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Long-term antibiotic use can have consequences on systemic diseases, such as obesity, allergy, and depression, implicating the causal role of gut microbiome imbalance. However, the evaluation of the effect of antibiotics in early infancy on alterations to the gut microbiome remains poorly understood. This study aimed to evaluate the gut microbiome state in infancy following systemic antibiotic treatment. Twenty infants under 3 months of age who had received antibiotics for at least 3 days were enrolled, and their fecal samples were collected 4 weeks after antibiotic administration finished. Thirty-four age-matched healthy controls without prior exposure to antibiotics were also assessed. The relative bacterial abundance in feces was obtained via sequencing of 16 S rRNA genes, and alpha and beta diversities were evaluated. At the genus level, the relative abundance of Escherichia/Shigella and Bifidobacterium increased (p = 0.03 and p = 0.017, respectively) but that of Bacteroides decreased (p = 0.02) in the antibiotic treatment group. The microbiome of the antibiotic treatment group exhibited an alpha diversity lower than that of the control group. Thus, systemic antibiotic administration in early infancy affects the gut microbiome composition even after a month has passed; long-term studies are needed to further evaluate this.
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BACKGROUND: Tumor mutational burden (TMB) measurement is limited by low tumor purity of samples, which can influence prediction of the immunotherapy response, particularly when using whole-exome sequencing-based TMB (wTMB). This issue could be overcome by targeted panel sequencing-based TMB (pTMB) with higher depth of coverage, which remains unexplored. METHODS: We comprehensively reanalyzed four public datasets of immune checkpoint inhibitor (ICI)-treated cohorts (adopting pTMB or wTMB) to test each biomarker's predictive ability for low purity samples (cut-off: 30%). For validation, paired genomic profiling with the same tumor specimens was performed to directly compare wTMB and pTMB in patients with breast cancer (paired-BRCA, n=165) and ICI-treated patients with advanced non-small-cell lung cancer (paired-NSCLC, n=156). RESULTS: Low tumor purity was common (range 30%-45%) in real-world samples from ICI-treated patients. In the survival analyzes of public cohorts, wTMB could not predict the clinical benefit of immunotherapy when tumor purity was low (log-rank p=0.874), whereas pTMB could effectively stratify the survival outcome (log-rank p=0.020). In the paired-BRCA and paired-NSCLC cohorts, pTMB was less affected by tumor purity, with significantly more somatic variants identified at low allele frequency (p<0.001). We found that wTMB was significantly underestimated in low purity samples with a large proportion of clonal variants undetected by whole-exome sequencing. Interestingly, pTMB more accurately predicted progression-free survival (PFS) after immunotherapy than wTMB owing to its superior performance in the low tumor purity subgroup (p=0.054 vs p=0.358). Multivariate analysis revealed pTMB (p=0.016), but not wTMB (p=0.32), as an independent predictor of PFS even in low-purity samples. The net reclassification index using pTMB was 21.7% in the low-purity subgroup (p=0.016). CONCLUSIONS: Our data suggest that TMB characterization with targeted deep sequencing might have potential strength in predicting ICI responsiveness due to its enhanced sensitivity for hard-to-detect variants at low-allele fraction. Therefore, pTMB could act as an invaluable biomarker in the setting of both clinical trials and practice outside of trials based on its reliable performance in mitigating the purity-related bias.
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Biomarcadores de Tumor/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Carga Tumoral/inmunología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Masculino , MutaciónRESUMEN
BACKGROUND & AIMS: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice. METHODS: Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions. RESULTS: L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development. CONCLUSIONS: In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.
