AIM: To evaluate the potential of Polysol, a newly developed preservation solution, in cold storage of small bowel grafts, compared with the current standards, University of Wisconsin solution (UW), Celsior and histid...AIM: To evaluate the potential of Polysol, a newly developed preservation solution, in cold storage of small bowel grafts, compared with the current standards, University of Wisconsin solution (UW), Celsior and histidine-tryptophan-ketoglutarate solution (HTK). METHODS: Male Wistar rats were used as donors. Small bowels were retrieved, flushed and then stored in the respective 4 solutions for 18 h at 4℃. Functional integrity of the grafts was evaluated by isolated reperfusion with oxygenated Krebs-Henseleit buffer at 37℃ for 30 min in all 4 groups. RESULTS: Polysol preservation exhibited the highest tissue ATP concentration and the lowest release of LDH. Malondialdehyde, an index for tissue lipid peroxidation, was also the lowest in Polysol. Tissue oxygen consumption was significantly higher in Polysol than in the others. Of interest, UW-storage promoted 10-fold higher apoptosis than in the others. Moreover, electron microscopy revealed that the mucosal villi/micro-villi formation and the cell organelles, including mitochondria, were both significantly better preserved in Polysol, while deleterious alterations were apparent in the others, most notably in UW. Although Celsior and HTK exhibited the better trend of results than UW in some parameters, but could not reach the over-all superiority to UW.CONCLUSION: Cold storage using Polysol resulted in significantly better integrity and function of small bowel grafts than UW. Hence, Polysol may be a novel alternative for the small bowel preservation.展开更多
High dose radiation exposures involving medical treatments or accidental irradiation may lead to extended damage to the irradiated tissue. Alleviation or even eradication of irradiation induced adverse events is there...High dose radiation exposures involving medical treatments or accidental irradiation may lead to extended damage to the irradiated tissue. Alleviation or even eradication of irradiation induced adverse events is therefore crucial. Because developments in cell therapy have brought some hope for the treatment of tissues damages induced by irradiation, the Institute for Radiation and Nuclear Safety contributed to establish the clinical guidelines for the management of accidentally irradiated victims and to provide the best supportive care to patients all over the world. In the past 15 years, we contributed to develop and test cell therapy for protection against radiation side effects in several animalmodels, and we proposed mechanisms to explain the benefit brought by this new therapeutic approach. We established the proof of concept that mesenchymal stem cells (MSCs) migrate to damaged tissues in the nonobese diabetic/severe combined immunodeficiency immunotolerant mice model and in non-human primate after radiation exposure. We showed that the intravenous injection of MSCs sustains hematopoiesis after total body irradiation, improves wound healing after radiodermatitis and protects gut function from irradiation damages. Thanks to a tight collaboration with clinicians from several French hospitals, we report successful treatments of therapeutic/accidental radiation damages in several victims with MSC infusions for hematopoiesis correction, radio-induced burns, gastrointestinal disorders and protection homeostatic functions of gut management after radio-therapy.展开更多
Radiotherapy may induce irreversible damage on healthy tissues surrounding the tumor. It has been reported that the majority of patients receiving pelvic radiation therapy show early or late tissue reactions of graded...Radiotherapy may induce irreversible damage on healthy tissues surrounding the tumor. It has been reported that the majority of patients receiving pelvic radiation therapy show early or late tissue reactions of graded severity as radiotherapy affects not only the targeted tumor cells but also the surrounding healthy tissues. The late adverse effects of pelvic radiotherapy concern 5% to 10% of them, which could be life threatening. However, a clear medical consensus concerning the clinical management of such healthy tissue sequelae does not exist. Although no pharmacologic interventions have yet been proven to efficiently mitigate radiotherapy severe side effects, few preclinical researches show the potential of combined and sequential pharmacological treatments to prevent the onset of tissue damage. Our group has demonstrated in preclinical animal models that systemic mesenchymal stromal cell(MSC) injection is a promising approach for the medical management of gastrointestinal disorder after irradiation. We have shown that MSCs migrate to damaged tissues and restore gut functions after irradiation.We carefully studied side effects of stem cell injection for further application in patients. We have shown that clinical status of four patients suffering from severe pelvic side effects resulting from an over-dosage was improved following MSC injection in a compationnal situation.展开更多
In the last years, our knowledge of the pathogenesis in acute and chronic pancreatitis(AP/CP) as well as in pancreatic cancerogenesis has significantly diversified. Nevertheless, the medicinal therapeutic options are ...In the last years, our knowledge of the pathogenesis in acute and chronic pancreatitis(AP/CP) as well as in pancreatic cancerogenesis has significantly diversified. Nevertheless, the medicinal therapeutic options are still limited and therapeutic success and patient outcome are poor. Epigenetic deregulation of gene expression is known to contribute to development and progression of AP and CP as well as of pancreatic cancer. Therefore, the selective inhibition of aberrantly active epigenetic regulators can be an effective option for future thera-pies. Histone deacetylases(HDACs) are enzymes that remove an acetyl group from histone tails, thereby causing chromatin compaction and repression of transcri-ption. In this review we present an overview of the currently available literature addressing the role of HDACs in the pancreas and in pancreatic diseases. In pancreatic cancerogenesis, HDACs play a role in the important process of epithelial-mesenchymal-transition, ubiquitin-proteasome pathway and, hypoxia-inducible-factor-1-angiogenesis. Finally, we focus on HDACs as potential therapeutic targets by summarizing currently available histone deacetylase inhibitors.展开更多
To formulate the optimal strategy of combatting bacterial biofilms,in this review we update current knowledge on the growing problem of biofilm formation and its resistance to antibiotics which has spurred the search ...To formulate the optimal strategy of combatting bacterial biofilms,in this review we update current knowledge on the growing problem of biofilm formation and its resistance to antibiotics which has spurred the search for new strategies to deal with this complication.Based on recent findings,the role of bacteriophages in the prevention and elimination of biofilm-related infections has been emphasized.In vitro,ex vivo and in vivo biofilm treatment models with single bacteriophages or phage cocktails have been compared.A combined use of bacteriophages with antibiotics in vitro or in vivo confirms earlier reports of the synergistic effect of these agents in improving biofilm removal.Furthermore,studies on the application of phage-derived lysins in vitro,ex vivo or in vivo against biofilm-related infections are encouraging.The strategy of combined use of phage and antibiotics seems to be different from using lysins and antibiotics.These findings suggest that phages and lysins alone or in combination with antibiotics may be an efficient weapon against biofilm formation in vivo and ex vivo,which could be useful in formulating novel strategies to combat bacterial infections.Those findings proved to be relevant in the prevention and destruction of biofilms occurring during urinary tract infections,orthopedic implant-related infections,periodontal and peri-implant infections.In conclusion,it appears that most efficient strategy of eliminating biofilms involves phages or lysins in combination with antibiotics,but the optimal scheme of their administration requires further studies.展开更多
