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3.
J Mycol Med ; 30(4): 101046, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33067115
4.
Ann Hematol ; 99(8): 1741-1747, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32399706

ABSTRACT

To describe and compare the characteristics of necrotizing fasciitis (NF) in patients with and without haematological malignancy. All adult patients diagnosed with NF and treated at our hospital were included (January 2010-March 2019). Diagnosis was based on intraoperative findings or consistent clinical/radiological characteristics, and patients were classified as group A (with haematological malignancy) or group B (without haematological malignancy). Student's t (quantitative), Fisher's exact (qualitative), and Kaplan-Meyer tests were used for the statistical analysis. The study included 29 patients: 8 in group A and 21 in group B. All haematological patients had severe neutropenia (0.2 [0.02-0.5] ×109 cells/L; p < 0.001) and positive blood cultures (100% vs. 61.9%; p = 0.04) at diagnosis. Gram-negative bacilli NF was more common in group A (87.5% vs. 9.5%; p = 0.001), predominantly due to Escherichia coli (50% vs. 9.5%; p = 0.056). Surgical treatment was less common in haematological patients (5 [62.5%] vs. 21 [100%]; p = 0.015). Overall, 9 (31%) patients died: 4 (50%) in group A and 5 (23.8%) in group B (p = 0.17). The univariate analysis showed that mortality tended to be higher (OR 3.2; 95%CI 0.57-17.7; p = 0.17) and to occur earlier (2.2 ± 2.6 vs. 14.2 ± 19.9 days; p = 0.13) in haematological patients. The LRINEC index > 6 did not predict mortality in either group. In our study, NF in patients with haematological malignancies was mainly due to Gram-negative bacilli, associated to high and early mortality rates. In our experience, the LRINEC scale was not useful for predicting mortality.


Subject(s)
Escherichia coli Infections/mortality , Escherichia coli , Fasciitis, Necrotizing/mortality , Hematologic Neoplasms/mortality , Neutropenia , Adult , Aged , Disease-Free Survival , Escherichia coli Infections/therapy , Fasciitis, Necrotizing/microbiology , Fasciitis, Necrotizing/therapy , Female , Hematologic Neoplasms/microbiology , Hematologic Neoplasms/therapy , Humans , Male , Middle Aged , Neutropenia/microbiology , Neutropenia/therapy , Retrospective Studies , Spain/epidemiology , Survival Rate
5.
Neumol. pediátr. (En línea) ; 15(4): 484-490, 2020. tab, ilus
Article in Spanish | LILACS | ID: biblio-1146395

ABSTRACT

Cystic Fibrosis is a multisystemic inherited disease that requires ongoing care by multidisciplinary teams. The objective of this study is to describe changes on nutrition and lung function in a cohort of patients in a Cystic Fibrosis (CF) Care Center at the Hospital Infantil Universitario San José in Bogotá (HIUSJ), between 2010 and 2013.Is a descriptive study in a cohort of CF patients during four years of follow-up. The quantitative variables were described using medians and interquartile ranges, and the qualitative variables with absolute frequencies and percentages. Descriptive statistics was used to summarize the findings. Of the 63 patients in the initial group, 47 (74.6%) completed the follow-up time. The age range was between 3 to 30 years. The median BMI increased as follows: 17.9 (RIQ: 12.5-25.6) in 2010, 18.6 (RIQ: 12.9-24.8) in 2011, 18.9 RIQ (13.6-26.5) in 2012 and 19.0 (RIQ: 13.5-25.8) in 2013, with lower values in men. The forced expiratory volume in the first second (FEV1) at admission was classified as severe (FEV1 <40%) in 7.1%, moderate (FEV1 40-69%) in 35.7%, mild (FEV1 70-79%) in 7.1% and as normal (FEV1> 80%) in 50%. It is concluded that during the 4 years of follow-up at the HIUSJ CF Center there is an improvement in BMI and a deterioration in lung function in the whole group. The importance of establishing more reference centers to improve clinical outcomes and of implement a National registry to follow up over time are highlighted.


