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1.
Ann Surg ; 2020 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-32649472

RESUMO

OBJECTIVE: In this retrospective cohort study, we describe the clinical presentation and workup of parathyroid carcinoma (PC) and determine its clinical prognostic parameters. Primary outcome was recurrence free survival. SUMMARY BACKGROUND DATA: PC is an orphan malignancy for which diagnostic workup and treatment is not established. METHODS: Eighty-three patients were diagnosed with PC between 1986 and 2018. Disease-specific and recurrence-free survivals were estimated with the Kaplan-Meier method. Risk factors for recurrence were identified by binary logistic regression with adjustment for age and sex. Thirty-nine tumors underwent central histopathological review. RESULTS: Renal (39.8%), gastrointestinal (24.1%), bone (22.9%), and psychiatric (19.3%) symptoms were the most common symptoms. Surgical treatment was heterogeneous [parathyroidectomy [PTx)] alone: 22.9%; PTx and hemithyroidectomy: 24.1%; en bloc resection 15.7%; others 37.3%] and complications of surgery were frequent (recurrent laryngeal nerve palsy 25.3%; hypoparathyroidism 6%). Recurrence of PC was observed in 32 of 83 cases. In univariate analysis, rate of recurrence was reduced when extended initial surgery had been performed (P = 0.04). In multivariate analysis low T status [odds ratio (OR) = 2.65, 95% confidence interval (CI) 1.02-6.88, P = 0.045], N0 stage at initial diagnosis (OR = 6.32, 95% CI 1.33-30.01, P = 0.02), Ki-67 <10% (OR = 14.07, 95% CI 2.09-94.9, P = 0.007), and postoperative biochemical remission (OR = 0.023, 95% CI 0.001-0.52, P = 0.018) were beneficial prognostic parameters for recurrence-free survival. CONCLUSION: Despite a favorable overall prognosis, PC shows high rates of recurrence leading to repeated surgery and postoperative recurrent laryngeal nerve palsy and hypoparathyroidism. In view of the reduced recurrence rate in cases of extended surgery, ipsilateral completion surgery may be considered when PC is confirmed.

2.
J Clin Endocrinol Metab ; 105(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32449514

RESUMO

CONTEXT: Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells. OBJECTIVE: To investigate SOAT1 protein expression as a marker of treatment response to mitotane. PATIENTS: A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens. SETTING: Retrospective study at 12 ACC referral centers. MAIN OUTCOME MEASURE: Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). RESULTS: Sixty-one of 135 patients (45%) with adjuvant mitotane treatment had recurrences and 45/68 patients (66%) with mitotane treatment for advanced disease had progressive disease. After multivariate adjustment for sex, age, hormone secretion, tumor stage, and Ki67 index, RFS (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 0.61-1.85; P = 0.82), and DSS (HR = 1.30; 95% CI, 0.58-2.93; P = 0.53) in adjuvantly treated ACC patients did not differ significantly between tumors with high and low SOAT1 expression. Similarly, in the advanced stage setting, PFS (HR = 1.34; 95% CI, 0.63-2.84; P = 0.45) and DSS (HR = 0.72; 95% CI, 0.31-1.70; P = 0.45) were comparable and response rates not significantly different. CONCLUSIONS: SOAT1 expression was not correlated with clinical endpoints RFS, PFS, and DSS in ACC patients with mitotane monotherapy. Other factors appear to be relevant for mitotane treatment response and ACC patient survival.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32373071

