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1.
Medicina (B.Aires) ; 82(5): 708-713, Oct. 2022. graf
Article in English | LILACS-Express | LILACS | ID: biblio-1405726

ABSTRACT

Abstract Fine-needle aspiration (FNA) for the histological diagnosis of occupying lesions in the pancreas as opposed to tru-cut needle biopsy to obtain tissue for analysis has been associated with a lower incidence of post-procedure complications, with almost immediate recovery and no need for hospital stay. Nev ertheless, the question of the diagnostic effectiveness of percutaneous computed axial tomography (CT)-guided FNA in solid pancreatic lesions has been raised. The aim of this study was to confirm the diagnostic effectivity of percutaneous CT-guided FNA in pancreatic space-occupying lesions and to assess short-term complications. All percutaneous CT-guided FNA with real-time monitoring, performed between April 2010 and December 2015, were retrospectively analyzed. In all cases 21-gauge needles were used. All FNA were performed in the pres ence of a pathologist who immediately stained and reported as adequate for analysis in all cases. The diagnosis was confirmed by histopathological evaluation. Of 54 FNA performed, final histopathological evaluation revealed neoplastic cells compatible with adenocarcinoma in 52 patients (96%) and was negative for neoplastic cells in two patients (4%). The sensitivity was 94%, and the specificity 100%. Post-FNA morbidity was observed in four patients, consisting of epigastric pain in two and abdominal wall hematoma in two other patients. Percutaneous CT-guided FNA of pancreatic space-occupying lesions was found to be a good, minimally invasive and safe method with low morbidity. The presence of the pathologist in the procedure allowed for immediate cytological diagnosis.


Resumen El uso de la punción-aspiración con aguja fina (PAAF) en el diagnóstico histológico de lesiones ocupantes de páncreas es una alternativa frente al uso de agujas tru-cut en la obtención de tejido para su análisis, con una incidencia más baja de complicaciones y una recuperación casi inmediata sin necesidad de internación. El objetivo fue valorar la efectividad diagnóstica de las PAAF de lesiones ocupantes pancreáticas guiadas por tomografía axial computada (TAC) por vía percutánea, y su tasa de complicaciones a corto plazo. Se analizaron de forma retrospectiva todas las PAAF realizadas mediante guía tomográfica por vía percutánea con control en tiempo real, entre abril 2010 y diciembre 2015. Todas las PAAF se realizaron en presencia de un patólogo que inmediatamente tiñó e informó como adecuado para el análisis. La confirmación diagnóstica se hizo con el análisis anatomopatológico diferido. De las 54 PAAF realizadas, el diagnóstico anatomopatológico informó positivo para células neoplásicas compatible con adenocarcinoma en 52 pacientes (96%) y en otros dos (4%) como negativo para células neoplásicas. La sensibilidad del método fue 94% y la especificidad del 100%. Se registraron 4 casos de morbilidad post punción (2 dolores epigástricos y 2 hematomas de pared abdominal). Las punciones percutáneas de lesiones ocupantes pancreáticas guiadas por TC pueden considerarse un buen método diagnóstico mini invasivo, seguro, con una morbilidad post punción baja. La presencia del patólogo en el procedimiento permitió el diagnóstico citológico inmediato.

2.
Medicentro (Villa Clara) ; 26(3): 715-733, jul.-set. 2022.
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1405665

ABSTRACT

RESUMEN Introducción: El cáncer pancreático es aquel que comienza en el páncreas, que es una pequeña glándula localizada en el abdomen, detrás del estómago. Esta enfermedad constituye la neoplasia más letal que puede padecer un ser humano. Objetivo: Recopilar información sobre la morbilidad y mortalidad en pacientes con cáncer de páncreas que fueron sometidos a pancreatectomías. Métodos: Se realizó una revisión actualizada de la literatura disponible. Los artículos se identificaron a través de la búsqueda automatizada en las bases de datos: PubMed, SciELO, y Google académico. Se consultaron un total de 26 referencias bibliográficas, de ellas, 25 corresponden a los últimos cinco años. Conclusiones: El diagnóstico precoz, las mejores técnicas quirúrgicas, la disponibilidad de unidades de cuidados intensivos, cuando son necesarias, y la aplicación de medidas para disminuir la estancia hospitalaria, son los aspectos principales para la obtención de mejores índices de morbilidad y mortalidad quirúrgica en pacientes que fueron sometidos a pancreatectomías.


ABSTRACT Introduction: pancreatic cancer is one that begins in the pancreas, which is a small gland located in the abdomen, behind the stomach. This disease is the most lethal neoplasm that a human being can suffer. Objective: to collect information on morbidity and mortality in pancreatic cancer patients who underwent pancreatectomies. Methods: an updated review of the available literature was performed. The articles were identified through the automated search in PubMed, SciELO, and Google Scholar databases. A total of 26 bibliographic references were consulted, 25 of them corresponded to the last five years. Conclusions: early diagnosis, the best surgical techniques, the availability of intensive care units, when necessary, as well as the application of measures to reduce hospital stay are the main aspects for obtaining better rates of surgical morbidity and mortality in patients who underwent pancreatectomies.