La fibrosis quística es una enfermedad hereditaria, multisistémica, cuyo manejo continuo requiere de equipos multidisciplinarios de salud. El objetivo de este trabajo es describir la evolución nutricional y de la función pulmonar en una cohorte de pacientes en el centro de atención integral de la fibrosis quística (FQ), del Hospital Infantil Universitario San José de Bogotá (HIUSJB), entre 2010 y 2013. Estudio descriptivo, en una cohorte de pacientes, en seguimiento durante cuatro años. Las variables cuantitativas fueron descritas mediante medianas y rangos intercuartílicos y las cualitativas con frecuencias absolutas y porcentajes. De los 63 pacientes del grupo inicial, 47 (74.6%), completaron el tiempo de seguimiento. El rango de edad fue de 3 a 30 años. La mediana del IMC (índice de masa corporal) se incrementó así: 17.9 (RIQ:12.5-25.6) en el 2010, 18.6 (RIQ:12.9-24.8) en el 2011, 18.9 ( RIQ(13.6-26.5) en el 2012 y 19.0 (RIQ:13.5-25.8) en el 2013, con menores valores en los hombres. El volumen espiratorio forzado en el primer segundo (VEF1) al ingreso fue clasificado como severo (VEF1<40%) en el 7.1%, moderado (VEF1 40-69%) en el 35.7%, leve (VEF1 70-79%) en el 7.1% y como normal (VEF1>80%) en el 50%. Se concluye que durante los 4 años de seguimiento en el programa de FQ del HIUSJ, ocurre una mejoría del IMC en todo el grupo y un deterioro de la función pulmonar. Se resalta la importancia de constituir más centros de referencia para mejorar los desenlaces clínicos e implementar un registro Nacional para hacer seguimiento a través del tiempo.


Subject(s)
Humans , Male , Female , Child, Preschool , Child , Adolescent , Adult , Young Adult , Respiratory Function Tests , Nutritional Status , Delivery of Health Care, Integrated , Cystic Fibrosis/physiopathology , Pseudomonas aeruginosa/isolation & purification , Staphylococcus aureus/isolation & purification , Body Mass Index , Clinical Evolution , Forced Expiratory Volume , Epidemiology, Descriptive , Cohort Studies , Follow-Up Studies , Cystic Fibrosis/microbiology , Hospitalization/statistics & numerical data
7.
Intern Med J ; 45(5): 482-91, 2015 May.
Article in English | MEDLINE | ID: mdl-25955461

ABSTRACT

Identifying individuals with a genetic predisposition to developing familial colorectal cancer (CRC) is crucial to the management of the affected individual and their family. In order to do so, the physician requires an understanding of the different gene mutations and clinical manifestations of familial CRC. This review summarises the genetics, clinical manifestations and management of the known familial CRC syndromes, specifically Lynch syndrome, familial adenomatous polyposis, MUTYH-associated neoplasia, juvenile polyposis syndrome and Peutz-Jeghers syndrome. An individual suspected of having a familial CRC with an underlying genetic predisposition should be referred to a familial cancer centre to enable pre-test counselling and appropriate follow up.


Subject(s)
Adenomatous Polyposis Coli/epidemiology , Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology , Colorectal Neoplasms/epidemiology , Genetic Predisposition to Disease/epidemiology , Intestinal Polyposis/congenital , Neoplastic Syndromes, Hereditary/epidemiology , Peutz-Jeghers Syndrome/epidemiology , Adenomatous Polyposis Coli/diagnosis , Adenomatous Polyposis Coli/genetics , Australia/epidemiology , Chemoprevention/methods , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Female , Genetic Counseling , Genetic Testing , Humans , Intestinal Polyposis/diagnosis , Intestinal Polyposis/epidemiology , Intestinal Polyposis/genetics , Male , Mutation/genetics , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/genetics , New Zealand/epidemiology , Peutz-Jeghers Syndrome/diagnosis , Peutz-Jeghers Syndrome/genetics , Prevalence
8.
Cancer Gene Ther ; 22(4): 207-14, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25721206

ABSTRACT

Many of the cancer cell lines derived from solid tumors are difficult to transfect using commonly established transfection approaches. This hurdle for some DNA transfection systems has hindered cancer biology studies. Moreover, there are limited tools for studying pathway activities. Therefore, highly efficient improved gene transfer and versatile genetic tools are required. In this study, we established and developed a comprehensive set of new lentiviral tools to study gene functions and pathway activities. Using the optimized conditions, cancer cell lines achieved >90% transduction efficiency. Novel lentiviral doxycycline-regulated pTet-IRES-EGFP (pTIE) systems for transgene expression and TRE reporters used for pathway activity determination were developed and tested. The pTIE Tet-Off system showed in vitro doxycycline-sensitive responses with low or undetectable leakage of protein expression and in vivo tumor suppression as illustrated using candidate tumor suppressors, Fibulin-2 and THY1. In contrast, the Tet-On system showed dose-dependent responses. The pTRE-EGFP (pTE) and pTRE-FLuc-EF1α-RLuc (pT-FER) reporters with the NFκB p65 subunit consensus sequence showed GFP and firefly luciferase responses, which were directly correlated with TNFα stimulation, respectively. Taken together, these newly developed lentiviral systems provide versatile in vitro and in vivo platforms to strengthen our capabilities for cancer biology studies.


