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Casposons are transposable elements containing the CRISPR associated gene Cas1solo. Identified in many archaeal genomes, casposons are discussed as the origin of CRISPR-Cas systems due to their proposed Cas1solo-dependent translocation. However, apart from bioinformatic approaches and the demonstration of Cas1solo integrase and endonuclease activity in vitro, casposon transposition has not yet been shown in vivo. Here, we report on active casposon translocations in Methanosarcina mazei Gö1 using two independent experimental approaches. First, mini-casposons, consisting of a R6Kγ origin and two antibiotic resistance cassettes, flanked by target site duplications (TSDs) and terminal inverted repeats (TIRs), were generated, and shown to actively translocate from a suicide plasmid and integrate into the chromosomal MetMaz-C1 TSD IS1a. Second, casposon excision activity was confirmed in a long-term evolution experiment using a Cas1solo overexpression strain in comparison to an empty vector control under four different treatments (native, high temperature, high salt, mitomycin C) to study stress-induced translocation. Analysis of genomic DNA using a nested qPCR approach provided clear evidence of casposon activity in single cells and revealed significantly different casposon excision frequencies between treatments and strains. Our results, providing the first experimental evidence for in vivo casposon activity are summarized in a modified hypothetical translocation model.
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Elementos de DNA Transponíveis , Methanosarcina , Humanos , Proteínas Arqueais/genética , Integrases/genética , Methanosarcina/genética , Plasmídeos/genética , Sequências Repetidas Terminais , Translocação GenéticaRESUMO
Direct exploitation through fishing is driving dramatic declines of wildlife populations in ocean environments, particularly for predatory and large-bodied taxa. Despite wide recognition of this pattern and well-established consequences of such trophic downgrading on ecosystem function, there have been few empirical studies examining the effects of fishing on whole system trophic architecture. Understanding these kinds of structural impacts is especially important in coral reef ecosystems-often heavily fished and facing multiple stressors. Given the often high dietary flexibility and numerous functional redundancies in diverse ecosystems such as coral reefs, it is important to establish whether web architecture is strongly impacted by fishing pressure or whether it might be resilient, at least to moderate-intensity pressure. To examine this question, we used a combination of bulk and compound-specific stable isotope analyses measured across a range of predatory and low-trophic-level consumers between two coral reef ecosystems that differed with respect to fishing pressure but otherwise remained largely similar. We found that even in a high-diversity system with relatively modest fishing pressure, there were strong reductions in the trophic position (TP) of the three highest TP consumers examined in the fished system but no effects on the TP of lower-level consumers. We saw no evidence that this shortening of the affected food webs was being driven by changes in basal resource consumption, for example, through changes in the spatial location of foraging by consumers. Instead, this likely reflected internal changes in food web architecture, suggesting that even in diverse systems and with relatively modest pressure, human harvest causes significant compressions in food chain length. This observed shortening of these food webs may have many important emergent ecological consequences for the functioning of ecosystems impacted by fishing or hunting. Such important structural shifts may be widespread but unnoticed by traditional surveys. This insight may also be useful for applied ecosystem managers grappling with choices about the relative importance of protection for remote and pristine areas and the value of strict no-take areas to protect not just the raw constituents of systems affected by fishing and hunting but also the health and functionality of whole systems.
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Recifes de Corais , Peixes , Cadeia Alimentar , Animais , Peixes/fisiologia , Pesqueiros , Isótopos de Carbono/análise , Conservação dos Recursos Naturais , Isótopos de Nitrogênio/análiseRESUMO
The linear chromosome of the Methanosarcina spherical virus with 10,567 bp exhibits 22 ORFs with mostly unknown functions. Annotation using common tools and databases predicted functions for a few genes like the type B DNA polymerase (MetSVORF07) or the small (MetSVORF15) and major (MetSVORF16) capsid proteins. For verification of assigned functions of additional ORFs, biochemical or genetic approaches were found to be essential. Consequently, we established a genetic system for MetSV by cloning its genome into the E. coli plasmid pCR-XL-2. Comparisons of candidate plasmids with the MetSV reference based on Nanopore sequencing revealed several mutations of yet unknown provenance with an impact on protein-coding sequences. Linear MetSV inserts were generated by BamHI restriction, purified and transformed in Methanosarcina mazei by an optimized liposome-mediated transformation protocol. Analysis of resulting MetSV virions by TEM imaging and infection experiments demonstrated no significant differences between plasmid-born viruses and native MetSV particles regarding their morphology or lytic behavior. The functionality of the genetic system was tested by the generation of a ΔMetSVORF09 mutant that was still infectious. Our genetic system of MetSV, the first functional system for a virus of methanoarchaea, now allows us to obtain deeper insights into MetSV protein functions and virus-host interactions.
