The effects of analgesics and local anesthetics on gene transcription mediated by NFATc2 and Sp1 in pancreatic carcinoma

Mapping Intimacies ◽

10.21203/rs.2.13243/v1 ◽

2019 ◽

Author(s):

Manuela Malsy ◽

Bernhard Graf ◽

Anika Bundscherer

Keyword(s):

Transcription Factors ◽

Pancreatic Carcinoma ◽

Radiation Treatment ◽

Carcinoma Cells ◽

Surgical Removal ◽

Regulation Of Transcription ◽

Detailed Knowledge ◽

Term Survival ◽

The Impact

Abstract Background Pancreatic adenocarcinoma is one of the most lethal cancers worldwide with very poor long-term survival. The treatment of choice next to chemotherapy or radiation treatment is surgical removal of the tumor. However, medication, surgery, and perioperative immunosuppression induce the constitutive activation of important signaling pathways and change the regulation of transcription factors, which may facilitate tumor progression and metastasis. Recent research has identified the transcription factors NFATc2 and Sp1 as key regulators in the carcinogenesis of pancreatic carcinoma. It is still unclear to what extent the transcription factors NFATc2 and Sp1 are influenced by analgesics given via peridural anesthetics or lidocaine infusions administered in perioperative settings or as postoperative pain therapy.Aims To conduct an in vitro analysis of the impact of clinically achievable dosages of ketamine, s-ketamine, metamizole, and paracetamol as well as of sufentanil, ropicavaine, and lidocaine on pancreatic carcinoma cells in dependency of NFATc2 and Sp1.Methods Analgesic stimulation and its effects on the expression of NFATc2 and Sp1 were investigated with immunoblot. Cell proliferation was measured with the ELISA BrdU assay.Results In PaTu8988t pancreatic carcinoma cells, 48h stimulation with ketamine and s-ketamine significantly inhibited proliferation and contemporaneously decreased endogen expression of NFATc2 in the nucleus. The addition of metamizole and lidocaine to PaTu8988t cells reduced proliferation after 48h.Conclusions New treatment concepts target the efficient modulation of specific signaling and transcription pathways. The extent to which drugs influence these mechanisms in vulnerable phases of pancreatic carcinoma cells needs to be investigated in future studies. The basis of novel therapeutic approaches to any disease is detailed knowledge of the carcinogenesis and profound molecular and biological understanding of the mechanisms.

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The effects of analgesics and local anesthetics on gene transcription mediated by NFATc2 and Sp1 in pancreatic carcinoma

10.21203/rs.2.14445/v1 ◽

2019 ◽

Author(s):

Manuela Malsy ◽

Bernhard Graf ◽

Anika Bundscherer

Keyword(s):

Transcription Factors ◽

Pancreatic Carcinoma ◽

Radiation Treatment ◽

Carcinoma Cells ◽

Surgical Removal ◽

Regulation Of Transcription ◽

Detailed Knowledge ◽

Term Survival ◽

The Impact

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MALIGNANT LYMPHOMA IN CHILDREN

PEDIATRICS ◽

10.1542/peds.28.6.985 ◽

1961 ◽

Vol 28 (6) ◽

pp. 985-992

Author(s):

Richard J. Bailey ◽

E. Omer Burgert ◽

David C. Dahlin

Keyword(s):

Follicular Lymphoma ◽

Malignant Lymphoma ◽

Hodgkin's Disease ◽

Radiation Treatment ◽

Hodgkin’S Disease ◽

Effective Means ◽

Surgical Removal ◽

Term Survival ◽

Localized Disease

On the basis of observations made on 76 children with malignant lymphoma, of whom 28 had Hodgkin's disease (25 with Hodgkin's granuloma and 3 with Hodgkin's sarcoma) and 48 had lymphosarcoma, the following conclusions are drawn: Hodgkin's granuloma has a fairly prolonged course in childhood with a relatively good outlook for 5-year survival, but late recurrences are more common than in the lymphosarcoma group. Lymphosarcoma, excluding giant follicular lymphoma, has a more rapidly malignant course than does Hodgkin's granuloma, but long-term survival does occur in instances of localized disease involving the peripheral nodes on the small intestine. Chemotherapy and radiation therapy provide effective means for controlling Hodgkin's disease and giant follicular lymphoma, even when disease is widespread. Localized disease, when it occurs in malignant lymphoma, requires vigorous radiation treatment. In selected cases, radical surgical removal prior to radiation is indicated. The outlook for these patients is good.

