exist that can predict the toxicity of PRRT. Candidate molecular targets include seven single nucleotide polymorphisms (SNPs) that are susceptible to radiation. Transcriptomic evaluations of blood and a combination of gene expression and specific SNPs, assessed by machine learning with algorithms that are tumour-specific, might yield molecular tools to enhance the efficacy and safety of PRRT.


Assuntos
Proteínas de Neoplasias/genética , Tumores Neuroendócrinos/radioterapia , Neoplasias Pancreáticas/radioterapia , Receptores de Formil Peptídeo/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Masculino , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único/genética , Radioisótopos/uso terapêutico , Transcriptoma/efeitos da radiação
5.
Medicine (Baltimore) ; 99(37): e22089, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925749

RESUMO

Several indexes evaluating the lymph node metastasis of pancreatic neuroendocrine tumor (pNET) have been raised. We aimed to compare the prognostic value of the indexes via the analysis of Surveillance, Epidemiology, and End Results (SEER) database.We identified pNETs patients from SEER database (2004-2015). The prognostic value of N classification which adopted the 8th American Joint Committee on Cancer (AJCC) N classification for well differentiated pNET, revised N classification (rN) which adopted the AJCC 8th N classification for exocrine pancreatic cancer (EPC) and high grade pNET, lymph node ratio and log odds of positive nodes were analyzed.A total of 1791 eligible patients in the SEER cohort were included in this study. The indexes N, rN, lymph node ratio, and log odds of positive nodes were all significant independent prognostic factors for the overall survival. Specifically, the rN had the lowest akaike information criterion of 4050.19, the highest likelihood ratio test (χ) of 48.87, and the highest C-index of 0.6094. The rN was significantly associated with age, tumor location, tumor differentiation, T classification and M classification (P < .05 for all).The 8th version of AJCC N classification for high grade pNET could be generalized for the pNET population.


Assuntos
Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/secundário , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Idoso , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Razão de Chances , Valor Preditivo dos Testes , Prognóstico , Programa de SEER , Taxa de Sobrevida , Estados Unidos
6.
Medicine (Baltimore) ; 99(37): e22092, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925750

RESUMO

Pancreatic cancer (PaCa) is one of the most fatal cancers in the world. Although great efforts have made to explore the mechanisms of PaCa oncogenesis, the prognosis of PaCa patients is still unsatisfactory. Thus, it is imperative to further understand the potential carcinogenesis of PaCa and reliable prognostic models.The gene expression profile and clinical information of GSE21501 were downloaded from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was applied to explore the potent genes associated with the overall survival (OS) events of PaCa patients. Cox regression model was applied to selecting prognostic genes and establish prognostic model. The prognostic values of six-gene signature were validated in TCGA-PAAD cohort.According to the WGCNA analysis, a total of 19 modules were identified and 115 hub genes in the mostly associated module were reserved for next analysis. According to the univariate and multivariate Cox regression analysis, we established a six-gene signature (FTSJ3, STAT1, STX2, CDX2, RASSF4, MACF1) which could effectively evaluate the overall survival (OS) of PaCa patients. In validated patients' cohorts, the six-gene signature exhibited excellent prognostic value in TCGA-PAAD cohort as well.We developed a six-gene signature to exactly predict OS of PaCa patients and provide a novel personalized strategy for evaluating prognosis. The findings may be contributed to medical customization and therapeutic decision in clinical practice.


Assuntos
Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Fator de Transcrição CDX2/genética , Perfilação da Expressão Gênica , Humanos , Metiltransferases/genética , Proteínas dos Microfilamentos/genética , Modelos Estatísticos , Neoplasias Pancreáticas/patologia , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Fator de Transcrição STAT1/genética , Sintaxina 1/genética , Proteínas Supressoras de Tumor/genética
7.
Medicine (Baltimore) ; 99(37): e22115, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925757