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Adenocarcinoma/patología , Esófago de Barrett/patología , Neoplasias Esofágicas/patología , Microbioma Gastrointestinal/fisiología , Interleucina-8/metabolismo , Obesidad/patología , Adenocarcinoma/inmunología , Adulto , Anciano , Animales , Esófago de Barrett/inmunología , Carcinogénesis/inmunología , Carcinogénesis/patología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Neoplasias Esofágicas/inmunología , Esófago/inmunología , Esófago/patología , Heces/microbiología , Femenino , Voluntarios Sanos , Humanos , Interleucina-8/genética , Interleucina-8/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Obesidad/sangre , Obesidad/inmunología , Organoides , Suero/inmunología , Suero/metabolismo , Factores de Tiempo , Técnicas de Cultivo de TejidosRESUMEN
Cancers of the gastrointestinal (GI) tract are among the most frequent and most lethal cancers worldwide. An important reason for this high mortality is that early disease is typically asymptomatic, and patients often present with advanced, incurable disease. Even in high-risk patients who routinely undergo endoscopic screening, lesions can be missed due to their small size or subtle appearance. Thus, current imaging approaches lack the sensitivity and specificity to accurately detect incipient GI tract cancers. Here we report our finding that a single dose of a high-sensitivity surface-enhanced resonance Raman scattering nanoparticle (SERRS-NP) enables reliable detection of precancerous GI lesions in animal models that closely mimic disease development in humans. Some of these animal models have not been used previously to evaluate imaging probes for early cancer detection. The studies were performed using a commercial Raman imaging system, a newly developed mouse Raman endoscope, and finally a clinically applicable Raman endoscope for larger animal studies. We show that this SERRS-NP-based approach enables robust detection of small, premalignant lesions in animal models that faithfully recapitulate human esophageal, gastric, and colorectal tumorigenesis. This method holds promise for much earlier detection of GI cancers than currently possible and could lead therefore to marked reduction of morbidity and mortality of these tumor types.
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Endoscopía/métodos , Neoplasias Gastrointestinales/diagnóstico , Tracto Gastrointestinal/metabolismo , Nanopartículas/química , Espectrometría Raman/métodos , Animales , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
There is no treatment of choice for irritable bowel syndrome, which affects up to 20% of school-aged children. This cross-sectional study evaluated the difference in the average vitamin D level between subtypes of irritable bowel syndrome, and the relationship between the vitamin D level as well as the severity of irritable bowel syndrome symptoms. We included 124 adolescents aged 10â»17 years (68 boys, 56 girls; mean age 12.29 ± 1.92 years) from 2014 to 2016. Patients with irritable bowel syndrome were diagnosed by Rome III criteria and classified by clinical manifestation: irritable bowel syndrome with constipation (n = 29), irritable bowel syndrome with diarrhea (n = 63), and irritable bowel syndrome with constipation and diarrhea (n = 32). The severity of irritable bowel syndrome symptoms and school absence were evaluated. Vitamin D levels were measured by serum 25-hydroxyvitamin D. The chi-square test and analysis of variance were used. The patients' average vitamin D level was 16.25 ± 6.58 ng/mL. There was a significant negative association of the 25-hydroxyvitamin D level with symptom severity and school absence (p = 0.022 and p < 0.001, respectively). Vitamin D supplementation could be considered as a choice of therapeutic method.
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OBJECTIVE: The incidence of esophageal adenocarcinoma (EAC) is increasing, but factors contributing to malignant progression of its precursor lesion, Barrett's esophagus (BE), have not been defined. Hypergastrinemia caused by long-term use of proton pump inhibitors (PPIs), has been suggested as one possible risk factor. The gastrin receptor, CCK2R, is expressed in the cardia and upregulated in BE, suggesting the involvement of the gastrin-CCK2R pathway in progression. In the L2-IL-1ß mouse model, Barrett's-like esophagus arises from the gastric cardia. Therefore, we aimed to analyze the effect of hypergastrinemia on CCK2R+ progenitor cells in L2-IL-1ß mice. DESIGN: L2-IL-1ß mice were mated with hypergastrinemic (INS-GAS) mice or treated with PPIs to examine the effect of hypergastrinemia in BE progression. CCK2R-CreERT crossed with L2-IL-1ß mice were used to analyze the lineage progenitor potential of CCK2R+ cells. Cardia glands were cultured in vitro, and the effect of gastrin treatment analyzed. L2-IL-1ß mice were treated with a CCK2R antagonist YF476 as a potential chemopreventive drug. RESULTS: Hypergastrinemia resulted in increased proliferation and expansion of Barrett's-like esophagus. Lineage tracing experiments revealed that CCK2R+ cells are long-lived progenitors that can give rise to such lesions under chronic inflammation. Gastrin stimulated organoid growth in cardia culture, while CCK2R inhibition prevented Barrett's-like esophagus and dysplasia. CONCLUSIONS: Our data suggest a progression model for BE to EAC in which CCK2R+ progenitor cells, stimulated by hypergastrinemia, proliferate to give rise to metaplasia and dysplasia. Hypergastrinemia can result from PPI use, and the effects of hypergastrinemia in human BE should be studied further.
