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1.
Acta Cytol ; 64(1-2): 103-123, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30970350

RESUMO

Advanced methods of molecular characterization have elucidated the genetic, epigenetic, and proteomic alterations associated with the broad spectrum of pancreatic disease, particularly neoplasia. Next-generation sequencing, in particular, has revealed the genomic diversity among pancreatic ductal adenocarcinoma, neuroendocrine and acinar tumors, solid pseudopapillary neoplasm, and other pancreatico-biliary neoplasms. Differentiating these entities from one another by morphologic analysis alone may be challenging, especially when examining the small quantities of diagnostic material inherent to cytologic specimens. In order to enhance the sensitivity and specificity of pancreatic cytomorphology, multiple diagnostic, prognostic, and predictive ancillary tests have been and continue to be developed. Although a great number of such tests have been developed for evaluation of specimens collected from cystic lesions and strictures, ancillary techniques also play a significant role in the evaluation of cytologic specimens obtained from solid lesions of the pancreas. Furthermore, while some tests have been developed to differentiate diagnostic entities from one another, others have been developed to simply identify dysplasia and malignancy. Ancillary studies are particularly important in the subset of cases for which cytomorphologic analysis provides a result that is equivocal or insufficient to guide clinical management. Selection of appropriate ancillary testing modalities requires familiarity with both their methodology and the molecular basis of the pancreatic diseases for which testing is being performed.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Citodiagnóstico/métodos , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , MicroRNAs/genética , Pâncreas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Sensibilidade e Especificidade , Proteína Smad4/genética , Proteína Smad4/metabolismo
2.
Cancer Sci ; 111(1): 266-278, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31746520

RESUMO

According to cancer genome sequences, more than 90% of cases of pancreatic ductal adenocarcinoma (PDAC) harbor active KRAS mutations. Digital PCR (dPCR) enables accurate detection and quantification of rare mutations. We assessed the dynamics of circulating tumor DNA (ct-DNA) in patients with advanced PDAC undergoing chemotherapy using dPCR. KRAS G12/13 mutation was assayed by dPCR in 47 paired tissue- and ct-DNA samples. The 21 patients were subjected to quantitative ct-DNA monitoring at 4 to 8-week intervals during chemotherapy. KRAS mutation was detected in 45 of those 47 patients using tissue DNA. In the KRAS mutation-negative cases, next-generation sequencing revealed KRAS Q61K and NRAS Q61R mutations. KRAS mutation was detected in 23/45 cases using ct-DNA (liver or lung metastasis, 18/19; mutation allele frequency [MAF], 0.1%-31.7%; peritoneal metastasis, 3/9 [0.1%], locally advanced, 2/17 [0.1%-0.2%]). In the ct-DNA monitoring, the MAF value changed in concordance with the disease state. In the 6 locally advanced cases, KRAS mutation appeared concurrently with liver metastasis. Among the 6 cases with liver metastasis, KRAS mutation disappeared during the duration of stable disease or a partial response, and reappeared at the time of progressive disease. The median progression-free survival was longer in cases in which KRAS mutation disappeared after an initial course of chemotherapy than in those in which it was continuously detected (248.5 vs 50 days, P < .001). Therefore, ct-DNA monitoring enables continuous assessment of disease state and could have prognostic utility during chemotherapy.


Assuntos
DNA Tumoral Circulante/genética , DNA/sangue , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética , Adulto , Idoso , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Estudos de Avaliação como Assunto , Feminino , Frequência do Gene/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Prognóstico , Intervalo Livre de Progressão
3.
Nat Med ; 25(12): 1865-1872, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792456

RESUMO

Viruses are implicated in autoimmune destruction of pancreatic islet ß cells, which results in insulin deficiency and type 1 diabetes (T1D)1-4. Certain enteroviruses can infect ß cells in vitro5, have been detected in the pancreatic islets of patients with T1D6 and have shown an association with T1D in meta-analyses4. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses7 and the selection of variants with altered pathogenicity and ability to spread in populations. ß cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection8. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to ß cells between serotypes and within the same serotype9,10. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.