RESUMO

Pancreatectomy for pancreatic cancer with arterial invasion is controversial and performed infrequently. As its indication evolves and neoadjuvant chemotherapy also evolves, it is meaningful to identify short- and long-term outcomes of pancreatectomy with arterial resection (AR). This study aimed to retrospectively analyze the clinical outcomes of pancreatectomy with AR for pancreatic ductal adenocarcinoma.Patients with pancreatic ductal adenocarcinoma treated with pancreatectomy with AR at our institute between January 2000 and April 2017 were retrospectively reviewed. Operative outcome and survival were compared according to the presence of neoadjuvant chemotherapy.This study included 109 patients (38 underwent surgery after neoadjuvant chemotherapy, 71 underwent upfront surgery). The median hospital stay was 17 (interquartile range, 12-26.5) days. Clinically relevant postoperative pancreatic fistula (grade B or C) occurred in 14 patients (12.8%). The major morbidity (≥grade III) and mortality rates were 26.6% and 0.9%, respectively. R0 resection was achieved in 80 patients (73.4%). Microscopic actual tumor invasion into the arterial wall was identified in 25 patients (22.9%). The median overall survival (OS) of all patients was 18.4 months. The neoadjuvant chemotherapy group showed better OS than the upfront surgery group, without statistical significance (25.3 vs 16.2 months, P = .06). Progression-free survival was better in patients with neoadjuvant chemotherapy (13.2 vs 7.1 months, P = .01). Patients with partial response to neoadjuvant chemotherapy showed better OS than those with stable disease (33.7 vs 17.5 months, P = .04).Pancreatectomy with AR for advanced pancreatic cancer showed acceptable procedure-related morbidity and mortality. A survival benefit of neoadjuvant chemotherapy was identified, compared to upfront surgery.


Assuntos
Carcinoma Ductal Pancreático/cirurgia , Artéria Celíaca/cirurgia , Artéria Hepática/cirurgia , Artéria Mesentérica Superior/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Idoso , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Taxa de Sobrevida
8.
Medicine (Baltimore) ; 99(36): e22090, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899087

RESUMO

BACKGROUND: Although surgical resection holds promise for curing pancreatic cancer, <20% of patients are suitable; however, early postoperative recurrence is common. Currently, radiographic examination is the primary method to determine whether pancreatic cancer has metastasized and to inform clinical staging before surgery. However, the method has a limited detection rate for micro-metastasis within the abdominal cavity; therefore, patients with advanced pancreatic cancer and existing micro-metastasis may receive unnecessary surgical treatment, delaying the timing of adjuvant chemotherapy and resulting in poor prognosis. Laparoscopic staging might be used as a supplement to detect micro-metastasis in patients with pancreatic cancer; however, there is no consistent standard to guide the use of this procedure. Therefore, it is necessary to conduct a trial to further explore the consistency and short-term and long-term efficacy of an intraoperative staging strategy for patients with radiographic non-metastasis. METHODS/DESIGN: This is a single-center cross-sectional and follow-up study. Patients diagnosed with pancreatic cancer without metastasis by radiographic examination and histopathological biopsy, who received intraoperative restaging, will be enrolled. The total sample size required for the trial is approximately 125 patients from May 2020 to December 2022. First, radiographic examination staging will be used. Then, laparoscopic exploration will be performed for patients without definite metastatic lesions. Data collection will include preoperative blood examination, radiographic examination, surgical information, and postoperative recovery. The patients will undergo follow-up every 3 months after surgery until death. The primary endpoint is the metastasis-positive rate via laparoscopic exploration. The secondary endpoints are the consistency, sensitivity, and specificity of the intraoperative restaging strategy and radiographic examination, the incidence of postoperative complications within 30 days, the 6-month relapse-free survival rate, and perioperative indicators (total cost, hospital stay, length of surgery, and intraoperative blood loss). DISCUSSION: We are conducting the trial to explore the metastasis-positive rate of intraoperative restaging strategy for diagnosing pancreatic cancer micro-metastasis. This new intraoperative restaging strategy would help pancreatic cancer patients with potential micro-metastasis avoid receiving unnecessary resection, allow systemic treatment as early as possible, and improve the prognosis of patients.


Assuntos
Endoscopia do Sistema Digestório/métodos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Seguimentos , Testes Hematológicos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/diagnóstico por imagem , Assistência Perioperatória/economia , Assistência Perioperatória/estatística & dados numéricos , Sensibilidade e Especificidade , Adulto Jovem
9.
Nat Commun ; 11(1): 4516, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908137

RESUMO

Acinar metaplasia is an initial step in a series of events that can lead to pancreatic cancer. Here we perform single-cell RNA-sequencing of mouse pancreas during the progression from preinvasive stages to tumor formation. Using a reporter gene, we identify metaplastic cells that originated from acinar cells and express two transcription factors, Onecut2 and Foxq1. Further analyses of metaplastic acinar cell heterogeneity define six acinar metaplastic cell types and states, including stomach-specific cell types. Localization of metaplastic cell types and mixture of different metaplastic cell types in the same pre-malignant lesion is shown. Finally, single-cell transcriptome analyses of tumor-associated stromal, immune, endothelial and fibroblast cells identify signals that may support tumor development, as well as the recruitment and education of immune cells. Our findings are consistent with the early, premalignant formation of an immunosuppressive environment mediated by interactions between acinar metaplastic cells and other cells in the microenvironment.