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Escherichia coli , Escherichia coli/genética , Plasmídeos/genética , MutaçãoRESUMO
BACKGROUND & AIMS: Late diagnosis is a critical factor undermining clinical management of patients with biliary tract cancer (BTC). While biliary tumours display extensive inter-patient heterogeneity, the host immune response may be comparatively homogenous, providing diagnostic opportunities. Herein, we investigated whether cancer-associated systemic reprogramming could be detected non-invasively to improve diagnosis of BTC. METHODS: In this prospective Danish study, whole blood (WB) microRNA (miRNA) profiling was performed in samples from 218 patients with BTC, 99 healthy participants, and 69 patients with differential diagnoses split into discovery (small RNA-sequencing) and validation (RT-qPCR) cohorts. miRNA expression and activity were further investigated in 119 and 660 BTC tissues, respectively. RESULTS: Four WB miRNAs (let-7a-3p, miR-92b-5p, miR-145-3p, miR-582-3p) were identified and validated as diagnostic of BTC on univariable analysis. Two diagnostic miRNA indexes were subsequently identified that were elevated in patients with BTC and in patients with differential diagnoses, compared to healthy participants. The combination of these miRNA indexes with serum CA 19-9 significantly improved the diagnostic performance of CA 19-9 alone, consistently achieving superior AUC values irrespective of clinical setting (minimum AUC >0.84) or tumour location (minimum AUC >0.87). The diagnostic information captured by miRNA indexes was not recapitulated by routine clinical measurements. Index miRNA expression in BTC tissues was associated with distinct pathobiological and immune features. CONCLUSIONS: WB miRNA profiles are altered in patients with BTC. Quantification of miRNA indexes in combination with serum CA 19-9 has the potential to improve early diagnosis of BTC, pending further validation. LAY SUMMARY: Surgery is currently the only curative intervention for patients with biliary tract cancer (BTC). However, resection is not possible for most patients who are diagnosed with late-stage disease. With the aim of identifying new early diagnostic opportunities, we analysed circulating microRNAs (small non-coding RNAs whose role in cancer is being increasingly recognised) in whole blood samples. We identified a microRNA signature that could distinguish patients with BTC from healthy participants. These miRNAs significantly improved the diagnostic potential of the routinely measured biomarker, CA 19-9, and were implicated in distinct immune processes in tumour tissues.
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Neoplasias do Sistema Biliar , MicroRNA Circulante , MicroRNAs , Neoplasias do Sistema Biliar/diagnóstico , Neoplasias do Sistema Biliar/genética , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Humanos , MicroRNAs/genética , Estudos ProspectivosRESUMO
BACKGROUND: Older patients with cancer are at risk of physical decline and impaired quality of life during oncological treatment. Exercise training has the potential to reduce these challenges. The study aim was to investigate the feasibility and effect of a multimodal exercise intervention in older patients with advanced cancer (stages III/IV). PATIENTS AND METHODS: Eighty-four older adults (≥65 years) with advanced pancreatic, biliary tract, or non-small cell lung cancer who received systemic oncological treatment were randomized 1:1 to an intervention group or a control group. The intervention was a 12-week multimodal exercise-based program including supervised exercise twice weekly followed by a protein supplement, a home-based walking program, and nurse-led support and counseling. The primary endpoint was change in physical function (30-second chair stand test) at 13 weeks. RESULTS: Median age of the participants was 72 years (interquartile range [IQR] 68-75). Median adherence to the exercise sessions was 69% (IQR 21-88) and 75% (IQR 33-100) for the walking program. At 13 weeks, there was a significant difference in change scores of 2.4 repetitions in the chair stand test, favoring the intervention group (p < .0001). Furthermore, significant beneficial effects were seen for physical endurance (6-minute walk test), hand grip strength, physical activity, symptom burden, symptoms of depression and anxiety, global health status (quality of life), and lean body mass. No effects were seen for dose intensity, hospitalizations, or survival. CONCLUSION: A 12-week multimodal exercise intervention with targeted support proved effective in improving physical function in older patients with advanced cancer during oncological treatment.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Idoso , Terapia por Exercício , Força da Mão , Humanos , Neoplasias Pulmonares/terapia , Qualidade de VidaRESUMO