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A marginal anticancer effect of regorafenib on pancreatic carcinoma cells in vitro, ex vivo, and in vivo

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-017-1412-1 ◽

2017 ◽

Vol 390 (11) ◽

pp. 1125-1134 ◽

Cited By ~ 2

Author(s):

Barbara Mayer ◽

Svetlana Karakhanova ◽

Nathalie Bauer ◽

Li Liu ◽

Yifan Zhu ◽

...

Keyword(s):

Pancreatic Carcinoma ◽

Ex Vivo ◽

Carcinoma Cells ◽

Anticancer Effect

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Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Human Pancreatic Adenocarcinomas: Clinicopathologic and Prognostic Significance of Matrilysin Expression

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.4.1118 ◽

2001 ◽

Vol 19 (4) ◽

pp. 1118-1127 ◽

Cited By ~ 109

Author(s):

Hiroyuki Yamamoto ◽

Fumio Itoh ◽

Shouhei Iku ◽

Yasushi Adachi ◽

Hiroshi Fukushima ◽

...

Keyword(s):

Overall Survival ◽

Matrix Metalloproteinases ◽

Pancreatic Carcinoma ◽

Prognostic Significance ◽

Carcinoma Cells ◽

Tissue Inhibitors Of Metalloproteinases ◽

Invasive Front ◽

Clinicopathologic Characteristics ◽

Tissue Inhibitors

PURPOSE: A disruption in the balance between the matrix metalloproteinases (MMPs) and their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), has been implicated in the progression of many types of cancer. The aim of this study was to determine whether a specific MMP or TIMP has clinicopathologic and prognostic significance in pancreatic carcinoma. PATIENTS AND METHODS: Using immunohistochemistry, we analyzed 70 pancreatic ductal adenocarcinoma tissues for expression of MMP-1, MMP-2, MMP-3, MMP-7 (matrilysin), MMP-9, MT1-MMP, TIMP-1, and TIMP-2. The results were matched with clinicopathologic characteristics and patients’ survival. The effects of the suppression of a specific MMP on in vitro invasiveness of pancreatic carcinoma cells were also examined. RESULTS: Expression of MMP-1, MMP-2, MMP-3, matrilysin, MMP-9, MT1-MMP, TIMP-1, and TIMP-2 was detected in either tumor cells or tumor stromal cells, or in both components, at varying frequencies. Among MMPs, matrilysin showed a unique distribution in the tumor nests; its expression was usually most pronounced at the invasive front of the tumors. Sections with immunostaining signals in more than 30% of carcinoma cells at the invasive front, which were observed in 40 cases (57%), were judged to be positive for matrilysin. Matrilysin positivity was significantly correlated with pT, pN, and pM categories and with more advanced pathologic tumor-node-metastasis stages. Patients with matrilysin-positive carcinoma had a significantly shorter overall survival time than did those with matrilysin-negative carcinoma. Matrilysin was a significant independent prognostic factor for overall survival in multivariate analysis. In contrast, there was no correlation between the presence of other MMPs or TIMPs and clinicopathologic characteristics, nor was the presence of individual MMPs or TIMPs related to survival. Antisense matrilysin-transfected CFPAC-1 cells expressed reduced levels of matrilysin and demonstrated a similar growth potential but were less invasive in vitro compared with neotransfected CFPAC-1 cells. CONCLUSION: Our results suggest that matrilysin may play a key role in progression of pancreatic carcinoma and thereby contribute to a poor prognosis. Because different synthetic MMP inhibitors affect different types of MMPs to a different degree, examination of the expression of MMPs, especially that of matrilysin, may serve as an indicator for selecting the most effective MMP inhibitor.

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The ATP-Competitive mTOR Inhibitor INK128 Enhances In Vitro and In Vivo Radiosensitivity of Pancreatic Carcinoma Cells

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-13-2136 ◽

2013 ◽

Vol 20 (1) ◽

pp. 110-119 ◽

Cited By ~ 29

Author(s):

Thomas J. Hayman ◽

Amy Wahba ◽

Barbara H. Rath ◽

Heekyong Bae ◽

Tamalee Kramp ◽

...

Keyword(s):

Pancreatic Carcinoma ◽

Mtor Inhibitor ◽

Carcinoma Cells

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The Impact of Age in Prosthesis-patient Mismatch on Long-term Survival after Aortic Valve Replacement: in-vitro versus in-vivo Values

Journal of Advances in Medical and Pharmaceutical Sciences ◽

10.9734/jamps/2016/28381 ◽

2016 ◽

Vol 9 (4) ◽

pp. 1-8

Author(s):

Alexander Manché ◽

Aaron Casha ◽

Liberato Camilleri

Keyword(s):

Aortic Valve ◽

Aortic Valve Replacement ◽

Valve Replacement ◽

Term Survival ◽

Long Term Survival ◽

The Impact

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New Approaches for Mapping Epigenome Dynamics