Assuntos
Células Acinares/patologia , Carcinoma Ductal Pancreático/genética , Regulação Neoplásica da Expressão Gênica , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Lesões Pré-Cancerosas/genética , Animais , Animais Geneticamente Modificados , Biópsia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Diferenciação Celular , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Heterogeneidade Genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Metaplasia/genética , Camundongos , Mutação , Pâncreas/citologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Lesões Pré-Cancerosas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA-Seq , Análise de Célula Única , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Microambiente Tumoral/genética
10.
Anticancer Res ; 40(9): 4969-4978, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878785

RESUMO

BACKGROUND/AIM: Traditional Chinese medicine (TCM) Brucea javanica (BJO) has shown anti-proliferation efficacy on human carcinoma cells in vitro. The aim of the present study was to evaluate for the first time the efficacy of BJO combined with the first-line chemotherapeutic drug gemcitabine (GEM) on tumor growth-inhibition and survival in a pancreatic cancer patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: The pancreatic cancer tumor fragment originated from a patient at the Hefei First People's Hospital (Anhui, PR China). The surgical specimen was transplanted orthotopically in nude mice using surgical orthotopic implantation (SOI). All mice were randomized and assigned to 5 groups: G1: saline vehicle (0.1ml per mouse, oral, once per day); G2: GEM [100 mg/kg, intraperitoneal (i.p), twice per week]; G3: GEM+BJO [100 mg/kg GEM, i.p, twice per week+1g/kg BJO, oral, once per day (qd)]; G4: BJO (1g/kg, oral, qd). Group 5 and Group 6 were used to observe survival [G5: saline vehicle (0.1ml per mouse, oral, qd), G6: BJO (1g/kg, oral, qd)]. Body weight and tumor volume were measured twice per week. TUNEL staining was used to determine apoptosis. RESULTS: The combination of GEM + BJO resulted in a reduced tumor growth rate (p<0.05) and greater apoptosis (p<0.05) compared to the vehicle control and GEM monotherapy. In addition, the BJO-treated group showed a statistically significant increase in survival compared to the vehicle control (p<0.05). CONCLUSION: BJO is a promising non-toxic TCM to effectively treat pancreatic cancer, both as monotherapy and in combination with first-line GEM therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brucea/química , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Desoxicitidina/uso terapêutico , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/patologia , Óleos Vegetais/uso terapêutico , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Anticancer Res ; 40(9): 5181-5189, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878806

RESUMO

BACKGROUND/AIM: Mathematical models have long been considered as important tools in cancer biology and therapy. Herein, we present an advanced non-linear mathematical model that can predict accurately the effect of an anticancer agent on the growth of a solid tumor. MATERIALS AND METHODS: Advanced non-linear mathematical optimization techniques and human-to-mouse experimental data were used to develop a tumor growth inhibition (TGI) estimation model. RESULTS: Using this mathematical model, we could accurately predict the tumor mass in a human-to-mouse pancreatic ductal adenocarcinoma (PDAC) xenograft under gemcitabine treatment up to five time periods (points) ahead of the last treatment. CONCLUSION: The ability of the identified TGI dynamic model to perform satisfactory short-term predictions of the tumor growth for up to five time periods ahead was investigated, evaluated and validated for the first time. Such a prediction model could not only assist the pre-clinical testing of putative anticancer agents, but also the early modification of a chemotherapy schedule towards increased efficacy.