3.
Rev. Assoc. Med. Bras. (1992, Impr.) ; 68(8): 1023-1026, Aug. 2022. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1406600

ABSTRACT

SUMMARY OBJECTIVES: Black cumin is widely used as a spice and as a traditional treatment. The active ingredient in black cumin seeds is thymoquinone. Thymoquinone has shown anticancer effects in some cancers. We planned to investigate its anticancer effect on pancreatic cancer cell lines. METHODS: Thymoquinone chemical component in various doses was prepared and inoculated on pancreatic cancer cell culture, healthy mesenchymal stem cells, and peripheral blood mononuclear cell culture. IC50 values were calculated by absorbance data and measuring cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide staining of cells incubated with thymoquinone at 24, 48, and 72 h. RESULTS: There was dose-related cytotoxicity. Maximal cytotoxicity was observed at 24 h and 100 μM thymoquinone concentrations in pancreatic cancer cell culture and mesenchymal stem cells. Any concentration of thymoquinone was not cytotoxic to peripheral blood mononuclear cell. Thymoquinone even caused proliferation at a concentration of 6.25 μM. CONCLUSIONS: Since the cytotoxic concentration of thymoquinone on pancreatic cancer cell culture and mesenchymal stem cells is the same, it is not appropriate to use thymoquinone to achieve cytotoxicity in pancreatic cancer. However, since thymoquinone provides proliferation in peripheral blood mononuclear cell at a noncytotoxic dose, it may have an immune activator effect. Therefore, in vivo studies are needed to investigate the effect of thymoquinone on the immune system.

4.
An. Fac. Cienc. Méd. (Asunción) ; 55(2): 97-104, 20220801.
Article in Spanish | LILACS | ID: biblio-1380451

ABSTRACT

El adenocarcinoma pancreático ductal (APD) es la cuarta causa de muerte por cáncer y se proyecta que para el 2030 ocupe el segundo lugar. El pronóstico es sombrío, siendo la sobrevida menor a 9% en 5 años. Se consideró durante mucho tiempo a la resección quirúrgica como el único tratamiento curativo, sin embargo, sólo el 15 a 20% de los pacientes pueden ser beneficiados con la misma. La clasificación pre terapéutica más utilizada es la del National Comprehensive Cáncer Network (NCCN), basada en la relación del tumor con estructuras vasculares, clasificándolos en tumores "resecables", de resección límite "Borderlines" y "localmente avanzados". Se presenta el primer caso registrado en Paraguay de APD con infiltración de la Vena Mesentérica Superior (VMS) tratado con duodenopancreatectomía cefálica (DPC) asociada a resección vascular mayor.


Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death and is projected to rank second by 2030. The prognosis is bleak, with survival being less than 9% in 5 years. For a long time, surgical resection was considered the only curative treatment, however, only 15 to 20% of patients can benefit from it. The most widely used pre-therapeutic classification is that of the National Comprehensive Cancer Network (NCCN), based on the relationship of the tumor with vascular structures, classifying them into "resectable", "borderline" and "locally advanced" tumors. We present the first registered case in Paraguay of PDA with infiltration of the Superior Mesenteric Vein (SMV) treated with cephalic duodenopancreatectomy (CPD) associated with major vascular resection.


Subject(s)
Adenocarcinoma , Pancreaticoduodenectomy , Proctectomy/methods
5.
Medicina (B.Aires) ; 82(4): 571-575, 20220509. graf
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1405704

ABSTRACT

Resumen El adenocarcinoma pancreático es una enfermedad heterogénea. Sin dudas la aparición y la acumulación de mutaciones genéticas promueven el desarrollo del adenocarcinoma pancreático. Sin embargo, de manera contra-intuitiva, los análisis genéticos, por más precisos y profundos que sean, no permi ten la estratificación de los pacientes para predecir la evolución clínica ni para seleccionar el tratamiento más eficaz para cada paciente. Esto es debido a que la evolución clínica y la sensibilidad a los tratamientos están asociadas con su fenotipo, el que, a su vez, está determinado por la expresión global de los genes, es decir están regulados a nivel transcriptómico. Por lo tanto, la estratificación de esos pacientes debe hacerse a través de la lectura transcriptómica y no a través de su análisis genético. Los datos obtenidos sobre grandes cohortes de pacientes indican que el estudio de un conjunto de transcriptos seleccionados podría predecir la evolución clínica y ayudar a decidir el tratamiento más apropiado. Se está avanzando rápidamente hacia una medicina personalizada para esta enfermedad, que de por sí tiene un mal pronóstico, pero que es aún peor si la deci sión terapéutica no es la más adaptada a cada paciente. Estamos convencidos de que en un futuro próximo el tratamiento de los cánceres estará precedido por una caracterización transcriptómica extensa con el fin de seleccionar los tratamientos "a la carta" más adecuados.


Abstract Pancreatic adenocarcinoma is a heterogeneous disease. Undeniably, the appearance and accumulation of genetic muta tions promote the development of pancreatic adenocarcinoma. However, counterintuitively, genetic analyzes, no matter how precise and in-depth they may be, do not allow stratification of patients to predict their clinical evolution or to select the most effective treatment in each case. This is due to the fact that the clinical evolution and sensitivity to treatments are associated with the tumoral phenotype, which, in turn, is determined by the global expression of genes that is regulated at the transcriptomic level. Therefore, the stratification of these patients must be done by analysis at the transcriptomic level and not by genetic analysis. The data obtained from large cohorts of patients indicate that studying the transcription of a selected set of genes could predict the clinical outcome and can help to decide about the most appropriate treatment. We are moving very rapidly towards a personalized medicine for this disease, which in itself has a poor prognosis, even worse if the therapeutic deci sion is not the most adapted to each patient. We are convinced that in the near future the treatment of cancers will be preceded by an extensive transcriptomic characterization in order to select the most suitable "à la carte" treatments.

