Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 386
Filtrar
2.
Nature ; 577(7792): 660-664, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31996820

RESUMO

Sea-level histories during the two most recent deglacial-interglacial intervals show substantial differences1-3 despite both periods undergoing similar changes in global mean temperature4,5 and forcing from greenhouse gases6. Although the last interglaciation (LIG) experienced stronger boreal summer insolation forcing than the present interglaciation7, understanding why LIG global mean sea level may have been six to nine metres higher than today has proven particularly challenging2. Extensive areas of polar ice sheets were grounded below sea level during both glacial and interglacial periods, with grounding lines and fringing ice shelves extending onto continental shelves8. This suggests that oceanic forcing by subsurface warming may also have contributed to ice-sheet loss9-12 analogous to ongoing changes in the Antarctic13,14 and Greenland15 ice sheets. Such forcing would have been especially effective during glacial periods, when the Atlantic Meridional Overturning Circulation (AMOC) experienced large variations on millennial timescales16, with a reduction of the AMOC causing subsurface warming throughout much of the Atlantic basin9,12,17. Here we show that greater subsurface warming induced by the longer period of reduced AMOC during the penultimate deglaciation can explain the more-rapid sea-level rise compared with the last deglaciation. This greater forcing also contributed to excess loss from the Greenland and Antarctic ice sheets during the LIG, causing global mean sea level to rise at least four metres above modern levels. When accounting for the combined influences of penultimate and LIG deglaciation on glacial isostatic adjustment, this excess loss of polar ice during the LIG can explain much of the relative sea level recorded by fossil coral reefs and speleothems at intermediate- and far-field sites.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31943599

RESUMO

A scalable, metal-, azide- and halogen-free method for the synthesis of substituted 1,2,3-triazoles has been developed. The reaction proceeds through a 3-component coupling of α-ketoacetals, tosyl hydrazide, and a primary amine. Functional group tolerance is outstanding in both the α-ketoacetal and amine coupling partners providing access to 4-, 1,4-, 1,5-, and 1,4,5- substituted triazoles in excellent yield. This robust method results in densely functionalised 1,2,3-triazoles that remain challenging to prepare by azide-alkyne cycloaddition (AAC, CuAAC, RuAAC) methods and can be scaled in either batch or flow reactors. Methods for the chemoselective reaction of either aliphatic amines or anilines are also described revealing some of the potential of this novel and highly versatile transformation.

4.
Proc Natl Acad Sci U S A ; 117(1): 563-572, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31871155

RESUMO

Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenotypes. We demonstrate that SCCB shares a urothelial origin with other bladder cancer phenotypes by showing that urothelial cells driven by a set of defined oncogenic factors give rise to a mixture of tumor phenotypes, including small cell carcinoma, urothelial carcinoma, and squamous cell carcinoma. Tumor-derived single-cell clones also give rise to both SCCB and urothelial carcinoma in xenografts. Despite this shared urothelial origin, clinical SCCB samples have a distinct transcriptional profile and a unique transcriptional regulatory network. Using the transcriptional profile from our cohort, we identified cell surface proteins (CSPs) associated with the SCCB phenotype. We found that the majority of SCCB samples have PD-L1 expression in both tumor cells and tumor-infiltrating lymphocytes, suggesting that immune checkpoint inhibitors could be a treatment option for SCCB. We further demonstrate that our genetically engineered tumor model is a representative tool for investigating CSPs in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB-up-regulated CSPs at both the mRNA and protein levels. Our findings reveal distinct molecular features of SCCB and provide a transcriptional dataset and a preclinical model for further investigating SCCB biology.

5.
Nat Commun ; 10(1): 5444, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784510

RESUMO

Elevated glucose consumption is fundamental to cancer, but selectively targeting this pathway is challenging. We develop a high-throughput assay for measuring glucose consumption and use it to screen non-small-cell lung cancer cell lines against bioactive small molecules. We identify Milciclib that blocks glucose consumption in H460 and H1975, but not in HCC827 or A549 cells, by decreasing SLC2A1 (GLUT1) mRNA and protein levels and by inhibiting glucose transport. Milciclib blocks glucose consumption by targeting cyclin-dependent kinase 7 (CDK7) similar to other CDK7 inhibitors including THZ1 and LDC4297. Enhanced PIK3CA signaling leads to CDK7 phosphorylation, which promotes RNA Polymerase II phosphorylation and transcription. Milciclib, THZ1, and LDC4297 lead to a reduction in RNA Polymerase II phosphorylation on the SLC2A1 promoter. These data indicate that our high-throughput assay can identify compounds that regulate glucose consumption and that CDK7 is a key regulator of glucose consumption in cells with an activated PI3K pathway.