RESUMO

Adrenocortical carcinomas (ACC) are aggressive tumors with a heterogeneous prognosis and limited therapeutic options for advanced stages. This study aims to identify novel drug targets for a personalized treatment in ACC. RNA was isolated from 40 formalin-fixed paraffin-embedded ACC samples. We evaluated gene expression of 84 known cancer drug targets by reverse transcriptase quantitative real time-PCR and calculated fold change using 5 normal adrenal glands as reference (overexpression by fold change >2.0). The most promising candidate cyclin-dependent kinase 4 (CDK4) was investigated at protein level in 104 ACC samples and tested by in vitro experiments in two ACC cell lines (NCI-H295R and MUC1). The most frequently overexpressed genes were TOP2A (100% of cases, median fold change = 16.5), IGF2 (95%, fold change = 52.9), CDK1 (80%, fold change = 6.7), CDK4 (62%, fold change = 2.6), PLK4 (60%, fold change = 2.8), and PLK1 (52%, fold change = 2.3). CDK4 was chosen for functional validation, as it is actionable by approved CDK4/6-inhibitors (e.g., palbociclib). Nuclear immunostaining of CDK4 significantly correlated with mRNA expression (R = 0.52, P < 0.005). We exposed both NCI-H295R and MUC1 cell lines to palbociclib and found a concentration- and time-dependent reduction of cell viability, which was more pronounced in the NCI-H295R cells in line with higher CDK4 expression. Furthermore, we tested palbociclib in combination with insulin-like growth factor 1/insulin receptor inhibitor linsitinib showing an additive effect. In conclusion, we demonstrate that RNA profiling is useful to discover potential drug targets and that CDK4/6 inhibitors are promising candidates for treatment of selected patients with ACC.

4.
Int J Colorectal Dis ; 35(2): 365-370, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31828368

RESUMO

INDROCUTION: The local immune contexture in patients with locally advanced rectal cancer (LARC) has important prognostic value after neoadjuvant chemoradiation and surgical resection. In this study, we examined the prognostic role of Indoleamine-2,3-Dioxygenase (IDO1) and infiltrating cytotoxic T lymphocytes (CD8+) according to the nodal stage of LARC patients. MASTERIAL AND METHODS: Expression of IDO1 and CD8 was evaluated through immunohistochemistry in 106 archival tumour tissue samples from patients following neoadjuvant chemoradiation and radical resection. The average infiltration of IDO1+ and CD8+ cells was calculated and expressed as total scores as previously described. Kaplan-Meier curves were used to describe overall and disease-free survival. RESULTS: In nodal-positive tumours (N+), IDO-positivity was associated with a reduced disease-free survival (DFS) (p = 0.063) and CD8-positivity with an impaired OS (p = 0.024). Patients with a N+ LARC and a high total IDO1 score showed a clear advantage regarding five-year disease-free survival rates compared with patients with a low total IDO1 score (N+ 5y-DFS IDO1 high: 66.7% vs IDO low: 19%). We also detected better 5-years-OS rates in N+ LARC with a high total CD8 score (N+ 5y-OS CD8 high: 83.3% vs CD8 low: 32.3%). These survival benefits were not evident in patients with N-tumours. CONCLUSION: Analysis of the local CD8 and IDO1 expression influences prognosis in nodal-positive LARC patients after multimodal therapy and may be a helpful tool in specifying individual adjuvant treatment strategies according to different immune profiles.

5.
Eur J Nucl Med Mol Imaging ; 47(1): 168-177, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31529265

RESUMO

PURPOSE: The present study is based on a retrospective analysis of Gallium-68 (68Ga)-labelled prostate-specific membrane antigen (68Ga-PSMA I&T) PET/CT performed in newly diagnosed, treatment-naïve prostate cancer (PCa) patients prior to definitive treatment. METHODS: A total of 82 men were included in the study and were imaged with 68Ga-PSMA I&T PET/CT to assess the distribution of PSMA-avid disease for staging purposes (11 with low-risk, 32 with intermediate-risk, and 39 with high-risk PCa). Forty patients (20 with intermediate- and 20 with high-risk disease) underwent subsequent radical prostatectomy with extended pelvic lymph node dissection which allowed for correlation of imaging findings with histopathologic data. RESULTS: PSMA-positive disease was detected in 83% of patients with 66/82 (80.5%) primary tumours being visualized. PSMA-avid lymph nodes were recorded in 17/82 patients (20.7%, 3 with intermediate-risk and 14 with high-risk PCa); distant disease was found in 14/82 subjects (17.1%, 2 with intermediate-risk and 12 with high-risk PCa). No extraprostatic disease was found in low-risk PCa. SUVmax of primary tumours showed a weak but significant correlation with serum PSA values (r = 0.51, p < 0.001) and Gleason scores (GSC; r = 0.35, p = 0.001), respectively. In correlation with histopathology, calculated per-region sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for detection of lymph node metastases were 35.0%, 98.4%, 63.6%, 95.0%, and 93.0%, respectively. CONCLUSIONS: In patients with initial diagnosis of intermediate- and high-risk prostate cancer, 68Ga-PSMA I&T PET/CT emerges as a relevant staging procedure by identifying nodal and/or distant metastases. Due to the low prevalence of extraprostatic disease, its value seems to be limited in low-risk disease.

