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1.
Immunity ; 57(6): 1378-1393.e14, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38749447

RESUMEN

Tumors weakly infiltrated by T lymphocytes poorly respond to immunotherapy. We aimed to unveil malignancy-associated programs regulating T cell entrance, arrest, and activation in the tumor environment. Differential expression of cell adhesion and tissue architecture programs, particularly the presence of the membrane tetraspanin claudin (CLDN)18 as a signature gene, demarcated immune-infiltrated from immune-depleted mouse pancreatic tumors. In human pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer, CLDN18 expression positively correlated with more differentiated histology and favorable prognosis. CLDN18 on the cell surface promoted accrual of cytotoxic T lymphocytes (CTLs), facilitating direct CTL contacts with tumor cells by driving the mobilization of the adhesion protein ALCAM to the lipid rafts of the tumor cell membrane through actin. This process favored the formation of robust immunological synapses (ISs) between CTLs and CLDN18-positive cancer cells, resulting in increased T cell activation. Our data reveal an immune role for CLDN18 in orchestrating T cell infiltration and shaping the tumor immune contexture.


Asunto(s)
Carcinoma Ductal Pancreático , Claudinas , Activación de Linfocitos , Neoplasias Pancreáticas , Linfocitos T Citotóxicos , Animales , Humanos , Ratones , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Claudinas/metabolismo , Claudinas/genética , Regulación Neoplásica de la Expresión Génica/inmunología , Sinapsis Inmunológicas/metabolismo , Sinapsis Inmunológicas/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Microdominios de Membrana/metabolismo , Microdominios de Membrana/inmunología , Ratones Endogámicos C57BL , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral/inmunología
2.
Arterioscler Thromb Vasc Biol ; 40(12): 2975-2989, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33052054

RESUMEN

OBJECTIVE: Pulmonary thrombosis is observed in severe acute respiratory syndrome coronavirus 2 pneumonia. Aim was to investigate whether subpopulations of platelets were programmed to procoagulant and inflammatory activities in coronavirus disease 2019 (COVID-19) patients with pneumonia, without comorbidities predisposing to thromboembolism. Approach and Results: Overall, 37 patients and 28 healthy subjects were studied. Platelet-leukocyte aggregates, platelet-derived microvesicles, the expression of P-selectin, and active fibrinogen receptor on platelets were quantified by flow cytometry. The profile of 45 cytokines, chemokines, and growth factors released by platelets was defined by immunoassay. The contribution of platelets to coagulation factor activity was selectively measured. Numerous platelet-monocyte (mean±SE, 67.9±4.9%, n=17 versus 19.4±3.0%, n=22; P<0.0001) and platelet-granulocyte conjugates (34.2±4.04% versus 8.6±0.7%; P<0.0001) were detected in patients. Resting patient platelets had similar levels of P-selectin (10.9±2.6%, n=12) to collagen-activated control platelets (8.7±1.5%), which was not further increased by collagen activation on patient platelets (12.4±2.5%, P=nonsignificant). The agonist-stimulated expression of the active fibrinogen receptor was reduced by 60% in patients (P<0.0001 versus controls). Cytokines (IL [interleukin]-1α, IL-1ß, IL-1RA, IL-4, IL-10, IL-13, IL, 17, IL-27, IFN [interferon]-α, and IFN-γ), chemokines (MCP-1/CCL2 [monocyte chemoattractant protein 1]), and growth factors (VEGF [vascular endothelial growth factor]-A/D) were released in significantly larger amounts upon stimulation of COVID-19 platelets. Platelets contributed to increased fibrinogen, VWF (von Willebrand factor), and factor XII in COVID-19 patients. Patients (28.5±0.7 s, n=32), unlike controls (31.6±0.5 s, n=28; P<0.001), showed accelerated factor XII-dependent coagulation. CONCLUSIONS: Platelets in COVID-19 pneumonia are primed to spread proinflammatory and procoagulant activities in systemic circulation.


