RESUMO
Inflammatory bowel disease such as chronic colitis promotes colorectal cancer, which is a common cause of cancer mortality worldwide. Hypoxia is a characteristic of inflammation as well as of solid tumors and enforces a gene expression response controlled by hypoxia-inducible factors (HIFs). Once established, solid tumors are immunosuppressive to escape their abatement through immune cells. Although HIF activity is known to 1) promote cancer development and 2) drive tumor immune suppression through the secretion of adenosine, both prolyl hydroxylases and an asparaginyl hydroxylase termed factor-inhibiting HIF (FIH) negatively regulate HIF. Thus, FIH may act as a tumor suppressor in colorectal cancer development. In this study, we examined the role of colon epithelial FIH in a mouse model of colitis-induced colorectal cancer. We recapitulated colitis-associated colorectal cancer development in mice using the azoxymethane/dextran sodium sulfate model in Vil1-Cre/FIH+f/+f and wild-type siblings. Colon samples were analyzed regarding RNA and protein expression and histology. Vil1-Cre/FIH+f/+f mice showed a less severe colitis progress compared with FIH+f/+f animals and a lower number of infiltrating macrophages in the inflamed tissue. RNA sequencing analyses of colon tissue revealed a lower expression of genes associated with the immune response in Vil1-Cre/FIH+f/+f mice. However, tumor occurrence did not significantly differ between Vil1-Cre/FIH+f/+f and wild-type mice. Thus, FIH knockout in colon epithelial cells did not modulate colorectal cancer development but reduced the inflammatory response in chronic colitis.
Assuntos
Neoplasias Associadas a Colite/patologia , Colite/patologia , Neoplasias Colorretais/patologia , Mucosa Intestinal/patologia , Oxigenases de Função Mista/metabolismo , Adenosina/metabolismo , Animais , Azoximetano/toxicidade , Hipóxia Celular/fisiologia , Colite/induzido quimicamente , Colite/genética , Neoplasias Associadas a Colite/genética , Colo/patologia , Neoplasias Colorretais/genética , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Células Epiteliais/patologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxigenases de Função Mista/genética , Prolil Hidroxilases/metabolismo , Transdução de Sinais/fisiologia , Evasão Tumoral/imunologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Malignant pleural mesothelioma (MPM) is a mainly asbestos-related tumour associated with a very poor prognosis. Therapeutic approaches include multimodal therapy and chemotherapeutics, with cisplatin being the drug of choice, but response rates of only up to 14% indicate very poor outcomes. Effective treatment options are lacking. Besides the diagnostic usage of radioligands in positron emission tomography (PET)/computed tomography (CT), the endo-radioligand therapy with Lu177 has been proven as a powerful tool in cancer therapy. Mesothelin (MSLN) and C-XC chemokine receptor 4 (CXCR4) are membrane-bound proteins, expressed in certain cancers, and thus are promising targets for endo-radiotherapy. A significant portion of high MSLN- or CXCR4-expressing tumors within the MPM may open the field for this sophisticated treatment approach in the near future. Formalin-fixed, paraffin-embedded (FFPE) tumour specimens from 105 patients suffering from MPM and treated at the Lung Cancer Centre of Essen and at the Helios Klinikum Emil von Behring Berlin were screened. The tumour samples were arranged in tissue microarrays. We immunohistochemically stained the tumour samples against MSLN and CXCR4. The protein expressions of the stainings were scored by a pathologist by using a semiquantitative method. The data obtained were correlated with the clinical outcome. Overall, 77.1% of the analysed tumours showed CXCR4 protein expression (25.7% of them at high expression level (Score 3)). 48.6% of all samples showed an overall strong staining (Score ≥ 2), 59% of the investigated tumours showed MSLN protein expression (10.5% of them at high expression (Score 3)), and 36.2% of all samples showed an overall strong staining (Score ≥ 2). Our results show significant tissue expression levels, for both CXCR4 and MSLN protein, in a major portion of clinical MPM samples. One-third of patients showed outstanding immunoexpression of at least one of these markers, making them interesting candidates for radioligand-based PET/CT diagnostics and follow-up and furthermore may profit from endo-radiotherapy.
Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Humanos , Mesotelina , Mesotelioma/tratamento farmacológico , Mesotelioma/radioterapia , Mesotelioma/diagnóstico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Neoplasias Pleurais/metabolismo , Neoplasias Pulmonares/metabolismo , Receptores CXCR4/genéticaRESUMO
Background: Chronic deciduitis is a chronic inflammatory placental disease. It is associated with severe perinatal complications, especially recurrent miscarriage, preterm birth, preterm labor, and preterm prelabor rupture of membranes.Methods: This study presents a detailed quantification of plasma cells and lymphocytes, and regards clinicopathological associations concerning different trimesters in 99 cases displaying chronic deciduitis with plasma cells (CD), 23 cases from the second trimester and 76 cases from the third trimester, respectively. The control group without CD consisted of matched placentas concerning the gestational weeks.Results: In every instance lymphocytes were more numerous than plasma cells. The mean value/highest score in ten high power fields were 50/321 for plasma cells, and 460/995 for lymphocytes, respectively. In the second trimester the scores for plasma cells were significantly higher than in the third trimester. In the third trimester preterm labor occurred significantly more often in cases with chronic deciduitis related to the control group (P < .05).Conclusion: In chronic deciduitis the plasma cell count is usually higher in the second compared to the third trimester. A brisk infiltration of the decidua with plasma cells could probably point to a more severe clinical manifestation and a higher risk for preterm labor and preterm birth.
Assuntos
Corioamnionite , Decídua , Trabalho de Parto Prematuro , Plasmócitos , Nascimento Prematuro , Corioamnionite/patologia , Doença Crônica , Decídua/fisiopatologia , Feminino , Humanos , Recém-Nascido , Trabalho de Parto Prematuro/patologia , Placenta/patologia , Plasmócitos/patologia , Gravidez , Nascimento Prematuro/patologiaRESUMO
BACKGROUND: Endobronchial ultrasound (EBUS) with transbronchial needle aspiration increases the diagnostic yield of lung cancer staging. The left adrenal gland (LAG) is a common site for lung cancer metastasis. The modality of transesophageal examination with an EBUS bronchoscope (EUS-B) routinely for LAG has not been assessed. OBJECTIVE: The aim of this study was to prospectively assess if evaluation and tissue sampling of the LAG could routinely be implemented in an EBUS procedure. METHODS: Patients referred for EBUS between March and August 2017 had assessment of the LAG via EUS-B. Fine-needle aspiration (FNA) was performed in cases with a suspicious LAG. The detection rate, procedure time, and learning curve of four experienced EBUS-bronchoscopists was assessed, plus the diagnostic accuracy and complication rate of FNA. RESULTS: In total, 313 consecutive patients were included. The overall LAG detection rate was 87.5%. After the initial learning curve, the detection rate for all four bronchoscopists was >93%. The detection rate did not correlate with any patient characteristics. EUS-B-FNA revealed nine LAG metastases, with a sensitivity, specificity, and accuracy of 75%, 100%, and 99%, respectively. The mean EUS-B operation time was 194.4 s, with 594.8 s for FNA. There were no FNA-associated complications. CONCLUSIONS: Evaluation of the LAG with EUS-B could routinely be included in an EBUS procedure if necessary. A high detection rate can be achieved after an initial learning period. FNA of the LAG was feasible and safe. EUS-B of the LAG could be integrated into the usual EBUS/EUS-B procedure in lung cancer staging workup.
Assuntos
Neoplasias das Glândulas Suprarrenais/secundário , Glândulas Suprarrenais/patologia , Broncoscopia/métodos , Carcinoma Pulmonar de Células não Pequenas/secundário , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Esofagoscopia/métodos , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/secundário , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Broncoscópios , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/secundário , Endossonografia , Feminino , Humanos , Curva de Aprendizado , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/secundárioRESUMO
INTRODUCTION: Urachal cancer (UrC) is a rare but aggressive cancer. Due to its low incidence, structured epidemiological data have only rarely been reported. To date, no valid data on UrC are available for the German population. METHODS: Data on incidence and relative 5-year survival of urachal lesions (ICD-10: C67.7) were collected from all population-based cancer registries in Germany, provided by the Robert Koch-Institut (RKI). Data were anonymized and included age, sex, and general histology (ICD-O-3). For comparison, a similar inquiry of the "Surveillance, Epidemiology, and End Results program" (SEER-18) database for the USA was conducted. RESULTS: From 2011 to 2015, a total of 154 and 152 cases of UrC were reported for Germany (RKI) and the USA (SEER-18 area), respectively. Age-standardized incidence was 0.32/1,000,000 age-standardized cases/year in both cohorts, and elderly persons were more often affected. The major histological type was adenocarcinoma (64.9 and 81.6%). Relative 5-year survival was 54.8% (CI: 45.0-64.6) in Germany (RKI) and 64.4% (54.1-72.1) in the USA (SEER-18 cohort). Discusssion/Conclusion: The collected data demonstrate low incidence rates and similar epidemiological and clinicopathological characteristics of UrC for both registries. This is the first report of structured epidemiological data for UrC for the German population.