6.
Clin Chem ; 65(10): 1276-1286, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31492715

RESUMO

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare tumor with variable prognosis even within the same tumor stage. Cancer-related sex hormones and their sulfated metabolites in body fluids can be used as tumor markers. The role of steroid sulfation in ACC has not yet been studied. MALDI mass spectrometry imaging (MALDI-MSI) is a novel tool for tissue-based chemical phenotyping. METHODS: We performed phenotyping of formalin-fixed, paraffin-embedded tissue samples from 72 ACC by MALDI-MSI at a metabolomics level. RESULTS: Tumoral steroid hormone metabolites-estradiol sulfate [hazard ratio (HR) 0.26; 95% CI, 0.10-0.69; P = 0.005] and estrone 3-sulfate (HR 0.22; 95% CI, 0.07-0.63; P = 0.003)-were significantly associated with prognosis in Kaplan-Meier analyses and after multivariable adjustment for age, tumor stage, and sex (HR 0.29; 95% CI, 0.11-0.79; P = 0.015 and HR 0.30; 95% CI, 0.10-0.91; P = 0.033, respectively). Expression of sulfotransferase SULT2A1 was associated with prognosis to a similar extent and was validated to be a prognostic factor in two published data sets. We discovered the presence of estradiol-17ß 3,17-disulfate (E2S2) in a subset of tumors with particularly poor overall survival. Electron microscopy revealed novel membrane-delimited organelles in only these tumors. By applying cluster analyses of metabolomic data, 3 sulfation-related phenotypes exhibited specific metabolic features unrelated to steroid metabolism. CONCLUSIONS: MALDI-MSI provides novel insights into the pathophysiology of ACC. Steroid hormone sulfation may be used for prognostication and treatment stratification. Sulfation-related metabolic reprogramming may be of relevance also in conditions beyond the rare ACC and can be directly investigated by the use of MALDI-MSI.

7.
Front Oncol ; 9: 770, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475113

RESUMO

Despite histological evidence in various solid tumor entities, available experience with CXCR4-directed diagnostics and endoradiotherapy mainly focuses on hematologic diseases. With the goal of expanding the application of CXCR4 theranostics to solid tumors, we aimed to elucidate the feasibility of CXCR4-targeted imaging in a variety of such neoplasms. Methods: Nineteen patients with newly diagnosed, treatment-naïve solid tumors including pancreatic adenocarcinoma or neuroendocrine tumor, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, and prostate cancer underwent [68Ga]Pentixafor PET/CT. CXCR4-mediated uptake was assessed both visually and semi-quantitatively by evaluation of maximum standardized uptake values (SUVmax) of both primary tumors and metastases. With physiologic liver uptake as reference, tumor-to-background ratios (TBR) were calculated. [68Ga]Pentixafor findings were further compared to immunohistochemistry and [18F]FDG PET/CT. Results: On [68Ga]Pentixafor PET/CT, 10/19 (52.6%) primary tumors were visually detectable with a median SUVmax of 5.4 (range, 1.7-16.0) and a median TBR of 2.6 (range, 0.8-7.4), respectively. The highest level of radiotracer uptake was identified in a patient with cholangiocarcinoma (SUVmax, 16.0; TBR, 7.4). The relatively low uptake on [68Ga]Pentixafor was also noted in metastases, exhibiting a median SUVmax of 4.5 (range, 2.3-8.8; TBR, 1.7; range, 1.0-4.1). A good correlation between uptake on [68Ga]Pentixafor and histological derived CXCR4 expression was noted (R = 0.62, P < 0.05). In the 3 patients in whom [18F]FDG PET/CT was available, [68Ga]Pentixafor exhibited lower uptake in all lesions. Conclusions: In this cohort of newly diagnosed, treatment-naïve patients with solid malignancies, CXCR4 expression as detected by [68Ga]Pentixafor-PET/CT and immunohistochemistry was rather moderate. Thus, CXCR4-directed imaging may not play a major role in the management of solid tumors in the majority of patients.