To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODSSerum IL9 as well as other cytokines (IL1β, IL6, IL13, IFN...To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODSSerum IL9 as well as other cytokines (IL1β, IL6, IL13, IFNγ, TNFα, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn’s disease (CD) and 74 with ulcerative colitis (UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn’s Disease Activity Index (CDAI) and the Mayo Scoring System (MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex xMAP<sup>®</sup> technology. High-sensitive C-reactive protein concentrations (hsCRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method.RESULTSSystemic IL9 was significantly lower in healthy individuals [9 pg/mL (95%CI: 8.2-10)] than in patients with inflammatory bowel disease (IBD): both inactive [14.3 pg/mL (11.9-19.9)] and active [27.6 pg/mL (24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/mL (23.4-32.2)] and in active UC [32.7 pg/mL (27-38.9)] compared to inactive diseases [15.9 pg/mL (10.8-23.4) in CD and 19.4 pg/mL (13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI (ρ = 0.32, P = 0.003) and MDAI (ρ = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC (ρ = 0.74, P < 0.0001). As a negative marker of mucosal healing (MH), IL9 had an accuracy superior to hsCRP and IL6 [97% (P < 0.0001), 67% (P = 0.071), and 55% (P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/mL (24.4-37.5) vs 21.88 pg/mL (18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations (ρ = -0.27, P < 0.001). Multiple regression showed IL1β and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNγ or IL6 in active and inactive UC, respectively, and IL13 and VEGF-A in both active and inactive CD.CONCLUSIONThe systemic IL9 level is higher in IBD and corresponds with endoscopic inflammation, suggesting its possible application as a negative marker of mucosal healing in UC.展开更多
Acinetobacter baumannii causes serious infections especially in immunocompromised and/or hospitalized patients.Several A.baumannii strains are multidrug resistant and infect wounds,bones,and the respiratory tract.Curr...Acinetobacter baumannii causes serious infections especially in immunocompromised and/or hospitalized patients.Several A.baumannii strains are multidrug resistant and infect wounds,bones,and the respiratory tract.Current studies are focused on finding new effective agents against A.baumannii.Phage therapy is a promising means to fight this bacterium and many studies on procuring and applying new phages against A.baumannii are currently being conducted.As shown in animal models,phages against multidrug-resistant A.baumannii may control bacterial infections caused by this pathogen and may be a real hope to solve this dangerous health problem.展开更多
BACKGROUND Mesenchymal stromal/stem cells (MSCs) constitute a promising tool in regenerative medicine and can be isolated from different human tissues. However, their biological properties are still not fully characte...BACKGROUND Mesenchymal stromal/stem cells (MSCs) constitute a promising tool in regenerative medicine and can be isolated from different human tissues. However, their biological properties are still not fully characterized. Whereas MSCs from different tissue exhibit many common characteristics, their biological activity and some markers are different and depend on their tissue of origin. Understanding the factors that underlie MSC biology should constitute important points for consideration for researchers interested in clinical MSC application. AIM To characterize the biological activity of MSCs during longterm culture isolated from: bone marrow (BM-MSCs), adipose tissue (AT-MSCs), skeletal muscles (SMMSCs), and skin (SK-MSCs). METHODS MSCs were isolated from the tissues, cultured for 10 passages, and assessed for: phenotype with immunofluorescence and flow cytometry, multipotency with differentiation capacity for osteo-, chondro-, and adipogenesis, stemness markers with qPCR for mRNA for Sox2 and Oct4, and genetic stability for p53 and c-Myc;27 bioactive factors were screened using the multiplex ELISA array, and spontaneous fusion involving a co-culture of SM-MSCs with BM-MSCs or AT-MSCs stained with PKH26 (red) or PKH67 (green) was performed. RESULTS All MSCs showed the basic MSC phenotype;however, their expression decreased during the follow-up period, as confirmed by fluorescence intensity. The examined MSCs express CD146 marker associated with proangiogenic properties;however their expression decreased in AT-MSCs and SM-MSCs, but was maintained in BM-MSCs. In contrast, in SK-MSCs CD146 expression increased in late passages. All MSCs, except BM-MSCs, expressed PW1, a marker associated with differentiation capacity and apoptosis. BM-MSCs and AT-MSCs expressed stemness markers Sox2 and Oct4 in long-term culture. All MSCs showed a stable p53 and c-Myc expression. BM-MSCs and AT-MSCs maintained their differentiation capacity during the follow-up period. In contrast, SK-MSCs and SM-MSCs had a limited ability to differentiate into adipocytes. BM-MSCs and AT-MSCs revealed similarities in phenotype maintenance, capacity for multilineage differentiation, and secretion of bioactive factors. Because AT-MSCs fused with SM-MSCs as effectively as BM-MSCs, AT-MSCs may constitute an alternative source for BM-MSCs. CONCLUSION Long-term culture affects the biological activity of MSCs obtained from various tissues. The source of MSCs and number of passages are important considerations in regenerative medicine.展开更多
Optical imaging plays an important role in biomedical research being extremely useful for early detection, screening and image-guided therapy. Lanthanide-doped up-converting nanoparticles were ideally suited for bioim...Optical imaging plays an important role in biomedical research being extremely useful for early detection, screening and image-guided therapy. Lanthanide-doped up-converting nanoparticles were ideally suited for bioimaging because they could be ex- cited in near infrared （NIR） and emit in NIR or visible （VIS）. Here, we compared lanthanide doped up-converting NaYF4 and organic fluorophores for application in deep-tissue imaging. For that purpose - tissue phantoms mimicking the natural properties of light scat- tering by living tissues were prepared. The studies allowed to quantitatively compare optical resolution of different fluorescent com- pounds, revealing that the NIR photoexcitation was favorable over conventional UV photoexcitation.展开更多
Even though Sorafenib has radically changed the natural history of those hepatocellular carcinoma patients who are not amenable for curative treatments, further therapeutic improvements are badly needed. As it was for...Even though Sorafenib has radically changed the natural history of those hepatocellular carcinoma patients who are not amenable for curative treatments, further therapeutic improvements are badly needed. As it was for Sorafenib, our increasingly refined understanding of the complex mechanisms underlying HCC carcinogenesis are the starting point for the future development of such treatments. Presently, a number of molecularly targeted agents are in different stages of development for this once orphan cancer. Indeed, several pathways are presently being explored to identify potentially active drugs, including epidermal growth factor receptor, vascular endothelial growth factor/vascular endothelial growth factor receptors, mammalian target of rapamycin, phosphatidyl-inositol-3-kinase/Akt, insulin growth factor, Aurora kinase, Wnt/β-catenin, retinoic acid receptor and hepatocyte growth factor/C-Met. This review is aimed at addressing the results obtained so far with these newer drugs, also considering the challenges we shall face in the near future, including the issue of response evaluation and identification of predictive/ prognostic biomarkers.展开更多
