222 research outputs found
Identification of a Proliferation Gene Cluster Associated with HPV E6/E7 Expression Level and Viral DNA Load in Invasive Cervical Carcinoma
Specific HPV DNA sequences are associated with more than 90% of invasive
carcinomas of the uterine cervix. Viral E6 and E7 oncogenes are key mediators
in cell transformation by disrupting TP53 and RB pathways. To investigate
molecular mechanisms involved in the progression of invasive cervical
carcinoma, we performed a gene expression study on cases selected according to
viral and clinical parameters. Using Coupled Two-Way Clustering and Sorting
Points Into Neighbourhoods methods, we identified a Cervical Cancer
Proliferation Cluster composed of 163 highly correlated transcripts, many of
which corresponded to E2F pathway genes controlling cell proliferation, whereas
no primary TP53 targets were present in this cluster. The average expression
level of the genes of this cluster was higher in tumours with an early relapse
than in tumours with a favourable course (P=0.026). Moreover, we found that
E6/E7 mRNA expression level was positively correlated with the expression level
of the cluster genes and with viral DNA load. These findings suggest that HPV
E6/E7 expression level plays a key role in the progression of invasive
carcinoma of the uterine cervix via the deregulation of cellular genes
controlling tumour cell proliferation. HPV expression level may thus correspond
to a biological marker useful for prognosis assessment and specific therapy of
the disease
Combined microsatellite and FGFR3 mutation analysis enables a highly sensitive detection of urothelial cell carcinoma in voided urine
PURPOSE: Fibroblast growth factor receptor 3 (FGFR3) mutations were
reported recently at a high frequency in low-grade urothelial cell
carcinoma (UCC). We investigated the feasibility of combining
microsatellite analysis (MA) and the FGFR3 status for the detection of UCC
in voided urine. EXPERIMENTAL DESIGN: In a prospective setting, 59 UCC
tissues and matched urine samples were obtained, and subjected to MA (23
markers) and FGFR3 mutation analysis (exons 7, 10, and 15). In each case,
a clinical record with tumor and urine features was provided. Fifteen
patients with a negative cystoscopy during follow-up served as controls.
RESULTS: A mutation in the FGFR3 gene was found in 26 (44%) UCCs of which
22 concerned solitary pTaG1/2 lesions. These mutations were absent in the
15 G3 tumors. For the 6 cases with leukocyturia, 46 microsatellite
alterations were found in the tumor. Only 1 of these was also detected in
the urine. This was 125 of 357 for the 53 cases without leukocyte
contamination. The sensitivity of MA on voided urine was lower for
FGFR3-positive UCC (15 of 21; 71%) as compared with FGFR3 wild-type UCC
(29 of 32; 91%). By including the FGFR3 mutation, the sensitivity of
molecular cytology increased to 89% and was superior to the sensitivity of
morphological cytology (25%) for every clinical subdivision. The
specificity was 14 of 15 (93%) for the two (molecular and morphological)
cytological approaches. CONCLUSIONS: Molecular urine cytology by MA and
FGFR3 mutation analysis enables a highly sensitive and specific detection
of UCC. The similarity of molecular profiles in tumor and urine
corroborate their clonal relation
Low E-cadherin expression in bladder cancer at the transcriptional and protein level provides prognostic information
We studied E-cadherin down-regulation at the protein level in frozen sections of 111 bladder tumours and 13 normal bladder specimens by means of immunohistochemistry, and at the mRNA level by semi-quantitative RT-PCR in 40 of the same tumours. Results indicate that E-cadherin expression detected by immunohistochemistry correlated with both stage and grade (P< 0.0001 and P< 0.001, respectively). Analysis of recurrence, progression and survival over a mean period of 36 months after surgery in the entire cohort showed that abnormal E-cadherin immunoreactivity correlated strongly with poor outcome (log-rank test: P = 0.001, P = 0.0001 and P = 0.0003, respectively). In multistep logistic regression analysis, only E-cadherin status and stage had significant additional prognostic value (P = 0.008 and OR = 0.2;P = 0.03 and OR = 3.6, respectively). Survival estimates derived from RT-PCR transcript quantification differed significantly for low and high expression (log-rank test: P = 0.0006). These results suggest that the alteration occurs at the transcriptional level and support the clinical and biological relevance of cell adhesion molecules in bladder cancer. © 2000 Cancer Research Campaig
Reappraisal of Vipera aspis Venom Neurotoxicity
BACKGROUND: The variation of venom composition with geography is an important aspect of intraspecific variability in the Vipera genus, although causes of this variability remain unclear. The diversity of snake venom is important both for our understanding of venomous snake evolution and for the preparation of relevant antivenoms to treat envenomations. A geographic intraspecific variation in snake venom composition was recently reported for Vipera aspis aspis venom in France. Since 1992, cases of human envenomation after Vipera aspis aspis bites in south-east France involving unexpected neurological signs were regularly reported. The presence of genes encoding PLA(2) neurotoxins in the Vaa snake genome led us to investigate any neurological symptom associated with snake bites in other regions of France and in neighboring countries. In parallel, we used several approaches to characterize the venom PLA(2) composition of the snakes captured in the same areas. [br/]
METHODOLOGY/PRINCIPAL FINDINGS: We conducted an epidemiological survey of snake bites in various regions of France. In parallel, we carried out the analysis of the genes and the transcripts encoding venom PLA(2)s. We used SELDI technology to study the diversity of PLA(2) in various venom samples. Neurological signs (mainly cranial nerve disturbances) were reported after snake bites in three regions of France: Languedoc-Roussillon, Midi-Pyrénées and Provence-Alpes-Côte d'Azur. Genomes of Vipera aspis snakes from south-east France were shown to contain ammodytoxin isoforms never described in the genome of Vipera aspis from other French regions. Surprisingly, transcripts encoding venom neurotoxic PLA(2)s were found in snakes of Massif Central region. Accordingly, SELDI analysis of PLA(2) venom composition confirmed the existence of population of neurotoxic Vipera aspis snakes in the west part of the Massif Central mountains. [br/]
CONCLUSIONS/SIGNIFICANCE: The association of epidemiological studies to genetic, biochemical and immunochemical analyses of snake venoms allowed a good evaluation of the potential neurotoxicity of snake bites. A correlation was found between the expression of neurological symptoms in humans and the intensity of the cross-reaction of venoms with anti-ammodytoxin antibodies, which is correlated with the level of neurotoxin (vaspin and/or ammodytoxin) expression in the venom. The origin of the two recently identified neurotoxic snake populations is discussed according to venom PLA(2) genome and transcriptome data
Toward a comprehensive view of cancer immune responsiveness: A synopsis from the SITC workshop
Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host's response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14-15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual's recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4-5, 2019
Design of Group IIA Secreted/Synovial Phospholipase A2 Inhibitors: An Oxadiazolone Derivative Suppresses Chondrocyte Prostaglandin E2 Secretion
Group IIA secreted/synovial phospholipase A2 (GIIAPLA2) is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E2 (PGE2), the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-yl)pentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA2 enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA2, along with their chemical synthesis and results from PLA2 inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA2 affinities than did C1, and such predictions were confirmed by in vitro PLA2 enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA2 inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1β-stimulated PGE2 secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio. C8 is therefore a potential candidate for anti-inflammatory therapy in joints
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