Assuntos
Autoimunidade/imunologia , Diabetes Mellitus Tipo 1/virologia , Enterovirus/isolamento & purificação , RNA Viral/isolamento & purificação , Adolescente , Autoimunidade/genética , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/patologia , Enterovirus/imunologia , Enterovirus/patogenicidade , Fezes/virologia , Feminino , Humanos , Lactente , Insulina/metabolismo , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/virologia , Ilhotas Pancreáticas/imunologia , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/virologia , Masculino , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/virologia
4.
Genes Dev ; 33(21-22): 1475-1490, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676735

RESUMO

A comprehensive understanding of mechanisms that underlie the development and function of human cells requires human cell models. For the pancreatic lineage, protocols have been developed to differentiate human pluripotent stem cells (hPSCs) into pancreatic endocrine and exocrine cells through intermediates resembling in vivo development. In recent years, this differentiation system has been employed to decipher mechanisms of pancreatic development, congenital defects of the pancreas, as well as genetic forms of diabetes and exocrine diseases. In this review, we summarize recent insights gained from studies of pancreatic hPSC models. We discuss how genome-scale analyses of the differentiation system have helped elucidate roles of chromatin state, transcription factors, and noncoding RNAs in pancreatic development and how the analysis of cells with disease-relevant mutations has provided insight into the molecular underpinnings of genetically determined diseases of the pancreas.


Assuntos
Modelos Biológicos , Pâncreas/citologia , Pâncreas/crescimento & desenvolvimento , Células-Tronco Pluripotentes/citologia , Diferenciação Celular , Estudo de Associação Genômica Ampla , Humanos , Pâncreas/patologia , Pancreatopatias/genética , Pancreatopatias/fisiopatologia , Células-Tronco Pluripotentes/fisiologia
5.
Anticancer Res ; 39(11): 6283-6290, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704858

RESUMO

BACKGROUND/AIM: The usefulness of C-reactive protein-to-albumin ratio (CAR) as a predictive indicator for clinically-relevant postoperative pancreatic fistula (CR-POPF) after pancreaticoduodenectomy (PD) is unclear. We performed a retrospective analysis to identify reliable inflammatory indicators for prediction of CR-POPF after PD. PATIENTS AND METHODS: We enrolled 160 consecutive patients who underwent PD. Multivariate logistic regression analysis was performed. The areas under curves (AUCs) were compared with the discriminatory ability of inflammatory indicators, namely, C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), platelet count multiplied by C-reactive protein (P-CRP), and CAR. RESULTS: The AUC for CAR on POD 3 to predict CR-POPF was 0.782 (p<0.001) and higher than that for CRP (0.773), NLR (0.652), PLR (0.504), and P-CRP (0.703). Multivariate analysis revealed that CAR on POD 3 was an independent predictive indicator of CR-POPF. CONCLUSION: CAR on POD 3 is a reliable predictor of CR-POPF after PD.


Assuntos
Proteína C-Reativa/análise , Fístula Pancreática/sangue , Pancreaticoduodenectomia/efeitos adversos , Complicações Pós-Operatórias/sangue , Albumina Sérica/análise , Idoso , Amilases/análise , Biomarcadores/sangue , Feminino , Humanos , Modelos Logísticos , Contagem de Linfócitos , Masculino , Neutrófilos/citologia , Pâncreas/patologia , Ductos Pancreáticos/patologia , Fístula Pancreática/diagnóstico , Fístula Pancreática/etiologia , Contagem de Plaquetas , Complicações Pós-Operatórias/diagnóstico , Curva ROC , Estudos Retrospectivos
6.
Klin Lab Diagn ; 64(11): 644-648, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31747490

RESUMO

The aim of the study was to assess the information content of volatile fatty acid parameters for the differential diagnosis of infected and sterile pancreatic necrosis. The work is based on the results of examination and treatment of 34 patients with pancreatic necrosis. The analysis of concentrations of volatile fatty acids: acetic, propionic, butyric and isovaleric was carried out on an automated gas chromatograph «Crystallux-4000¼ with a capillary column «HP-FFAP¼ and flame ionization detector. The indicators of acetic, propionic, butyric, isovaleric acid and the sum of volatile fatty acids are statistically significantly higher in patients with infected pancreatic necrosis compared with the indicators of volatile fatty acids in patients with sterile pancreatic necrosis. Volatile fatty acid values can be used for the differential diagnosis of infected and sterile pancreatic necrosis.