Assuntos
Antineoplásicos/farmacologia , Modelos Teóricos , Dinâmica não Linear , Ensaios Antitumorais Modelo de Xenoenxerto , Algoritmos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia
12.
Nat Commun ; 11(1): 4611, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929072

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) and cancer-associated cachexia (CAC) are multifactorial and characterized by dysregulated inflammatory networks. Whether the proinflammatory cytokine IL-20 is involved in the complex networks of PDAC and CAC remains unclear. Here, we report that elevated IL-20 levels in tumor tissue correlate with poor overall survival in 72 patients with PDAC. In vivo, we establish a transgenic mouse model (KPC) and an orthotopic PDAC model and examine the therapeutic efficacy of an anti-IL-20 monoclonal antibody (7E). Targeting IL-20 not only prolongs survival and attenuates PD-L1 expression in both murine models but also inhibits tumor growth and mitigates M2-like polarization in the orthotopic PDAC model. Combination treatment with 7E and an anti-PD-1 antibody shows better efficacy in inhibiting tumor growth than either treatment alone in the orthotopic PDAC model. Finally, 7E mitigates cachexic symptoms in CAC models. Together, we conclude IL-20 is a critical mediator in PDAC progression.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/metabolismo , Interleucinas/antagonistas & inibidores , Modelos Biológicos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Caquexia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Análise de Sobrevida , Resultado do Tratamento , Triglicerídeos/sangue , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Anticancer Res ; 40(10): 5545-5556, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988878

RESUMO

BACKGROUND/AIM: The p38 family of mitogen-activated protein kinases (MAPK) includes four isoforms: p38α, -ß, -γ and -δ. The aim of this study was to elucidate possible functions of p38α and p38ß in human pancreatic cancer. MATERIALS AND METHODS: Isoform expression was determined in seven human pancreatic cancer cell lines. After shRNA based selective knockdown of p38α and p38ß, in vitro growth and migration as well as in vivo tumorigenicity were assessed. RESULTS: All pancreatic cancer cells expressed p38 isoforms. Knockdown of p38α and p38ß inhibited in vitro growth. Migration was markedly reduced in p38α shRNA expressing clones, but not altered by p38ß knockdown. While in vivo inhibition of p38ß decreased tumor formation and growth, the knockdown of p38α significantly enhanced tumorigenicity. CONCLUSION: p38 MAPKs may exert isoform specific functions in pancreatic cancer. Selective targeting may contribute to individualized treatment of pancreatic cancer in the future.


Assuntos
Proteína Quinase 11 Ativada por Mitógeno/genética , Proteína Quinase 14 Ativada por Mitógeno/genética , Neoplasias Pancreáticas/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Neoplasias Pancreáticas/patologia , Fosforilação , Isoformas de Proteínas/genética , RNA Interferente Pequeno/genética
14.
Anticancer Res ; 40(10): 5845-5851, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988914

RESUMO

BACKGROUND: Pancreatic mass sampling has historically been performed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). However, its sensitivity has been reported to be within a wide range, which limits its reliability. Fine needle biopsy (FNB) has been shown to have superior diagnostic performance and is increasingly replacing fine needle aspiration. In FNA, 25 gauge (G) needles appear to outperform 22G. Data comparing these sizes in FNB platforms is limited. We aimed to prospectively compare the performance of 22G and 25G Franseen-tip core biopsy needles in the sampling of solid pancreatic lesions. PATIENTS AND METHODS: Patients who underwent EUS-FNB of pancreatic lesions at the Indiana University Hospital using 2 needle sizes: 25G (Study group) and 22G (Control group) using the Acquire needle (Boston Scientific Co., Natick, MA, USA) were enrolled. Needle choice was left to the discretion of the endosonographer. Tissue specimens were evaluated onsite, and underwent touch and smear and cellblock preparation. Specimens were independently evaluated by 2 expert cytopathologists blinded to diagnosis. Cytopathologists assessed cytological yield (on smears) and histological yield (on cellblock) using a validated scoring system reached by a consensus among our cytopathologists as we have previously published. RESULTS: A total of 75 patients (42 males, median=65 years) underwent EUS-FNB during the study period (2017-2018): 50 using 25G and 25 using 22G needle. Diagnostic yield was numerically higher in 25G (98% vs. 88%, p=0.105). Number of passes for smears were similar, however the 25G group required additional passes for cell-block (1.6 vs. 0.4, p=0.001). 25G was used more frequently for pancreatic head and uncinate process sampling (70% vs. 52%, p=0.126). Four patients had self-limited adverse events in the 22G group, but none in the 25G group. CONCLUSION: We report no difference in the diagnostic yield between 25G FNB vs. 22G sampling device with Franseen style tip, however, the 25G needle use was associated with the need of additional passes to collect a sufficient cell block.