8.
J Mol Biol ; 431(15): 2884-2893, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31150736

RESUMO

Precision medicine requires in vitro models which will both faithfully recapitulate the features of an individual's disease and enable drug testing on a wide variety of samples covering the greatest range of phenotypes possible for a particular disease. Organoid technology has immense potential to fulfill this demand, but it will be necessary to develop robust protocols that enable the generation of organoids in a dependable manner from nearly every patient. Here we provide a user's guide, including detailed step-by-step protocols, to the establishment, isolation and verification of gastric cancer organoids. Selection strategies include omission of growth factors, addition of drugs, isolation of distinct phenotypes and generation of monoclonal lines. For confirmation of cancer identity, we use sequencing, drug selection, karyotyping and histology. While we specify these protocols for human gastric cancer organoids here, the methods described are applicable to organoids derived from other tissues as well.

9.
Nuklearmedizin ; 58(3): 282-284, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31064028

RESUMO

Lymphatic mapping for identification and subsequent removal of the sentinel lymph node (SLN) is an established procedure in breast cancer and cutaneous melanoma to minimize the extent of surgery (and thus, associated morbidity), simplify histopathological processing and subsequently provide prognostic information and help choose the optimal patient management. Established methods for SLN mapping include visual identification of nodal staining after peritumoral injection of a (blue) dye or the use of lymphoscintigraphy with technetium-labelled nanocolloid. In experienced hands, success rates for both methods exceed 95 %, nonetheless in some patients they fail despite correct application and imaging techniques. Potential reasons for false-negative SLN detection rates -beyond poor tracer injection technique or imaging of the wrong nodal basin- include inadequate pathologic examination of the SLN or complete replacement of the SLN with neoplastic disease, causing the injected tracer to completely bypass the infiltrated node 1.Beyond colloid particles, the more specific receptor-targeting small molecule [99mTc]Tilmanocept has recently been approved for scintigraphic SLN detection. Tilmanocept, or mannosyl diethylene-triamine-pentaacetate (DTPA) dextran, has a small molecular size of approximately 7 nm and works via specific binding to the mannose receptor (CD206) 2. The mannose receptor is particularly overexpressed on macrophages and dendritic precursor cells within lymph nodes, thus uptake in lymph nodes is not dependent on particle size 2, 3. In pilot studies scintigraphic SLN detection with [99mTc]Tilmanocept was superior to dye staining 4. Given its beneficial properties, [99mTc]Tilmanocept might offer advantages over the alternatively used radiocolloids. We present four cases of [99mTc]Tilmanocept application after inconclusive or unsuccessful attempts of SLN detection using [99mTc]nanocolloid lymphoscintigraphy.