6.
Rev. Assoc. Med. Bras. (1992) ; 68(4): 470-475, Apr. 2022. graf
Article in English | LILACS-Express | LILACS | ID: biblio-1376146

ABSTRACT

SUMMARY OBJECTIVE: Heat shock protein A2 has been reported to be tightly associated with tumorigenesis and tumor progression. This study aimed to determine the oncogenic and immunological roles of Heat shock protein A2 in pancreatic cancer by bioinformatics. METHODS: Expression of Heat shock protein A2 in tumorous and normal specimens of pancreatic cancer was analyzed using the Cancer Genome Atlas and the Cancer Genome Atlas + Genotype-Tissue Expression data sets, respectively. Relationships of Heat shock protein A2 expression with immune infiltrates in pancreatic cancer were assessed. Heat shock protein A2-associated coexpressed genes in pancreatic cancer were obtained, followed by the implementation of enrichment analysis. RESULTS: The data demonstrated that Heat shock protein A2 was significantly overexpressed in tumorous samples compared with normal samples. Heat shock protein A2 expression was remarkably positively interrelated with CD8+ T cell, neutrophil, dendritic cell, and macrophage, but not with CD4+ T and B cells. Heat shock protein A2 expression was markedly positively relevant to both cancer-associated fibroblast and endothelial cell. Enrichment data revealed that Heat shock protein A2 was intimately involved in the tumorigenesis and progression of pancreatic cancer. CONCLUSION: Heat shock protein A2 is upregulated in pancreatic cancer and is closely associated with tumor immunity and aggressive progression.

7.
Rev. colomb. gastroenterol ; 37(1): 10-23, Jan.-Mar. 2022. tab, graf
Article in Spanish | LILACS | ID: biblio-1376901

ABSTRACT

El ultrasonido endoscópico ha cambiado la evaluación de las enfermedades pancreáticas y ha logrado un diagnóstico histopatológico (cuando se asocia con la punción); sin embargo, este procedimiento requiere de entrenamiento, no está libre de complicaciones y alrededor de 25% de los pacientes puede tener falsos negativos. Por esto se ha implementado el uso de la elastografía cuantitativa con el strain ratio, el cual permite diferenciar las masas benignas de las malignas. Existe evidencia creciente, pero aún no conclusiva, dada la heterogeneidad de los resultados (sin consenso para su realización), por lo que es necesario desarrollar otros métodos, que permitan una mayor certeza diagnóstica, como el índice de fibrosis hepática (IFH) medido por ultrasonografía endoscópica, el cual tienen como base la inteligencia artificial, validado para el diagnóstico y el seguimiento de la fibrosis hepática. Nuestro grupo considera que se podría usar de la misma forma para valorar el parénquima pancreático. Objetivo: evaluar si el IFH puede diferenciar tres tipos diferentes de tejidos pancreáticos: páncreas normal, páncreas graso y cáncer de páncreas. Metodología: estudio prospectivo de corte transversal en un solo centro. Se incluyeron 66 pacientes mayores de 18 años, con indicación de ultrasonografía endoscópica. El grupo 1 fue de pacientes con indicación diferente a la enfermedad biliopancreática (55 pacientes). En este grupo se aplicó la escala de clasificación de páncreas graso por ultrasonografía endoscópica (USE), utilizando como referencia la ecogenicidad del bazo (previamente validada); este grupo se subdividió en uno con parénquima pancreático normal y en otro con páncreas graso. En el grupo 2 (11 pacientes) se incluyeron los pacientes llevados para el estudio de lesión sólida pancreática, con diagnóstico citológico positivo para carcinoma de páncreas. Como herramienta de recolección de datos se utilizó un formulario virtual de Google Drive, disponible con dirección acortada: shorturl.at/pIMWX, diligenciado antes y después del procedimiento por fellows de Gastroenterología, previamente entrenados para este fin. El IFH se tomó en el páncreas en tiempo real mediante un software suministrado por el fabricante (Hitachi-Noblus), en un período comprendido entre enero de 2019 y enero 2020. A todos los pacientes se les realizó una ecoendoscopia biliopancreática completa, con un ecoendoscopio Pentax lineal y procesador Hitachi-Noblus; luego se efectuó una elastografía cualitativa y una cuantitativa, la cual incluyó la medición del IFH. Resultados: en total se incluyeron 66 pacientes: 11 pacientes con diagnóstico confirmado por citología de cáncer de páncreas y 55 pacientes que se enviaron para ecoendoscopia por evaluación de otras patologías diferentes a la biliopancreática. El rango de edad fue de 23-89, media de 56,75 años. El antecedente más frecuente fue la esteatosis o esteatohepatitis (n = 14) (25,45%). La indicación para la realización del procedimiento más frecuente fue la lesión subepitelial (n = 29) (52,73 %). Los porcentajes de pacientes según los grados de ecogenicidad del páncreas fueron de grado I (n = 29) (52,73 %); grado II (n = 5) (9,09 %); grado III (n = 18) (32,73 %); grado IV (n = 3) (5,45 %). Se tomaron los grados I y II como páncreas normal, y los grado III y IV como páncreas graso. Estos se dividieron en n = 34 pacientes (61,82 %) para páncreas normal y n = 21 (38 %) para páncreas graso; es decir, que de acuerdo con la escala utilizada hay una prevalencia para páncreas graso de 38,18 %. Se realizó el IFH en los tres subgrupos diferentes: los considerados como ecoendoscópicamente normales, los clasificados como páncreas graso y los pacientes con diagnóstico de cáncer de páncreas confirmado por citología, tomado en el páncreas. El IFH para los tres diferentes grupos fueron, respectivamente, normal: IFH 2,60, rango 0,97-3,47 (IC 95 % 2,17-3,02); páncreas graso: IFH 3,87, rango 2-5,5 (IC 95 % 3,44-4,29); cáncer de páncreas: IFH 6,35, rango 5,8-7,8 (IC 95 % 5,92-6,77). Conclusiones: este es el primer estudio piloto que usa el IFH aplicado al parénquima pancreático, y se sugiere su utilidad para diferenciar, de manera no invasiva, el páncreas normal, el graso y el carcinoma de páncreas. Este hallazgo se debe confirmar en poblaciones más amplias y heterogéneas, con el fin de ser validado.