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Esófago de Barrett/etiología , Esófago de Barrett/metabolismo , Gastrinas/metabolismo , Regulación de la Expresión Génica , Mioblastos Cardíacos/metabolismo , Receptor de Colecistoquinina B/genética , Animales , Esófago de Barrett/patología , Biomarcadores , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Gastrinas/farmacología , Hiperglucemia , Inmunohistoquímica , Metaplasia , Ratones , Ratones Transgénicos , Mioblastos Cardíacos/efectos de los fármacos , Fenotipo , Receptor de Colecistoquinina B/metabolismoRESUMEN
A xerogel was interfaced onto biopolymer nanofibers though a coreshell electrospinning design for bone regeneration. The xerogel-interfaced biopolymer nanofibrous matrix was bioactive and highly hydrophilic, with a significant decrease in the water contact angle. The matrix showed excellent in vitro responses of primary osteoblasts in terms of adhesion, proliferation, and migration. Furthermore, the osteoblastic differentiation of cells, including alkaline phosphatase activity, mineralization, and gene expression, was significantly upregulated by the xerogel interface. In vivo animal tests in a critical-sized calvarial defect confirmed the new bone formation ability of the xerogel-surfaced nanofiber matrices. The underlying signaling mechanisms of the stimulation were implied to be integrin and bone morphogenetic protein (BMP) pathways, as demonstrated by the activation of integrin (α2ß1) and downstream signaling molecules (FAK, paxillin, RhoA, MAPK, and NF-κB), as well as the BMPs and the downstream transcription factor Smad1/5/8. Taking these findings together, the xerogel-surfaced biopolymer nanofibers are proposed to be a promising scaffold candidate for bone regeneration.
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Proteínas Morfogenéticas Óseas/metabolismo , Regeneración Ósea/efectos de los fármacos , Geles/farmacología , Integrinas/metabolismo , Nanofibras/química , Animales , Técnicas de Cultivo de Célula/métodos , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Geles/química , Ratones , Ratones Endogámicos ICR , Osteoblastos/efectos de los fármacos , Andamios del Tejido/químicaRESUMEN
Therapeutically relevant design of scaffolds is of special importance in the repair and regeneration of tissues including dentin and pulp. Here we exploit nanofiber matrices that incorporate bioactive glass nanoparticles (BGNs) and deliver the odontogenic drug dexamethasone (DEX) to stimulate the odontogenic differentiation of human dental pulp cells (HDPCs). DEX molecules were first loaded onto the BGN, and then the DEX-BGN complex was incorporated within the biopolymer nanofiber matrix through electrospinning. The release of DEX continued over a month, showing a slow releasing profile. HDPCs cultured on the DEX-releasing BGN matrices were viable, proliferating well up to 14 days. The odontogenic differentiation, as assessed by alkaline phosphatase activity, mRNA expression of genes, and mineralization, was significantly stimulated on the matrices incorporating BGN and further on those releasing DEX. The DEX-releasing BGN matrices highly upregulated the expression of the integrin subsets α1, α5, and ß3 as well as integrin downstream signaling molecules, including focal adhesion kinase (FAK), Paxillin, and RhoA, and activated bone morphogenetic protein mRNA and phosphorylation of Smad1/5/8. Furthermore, the DEX-releasing BGN-matrices stimulated Akt and mammalian target of rapamycin (mTOR), which was proven by the inhibition study. Collectively, the designed therapeutic nanofiber matrices that incorporate BGN and deliver DEX were demonstrated to promote odontogenesis of HDPCs, and the integrins, bone morphogenetic protein, and mTOR signaling pathways are proposed to be the possible molecular mechanisms. While further in vivo studies are still needed, the DEX-releasing bioactive scaffolds are considered as a potential therapeutic nanomatrix for regenerative endodontics and tissue engineering.