Since the discovery of the Hedgehog(Hh)pathway in drosophila melanogaster,our knowledge of the role of Hh in embryonic development,inflammation,and cancerogenesis in humans has dramatically increased over the last dec...Since the discovery of the Hedgehog(Hh)pathway in drosophila melanogaster,our knowledge of the role of Hh in embryonic development,inflammation,and cancerogenesis in humans has dramatically increased over the last decades.This is the case especially concerning the pancreas,however,real therapeutic breakthroughs are missing until now.In general,Hh signaling is essential for pancreatic organogenesis,development,and tissue maturation.In the case of acute pancreatitis,Hh has a protective role,whereas in chronic pancreatitis,Hh interacts with pancreatic stellate cells,leading to destructive parenchym fibrosis and atrophy,as well as to irregular tissue remodeling with potency of initiating cancerogenesis.In vitro and in situ analysis of Hh in pancreatic cancer revealed that the Hh pathway participates in the development of pancreatic precursor lesions and ductal adenocarcinoma including critical interactions with the tumor microenvironment.The application of specific inhibitors of components of the Hh pathway is currently subject of ongoing clinical trials(phases 1 and 2).Furthermore,a combination of Hh pathway inhibitors and established chemotherapeutic drugs could also represent a promising therapeutic approach.In this review,we give a structured survey of the role of the Hh pathway in pancreatic development,pancreatitis,pancreatic carcinogenesis and pancreatic cancer as well as an overview of current clinical trials concerning Hh pathway inhibitors and pancreas cancer.展开更多
The new coronavirus,severe acute respiratory syndrome coronavirus-2(SARSCoV-2),which emerged in December 2019 in Wuhan,China,has reached worldwide pandemic proportions,causing coronavirus disease 2019(COVID-19).The cl...The new coronavirus,severe acute respiratory syndrome coronavirus-2(SARSCoV-2),which emerged in December 2019 in Wuhan,China,has reached worldwide pandemic proportions,causing coronavirus disease 2019(COVID-19).The clinical manifestations of COVID-19 vary from an asymptomatic disease course to clinical symptoms of acute respiratory distress syndrome and severe pneumonia.The lungs are the primary organ affected by SARS-CoV-2,with a very slow turnover for renewal.SARS-CoV-2 enters the lungs via angiotensinconverting enzyme 2 receptors and induces an immune response with the accumulation of immunocompetent cells,causing a cytokine storm,which leads to target organ injury and subsequent dysfunction.To date,there is no effective antiviral therapy for COVID-19 patients,and therapeutic strategies are based on experience treating previously recognized coronaviruses.In search of new treatment modalities of COVID-19,cell-based therapy with mesenchymal stem cells(MSCs)and/or their secretome,such as soluble bioactive factors and extracellular vesicles,is considered supportive therapy for critically ill patients.Multipotent MSCs are able to differentiate into different types of cells of mesenchymal origin,including alveolar epithelial cells,lung epithelial cells,and vascular endothelial cells,which are severely damaged in the course of COVID-19 disease.Moreover,MSCs secrete a variety of bioactive factors that can be applied for respiratory tract regeneration in COVID-19 patients thanks to their trophic,anti-inflammatory,immunomodulatory,anti-apoptotic,pro-regenerative,and proangiogenic properties.展开更多
Over the past 5 years there has been a rapid increase in the use of microarray technology in the field of cancer research, The majority of studies use microarray analysis of tumor biopsies for profiling of molecular c...Over the past 5 years there has been a rapid increase in the use of microarray technology in the field of cancer research, The majority of studies use microarray analysis of tumor biopsies for profiling of molecular characteristics in an attempt to produce robust classifiers for prognosis. There are now several published gene sets that have been shown to predict for aggressive forms of breast cancer, where patients are most likely to benefit from adjuvant chemotherapy and tumors most likely to develop distant metastases, or be resistant to treatment. The number of publications relating to the use of microarrays for analysis of normal tissue damage, after cancer treatment or genotoxic exposure, is much more limited. A PublVled literature search was conducted using the following keywords and combination of terms： radiation, normal tissue, microarray, gene expression profiling, prediction. With respect to normal tissue radiation injury, microarrays have been used in three ways： （1） to generate gene signatures to identify sensitive and resistant populations （prognosis）; （2） to identify sets of biomarker genes for estimating radiation exposure, either accidental or as a result of terrorist attack （diagnosis）; （3） to identify genes and pathways involved in tissue response to injury （mechanistic）. In this article we will review all （relevant） papers that covered our literature search criteria on microarray technology as it has been applied to normal tissue radiation biology and discuss how successful this has been in defining predisposition markers for radiation sensitivity or how it has helped us to unravel molecular mechanisms leading to acute and late tissue toxicity. We also discuss some of the problems and limitations in application and interpretation of such data.展开更多
Characterization of disease models of neurodegenerative disorders requires a systematic and comprehensive phenotyping in a highly standardized manner. Therefore, automated high-resolution behavior test systems such as...Characterization of disease models of neurodegenerative disorders requires a systematic and comprehensive phenotyping in a highly standardized manner. Therefore, automated high-resolution behavior test systems such as the homecage based LabMaster system are of particular interest. We demonstrate the power of the automated LabMaster system by discovering previously unrecognized features of a recently characterized atxn3 mutant mouse model. This model provided neurological symptoms including gait ataxia, tremor, weight loss and premature death at the age of 12 months usually detectable just 2 weeks before the mice died. Moreover, using the LabMaster system we were able to detect hypoactivity in presymptomatic mutant mice in the dark as well as light phase. Additionally, we analyzed inflammation, immunological and hematological parameters, which indicated a reduced immune defense in phenotypic mice. Here we demonstrate that a detailed characterization even of organ systems that are usually not affected in SCA3 is important for further studies of pathogenesis and required for the preclinical therapeutic studies.展开更多
Adult stem cells are necessary for self-renewal tissues and regeneration after damage.Especially in the intestine,which self-renews every few days,they play a key role in tissue homeostasis.Therefore,complex regulator...Adult stem cells are necessary for self-renewal tissues and regeneration after damage.Especially in the intestine,which self-renews every few days,they play a key role in tissue homeostasis.Therefore,complex regulatory mechanisms are needed to prevent hyperproliferation,which can lead in the worst case to carcinogenesis or under-activation of stem cells,which can result in dysfunctional epithelial.One main regulatory signaling pathway is the Wnt/β-catenin signaling pathway.It is a highly conserved pathway,withβ-catenin,a transcription factor,as target protein.Translocation ofβ-catenin from cytoplasm to nucleus activates the transcription of numerous genes involved in regulating stem cell pluripotency,proliferation,cell differentiation and regulation of cell death.This review presents a brief overview of the Wnt/β-catenin signaling pathway,the regulatory mechanism of this pathway and its role in intestinal homeostasis.Additionally,this review highlights the molecular mechanisms and the histomorphological features of Wnt hyperactivation.Furthermore,the central role of the Wnt signaling pathway in intestinal carcinogenesis as well as its clinical relevance in colorectal carcinoma are discussed.展开更多