Asunto(s)
Plaquetas/metabolismo , COVID-19/sangre , Tromboembolia/etiología , Anciano , Anciano de 80 o más Años , COVID-19/complicaciones , Citocinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Pronóstico , Tromboembolia/sangre
3.
Proc Natl Acad Sci U S A ; 115(46): E10869-E10878, 2018 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-30381462

RESUMEN

Mutations in the TP53 gene and microenvironmentally driven activation of hypoxia-inducible factor-1 (HIF-1) typically occur in later stages of tumorigenesis. An ongoing challenge is the identification of molecular determinants of advanced cancer pathogenesis to design alternative last-line therapeutic options. Here, we report that p53 mutants influence the tumor microenvironment by cooperating with HIF-1 to promote cancer progression. We demonstrate that in non-small cell lung cancer (NSCLC), p53 mutants exert a gain-of-function (GOF) effect on HIF-1, thus regulating a selective gene expression signature involved in protumorigenic functions. Hypoxia-mediated activation of HIF-1 leads to the formation of a p53 mutant/HIF-1 complex that physically binds the SWI/SNF chromatin remodeling complex, promoting expression of a selective subset of hypoxia-responsive genes. Depletion of p53 mutants impairs the HIF-mediated up-regulation of extracellular matrix (ECM) components, including type VIIa1 collagen and laminin-γ2, thus affecting tumorigenic potential of NSCLC cells in vitro and in mouse models in vivo. Analysis of surgically resected human NSCLC revealed that expression of this ECM gene signature was highly correlated with hypoxic tumors exclusively in patients carrying p53 mutations and was associated with poor prognosis. Our data reveal a GOF effect of p53 mutants in hypoxic tumors and suggest synergistic activities of p53 and HIF-1. These findings have important implications for cancer progression and might provide innovative last-line treatment options for advanced NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Factor 1 Inducible por Hipoxia/genética , Neoplasias Pulmonares/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Hipoxia de la Célula/genética , Línea Celular Tumoral , Matriz Extracelular , Genes p53 , Xenoinjertos , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mutación , Activación Transcripcional , Microambiente Tumoral , Proteína p53 Supresora de Tumor/genética
4.
Biochem Biophys Res Commun ; 482(3): 498-505, 2017 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-28212736

RESUMEN

p73 is a transcription factor belonging to the p53 tumour suppressor family. p73-/- mice exhibit a range of phenotypes including neurological, reproductive and inflammatory defects. Although the role of p73 in the control of genomic stability explains part of these phenotypes, a clear mechanism of how p73 participates in the inflammatory response is still elusive. Interleukin-1ß (IL-1ß) has a crucial role in mediating the inflammatory response. Because of its high potency to induce inflammation, the activation and secretion of IL-1ß is tightly regulated by large protein complexes, named inflammasomes. Inflammasomes regulate activation of proinflammatory caspase-1, which in turn proteolytically processes its substrates, including pro-IL-1ß. Caspase-1 gene transcription is strongly activated by p53 protein family members including p73. Here, we have addressed whether p73 might be directly involved in IL-1ß regulation and therefore in the control of the inflammatory response. Our results show that TAp73ß upregulates pro-IL-1ß mRNA and processed IL-1ß protein. In addition, analysis of breast and lung cancer patient cohorts demonstrated that interaction between p73 and IL-1ß predicts a negative survival outcome in these human cancers.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteína Tumoral p73/metabolismo , Animales , Biomarcadores de Tumor/genética , Caspasa 1/metabolismo , Línea Celular Tumoral , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Inflamasomas/metabolismo , Ratones , Ratones Noqueados , Pronóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Proteína Tumoral p73/antagonistas & inhibidores , Proteína Tumoral p73/deficiencia , Proteína Tumoral p73/genética , Regulación hacia Arriba
5.
Stem Cell Res Ther ; 12(1): 316, 2021 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-34078447

RESUMEN

Coronavirus disease 2019 (COVID-19) may result in a life-threatening condition due to a hyperactive immune reaction to severe acute respiratory syndrome-coronavirus-2 infection, for which no effective treatment is available. Based on the potent immunomodulatory properties of mesenchymal stromal cells (MSCs), a growing number of trials are ongoing. This prompted us to carry out a thorough immunological study in a patient treated with umbilical cord-derived MSCs and admitted to the Intensive Care Unit for COVID-19-related pneumonia. The exploratory analyses were assessed on both peripheral blood and bronchoalveolar fluid lavage samples at baseline and after cellular infusion by means of single-cell RNA sequencing, flow cytometry, ELISA, and functional assays. Remarkably, a normalization of circulating T lymphocytes count paralleled by a reduction of inflammatory myeloid cells, and a decrease in serum levels of pro-inflammatory cytokines, mostly of interleukin-6 and tumor necrosis factor-α, were observed. In addition, a drop of plasma levels of those chemokines essential for neutrophil recruitment became evident that paralleled the decrease of lung-infiltrating inflammatory neutrophils. Finally, circulating monocytes and low-density gradient neutrophils acquired immunosuppressive function. This scenario was accompanied by an amelioration of respiratory, renal, inflammatory, and pro-thrombotic indexes. Our results provide the first immunological data possibly related to the use of umbilical cord-derived MSCs in severe COVID-19 context.