6.
Proc Natl Acad Sci U S A ; 116(47): 23487-23492, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31685608

RESUMO

The main contributors to sea-level rise (oceans, glaciers, and ice sheets) respond to climate change on timescales ranging from decades to millennia. A focus on the 21st century thus fails to provide a complete picture of the consequences of anthropogenic greenhouse gas emissions on future sea-level rise and its long-term impacts. Here we identify the committed global mean sea-level rise until 2300 from historical emissions since 1750 and the currently pledged National Determined Contributions (NDC) under the Paris Agreement until 2030. Our results indicate that greenhouse gas emissions over this 280-y period result in about 1 m of committed global mean sea-level rise by 2300, with the NDC emissions from 2016 to 2030 corresponding to around 20 cm or 1/5 of that commitment. We also find that 26 cm (12 cm) of the projected sea-level-rise commitment in 2300 can be attributed to emissions from the top 5 emitting countries (China, United States of America, European Union, India, and Russia) over the 1991-2030 (2016-2030) period. Our findings demonstrate that global and individual country emissions over the first decades of the 21st century alone will cause substantial long-term sea-level rise.

7.
J Nucl Med ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31653711

RESUMO

Brain-infiltrating leukocytes contribute to multiple sclerosis (MS) and autoimmune encephalomyelitis and likely play a role in traumatic brain injury, seizure, and stroke. Brain-infiltrating leukocytes are also primary targets for MS disease-modifying therapies. However, no method exists for non-invasively visualizing these cells in a living organism. 1-(2'-deoxy-2'-18F-fluoroarabinofuranosyl) cytosine (18F-FAC) is a PET radiotracer that measures deoxynucleoside salvage and accumulates preferentially in immune cells. We hypothesized that 18F-FAC PET could non-invasively image brain-infiltrating leukocytes. Methods: Healthy mice were imaged with 18F-FAC PET to quantify if this radiotracer crosses the blood-brain barrier (BBB). Experimental autoimmune encephalomyelitis (EAE) is a mouse disease model with brain-infiltrating leukocytes. To determine whether 18F-FAC accumulates in brain-infiltrating leukocytes, EAE mice were analyzed with 18F-FAC PET, digital autoradiography, and immunohistochemistry, and 18F-FAC accumulation in brain-infiltrating leukocytes was analyzed ex vivo. Fingolimod-treated EAE mice were imaged with 18F-FAC PET to assess if this approach can monitor the effect of an immunomodulatory drug on brain-infiltrating leukocytes. PET scans of individuals injected with 2-chloro-2'-deoxy-2'-18F-fluoro-9-ß-D-arabinofuranosyl-adenine (18F-CFA), a PET radiotracer that measures deoxynucleoside salvage in humans, were analyzed to evaluate whether 18F-CFA crosses the human BBB. Results: 18F-FAC accumulates in the healthy mouse brain at similar levels to 18F-FAC in the blood (2.54±0.2 and 3.04±0.3 %ID/g, respectively) indicating that 18F-FAC crosses the BBB. EAE mice accumulate 18F-FAC in the brain at 180% of the levels of control mice. Brain 18F-FAC accumulation localizes to periventricular regions with significant leukocyte infiltration, and 18F-FAC accumulates at similar levels in brain-infiltrating T and innate immune cells. These data suggest that 18F-FAC accumulates in brain-infiltrating leukocytes in this model. Fingolimod-treated EAE mice accumulate 18F-FAC in the brain at 37% lower levels than control-treated EAE mice demonstrating that 18F-FAC PET can monitor therapeutic interventions in this mouse model. 18F-CFA accumulates in the human brain at 15% of blood levels (0.08±0.01 and 0.54±0.07 SUV, respectively), indicating that 18F-CFA does not cross the BBB in humans. Conclusion: 18F-FAC PET can visualize brain-infiltrating leukocytes in a mouse MS model and can monitor the response of these cells to an immunomodulatory drug. Translating this strategy into humans will require exploring additional radiotracers.