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Pulpa Dental/efectos de los fármacos , Dexametasona/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Nanofibras/química , Odontogénesis/efectos de los fármacos , Proteínas Morfogenéticas Óseas/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Pulpa Dental/citología , Pulpa Dental/metabolismo , Dexametasona/farmacología , Vidrio , Humanos , Integrinas/metabolismo , Nanofibras/administración & dosificación , Nanopartículas/química , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Ingeniería de Tejidos/métodosRESUMEN
Delays in trial opening should be considered critical for the sake of not only the sponsor but the patients, as they may result in inequities of care. The Asan Medical Center, in Seoul, Korea, implemented a trial activation initiative in July 2012, in an aim to expedite the trial initiation timeline. Time intervals between trial initiation steps and the rate of institutional review board (IRB) and clinical trial agreement (CTA) parallel submission were assessed. A higher rate of parallel IRB and CTA submissions was observed after initiative implementation (25.5% vs 52.3%; P < .001). Initiative applications were shown to significantly accelerate the median trial opening time, from 114 to 81 days ( P < .001). Strategic processing of parallel submissions greatly shortened the median time required for trial initiation from 117 to 61 days compared with sequential submissions ( P < .001). A trial activation initiative including parallel IRB and CTA submissions is an effective tool for accelerating trial commencements.
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OBJECTIVE: Progastrin is the incompletely cleaved precursor of gastrin that is secreted by G-cells in the gastric antrum. Both gastrin and progastrin bind to the CCK2 receptor (Cckbr or CCK2R) expressed on a subset of gastric epithelial cells. Little is known about how gastrin peptides and CCK2R regulate gastric stem cells and carcinogenesis. Interconversion among progenitors in the intestine is documented, but the mechanisms by which this occurs are poorly defined. DESIGN: We generated CCK2R-CreERT mice and performed inducible lineage tracing experiments. CCK2R+ antral cells and Lgr5+ antral stem cells were cultured in a three-dimensional in vitro system. We crossed progastrin-overexpressing mice with Lgr5-GFP-CreERT mice and examined the role of progastrin and CCK2R in Lgr5+ stem cells during MNU-induced carcinogenesis. RESULTS: Through lineage tracing experiments, we found that CCK2R defines antral stem cells at position +4, which overlapped with an Lgr5(neg or low) cell population but was distinct from typical antral Lgr5(high) stem cells. Treatment with progastrin interconverts Lgr5(neg or low) CCK2R+ cells into Lgr5(high) cells, increases CCK2R+ cell numbers and promotes gland fission and carcinogenesis in response to the chemical carcinogen MNU. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansion and carcinogenesis. CONCLUSIONS: CCK2R labels +4 antral stem cells that can be activated and expanded by progastrin, thus identifying one hormonal trigger for gastric stem cell interconversion and a potential target for gastric cancer chemoprevention and therapy.
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Carcinogénesis , Antro Pilórico/citología , Receptor de Colecistoquinina B/fisiología , Células Madre/fisiología , Animales , Células Cultivadas , Gastrinas/fisiología , Ratones , Precursores de Proteínas/fisiologíaRESUMEN
PURPOSE: Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients. PATIENTS AND METHODS: We performed whole-exome sequencing of DNA from 104 lung SCC samples from Korean patients and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated. RESULTS: This cancer cohort is characterized by a high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of exposure to cigarette smoke. Seven genes demonstrated statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA). Comparative analysis between Korean and North American lung SCC samples demonstrated a similar spectrum of alterations in these two populations in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SCC. CONCLUSION: These findings provide new steps toward the identification of genomic target candidates for precision medicine in lung SCC, a disease with significant unmet medical needs.