Assuntos
Ácidos Graxos Voláteis/análise , Necrose/diagnóstico , Pâncreas/patologia , Cromatografia Gasosa , Diagnóstico Diferencial , Humanos
8.
Postepy Biochem ; 65(3): 224-230, 2019 10 01.
Artigo em Polonês | MEDLINE | ID: mdl-31643170

RESUMO

Berberine (BRB) is a compound belonging to the group of isoquinoline alkaloids of plant origin that has long been used in traditional chinese medicine (TMC). Due to, among others anti-inflammatory properties BRB is a potential therapeutic in the treatment of acute pancreatitis (OZT). In a study in the mouse model of L-arginine-induced acute pancreatitis, we showed that BRB administered by the intravenous route at 0.1 and 0.5 mg / kg body weight significantly reduces the level of myeloperoxidase activity (an indicator of inflammation) in the pancreas and lungs. Promising results point to the need for larger, randomized studies to assess the long-term efficacy and side effects of BRB therapy.


Assuntos
Berberina/uso terapêutico , Pancreatite/tratamento farmacológico , Doença Aguda/terapia , Animais , Berberina/farmacologia , Modelos Animais de Doenças , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pâncreas/efeitos dos fármacos , Pâncreas/patologia
9.
Arkh Patol ; 81(5): 22-29, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31626201

RESUMO

OBJECTIVE: To determine the morphological features of IgG4-related lesions and to improve pathomorphological criteria for diagnosing various clinical variants of IgG4-related disease. MATERIAL AND METHODS: Biopsy and surgical materials from 100 patients with tumor-like lesions at various sites (63 cases of IgG4-related lesion and 37 cases of non-IgG4-related inflammatory processes) were studied. Histological and immunohistochemical studies were conducted to determine the absolute counts of CD138+ cells, IgG+ and IgG4+ in the inflammatory infiltrates, as well as IgG4/IgG and IgG4/CD138 cell ratios. RESULTS: When IgG4-related disease manifested, pancreatic, lacrimal, and salivary gland lesions prevailed. Brisk lymphoplasmacytic infiltration is characteristic for tissue damage in the eye, salivary glands, thyroid, pancreas, and skin. The formation of moiré fibrosis was specific to damages to the pancreas, liver and bile ducts, and eye tissues. Obliterative phlebitis is most often observed in pancreatic and salivary gland lesions. According to international criteria, the frequency of achieving the required level of IgG4+ plasma cells in each organ was high in lesions of the pancreas, bile ducts, and lymph nodes and that was low in lesions of the salivary and lacrimal glands and skin. The IgG4+/CD138+ and IgG4+/IgG+ cell ratios exceeded 40% in all cases. CONCLUSION: The morphologic diagnosis of IgG4-related disease is based on the detection of lymphoplasmacytic infiltration, moiré fibrosis, and obliterative phlebitis, as well as on the calculation of the absolute number of IgG4+ plasma cells in the inflammatory infiltrate and on the determination of IgG4+/IgG+ and IgG4+/CD138+ cell ratios. The number of IgG4+ plasma cells depends on the location of the lesion and on the phase of the process.