Subject(s)
Genetic Therapy , Lentivirus/genetics , Neoplasms/therapy , Transcriptional Activation , Animals , COS Cells , Carcinogenesis/pathology , Cell Line, Tumor , Chlorocebus aethiops , Female , Gene Expression , Genes, Reporter , Genetic Vectors , HEK293 Cells , Humans , Luciferases, Renilla/biosynthesis , Luciferases, Renilla/genetics , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Neoplasms/pathology , Plasmids/genetics , Promoter Regions, Genetic , Transduction, Genetic , Transgenes
9.
Oncogene ; 34(32): 4219-28, 2015 Aug 06.
Article in English | MEDLINE | ID: mdl-25347745

ABSTRACT

Zinc-finger, MYND-type containing 10 (ZMYND10), or more commonly called BLU, expression is frequently downregulated in nasopharyngeal carcinoma (NPC) and many other tumors due to promoter hypermethylation. Functional evidence shows that the BLU gene inhibits tumor growth in animal assays, but the detailed molecular mechanism responsible for this is still not well understood. In current studies, we find that 93.5% of early-stage primary NPC tumors show downregulated BLU expression. Using a PCR array, overexpression of the BLU gene was correlated to the angiogenesis network in NPC cells. Moreover, expression changes of the MMP family, VEGF and TSP1, were often detected in different stages of NPC, suggesting the possibility that BLU may be directly involved in the microenvironment and anti-angiogenic activity in NPC development. Compared with vector-alone control cells, BLU stable transfectants, derived from poorly-differentiated NPC HONE1 cells, suppress VEGF165, VEGF189 and TSP1 expression at both the RNA and protein levels, and significantly reduce the secreted VEGF protein in these cells, reflecting an unknown regulatory mechanism mediated by the BLU gene in NPC. Cells expressing BLU inhibited cellular invasion, migration and tube formation. These in vitro results were further confirmed by in vivo tumor suppression and a matrigel plug angiogenesis assay in nude mice. Tube-forming ability was clearly inhibited, when the BLU gene is expressed in these cells. Up to 70-90% of injected tumor cells expressing increased exogenous BLU underwent cell death in animal assays. Overexpressed BLU only inhibited VEGF165 expression in differentiated squamous NPC HK1 cells, but also showed an anti-angiogenic effect in the animal assay, revealing a complicated mechanism regulating angiogenesis and the microenvironment in different NPC cell lines. Results of these studies indicate that alteration of BLU gene expression influences anti-angiogenesis pathways and is important for the development of NPC.


Subject(s)
Chromosomes, Human, Pair 3/genetics , Nasopharyngeal Neoplasms/genetics , Neovascularization, Pathologic/genetics , Signal Transduction/genetics , Tumor Suppressor Proteins/genetics , Animals , Blotting, Western , Carcinoma , Cell Line, Tumor , Cell Movement/genetics , Cells, Cultured , Chromosome Mapping , Cytoskeletal Proteins , Down-Regulation , Female , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Male , Matrix Metalloproteinases/genetics , Matrix Metalloproteinases/metabolism , Mice, Nude , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , Reverse Transcriptase Polymerase Chain Reaction , Thrombospondin 1/genetics , Thrombospondin 1/metabolism , Transplantation, Heterologous , Tumor Microenvironment/genetics , Tumor Suppressor Proteins/metabolism , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
10.
Oncogene ; 34(7): 878-89, 2015 Feb 12.
Article in English | MEDLINE | ID: mdl-24608426