Asunto(s)
COVID-19 , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Humanos , SARS-CoV-2 , Cordón Umbilical
6.
Front Oncol ; 10: 165, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32133298

RESUMEN

Tumor metastases represent the major cause of cancer-related mortality, confirming the urgent need to identify key molecular pathways and cell-associated networks during the early phases of the metastatic process to develop new strategies to either prevent or control distal cancer spread. Several data revealed the ability of cancer cells to establish a favorable microenvironment, before their arrival in distant organs, by manipulating the cell composition and function of the new host tissue where cancer cells can survive and outgrow. This predetermined environment is termed "pre-metastatic niche" (pMN). pMN development requires that tumor-derived soluble factors, like cytokines, growth-factors and extracellular vesicles, genetically and epigenetically re-program not only resident cells (i.e., fibroblasts) but also non-resident cells such as bone marrow-derived cells. Indeed, by promoting an "emergency" myelopoiesis, cancer cells switch the steady state production of blood cells toward the generation of pro-tumor circulating myeloid cells defined as myeloid-derived suppressor cells (MDSCs) able to sustain tumor growth and dissemination. MDSCs are a heterogeneous subset of myeloid cells with immunosuppressive properties that sustain metastatic process. In this review, we discuss current understandings of how MDSCs shape and promote metastatic dissemination acting in each fundamental steps of cancer progression from primary tumor to metastatic disease.

7.
J Clin Invest ; 130(12): 6409-6416, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-32809969

RESUMEN

BACKGROUNDPatients with coronavirus disease 2019 (COVID-19) develop pneumonia generally associated with lymphopenia and a severe inflammatory response due to uncontrolled cytokine release. These mediators are transcriptionally regulated by the JAK/STAT signaling pathways, which can be disabled by small molecules.METHODSWe treated a group of patients (n = 20) with baricitinib according to an off-label use of the drug. The study was designed as an observational, longitudinal trial and approved by the local ethics committee. The patients were treated with 4 mg baricitinib twice daily for 2 days, followed by 4 mg per day for the remaining 7 days. Changes in the immune phenotype and expression of phosphorylated STAT3 (p-STAT3) in blood cells were evaluated and correlated with serum-derived cytokine levels and antibodies against severe acute respiratory syndrome-coronavirus 2 (anti-SARS-CoV-2). In a single treated patient, we also evaluated the alteration of myeloid cell functional activity.RESULTSWe provide evidence that patients treated with baricitinib had a marked reduction in serum levels of IL-6, IL-1ß, and TNF-α, a rapid recovery of circulating T and B cell frequencies, and increased antibody production against the SARS-CoV-2 spike protein, all of which were clinically associated with a reduction in the need for oxygen therapy and a progressive increase in the P/F (PaO2, oxygen partial pressure/FiO2, fraction of inspired oxygen) ratio.CONCLUSIONThese data suggest that baricitinib prevented the progression to a severe, extreme form of the viral disease by modulating the patients' immune landscape and that these changes were associated with a safer, more favorable clinical outcome for patients with COVID-19 pneumonia.TRIAL REGISTRATIONClinicalTrials.gov NCT04438629.FUNDINGThis work was supported by the Fondazione Cariverona (ENACT Project) and the Fondazione TIM.


Asunto(s)
Azetidinas/administración & dosificación , Tratamiento Farmacológico de COVID-19 , COVID-19 , Uso Fuera de lo Indicado , Purinas/administración & dosificación , Pirazoles/administración & dosificación , SARS-CoV-2 , Sulfonamidas/administración & dosificación , Anciano , Anciano de 80 o más Años , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos B/patología , COVID-19/sangre , COVID-19/inmunología , COVID-19/patología , Citocinas/sangre , Citocinas/inmunología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo , Índice de Severidad de la Enfermedad , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/patología
8.
Oncogenesis ; 7(1): 10, 2018 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-29362402

RESUMEN

Cancer progression often benefits from the selective conditions present in the tumour microenvironment, such as the presence of cancer-associated fibroblasts (CAFs), deregulated ECM deposition, expanded vascularisation and repression of the immune response. Generation of a hypoxic environment and activation of its main effector, hypoxia-inducible factor-1 (HIF-1), are common features of advanced cancers. In addition to the impact on tumour cell biology, the influence that hypoxia exerts on the surrounding cells represents a critical step in the tumorigenic process. Hypoxia indeed enables a number of events in the tumour microenvironment that lead to the expansion of aggressive clones from heterogeneous tumour cells and promote a lethal phenotype. In this article, we review the most relevant findings describing the influence of hypoxia and the contribution of HIF activation on the major components of the tumour microenvironment, and we summarise their role in cancer development and progression.

