28 research outputs found
Insights into the structure/function of HGF/SF from studies with individual domains.
No full textHepatocyte growth factor/scatter factor (HGF/SF), the ligand for the receptor tyrosine kinase encoded by the c-Met proto-oncogene, is a multidomain protein structurally related to the pro-enzyme plasminogen and with major roles in development, tissue regeneration and cancer. We have expressed the N-terminal (N) domain, the four kringle domains (K1 to K4) and the serine proteinase homology domain (SP) of HGF/SF individually in yeast or mammalian cells and studied their ability to: (i) bind the Met receptor as well as heparan sulphate and dermatan sulphate co-receptors, (ii) activate Met in target cells and, (iii) map their binding sites onto the beta-propeller domain of Met. The N, K1 and SP domains bound Met directly with comparable affinities (K(d)=2.4, 3.3 and 1.4 microM). The same domains also bound heparin with decreasing affinities (N>K1>>SP) but only the N domain bound dermatan sulphate. Three kringle domains (K1, K2 and K4) displayed agonistic activity on target cells. In contrast, the N and SP domains, although capable of Met binding, displayed no or little activity. Further, cross-linking experiments demonstrated that both the N domain and kringles 1-2 bind the beta-chain moiety (amino acid residues 308-514) of the Met beta-propeller. In summary, the K1, K2 and K4 domains of HGF/SF are sufficient for Met activation, whereas the N and SP domains are not, although the latter domains contribute additional binding sites necessary for receptor activation by full length HGF/SF. The results provide new insights into the structure/function of HGF/SF and a basis for engineering the N and K1 domains as receptor antagonists for cancer therapy
Structure of the human receptor tyrosine kinase met in complex with the Listeria invasion protein InlB
No full textNiemann H, Jager V, Butler PJ, et al. Structure of the human receptor tyrosine kinase met in complex with the Listeria invasion protein InlB. Cell. 2007;130(2):235-246
Transjugular liver biopsy: the key to a rare etiology of cholestatic hepatitis after bone marrow transplantation
No full text© 2024 The Author(s). Published by S. Karger AG, Basel. Open Access License. This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission.Introduction: Hematopoietic stem cell transplantation (HSCT) is associated with multiple complications, such as sinusoidal obstruction syndrome (SOS) (hepatomegaly, ascites, jaundice, and thrombocytopenia) and graft-versus-host disease (GVHD) (with the skin, gastrointestinal tract, and liver being the main targets). These entities may present overlapping clinical findings, being considered differential diagnoses, but their coexistence is rare.
Case presentation: A 29-year-old male with acute myeloid leukemia underwent HSCT. On day (D)+20, he developed hyperbilirubinemia, pleural effusion, ascites, and painful hepatomegaly. Abdominal ultrasound was suggestive of SOS, and defibrotide was initiated. On D+44, acute cutaneous, intestinal, and hepatic GVHD developed which improved after treatment with methylprednisolone. On D+132, there was worsening cholestasis and abdominal pain. MRCP revealed strictures in several segments of the intrahepatic bile ducts and irregularity of the main bile duct. Due to aggravation of liver enzyme changes and clinical worsening, he was admitted to the Intensive Care Unit. Due to persistence of severe hyperbilirubinemia (30 mg/dL) and thrombocytopenia (30,000 cell/uL), he underwent a hepatic hemodynamic study which revealed a hepatic venous pressure gradient of 10 mm Hg. The transjugular liver biopsy revealed canalicular hepatic cholestasis, bile duct injury, and focal hepatocellular necrosis suggestive of GVHD as well as injury to centrilobular veins and centrilobular necrosis compatible with possible SOS. Mycophenolate mofetil was started, but on D+195, the patient died of septic shock.