Assuntos
Biópsia com Agulha de Grande Calibre , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Neoplasias Pancreáticas/diagnóstico , Idoso , Endossonografia , Feminino , Humanos , Indiana , Masculino , Pessoa de Meia-Idade , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Manejo de Espécimes
15.
Medicine (Baltimore) ; 99(33): e21682, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872039

RESUMO

To investigate the clinicopathological characteristics and relevant prognostic factors of gastro-entero-pancreatic neuroendocrine neoplasm (GEP-NEN), to improve our understanding of GEP-NEN.This was a retrospective analysis of 155 patients (average age 53.7 ±â€Š13.6 years) pathologically diagnosed with GEP-NEN. We analyzed the clinicopathological characteristics, treatment, and prognostic factors of GEP-NEN.The most common primary site was the pancreas (41.9%), followed by the rectum, stomach and duodenum. Most cases were nonfunctional GEP-NENs (149/155) with nonspecific symptoms. TNM stage and histological grade were determined by the latest criteria. Surgical resection was the mainstay of treatment in 150 patients, and 22 patients received chemotherapy under different circumstances. A total of 130 patients were followed up for a median of 44 months, and 1-year and 3-year survival rates were 82.3% and 72.3%, respectively. According to univariate and multivariate analysis, incidental diagnosis, maximum tumor diameter, tumor stage, lymph node and distant metastasis, TNM stage, and histological grade were significantly correlated with overall survival, but histological grade was the only factor confirmed as an independent prognostic factor for long-term survival of GEP-NEN.GEP-NEN, with an increasing trend in incidence, occurred most frequently in the pancreas. Nonfunctional tumors with nonspecific symptoms comprised the majority of cases. The main treatment was surgical resection. Histological grade was confirmed as the only independent prognostic factor.


Assuntos
Neoplasias Intestinais/mortalidade , Tumores Neuroendócrinos/mortalidade , Neoplasias Pancreáticas/mortalidade , Neoplasias Gástricas/mortalidade , Adulto , Idoso , Feminino , Humanos , Neoplasias Intestinais/patologia , Neoplasias Intestinais/terapia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia
16.
Medicine (Baltimore) ; 99(31): e21471, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756169

RESUMO

RATIONALE: Although rare, pancreatic neoplasms can occur during pregnancy, both in benign and malignant forms. Mucinous cystic neoplasms (MCNs) of the pancreas, a type of these neoplasms, are precursor lesions to invasive pancreatic cancer. The presence of the ovarian-type stroma is a defining feature. PATIENT CONCERNS: The first case was a 38-year-old woman in her 18th week of pregnancy with abdominal pain that worsens a few weeks later. The second case was a 30-year-old woman in her 17th week of pregnancy with abdominal pain in the left hypochondrium. DIAGNOSIS: The patients were under clinical examination and laboratory test including carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA). Both patients had magnetic resonance imaging (MRI). The diagnosis of a MCNs of the pancreas was done preoperatively in the 2 cases. INTERVENTIONS: Both patients underwent distal pancreatectomy during pregnancy. One of them was an emergency laparotomy because of a ruptured MCN. OUTCOMES: Both patients were completely recovered from distal pancreatectomy and continued to full term, delivering a healthy baby by Caesarean section. After 6 years of follow-up, the first patient underwent a total gastrectomy, because of a gastric cancer with carcinomatosis. Currently the 2 patients are still alive after 8 years and 5 years of follow-up, respectively. LESSONS: Surgical resection of MCNs during pregnancy should be considered during the second trimester given common distal pancreas location, rapid growth, risk of spontaneous rupture, and malignant potential.


Assuntos
Dor Abdominal/etiologia , Cistadenoma Mucinoso/cirurgia , Neoplasias Pancreáticas/patologia , Adulto , Assistência ao Convalescente , Antígeno CA-19-9/metabolismo , Antígeno Carcinoembrionário/metabolismo , Cesárea/métodos , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Pancreatectomia/métodos , Neoplasias Pancreáticas/diagnóstico por imagem , Gravidez , Complicações Neoplásicas na Gravidez/epidemiologia , Período Pré-Operatório , Resultado do Tratamento
17.
Internist (Berl) ; 61(9): 964-968, 2020 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-32734334

RESUMO

BACKGROUND: We report the case of a 46-year-old female patient who presented in the emergency department with intermittent disturbances of perception when fasting. DIAGNOSTICS: In the diagnostic fasting test, a hyperinsulinemic hypoglycemia already occurred after 7h. A sonographic examination was inconspicuous, therefore, a Ga 68-HA-DOTATATE positron emission tomography computed tomography (PET-CT) was carried out. The results were indicative of a neuroendocrine neoplasm, which gave rise to the suspicion of an insulinoma. CLINICAL COURSE: For surgical treatment the patient was transferred to an external hospital. Following surgery, the patient was free of symptoms. CONCLUSION: If multiple symptoms of hypoglycemia are present, an insulinoma as the cause must be considered in the differential diagnostics.