BACKGROUND In Wilson disease lack of biliary copper excretion causes hepatocellular injury by accumulation of free toxic copper.Its overspill to serum accounts for neuronal damage as second common manifestation.Therap...BACKGROUND In Wilson disease lack of biliary copper excretion causes hepatocellular injury by accumulation of free toxic copper.Its overspill to serum accounts for neuronal damage as second common manifestation.Therapy with copper chelators or zinc targets the removal of this free copper.However,in some patients liver disease persists for unknown reason despite normalized free copper.The discovery of a hyperimmunity as a contributing pathogenetic factor was discovered in this case report with implication also for other liver diseases.CASE SUMMARY A 9-year-old girl was diagnosed in August 2009 by family screening of having asymptomatic Wilson disease with elevated transaminases.Already at time of diagnosis antinuclear antibodies(ANA)were elevated without hyperimmunoglobulinemia(immunoglobulin G,IgG).After one year of therapy with Dpenicillamine transaminases normalized together with free serum copper.Under continuous therapy with copper chelators free copper remained normal until today,whereas transaminases raised to alanine aminotransferase values of 571 U/L in December 2019.For hyperimmunity a tentative steroid course on top of Dpenicillamine improved transaminases.Thus,hyperimmunity may have impact on liver inflammation after control of the metabolic disturbance.A retrospective cohort study confirmed the common association of elevated transaminases with ANA,but no IgG elevation.CONCLUSION This hyperimmune-triggered condition may represent a new entity which per se or on top of other liver diseases induces liver inflammation responsive to steroids.展开更多
In the brain, there are hundreds of types of specialized neurons and to generate one type of them we need to have neural progenitors for differentiation to specific neuron type. Mesenchymal stem cells (MSCs) are easil...In the brain, there are hundreds of types of specialized neurons and to generate one type of them we need to have neural progenitors for differentiation to specific neuron type. Mesenchymal stem cells (MSCs) are easily isolated, cultured, manipulated ex vivo, showing great potential for therapeutic applications. The adult MSCs have the potential to produce progeny that differentiate into a variety of cell types such as neurons. This fact suggests that MSCs derived neurons are an important cell type and a deep understanding of the molecular characteristics of it would significantly enhance the advancement of cell therapy for neurological disorders. Therefore, in this study, we isolated, identified, and studied neural progenitors by measuring expression levels through neurogenesis pathway of three neural differentiation markers nestin (NES), neurofilament (NF-L), and microtubule association protein (MAP-2) from mouse bone marrow MSCs (mouse bmMSCs) by using butylated hydroxyanisole (BHA) and diethyl sulfoxide (DMSO) as neural inducers agents. The results of immunocytochemistry and Real Time-PCR showed that in contrast to MSCs, neural differentiated cells showed neural progenitor pattern by showing stable increase in NES gene expression through differentiation process with increasing the protein expression through different exposures times, while NF-L gene and protein expression start to increased after 48 h but not replaced the NES expression completely even when its expression passed NES levels. The maturation marker Map-2 expression was low during the duration of differentiation period in protein and gene expression, which prove that these cells are still progenitors and can be redirected into specific type of neurons by further treatments.展开更多
Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a...Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells-the cancer stem cells-possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.展开更多
Carcinoembryonic antigen(CEA)is a surface glycoprotein expressed in human epithelial cells and is released from their surface,especially during colorectal cancer.Frequently,colorectal cancer is accompanied by in...Carcinoembryonic antigen(CEA)is a surface glycoprotein expressed in human epithelial cells and is released from their surface,especially during colorectal cancer.Frequently,colorectal cancer is accompanied by inflammation,where tumor-infiltrating neutrophils play an important role.CEA was also found to be a strong chemotactic agent for neutrophils.The purpose of this study was to find out if CEA can enhance neutrophil priming and activation.Primed neutrophils were activated by N-formyl-methionyl-leucyl-phenylalanine(formyl-MLP)and the resulting oxidative burst was measured luminometrically.Unexpectedly,in vitro priming of neutrophils by CEA,alone or preceded by LPS,inhibited subsequent activation of these cells by formyl-MLP.CEA may have anti-inflammatory properties in vivo.展开更多
Background: AMJ13 is a new breast cancer cell line that has been established from a 70-year-old Iraqi woman with a histological diagnosis of infiltrating ductal carcinoma. It is the first for an Iraqi population. In b...Background: AMJ13 is a new breast cancer cell line that has been established from a 70-year-old Iraqi woman with a histological diagnosis of infiltrating ductal carcinoma. It is the first for an Iraqi population. In breast cancer, angiogenesis provides the tumor tissue, which is rapidly proliferated with oxygen and nutrients, removes wastes and increases the opportunity of cancer cells to invade other organs. Methods: The AMJ13 breast cancer cell line was represented at three different passages and incubated for interval times. Microarray panel of 43 different angiogenesis markers was used to scan the supernatant for the factors. ELISA was used to quantify some of the important angiogenesis factors released in the culture medium and to confirm absence of those who was not detected by the antibody array. RT-PCR was used to confirm the gene expression (mRNA) of studied factors. Results: Microarray analysis showed that TIMP1 and two secreted at highest levels compared to the rest of the factors with low presence of endostatin. Other non-detectable factors by microarray examined by ELISA assay that showed highest expression level of VEGF-A were obtained at earliest passage, while the highest levels of FGF-b were obtained at late passage. The VEGF-D secretion was shown low concentrations at all studied passages. There is no detectable level of EGF protein in different passages and times interval tested. There are no significant differences in secretion of sICAM between different passages and incubation periods. Conclusion is that AMJ13 cell line depends on VEGF-A as main angiogenesis factor to induce micro-vessels supported by low levels of VEGF-D for lymphatic vessels formation. AMJ13 cell line depends on FGF as growth factors as in late passages it was shifted to depend mainly on FGF completely. All of this process may be regulated by TGF-β. TIMP-1 has proangiogentic effect and has feedback talk with TIMP-2. Understanding the angiogenesis process for breast cancer can give us better targets for therapy and more effective treatments.展开更多
基金BONFOR-Grant and the DFG grant, No. TO 542/1-1 to RHT
文摘AIM: To evaluate the potential of Polysol, a newly developed preservation solution, in cold storage of small bowel grafts, compared with the current standards, University of Wisconsin solution (UW), Celsior and histidine-tryptophan-ketoglutarate solution (HTK). METHODS: Male Wistar rats were used as donors. Small bowels were retrieved, flushed and then stored in the respective 4 solutions for 18 h at 4℃. Functional integrity of the grafts was evaluated by isolated reperfusion with oxygenated Krebs-Henseleit buffer at 37℃ for 30 min in all 4 groups. RESULTS: Polysol preservation exhibited the highest tissue ATP concentration and the lowest release of LDH. Malondialdehyde, an index for tissue lipid peroxidation, was also the lowest in Polysol. Tissue oxygen consumption was significantly higher in Polysol than in the others. Of interest, UW-storage promoted 10-fold higher apoptosis than in the others. Moreover, electron microscopy revealed that the mucosal villi/micro-villi formation and the cell organelles, including mitochondria, were both significantly better preserved in Polysol, while deleterious alterations were apparent in the others, most notably in UW. Although Celsior and HTK exhibited the better trend of results than UW in some parameters, but could not reach the over-all superiority to UW.CONCLUSION: Cold storage using Polysol resulted in significantly better integrity and function of small bowel grafts than UW. Hence, Polysol may be a novel alternative for the small bowel preservation.