Assuntos
Neoplasias da Mama/diagnóstico , Dextranos/metabolismo , Linfocintigrafia/métodos , Mananas/metabolismo , Cintilografia/métodos , Compostos Radiofarmacêuticos/metabolismo , Agregado de Albumina Marcado com Tecnécio Tc 99m/metabolismo , Pentetato de Tecnécio Tc 99m/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Biópsia de Linfonodo Sentinela , Padrão de Cuidado , Pentetato de Tecnécio Tc 99m/metabolismo
10.
Cancer Immunol Immunother ; 68(4): 563-575, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30671614

RESUMO

The prognostic value of the local immune phenotype in patients with colorectal cancer has been extensively studied. Neoadjuvant radiotherapy and/or chemotherapy may potentially influence these immune responses. In this study, we examined the prognostic role of indoleamine-2,3-Dioxygenase (IDO1) and infiltrating cytotoxic T lymphocytes (CD8+) in locally advanced rectal carcinomas after neoadjuvant treatment. Expression of IDO1 and CD8 was evaluated by immunohistochemistry in 106 archival tumour tissue samples from patients following neoadjuvant chemoradiation and radical resection. The average infiltration of IDO1+ and CD8+ cells was calculated along the tumour invasive front, in the tumour centre and within the neoplastic cells and expressed as total scores. Of the tumour specimens evaluable for immunohistochemistry, 100% showed CD8+ lymphocyte infiltration and 93.4% stained positive for IDO1. Total IDO1 score positively correlated with total CD8 score for all three subsites (p = 0.002, Kendall-tau-b 0.357). A high total CD8 score was positively correlated with lower ypUICC-stages (p = 0.047) and lower ypT-categories (p = 0.032). Total IDO1 expression showed a clear trend towards a lower risk of recurrence (p = 0.078). A high total IDO1 score was an independent prognostic marker for prolonged disease-free survival (HR 0.38, p = 0.046) and a high total CD8 score for favourable overall survival (HR 0.16, p = 0.029). Analysis of the local CD8 and IDO1 expression profile may be a helpful tool in predicting prognosis for patients with locally advanced rectal cancer following neoadjuvant chemoradiation.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Neoplasias Retais/imunologia , Neoplasias Retais/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Linfócitos T CD8-Positivos/metabolismo , Quimiorradioterapia , Feminino , Humanos , Imuno-Histoquímica , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Neoplasias Retais/patologia , Neoplasias Retais/terapia
11.
Nutrients ; 11(1)2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30609782

RESUMO

Serum vitamin D levels negatively correlate with obesity and associated disorders such as non-alcoholic steatohepatitis (NASH). However, the mechanisms linking low vitamin D (VD) status to disease progression are not completely understood. In this study, we analyzed the effect of VD treatment on NASH in mice. C57BL6/J mice were fed a high-fat/high-sugar diet (HFSD) containing low amounts of VD for 16 weeks to induce obesity, NASH and liver fibrosis. The effects of preventive and interventional VD treatment were studied on the level of liver histology and hepatic/intestinal gene expression. Interestingly, preventive and to a lesser extent also interventional VD treatment resulted in improvements of liver histology. This included a significant decrease of steatosis, a trend towards lower non-alcoholic fatty liver disease (NAFLD) activity score and a slight non-significant decrease of fibrosis in the preventive treatment group. In line with these changes, preventive VD treatment reduced the hepatic expression of lipogenic, inflammatory and pro-fibrotic genes. Notably, these beneficial effects occurred in conjunction with a reduction of intestinal inflammation. Together, our observations suggest that timely initiation of VD supplementation (preventive vs. interventional) is a critical determinant of treatment outcome in NASH. In the applied animal model, the improvements of liver histology occurred in conjunction with reduced inflammation in the gut, suggesting a potential relevance of vitamin D as a therapeutic agent acting on the gut⁻liver axis.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Carboidratos da Dieta/administração & dosagem , Obesidade/induzido quimicamente , Vitamina D/uso terapêutico , Animais , Glicemia/efeitos dos fármacos , Composição Corporal , Peso Corporal/efeitos dos fármacos , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Intolerância à Glucose/tratamento farmacológico , Intestinos/efeitos dos fármacos , Intestinos/fisiologia , Fígado/anatomia & histologia , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Esteroide 12-alfa-Hidroxilase/genética , Esteroide 12-alfa-Hidroxilase/metabolismo , Regulação para Cima/efeitos dos fármacos
12.
Biochim Biophys Acta Mol Basis Dis ; 1865(5): 943-953, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29990551