Abstract Endoscopic ultrasound has changed the evaluation of pancreatic diseases and has achieved a histopathological diagnosis (when associated with a puncture); however, this procedure requires training, is not free of complications, and around 25 % of patients may have false negatives. Therefore, quantitative elastography with the strain ratio has been implemented to differentiate benign masses from malignant ones. There is growing but not yet conclusive evidence, given the heterogeneity of the results (without consensus on its performance). It is necessary to develop other methods that allow for greater diagnostic certainty, such as the liver fibrosis index (LFI) measured by endoscopic ultrasonography. This method is based on artificial intelligence and validated for diagnosing and monitoring liver fibrosis. Our group considers that it could also be used to assess the pancreatic parenchyma. Aim: To evaluate whether the LFI can differentiate three types of pancreatic tissues: normal pancreas, fatty pancreas, and pancreatic cancer. Materials and methods: Prospective cross-sectional single-center study. We included sixty-six patients over 18 years of age with an indication for endoscopic ultrasonography. Group 1 consisted of patients with an indication other than the biliopancreatic disease (55 patients). The endoscopic ultrasonography (EUS) fatty pancreas classification scale was applied to this group, taking the echogenicity of the spleen (previously validated) as a reference; this group was subdivided into normal pancreatic parenchyma and fatty pancreas. Group 2 (11 patients) included those examined for solid pancreatic lesions with a positive cytological diagnosis of pancreatic carcinoma. We used a Google Form as a data collection tool, available with a shortened address (shorturl.at/pIMWX). It was filled out before and after the procedure by Gastroenterology fellows, previously trained for this purpose. The LFI was measured in the pancreas in real-time using software supplied by the manufacturer (Hitachi Noblus) between January 2019 and January 2020. All patients underwent a complete biliopancreatic echoendoscopy, with a linear Pentax echoendoscope and Hitachi Noblus processor. Then, qualitative and quantitative elastography was performed, including LFI measurement. Results: We included a total of 66 patients: 11 with a diagnosis of pancreatic cancer confirmed by cytology and 55 sent for ultrasound endoscopy due to pathologies other than the biliopancreatic disease. The age range was 23-89, with a mean of 56.75 years. The most frequent history was steatosis or steatohepatitis (n = 14) (25.45 %). The most frequent indication for performing the procedure was subepithelial lesion (n = 29) (52.73 %). The percentages of patients according to pancreatic echogenicity were Grade I (n = 29) (52.73 %); Grade II (n = 5) (9.09 %); Grade III (n = 18) (32.73 %); Grade IV (n = 3) (5.45 %). Grades I and II were taken as a normal pancreas and Grades III and IV as a fatty pancreas, divided into n = 34 patients (61.82 %) for a normal pancreas and n = 21 (38 %) for a fatty pancreas. According to the scale used, there is a fatty pancreas prevalence of 38.18 %. The LFI was measured in three subgroups: those considered endoscopically normal, those classified as fatty pancreas, and patients diagnosed with pancreatic cancer confirmed by cytology taken from the pancreas. The LFI for these groups were, respectively, normal pancreas: LFI 2.60, range 0.97-3.47 (95 % CI 2.17-3.02); fatty pancreas: LFI 3.87, range 2-5.5 (95 % CI 3.44-4.29); pancreatic cancer: LFI 6.35, range 5.8-7.8 (95 % CI 5.92-6.77). Conclusions: This is the first pilot study that applies the LFI to the pancreatic parenchyma. It is useful in differentiating a normal pancreas, a fatty pancreas, and pancreatic carcinoma non-invasively. This finding must be validated in larger and more heterogeneous populations.


Subject(s)
Humans , Male , Female , Adolescent , Adult , Middle Aged , Aged , Pancreas , Pancreatic Neoplasms , Ultrasonics , Liver Cirrhosis , Pancreatic Diseases , Data Collection , Parenchymal Tissue
8.
Journal of Preventive Medicine ; (12): 185-189, 2022.
Article in Chinese | WPRIM | ID: wpr-920621

ABSTRACT

Objective@#To investigate the mortality trends and life loss due to pancreatic cancer death among residents in Suzhou City from 2006 to 2020, so as to provide insights into the management of pancreatic cancer.@*Methods @#The data pertaining to the death of pancreatic cancer in Suzhou City from 2006 to 2020 were collected from the Jiangsu provincial mortality surveillance system. The crude mortality, standardized mortality, years of potential life lost ( YPL L), rate of YPLL ( YPLLR ), average years of life lost ( AYLL ) and annual percent change (APC) were calculated to analyze the changing trend in mortality and life loss due to pancreatic cancer.@*Results@#The crude mortality of pancreatic cancer was 13.57/105 in Suzhou City from 2006 to 2020, appearing a tendency towards a rise ( P<0.05) with APC of 2.95%. The standardized mortality of pancreatic cancer was 6.39/105. The crude mortality of pancreatic cancer was 15.14/105 in men and 12.06/105 in women, which both showed a tendency towards a rise ( P<0.05 ) with APC of 3.18% and 2.73%. The crude mortality of pancreatic cancer appeared a tendency towards a decline in residents at ages of 30 to 45 years and 45 to 60 years ( P<0.05 ), with APC of -4.93% and -1.63%, and appeared a tendency towards a rise in residents at ages of 60 years and greater ( P<0.05 ), with APC of 0.53%. The YPLL and YPLLR of pancreatic cancer were 55 340 person-years and 0.06% in Suzhou City from 2006 to 2020, while the AYLL of pancreatic cancer was 9.81 years per person, which appeared a tendency towards a decline ( P<0.05 ), with APC of -2.35%.@*Conclusions@#The crude mortality of pancreatic cancer appeared a tendency towards a rise in Suzhou City from 2006 to 2020, and the AYLL showed a tendency towards a decline. Health education and screening of pancreatic cancer should be reinforced among men and the elderly.