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Carcinoma de Células Escamosas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Carcinoma de Células Escamosas/etnología , Fosfatidilinositol 3-Quinasa Clase I , Proteínas de Unión al ADN/genética , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína 1 Asociada A ECH Tipo Kelch , Neoplasias Pulmonares/etnología , Masculino , Persona de Mediana Edad , Modelos Genéticos , Mutación , Factor 2 Relacionado con NF-E2/genética , Proteínas de Neoplasias/genética , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/genética , República de Corea , Proteína de Retinoblastoma/genética , Fumar , Proteína p53 Supresora de Tumor/genética , Estados Unidos , Población Blanca/genéticaRESUMEN
Pancreatic cancer is a lethal malignancy with a 5-year survival rate of only 6%. Surgical resection remains the only cure, yet even after resection the 5-year survival is only 20% due to a high recurrence rate. Thus, a high proportion of patients with this disease will ultimately require systemic chemotherapy for advanced pancreatic cancer (APC). While the advent of personalized medicine has resulted in significant advances in the management of many cancer types, the standard of care for pancreatic cancer remains gemcitabine based, with very few exceptions. This article first aims to provide an overview of the benefits and limitations of gemcitabine alone, gemcitabine combinations, and different modes of administration of gemcitabine in APC. It then discusses research, suggesting that pharmacogenomic differences in enzymes that affect gemcitabine transport and metabolism can predict benefit from this drug in pancreatic cancer. Finally, the article outlines novel therapies and combinations that exploit these interindividual variations in gemcitabine metabolism to improve the efficacy of this drug in the management of APC.
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The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the western world and accounts for 2% of all cancer-related deaths. The precursor lesion for EAC is Barrett esophagus (BE), which is strongly associated with gastresophageal reflux disease. A major limitation to the study of EAC has been the absence of tractable and genetically modifiable preclinical models of BE. A mouse model of BE and EAC that resembles human disease could provide novel insights into the origins and molecular pathogenesis of BE. In addition, validated animal models could help stratify BE patients given the limited predictive power of current standard endoscopic measures and clinical assessment. Here, we review the findings from recently developed mouse models of BE and EAC and their impact on clinical decision making, surveillance programs and therapeutic options. The data, taken together, suggest potential origins of BE from the gastric cardia, a role of bile acid and hypergatrinemia for carcinogenesis, a growing importance for columnar-like epithelium and a critical role for Notch signaling.
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Esófago de Barrett/patología , Animales , Esófago de Barrett/complicaciones , Esófago de Barrett/tratamiento farmacológico , Ácidos y Sales Biliares/metabolismo , Modelos Animales de Enfermedad , Neoplasias Esofágicas/etiología , Reflujo Gastroesofágico/complicaciones , Humanos , Inhibidores de la Bomba de Protones/uso terapéutico , Receptores Notch/metabolismo , Células Madre/citología , Células Madre/metabolismoRESUMEN
Metastatic carcinoma of the pancreas from another primary site is uncommon and it accounts for 2-5% of all pancreatic cancer cases. We reported the case of one patient with pancreatic metastasis from colon carcinoma in the past and would like to add another six cases of pancreatic metastases from different types of cancer. The diagnosis of cancer metastatic to the pancreas should be suspected when patients have a history of malignancy, especially of kidney, skin, lung, colon and breast cancer. Besides imaging studies, such as computed tomography (CT) scan, bone scan and positron emission tomography (PET)/CT scan, endoscopic ultrasound (EUS)-guided biopsy has most value in ruling out second primary pancreatic cancer. The prognosis of pancreatic metastases is essentially determined by the underlying primary cancer and the potential treatment options.
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Neoplasias Pancreáticas/secundario , Adulto , Anciano , Neoplasias del Colon/patología , Femenino , Humanos , MasculinoRESUMEN
Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1ß phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely resembled human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1, and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5(+) gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1ß-IL-6 signaling cascade and Dll1-dependent Notch signaling.