Metastatic colorectal cancer (mCRC) is treated with cetuximab 250 mg/m2 administered weekly over 1 hour or biweekly (q2w) over 3.5 hours when combined with irinotecan. This prospective study investigated cetuximab 500 mg/m2 plus irinotecan 180 mg/m2 administered q2w over 1.5 hours independent of RAS or BRAF mutation status in mCRC patients in a third-line setting. The intention-to-treat population included 181 patients. No patients had complete response, 18% had partial responses (PR) and 48% stable disease (SD). For cetuximab, a relative dose intensity of ≥90% was reached in 78% and for irinotecan in 67% of the patients. Grade 3 to 4 toxicities were pain (17%), fatigue (9%), neutropenia (8%), diarrhea (8%), rash (8%), infection (7%) and hypersensitivity (3%). No deaths occurred. Next-generation sequencing in 96.7% of the patients revealed that 50.3% had RAS and BRAFV600E wild type (WT), with a mutation type (MT) in 45.1% of the RAS and 4.4% of the BRAFV600E genes. In patients with RAS-WT and RAS-MT tumors, a PR was obtained in 32% and 4% (P = .000003) and an SD in 43% and 53%, respectively, with a superior PFS (6.2 vs 3.7 months; hazard ratio [HR] 2.12, P = .00001) and OS (12.9 vs 8.8 months; HR 1.71, P = .0008). Treatment efficacy was poor in 7.4% of patients with an RAS mutation outside KRAS exon 2 and in 38% of patients with KRAS exon 2 mutations. Administration of cetuximab and irinotecan q2w, shortening treatment time from 3.5 to 1.5 hours, is recommended as standard therapy.
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In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.
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Antineoplásicos/administração & dosagem , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Imunidade/efeitos dos fármacos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Oxaliplatina/administração & dosagem , Adulto , Idoso , Biomarcadores , Ablação por Cateter , Neoplasias Colorretais/metabolismo , Terapia Combinada , Feminino , Seguimentos , Humanos , Infusões Intra-Arteriais , Neoplasias Hepáticas/terapia , Masculino , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
PURPOSE: The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC). PATIENTS AND METHODS: The study was a phase 2 randomized trial with Simon's optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage. RESULTS: Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6-47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1-21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3-33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group. CONCLUSIONS: Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC.
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Neoplasias do Sistema Biliar , Ipilimumab , Nivolumabe , Radiocirurgia , Humanos , Radiocirurgia/métodos , Radiocirurgia/efeitos adversos , Nivolumabe/administração & dosagem , Nivolumabe/uso terapêutico , Feminino , Masculino , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/terapia , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/mortalidade , Ipilimumab/administração & dosagem , Ipilimumab/uso terapêutico , Idoso , Pessoa de Meia-Idade , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso de 80 Anos ou mais , Terapia CombinadaRESUMO
PURPOSE: Bibliometric analysis of publications was used to investigate the research output relating to the development of drugs in Norway and to evaluate the impact of Norwegian involvement in this research. MATERIAL AND METHODS: One hundred and nine articles published between 2002 and 2008 were analysed. Bibliometric methods used were as follows: information on peer review, impact factor (IF), the Science Citation Index (SCI) and the representation of Norwegians in the list of authors. RESULTS: All publications were in journals with peer review or in publications with corresponding evaluation. Industrial support, international research cooperation and drug development in phases I, II and III seem to promote publication in journals with high IF and a high SCI. In 63% of the international project articles, the Norwegian contributors were not represented in the list of authors. CONCLUSION: In addition to a scientific standard secured by referees, three probably independent factors - industrial support, international cooperation and early phases of the research (phases I, II and III) - seem to promote publications in journals with high IF and a high SCI. A more active Norwegian contribution to the research should be encouraged.