9.
Article in Chinese | WPRIM | ID: wpr-932570

ABSTRACT

Objective:To compare dose distributions of hypofractionated radiotherapy for pancreatic cancer between IMPT and VMAT.Methods:Ten pancreatic cancer cases were included in this retrospective study. Photon (Edge) and proton (Proteus?PLUS) plans were designed by Eclipse and RayStation TPS, respectively. All plans were transferred to MIM system for extraction of parameters, which included Dmin, Dmean and Dmax of PTV, conformity index (CI), new conformity index (nCI), homogeneity index (HI), gradient index (GI), coverage, Dmax and dose-volume of the organs at risk (OARs). Results:There was no significant difference in CI between the two groups. The higher PTV Dmin, Dmean, Dmax, D98%, D2%, HI, coverage and the better GI, D2 cmwere found in VMAT ( t/ Z=-4.63-5.32, P<0.05). The lower 10%_PD was found in IMPT ( t=-7.47, P<0.05). Regarding the OARs, Dmax of the intestine, stomach, and duodenum and Dmean of the left kidney were similar between two groups without significant difference ( P>0.05). The D5 cm 3 of the intestine, D10 cm 3 of the stomach, D5 cm 3 and D10 cm 3 of the duodenum, D2/3 of the left kidney, Dmean and D2/3 of the right kidney were lower in IMPT than those in VMAT ( t/ Z=-8.12--2.60, P<0.05). However, the Dmax and D0.35 cm 3 of the spinal cord were higher in IMPT than those in VMAT ( t=7.30, 6.77, P<0.05). Conclusions:Both of hypofractionated radiotherapy plans of pancreatic cancer designed by VMAT and IMPT could meet clinical needs. No significant difference was found in Dmax of the adjacent gastrointestinal tracts between the two groups. While IMPT had the advantage over VMAT in the case of lower dose-volumes of the gastrointestinal tracts. Nevertheless, less protections of the OARs in front of the tumor volume could be provided by IMPT compared with VMAT.

10.
Article in Chinese | WPRIM | ID: wpr-931250

ABSTRACT

Folate receptor(FR)overexpression occurs in a variety of cancers,including pancreatic cancer.In addi-tion,enhanced macropinocytosis exists in K-Ras mutant pancreatic cancer.Furthermore,the occurrence of intensive desmoplasia causes a hypoxic microenvironment in pancreatic cancer.In this study,a novel FR-directed,macropinocytosis-enhanced,and highly cytotoxic bioconjugate folate(F)-human serum albumin(HSA)-apoprotein of lidamycin(LDP)-active enediyne(AE)derived from lidamycin was designed and prepared.F-HSA-LDP-AE consisted of four moieties:F,HSA,LDP,and AE.F-HSA-LDP presented high binding efficiency with the FR and pancreatic cancer cells.Its uptake in wild-type cells was more extensive than in K-Ras mutant-type cells.By in vivo optical imaging,F-HSA-LDP displayed prominent tumor-specific biodistribution in pancreatic cancer xenograft-bearing mice,showing clear and lasting tumor localization for 360 h.In the MTT assay,F-HSA-LDP-AE demonstrated potent cytotoxicity in three types of pancreatic cancer cell lines.It also induced apoptosis and caused G2/M cell cycle arrest.F-HSA-LDP-AE markedly suppressed the tumor growth of AsPc-1 pancreatic cancer xenografts in athymic mice.At well-tolerated doses of 0.5 and 1 mg/kg,(i.v.,twice),the inhibition rates were 91.2%and 94.8%,respectively(P<0.01).The results of this study indicate that the F-HSA-LDP multi-functional bioconjugate might be effective for treating K-Ras mutant pancreatic cancer.

11.
Article in Chinese | WPRIM | ID: wpr-930329

ABSTRACT

Objective:To investigate the expression of immunoglobulin heavy constant gamma 1 (IGHG1) in pancreatic cancer and its effects on proliferation, migration and invasion of pancreatic cancer cell line PANC-1.Methods:From Jun. 2018 to Dec. 2020, 65 patients with pancreatic cancer who underwent surgical treatment at Xiang Yang No.1 People’s Hospital, Affiliated Hospital of Hubei University of Medicine were selected. The tumor tissue and normal adjacent tissues were removed, and the expression level of IGHG1 mRNA in pancreatic cancer tissues and adjacent tissues was detected by real-time quantitative PCR (RT-qPCR) . The correlation between IGHG1 expression and clinicopathological features of pancreatic cancer was analyzed. PANC-1 cells were divided into control group, IGHG1 negative control group (si-NC) and interference IGHG1 expression group (si-IGHG1) . IGHG1 mRNA expression, proliferation, migration, invasion and apoptosis of PANC-1 cells, as well as epithelial-mesenchymal transition (EMT) -related proteins E-cadherin and N-cadherin, Vimentin and Bax, Bcl-2, caspase3 protein expression were detected.Results:The expression level of IGHG1 mRNA in pancreatic cancer tissue was 2.47±0.23, significantly higher than 1.03±0.12 in adjacent tissues ( P<0.05) . the expression of IGHG1 was correlated with tumor differentiation, TNM stage and lymph node metastasis ( P<0.05) . Compared with the control group and si-NC group, the apoptosis rate of PANC-1 cells in the si-IGHG1 group was [ (5.34±0.65) %, (5.54±0.81) % vs (45.62±2.84) %]. Bax[0.34 ±0.05, 0.32±0.04 vs 1.13±0.12], caspase3 [0.43±0.05, 0.45±0.06 vs 1.22±0.13], and E-cadherin [0.78±0.12, 0.81±0.11 vs 1.34±0.08] protein expression levels increased significantly ( P<0.05) . The protein expression level was significantly increased ( P<0.05) , the expression level of IGHG1 mRNA [2.67±0.23, 2.61±0.21 vs 0.87±0.11] and protein [0.97±0.11, 1.01±0.10 vs 0.51±0.04], cell survival rate [ (98.21±0.56) %, (97.89±0.67) % vs (46.67±1.23) %], migration [ (76.12±2.72) %, (74.23±3.41) % vs (28.55±2.63) %] and invasion [ (85.32±3.71) %, 83.27±3.45) % vs (37.58±2.63) %] ability, and N-cadherin[1.12±0.13, 1.04±0.11 vs 0.61±0.08%], Vimentin[1.03±0.11, 0.97± 0.09 vs 0.49±0.07], and Bcl-2[0.87±0.08, 0.89±0.09 vs 0.62±0.07] protein expression levels were significantly reduced ( P<0.05) . Conclusions:The expression of IGHG1 is increased in pancreatic cancer, which is related to the occurrence and development of pancreatic cancer. Interference with IGHG1 expression can inhibit the proliferation, migration, invasion and EMT of pancreatic cancer cells.