Assuntos
Neoplasias da Bexiga Urinária/epidemiologia , Adolescente , Adulto , Idoso , Criança , Estudos de Coortes , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Sixty-one subjects with fibrosing interstitial lung disease were prospectively analysed to determine the efficacy of transbronchial cryobiopsy (CryoTBB) and the effect of procedural modifications which were introduced after an interim analysis of the first 19 subjects. The modifications significantly reduced complication rates from 84% to 14% (p<0.001). 30-day-mortality was 2%. The algorithm with initial CryoTBB and surgical lung biopsy (SLB) as optional step-up procedure was feasible. CryoTBB led to a confident diagnosis in 46/61 subjects (75%). Only 21% out of all subjects were forwarded for SLB. As the modified CryoTBB reduced but not eliminated the risk of severe complications, tissue sampling should be limited to patients where confident diagnosis enables life prolonging therapy. Trial registration number: NCT01714518.
Assuntos
Doenças Pulmonares Intersticiais/patologia , Pulmão/patologia , Idoso , Algoritmos , Biópsia/efeitos adversos , Biópsia/métodos , Criocirurgia/efeitos adversos , Criocirurgia/métodos , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Comportamento de Redução do RiscoRESUMO
BACKGROUND: Malignant pleural mesothelioma (MPM) is a tumour arising from pleural cavities with poor prognosis. Multimodality treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy of chemotherapeutic treatment are largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed genes compiled under the term "BRCAness". An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis. METHODS: We investigated the response of three MPM cell lines and lung fibroblasts serving as a control to treatment with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find possible correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members. RESULTS: A BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines was observed. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM. CONCLUSIONS: Defects in HR compiled under the term BRCAness are a common event in MPM. The present data can lead to a better understanding of the underlaying cellular mechanisms and leave the door wide open for new therapeutic approaches for this severe disease with infaust prognosis. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. Thus, this combination therapy might be effective for up to 2/3 of patients, promising to enhance patients' clinical management and outcome.
Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/genética , Mesotelioma/genética , Ftalazinas/farmacologia , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Reparo de DNA por Recombinação/genética , Hidrolases Anidrido Ácido , Apoptose/efeitos dos fármacos , Aurora Quinase A/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Recombinação Homóloga/genética , Humanos , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Mesotelioma Maligno , Pemetrexede/farmacologiaRESUMO
Papillomas of the fallopian tube are exceedingly rare benign tumors, and only very few cases have been reported in the literature. Clinically, they may present as a mass lesion or occur without symptoms. Histomorphologically, they are papillary tumors covered by nonatypical epithelium with occasional ciliated or goblet cells growing in the lumen, and they are most frequently located in the infundibular region of the fallopian tube. They require a number of differential diagnostic evaluations and can be mistaken for either other benign tumors or malignant neoplasms. Because of their rare occurrence, molecular data about this entity have been lacking so far. Herein, a case of a papilloma with a BRAF (c.1799T>A) mutation (V600E) in a 45-yr-old woman with tumor-like dilation of the fallopian tube is presented.