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Bibliometria , Avaliação de Medicamentos/estatística & dados numéricos , Humanos , Fator de Impacto de Revistas , NoruegaRESUMO
The immune system has the greatest potential for the specific destruction of tumours with no toxicity to normal tissue and for long-term memory that can prevent cancer recurrence. The last 30 years of immuno-oncology research have provided solid evidence that tumours are recognised by the immune system and their development can be stopped or controlled long term through a process known as immunosurveillance. Tumour specificity of the immune response resides in the recognition of tumour antigens. Viral proteins in tumours caused by viruses and mutated proteins from oncogenes or other genes, as well as nonmutated but abnormally expressed self proteins found on all tumours, have been shown to be good antigens and good targets for immunosurveillance. In many cancers, however, malignant progression is accompanied by profound immune suppression that interferes with an effective antitumour response and tumour elimination. Initially, most of the escape from immunosurveillance was ascribed to changes in the tumour cells themselves (loss of tumour antigens, loss of human leukocyte antigen molecules, loss of sensitivity to complement, or T cell or natural killer (NK) cell lysis), making them a poor target of an immune attack. However, it has become clear that the suppression comes from the ability of tumours to subvert normal immune regulation to their advantage. The tumour microenvironment can prevent the expansion of tumour antigen-specific helper and cytotoxic T cells and instead promote the production of proinflammatory cytokines and other factors, leading to the accumulation of suppressive cell populations that inhibit instead of promote immunity. The best described are regulatory T cells and myeloid-derived suppressor cells. Great conceptual and technical advances in the field of immuno-oncology over the past 30 years have provided us with the knowledge and techniques to develop novel immunotherapeutic approaches for the treatment of cancer. These include methods that enhance tumour immunity by blocking inhibitory pathways and inhibitory cells in the tumour microenvironment (e.g. antibodies against cytotoxic T-lymphocyte-associated antigen-4, programmed death 1 or its ligand programmed death ligand 1, or low-dose chemotherapy). Of equal importance, they include methods that can enhance the specificity of antitumour immunity by inducing the expansion of T cells and antibodies directed to well-defined tumour antigens (e.g. cancer vaccines, potent adjuvants, immunostimulatory cytokines). Even as monotherapies, these approaches are having a substantial impact on the treatment of some patients with advanced, previously untreatable, malignancies. Most exciting of all, these successes provide a rationale to expect that used in various combinations or earlier in disease, current and future immunotherapies may transform cancer treatment, improving a prognosis for many patients.
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Antígenos de Neoplasias/imunologia , Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Microambiente Tumoral/imunologia , Citocinas/biossíntese , Humanos , Terapia de Imunossupressão , Monitorização Imunológica , Linfócitos T Citotóxicos/imunologiaRESUMO
Methanosarcina spherical virus (MetSV), infecting Methanosarcina species, encodes 22 genes, but their role in the infection process in combination with host genes has remained unknown. To study the infection process in detail, infected and uninfected M. mazei cultures were compared using dual-RNAseq, qRT-PCRs, and transmission electron microscopy (TEM). The transcriptome analysis strongly indicates a combined role of virus and host genes in replication, virus assembly, and lysis. Thereby, 285 host and virus genes were significantly regulated. Within these 285 regulated genes, a network of the viral polymerase, MetSVORF6, MetSVORF5, MetSVORF2, and the host genes encoding NrdD, NrdG, a CDC48 family protein, and a SSB protein with a role in viral replication was postulated. Ultrastructural analysis at 180 min p.i. revealed many infected cells with virus particles randomly scattered throughout the cytoplasm or attached at the cell surface, and membrane fragments indicating cell lysis. Dual-RNAseq and qRT-PCR analyses suggested a multifactorial lysis reaction in potential connection to the regulation of a cysteine proteinase, a pirin-like protein and a HicB-solo protein. Our study's results led to the first preliminary infection model of MetSV infecting M. mazei, summarizing the key infection steps as follows: replication, assembly, and host cell lysis.