Blood ◽

10.1182/blood.v126.23.sci-21.sci-21 ◽

2015 ◽

Vol 126 (23) ◽

pp. SCI-21-SCI-21

Author(s):

Steven Henikoff

Keyword(s):

Transcription Factors ◽

Rna Polymerase Ii ◽

Conflicts Of Interest ◽

Regulation Of Transcription ◽

Base Pairs ◽

Simple Method ◽

Genome Wide ◽

Resolution Mapping

Abstract The protein complexes that package our genomes must be mobilized for active processes to occur, including replication and transcription, but until recently we have only had a static, low resolution view of the "epigenome". Genomes are packaged into nucleosomes, octamers of four core histones wrapped by 147 base pairs of DNA. Nucleosomes present obstacles to transcription, which over genes is the RNA Polymerase II (RNAPII) complex, and one current challenge is to understand what happens to a nucleosome when RNAPII transcribes through the DNA that it occupies. We study this process by developing methods for following nucleosomes as they are evicted and replaced. Among the factors that we have implicated in the process is torsional stress, which we can now measure genome-wide. RNAPII movement can unwrap nucleosomes and thus destabilize them, causing them to be occasionally evicted and replaced. Interestingly, we find that destabilization of nucleosomes during transcription is enhanced by anthracycline compounds, widely used chemotherapeutic drugs that intercalate between DNA base pairs, thus suggesting a new mechanism for cell killing during chemotherapy. We are also interested in what happens to RNAPII during its encounter with a nucleosomes. In vitro, RNAPII cannot transcribe completely through a nucleosome, but rather stalls as it tries to unwrap the DNA from around the core. We have been studying this process in vivo, and have developed a simple method for precisely mapping RNAPII genome-wide. We have used this method to show exactly where RNAPII stalls as it unwraps a nucleosome in vivo, surprisingly in a different place in vivo from where it stalls in vitro. We also have discovered that a variant histone, H2A.Z, which is found in essentially all eukaryotes, helps to reduce the nucleosome barrier to transcription, and in this way may modulate transcription. Other protein components of the epigenome involved in dynamic processes are nucleosome remodelers, which use the energy of ATP to slide or even evict nucleosomes from DNA. Some remodelers help RNAPII get started and others help it overcome the nucleosome barrier to transcription, and by mapping them at base-pair resolution, we can gain insight into how they act. We have also applied our high-resolution mapping tools to transcription factors, which bind DNA at specific sites to regulate transcription and other processes. Our ability to achieve high spatial and temporal resolution mapping of the binding and action of nucleosomes, transcription factors, remodelers and RNAPII provides us with a detailed picture of epigenome dynamics. By using these tools we are beginning to understand how DNA sequence and conformation are recognized for regulation of transcription and other epigenomic processes. Disclosures No relevant conflicts of interest to declare.

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Adverse biological effects of Milan urban PM looking for suitable molecular markers of exposure

Chemical Industry and Chemical Engineering Quarterly ◽

10.2298/ciceq120206114m ◽

2012 ◽

Vol 18 (4-2) ◽

pp. 635-641 ◽

Cited By ~ 5

Author(s):

Paride Mantecca ◽

Maurizio Gualtieri ◽

Eleonora Longhin ◽

Giuseppina Bestetti ◽

Paola Palestini ◽

...

Keyword(s):

Molecular Markers ◽

Chemical Composition ◽

Biological Effects ◽

Detailed Knowledge ◽

Biological Responses ◽

Physico Chemical ◽

Biological Hazard ◽

The Impact

The results presented summarise the ones obtained in the coordinated research project Tosca, which extensively analysed the impact of Milan urban PM on human health. The molecular markers of exposure and effects of seasonally and size-fractionated PMs (summer and winter PM10, PM2.5) were investigated in in vitro (human lung cell lines) and in vivo (mice) systems. The results obtained by the analyses of cytotoxic, pro-inflammatory and genotoxic parameters demonstrate that the biological responses are strongly dependent upon the PM samples seasonal and dimensional variability, that ultimately reflect their chemical composition and source. In fact summer PM10, enriched in crustal elements and endotoxins, was the most cytotoxic and pro-inflammatory fraction, while fine winter PMs induced genotoxic effects and xenobiotic metabolizing enzymes (like CYP1B1) production, likely as a consequence of the higher content in combustion derived particles reach in PAHs and heavy toxic metals. These outcomes outline the need of a detailed knowledge of the PMs physico-chemical composition on a local scale, coupled with the biological hazard directly associated to PM exposure. Apparently this is the only way allowing scientists and police-makers to establish the proper relationships between the respirable PM quantity/quality and the health outcomes described by clinicians and epidemiologists.

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