Assuntos
Neoplasias das Tubas Uterinas/genética , Mutação , Papiloma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Papiloma/patologiaRESUMO
INTRODUCTION: Ovarian carcinoma is associated with the highest mortality of all gynecologic malignancies. Even after optimal treatment, prognosis remains poor. There is no established biomarker to predict individual patient outcome. OBJECTIVE: To evaluate the prognostic significance of PD-1 and PD-L1 expression in tumor tissues from patients with ovarian cancer. METHODS: Tissue micro-arrays were prepared from routinely formalin-fixed, paraffin-embedded tumor tissues and examined immunohistochemically for the expression of programed cell death protein 1 (PD-1) and one of its ligands (PD-L1) on epithelial tumor cells, as well as on tumor- and stroma-infiltrating immune cells. RESULTS: The presence of PD-1 positive tumor-infiltrating immune cells was significantly associated with prolonged overall survival. PD-1 and PD-L1 positive tumor-infiltrating immune cells were associated with the presence of lymph node metastases and higher tumor grade. Interestingly, the amount of PD-1/PD-L1 positive tumor- and stroma-infiltrating immune cells independent of PD-1 or PD-L1 expression did not show any significant correlation with prognostic variables. CONCLUSION: Our results highlight the prognostic value of PD-1 and PD-L1 positive tumor-infiltrating immune cells in ovarian carcinoma. Their association with favorable prognosis supports the hypothesis that the expression of PD-1 and PD-L1 on tumor-infiltrating immune cells represents a strong immune response.
Assuntos
Antígeno B7-H1/imunologia , Carcinoma Epitelial do Ovário/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Ovarianas/imunologia , Receptor de Morte Celular Programada 1/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/biossíntese , Carcinoma Epitelial do Ovário/patologia , Feminino , Humanos , Imuno-Histoquímica , Metástase Linfática , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Prognóstico , Receptor de Morte Celular Programada 1/biossíntese , Estudos Retrospectivos , Análise de Sobrevida , Análise Serial de Tecidos , Adulto JovemRESUMO
The ubiquitous mold Aspergillus fumigatus threatens immunosuppressed patients as inducer of lethal invasive aspergillosis. A. fumigatus conidia are airborne and reach the alveoli, where they encounter alveolar epithelial cells (AEC). Previous studies reported the importance of the surfactant-producing AEC II during A. fumigatus infection via in vitro experiments using cell lines. We established a negative isolation protocol yielding untouched primary murine AEC II with a purity >90%, allowing ex vivo analyses of the cells, which encountered the mold in vivo By label-free proteome analysis of AEC II isolated from mice 24h after A. fumigatus or mock infection we quantified 2256 proteins and found 154 proteins to be significantly differentially abundant between both groups (ANOVA p value ≤ 0.01, ratio of means ≥1.5 or ≤0.67, quantified with ≥2 peptides). Most of these proteins were higher abundant in the infected condition and reflected a comprehensive activation of AEC II on interaction with A. fumigatus This was especially represented by proteins related to oxidative phosphorylation, hence energy production. However, the most strongly induced protein was the l-amino acid oxidase (LAAO) Interleukin 4 induced 1 (IL4I1) with a 42.9 fold higher abundance (ANOVA p value 2.91-10). IL4I1 has previously been found in B cells, macrophages, dendritic cells and rare neurons. Increased IL4I1 abundance in AEC II was confirmed by qPCR, Western blot and immunohistology. Furthermore, A. fumigatus infected lungs showed high levels of IL4I1 metabolic products. Importantly, higher IL4I1 abundance was also confirmed in lung tissue from human aspergilloma. Because LAAO are key enzymes for bactericidal product generation, AEC II might actively participate in pathogen defense. We provide insights into proteome changes of primary AEC II thereby opening new avenues to analyze the molecular changes of this central lung cell on infectious threats. Data are available via ProteomeXchange with identifier PXD005834.