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Interações entre Hospedeiro e Microrganismos , Tectiviridae , Methanosarcina/genética , Genes Virais , Replicação ViralRESUMO
Sarcoidosis is characterized by the presence of noncaseating granulomatous inflammation in the affected organs. Neurosarcoidosis denotes the involvement of the nervous system and can be either isolated or coexisting with extraneural systemic inflammation. The diagnosis of isolated neurosarcoidosis may be challenging due to unspecific symptoms and similar appearances with other disease processes. This report presents an uncommon case of intracranial sarcoidosis mimicking multiple meningiomas. Familiarity with the spectrum of magnetic resonance imaging findings in neurosarcoidosis is crucial to prevent interpretive errors which may in turn lead to an inappropriate diagnosis and treatment.
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We report the development of extrathymic lymphoblastic lymphomas in RadLV-inoculated congenitally athymic nude mice. Thus, a leukemogenic virus which appears to require the presence of a thymus for its replication in normothymic mice can infect and transform target cells in the absence of this organ in the athymic host. The cells of one of these lymphomas have been established in vitro as a permanent cell line, BALB/Nu1. This cell line as well as a lymphoma induced in NIH/Swiss nude mice exhibit several T-cell markers, including terminal deoxynucleotidyl transferase activity, Thy-1.2, and Ly-2.2, but not Ly-1.2 nor TL. Ig determinants were not detected. The characteristics of the tumor cells support the view that cells with T-cell markers may normally exist in nude mice and undergo neoplastic transformation and clonal expansion after infection with a leukemogenic virus. The alternative possibility that virus-induced differentiation of prothymocytes may lead to the expression of Thy-1.2 and Ly-2.2 antigens is also considered. BALB/Nu1 cells release large numbers of type C viral particles. The virus, designated radiation leukemia virus (RadLV)/Nu1, has RTase activity and the protein profile characteristic of murine leukemia virus (MuLV). In radioimmunoassays, it cross-reacts completely with RadLV/VL3, a virus obtained from RadLV-induced C57BL/Ka thymic lymphoma cells in culture, and slightly with a xenotropic virus (BALB:virus-2) and with AKR MuLV. On inoculation into C57BL/Ka mice it has thymotropic and leukemogenic activity. In vitro it is B-tropic, poorly fibrotropic, and has limited xenotropic activity. Thus, RadLV/Nu1 appears to be biologically and serologically similar or identical to its parent virus, RadLV.
Assuntos
Linfoma/classificação , Camundongos Nus/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Superfície/análise , Linhagem Celular , DNA Nucleotidiltransferases/metabolismo , Vírus da Leucemia Murina , Leucemia Experimental/classificação , Linfoma/imunologia , Linfoma/patologia , Camundongos , Receptores de Antígenos de Linfócitos B/análise , Replicação ViralRESUMO
We have presented evidence that a mouse monoclonal antibody 1,227, which was previously shown to recognize a determinant on the light chains beta 1 and beta 2 of human Ia antigens, also recognizes a determinant on the invariant chain (1) associated with these molecules. Ia-specific proteins were resolved by two-dimensional (2D) PAGE and electrophoretically transferred onto nitrocellulose filters. The presence of a determinant shared between beta 1, beta 2 and I was established using "Western blotting" technique. In addition, we demonstrated that 1,227 can immunoprecipitate isolated beta 1, beta 2, and the invariant chain proteins following their separate elution from SDS-PAGE.
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Epitopos/imunologia , Genes MHC da Classe II , Polimorfismo Genético , Animais , Anticorpos Monoclonais/imunologia , Reações Antígeno-Anticorpo , Fenômenos Químicos , Química , Epitopos/genética , Antígenos HLA-DR , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/isolamento & purificação , Humanos , Camundongos , Peso Molecular , CoelhosRESUMO
We eluted peptides from class I molecules of HLA-A2.1(+) breast adenocarcinoma and loaded reverse phase high-performance liquid chromatography (HPLC) fractions onto dendritic cells to prime naive CD8(+) T cells. Fractions that supported growth of tumor-specific cytotoxic T lymphocytes were analyzed by nano-HPLC micro-ESI tandem mass spectrometry. Six HLA-A2.1-binding peptides, four 9-mers (P1-P4) differing in the COOH-terminal residue, and two 10-mers (P5 and P6) with an additional COOH-terminal alanine, were identified in one fraction. Peptide sequences were homologous to cyclin B1. We primed CD8(+) T cells from another HLA-A2.1(+) healthy donor with synthetic peptides and generated P4-specific responses. We also detected memory T cells specific for one or more of these peptides in patients with breast cancer and squamous cell carcinomas of the head and neck (SCCHN). T cells from one patient, restimulated once in vitro, could kill the tumor cell line from which the peptides were derived. Immunohistochemical analysis of tumor lines and tissue sections showed cyclin B1 overexpression and aberrant localization in the cytoplasm instead of the nucleus. Sequencing genomic DNA and cDNA corresponding to P1-P6 region showed that differences in COOH-terminal residues were not due to either DNA mutations or errors in transcription, suggesting a high error rate in translation of cyclin B1 protein in tumors.