12.
Acta Pharmaceutica Sinica B ; (6): 876-889, 2022.
Article in English | WPRIM | ID: wpr-929332

ABSTRACT

SIRT6 belongs to the conserved NAD+-dependent deacetylase superfamily and mediates multiple biological and pathological processes. Targeting SIRT6 by allosteric modulators represents a novel direction for therapeutics, which can overcome the selectivity problem caused by the structural similarity of orthosteric sites among deacetylases. Here, developing a reversed allosteric strategy AlloReverse, we identified a cryptic allosteric site, Pocket Z, which was only induced by the bi-directional allosteric signal triggered upon orthosteric binding of NAD+. Based on Pocket Z, we discovered an SIRT6 allosteric inhibitor named JYQ-42. JYQ-42 selectively targets SIRT6 among other histone deacetylases and effectively inhibits SIRT6 deacetylation, with an IC50 of 2.33 μmol/L. JYQ-42 significantly suppresses SIRT6-mediated cancer cell migration and pro-inflammatory cytokine production. JYQ-42, to our knowledge, is the most potent and selective allosteric SIRT6 inhibitor. This study provides a novel strategy for allosteric drug design and will help in the challenging development of therapeutic agents that can selectively bind SIRT6.

13.
Acta Pharmaceutica Sinica B ; (6): 274-290, 2022.
Article in English | WPRIM | ID: wpr-929293

ABSTRACT

KRAS‒PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36l (K D = 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS-PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft (PDX) models. It represents a promising lead compound for investigating the druggability of KRAS‒PDEδ interaction.

14.
Acta Pharmaceutica Sinica B ; (6): 210-227, 2022.
Article in English | WPRIM | ID: wpr-929289

ABSTRACT

Pancreatic adenocarcinoma (PAAD) is one of the most lethal malignancies. Although gemcitabine (GEM) is a standard treatment for PAAD, resistance limits its application and therapy. Secoemestrin C (Sec C) is a natural compound from the endophytic fungus Emericella, and its anticancer activity has not been investigated since it was isolated. Our research is the first to indicate that Sec C is a broad-spectrum anticancer agent and could exhibit potently similar anticancer activity both in GEM-resistant and GEM-sensitive PAAD cells. Interestingly, Sec C exerted a rapid growth-inhibiting effect (80% death at 6 h), which might be beneficial for patients who need rapid tumor shrinkage before surgery. Liquid chromatography/mass spectrometry and N-acetyl-l-cysteine (NAC) reverse assays show that Sec C sulfates cysteines to disrupt disulfide-bonds formation in endoplasmic reticulum (ER) proteins to cause protein misfolding, leading to ER stress and disorder of lipid biosynthesis. Microarray data and subsequent assays show that ER stress-mediated ER-associated degradation (ERAD) ubiquitinates and downregulates YAP to enhance ER stress via destruction complex (YAP-Axin-GSK-βTrCP), which also elucidates a unique degrading style for YAP. Potent anticancer activity in GEM-resistant cells and low toxicity make Sec C a promising anti-PAAD candidate.

15.
Article in Chinese | WPRIM | ID: wpr-940450

ABSTRACT

ObjectiveTo observe the effects of Wumeiwan-medicated serum on the proliferation, invasion, migration, and apoptosis of human pancreatic cancer SW1990 cells and explore the underlying mechanism. MethodThe Wumeiwan-medicated serum was prepared and the pancreatic cancer SW1990 cell line was cultured in vitro. The optimal time of Wumeiwan-medicated serum was selected for subsequent experiments by cell counting kit-8(CCK-8). SW1990 cells were divided into a control group and low- (2%), medium- (4%), and high-dose (8%) Wumeiwan-medicated serum groups. The colony-forming, migration, and invasion abilities were detected by clonogenic assay, wound healing assay, and transwell migration assay. Flow cytometry was used to detect the effect of Wumeiwan-medicated serum on the apoptosis of pancreatic cancer SW1900 cells. Western blot was used to detect the expression levels of apoptosis-related proteins, such as B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein (Bax), cytochrome C (Cyt C), cleaved cysteinyl aspartate-specific protease-3 (cleaved Caspase-3), cleaved cysteinyl aspartate-specific protease-9 (cleaved Caspase-9), as well as phosphatidylinositol 3-kinase(PI3K), phosphorylated PI3K(p-PI3K), protein kinase B (Akt), and phosphorylated Akt(p-Akt)in PI3K/Akt pathway in SW1990 cells. ResultCompared with blank group, Wumeiwan groups showed decreased absorbance (A) 72 h after drug intervention (P<0.01). Compared with the low-dose group, the medium- and high-dose groups showed decreased A (P<0.01). Compared with the medium-dose group, the high-dose group showed decreased A (P<0.01). It indicates that Wumeiwan can inhibit SW1990 cell proliferation in a dose-dependent manner after 72 h, and the optimal action time is 72 h. Compared with the blank group, the Wumeiwan groups showed weakened invasion of SW1990 cells (P<0.01), reduced colony-forming and migration abilities (P<0.05, P<0.01) in a dose-dependent manner, and increased total apoptosis rates (P<0.01). The inducing effect of Wumeiwan on apoptosis increased with the increase in dosage. Compared with the blank group, the Wumeiwan groups showed decreased protein expression of Bcl-2 (P<0.01), increased protein expression of cleaved Caspase-3, cleaved Caspase-9, Cyt C, and Bax (P<0.05, P<0.01) in a certain dose-effect relationship, reduced protein expression of p-PI3K and p-Akt (P<0.05, P<0.01) with the increase in dosage, and declining p-PI3K/PI3K and p-Akt/Akt (P<0.05, P<0.01) with the increase in dosage. ConclusionWumeiwan-medicated serum can significantly inhibit the malignant biological behaviors of pancreatic cancer SW1990 cells and induce apoptosis. The mechanism may be related to the inhibition of the PI3K/Akt signaling pathway and down-regulation of protein phosphorylation level in the PI3K/Akt signaling pathway.