8.
Vet Rec ; 185(16): 514, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31653745
9.
Urol Oncol ; 37(12): 900-906, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31597600

RESUMO

OBJECTIVES: Overexpression of aurora kinase A (AURKA) confers a poor prognosis in patients with urothelial carcinoma of the bladder. The prognostic value of high aurora kinase B (AURKB) expression in local bladder cancer is not well defined, and whether the prognostic value of either AURKA or AURKB is affected by the use of chemotherapy is unknown. We sought to characterize the impact of high AURKA and AURKB expression on clinical outcome in patients with muscle-invasive bladder cancer (MIBC) who received neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Immunohistochemistry for AURKA and AURKB was performed on pretreatment diagnostic transurethral resection of bladder tumor (TURBT) and matched cystectomy specimens in 50 subjects with MIBC who received NAC. Receiver operator characteristic curves (ROC) were calculated to assess the impact of AURKA and AURKB expression on pathologic response rate. Kaplan-Meier techniques and Cox proportional hazards models were used to assess the association with relapse-free survival (RFS) and overall survival (OS). RESULTS: Twenty-two of 50 [44%] patients had residual muscle-invasive (ypT2-4) urothelial carcinoma after NAC. Neither baseline tumor expression of AURKA (ROC = 0.57, P = 0.46) nor AURKB (ROC = 0.56, P = 0.87) predicted for ypT2-4 status. However, baseline expression of AURKA above the 75th percentile for this cohort was associated with an inferior RFS, (HR = 3.88, P = 0.008) and OS, (HR = 6.10, P < 0.001). Similar trends for worse survival outcomes were also observed for high AURKB levels (RFS, [HR = 2.2, P = 0.13] and OS, (HR = 2.25, P = 0.09). CONCLUSIONS: High baseline tumor AURKA and AURKB expression identified MIBC patients with inferior RFS and OS despite the use of NAC and may identify patients who should be prioritized for clinical trial enrollment rather than standard cisplatin-based chemotherapy.

10.
Org Biomol Chem ; 17(34): 7943-7955, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31429459

RESUMO

This paper describes the development, optimisation and exemplification of a copper-catalysed C-H functionalisation to form pharmaceutically relevant 2-aminobenzimidazoles from aryl-guanidines. High throughput screening was used as a tool to identify a catalytically active copper source, DoE was used for reaction optimisation and a range of aryl-guanidines were prepared and exposed to the optimum conditions to afford a range of 2-aminobenzimidazoles in moderate to good yields. The methodology has been applied to the synthesis of Emedastine, a marketed anti-histamine pharmaceutical compound, with the key cyclisation step performed on a gram-scale.

11.
J Clin Oncol ; 37(29): 2689-2692, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31408416
13.
Mol Ther ; 27(5): 912-921, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-30819613

RESUMO

Efficient delivery of gene therapy vectors across the blood-brain barrier (BBB) is the holy grail of neurological disease therapies. A variant of the neurotropic vector adeno-associated virus (AAV) serotype 9, called AAV-PHP.B, was shown to very efficiently deliver transgenes across the BBB in C57BL/6J mice. Based on our recent observation that this phenotype is mouse strain dependent, we used whole-exome sequencing-based genetics to map this phenotype to a specific haplotype of lymphocyte antigen 6 complex, locus A (Ly6a) (stem cell antigen-1 [Sca-1]), which encodes a glycosylphosphatidylinositol (GPI)-anchored protein whose function had been thought to be limited to the biology of hematopoiesis. Additional biochemical and genetic studies definitively linked high BBB transport to the binding of AAV-PHP.B with LY6A (SCA-1). These studies identify, for the first time, a ligand for this GPI-anchored protein and suggest a role for it in BBB transport that could be hijacked by viruses in natural infections or by gene therapy vectors to treat neurological diseases.

14.
Urol Oncol ; 37(5): 299.e19-299.e25, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30660491

RESUMO

Immune checkpoint inhibitors (ICI) targeting PD-(L)1 are effective in select patients with advanced urothelial carcinoma (UC). High PD-L1 expression enriches for response to ICIs; however, the predictive value of PD-L1 expression is limited, which may be due in part to dynamic expression of PD-L1 in the tumor environment. We sought to characterize PD-L1 expression in primary UC and paired metastatic lesions to gain insight into the potential discordance of tumor PD-L1 expression during the metastatic process. MATERIALS AND METHODS: Immunohistochemical staining for PD-L1 using the SP-142 antibody was performed on primary tumors and matched metastatic specimens in 77 evaluable subjects with advanced UC. Immunohistochemical staining was scored for the percentage of cells positive (<5%, ≥5%) in tumor cell (TC) and immune cell (IC) compartments. Correlation of PD-L1 expression in TCs and ICs was estimated using Spearman's correlation coefficients (rho, ρ). Cohen's kappa statistics (κ) were utilized to assess the agreement in PD-L1 expression between groups. RESULTS: High (≥5%) PD-L1 expression in primary and metastatic biopsies, respectively, was observed in 6.0% and 7.7% of TCs and in 14.5% and 11.5% of ICs. IC PD-L1 expression in primary tumors was not correlated with IC PD-L1 expression in paired metastatic lesions (ρ = 0.05, P = 0.67) and there was poor agreement in high expression rates between primary and metastatic lesions in the IC compartment (κ= 0.086). CONCLUSION: High PD-L1 IC expression is temporally and spatially discordant between primary and metastatic UC lesions. Future studies of PD-(L)1 targeted therapies in patients with metastatic UC may benefit from use of fresh biopsies of metastatic lesions to define PD-L1 expression when feasible.