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disorder closely linked to obesity, hyperlipidemia and type 2 diabetes and is increasingly recognized as a major health problem in many parts of the world. While early stages of NAFLD are characterized by a bland accumulation of fat (steatosis) in hepatocytes, the disease can progress to non-alcoholic steatohepatitis (NASH) which involves chronic liver inflammation, tissue damage and fibrosis and can ultimately lead to end-stage liver disease including cirrhosis and cancer. As no approved pharmacological treatment for NAFLD exists today, there is an urgent need to identify promising pharmacological targets and develop future therapies. For this purpose, basic and translational research in NAFLD animal models is indispensable. While a large number of diverse animal models are currently used in the field, there is an ongoing challenge to identify those models that mirror human pathology the closest to allow good translation of obtained results into further clinical development. This review is meant to provide a concise overview of the most relevant NAFLD animal models currently available and will discuss the strengths and weaknesses of these models with regard to their comparability to human disease conditions.


Assuntos
Modelos Animais de Doenças , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia
13.
J Nucl Med ; 60(3): 348-352, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30389821

RESUMO

PET with 18F-FDG is the standard modality in nuclear medicine for imaging multiple myeloma (MM). However, viable MM as detected by MRI or PET with other metabolic tracers, including 11C-methionine, may be missed-for example, because of low hexokinase 2 (HK2) expression of tumor cells. The aim of this study was to further investigate potential reasons for PET false negativity. Methods: A cohort of 15 mainly pretreated patients with relapsed or refractory biopsy-proven, serologically active MM who underwent both 18F-FDG and 11C-methionine PET/CT was retrospectively analyzed. Results: In 9 of the 15 patients, 18F-FDG PET was negative in the presence of viable disease. In the remaining 6 patients, both 18F-FDG and 11C-methionine PET/CT revealed the same number of MM lesions. At immunohistochemistry, 18F-FDG-negative myeloma did not exhibit significant differences in HK2 or glucose-6-phosphatase expression from 18F-FDG-positive disease (P = 0.57 and P = 0.44, respectively). Conclusion: Beyond HK2 expression, 18F-FDG negativity in (mainly pretreated) MM patients seems to be associated with additional causes not yet known.


Assuntos
Radioisótopos de Carbono , Fluordesoxiglucose F18 , Regulação Neoplásica da Expressão Gênica , Hexoquinase/metabolismo , Metionina , Mieloma Múltiplo/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Idoso , Reações Falso-Negativas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico por imagem , Estudos Retrospectivos
15.
Development ; 145(23)2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30389851

RESUMO

The molecular mechanism underlying the periodic induction of lateral roots, a paradigmatic example of clock-driven organ formation in plant development, is a matter of ongoing, controversial debate. Here, we provide experimental evidence that this clock is frequency modulated by light and that auxin serves as a mediator for translating continuous light signals into discontinuous gene activation signals preceding the initiation of lateral roots in Arabidopsis seedlings. Based on this evidence, we propose a molecular model of an ultradian biological clock involving auxin-dependent degradation of an AUX/IAA-type transcription repressor as a flexible, frequency-controlling delay element. This model widens the bandwidth of biological clocks by adding a new type that allows the pace of organ formation to adapt to the changing environmental demands of the growing plant.


Assuntos
Arabidopsis/crescimento & desenvolvimento , Ácidos Indolacéticos/farmacologia , Luz , Reguladores de Crescimento de Planta/farmacologia , Raízes de Plantas/crescimento & desenvolvimento , Arabidopsis/efeitos dos fármacos , Arabidopsis/efeitos da radiação , Escuridão , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/efeitos da radiação , Plântula/efeitos dos fármacos , Plântula/crescimento & desenvolvimento , Plântula/efeitos da radiação , Fatores de Tempo , Triptofano/farmacologia
16.
Clin Nucl Med ; 43(11): 835-836, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30179908

RESUMO

Ga-pentixafor is a novel radioligand of C-X-C motif chemokine receptor 4. A 55-year-old woman with a history of primary Sjögren's syndrome underwent Ga-pentixafor PET/CT for staging of lymphoma originating from mucosa-associated lymphoid tissue. Whereas no lymphoma manifestation could be detected, imaging revealed bilateral intense radiotracer uptake in both parotid and submandibular salivary glands, consistent with inflammatory cell infiltration.