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Esófago de Barrett/patología , Ácidos y Sales Biliares/farmacología , Cardias/patología , Esofagitis/patología , Células Madre/patología , Adenocarcinoma/patología , Animales , Esófago de Barrett/etiología , Proteína Morfogenética Ósea 4/genética , Proteína Morfogenética Ósea 4/metabolismo , Factor de Transcripción CDX2 , Neoplasias Esofágicas/patología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Metaplasia/patología , Ratones , Ratones Transgénicos , Mucinas/genética , Mucinas/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Péptidos/genética , Péptidos/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transducción de Señal , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factor Trefoil-2 , Regulación hacia ArribaRESUMEN
Only rarely do corticotroph pituitary tumors become invasive leading to symptoms caused by compression of cranial nerves and other local structures. When aggressive pituitary neuroendocrine tumors do develop, conventional treatment options are of limited success. A 50-year-old man developed a giant invasive corticotroph pituitary tumor 2 years after initial presentation. His tumor and symptoms failed to respond to maximal surgical, radio-surgical, radiation and medical therapy and a bilateral adrenalectomy was done. He subsequently developed rapid growth of his tumor leading to multiple cranial nerve deficits. He was administered salvage chemotherapy with capecitabine and temozolomide (CAPTEM), a novel oral chemotherapy regimen developed at our institution for treatment of neuroendocrine tumors. After two cycles of CAPTEM, his tumor markedly decreased in size and ACTH levels fell by almost 90%. Despite further decreases in ACTH levels, his tumor recurred after 5 months with increased avidity on PET scan suggesting a transformation to a more aggressive phenotype. Temozolomide had been reported to be effective against other pituitary tumors and this case adds to this literature demonstrating its use along with capecitabine (CAPTEM) against a corticotroph tumor. Further evaluation of the CAPTEM regimen in patients with pituitary neuroendocrine tumors which fail to respond to classic treatments is warranted.
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Adenoma Hipofisario Secretor de ACTH/tratamiento farmacológico , Adenoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dacarbazina/análogos & derivados , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Adenoma Hipofisario Secretor de ACTH/diagnóstico por imagen , Adenoma Hipofisario Secretor de ACTH/patología , Adenoma/diagnóstico por imagen , Adenoma/patología , Capecitabina , Dacarbazina/administración & dosificación , Desoxicitidina/administración & dosificación , Fluorouracilo/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Radiografía , Temozolomida , Resultado del TratamientoRESUMEN
POTE is a primate-specific gene family that encodes cancer testis antigens that contain three domains, although the proteins vary greatly in size. The amino-terminal domain is novel and has three cysteine-rich domains of 37 amino acids. The second and third domains are rich in ankyrin repeats and spectrin-like helices respectively. In humans, 13 highly homologous paralogs are dispersed among eight chromosomes. Some members of the POTE gene family have an actin insertion at the carboxyl end of the protein. The expression of the POTE gene in normal adult tissues is restricted, but several POTE paralogs are frequently expressed in many cancers including breast, prostate, and lung cancers. We show here that POTE is expressed in several human embryonic stem (ES) cell lines. We found that UC06, WA01 and ES03 cell lines express mainly a POTE-2gamma transcript but ES02 and ES04 cell lines predominantly express POTE-2alpha. The WA09 cell line expressed both POTE-2gamma and POTE-2alpha. There is no detectable POTE gene expression in fetal tissues (ages 16-36 weeks). The POTE paralogs that are expressed in ES cells may have a specific function during lineage-specific differentiation of ES cells.
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Antígenos de Neoplasias/genética , Cromosomas Humanos Par 2 , Células Madre Embrionarias/metabolismo , Homología de Secuencia de Aminoácido , Secuencia de Aminoácidos , Antígenos de Neoplasias/metabolismo , Antígenos de Neoplasias/fisiología , Azacitidina/análogos & derivados , Azacitidina/farmacología , Encéfalo/metabolismo , Diferenciación Celular/genética , Linaje de la Célula/genética , Células Cultivadas , Mapeo Cromosómico , Clonación Molecular , Metilación de ADN/efectos de los fármacos , Decitabina , Células Madre Embrionarias/fisiología , Feto/metabolismo , Expresión Génica/efectos de los fármacos , Humanos , Masculino , Datos de Secuencia Molecular , Familia de Multigenes , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/fisiología , Testículo/metabolismoRESUMEN
The POTE gene family is composed of 13 highly homologous paralogs preferentially expressed in prostate, ovary, testis, and placenta. We produced 10 monoclonal antibodies (MAbs) against three representative POTE paralogs: POTE-21, POTE-2gammaC, and POTE-22. One reacted with all three paralogs, six MAbs reacted with POTE-2gammaC and POTE-22, and three MAbs were specific to POTE-21. Epitopes of all 10 MAbs were located in the cysteine-rich repeats (CRRs) motifs located at the N-terminus of each POTE paralog. Testing the reactivity of each MAb with 12 different CRRs revealed slight differences among the antigenic determinants, which accounts for differences in cross-reactivity. Using MAbs HP8 and PG5 we were able to detect a POTE-actin fusion protein in human testis by immunoprecipitation followed by Western blotting. By immunohistochemistry we demonstrated that the POTE protein is expressed in primary spermatocytes, implying a role in spermatogenesis.