Discussion/conclusion: This case is notable for its complexity and for demonstrating the rare coexistence of histological features of SOS and GVHD. Although the clinical and laboratory findings may be sufficient for the diagnosis, it is important to highlight the importance of liver hemodynamic study and transjugular liver biopsy in these patients who often have severe thrombocytopenia, for the characterization and histological confirmation of cholestatic hepatitis, especially when the etiology may be multifactorial.info:eu-repo/semantics/publishedVersio
O crescente panorama do carcinoma hepatocelular associado ao fígado gordo não alcoólico e o seu impacto no rastreio
No full text© 2023 The Author(s). Published by S. Karger AG, Basel. This article is licensed under the Creative Commons Attribution- NonCommercial 4.0 International License (CC BY-NC) (http://www. karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes require written permission.Liver cancer is globally the third leading cause of death from cancer. Hepatocellular carcinoma (HCC) develops in patients with underlying liver disease. The fraction of HCC attributed to nonalcoholic fatty liver disease (NAFLD) shows an accelerated increase in the last decades, being already responsible for 15% of all HCC cases. Similar to other causes of liver cirrhosis, patients with NAFLD-associated cirrhosis should be enrolled in HCC-screening programs, yet these patients are under-screened, and currently are less than half likely to be proposed for HCC screening as compared to patients with HCV-associated cirrhosis. NAFLD-associated HCC has the peculiarity of occurring in precirrhotic phases in 20-50% of the cases. Currently, HCC screening in precirrhotic NAFLD patients is not routinely recommended, since the risk of developing HCC is very low. However, because NAFLD affects one-third of the worldwide population, noncirrhotic NAFLD already accounts for 6% of HCC cases. As such, it is pressing to develop stratification tools, in order to personalize the individual risk of HCC development in a patient with NAFLD, allowing precision HCC-screening programs. This review summarizes the epidemiology of NAFLD-associated HCC with a critical analysis of current HCC-screening recommendations.O cancro do fígado é, globalmente, a terceira causa de morte por cancro. O carcinoma hepatocelular (CHC) desenvolve-se em doentes com doença hepática crónica subjacente. A fracção de CHC atribuível ao fígado gordo não alcoólico (FGNA) tem vindo a aumentar com uma aceleração no seu crescimento nas últimas décadas, sendo atualmente responsável por 15% dos casos de CHC. À semelhança do que ocorre com outras causas de cirrose hepática, os doentes com cirrose associada a FGNA devem ser inseridos em programas de rastreio de CHC. Contudo, esses doentes são sub-rastreados, já que a probabilidade de serem incluídos em programas de rastreio de CHC é menos de metade comparando com doentes com cirrose associada a hepatite C crónica. O CHC associado ao FGNA tem a particularidade de ocorrer em fases pré-cirróticas em 20 a 50% dos casos. O rastreio de CHC em doentes com FGNA em fase pré-cirrótica não está recomendado por rotina, uma vez que, ainda assim, o risco destes doentes desenvolverem CHC é muito baixo. No entanto, uma vez que um terço da população mundial tem FGNA, o FGNA em não cirróticos corresponde a 6% de todos os casos de CHC. Assim sendo, é urgente o desenvolvimento de métodos de estratificação, por forma a personalizar o risco individual de desenvolvimento de CHC em doentes com FGNA, permitindo maior precisão nos programas de rastreio de CHC. Esta revisão sumariza a epidemiologia de CHC associado ao FGNA, com uma análise crítica das atuais recomendações de rastreio de CHC.info:eu-repo/semantics/publishedVersio
A generalized Kalman filter with its precision in recursive form when the stochastic model is misspecified
Get PDFIn this contribution, we introduce a generalized Kalman filter with precision in recursive form when the stochastic model is misspecified. The filter allows for a relaxed dynamic model in which not all state vector elements are connected in time. The filter is equipped with a recursion of the actual error-variance matrices so as to provide an easy-to-use tool for the efficient and rigorous precision analysis of the filter in case the underlying stochastic model is misspecified. Different mechanizations of the filter are presented, including a generalization of the concept of predicted residuals as needed for the recursive quality control of the filter.Mathematical Geodesy and Positionin
C-reactive protein is essential for innate resistance to pneumococcal infection.