文摘High dose radiation exposures involving medical treatments or accidental irradiation may lead to extended damage to the irradiated tissue. Alleviation or even eradication of irradiation induced adverse events is therefore crucial. Because developments in cell therapy have brought some hope for the treatment of tissues damages induced by irradiation, the Institute for Radiation and Nuclear Safety contributed to establish the clinical guidelines for the management of accidentally irradiated victims and to provide the best supportive care to patients all over the world. In the past 15 years, we contributed to develop and test cell therapy for protection against radiation side effects in several animalmodels, and we proposed mechanisms to explain the benefit brought by this new therapeutic approach. We established the proof of concept that mesenchymal stem cells (MSCs) migrate to damaged tissues in the nonobese diabetic/severe combined immunodeficiency immunotolerant mice model and in non-human primate after radiation exposure. We showed that the intravenous injection of MSCs sustains hematopoiesis after total body irradiation, improves wound healing after radiodermatitis and protects gut function from irradiation damages. Thanks to a tight collaboration with clinicians from several French hospitals, we report successful treatments of therapeutic/accidental radiation damages in several victims with MSC infusions for hematopoiesis correction, radio-induced burns, gastrointestinal disorders and protection homeostatic functions of gut management after radio-therapy.
文摘Radiotherapy may induce irreversible damage on healthy tissues surrounding the tumor. It has been reported that the majority of patients receiving pelvic radiation therapy show early or late tissue reactions of graded severity as radiotherapy affects not only the targeted tumor cells but also the surrounding healthy tissues. The late adverse effects of pelvic radiotherapy concern 5% to 10% of them, which could be life threatening. However, a clear medical consensus concerning the clinical management of such healthy tissue sequelae does not exist. Although no pharmacologic interventions have yet been proven to efficiently mitigate radiotherapy severe side effects, few preclinical researches show the potential of combined and sequential pharmacological treatments to prevent the onset of tissue damage. Our group has demonstrated in preclinical animal models that systemic mesenchymal stromal cell(MSC) injection is a promising approach for the medical management of gastrointestinal disorder after irradiation. We have shown that MSCs migrate to damaged tissues and restore gut functions after irradiation.We carefully studied side effects of stem cell injection for further application in patients. We have shown that clinical status of four patients suffering from severe pelvic side effects resulting from an over-dosage was improved following MSC injection in a compationnal situation.
文摘In the last years, our knowledge of the pathogenesis in acute and chronic pancreatitis(AP/CP) as well as in pancreatic cancerogenesis has significantly diversified. Nevertheless, the medicinal therapeutic options are still limited and therapeutic success and patient outcome are poor. Epigenetic deregulation of gene expression is known to contribute to development and progression of AP and CP as well as of pancreatic cancer. Therefore, the selective inhibition of aberrantly active epigenetic regulators can be an effective option for future thera-pies. Histone deacetylases(HDACs) are enzymes that remove an acetyl group from histone tails, thereby causing chromatin compaction and repression of transcri-ption. In this review we present an overview of the currently available literature addressing the role of HDACs in the pancreas and in pancreatic diseases. In pancreatic cancerogenesis, HDACs play a role in the important process of epithelial-mesenchymal-transition, ubiquitin-proteasome pathway and, hypoxia-inducible-factor-1-angiogenesis. Finally, we focus on HDACs as potential therapeutic targets by summarizing currently available histone deacetylase inhibitors.
文摘To formulate the optimal strategy of combatting bacterial biofilms,in this review we update current knowledge on the growing problem of biofilm formation and its resistance to antibiotics which has spurred the search for new strategies to deal with this complication.Based on recent findings,the role of bacteriophages in the prevention and elimination of biofilm-related infections has been emphasized.In vitro,ex vivo and in vivo biofilm treatment models with single bacteriophages or phage cocktails have been compared.A combined use of bacteriophages with antibiotics in vitro or in vivo confirms earlier reports of the synergistic effect of these agents in improving biofilm removal.Furthermore,studies on the application of phage-derived lysins in vitro,ex vivo or in vivo against biofilm-related infections are encouraging.The strategy of combined use of phage and antibiotics seems to be different from using lysins and antibiotics.These findings suggest that phages and lysins alone or in combination with antibiotics may be an efficient weapon against biofilm formation in vivo and ex vivo,which could be useful in formulating novel strategies to combat bacterial infections.Those findings proved to be relevant in the prevention and destruction of biofilms occurring during urinary tract infections,orthopedic implant-related infections,periodontal and peri-implant infections.In conclusion,it appears that most efficient strategy of eliminating biofilms involves phages or lysins in combination with antibiotics,but the optimal scheme of their administration requires further studies.