Assuntos
Aspergillus fumigatus/patogenicidade , Flavoproteínas/metabolismo , L-Aminoácido Oxidase/metabolismo , Proteômica/métodos , Alvéolos Pulmonares/citologia , Aspergilose Pulmonar/metabolismo , Adulto , Idoso , Animais , Linhagem Celular , Metabolismo Energético , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Flavoproteínas/genética , Regulação da Expressão Gênica , Humanos , L-Aminoácido Oxidase/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Fosforilação Oxidativa , Mapas de Interação de Proteínas , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/microbiologia , Aspergilose Pulmonar/genéticaRESUMO
Urachal cancer (UrC) is a rare but aggressive malignancy often diagnosed in advanced stages requiring systemic treatment. Although cytotoxic chemotherapy is of limited effectiveness, prospective clinical studies can hardly be conducted. Targeted therapeutic treatment approaches and potentially immunotherapy based on a biological rationale may provide an alternative strategy. We therefore subjected 70 urachal adenocarcinomas to targeted next-generation sequencing, conducted in situ and immunohistochemical analyses (including PD-L1 and DNA mismatch repair proteins [MMR]) and evaluated the microsatellite instability (MSI) status. The analytical findings were correlated with clinicopathological and outcome data and Kaplan-Meier and univariable/multivariable Cox regression analyses were performed. The patients had a mean age of 50 years, 66% were male and a 5-year overall survival (OS) of 58% and recurrence-free survival (RFS) of 45% was detected. Sequence variations were observed in TP53 (66%), KRAS (21%), BRAF (4%), PIK3CA (4%), FGFR1 (1%), MET (1%), NRAS (1%), and PDGFRA (1%). Gene amplifications were found in EGFR (5%), ERBB2 (2%), and MET (2%). We detected no evidence of MMR-deficiency (MMR-d)/MSI-high (MSI-h), whereas 10 of 63 cases (16%) expressed PD-L1. Therefore, anti-PD-1/PD-L1 immunotherapy approaches might be tested in UrC. Importantly, we found aberrations in intracellular signal transduction pathways (RAS/RAF/PI3K) in 31% of UrCs with potential implications for anti-EGFR therapy. Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA. The molecular profile strengthens the notion that UrC is a distinct entity on the genomic level with closer resemblance to colorectal than to bladder cancer.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Instabilidade de Microssatélites , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Carcinoma de Células em Anel de Sinete/genética , Carcinoma de Células em Anel de Sinete/patologia , Feminino , Seguimentos , Amplificação de Genes , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Adulto JovemRESUMO
INTRODUCTION: For ultrasonographic diagnosis of a fetal trisomy so-called "soft markers" (=ultrasonographically detectable morphological variants) are used. Detection of a certain number of them increases the diagnostic certainty of a fetal trisomy. Up to now there are very few diagnostically accepted osseous soft markers for trisomy. Hence potential osseous soft markers applicable for first and second trimester ultrasound screening for trisomy 21, 18 or 13 were studied. METHODS: Postmortal fetal X-rays (ap, lateral) of 358 fetuses (trisomy 21: n = 109, trisomy 18: n = 46; trisomy 13: n = 38, control group: n = 165). RESULTS: Not yet described but with trisomy 21 statistically associated soft markers were un-timely os sternale ossification, delayed os sacrum ossification, shortened os maxillare, reduced os maxillare-jaw-corner distance, augmented orbita height, premature os calcaneus ossification, bell-shaped thorax, coronal clefts, trend to wider binocular as well as wider intraocular distances; for trisomy 18: elevated clavicula slope, reduced number of ribs, bell-shaped thorax, coronal clefts, reduced os maxillare-jaw-corner distance, shortened ramus mandibulare, shortened os metacarpale IV and V, augmented ratio between biparietal diameter and (osseus and soft-tissue) shoulder width; for trisomy 13: longer os nasale, elevated clavicula slope, premature sternum, delayed os sacrum ossification, delayed/premature cranium ossification, reduced number of ribs, coronal clefts, reduced os maxillare-jaw-corner distance, shortened ramus mandibulare, augmented orbita height, shortened os metacarpale V and a tendency for a shortened os metacarpale IV. CONCLUSION: We found several not yet published osseous soft markers statistically associated with trisomy 21, 18 and 13, which can help to ensure sonographically these aneuploidy diagnoses.