ABSTRACT

Nasopharyngeal carcinoma (NPC) is a cancer that occurs in high frequency in Southern China. A previous functional complementation approach and the subsequent cDNA microarray analysis have identified that serum amyloid A1 (SAA1) is an NPC candidate tumor suppressor gene. SAA1 belongs to a family of acute-phase proteins that are encoded by five polymorphic coding alleles. The SAA1 genotyping results showed that only three SAA1 isoforms (SAA1.1, 1.3 and 1.5) were observed in both Hong Kong NPC patients and healthy individuals. This study aims to determine the functional role of SAA1 polymorphisms in tumor progression and to investigate the relationship between SAA1 polymorphisms and NPC risk. Indeed, we have shown that restoration of SAA1.1 and 1.3 in the SAA1-deficient NPC cell lines could suppress tumor formation and angiogenesis in vitro and in vivo. The secreted SAA1.1 and SAA1.3 proteins can block cell adhesion and induce apoptosis in the vascular endothelial cells. In contrast, the SAA1.5 cannot induce apoptosis or inhibit angiogenesis because of its weaker binding affinity to αVß3 integrin. This can explain why SAA1.5 has no tumor-suppressive effects. Furthermore, the NPC tumors with this particular SAA1.5/1.5 genotype showed higher levels of SAA1 gene expression, and SAA1.1 and 1.3 alleles were preferentially inactivated in tumor tissues that were examined. These findings further strengthen the conclusion for the defective function of SAA1.5 in suppression of tumor formation and angiogenesis. Interestingly, the frequency of the SAA1.5/1.5 genotype in NPC patients was ~2-fold higher than in the healthy individuals (P=0.00128, odds ratio=2.28), which indicates that this SAA1 genotype is significantly associated with a higher NPC risk. Collectively, this homozygous SAA1.5/1.5 genotype appears to be a recessive susceptibility gene, which has lost the antiangiogenic function, whereas SAA1.1 and SAA1.3 are the dominant alleles of the tumor suppressor phenotype.


Subject(s)
Gene Expression Regulation, Neoplastic , Genetic Predisposition to Disease , Nasopharyngeal Neoplasms , Neovascularization, Pathologic , Polymorphism, Genetic , Serum Amyloid A Protein , Tumor Suppressor Proteins , Alleles , Apoptosis , Carcinoma , Cell Adhesion , Cell Line, Tumor , Coculture Techniques , Endothelial Cells , Humans , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology , Serum Amyloid A Protein/biosynthesis , Serum Amyloid A Protein/genetics , Tumor Suppressor Proteins/biosynthesis , Tumor Suppressor Proteins/genetics
11.
Am J Physiol Heart Circ Physiol ; 303(7): H910-7, 2012 Oct 01.
Article in English | MEDLINE | ID: mdl-22886412

ABSTRACT

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neuropeptide that plays an important role in hypertension and stress responses. PACAP acts at three G protein-coupled receptors [PACAP type 1 receptor (PAC(1)) and vasoactive intestinal peptide receptor types 1 and 2 (VPAC(1) and VPAC(2))] and is localized to sites involved in cardiovascular control, most significantly the rostral ventrolateral medulla (RVLM). The RVLM is crucial for the tonic and reflex control of efferent sympathetic activity. Increases in sympathetic activity are observed in most types of hypertension and heart failure. PACAP delivered intrathecally also causes massive sympathoexcitation. We aimed to determine the presence and abundance of the three PACAP receptors in the RVLM, the role, in vivo, of PACAP in the RVLM on tonic and reflex cardiovascular control, and the contribution of PACAP to hypertension in the spontaneously hypertensive rat (SHR). Data were obtained using quantitative PCR and microinjection of PACAP and its antagonist, PACAP(6-38), into the RVLM of anesthetized artificially ventilated normotensive rats or SHRs. All three receptors were present in the RVLM. PACAP microinjection into the RVLM caused sustained sympathoexcitation and tachycardia with a transient hypertension but did not affect homeostatic reflexes. The responses were partially mediated through PAC(1)/VPAC(2) receptors since the effect of PACAP was attenuated (∼50%) by PACAP(6-38). PACAP was not tonically active in the RVLM in this preparation because PACAP(6-38) on its own had no inhibitory effect. PACAP has long-lasting cardiovascular effects, but altered PACAP signaling within the RVLM is not a cause of hypertension in the SHR.


Subject(s)
Blood Pressure , Hypertension/metabolism , Medulla Oblongata/metabolism , Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Receptors, Vasoactive Intestinal Peptide, Type II/metabolism , Sympathetic Nervous System/physiopathology , Animals , Blood Pressure/drug effects , Disease Models, Animal , Heart Rate , Hypertension/genetics , Hypertension/physiopathology , Male , Medulla Oblongata/drug effects , Microinjections , Peptide Fragments/administration & dosage , Pituitary Adenylate Cyclase-Activating Polypeptide/administration & dosage , Pituitary Adenylate Cyclase-Activating Polypeptide/antagonists & inhibitors , RNA, Messenger/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , Receptors, Vasoactive Intestinal Peptide, Type II/genetics , Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism , Reflex , Sympathetic Nervous System/drug effects , Time Factors
12.
Oncogene ; 31(6): 728-38, 2012 Feb 09.
Article in English | MEDLINE | ID: mdl-21743496

ABSTRACT

Fibulin-2 (FBLN2) has been identified as a candidate tumor-suppressor gene in nasopharyngeal carcinoma (NPC). Originally identified through a chromosome 3 NotI genomic microarray screen, it shows frequent deletion or methylation in NPC. FBLN2 is located on chromosome 3p25.1 and is associated with tumor development through its important interactions with the extracellular matrix (ECM) proteins. FBLN2 encodes two isoforms. The short isoform (FBLN2S) is expressed abundantly in normal tissues, but is dramatically downregulated in NPC, while the long isoform (FBLN2L) is either not detectable or is expressed only at low levels in both normal and tumor tissues. Reintroduction of this FBLN2S inhibited cell proliferation, migration, invasion and angiogenesis in vitro. Furthermore, in vivo studies in nude mice show its expression is associated with tumor and angiogenesis suppression. FBLN2-associated angiogenesis occurs via concomitant downregulation of vascular endothelial growth factor and matrix metalloproteinase 2. This study provides compelling evidence that FBLN2S has an important tumor-suppressive and anti-angiogenic role in NPC.


Subject(s)
Calcium-Binding Proteins/metabolism , Extracellular Matrix Proteins/metabolism , Nasopharyngeal Neoplasms/metabolism , Neovascularization, Pathologic/metabolism , Tumor Suppressor Proteins/metabolism , Animals , Base Sequence , Blotting, Western , Calcium-Binding Proteins/genetics , Carcinoma , Cell Line , Cell Line, Tumor , Cell Movement , Cell Proliferation , DNA Methylation , Extracellular Matrix Proteins/genetics , Gene Expression Regulation, Neoplastic , Humans , Matrix Metalloproteinase 2/genetics , Matrix Metalloproteinase 2/metabolism , Mice , Mice, Nude , Molecular Sequence Data , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/pathology , Neoplasm Invasiveness , Neovascularization, Pathologic/genetics , Protein Isoforms/genetics , Protein Isoforms/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transplantation, Heterologous , Tumor Burden , Tumor Suppressor Proteins/genetics , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
13.
Oncogene ; 31(32): 3709-20, 2012 Aug 09.
Article in English | MEDLINE | ID: mdl-22158051

ABSTRACT

Alpha B-crystallin (CRYAB) maps within the nasopharyngeal carcinoma (NPC) tumor-suppressive critical region 11q22-23 and its downregulation is significantly associated with the progression of NPC. However, little is known about the functional impact of CRYAB on NPC progression. In this study we evaluated the NPC tumor-suppressive and progression-associated functions of CRYAB. Activation of CRYAB suppressed NPC tumor formation in nude mice. Overexpression of CRYAB affected NPC progression-associated phenotypes such as loss of cell adhesion, invasion, interaction with the tumor microenvironment, invasive protrusion formation in three dimensional Matrigel culture, as well as expression of epithelial-mesenchymal transition-associated markers. CRYAB mediates this ability to suppress cancer progression by inhibition of E-cadherin cytoplasmic internalization and maintenance of ß-catenin in the membrane that subsequently reduces the levels of expression of critical downstream targets such as cyclin-D1 and c-myc. Both ectopically expressed and recombinant CRYAB proteins were associated with endogenous E-cadherin and ß-catenin, and, thus, the cadherin/catenin adherens junction. The CRYAB α-crystallin core domain is responsible for the interaction of CRYAB with both E-cadherin and ß-catenin. Taken together, these results indicate that CRYAB functions to suppress NPC progression by associating with the cadherin/catenin adherens junction and modulating the ß-catenin function.


Subject(s)
Adherens Junctions/metabolism , Cadherins/metabolism , Carcinoma/metabolism , Nasopharyngeal Neoplasms/metabolism , Tumor Suppressor Proteins/metabolism , alpha-Crystallin B Chain/metabolism , beta Catenin/metabolism , Animals , Carcinoma/pathology , Cell Adhesion , Cell Line, Tumor , Cell Movement , Disease Progression , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/pathology , Neoplasm Invasiveness , Neoplasm Transplantation , Protein Transport , Tumor Burden
14.
Neuroscience ; 199: 429-37, 2011 Dec 29.
Article in English | MEDLINE | ID: mdl-22056601

ABSTRACT

Migraine headaches are more prevalent in women and often occur during the early phases of the menstrual cycle, implying a link between migraine and ovarian steroids. Serotonin (5-HT) and its receptors have been proposed to play a key role in the pathophysiology of migraine. The trigeminal ganglion (TG) has been proposed as a site for 5-HT synthesis based on the expression of the rate limiting enzyme in peripheral 5-HT synthesis, tryptophan hydroxylase 1 (TPH1), in female rodent trigeminal ganglia. Tryptophan hydroxylase levels vary over the estrus cycle, however, the expression and potential regulation of other enzymes involved in 5-HT synthesis has not been reported in this tissue. C57/BL6 mice of both sexes expressed TPH1 and aromatic amino acid decarboxylase (AADC), the key enzymes involved in 5-HT synthesis. Levels of both enzymes were significantly higher in juvenile males compared with females. In naturally cycling females TPH1 and AADC expression was highest during proestrus when compared with the other phases of the cycle, and this regulation was mirrored at the mRNA level. In situ hybridization experiments detected TPH1 and AADC mRNA in presumptive neurons in the trigeminal ganglion. Both key enzymes involved in the synthesis of 5-HT are expressed in mouse trigeminal ganglion and are localized to neurons. The levels of these enzymes are dependent on gender and estrus cycle stage, suggesting that ovarian steroids might play a role in the regulation of sensory neuron 5-HT synthesis.


Subject(s)
Aromatic-L-Amino-Acid Decarboxylases/biosynthesis , Serotonin/biosynthesis , Trigeminal Ganglion/enzymology , Tryptophan Hydroxylase/biosynthesis , Animals , Aromatic-L-Amino-Acid Decarboxylases/analysis , Blotting, Western , Estrous Cycle/physiology , Female , Gene Expression Profiling , In Situ Hybridization , Male , Mice , Mice, Inbred C57BL , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Sex Characteristics , Tryptophan Hydroxylase/analysis
15.
Br J Cancer ; 104(5): 841-9, 2011 Mar 01.
Article in English | MEDLINE | ID: mdl-21326238

ABSTRACT

BACKGROUND: Oesophageal squamous cell carcinoma (SCC) causes the highest number of cancer deaths in some regions of Northern China. Previously, we narrowed down a critical region at 9q33-34, identified to be associated with tumour-suppressive function of deleted in oesophageal cancer 1 (DEC1) in oesophageal SCC. METHODS: We generated DEC1 antibody and constructed tissue microarrays (TMAs) utilising tissue specimens from Henan, a high-risk region for oesophageal SCC, to investigate the importance of DEC1 expression in this cancer. RESULTS: Tissue microarray immunohistochemical staining reveals significant loss of DEC1 from hyperplasia, to tumour, and to lymph node metastasis. In addition, the loss of DEC1 in tumour is age-dependent. Interestingly, there is significant abrogation of DEC1 expression in patients with a family history of oesophageal SCC. Deleted in oesophageal cancer 1 localises to both the cytoplasm and nucleus. The vesicular pattern of DEC1 in the cytoplasm appears to localise at the Golgi and Golgi-endoplasmic reticulum intermediate compartment. CONCLUSION: This is the first TMA study to suggest a clinical association of DEC1 in lymph node metastatic oesophageal SCC, early onset oesophageal SCC and familial oesophageal SCC development. Subcellular localisation of DEC1 and its expression in oesophageal SCC tissues provide important insight for further deciphering the molecular mechanism of DEC1 in oesophageal SCC development.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Esophageal Neoplasms/metabolism , Family Health , Lymphatic Metastasis , Tumor Suppressor Proteins/metabolism , Adult , Aged , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cytoplasm/metabolism , Disease Progression , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Female , Humans , Immunohistochemistry , Male , Middle Aged , Tissue Array Analysis
16.
Phys Rev E Stat Nonlin Soft Matter Phys ; 82(2 Pt 1): 021601, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20866820