Get PDFNo deficiency of human C-reactive protein (CRP), or even structural polymorphism of the protein, has yet been reported so its physiological role is not known. Here we show for the first time that CRP-deficient mice are remarkably susceptible to Streptococcus pneumoniae infection and are protected by reconstitution with isolated pure human CRP, or by anti-pneumococcal antibodies. Autologous mouse CRP is evidently essential for innate resistance to pneumococcal infection before antibodies are produced. Our findings are consistent with the significant association between clinical pneumococcal infection and non-coding human CRP gene polymorphisms which affect CRP expression. Deficiency or loss of function variation in CRP may therefore be lethal at the first early-life encounter with this ubiquitous virulent pathogen, explaining the invariant presence and structure of CRP in human adults
Perinatal asphyxia: current status and approaches towards neuroprotective strategies, with focus on sentinel proteins
Get PDFArtículo de publicación ISIDelivery is a stressful and risky event menacing
the newborn. The mother-dependent respiration has to be
replaced by autonomous pulmonary breathing immediately
after delivery. If delayed, it may lead to deficient oxygen
supply compromising survival and development of the
central nervous system. Lack of oxygen availability gives
rise to depletion of NAD? tissue stores, decrease of ATP
formation, weakening of the electron transport pump and
anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established.
Re-oxygenation triggers a cascade of compensatory biochemical
events to restore function, which may be accompanied
by improper homeostasis and oxidative stress.
Consequences may be incomplete recovery, or excess reactions
that worsen the biological outcome by disturbed
metabolism and/or imbalance produced by over-expression
of alternative metabolic pathways. Perinatal asphyxia has
been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments
have yet been established. In the clinical setting, after
resuscitation of an infant with birth asphyxia, the emphasis is
on supportive therapy. Several interventions have been
proposed to attenuate secondary neuronal injuries elicited by
asphyxia, including hypothermia. Although promising, the
clinical efficacy of hypothermia has not been fully demonstrated.
It is evident that new approaches are warranted. The
purpose of this review is to discuss the concept of sentinel
proteins as targets for neuroprotection. Several sentinel
proteins have been described to protect the integrity of the
genome (e.g. PARP-1; XRCC1; DNA ligase IIIa; DNA
polymerase b, ERCC2, DNA-dependent protein kinases).
They act by eliciting metabolic cascades leading to (i) activation
of cell survival and neurotrophic pathways; (ii) early
and delayed programmed cell death, and (iii) promotion of
cell proliferation, differentiation, neuritogenesis and synaptogenesis.
It is proposed that sentinel proteins can be used as
markers for characterising long-term effects of perinatal
asphyxia, and as targets for novel therapeutic development
and innovative strategies for neonatal care.Contract grant sponsors: FONDECYT-Chile
(contracts: 1080447; 11070192; 1070699) (MH-M, PM, DB, LL);
CONICYT/DAAD (contract: 137829-May-2009) (PJG-H; MH-M);
Fogarty International Center-NIH (contract: 1R03TW007810-01A1
(LL); Regione Autonoma della Sardegna for Scientific Cooperation
between Italy and Chile (Italy) (contract: 19/96-2003) (MM,
MHM); Atlantic Innovation Fund (Canada) (contract: 181780);
BMBF (NGFN ? TP9) and DAAD (415/alechile) (PJ G-H)
An assessment of water demand management options from a systems approach
No full textA systems approach is used to model the urban water and wastewater system. Scenarios are developed for the implementation of a range of water demand management measures, including (a) leakage reduction, (b) the increasing use of water metering, (c) the replacement of standard WCs by low-flow WCs, and (d) the introduction of greywater recycling systems. These measures are assessed according to the water saving, cost per unit of water saved, and other indicators of the relative contribution to the sustainability of the system. Preliminary assessments of selected environmental costs and benefits are also included
An assessment of water demand management options from a systems approach
No full textA systems approach is used to model the urban water and wastewater system. Scenarios are developed for the implementation of a range of water demand management measures, including (a) leakage reduction, (b) the increasing use of water metering, (c) the replacement of standard WCs by low-flow WCs, and (d) the introduction of greywater recycling systems. These measures are assessed according to the water saving, cost per unit of water saved, and other indicators of the relative contribution to the sustainability of the system. Preliminary assessments of selected environmental costs and benefits are also included