Assuntos
Fibrose , Doença Relacionada a Imunoglobulina G4/patologia , Ductos Biliares/patologia , Biópsia , Humanos , Imunoglobulina G , Aparelho Lacrimal/patologia , Fígado/patologia , Pâncreas/patologia , Plasmócitos , Glândulas Salivares/patologia
10.
Anticancer Res ; 39(10): 5821-5830, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570487

RESUMO

BACKGROUND/AIM: The significance of the anatomical variations of proximal jejunal vein [the so-called 1st jejunal vein (J1v)] has been reported from a technical standpoint. The aim of this study was to retrospectively investigate the prognostic impact of the anatomical variations of J1v in the surgical treatment of resectable pancreatic cancer (PC). PATIENTS AND METHODS: A total of 49 patients with resectable PC located in the uncinate process were included in this study. The J1v converging pattern was divided into 2 groups in terms of its relation to the SMA (i.e., the J1v status): i) group D: the J1v travels posterior to the SMA; ii) group V: the J1v travels anterior to the SMA. The associations between the J1v status and surgical outcome were assessed. RESULTS: The 5-year survival rate after resection in group V (35%) was significantly lower than that in group D (70%) (p=0.029), and the J1v status of group V was the only independent negative prognostic factor (HR=5.49; 95% CI=1.69-19.3; p=0.005). CONCLUSION: The J1v converging pattern is a significant prognostic variable in patients with PC located in the uncinate process: the J1v status of group V was significantly associated with impaired survival.


Assuntos
Jejuno/patologia , Neoplasias Pancreáticas/patologia , Veia Porta/patologia , Idoso , Quimiorradioterapia/métodos , Feminino , Humanos , Jejuno/efeitos dos fármacos , Jejuno/efeitos da radiação , Masculino , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias/métodos , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pâncreas/efeitos da radiação , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/radioterapia , Veia Porta/efeitos dos fármacos , Veia Porta/efeitos da radiação , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
11.
Khirurgiia (Mosk) ; (9): 25-31, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31532163

RESUMO

OBJECTIVE: To evaluate the outcomes in patients undergoing surgery for metastatic renal cell carcinoma (RCC) to the pancreas. MATERIAL AND METHODS: A retrospective analysis included 54 patients with pancreatic metastases (PM) of RCC who underwent surgical treatment at the Blokhin National Cancer Medical Research Center and Vishnevsky National Medical Research Center of Surgery in 1995-2018. PM were synchronous in 6 (11%) patients and metachronous in 48 (89%) patients. Solitary metastases were identified in 35 (65%), single metastases - in 14 (26%), multiple metastases - in 5 (9%) patients. Thirty (56%) patients had isolated PM, 24 (44%) patients - PM associated with another metastatic site. The following surgical procedures were performed: distal pancreatectomy (n=30, 55%), pancreatoduodenectomy (n=12, 21%), total pancreatectomy (n=6, 12%), pancreatic head resection (n=3, 6%), middle-preserving pancreatectomy (n=1, 2%), middle pancreatectomy (n=1, 2%), cryosurgical destruction of tumor (n=1, 2%). RESULTS: Median blood loss was 950 ml (interquartile range 400-1800 ml). Postoperative complications occurred in 52% patients. The 90-day mortality rate was 6%, overall 5-year survival 74±7%, median - 84 months. CONCLUSION: Surgery is associated with an acceptable perioperative complications and long-term survival in patients with synchronous and metachronous, solitary and multiple PM of RCC, including cases of extrapancreatic disease. This approach may be considered as a management option in these patients.


Assuntos
Carcinoma de Células Renais/cirurgia , Neoplasias Renais/patologia , Neoplasias Pancreáticas/cirurgia , Carcinoma de Células Renais/secundário , Humanos , Neoplasias Primárias Múltiplas/cirurgia , Segunda Neoplasia Primária/cirurgia , Pâncreas/patologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/secundário , Pancreaticoduodenectomia , Estudos Retrospectivos
12.
Eur J Radiol ; 120: 108673, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31550640