Assuntos
Complexos de Coordenação , Peptídeos Cíclicos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Síndrome de Sjogren/diagnóstico por imagem , Feminino , Humanos , Pessoa de Meia-Idade
17.
J Clin Endocrinol Metab ; 103(12): 4511-4523, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30113656

RESUMO

Context: Adrenocortical carcinoma (ACC) has a heterogeneous prognosis, and current medical therapies have limited efficacy in its advanced stages. Genome-wide multiomics studies identified molecular patterns associated with clinical outcome. Objective: Here, we aimed at identifying a molecular signature useful for both personalized prognostic stratification and druggable targets, using methods applicable in clinical routine. Design: In total, 117 tumor samples from 107 patients with ACC were analyzed. Targeted next-generation sequencing of 160 genes and pyrosequencing of 4 genes were applied to formalin-fixed, paraffin-embedded (FFPE) specimens to detect point mutations, copy number alterations, and promoter region methylation. Molecular results were combined with clinical/histopathological parameters (tumor stage, age, symptoms, resection status, and Ki-67) to predict progression-free survival (PFS). Results: In addition to known driver mutations, we detected recurrent alterations in genes not previously associated with ACC (e.g., NOTCH1, CIC, KDM6A, BRCA1, BRCA2). Best prediction of PFS was obtained integrating molecular results (more than one somatic mutation, alterations in Wnt/ß-catenin and p53 pathways, high methylation pattern) and clinical/histopathological parameters into a combined score (P < 0.0001, χ2 = 68.6). Accuracy of prediction for early disease progress was 83.3% (area under the receiver operating characteristic curve: 0.872, 95% confidence interval 0.80 to 0.94). Furthermore, 17 potentially targetable alterations were found in 64 patients (e.g., in CDK4, NOTCH1, NF1, MDM2, and EGFR and in DNA repair system). Conclusions: This study demonstrates that molecular profiling of FFPE tumor samples improves prognostication of ACC beyond clinical/histopathological parameters and identifies new potential drug targets. These findings pave the way to precision medicine in this rare disease.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Carcinoma Adrenocortical/genética , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Medicina de Precisão/métodos , Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Variações do Número de Cópias de DNA , Metilação de DNA , Análise Mutacional de DNA , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação Puntual , Prognóstico , Intervalo Livre de Progressão , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
18.
Phys Biol ; 15(5): 056003, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29714708

RESUMO

Spatial relocalization of proteins is crucial for the correct functioning of living cells. An interesting example of spatial ordering is the light-induced clustering of plant photoreceptor proteins. Upon irradiation by white or red light, the red light-active phytochrome, phytochrome B, enters the nucleus and accumulates in large nuclear bodies (NBs). The underlying physical process of nuclear body formation remains unclear, but phytochrome B is thought to coagulate via a simple protein-protein binding process. We measure, for the first time, the distribution of the number of phytochrome B-containing NBs as well as their volume distribution. We show that the experimental data cannot be explained by a stochastic model of nuclear body formation via simple protein-protein binding processes using physically meaningful parameter values. Rather modelling suggests that the data is consistent with a two step process: a fast nucleation step leading to macroparticles followed by a subsequent slow step in which the macroparticles bind to form the nuclear body. An alternative explanation for the observed nuclear body distribution is that the phytochromes bind to a so far unknown molecular structure. We believe it is likely this result holds more generally for other nuclear body-forming plant photoreceptors and proteins.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Núcleo Celular/metabolismo , Fitocromo B/metabolismo , Transporte Ativo do Núcleo Celular/efeitos da radiação , Arabidopsis/citologia , Arabidopsis/efeitos da radiação , Proteínas de Arabidopsis/análise , Núcleo Celular/efeitos da radiação , Simulação por Computador , Luz , Modelos Biológicos , Fitocromo B/análise , Ligação Proteica/efeitos da radiação , Processos Estocásticos
19.
Endocrinology ; 159(3): 1511-1524, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29385420