Assuntos
Jejum/efeitos adversos , Hipoglicemia/diagnóstico , Hipoglicemia/etiologia , Insulinoma/complicações , Insulinoma/diagnóstico por imagem , Tumores Neuroendócrinos/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Compostos Organometálicos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Tomografia por Emissão de Pósitrons , Cintilografia
18.
Nat Commun ; 11(1): 4055, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32792504

RESUMO

Although metastasis is the most common cause of cancer deaths, metastasis-intrinsic dependencies remain largely uncharacterized. We previously reported that metastatic pancreatic cancers were dependent on the glucose-metabolizing enzyme phosphogluconate dehydrogenase (PGD). Surprisingly, PGD catalysis was constitutively elevated without activating mutations, suggesting a non-genetic basis for enhanced activity. Here we report a metabolic adaptation that stably activates PGD to reprogram metastatic chromatin. High PGD catalysis prevents transcriptional up-regulation of thioredoxin-interacting protein (TXNIP), a gene that negatively regulates glucose import. This allows glucose consumption rates to rise in support of PGD, while simultaneously facilitating epigenetic reprogramming through a glucose-fueled histone hyperacetylation pathway. Restoring TXNIP normalizes glucose consumption, lowers PGD catalysis, reverses hyperacetylation, represses malignant transcripts, and impairs metastatic tumorigenesis. We propose that PGD-driven suppression of TXNIP allows pancreatic cancers to avidly consume glucose. This renders PGD constitutively activated and enables metaboloepigenetic selection of additional traits that increase fitness along glucose-replete metastatic routes.


Assuntos
Cromatina/metabolismo , Glucose/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Transporte Biológico/genética , Transporte Biológico/fisiologia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Reprogramação Celular/genética , Reprogramação Celular/fisiologia , Imunoprecipitação da Cromatina , Epigênese Genética/genética , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/genética , Fosfogluconato Desidrogenase/genética , Fosfogluconato Desidrogenase/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo
19.
AAPS PharmSciTech ; 21(6): 231, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778980

RESUMO

The classically used nontargeted chemotherapeutic approach to pancreatic cancer has a dual drawback of suboptimal drug delivery at the target site and the systemic side effects produced by the unfettered exposure of the drug to healthy tissue. This study has the objective of developing novel poly(2-ethyl-2-oxazoline) (PETOX)-based long circulating liposomes loaded with gemcitabine and irinotecan for the treatment of pancreatic ductal adenocarcinoma, with a juxtaposition to PEGylated and uncoated liposomes. A PETOX-cholesteryl chloroformate lipopolymer conjugate (PETOX-ChC) with a carbonate linkage was prepared and characterized by 1H NMR, FTIR, and DSC. Liposomes were prepared using the thin film hydration technique followed by freeze-thaw and membrane extrusion methods. Liposome characterization includes particle size determination, zeta potential determination using a zetameter, and structural elucidation using 31P NMR and cryo-TEM. The PETOXylated liposomes showed a particle size of 180.1 ± 2.2 nm and a zeta potential of - 33.63 ± 1.23 mV. The liposomal combination therapy of gemcitabine and irinotecan was found to have an IC50 value 39 times lower in comparison to the drug combination in solution, while the PEGylated and PETOXylated liposomes showed IC50 values 1.6 times lower and 2 times lower than that of uncoated liposomes, respectively, against Mia PaCa II pancreatic cancer cell line. The PEGylated and PETOXylated liposomes showed 4.1 and 5.4 times slower macrophagial uptake in vitro in comparison to the uncoated liposomes respectively. The PEGylated liposomes showed 11% higher in vitro macrophagial uptake in comparison to PETOXylated liposomes.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Irinotecano/administração & dosagem , Lipossomos , Neoplasias Pancreáticas/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias Pancreáticas/patologia , Tamanho da Partícula , Polietilenoglicóis/química
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