16.
Acta Pharmaceutica Sinica B ; (6): 3167-3176, 2022.
Article in English | WPRIM | ID: wpr-939956

ABSTRACT

Both natural ginsenoside F2 and unnatural ginsenoside 3β,20S-Di-O-Glc-DM were reported to exhibit anti-tumor activity. Traditional approaches for producing them rely on direct extraction from Panax ginseng, enzymatic catalysis or chemical synthesis, all of which result in low yield and high cost. Metabolic engineering of microbes has been recognized as a green and sustainable biotechnology to produce natural and unnatural products. Hence we engineered the complete biosynthetic pathways of F2 and 3β,20S-Di-O-Glc-DM in Saccharomyces cerevisiae via the CRISPR/Cas9 system. The titers of F2 and 3β,20S-Di-O-Glc-DM were increased from 1.2 to 21.0 mg/L and from 82.0 to 346.1 mg/L at shake flask level, respectively, by multistep metabolic engineering strategies. Additionally, pharmacological evaluation showed that both F2 and 3β,20S-Di-O-Glc-DM exhibited anti-pancreatic cancer activity and the activity of 3β,20S-Di-O-Glc-DM was even better. Furthermore, the titer of 3β,20S-Di-O-Glc-DM reached 2.6 g/L by fed-batch fermentation in a 3 L bioreactor. To our knowledge, this is the first report on demonstrating the anti-pancreatic cancer activity of F2 and 3β,20S-Di-O-Glc-DM, and achieving their de novo biosynthesis by the engineered yeasts. Our work presents an alternative approach to produce F2 and 3β,20S-Di-O-Glc-DM from renewable biomass, which lays a foundation for drug research and development.

17.
Article in Chinese | WPRIM | ID: wpr-923118

ABSTRACT

@#[Abstract] Objective: To investigate the expression of tight junction protein claudin-7 (CLDN-7) in pancreatic cancer and its correlation with the clinicopathological features and prognosis of pancreatic cancer patients. Methods: Oncomine, GEPIA and GEO databases were used to comprehensively analyze the mRNA expression level of CLDN-7 in pancreatic cancer, and Kaplan-Meier Plotter database was used to analyze the relationship between the expression of CLDN-7 and the survival prognosis of pancreatic cancer patients. Immunohistochemical staining was used to detect the protein level of CLDN-7 in 44 cases of pancreatic cancer tissues and 31 cases of para-cancerous tissues resected in the Department of General Surgery of the Second Hospital of Lanzhou University from 2015 to 2018, and the relationship between CLDN-7 expression and clinicopathological characteristics and prognosis of patients was also analyzed. GO (Gene Ontology) analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis were conducted to analyze the possible signaling pathways that CLDN-7 may involve in and their main functions, which were further verified in TCGA and GEPIA databases. Results: Analysis of both the databases and the clinical samples showed that CLDN-7 was significantly over-expressed in pancreatic cancer tissues, and its high expression was correlated with clinical prognosis of pancreatic cancer patients; moreover, CLDN-7 expression was an independent factor affecting the overall survival time of pancreatic cancer patients (all P<0.05). GO analysis and KEGG pathway enrichment analysis confirmed that CLDN-7 was involved in DNA damage repair and glucose metabolism in pancreatic cancer patients. TCGA and GEPIA database validation showed that CLDN-7 expression in pancreatic cancer was significantly and positively correlated with the expression of DNA damage repair related genes (POLD4, SMUG1, NTHL1) and glucose metabolism related genes (ALDOA, TALDO1, PGLS) (all P<0.01). Conclusion: CLDN-7 is highly expressed in pancreatic cancer and indicates a worse clinical prognosis; moreover, CLDN-7 is associated with DNA damage repair and intratumoral glucose metabolism in pancreatic cancer.