9.
Cell Cycle ; 17(15): 1917-1930, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30109812

RESUMEN

The p53 protein is a key tumor suppressor in mammals. In response to various forms of genotoxic stress p53 stimulates expression of genes whose products induce cell cycle arrest and/or apoptosis. An E3-ubiquitin ligase, Mdm2 (mouse-double-minute 2) and its human ortholog Hdm2, physically interact with the amino-terminus of p53 to mediate its ubiquitin-mediated degradation via the proteasome. Thus, pharmacological inhibition of the p53-Mdm2 interaction leads to overall stabilization of p53 and stimulation of its anti-tumorigenic activity. In this study we characterize the biological effects of a novel class of non-genotoxic isatin Schiff and Mannich base derivatives (ISMBDs) that stabilize p53 on the protein level. The likely mechanism behind their positive effect on p53 is mediated via the competitive interaction with Mdm2. Importantly, unlike Nutlin, these compounds selectively promoted p53-mediated cell death. These novel pharmacological activators of p53 can serve as valuable molecular tools for probing p53-positive tumors and set up the stage for development of new anti-cancer drugs.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Isatina/farmacología , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/genética , Línea Celular Tumoral , Histonas/metabolismo , Humanos , Imidazoles/farmacología , Isatina/análogos & derivados , Ratones , Piperazinas/farmacología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores
10.
Environ Sci Pollut Res Int ; 14(6): 366-76, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17993219

