92 research outputs found
Patient perspectives in the management of asthma: improving patient outcomes through critical selection of treatment options
Asthma is a chronic inflammatory disorder of the airways that requires long-term treatment, the goal of which is to control clinical symptoms for extended periods with the least possible amount of drugs. International guidelines recommend the addition of an inhaled long-acting beta2-agonist (LABA) to a low- to medium-dose inhaled corticosteroid (ICS) when low doses of ICS fail to control asthma symptoms. The fixed combined administration of ICS/LABA improves patient compliance, reducing the risk of therapy discontinuation. The relative deposition pattern of the inhaled drug to the target site is the result of a complex interaction between the device used, the aerosol formulation and the patient’s adherence to therapy. Different inhalation devices have been introduced in clinical practice over time. The new hydrofluoroalkane (HFA) solution aerosols allow for the particle size to be modified, thus leading to deeper penetration of the medication into the lung. The Modulite® technology allows for the manipulation of inhaled HFA-based solution formulations, such as the fixed beclomethasone/formoterol combination, resulting in a uniform treatment of inflammation and bronchoconstriction. The success of any anti-asthmatic treatment depends on the choice of the correct device and the adherence to therapy
Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities
The First Level Trigger of JEM-EUSO: Concept and tests
The trigger system of JEM-EUSO is designed to meet specific challenging requirements. These include managing a large number of pixels ( 3·10^5) and using a very fast, low power consuming, and radiation hard electronics. It must achieve a high signal-to-noise performance and flexibility and cope with the limited down-link transmission rate from the International Space Station (ISS) to Earth. The general overview of the First Level Trigger for cosmic ray detection is reviewed; tests that validate its performance are discussed
RIP-Chip analysis supports different roles for AGO2 and GW182 proteins in recruiting and processing microRNA targets
MicroRNAs (miRNAs) are small non-coding RNA molecules mediating the translational repression and degradation of target mRNAs in the cell. Mature miRNAs are used as a template by the RNA-induced silencing complex (RISC) to recognize the complementary mRNAs to be regulated. To discern further RISC functions, we analyzed the activities of two RISC proteins, AGO2 and GW182, in the MCF-7 human breast cancer cell lin
Negative transcriptional control of ERBB2 gene by MBP-1 and HDAC1: diagnostic implications in breast cancer
Backgound: The human ERBB2 gene is frequently amplified in breast tumors, and its high expression is associated with poor prognosis. We previously reported a significant inverse correlation between Myc promoter-binding protein-1 (MBP-1) and ERBB2 expression in primary breast invasive ductal carcinoma (IDC). MBP-1 is a transcriptional repressor of the c-MYC gene that acts by binding to the P2 promoter; only one other direct target of MBP-1, the COX2 gene, has been identified so far.
Methods: To gain new insights into the functional relationship linking MBP-1 and ERBB2 in breast cancer, we have investigated the effects of MBP-1 expression on endogenous ERBB2 transcript and protein levels, as well as on transcription promoter activity, by transient-transfection of SKBr3 cells. Reporter gene and chromatin immunoprecipitation assays were used to dissect the ERBB2 promoter and identify functional MBP-1 target sequences. We also investigated the relative expression of MBP-1 and HDAC1 in IDC and normal breast tissues by immunoblot analysis and immunohistochemistry.
Results: Transfection experiments and chromatin immunoprecipitation assays in SKBr3 cells indicated that MBP-1 negatively regulates the ERBB2 gene by binding to a genomic region between nucleotide -514 and - 262 of the proximal promoter; consistent with this, a concomitant recruitment of HDAC1 and loss of acetylated histone H4 was observed. In addition, we found high expression of MBP-1 and HDAC1 in normal tissues and a statistically significant inverse correlation with ErbB2 expression in the paired tumor samples.
Conclusions: Altogether, our in vitro and in vivo data indicate that the ERBB2 gene is a novel MBP-1 target, and immunohistochemistry analysis of primary tumors suggests that the concomitant high expression of MBP-1 and HDAC1 may be considered a diagnostic marker of cancer progression for breast IDC
Myc Promoter-Binding Protein-1 (MBP-1) Is a Novel Potential Prognostic Marker in Invasive Ductal Breast Carcinoma
Background
Alpha-enolase is a glycolytic enzyme that catalyses the formation of phosphoenolpyruvate in the cell cytoplasm. \u3b1-Enolase and the predominantly nuclear Myc promoter-binding protein-1 (MBP-1) originate from a single gene through the alternative use of translational starting sites. MBP-1 binds to the P2 c-myc promoter and competes with TATA-box binding protein (TBP) to suppress gene transcription. Although several studies have shown an antiproliferative effect of MBP-1 overexpression on several human cancer cells, to date detailed observations of \u3b1-enolase and MBP-1 relative expression in primary tumors versus normal tissues and their correlation with clinicopathological features have not been undertaken.