基金Supported by National Science Center,No.DEC-2011/01/D/NZ5/02835
文摘To evaluate circulating IL9 in inflammatory bowel disease and disease-associated anemia/cachexia and assess its potential as a mucosal healing marker.METHODSSerum IL9 as well as other cytokines (IL1β, IL6, IL13, IFNγ, TNFα, and VEGF-A) were determined in 293 individuals: 97 patients with Crohn’s disease (CD) and 74 with ulcerative colitis (UC) and in 122 apparently healthy controls. The clinical activity of CD and UC was expressed in terms of the Crohn’s Disease Activity Index (CDAI) and the Mayo Scoring System (MDAI), respectively, and the severity of bowel inflammation in UC patients was assessed using Mayo endoscopic score. Cytokine concentrations were measured by a flow cytometry-based method using Luminex xMAP<sup>®</sup> technology. High-sensitive C-reactive protein concentrations (hsCRP) were determined in CD and UC patients using the enhanced immunoturbidimetric method.RESULTSSystemic IL9 was significantly lower in healthy individuals [9 pg/mL (95%CI: 8.2-10)] than in patients with inflammatory bowel disease (IBD): both inactive [14.3 pg/mL (11.9-19.9)] and active [27.6 pg/mL (24.5-32), P < 0.0001]. Cytokine concentrations were significantly higher in active CD [27.4 pg/mL (23.4-32.2)] and in active UC [32.7 pg/mL (27-38.9)] compared to inactive diseases [15.9 pg/mL (10.8-23.4) in CD and 19.4 pg/mL (13.9-27.1) in UC, P = 0.001]. IL9 correlated weakly with CDAI (ρ = 0.32, P = 0.003) and MDAI (ρ = 0.35, P = 0.002) and strongly with endoscopic inflammation in UC (ρ = 0.74, P < 0.0001). As a negative marker of mucosal healing (MH), IL9 had an accuracy superior to hsCRP and IL6 [97% (P < 0.0001), 67% (P = 0.071), and 55% (P = 0.525), respectively]. IL9 was significantly higher in cachectic IBD patients [30.25 pg/mL (24.4-37.5) vs 21.88 pg/mL (18-26.5), P = 0.026] and negatively correlated with hemoglobin concentrations (ρ = -0.27, P < 0.001). Multiple regression showed IL1β and IL13 to be the independent predictors of circulating IL9 in healthy individuals, IFNγ or IL6 in active and inactive UC, respectively, and IL13 and VEGF-A in both active and inactive CD.CONCLUSIONThe systemic IL9 level is higher in IBD and corresponds with endoscopic inflammation, suggesting its possible application as a negative marker of mucosal healing in UC.
基金supported by the statutory funds from the Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences
文摘Acinetobacter baumannii causes serious infections especially in immunocompromised and/or hospitalized patients.Several A.baumannii strains are multidrug resistant and infect wounds,bones,and the respiratory tract.Current studies are focused on finding new effective agents against A.baumannii.Phage therapy is a promising means to fight this bacterium and many studies on procuring and applying new phages against A.baumannii are currently being conducted.As shown in animal models,phages against multidrug-resistant A.baumannii may control bacterial infections caused by this pathogen and may be a real hope to solve this dangerous health problem.
基金the National Science Center,No.N407121940the Wroclaw Centre of Biotechnology,the Leading National Research Centre(KNOW)program for the years 2014-2018
文摘BACKGROUND Mesenchymal stromal/stem cells (MSCs) constitute a promising tool in regenerative medicine and can be isolated from different human tissues. However, their biological properties are still not fully characterized. Whereas MSCs from different tissue exhibit many common characteristics, their biological activity and some markers are different and depend on their tissue of origin. Understanding the factors that underlie MSC biology should constitute important points for consideration for researchers interested in clinical MSC application. AIM To characterize the biological activity of MSCs during longterm culture isolated from: bone marrow (BM-MSCs), adipose tissue (AT-MSCs), skeletal muscles (SMMSCs), and skin (SK-MSCs). METHODS MSCs were isolated from the tissues, cultured for 10 passages, and assessed for: phenotype with immunofluorescence and flow cytometry, multipotency with differentiation capacity for osteo-, chondro-, and adipogenesis, stemness markers with qPCR for mRNA for Sox2 and Oct4, and genetic stability for p53 and c-Myc;27 bioactive factors were screened using the multiplex ELISA array, and spontaneous fusion involving a co-culture of SM-MSCs with BM-MSCs or AT-MSCs stained with PKH26 (red) or PKH67 (green) was performed. RESULTS All MSCs showed the basic MSC phenotype;however, their expression decreased during the follow-up period, as confirmed by fluorescence intensity. The examined MSCs express CD146 marker associated with proangiogenic properties;however their expression decreased in AT-MSCs and SM-MSCs, but was maintained in BM-MSCs. In contrast, in SK-MSCs CD146 expression increased in late passages. All MSCs, except BM-MSCs, expressed PW1, a marker associated with differentiation capacity and apoptosis. BM-MSCs and AT-MSCs expressed stemness markers Sox2 and Oct4 in long-term culture. All MSCs showed a stable p53 and c-Myc expression. BM-MSCs and AT-MSCs maintained their differentiation capacity during the follow-up period. In contrast, SK-MSCs and SM-MSCs had a limited ability to differentiate into adipocytes. BM-MSCs and AT-MSCs revealed similarities in phenotype maintenance, capacity for multilineage differentiation, and secretion of bioactive factors. Because AT-MSCs fused with SM-MSCs as effectively as BM-MSCs, AT-MSCs may constitute an alternative source for BM-MSCs. CONCLUSION Long-term culture affects the biological activity of MSCs obtained from various tissues. The source of MSCs and number of passages are important considerations in regenerative medicine.
基金Project supported by Wroclaw Research Centre EIT+within the project"The Application of Nanotechnology in Advanced Materials"-NanoMat(POIG.01.01.02-02-002/08)financed by the European Regional Development Fund(Operational Programme Innovative Economy,1.1.2)
文摘Optical imaging plays an important role in biomedical research being extremely useful for early detection, screening and image-guided therapy. Lanthanide-doped up-converting nanoparticles were ideally suited for bioimaging because they could be ex- cited in near infrared （NIR） and emit in NIR or visible （VIS）. Here, we compared lanthanide doped up-converting NaYF4 and organic fluorophores for application in deep-tissue imaging. For that purpose - tissue phantoms mimicking the natural properties of light scat- tering by living tissues were prepared. The studies allowed to quantitatively compare optical resolution of different fluorescent com- pounds, revealing that the NIR photoexcitation was favorable over conventional UV photoexcitation.