RESUMEN

BACKGROUND, AIMS AND SCOPE: Despite the large number of studies on the forms of sulfur in marine deposits, investigations on sulfur organic compounds are still rare. It is known that the processes leading to formation of intermediate and final sulfur compounds (including organic ones) in modern deposits are the results of microbiological transformation of sulfur containing proteins, as well as the microbiological reduction of sulfate ions. The latter are finally reduced by anaerobic sulfate-reducing bacteria to H2S, HS- and S2-; the total sum of these is referred to as 'hydrogen sulfide' in chemical oceanography. Further, the formation of reduced sulfur organic derivatives (sulfides and polysulfides) is the result of interaction of the organic substance destruction products with the sulfide ions. In such cases, the main source of organic substances, as well as sulfates for the sulfur reducing processes, is the pore water in the sediments. The choice of the target of our study is based on the fact that the eastern part of the Gulf of Finland water area receives the bulk of the anthropogenic load of the St. Petersburg region. Low vertical intermixing of the water thickness is observed there (thus creating a deficiency of oxygen near the bottom), and the bottom sea current transfers the polluted salty water of the Baltic Sea into the Neva Bay. The whole of the above are the preconditions for the formation of sulfur-bearing organic compounds. A great number of bottom sediment samples for analytical surveys were collected in the Eastern Gulf of Finland during research expeditions in the years of 1997 and 2001. These were screened for structures of sulfur organic microcontaminants, including organic forms of sulfur, using advanced instrumentation and experienced personnel in our two, cooperating laboratories. This work is a part of the research being carried out on organic micro-admixtures present in bottom sediments, and is the summary of our findings on previously unstudied sulfur organic substances there. MATERIALS AND METHODS: A number of sulfur organic compounds present in nineteen bottom sediment samples from the Eastern Gulf of Finland (EGF) were characterized by high performance gas chromatography connected to low and high resolution mass spectrometers (GC/LRMS and GC/HRMS). The structure screening was carried out as compared with literature and library mass spectra, and taking the GC retention times into account. In the cases of an absence of mass spectra not in the literature, interpretation of the most probable structures was performed with the help of high resolution mass-spectrometric data, fragmentation rules for sulfur-bearing organic substances and ICLU simulation of spectra. These data were registered to form a conclusive 'fingerprint' for identification and confirmation of the structure of each novel compound found, e.g. by later syntheses of authentic model compounds. The relative contents of sulfur organic compounds were determined from MS response ratios of each compound to 2-fluorine naphthalene (internal standard). RESULTS: This paper is a completion of work, which has been published in part as three papers in the European Journal of Mass Spectrometry. As the total study result, 43 sulfur-bearing compounds were characterized. The mass spectra of 20 of them were found in the literature. The most probable structures for the 23 compounds whose mass-spectra were not available in the literature data were proposed. All of those 23 compounds were detected in bottom sediments for the first time, and 5 of them were described as originating from plants or being generated by chemical synthesis products, while the remaining 18 substances were previously unknown. The structures of these were deduced to be most probably the following (in order of their GC retention): dichloromethyl thiylsulfenylchloride, chloromethyl dichloromethyl disulfide, 3,4-dithiacyclohexene, 1,2,4-trithiacycloheptane, 1,2,3-trithiacyclohexane, tetrathiacyclopentane, 3,4,5-trithiacyclohexene, 1,2,4-trithiacyclohexane, cyclopropylhydrotrisulfide, 1,2-dithiane-3-thiol, 1,3-dithiane-2-thiol, bis(trichloromethyl)-tri-sulfide, 1,2,4,5-tetrathiacyclohexane, 1,2,3,4-tetrathiacycloheptane, 1,2,3,4-tetrathiacycloheptane, 1,2,3,4-tetrathia-cyclo-hexane, pentathiacyclohexane, and 1,2,4,6-tetrathiacyclooctane. The highest amounts of sulfur organic compounds were found in the deepest, bottom areas in the open part of the sea, where the salinity was highest, and oxygen deficiency occurred as well. Also, some coastal places with a high solid matter deposition rate had elevated contents of sulfur organic compounds. DISCUSSION: From the 43 sulfur organic compounds found, the HRMS data provided the atomic composition of the molecular ions for 16 compounds with a high confidence (see Table 3). The LRMS spectra could be identified with catalogue or literature spectra in 29 cases. The MS information obtained was insufficient in two cases: 1) The obvious molecular ion (at m/z 110) of compound 1 was not visible in LRMS. 2) For compound 43, the HRMS measurement, due to the low intensity (2%) of the molecular ion (m/z 210), could not exclude the presence of 2 oxygen atoms (instead of one sulfur atom) in the molecule. Major fragments, however, of our 43, certainly contained no oxygen atoms according to HRMS. The limited LRMS data in the literature, for an isomer of 43, had m/z values of all fragments different from those of the compound found by us. The retention times (RT) formed one more evidence for identity between compounds in different samples. The use of different non-polar columns in GC and similar, but not identical, temperature programs produced eluted peaks of novel and known compounds in each sample (mixture) in GC/HRMS and GC/LRMS. These gave sets of RTs which were in a very significant linear correlation (measured example R = 0.999866, p = 1.85E-06, N = 5). Therefore, the RTs in the HRMS analysis systems could be converted to values comparable with those from the LRMS device. The RT values, HRMS m/z values, LRMS spectra, and ICLU simulation results for each organic sulfur compound form an identification 'fingerprint'. The interpretation of these experimental data, with supporting use of fragmentation rules, allow the giving of a provisional name and structure to the 'suspect'. In this study and in environmental surveys of micropollutants in general, the compounds suspected of anthropogenic or natural origin occur at low levels in complex mixtures. Therefore, no bulk amount of an authentic, pure model substance for the suspect is available quite often. The most probable name and structure from the fingerprint data are very useful in guiding the preparation of the model substance for a conclusive identification. Similarly, the unknown criminal can be identified in advance by forensic science and his fingerprint, DNA, etc. as registered before the arrest. The analogy can be found in the literature and CAS register of organic polysulfides, which in great part consists of the results of sensitive mixture analysis methods. CONCLUSIONS: Sediment of the Eastern Gulf of Finland is over large areas anaerobic, as indicated by the existence of novel, non-oxygenated sulfur organic microcontaminants. These substances were most abundant in anoxic and saline, deep bottom regions, and, in addition, in one coastal area near industrial discharges. This occurrence, and also the limited information about sulfur organic compounds in scientific literature, is considered evidence for the dominantly natural processes in their formation. RECOMMENDATIONS AND PERSPECTIVES: The importance and necessity of investigating the sulfur organic compounds in the bottom sediments, result from the fact that their presence can be an indicator of stable anaerobic processes. Similarly, the oxygen disappearance (anoxia) in the marine water, due to a high concentration of the sulfate ions and relatively high content of organic matter, is practically always connected with the appearance of hydrogen sulfide and sulfides. The generation of sulfur organic compounds precedes the formation of the new, or expansion of the existing anaerobic ('hydrogen sulfide') zones, which lead to such environmental disasters as mass destruction of hydrobionts. Many organic compounds of sulfur, including sulfides and polysulfides, are toxic to the aquatic organisms. Therefore, in addition to the danger of mass wholesale deaths of marine fauna in the bottom sediments region, there exists a probability of secondary pollution of the water thickness as well, due to the entry of those substances from bottom sediments in the water when the environmental conditions are changed (stormy weather, floods, geological activity of the earth's crust, etc.).


