337 research outputs found
The Collagen Binding Domain of Gelatinase A Modulates Degradation of Collagen IV by Gelatinase B
Type IV collagen remodeling plays a critical role in inflammatory responses, angiogenesis and metastasis. Its remodeling is executed by a family of matrix metalloproteinases (MMPs), of which the constitutive gelatinase A (MMP2) and the inducible gelatinase B (MMP9) are key examples. Thus, in many pathological conditions, both gelatinases act together. Kinetic data are reported for the enzymatic processing at 37 degrees C of type IV collagen from human placenta by MMP9 and its modulation by the fibronectin-like collagen binding domain (CBD) of MMP2. The alpha l and alpha 2 chain components of type IV collagen were cleaved by gelatinases and identified by mass spectrometry as well as Edman sequencing. Surface plasmon resonance interaction assays showed that CBD bound type IV collagen at two topologically distinct sites. On the basis of linked-function analysis, we demonstrated that CBD of MMP2 tuned the cleavage of collagen IV by MMP9, presumably by inducing a ligand-linked structural change on the type IV collagen. At low, concentrations, the CBD bound the first site and thereby allosterically modulated the binding of MMP9 to collagen IV, thus enhancing the collagenolytic activity of MMP9. At high concentrations, CBD binding to the second site interfered with MMP9 binding to collagen IV, acting as a competitive inhibitor. Interestingly, modulation of collagen IV degradation by inactive forms of MMP2 also occurred in a cell-based system, revealing that this interrelationship affected neutrophil migration across a collagen IV membrane. The regulation of the proteolytic processing by a catalytically inactive domain (i.e., CBD) suggests that the two gelatinases might cooperate in degrading substrates even when either one is inactive. This observation reinforces the idea of exosite targets for MMP inhibitors, which should include all macromolecular substrate recognition site
Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas. effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization
Target therapies based on BRAF and MEK inhibitors (MAPKi) have changed the therapeutic landscape for metastatic melanoma patients bearing mutations in the BRAF kinase. However, the emergence of drug resistance imposes the necessity to conceive novel therapeutic strategies capable to achieve a more durable disease control. In the last years, retrotransposons laying in human genome have been shown to undergo activation during tumorigenesis, where they contribute to genomic instability. Their activation can be efficiently controlled with reverse transcriptase inhibitors (RTIs) frequently used in the treatment of AIDS. These drugs have demonstrated anti-proliferative effects in several cancer models, including also metastatic melanoma. However, to our knowledge no previous study investigated the capability of RTIs to mitigate drug resistance to target therapy in BRAF-mutant melanomas. In this short report we show that the non-nucleoside RTI, SPV122 in combination with MAPKi strongly inhibits BRAF-mutant melanoma cell growth, induces apoptosis, and delays the emergence of resistance to target therapy in vitro. Mechanistically, this combination strongly induces DNA double-strand breaks, mitochondrial membrane depolarization and increased ROS levels. Our results shed further light on the molecular activity of RTI in melanoma and pave the way to their use as a novel therapeutic option to improve the efficacy of target therapy. Video Abstract
Structural Brain MR Imaging Changes Associated with Obsessive-Compulsive Disorder in Patients with Multiple Sclerosis
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Beyond quantum mechanics? Hunting the 'impossible' atoms (Pauli Exclusion Principle violation and spontaneous collapse of the wave function at test)
The development of mathematically complete and consistent models solving the
so-called "measurement problem", strongly renewed the interest of the
scientific community for the foundations of quantum mechanics, among these the
Dynamical Reduction Models posses the unique characteristic to be
experimentally testable. In the first part of the paper an upper limit on the
reduction rate parameter of such models will be obtained, based on the analysis
of the X-ray spectrum emitted by an isolated slab of germanium and measured by
the IGEX experiment.