文摘Even though Sorafenib has radically changed the natural history of those hepatocellular carcinoma patients who are not amenable for curative treatments, further therapeutic improvements are badly needed. As it was for Sorafenib, our increasingly refined understanding of the complex mechanisms underlying HCC carcinogenesis are the starting point for the future development of such treatments. Presently, a number of molecularly targeted agents are in different stages of development for this once orphan cancer. Indeed, several pathways are presently being explored to identify potentially active drugs, including epidermal growth factor receptor, vascular endothelial growth factor/vascular endothelial growth factor receptors, mammalian target of rapamycin, phosphatidyl-inositol-3-kinase/Akt, insulin growth factor, Aurora kinase, Wnt/β-catenin, retinoic acid receptor and hepatocyte growth factor/C-Met. This review is aimed at addressing the results obtained so far with these newer drugs, also considering the challenges we shall face in the near future, including the issue of response evaluation and identification of predictive/ prognostic biomarkers.
文摘Since the discovery of the Hedgehog(Hh)pathway in drosophila melanogaster,our knowledge of the role of Hh in embryonic development,inflammation,and cancerogenesis in humans has dramatically increased over the last decades.This is the case especially concerning the pancreas,however,real therapeutic breakthroughs are missing until now.In general,Hh signaling is essential for pancreatic organogenesis,development,and tissue maturation.In the case of acute pancreatitis,Hh has a protective role,whereas in chronic pancreatitis,Hh interacts with pancreatic stellate cells,leading to destructive parenchym fibrosis and atrophy,as well as to irregular tissue remodeling with potency of initiating cancerogenesis.In vitro and in situ analysis of Hh in pancreatic cancer revealed that the Hh pathway participates in the development of pancreatic precursor lesions and ductal adenocarcinoma including critical interactions with the tumor microenvironment.The application of specific inhibitors of components of the Hh pathway is currently subject of ongoing clinical trials(phases 1 and 2).Furthermore,a combination of Hh pathway inhibitors and established chemotherapeutic drugs could also represent a promising therapeutic approach.In this review,we give a structured survey of the role of the Hh pathway in pancreatic development,pancreatitis,pancreatic carcinogenesis and pancreatic cancer as well as an overview of current clinical trials concerning Hh pathway inhibitors and pancreas cancer.
文摘The new coronavirus,severe acute respiratory syndrome coronavirus-2(SARSCoV-2),which emerged in December 2019 in Wuhan,China,has reached worldwide pandemic proportions,causing coronavirus disease 2019(COVID-19).The clinical manifestations of COVID-19 vary from an asymptomatic disease course to clinical symptoms of acute respiratory distress syndrome and severe pneumonia.The lungs are the primary organ affected by SARS-CoV-2,with a very slow turnover for renewal.SARS-CoV-2 enters the lungs via angiotensinconverting enzyme 2 receptors and induces an immune response with the accumulation of immunocompetent cells,causing a cytokine storm,which leads to target organ injury and subsequent dysfunction.To date,there is no effective antiviral therapy for COVID-19 patients,and therapeutic strategies are based on experience treating previously recognized coronaviruses.In search of new treatment modalities of COVID-19,cell-based therapy with mesenchymal stem cells(MSCs)and/or their secretome,such as soluble bioactive factors and extracellular vesicles,is considered supportive therapy for critically ill patients.Multipotent MSCs are able to differentiate into different types of cells of mesenchymal origin,including alveolar epithelial cells,lung epithelial cells,and vascular endothelial cells,which are severely damaged in the course of COVID-19 disease.Moreover,MSCs secrete a variety of bioactive factors that can be applied for respiratory tract regeneration in COVID-19 patients thanks to their trophic,anti-inflammatory,immunomodulatory,anti-apoptotic,pro-regenerative,and proangiogenic properties.
文摘Over the past 5 years there has been a rapid increase in the use of microarray technology in the field of cancer research, The majority of studies use microarray analysis of tumor biopsies for profiling of molecular characteristics in an attempt to produce robust classifiers for prognosis. There are now several published gene sets that have been shown to predict for aggressive forms of breast cancer, where patients are most likely to benefit from adjuvant chemotherapy and tumors most likely to develop distant metastases, or be resistant to treatment. The number of publications relating to the use of microarrays for analysis of normal tissue damage, after cancer treatment or genotoxic exposure, is much more limited. A PublVled literature search was conducted using the following keywords and combination of terms： radiation, normal tissue, microarray, gene expression profiling, prediction. With respect to normal tissue radiation injury, microarrays have been used in three ways： （1） to generate gene signatures to identify sensitive and resistant populations （prognosis）; （2） to identify sets of biomarker genes for estimating radiation exposure, either accidental or as a result of terrorist attack （diagnosis）; （3） to identify genes and pathways involved in tissue response to injury （mechanistic）. In this article we will review all （relevant） papers that covered our literature search criteria on microarray technology as it has been applied to normal tissue radiation biology and discuss how successful this has been in defining predisposition markers for radiation sensitivity or how it has helped us to unravel molecular mechanisms leading to acute and late tissue toxicity. We also discuss some of the problems and limitations in application and interpretation of such data.
基金supported by the European Union to OR(6th frame work programme.EuroSCA)
文摘Characterization of disease models of neurodegenerative disorders requires a systematic and comprehensive phenotyping in a highly standardized manner. Therefore, automated high-resolution behavior test systems such as the homecage based LabMaster system are of particular interest. We demonstrate the power of the automated LabMaster system by discovering previously unrecognized features of a recently characterized atxn3 mutant mouse model. This model provided neurological symptoms including gait ataxia, tremor, weight loss and premature death at the age of 12 months usually detectable just 2 weeks before the mice died. Moreover, using the LabMaster system we were able to detect hypoactivity in presymptomatic mutant mice in the dark as well as light phase. Additionally, we analyzed inflammation, immunological and hematological parameters, which indicated a reduced immune defense in phenotypic mice. Here we demonstrate that a detailed characterization even of organ systems that are usually not affected in SCA3 is important for further studies of pathogenesis and required for the preclinical therapeutic studies.
文摘Adult stem cells are necessary for self-renewal tissues and regeneration after damage.Especially in the intestine,which self-renews every few days,they play a key role in tissue homeostasis.Therefore,complex regulatory mechanisms are needed to prevent hyperproliferation,which can lead in the worst case to carcinogenesis or under-activation of stem cells,which can result in dysfunctional epithelial.One main regulatory signaling pathway is the Wnt/β-catenin signaling pathway.It is a highly conserved pathway,withβ-catenin,a transcription factor,as target protein.Translocation ofβ-catenin from cytoplasm to nucleus activates the transcription of numerous genes involved in regulating stem cell pluripotency,proliferation,cell differentiation and regulation of cell death.This review presents a brief overview of the Wnt/β-catenin signaling pathway,the regulatory mechanism of this pathway and its role in intestinal homeostasis.Additionally,this review highlights the molecular mechanisms and the histomorphological features of Wnt hyperactivation.Furthermore,the central role of the Wnt signaling pathway in intestinal carcinogenesis as well as its clinical relevance in colorectal carcinoma are discussed.