Methodology and Findings
We analyzed \u3b1-enolase and MBP-1 expression in normal breast epithelium and primary invasive ductal breast carcinoma (IDC) from 177 patients by Western blot and immunohistochemical analyses, using highly specific anti-\u3b1-enolase monoclonal antibodies. A significant increase in the expression of cytoplasmic \u3b1-enolase was observed in 98% of the tumors analysed, compared to normal tissues. Nuclear MBP-1 was found in almost all the normal tissues while its expression was retained in only 35% of the tumors. Statistically significant associations were observed among the nuclear expression of MBP-1 and ErbB2 status, Ki-67 expression, node status and tumor grade. Furthermore MBP-1 expression was associated with good survival of patients with IDC.
Conclusions
MBP-1 functions in repressing c-myc gene expression and the results presented indicate that the loss of nuclear MBP-1 expression in a large number of IDC may be a critical step in the development and progression of breast cancer and a predictor of adverse outcome. Nuclear MBP-1 appears to be a novel and valuable histochemical marker with potential prognostic value in breast cancer
Roles of Tumor-Educated Platelets (TEPs) in the biology of Non-Small Cell Lung Cancer (NSCLC): A systematic review. “Re-discovering the neglected biosources of the liquid biopsy family”
Due to their interactions with the neoplasm, platelets undergo various proteomic and transcriptomic modifications, resulting in the development of what is known as the “Tumor-Educated Platelets (TEPs) phenotype”.
Consequently, in addition to their suitability for Liquid Biopsy (LB) applications, they play a pivotal role in the
malignancy by communicating with Circulating Tumor Cells (CTCs), Tumor Microenvironment (TME), and the
tumor itself through multiple mechanisms and at multiple levels, ultimately promoting the metastasis of cancer.
Therefore, this Systematic Review of MEDLINE and the Cochrane Library present in-depth insights into these
phenomena, with the aim of enhancing the understanding of the complex interplay between TEPs and Non-Small
Cell Lung Cancer (NSCLC). This endeavor serves to provide context and drive medical research efforts, which are
increasingly focused on developing novel diagnostic and therapeutic technologies that leverage the specific binding of these platelets to the disease
Polθ: emerging synthetic lethal partner in homologous recombination-deficient tumors
The most remarkable finding in synthetic lethality (SL) is the hypersensitivity to PARP inhibitors (PARPis) of the tumors harboring defects in genes involved in homologous repair (HR) such as BRCA1/2. Despite initial responsiveness to PARPi, the penetrance of the synthetic lethal interactions between BRCA1/2 genes and PARPi is incomplete. Thus, a significant proportion of HR-defective tumors experience intrinsic or acquired resistance, representing a key challenge of clinical research. An expanded concept of SL is opening new ways and includes novel forms of genetic interactions, investigating not only traditional SL of pairs genes but also SL between biological pathways that regulate the same essential survival cell function. In this context, recent research showed that HR and theta-mediated end-joining (TMEJ) pathways exhibit SL. DNA polymerase theta (Pol theta) is encoded by the POLQ gene and is a key component of the TMEJ, an essential backup pathway, intrinsically mutagenic, to repair resected double-strand breaks (DSBs) when the non-homologous end joining (NHEJ) and HR are impaired. Pol theta is broadly expressed in normal tissues, overexpressed in several cancers, and typically associated with poor outcomes and shorter relapse-free survival. Notably, HR-deficient tumor cells present the characteristic mutational signatures of the error-prone TMEJ pathway. According to this observation, the loss of HR proteins, such as BRCA1 or BRCA2, contributes to increasing the TMEJ-specific genomic profile, suggesting synthetic lethal interactions between loss of the POLQ and HR genes, and resulting in the emerging interest for Pol theta as a potential therapeutic target in BRCA1/2-associated tumors.This review summarizes the converging roles of the POLQ and HR genes in DNA DSB repair, the early-stage clinical trials using Pol theta inhibitor to treat HR-defective tumors and to overcome BRCA-reversion mutations responsible for therapeutic resistance, and the novel pleiotropic effects of Pol theta, paving the way for the development of unexplored synthetic lethality strategies
Low Scale Flavor Gauge Symmetries
We study the possibility of gauging the Standard Model flavor group. Anomaly
cancellation leads to the addition of fermions whose mass is inversely
proportional to the known fermion masses. In this case all flavor violating
effects turn out to be controlled roughly by the Standard Model Yukawa,
suppressing transitions for the light generations. Due to the inverted
hierarchy the scale of new gauge flavor bosons could be as low as the
electroweak scale without violating any existing bound but accessible at the
Tevatron and the LHC. The mechanism of flavor protection potentially provides
an alternative to Minimal Flavor Violation, with flavor violating effects
suppressed by hierarchy of scales rather than couplings.Comment: 24 pages + appendices; v2) Refs. added and numerical examples
improved. Results unchanged; v3) small typos in appendix B correcte
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