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Antígenos de Neoplasias/imunologia , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Ciclina B/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Antígenos de Neoplasias/genética , Sequência de Bases , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/citologia , Carcinoma de Células Escamosas/patologia , Células Cultivadas , Ciclina B/biossíntese , Ciclina B/genética , Ciclina B1 , DNA , DNA Complementar , Feminino , Expressão Gênica , Antígeno HLA-A2/genética , Antígeno HLA-A2/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Nível de Saúde , Humanos , Memória Imunológica , Dados de Sequência Molecular , Mutagênese , Peptídeos/genética , Peptídeos/imunologia , RNA , Doadores de Tecidos , Células Tumorais CultivadasRESUMO
Cancer patients mount adaptive immune responses against their tumors. However, tumor develops many mechanisms to evade effective immunosurveillance. T-cell death caused by tumor plays a critical role in establishing tumor immunotolerance. Chronic stimulation of T cells by tumors leads to activation-induced cell death. Abortive stimulation of T cells by tolerogenic antigen-presenting cells loaded with tumor antigens leads to autonomous death of tumor-specific T cells. Therapeutic approaches that prevent T-cell death in the tumor microenvironment and tumor draining lymph nodes, therefore, should boost adaptive immune responses against cancer.
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Apoptose , Tolerância Imunológica , Vigilância Imunológica , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Evasão Tumoral , Antígenos de Neoplasias/imunologia , Autofagia , Células Dendríticas/imunologia , Humanos , Imunidade Celular , Imunoterapia , Neoplasias/patologia , Neoplasias/fisiopatologia , Neoplasias/terapia , Fatores Supressores Imunológicos/fisiologia , Subpopulações de Linfócitos T/fisiologiaRESUMO
OBJECTIVE: In Norway, very little data are available on the relation between the total number of research projects on the clinical development of drugs that have been started, the number of these projects in which the research phase has been completed and the number of projects for which results have been published. The aim of this study was to determine the number of projects in which the research phase had been completed and the results published. MATERIAL AND METHODS: Information on research projects carried out on the clinical development of drugs during the year 2000 was obtained from the archives of the Norwegian Research Ethical Committee (REC) and subsequently analysed. RESULTS: The final analysis revealed that 245 research projects on the clinical development of drugs had been started in 2000. Of these, 178 (73%) completed the research phase as planned. The results of 131 (54%) of these projects were published in a scientific journal, and another 34 (14%) were reported as a congress abstract or as report to a sponsor; 80 (33%) were not published at all. Industrial sponsors seemed to promote both the completion of the research process and the publication of results in scientific journals.
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Pesquisa Biomédica/economia , Ensaios Clínicos como Assunto/economia , Editoração/estatística & dados numéricos , Projetos de Pesquisa/normas , Apoio à Pesquisa como Assunto/estatística & dados numéricos , Academias e Institutos/economia , Academias e Institutos/estatística & dados numéricos , Pesquisa Biomédica/ética , Pesquisa Biomédica/estatística & dados numéricos , Ensaios Clínicos como Assunto/ética , Ensaios Clínicos como Assunto/estatística & dados numéricos , Indústria Farmacêutica/economia , Indústria Farmacêutica/ética , Indústria Farmacêutica/estatística & dados numéricos , Comitês de Ética em Pesquisa/ética , Comitês de Ética em Pesquisa/normas , Hospitais Privados/economia , Hospitais Privados/estatística & dados numéricos , Hospitais Públicos/economia , Hospitais Públicos/estatística & dados numéricos , Humanos , Disseminação de Informação/ética , Noruega , Editoração/ética , Editoração/normas , Projetos de Pesquisa/estatística & dados numéricos , Apoio à Pesquisa como Assunto/ética , Inquéritos e Questionários , Fatores de TempoRESUMO
Generations of immunologists have been searching for evidence to confirm the tantalizing notion that tumor-rejection antigens exist. If found, the ultimate reward was the possibility that these molecules might be used to induce tumor-specific immunity and effect tumor rejection. Until recently rewards have been few and far between. That is changing. The immediate rewards have become more satisfying and the ultimate reward almost palpable.