Assuntos
Transtornos Cromossômicos/diagnóstico , Síndrome de Down/diagnóstico , Trissomia/diagnóstico , Aneuploidia , Biomarcadores , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 18 , Feminino , Feto , Humanos , Masculino , Gravidez , Segundo Trimestre da Gravidez , Estudos Retrospectivos , Síndrome da Trissomia do Cromossomo 13 , Síndrome da Trissomía do Cromossomo 18RESUMO
BACKGROUND: An in-depth epidemiological investigation on intestinal parasite infections in an impoverished area of Port Elizabeth, South Africa provides a unique opportunity for research on its impact on children's physical fitness, cognitive performance and psychosocial health. Additionally, we will screen risk factors for the development of diabetes and hypertension in adulthood. METHODS/DESIGN: A 2-year longitudinal cohort study will be conducted, consisting of three cross-sectional surveys (baseline and two follow-ups), in eight historically black and coloured (mixed race) primary schools located in different townships in Port Elizabeth, South Africa. Approximately 1000 Grade 4 primary schoolchildren, aged 8 to 12 years, will be enrolled and followed. At each survey, disease status, anthropometry and levels of physical fitness, cognitive performance and psychosocial health will be assessed. After each survey, individuals diagnosed with parasitic worm infections will be treated with anthelminthic drugs, while children with other infections will be referred to local clinics. Based on baseline results, interventions will be tailored to the local settings, embedded within the study and implemented in half of the schools, while the remaining schools will serve as controls. Implementation of the interventions will take place over two 8-week periods. The effect of interventions will be determined with predefined health parameters. DISCUSSION: This study will shed new light on the health burden incurred by children in deprived urban settings of South Africa and provide guidance for specific health interventions. Challenges foreseen in the conduct of this study include: (i) difficulty in obtaining written informed consent from parents/guardians; (ii) administration of questionnaires in schools where three languages are spoken (Afrikaans, Xhosa and English); (iii) challenges in grasping concepts of psychosocial health among schoolchildren using a questionnaire; and (iv) loss to follow-up due to the study setting where illiteracy, mobility and violence are common. Finally, designing the health interventions together with local principals and teachers will allow all concerned with the research to bolster a sense of community ownership and sustained use of the interventions after the study has ceased. TRIAL REGISTRATION: Controlled-trials.com; identifier: ISRCTN68411960 (date assigned: 14 February 2014).
Assuntos
Proteção da Criança/estatística & dados numéricos , Promoção da Saúde/métodos , Enteropatias Parasitárias/epidemiologia , Enteropatias Parasitárias/prevenção & controle , Anti-Helmínticos/uso terapêutico , Criança , Desenvolvimento Infantil/efeitos dos fármacos , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Fatores de Risco , Instituições Acadêmicas , África do Sul , Inquéritos e QuestionáriosRESUMO
MicroRNAs (miRNAs) are a class of small (â¼22 nucleotides), non-coding, highly conserved single-stranded RNAs with posttranscriptional regulatory features, including the regulation of cell proliferation, differentiation, survival, and apoptosis. They are deregulated in a broad variety of tumors showing characteristic expression patterns and can, thus, be used as a diagnostic tool. In contrast to non-small cell carcinoma of the lung neuroendocrine lung tumors, encompassing typical and atypical carcinoids, small cell lung cancer and large cell neuroendocrine lung cancer, no data about deregulation of tumor entity-specific miRNAs are available to date. miRNA expression differences might give useful information about the biological characteristics of these tumors, as well as serve as helpful markers.In 12 pulmonary neuroendocrine tumors classified as either typical carcinoid, atypical, large cell neuroendocrine or small cell lung cancer, screening for 763 miRNAs known to be involved in pulmonary cancerogenesis was conducted by performing 384-well TaqMan low-density array real-time qPCR. In the entire cohort, 44 miRNAs were identified, which showed a significantly different miRNA expression. For 12 miRNAs, the difference was highly significant (P<0.01). Eight miRNAs showed a negative (miR-22, miR-29a, miR-29b, miR-29c, miR-367*; miR-504, miR-513C, miR-1200) and four miRNAs a positive (miR-18a, miR-15b*, miR-335*, miR-1201) correlation to the grade of tumor biology. The miRNAs let-7d; miR-19; miR-576-5p; miR-340*; miR-1286 are significantly associated with survival. Members of the miR-29 family seem to be extremely important in this group of tumors. We found a number of miRNAs, which showed a highly significant deregulation in pulmonary neuroendocrine tumors. Moreover, some of these deregulated miRNAs seem to allow discrimination of the various subtypes of pulmonary neuroendocrine tumors. Thus, the analysis of specific sets of miRNAs can be proposed as diagnostic and/or predictive markers in this group of neoplasias.
Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica/métodos , Neoplasias Pulmonares/genética , MicroRNAs/análise , Tumores Neuroendócrinos/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Tumores Neuroendócrinos/mortalidade , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Longitudinal mode competition in (Al,In)GaN laser diodes at λ = 445nm and 515 nm with mode competition frequencies from 10 MHz to 150 MHz is observed. Up to two dozen lasing modes oscillate with the lasing mode rolling from the short wavelength edge to the long wavelength edge of the gain profile. The experimental results can be described very well with a set of multi-mode rate equations including self-, symmetric and asymmetric cross gain saturation. By tuning essential parameters of the gain saturation terms, mode competition disappears and single mode operation as well as mode clustering is found. This proves that the mechanisms of gain saturation have not only a profound impact on the complex temporal-spectral behavior but also explains mode clustering in (Al,In)GaN laser diodes, both in pulsed and continuous wave (cw) operation as a natural nonlinear effect without the necessity to add noise.
RESUMO
AIMS: TP53 mutations are extremely rare in malignant pleural mesothelioma (MPM). In TP53 wild-type tumors, the functional p53 protein can be inactivated by MDM2. MATERIALS & METHODS: A total of 61 patient samples were tested for their Mdm2 and p53 protein expression levels via immunohistochemistry. RESULTS: This study demonstrates nuclear Mdm2 expression in three out of four mesothelioma cell lines and 21.3% of the MPM specimens investigated. After silencing of the MDM2 gene by siRNA in MPM cell lines, Mdm2 immunoexpression is lost and cells show changes indicative of severe damage. Mdm2 protein expression in MPM is detected in epithelioid and biphasic subtypes only and is significantly associated with poor survival compared with Mdm2-negative tumors. This may be explained by increased Mdm2 levels possibly leading to an increased ubiquitilation and proteasomal degradation of functional p53 protein. CONCLUSION: Expression of Mdm2 is a strong prognostic factor associated with shortened overall survival in MPM.
Assuntos
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Mesotelioma/metabolismo , Mesotelioma/mortalidade , Neoplasias Pleurais/metabolismo , Neoplasias Pleurais/mortalidade , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Mesotelioma/genética , Mesotelioma/patologia , Mesotelioma/terapia , Mesotelioma Maligno , Pessoa de Meia-Idade , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Neoplasias Pleurais/terapia , Prognóstico , Proteínas Proto-Oncogênicas c-mdm2/genética , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Currently, multimodality treatment including chemotherapy with cisplatin or carboplatin in combination with pemetrexed offers the best options. Detoxification of heavy metals in the cell by metallothioneins (MT) is associated with early failure to platin-based chemotherapy. The induction of MTs gene expression or its enzyme results in saturation by exposure to metal ions such as zinc or cadmium. Its therapeutically effect is still not analyzed in depth. Methods: In our study, we investigated three MPM cell lines and one fibroblast cell line in the course of cisplatin treatment and supplementation of zinc. Cell state analyses via an enzyme-activity based assay were performed. With this, we were able to analyze apoptosis, necrosis and viability of cells. Additionally, we tested treated cells for changes in metallothionein IIA (MT2A) expression by using quantitative realtime polymerase chain reaction. Results: Zinc supplementation induces gene expression of MT2A. Overall, a zinc dose-dependent induction of apoptosis under platin-based treatment could be observed. This effect could be verified in all analyzed cell lines in varying intensity. Conclusions: MT expression is induced by zinc in a dose-dependent manner and inhibits a successful cisplatin therapy. Therefore, heavy metal exposure during cisplatin therapy, e.g., via cigarette smoke, might be an important factor. This should be considered in further therapeutic approaches.
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BACKGROUND: The challenges in pathology and in structuring of data are increasing. Although considerable amounts of data are generated during the pathological diagnostic process, these data are often not available in a structured form and have to be extracted from the reports through a time-consuming and error-prone manual approach. However, the data are required for various internal and external purposes, such as for audits, tumor organ centers, reporting to cancer registries, different consortia, billing, various aspects within the organization, and for research. OBJECTIVES: The aim of the work was the development of a digital system for the direct and high-quality acquisition of structured pathology data using the example of biopsy-based diagnostics of prostate carcinoma. MATERIALS AND METHODS: A solution was created in cooperation with the pathology laboratory information system (LIS) provider imassense GmbH (Berlin, Germany), whose LIS 'Informationssystem der digitalen Pathologie' (IS-P) is used at the Institute of Pathology at the University Hospital Essen. RESULTS AND CONCLUSION: Over a period of about 1.5 years, a system that is capable of structured reporting according to local, national (S3 guidelines, German Cancer Society) and international (International Collaboration on Cancer Reporting [ICCR]) specifications was developed and subsequently used. The data are stored in readable databases and can easily be generated via ISP. Apart from the disadvantage of a highly specialized solution adapted to the LIS, the project also shows the feasibility in the local academic environment with the above-mentioned advantages.