18.
Braz. j. med. biol. res ; 55: e12324, 2022. graf
Article in English | LILACS-Express | LILACS | ID: biblio-1403907

ABSTRACT

Recombinant human peroxiredoxin-5 (hPRDX5), isolated from anti-cancer bioactive peptide (ACBPs), shows a homology of 89% with goat peroxiredoxin-5 (gPRDX5) and is reported to display anti-tumor activity in vivo. Herein, we explored the effect of hPRDX5 and the responsible mechanism in treating pancreatic cancer. Tumor-bearing mice were randomly divided into normal PBS group and treatment group (n=5; 10 mg/kg hPRDX5). Flow cytometry was employed to examine lymphocytes, myeloid-derived suppressor cell subsets, and the function proteins of natural killer (NK) cells in peripheral blood, spleen, and tumor tissues of mice. Western blot was used to measure the protein expressions of the key nodes in TLR4-MAPK-NF-κB signaling pathway. The rate of tumor suppression was 57.6% at a 10 mg/kg dose in orthotopic transplanted tumor mice. Moreover, the population of CD3+CD4+T cells, NK cells, and CD3+CD8+T cells was significantly increased in the tumor tissue of the hPRDX5 group, while the proportion of granulocytic-myeloid-derived suppressor cells decreased slightly. In addition, after treatment with hPRDX5, the percentage of NK cells in blood increased more than 4-fold. Our findings indicated that hPRDX5 effectively suppressed pancreatic cancer possibly via the TLR4-MAPK-NF-κB signaling cascade; hence hPRDX5 could be a prospective immunotherapy candidate for treating pancreatic cancer.

19.
Rev. cuba. invest. bioméd ; 41: e2408, 2022. tab, graf
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1408602

ABSTRACT

RESUMEN Introducción: El índice pronóstico nutricional es un marcador inmuno-nutricional que puede ser útil como factor pronóstico en tumores gastrointestinales. Objetivo: Evaluar supervivencia de pacientes con adenocarcinoma pancreático avanzado tratados con quimioinmunoterapia según índice pronóstico nutricional, según parámetros clínico-patológicos y tratamiento. Métodos: Se realizó estudio retrospectivo y observacional en pacientes que recibieron quimioterapia gemcitabina-oxaliplatino combinado a nimotuzumab (n=118), en el Hospital Ameijeiras, entre 2014 y 2019. Se evaluó supervivencia por método Kaplan-Meier, y regresión de Cox, para determinar los factores pronósticos independientes de supervivencia. Resultados: El punto de corte seleccionado fue 40 (sensibilidad 52,9 % y especificidad 85,7 % (p = 0,019), con área bajo la curva de 0,693. Para pacientes con índice menor de 40, la supervivencia fue más baja respecto a los pacientes con índice ≥ 40 (11,4 meses frente a 16,0 meses; p=0,001), con un HR de 1,7 (1,13-2,60; p=0,011). Las variables mayormente asociadas con índice pronóstico nutricional altos son pacientes con sesenta años o menos; ECOG cero, índice de masa corporal ≥25 Kg/m2 y albúmina sérica >3,5g/dL (x² < 0,05). Los pacientes con índice ≥ 40 tienen medianas de supervivencia más altas que pacientes con índice < 40 en las variables seleccionadas con p < 0,05, excepto el índice de masa corporal. Conclusiones: Este trabajo constituye el primer reporte nacional de utilización del índice pronóstico nutricional como pronóstico de supervivencia en pacientes con cáncer de páncreas avanzado.


ABSTRACT Background: The nutritional prognostic index is an immuno-nutritional marker that can be useful as a prognostic factor in gastrointestinal tumors. Aim: To evaluate the survival of patients with advanced pancreatic adenocarcinoma treated with chemoimmunotherapy according to the nutritional prognostic index, according to clinical-pathological parameters and treatment. Methods: A retrospective and observational study was carried out in patients who received gemcitabine-oxaliplatin chemotherapy combined with nimotuzumab (n=118), at the Ameijeiras Hospital, between 2014 and 2019. Survival was evaluated by the Kaplan-Meier method, and Cox regression, for determine independent prognostic factors for survival. Results: The selected cut-off point was 40 (52.9% sensitivity and 85.7% specificity) (p=0,019), with an area under the curve of 0,693. For patients with an index less than 40, survival was lower compared to patients with index ≥ 40 (11, 4 months vs. 16, 0 months; p=0,001), with a HR of 1, 7 (1, 13-2, 60; p=0,011). The variables mostly associated with nutritional prognostic index patients with 60 years or less, ECOG 0, body mass index ≥ 25 kg/m² and serum albumin >3,5g/dL (x² < 0, 05). Patients with index ≥ 40 have higher median survival than patients with index < 40 in the selected variables with p < 0, 05, except body mass index. Conclusions: This work constitutes the first national report on the use of the nutritional prognostic index as a prognosis of survival in patients with advanced pancreatic cancer.

20.
Clinics ; 77: 100044, 2022. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1384615

ABSTRACT

Abstract Background Importin 7 (IPO7) belongs to the Importin β family and is implicated in the progression of diverse human malignancies. This work is performed to probe the role of IPO7 in pancreatic cancer development and its potential downstream mechanisms. Methods IPO7 expression in PC and paracancerous tissues were measured using Immunohistochemistry (IHC) staining and qRT-PCR. Western blotting was utilized to detect the expression level of IPO7 in PC cells and immortalize the pancreatic ductal epithelial cell line. After constructing the IPO7 overexpression and knockdown models, the effect of IPO7 on the proliferation of PC cells was analyzed by the CCK-8 and EdU assay. The migration and invasion of PC cells were examined by wound healing assay and Transwell experiment. The apoptosis rate of PC cells was analyzed by flow cytometry and TUNEL assay. The Gene Set Enrichment Analysis (GSEA) was used to determine the enrichment pathways of IPO7. The effect of IPO7 on the ERBB2 expression was determined using Western blotting. A xenograft mouse model was applied to investigate the carcinogenic effect of IPO7 in vivo. Results IPO7 expression was remarkably elevated in the cancer tissues of PC patients. IPO7 overexpression remarkably enhanced PC cell proliferation, migration and invasion and suppressed apoptosis, while knockdown of IPO7 exerted the opposite effect. Mechanistically, IPO7 facilitated the malignant phenotype of PC cells by up-regulating ERBB2 expression. In addition, knockdown of IPO7 inhibited tumor growth and lung metastasis in vivo. Conclusion IPO7 can act as an oncogenic factor and accelerate PC progression by modulating the ERBB pathway.

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