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Antígenos de Neoplasias/imunologia , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Humanos , ImunidadeRESUMO
OBJECTIVE: Little has been published either concerning the total number of research projects in connection with clinical development of drugs or the number of projects financially supported by the industry. METHODS: From the archives of the five regional Norwegian Research Ethical Committees (REC), all research projects in connection with clinical development of drugs for the years 2000 and 2004 were analysed with the intention of finding the number of projects financially supported by the industry, the type of research institution, the industrial company, the topic of the research as classified in the international Anatomic Therapeutic Classification system (ATC), the research phase and the approval status of the drug by the Norwegian Medicines Agency (NMA). RESULTS: The total number of research projects for the clinical development of drugs for the years 2000 and 2004 was 489, and 75.7% were financially supported by the industry. More than two-thirds of the projects were done in academic institutions and about one-third were equally divided between public health hospitals and private health service/hospitals. Eight of the 88 drug companies involved were among the world's largest and supported 38% of the projects. Fifty-nine percent of all the projects were within four therapeutic groups: antineoplastic/immunomodulating agents, nervous system, cardiovascular system and alimentary tract/metabolism. The distribution of research phases was as follows: phase I 1.2%, phase II 16.4%, phase III 26.6% and phase IV 55.8%. In the phase IV drug trials, drugs had been approved for sale by the NMA. CONCLUSIONS: The share of research projects related to the development of drugs supported by the industry is high. Research independent of the industry is of importance to avoid bias and selective publications and to prevent research as a means of marketing. Independent research should be encouraged and financially supported by sources with no connection to the drug industry.
Assuntos
Pesquisa Biomédica/economia , Ensaios Clínicos como Assunto/economia , Indústria Farmacêutica/economia , Apoio à Pesquisa como Assunto/estatística & dados numéricos , Academias e Institutos/economia , Academias e Institutos/estatística & dados numéricos , Viés , Pesquisa Biomédica/ética , Pesquisa Biomédica/estatística & dados numéricos , Ensaios Clínicos como Assunto/ética , Ensaios Clínicos como Assunto/estatística & dados numéricos , Conflito de Interesses , Indústria Farmacêutica/ética , Indústria Farmacêutica/estatística & dados numéricos , Hospitais Privados/economia , Hospitais Privados/estatística & dados numéricos , Hospitais Públicos/economia , Hospitais Públicos/estatística & dados numéricos , Humanos , Noruega/epidemiologia , Apoio à Pesquisa como Assunto/ética , Fatores de TempoRESUMO
The immune system is alerted to the presence of a pathogen through the activation of the innate immune system. The message is transmitted to the cells of the adaptive immunity through activated antigen-presenting cells. The development of specific immunity capable of eliminating the pathogen is orchestrated by cytokines and chemokines produced by the innate system. When everything functions optimally, the pathogen is eradicated and specific memory response is established. This finely tuned system can be subverted by pathogens, leading to disease. Immunity to cancer is orchestrated in the same way and it is now recognized that the early stages of tumour development are recognized by the cells of innate immunity that transmit this message to the cells of adaptive immunity. The molecules that alert the immune system and are also its targets are tumour antigens. Two important antigens for lung tumour-specific immunity are MUC1 and cyclin B1. We discuss how each molecule interacts with the innate and the adaptive immunity and the types of the immune responses that result for these interactions. We also discuss the state of immunosuppression of adaptive immunity in cancer patients due to chronic activation of the innate immune system.