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Próstata , Neoplasias da Próstata , Masculino , Humanos , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Biópsia , Relatório de Pesquisa , Bases de Dados FactuaisRESUMO
BACKGROUND: Inhalation of N-chlorotaurine (NCT), an endogenous new broad spectrum non-antibiotic anti-infective, has been shown to be very well tolerated in the pig model recently. In the present study, inhaled NCT was tested for tolerability and efficacy in the infected bronchopulmonary system using the same model. METHODS: Anesthetized pigs were inoculated with 20 ml of a solution containing approximately 108 CFU/ml Streptococcus pyogenes strain d68 via a duodenal tube placed through the tracheal tube down to the carina. Two hours later, 5 ml of 1% NCT aqueous solution (test group, n = 15) or 5 ml of 0.9% NaCl (control group, n = 16) was inhaled via the tracheal tube connected to a nebulizer. Inhalation was repeated every hour, four times in total. Lung function and haemodynamics were monitored. Bronchoalveolar lavage samples were removed for determination of colony forming units (CFU), and lung samples for histology. RESULTS: Arterial pressure of oxygen (PaO2) decreased rapidly after instillation of the bacteria in all animals and showed only a slight further decrease at the end of the experiment without a difference between both groups. Pulmonary artery pressure increased to a peak 1-1.5 h after application of the bacteria, decreased in the following hour and remained constant during treatment, again similarly in both groups. Histology demonstrated granulocytic infiltration in the central parts of the lung, while this was absent in the periphery. Expression of TNF-alpha, IL-8, and haemoxygenase-1 in lung biopsies was similar in both groups. CFU counts in bronchoalveolar lavage came to 170 (10; 1388) CFU/ml (median and 25 and 75 percentiles) for the NCT treated pigs, and to 250 (10; 5.5 × 105) CFU/ml for NaCl treated pigs (p = 0.4159). CONCLUSIONS: Inhaled NCT at a concentration of 1% proved to be very well tolerated also in the infected bronchopulmonary system. This study confirms the tolerability in this delicate body region, which has been proven in healthy pigs previously. Regarding efficacy, no conclusions can be drawn, mainly because of the limited test period of the model.
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Anti-Infecciosos/efeitos adversos , Broncopneumonia/tratamento farmacológico , Infecções Estreptocócicas/tratamento farmacológico , Streptococcus pyogenes/efeitos dos fármacos , Doenças dos Suínos/tratamento farmacológico , Taurina/análogos & derivados , Administração por Inalação , Animais , Anti-Infecciosos/administração & dosagem , Líquido da Lavagem Broncoalveolar/microbiologia , Broncopneumonia/microbiologia , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/isolamento & purificação , Suínos , Doenças dos Suínos/microbiologia , Taurina/administração & dosagem , Taurina/efeitos adversos , Resultado do TratamentoRESUMO
Cystic echinococcosis is a widely endemic helminthic disease worldwide but occurs only rarely in Central Europe. Humans are infected as 'aberrant' hosts by Echinococcus granulosus and develop cysts in numerous different organs. 20%-30% of the affected individuals develop hydatid disease in the lungs with associated complications including pleuritis, lung abscess and pneumothorax. Radiologically, the pulmonary lesions of cystic echinococcosis occasionally pose difficulties in the differential diagnosis of primary lung carcinoma or metastatic disease and vice versa. Herein we report on a case of pulmonary hydatid disease in a 25-year-old Iraqi male presenting with a cystic lesion of the lung associated with thoracic pain and involuntary weight loss. Despite of its rare occurrence in Central Europe, clinicians, radiologists and pathologists should be aware of this entity and its pulmonary manifestations. During frozen section examination, imprint cytology specimens may facilitate the detection of the pathogens.