15.
Hum Immunol ; 80(1): 53-61, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30227197

RESUMO

Cell surface expression of HLA-DP is allele specific. SNP rs9277534 (A/G), located in the 3'UTR of the DPB1 gene, has been associated with either low (A) or high (G) expression of DP on the cell surface. Considering the role of miRNAs in the regulation of gene expression, we computationally identified the miRNAs of two BLCLs, PGF and COX, predicted to interact with their corresponding DPB1 transcripts, DPB1 * 04:01:01:01-low expression and DPB1 * 03:01:01:01-high expression. The identified target sequences are located primarily in intron 2 and the 3'UTR. We hypothesize that gene expression may be influenced first by nuclear pre-mRNA events involving intronic regions, followed by the usual 3'UTR-associated events in the cytoplasm. The low DP expression allele was found to interact in silico with a larger number of miRNAs than the high expression allele. This pattern holds when examining either the entire transcript unit or simply the polymorphic sites that differentiate the alleles. Interestingly, the rs9277534 A/G polymorphism appears to be in linkage disequilibrium with polymorphisms targeted by the identified miRNAs. The multiplicity of sites targeted by different miRNAs suggests that the expression of DPB1 may be a dynamic process, influenced by different miRNAs under different states of the cell.


Assuntos
Alelos , Sítios de Ligação , Biologia Computacional , Regulação da Expressão Gênica , Cadeias beta de HLA-DP/genética , MicroRNAs/genética , Interferência de RNA , Linhagem Celular , Biologia Computacional/métodos , Cadeias beta de HLA-DP/química , Humanos , MicroRNAs/química , Anotação de Sequência Molecular
16.
J Urol ; 201(3): 470-477, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30359680

RESUMO

PURPOSE: We designed a prospective randomized, controlled pilot trial to investigate the effects of an enriched oral nutrition supplement on body composition and clinical outcomes following radical cystectomy. MATERIALS AND METHODS: A total of 61 patients were randomized to an oral nutrition supplement or a multivitamin multimineral supplement twice daily during an 8-week perioperative period. Body composition was determined by analyzing abdominal computerized tomography images at the L3 vertebra. Sarcopenia was defined as a skeletal muscle index of less than 55 cm/m in males and less than 39 cm/m in females. The primary outcome was the difference in 30-day hospital free days. Secondary outcomes included hospital length of stay, complications, readmissions and mortality. RESULTS: The oral nutrition supplement group lost less weight (-5 vs -6.5 kg, p = 0.04) compared to the multivitamin multimineral supplement group. The proportion of patients with sarcopenia did not change in the oral nutrition supplement group but increased 20% in the multivitamin multimineral supplement group (p = 0.01). Mean length of stay and 30-day hospital free days were similar in the groups. The oral nutrition supplement group had a lower rate of overall and major (Clavien grade 3 or greater) complications (48% vs 67% and 19% vs 25%, respectively) and a lower readmission rate (7% vs 17%) but the differences did not reach statistical significance. CONCLUSIONS: Patients who undergo radical cystectomy after consuming an oral nutrition supplement perioperatively have a reduced prevalence of sarcopenia and may also experience fewer and less severe complications and readmissions. A larger blinded, randomized, controlled trial is necessary to determine whether oral nutrition supplement interventions can improve outcomes following radical cystectomy.


Assuntos
Cistectomia , Suplementos Nutricionais , Assistência Perioperatória , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/prevenção & controle , Sarcopenia/epidemiologia , Sarcopenia/prevenção & controle , Administração Oral , Idoso , Cistectomia/métodos , Feminino , Humanos , Masculino , Projetos Piloto , Prevalência , Estudos Prospectivos
17.
World J Urol ; 37(1): 3-13, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30105454