RESUMO

PURPOSE: To evaluate the imaging pattern of pancreaticobiliary lesions in patients with treated type 1AIP, to determine the incidence of disease relapse and malignancy, and to identify the risk factors. METHOD: The institutional review board approval was acquired. All patients gave written informed consent. From a prospective clinico-radiological database since 2012, consecutive patients with type 1 AIP who were treated and followed up (≥18 months) were identified. The presence/absence of pancreaticobiliary lesion(s) development during follow-up were assessed. The etiology was determined and the imaging pattern was compared to the initial attack. Risk factors were identified by univariate and multivariate analysis. RESULTS: Among 103 patients with treated type 1 AIP, 44 (42.7%) developed pancreaticobiliary lesions during follow up (median time interval to initial diagnosis: 17 months, range 3-62 months), mostly after steroid discontinuation (63.6%) or during maintenance therapy (29.5%). All lesions were disease relapse, which responded to steroid treatment. At relapse, pancreatic involvement was less frequent (81.8% vs 100%, p = 0.003), and the pancreas size was smaller (p < 0.01), whereas extra-pancreatic bile duct (ExPanBD) involvement was more severe and extensive (both p < 0.01). Multivariate analysis revealed ExPanBD involvement at initial diagnosis (hazard ratio 2.437, 95% CI 1.343-7.402, p = 0.002) and serum IgG4 response ratio at the induction phase (hazard ratio 0.357, 95% CI 0.055-0.804, p = 0.011) as significant independent predictors of relapse. CONCLUSIONS: In treated type 1 AIP, although imaging pattern may differ, pancreaticobiliary lesions are usually manifestations of disease relapse. ExPanBD involvement and poor serum response suggests high risk of relapse.


Assuntos
/patologia , Doenças dos Ductos Biliares/patologia , Adulto , Idoso , Biomarcadores/metabolismo , Esquema de Medicação , Feminino , Glucocorticoides/administração & dosagem , Humanos , Imunoglobulina G/metabolismo , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Imagem Multimodal/métodos , Pâncreas/patologia , Prednisolona/administração & dosagem , Estudos Prospectivos , Recidiva , Fatores de Risco
13.
Nat Rev Gastroenterol Hepatol ; 16(11): 676-689, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31527862

RESUMO

Pancreatic cystic neoplasms (PCN) are a heterogeneous group of pancreatic cysts that include intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, serous cystic neoplasms and other rare cystic lesions, all with different biological behaviours and variable risk of progression to malignancy. As more pancreatic cysts are incidentally discovered on routine cross-sectional imaging, optimal surveillance for patients with PCN is becoming an increasingly common clinical problem, highlighting the need to balance cancer prevention with the risk of (surgical) overtreatment. This Review summarizes the latest developments in the diagnosis and management of PCN, including the quality of available evidence. Also discussed are the most important differences between the PCN guidelines from the American Gastroenterological Association, the International Association of Pancreatology and the European Study Group on Cystic Tumours of the Pancreas, including diagnostic and follow-up strategies and indications for surgery. Finally, new developments in the management of patients with PCN are addressed.


Assuntos
Pâncreas/patologia , Cisto Pancreático/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Humanos , Cisto Pancreático/complicações , Cisto Pancreático/diagnóstico , Cisto Pancreático/terapia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/patologia
14.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(4): 575-578, 2019 Aug 30.
Artigo em Chinês | MEDLINE | ID: mdl-31484625

RESUMO

Autoimmune pancreatitis(AIP)is radiologically characterized by sausage-like diffuse swelling of the pancreatic parenchyma but may also be found as a localized mass that is easily misdiagnosed as a pancreatic neoplasm.AIP presenting as multifocal masses is rare.Here we report a case of multifocal IgG4-related AIP,in which the lesions grew in size and finally fused to become radiologically typical.


Assuntos
Doença Relacionada a Imunoglobulina G4/diagnóstico , Pancreatite/diagnóstico , Humanos , Doença Relacionada a Imunoglobulina G4/patologia , Pâncreas/patologia , Neoplasias Pancreáticas , Pancreatite/patologia
15.
Gastroenterology ; 157(6): 1660-1672.e2, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31493399

RESUMO

BACKGROUND & AIMS: Pancreatitis is characterized by increased influx of Ca2+ into acinar cells, by unknown mechanisms. Inhibitors of Ca2+ influx channels could be effective in treating acute pancreatitis, but these have deleterious side effects that can result in death. We investigated the expression patterns and functions of acinar cell Ca2+ channels and factors that regulate them during development of acute pancreatitis, along with changes in the channel inactivator store-operated calcium entry-associated regulatory factor (SARAF). We investigated whether SARAF is a target for treatment of acute pancreatitis and its status in human with pancreatitis. METHODS: We generated mice that expressed SARAF tagged with hemagglutinin, using CRISPR/Cas9 gene editing, and isolated acinar cells. We also performed studies with Saraf-/- mice, Sarafzf/zf mice, mice without disruption of Saraf (control mice), and mice that overexpress fluorescently labeled SARAF in acinar cells. We analyzed interactions between stromal interaction molecule 1 (STIM1) and SARAF in HEK cells stimulated with carbachol using fluorescence resonance energy transfer microscopy and immunoprecipitation. Mice were given injections of caerulein or L-arginine to induce pancreatitis. Pancreatic tissues and blood samples were collected and levels of serum amylase, trypsin, tissue damage, inflammatory mediators, and inflammatory cells were measured. We performed quantitative polymerase chain reaction analyses of pancreatic tissues from 6 organ donors without pancreatic disease (controls) and 8 patients with alcohol-associated pancreatitis. RESULTS: Pancreatic levels of Ca2+ influx channels or STIM1 did not differ significantly between acinar cells from mice with vs. without pancreatitis. By contrast, pancreatic levels of Saraf messenger RNA and SARAF protein initially markedly increased but then decreased during cell stimulation or injection of mice with caerulein, resulting in excessive Ca2+ influx. STIM1 interacted stably with SARAF following stimulation of HEK or mouse acinar cells with physiologic levels of carbachol, but only transiently following stimulation with pathologic levels of carbachol, leading to excessive Ca2+ influx. We observed reduced levels of SARAF messenger RNA in pancreatic tissues from patients with pancreatitis, compared with controls. SARAF knockout mice developed more severe pancreatitis than control mice after administration of caerulein or L-arginine, and pancreatic acinar cells from these mice had significant increases in Ca2+ influx. Conversely, overexpression of SARAF in acini reduced Ca2+ influx, eliminated inflammation, and reduced severity of acute pancreatitis. CONCLUSIONS: In mice with pancreatitis, SARAF initially increases but is then degraded, resulting in excessive, pathological Ca2+ influx by acinar cells. SARAF knockout mice develop more severe pancreatitis than control mice, whereas mice that express SARAF from a transgene in acinar cells develop less-severe pancreatitis. SARAF therefore appears to prevent pancreatic damage during development of acute pancreatitis. Strategies to stabilize or restore SARAF to acinar cells might be developed for treatment of pancreatitis.


Assuntos
Cálcio/metabolismo , Proteínas Sensoras de Cálcio Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Pâncreas/patologia , Pancreatite/patologia , Molécula 1 de Interação Estromal/metabolismo , Células Acinares/patologia , Animais , Ceruletídeo/toxicidade , Modelos Animais de Doenças , Células HEK293 , Humanos , Proteínas Sensoras de Cálcio Intracelular/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Pâncreas/citologia , Pancreatite/sangue , Pancreatite/induzido quimicamente , Índice de Gravidade de Doença
18.
Mol Carcinog ; 58(11): 2052-2064, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31397499