RESUMO

In the adrenal gland, neuroendocrine cells that synthesize catecholamines and epithelial cells that produce steroid hormones are united beneath a common organ capsule to function as a single stress-responsive organ. The functional anatomy of the steroid hormone-producing adrenal cortex and the catecholamine-producing medulla is ill defined at the level of small molecules. Here, we report a comprehensive high-resolution mass spectrometry imaging (MSI) map of the normal human adrenal gland. A large variety of biomolecules was accessible by matrix-assisted laser desorption/ionization-Fourier transform-ion cyclotron resonance MSI, including nucleoside phosphates indicative of oxidative phosphorylation, sterol and steroid metabolites, intermediates of glycolysis and the tricarboxylic acid cycle, lipids, and fatty acids. Statistical clustering analyses yielded a molecularly defined adrenal anatomy of 10 distinct molecular zones including a highly structured corticomedullary interface. By incorporating pathway information, activities of carbohydrate, amino acid, and lipid metabolism as well as endocrine bioactivity were revealed to be highly spatially organized, which could be visualized as different molecularly defined zones. Together, these findings provide a molecular definition of human adult adrenal gland structure beyond classical histological anatomy.


Assuntos
Glândulas Suprarrenais/anatomia & histologia , Glândulas Suprarrenais/química , Glândulas Suprarrenais/metabolismo , Adulto , Aminoácidos/metabolismo , Metabolismo dos Carboidratos , Feminino , Humanos , Imuno-Histoquímica , Metabolismo dos Lipídeos , Masculino , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Adulto Jovem
20.
Theranostics ; 8(2): 369-383, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29290814

RESUMO

C-X-C chemokine receptor 4 (CXCR4) is a transmembrane receptor with pivotal roles in cell homing and hematopoiesis. CXCR4 is also involved in survival, proliferation and dissemination of cancer, including acute lymphoblastic and myeloid leukemia (ALL, AML). Relapsed/refractory ALL and AML are frequently resistant to conventional therapy and novel highly active strategies are urgently needed to overcome resistance. Methods: We used patient-derived (PDX) and cell line-based xenograft mouse models of ALL and AML to evaluate the efficacy and toxicity of a CXCR4-targeted endoradiotherapy (ERT) theranostic approach. Results: The positron emission tomography (PET) tracer 68Ga-Pentixafor enabled visualization of CXCR4 positive leukemic burden. In xenografts, CXCR4-directed ERT with 177Lu-Pentixather distributed to leukemia harboring organs and resulted in efficient reduction of leukemia. Despite a substantial in vivo cross-fire effect to the leukemia microenvironment, mesenchymal stem cells (MSCs) subjected to ERT were viable and capable of supporting the growth and differentiation of non-targeted normal hematopoietic cells ex vivo. Finally, three patients with refractory AML after first allogeneic hematopoietic stem cell transplantation (alloSCT) underwent CXCR4-directed ERT resulting in leukemia clearance, second alloSCT, and successful hematopoietic engraftment. Conclusion: Targeting CXCR4 with ERT is feasible and provides a highly efficient means to reduce refractory acute leukemia for subsequent cellular therapies. Prospective clinical trials testing the incorporation of CXCR4 targeting into conditioning regimens for alloSCT are highly warranted.


Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Peptídeos/administração & dosagem , Receptores CXCR4/metabolismo , Nanomedicina Teranóstica/métodos , Idoso , Animais , Linhagem Celular Tumoral , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Pessoa de Meia-Idade
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