文摘BACKGROUND In Wilson disease lack of biliary copper excretion causes hepatocellular injury by accumulation of free toxic copper.Its overspill to serum accounts for neuronal damage as second common manifestation.Therapy with copper chelators or zinc targets the removal of this free copper.However,in some patients liver disease persists for unknown reason despite normalized free copper.The discovery of a hyperimmunity as a contributing pathogenetic factor was discovered in this case report with implication also for other liver diseases.CASE SUMMARY A 9-year-old girl was diagnosed in August 2009 by family screening of having asymptomatic Wilson disease with elevated transaminases.Already at time of diagnosis antinuclear antibodies(ANA)were elevated without hyperimmunoglobulinemia(immunoglobulin G,IgG).After one year of therapy with Dpenicillamine transaminases normalized together with free serum copper.Under continuous therapy with copper chelators free copper remained normal until today,whereas transaminases raised to alanine aminotransferase values of 571 U/L in December 2019.For hyperimmunity a tentative steroid course on top of Dpenicillamine improved transaminases.Thus,hyperimmunity may have impact on liver inflammation after control of the metabolic disturbance.A retrospective cohort study confirmed the common association of elevated transaminases with ANA,but no IgG elevation.CONCLUSION This hyperimmune-triggered condition may represent a new entity which per se or on top of other liver diseases induces liver inflammation responsive to steroids.
文摘In the brain, there are hundreds of types of specialized neurons and to generate one type of them we need to have neural progenitors for differentiation to specific neuron type. Mesenchymal stem cells (MSCs) are easily isolated, cultured, manipulated ex vivo, showing great potential for therapeutic applications. The adult MSCs have the potential to produce progeny that differentiate into a variety of cell types such as neurons. This fact suggests that MSCs derived neurons are an important cell type and a deep understanding of the molecular characteristics of it would significantly enhance the advancement of cell therapy for neurological disorders. Therefore, in this study, we isolated, identified, and studied neural progenitors by measuring expression levels through neurogenesis pathway of three neural differentiation markers nestin (NES), neurofilament (NF-L), and microtubule association protein (MAP-2) from mouse bone marrow MSCs (mouse bmMSCs) by using butylated hydroxyanisole (BHA) and diethyl sulfoxide (DMSO) as neural inducers agents. The results of immunocytochemistry and Real Time-PCR showed that in contrast to MSCs, neural differentiated cells showed neural progenitor pattern by showing stable increase in NES gene expression through differentiation process with increasing the protein expression through different exposures times, while NF-L gene and protein expression start to increased after 48 h but not replaced the NES expression completely even when its expression passed NES levels. The maturation marker Map-2 expression was low during the duration of differentiation period in protein and gene expression, which prove that these cells are still progenitors and can be redirected into specific type of neurons by further treatments.
基金Supported by Studies of the authors Mayr C,Pichler M,Neureiter D and Kiesslich T in the research field of this review were supported by research grants of the Jubilaumsfonds derosterreichischen Nationalbank,No.12677 and No.14842the research fund of the Paracelsus Medical University Salzburg,No.08/07/037,No.A-12/02/006-KIE and No.R-16/03/083-MAY
文摘Management of biliary tract cancer remains challenging. Tumors show high recurrence rates and therapeutic resistance, leading to dismal prognosis and short survival. The cancer stem cell model states that a tumor is a heterogeneous conglomerate of cells, in which a certain subpopulation of cells-the cancer stem cells-possesses stem cell properties. Cancer stem cells have high clinical relevance due to their potential contributions to development, progression and aggressiveness as well as recurrence and metastasis of malignant tumors. Consequently, reliable identification of as well as pharmacological intervention with cancer stem cells is an intensively investigated and promising research field. The involvement of cancer stem cells in biliary tract cancer is likely as a number of studies demonstrated their existence and the obvious clinical relevance of several established cancer stem cell markers in biliary tract cancer models and tissues. In the present article, we review and discuss the currently available literature addressing the role of putative cancer stem cells in biliary tract cancer as well as the connection between known contributors of biliary tract tumorigenesis such as oncogenic signaling pathways, micro-RNAs and the tumor microenvironment with cancer stem cells.
基金Grant No:N N401332236 from The Ministry of Science and Higher Education of Poland.
文摘Carcinoembryonic antigen(CEA)is a surface glycoprotein expressed in human epithelial cells and is released from their surface,especially during colorectal cancer.Frequently,colorectal cancer is accompanied by inflammation,where tumor-infiltrating neutrophils play an important role.CEA was also found to be a strong chemotactic agent for neutrophils.The purpose of this study was to find out if CEA can enhance neutrophil priming and activation.Primed neutrophils were activated by N-formyl-methionyl-leucyl-phenylalanine(formyl-MLP)and the resulting oxidative burst was measured luminometrically.Unexpectedly,in vitro priming of neutrophils by CEA,alone or preceded by LPS,inhibited subsequent activation of these cells by formyl-MLP.CEA may have anti-inflammatory properties in vivo.
文摘Background: AMJ13 is a new breast cancer cell line that has been established from a 70-year-old Iraqi woman with a histological diagnosis of infiltrating ductal carcinoma. It is the first for an Iraqi population. In breast cancer, angiogenesis provides the tumor tissue, which is rapidly proliferated with oxygen and nutrients, removes wastes and increases the opportunity of cancer cells to invade other organs. Methods: The AMJ13 breast cancer cell line was represented at three different passages and incubated for interval times. Microarray panel of 43 different angiogenesis markers was used to scan the supernatant for the factors. ELISA was used to quantify some of the important angiogenesis factors released in the culture medium and to confirm absence of those who was not detected by the antibody array. RT-PCR was used to confirm the gene expression (mRNA) of studied factors. Results: Microarray analysis showed that TIMP1 and two secreted at highest levels compared to the rest of the factors with low presence of endostatin. Other non-detectable factors by microarray examined by ELISA assay that showed highest expression level of VEGF-A were obtained at earliest passage, while the highest levels of FGF-b were obtained at late passage. The VEGF-D secretion was shown low concentrations at all studied passages. There is no detectable level of EGF protein in different passages and times interval tested. There are no significant differences in secretion of sICAM between different passages and incubation periods. Conclusion is that AMJ13 cell line depends on VEGF-A as main angiogenesis factor to induce micro-vessels supported by low levels of VEGF-D for lymphatic vessels formation. AMJ13 cell line depends on FGF as growth factors as in late passages it was shifted to depend mainly on FGF completely. All of this process may be regulated by TGF-β. TIMP-1 has proangiogentic effect and has feedback talk with TIMP-2. Understanding the angiogenesis process for breast cancer can give us better targets for therapy and more effective treatments.