ABSTRACT

We study the spontaneous formation of quantum dots in the form of three-dimensional (3D) islands on facetted surfaces in heteroepitaxy. Island development from fast kinetic Monte Carlo (KMC) simulations at low deposition rates is found to follow a layer-by-layer nucleation pathway characterized by energetics driven continuous lateral expansion interrupted by a sequence of independent two-dimensional (2D) upper-layer nucleation events. The process involves only unstable 2D upper-layer nuclei but no unstable 3D nucleus. We have calculated analytically the elastic strain energy of an island in the form of an axisymmetric stepped mound using a small-slope approximation. The total free energy of a system with a 3D island and an adatom bath is obtained. Our theory explains island formation via a free energy driven layer-by-layer nucleation mechanism. Upper-layer nucleation energy barrier, nucleation time, critical radius, and island step spacings are estimated. The relevance of entropic step-step repulsion is discussed. Our theory satisfactorily explains the 3D KMC simulations and may describe the initial evolution of islands in the form of stepped mounds observed in experiments.

17.
Cell Biochem Funct ; 28(3): 239-48, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20373469

ABSTRACT

Photodynamic therapy (PDT) with a recently developed photosensitizer Zn-BC-AM was found to effectively induce apoptosis in a well-differentiated nasopharyngeal carcinoma (NPC) HK-1 cell line. Sustained activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK) as well as a transient increase in activation of extracellular signal-regulated kinase (ERK) were observed immediately after Zn-BC-AM PDT. A commonly used p38 MAPK/JNK pharmacological inhibitor PD169316 was found to reduce PDT-induced apoptosis of HK-1 cells. PD169316 also prevented the loss of Bcl-2 and Bcl-xL in PDT-treated HK-1 cells. However, inhibition of JNK with SP600125 had no effect on Zn-BC-AM PDT-induced apoptosis while inhibition of ERK with PD98059 or p38 MAPK with SB203580 significantly increased Zn-BC-AM PDT-induced apoptosis. Further study showed that knockdown of the p38beta isoform with siRNA also increased Zn-BC-AM PDT-induced apoptosis, indicating that the anti-apoptotic effect of PD169316 in PDT-treated HK-1 cells was probably independent of p38 MAPK or JNK activation. Taken together, the results suggest that inhibition of p38beta and ERK may enhance the therapeutic efficacy of Zn-BC-AM PDT on NPC cells. It should be noted that data only based on the use of PD169316 should be interpreted in caution.


Subject(s)
Apoptosis/drug effects , JNK Mitogen-Activated Protein Kinases/metabolism , Metalloporphyrins/pharmacology , Nasopharyngeal Neoplasms , Photochemotherapy/methods , Photosensitizing Agents/pharmacology , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Cell Line, Tumor , Enzyme Activation , Enzyme Inhibitors/metabolism , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , JNK Mitogen-Activated Protein Kinases/genetics , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/enzymology , Nasopharyngeal Neoplasms/pathology , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , p38 Mitogen-Activated Protein Kinases/genetics
18.
Biochem Pharmacol ; 79(6): 825-41, 2010 Mar 15.
Article in English | MEDLINE | ID: mdl-19883629

ABSTRACT

2-Methoxyestradiol (2ME2) is a normal physiological metabolite of 17beta-estradiol with anti-proliferative and anti-angiogenic activities. The purpose of this study is to elucidate the mechanism whereby 2ME2 induces endoreduplication of the well-differentiated nasopharyngeal carcinoma (NPC) cells. We report here that 2ME2 induces G2/M phase cell cycle arrest followed by endoreduplication of the well-differentiated HK-1 cells. The increase in chromosome number was confirmed by cytogenetic study. Analysis of stress signaling pathways revealed the phosphorylation activation of ERK, JNK and p38 MAPKs at various times after 2ME2 treatment. Pre-treatment of 2ME2-treated HK-1 cells with JNK inhibitor (SP600125), ERK inhibitor (PD98059) and p38 MAPK inhibitor (SB203580) resulted in the reduction of endoreduplicating cells. Furthermore, the increase in the phosphorylation of JNK was accompanied by an increase in the reactive oxygen species. In addition, endoreduplication was observed in cells after treatment with superoxide donor, 2,3-dimethoxy-1,4-naphoquinone (DMNQ). Confocal microscopic analysis also revealed the increase in mitochondrial superoxide anion in 2ME2-treated HK-1 cells. Pre-treatment of HK-1 cells with superoxide dismutase mimetic 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) or overexpressing the mitochondrial enzyme MnSOD resulted in the reduction of phosphorylation of JNK and the formation of endoreduplicating cells. Furthermore, the tubulin filaments in cytoplasm remain intact in 2ME2-treated HK-1 cells after pre-treatment of TEMPO. Our results suggest that 2ME2 induces endoreduplication through the induction of oxidative stress and the activation of MAPK signal pathways. The biological significance of drug-induced endoreduplication will also be discussed.


Subject(s)
Estradiol/analogs & derivatives , MAP Kinase Signaling System/drug effects , Mitochondria/drug effects , Oxidative Stress/drug effects , Tubulin Modulators/pharmacology , 2-Methoxyestradiol , Cell Line , Cell Proliferation , Dose-Response Relationship, Drug , Enzyme Activation , Estradiol/pharmacology , Humans , Mitochondria/metabolism
19.
Lett Appl Microbiol ; 50(2): 198-204, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20002574

ABSTRACT

AIMS: To study the optimization of submerged culture conditions for exopolysaccharide (EPS) production by Armillaria mellea in shake-flask cultures and also to evaluate the performance of an optimized culture medium in a 5-l stirred tank fermenter. METHODS AND RESULTS: Shake flask cultures for EPS optimal nutritional production contained having the following composition (in g l(-1)): glucose 40, yeast extract 3, KH(2)PO(4) 4 and MgSO(4) 2 at an optimal temperature of 22 degrees C and an initial of pH 4.0. The optimal culture medium was then cultivated in a 5-l stirred tank fermenter at 1 vvm (volume of aeration per volume of bioreactor per min) aeration rate, 150 rev min(-1) agitation speed, controlled pH 4.0 and 22 degrees C. In the optimal culture medium, the maximum EPS production in a 5-l stirred tank fermenter was 588 mg l(-1), c. twice as great as that in the basal medium. The maximum productivity for EPS (Q(p)) and product yield (Y(P/S)) were 42.02 mg l(-1) d(-1) and 26.89 mg g(-1), respectively. CONCLUSIONS: The optimal culture conditions we proposed in this study enhanced the EPS production of A. mellea from submerged cultures. SIGNIFICANCE AND IMPACT OF THE STUDY: The optimal culturing conditions we have found will be a suitable starting point for a scale-up of the fermentation process, helping to develop the production of related medicines and health foods from A. mellea.


Subject(s)
Armillaria/growth & development , Armillaria/metabolism , Bioreactors , Polysaccharides/biosynthesis , Polysaccharides/chemistry , Polysaccharides/isolation & purification
20.
Oncogene ; 27(39): 5267-76, 2008 Sep 04.
Article in English | MEDLINE | ID: mdl-18469857

ABSTRACT

16q24 is frequently deleted in multiple tumors including cancers of nasopharynx, esophagus, breast, prostate and liver. By array comparative genomic hybridization (aCGH), we refined a 16q24 hemizygous deletion in nasopharyngeal carcinoma (NPC) cell lines. Semi-quantitative RT-PCR analysis revealed interferon regulatory factor 8 (IRF8) as the only downregulated gene within this deletion. IRF8 belongs to a family of interferon (IFN) regulatory factors that modulate various important physiologic processes including host defense, cell growth and differentiation and immune regulation. In contrast to the broad expression of IRF8 in normal adult and fetal tissues, transcriptional silencing and promoter methylation of IRF8 were frequently detected in multiple carcinoma (except for hepatocellular) cell lines (100% in NPC, 88% in esophageal and 18-78% in other carcinoma cell lines) and in a large collection of primary carcinomas (78% in NPC, 36-71% in other carcinomas). Methylation of the IRF8 promoter led to the disruption of its response to IFN-gamma stimulation. Pharmacological and genetic demethylation could restore IRF8 expression, indicating a direct epigenetic mechanism. Ectopic expression of IRF8 in tumor cells lacking its expression strongly inhibited their clonogenicity, confirming its tumor suppressor function. Thus, IRF8 was identified as a functional tumor suppressor, which is frequently silenced by epigenetic mechanism in multiple carcinomas.


Subject(s)
Epigenesis, Genetic , Esophageal Neoplasms/genetics , Gene Silencing , Interferon Regulatory Factors/genetics , Interferon-gamma/physiology , Nasopharyngeal Neoplasms/genetics , Cell Line, Tumor , DNA Methylation , Down-Regulation , Humans , Promoter Regions, Genetic , Reverse Transcriptase Polymerase Chain Reaction
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