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Ancirinas/metabolismo , Perfilación de la Expresión Génica/métodos , Espermatocitos/metabolismo , Testículo/metabolismo , Animales , Ancirinas/inmunología , Anticuerpos Monoclonales/inmunología , Células Cultivadas , Humanos , Inmunohistoquímica/métodos , Masculino , Ratones , Ratones Endogámicos BALB C , Espermatocitos/inmunología , Testículo/inmunologíaRESUMEN
We previously described a primate-specific gene family, POTE, that is expressed in many cancers but in a limited number of normal organs. The 13 POTE genes are dispersed among eight different chromosomes and evolved by duplications and remodeling of the human genome from an ancestral gene, ANKRD26. Based on sequence similarity, the POTE gene family members can be divided into three groups. By genome database searches, we identified an actin retroposon insertion at the carboxyl terminus of one of the ancestral POTE paralogs. By Northern blot analysis, we identified the expected 7.5-kb POTE-actin chimeric transcript in a breast cancer cell line. The protein encoded by the POTE-actin transcript is predicted to be 120 kDa in size. Using anti-POTE mAbs that recognize the amino-terminal portion of the POTE protein, we detected the 120-kDa POTE-actin fusion protein in breast cancer cell lines known to express the fusion transcript. These data demonstrate that insertion of a retroposon produced an altered functional POTE gene. This example indicates that new functional human genes can evolve by insertion of retroposons.
Asunto(s)
Actinas/genética , Evolución Molecular , Genoma Humano , Familia de Multigenes , Proteínas/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Actinas/metabolismo , Animales , Secuencia de Bases , Neoplasias de la Mama , Línea Celular Tumoral , Femenino , Haplorrinos , Humanos , Datos de Secuencia Molecular , Mutagénesis Insercional , Filogenia , Proteínas/química , Proteínas/genética , Proteínas Recombinantes de Fusión/genética , Retroelementos , Alineación de Secuencia , Distribución TisularRESUMEN
To identify new antigens that are targets for the immunotherapy of prostate and breast cancer, we used expressed sequence tag and genomic databases and discovered POTE, a new primate-specific gene family. Each POTE gene encodes a protein that contains three domains, although the proteins vary greatly in size. The NH2-terminal domain is novel and has properties of an extracellular domain but does not contain a signal sequence. The second and third domains are rich in ankyrin repeats and spectrin-like helices, respectively. The protein encoded by POTE-21, the first family member discovered, is localized on the plasma membrane of the cell. In humans, 13 highly homologous paralogs are dispersed among eight chromosomes. The expression of POTE genes in normal tissues is restricted to prostate, ovary, testis, and placenta. A survey of several cancer samples showed that POTE was expressed in 6 of 6 prostate, 12 of 13 breast, 5 of 5 colon, 5 of 6 lung, and 4 of 5 ovarian cancers. To determine the relative expression of each POTE paralog in cancer and normal samples, we employed a PCR-based cloning and analysis method. We found that POTE-2alpha, POTE-2beta, POTE-2gamma, and POTE-22 are predominantly expressed in cancers whereas POTE expression in normal tissues is somewhat more diverse. Because POTE is primate specific and is expressed in testis and many cancers but only in a few normal tissues, we conclude POTE is a new primate-specific member of the cancer-testis antigen family. It is likely that POTE has a unique role in primate biology.