The second part of the paper is devoted to present the results of the VIP
(Violation of the Pauli exclusion principle) experiment and to describe its
recent upgrade. The VIP experiment established a limit on the probability that
the Pauli Exclusion Principle (PEP) is violated by electrons, using the very
clean method of searching for PEP forbidden atomic transitions in copper
At the cutting edge against cancer: A perspective on immunoproteasome and immune checkpoints modulation as a potential therapeutic intervention
Simple Summary:& nbsp;Immunoproteasome plays a key role in the generation of antigenic peptides. Immune checkpoints therapy is a front-line treatment of advanced/metastatic tumors, and to improve its efficacy, a broader knowledge of the dynamics of antigen repertoire processing by cancer cells is mandatory. The scope of this review is to offer a picture of the role of immunoproteasome in antigen presentation to fuel the hypothesis of novel therapeutic interventions based on the modulation of this proteolytic complex and immune checkpoints.Immunoproteasome is a noncanonical form of proteasome with enzymological properties optimized for the generation of antigenic peptides presented in complex with class I MHC molecules. This enzymatic property makes the modulation of its activity a promising area of research. Nevertheless, immunotherapy has emerged as a front-line treatment of advanced/metastatic tumors providing outstanding improvement of life expectancy, even though not all patients achieve a long-lasting clinical benefit. To enhance the efficacy of the currently available immunotherapies and enable the development of new strategies, a broader knowledge of the dynamics of antigen repertoire processing by cancer cells is needed. Therefore, a better understanding of the role of immunoproteasome in antigen processing and of the therapeutic implication of its modulation is mandatory. Studies on the potential crosstalk between proteasome modulators and immune checkpoint inhibitors could provide novel perspectives and an unexplored treatment option for a variety of cancers
Searches for the Violation of Pauli Exclusion Principle at LNGS in VIP(-2) experiment
The VIP (Violation of Pauli exclusion principle) experiment and its follow-up
experiment VIP-2 at the Laboratori Nazionali del Gran Sasso (LNGS) search for
X-rays from Cu atomic states that are prohibited by the Pauli Exclusion
Principle (PEP). The candidate events, if they exist, will originate from the
transition of a orbit electron to the ground state which is already
occupied by two electrons. The present limit on the probability for PEP
violation for electron is 4.7 set by the VIP experiment. With
upgraded detectors for high precision X-ray spectroscopy, the VIP-2 experiment
will improve the sensitivity by two orders of magnitude.Comment: 5 pages, 3 figures, 1 table. Conference proceedings for oral
presentation at TAUP 2015, Torin
Application of photon detectors in the VIP2 experiment to test the Pauli Exclusion Principle
The Pauli Exclusion Principle (PEP) was introduced by the austrian physicist
Wolfgang Pauli in 1925. Since then, several experiments have checked its
validity. From 2006 until 2010, the VIP (VIolation of the Pauli Principle)
experiment took data at the LNGS underground laboratory to test the PEP. This
experiment looked for electronic 2p to 1s transitions in copper, where 2
electrons are in the 1s state before the transition happens. These transitions
violate the PEP. The lack of detection of X-ray photons coming from these
transitions resulted in a preliminary upper limit for the violation of the PEP
of . Currently, the successor experiment VIP2 is under
preparation. The main improvements are, on one side, the use of Silicon Drift
Detectors (SDDs) as X-ray photon detectors. On the other side an active
shielding is implemented, which consists of plastic scintillator bars read by
Silicon Photomultipliers (SiPMs). The employment of these detectors will
improve the upper limit for the violation of the PEP by around 2 orders of
magnitude
VIP 2: Experimental tests of the Pauli Exclusion Principle for electrons
The Pauli Exclusion Principle (PEP) was famously discovered in 1925 by the
austrian physicist Wolfgang Pauli. Since then, it underwent several
experimental tests. Starting in 2006, the VIP (Violation of the Pauli
Principle) experiment looked for 2p to 1s X-ray transitions in copper, where 2
electrons are present in the 1s state before the transition happens. These
transitions violate the PEP, and the lack of detection of the corresponding
X-ray photons lead to a preliminary upper limit for the violation of the PEP of
4.7 * 10^(-29). The follow-up experiment VIP 2 is currently in the testing
phase and will be transported to its final destination, the underground
laboratory of Gran Sasso in Italy, in autumn 2015. Several improvements
compared to its predecessor like the use of new X-ray detectors and active
shielding from background gives rise to a goal for the improvement of the upper
limit of the probability for the violation of the Pauli Exclusion Principle of
2 orders of magnitude
Testing the Pauli Exclusion Principle for electrons at LNGS
High-precision experiments have been done to test the Pauli exclusion
principle (PEP) for electrons by searching for anomalous -series X-rays from
a Cu target supplied with electric current. With the highest sensitivity, the
VIP (VIolation of Pauli Exclusion Principle) experiment set an upper limit at
the level of for the probability that an external electron captured
by a Cu atom can make the transition from the 2 state to a 1 state
already occupied by two electrons. In a follow-up experiment at Gran Sasso, we
aim to increase the sensitivity by two orders of magnitude. We show proofs that
the proposed improvement factor is realistic based on the results from recent
performance tests of the detectors we did at Laboratori Nazionali di Frascati
(LNF).Comment: 8 pages, 5 figures, conference proceedings on TAUP 201
Spontaneously emitted X-rays: an experimental signature of the dynamical reduction models
We present the idea of searching for X-rays as a signature of the mechanism
inducing the spontaneous collapse of the wave function. Such a signal is
predicted by the continuous spontaneous localization theories, which are
solving the "measurement problem" by modifying the Schrodinger equation. We
will show some encouraging preliminary results and discuss future plans and
strategy.Comment: to be published in Foundation of Physics 201
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