Asunto(s)
Sedimentos Geológicos/química , Compuestos de Azufre/análisis , Contaminantes Químicos del Agua/análisis , Finlandia
11.
Environ Sci Pollut Res Int ; 12(1): 8-9, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15768735

RESUMEN

A previously unknown pollutant in river water was identified to be 2-mercaptobenzothiazole (2-MBT) by interpretation and simulation of its GC/LRMS spectrum. Further GC/HRMS measurement of the isotope composition of the molecular ion verified this structure. 2-MBT is a well-known agent for corrosion inhibition and a stable metabolite of several other benzothiazoles. The present 2-MBT trace was most probably a metabolite of the wood preservative TCMTB which leaked from an upstream sawmill. The metabolite had been detected earlier in urine of the sawmill workers, but now was identified in the recipient water environment for the first time.


Asunto(s)
Industrias , Ríos/química , Tiazoles/análisis , Contaminantes Químicos del Agua/análisis , Madera , Benzotiazoles , Monitoreo del Ambiente , Finlandia , Fungicidas Industriales/química , Fungicidas Industriales/metabolismo , Espectrometría de Masas , Federación de Rusia , Tiazoles/química , Tiazoles/metabolismo , Tiocianatos/química , Tiocianatos/metabolismo
12.
Cell Cycle ; 14(15): 2484-93, 2015 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-25950386

RESUMEN

TAp73 is a tumor suppressor transcriptional factor, belonging to p53 family. Alteration of TAp73 in tumors might lead to reduced DNA damage response, cell cycle arrest and apoptosis. Carcinogen-induced TAp73(-/-) tumors display also increased angiogenesis, associated to hyperactivition of hypoxia inducible factor signaling. Here, we show that TAp73 suppresses BNIP3 expression, directly binding its gene promoter. BNIP3 is a hypoxia responsive protein, involved in a variety of cellular processes, such as autophagy, mitophagy, apoptosis and necrotic-like cell death. Therefore, through different cellular process altered expression of BNIP3 may differently contribute to cancer development and progression. We found a significant upregulation of BNIP3 in human lung cancer datasets, and we identified a direct association between BNIP3 expression and survival rate of lung cancer patients. Our data therefore provide a novel transcriptional target of TAp73, associated to its antagonistic role on HIF signaling in cancer, which might play a role in tumor suppression.


Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas de la Membrana/biosíntesis , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas/biosíntesis , Transcripción Genética/genética , Proteínas Supresoras de Tumor/genética , Apoptosis/genética , Sitios de Unión/genética , Línea Celular , Genes Supresores de Tumor , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neovascularización Patológica/genética , Proteína Tumoral p73
13.
Artículo en Inglés | MEDLINE | ID: mdl-15531807

RESUMEN

Structures of six cyclic polysulfides, previously unknown as organic environmental pollutants, were analyzed from a sediment sample from the Eastern Gulf of Finland. The determinations were done by gas chromatography connected to mass spectrometry. High resolution (HRMS) measurements of the isotopic composition of four compounds could be done to confirm their molecular formulae. Total low resolution (LRMS) spectra were used to elucidate structures of all six compounds by thermochemical approach, application of fragmentation rules and by ICLU simulation of the spectra. The compounds were deduced to be (in the order of GC- retention) 1,2,4-trithiacycloheptane, tetrathiacyclopentane, 1,2,4,5-tetrathia-cyclohexane, 1,2,3,4- tetrathiacycloheptane, 1,2,3,4-tetrathiacyclohexane and 1,2,4,6-tetrathiacyclooctane.


Asunto(s)
Cromatografía de Gases y Espectrometría de Masas/métodos , Sedimentos Geológicos/química , Compuestos Heterocíclicos/análisis , Sulfuros/análisis , Contaminantes Químicos del Agua/análisis , Finlandia , Residuos Industriales/análisis
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