RESUMO

Recent studies have indicated that using statins to inhibit the mevalonate pathway induces mutant p53 degradation by impairing the interaction of mutant p53 with DnaJ subfamily A member 1 (DNAJA1). However, the role of the C-terminus of DNAJA1 with a CAAX box for farnesylation in the binding, folding, and translocation of client proteins such as mutant p53 is not known. In the present study, we used a genetically engineered mouse model of pancreatic carcinoma and showed that atorvastatin significantly increased animal survival and inhibited pancreatic carcinogenesis. There was a dramatic decrease in mutant p53 protein accumulation in the pancreatic acini, pancreas intraepithelial neoplasia lesions, and adenocarcinoma. Supplementation with farnesyl pyrophosphate, a substrate for protein farnesylation, rescued atorvastatin-induced mutant p53 degradation in pancreatic cancer cells. Tipifarnib, a farnesyltransferase inhibitor, mirrored atorvastatin's effects on mutant p53, degraded mutant p53 in a dose-dependent manner, and converted farnesylated DNAJA1 into unfarnesylated DNAJA1. Farnesyltransferase gene knockdown also significantly promoted mutant p53 degradation. Coimmunoprecipitation either by an anti-DNAJA1 or p53 antibody confirmed the direct interaction of mutant p53 and DNAJA1 and higher doses of atorvastatin treatments converted more farnesylated DNAJA1 into unfarnesylated DNAJA1 with much less mutant p53 pulled down by DNAJA1. Strikingly, C394S mutant DNAJA1, in which the cysteine of the CAAX box was mutated to serine, was no longer able to be farnesylated and lost the ability to maintain mutant p53 stabilization. Our results show that farnesylated DNAJA1 is a crucial chaperone in maintaining mutant p53 stabilization and targeting farnesylated DNAJA1 by atorvastatin will be critical for inhibiting p53 mutant cancer.


Assuntos
Atorvastatina/farmacologia , Proteínas de Choque Térmico HSP40/genética , Neoplasias Pancreáticas/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Animais , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Farnesiltranstransferase/antagonistas & inibidores , Farnesiltranstransferase/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Chaperonas Moleculares/genética , Proteínas Mutantes/genética , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Prenilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/genética , Quinolonas/farmacologia
19.
Indian J Med Res ; 149(4): 479-488, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31411171

RESUMO

Background & objectives: In contrast to Caucasians of European origin, the aetiology of diabetes mellitus (DM) in young adults in other ethnic groups, including Indians is likely to be heterogeneous and difficult to determine. This study was undertaken to determine the aetiology of diabetes in young Indian adults using a protocol-based set of simple clinical and investigation tools. Methods: In this prospective study, 105 Indian young adults with diabetes (age at onset 18-35 yr; duration <2 yr) were studied for a period of 1-3 years. Pancreatic imaging, fasting C-peptide, islet antibodies (against glutamic acid decarboxylase, tyrosine phosphatase and zinc transporter-8) and mitochondrial A3243G mutational analysis were performed in all patients. Four patients were screened for maturity-onset diabetes of the young (MODY) using next-generation sequencing. Results: Type 1 and type 2 diabetes mellitus (T1DM and T2DM) were equally frequent (40% each), followed by fibrocalculous pancreatic diabetes (FCPD, 15%). Less common aetiologies included MODY (2%), mitochondrial diabetes (1%) and Flatbush diabetes (2%). There was considerable phenotypic overlap between the main aetiological subtypes. Elevated islet antibodies were noted in 62 per cent of T1DM patients [positive predictive value (PPV) 84%; negative predictive value (NPV) 78%] while low plasma C-peptide (<250 pmol/l) was present in 56 per cent of T1DM patients [PPV 96% (after excluding FCPD), NPV 72%]. Using these tests and observing the clinical course over one year, a final diagnosis was made in 103 (99%) patients, while the diagnosis at recruitment changed in 23 per cent of patients. Interpretation & conclusions: The aetiology of diabetes in young adults was heterogeneous, with T1DM and T2DM being equally common. FCPD was also frequent, warranting its screening in Indian patients. Testing for islet antibodies and C-peptide in this age group had good PPV for diagnosis of T1DM.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Adolescente , Adulto , Idade de Início , Peptídeo C/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Índia/epidemiologia , Ilhotas Pancreáticas/patologia , Masculino , Pâncreas/patologia , Estudos Prospectivos , Adulto Jovem
20.
Nat Commun ; 10(1): 3637, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406163

RESUMO

Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.


Assuntos
Fibroblastos Associados a Câncer/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteoglicanas de Heparan Sulfato/metabolismo , Neoplasias Pancreáticas/patologia , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica/genética , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica/patologia , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Transdução de Sinais/fisiologia , Proteína Supressora de Tumor p53/genética
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