RESUMO

PURPOSE: To update current recommendations on prevention, screening, diagnosis, and evaluation of bladder cancer (BC) based on a thorough assessment of the most recent literature on these topics. METHODS: A non-systematic review was performed, including articles until June 2017. A variety of original articles, reviews, and editorials were selected according to their epidemiologic, demographic, and clinical relevance. Assessment of the level of evidence and grade of recommendations was performed according to the International Consultation on Urological Diseases grading system. RESULTS: BC is the ninth most common cancer worldwide with 430,000 new cases in 2012. Currently, approximately 165,000 people die from the disease annually. Absolute incidence and prevalence of BC are expected to rise significantly during the next decades because of population ageing. Tobacco smoking is still the main risk factor, accounting for about 50% of cases. Smoking cessation is, therefore, the most relevant recommendation in terms of prevention, as the risk of developing BC drops almost 40% within 5 years of cessation. BC screening is not recommended for the general population. BC diagnosis remains mainly based on cystoscopy, but development of new endoscopic and imaging technologies may rapidly change the diagnosis algorithm. The same applies for local, regional, and distant staging modalities. CONCLUSIONS: A thorough understanding of epidemiology, risk factors, early detection strategies, diagnosis, and evaluation is essential for correct, evidence-based management of BC patients. Recent developments in endoscopic techniques and imaging raise the hope for providing better risk-adopted approaches and thereby improving clinical outcomes.


Assuntos
Carcinoma de Células de Transição/epidemiologia , Cistoscopia , Dinâmica Populacional , Abandono do Hábito de Fumar , Fumar Tabaco/epidemiologia , Neoplasias da Bexiga Urinária/epidemiologia , Algoritmos , Carcinoma de Células de Transição/diagnóstico , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/prevenção & controle , Detecção Precoce de Câncer , Humanos , Incidência , Imagem por Ressonância Magnética , Imagem de Banda Estreita , Estadiamento de Neoplasias , Guias de Prática Clínica como Assunto , Prevalência , Fatores de Risco , Sociedades Médicas , Tomografia Computadorizada por Raios X , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/prevenção & controle , Urologia
18.
Biol Blood Marrow Transplant ; 25(4): 785-790, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30579967

RESUMO

Hemorrhagic cystitis (HC) is a common and important complication of allogeneic hematopoietic cell transplantation (HCT). Reactivation of BK virus is its most common cause. The more intense immunosuppressive regimens administered to recipients of grafts from alternative donors have been reported to account for the increased susceptibility to HC in this population. This study compares patients undergoing HCT with either a haploidentical donor or a matched related donor, all of whom received identical immunosuppression with a post-transplantation cyclophosphamide-based regimen. The incidence of HC was significantly higher in the patients receiving a haploidentical graft (P = .01). The higher incidence of HC in haploidentical graft recipients is therefore directly related to the inherent immune deficiency that follows HLA-mismatched transplantation, independent of the intensity of pharmacologic immunosuppression. This finding carries significant clinical impact for the prevention and treatment of HC in haploidentical graft recipients.

19.
Nat Commun ; 9(1): 5399, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30559446

RESUMO

The original version of this Article contained an error in the Data Availability section, which incorrectly read 'All data will be freely available via https://www.ams.ethz.ch/research.html .' The correct version states ' http://www.ams.ethz.ch/research/published-data.html ' in place of ' https://www.ams.ethz.ch/research.html '. This has been corrected in both the PDF and HTML versions of the Article.

20.
Res Rep Urol ; 10: 181-187, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30464929

RESUMO

Purpose: To examine the variation in venous thromboembolism prophylactic treatment (VTEP) among renal cancer patients undergoing surgery. Materials and methods: An Internet-based questionnaire on renal tumor management before and after surgery was mailed to all Nordic departments of urology. The questions focused on the use of VTEP and were subdivided into different surgical modalities. Results: Questionnaires were mailed to 91 institutions (response rate 53%). None of the centers used VTEP before surgery, unless the patient had a vena caval tumor thrombus. Overall, the VTEP utilized during hospitalization for patients undergoing renal surgery included early mobilization (45%), compression stockings (52%) and low-molecular-weight heparin (89%). In patients undergoing open radical Nx, 80% of institutions used VTEP during their hospitalization (23% compression stockings and 94% low-molecular-weight heparin). After leaving the hospital, the proportion and type of VTEP received varied considerably across institutions. The most common interval, used in 60% of the institutions, was for a period of 4 weeks. The restriction to the Nordic countries was a limitation and, therefore, may not reflect the practice patterns elsewhere. It is a survey study and, therefore, cannot measure the behaviors of those institutions that did not participate. Conclusion: We found variation in the type and duration of VTEP use for each type of local intervention for renal cancer. These widely disparate variations in care strongly argue for the establishment of national and international guidelines regarding VTEP in renal surgery.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA