23 research outputs found
Inhibitor-Sensitive FGFR1 Amplification in Human Non-Small Cell Lung Cancer
Background
Squamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma.
Methodology/Principal Findings
Using SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes–WHSC1L1, LETM2, and FGFR1–is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas. Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition.
Conclusions/Significance
These studies show that FGFR1 amplification is common in squamous cell lung cancer, and that FGFR1 may represent a promising therapeutic target in non-small cell lung cancer.Novartis Pharmaceuticals CorporationAmerican Lung AssociationUniting Against Lung CancerSara Thomas Monopoli FundSeaman FoundationIndia. Dept. of BiotechnologyNational Lung Cancer Partnershi
Regioselective synthesis of novel heterophanes from 4-amino-triazoles<sup>†</sup>
670-673The
regioseiective synthesis of N-amino-benztriazolophanes has been achieved
by incorporation of benzene nucleus in the heterophane. The some of the novel
compounds have been studied for their use as PTC agents
Synthesis and structural studies of novel 1,3,4-oxadiazolophanes
397-400The title compounds have been prepared in
moderate yields from compound 2a/2b as starting unit, which are obtained,
in good yields by one-step process in high purity. Interesting results
have been obtained when the cyclisation
products were studied for structural analysis. The title compounds are also studied
for their use as PTC agents.
Functional Ionic Porous Frameworks Based on Triaminoguanidinium for CO2 Conversion and Combating Microbes
Porous organic frameworks
(POFs) with heteroatom rich ionic backbone have emerged as advanced materials
for catalysis, charge-specific molecular separation and antibacterial activity.
The loading of metal ions further enhances Lewis acidity augmenting the
activity associated with the frameworks. Metal-loaded ionic POFs however often
suffer from physicochemical instability, limiting their scope for diverse
applications. Herein, we report the fabrication of triaminoguanidinium-based
ionic POFs through Schiff base condensation in a cost-effective and scalable
manner. The resultant N-rich ionic frameworks facilitate selective CO2
uptake and provide high metal (ZnO, 57.3 ± 1.2%) loading capacity. The hierarchically mesoporous ZnO-rich
metalated frameworks (Zn/POFs) show remarkable catalytic activity in the
cycloaddition of CO2 and epoxides into cyclic organic carbonates
under solvent-free condition with high catalyst recyclability. In addition,
both ionic POFs and Zn/POFs exhibit robust antibacterial (Gram-positive, S.
aureus and Gram-negative, E. coli) and antiviral activity targeting
HIV and VSV-G enveloped lentiviral particles. The enhanced catalytic, as well
as broad-spectrum antimicrobial activity, are likely due to the synergistic
effect of triaminoguanidinium ions and ZnO infused with the frameworks. We thus
establish triaminoguanidinium-based POFs and Zn/POFs as a new class of
multifunctional materials for environmental remediation and biomedical
applications
Leishmania donovani exploits host deubiquitinating enzyme A20, a negative regulator of TLR signaling, to subvert host immune response
TLRs, which form an interface between mammalian host and microbe, play a key role in
pathogen recognition and initiation of proinflammatory response thus stimulating antimicrobial activity
and host survival. However, certain intracellular pathogens such as Leishmania can successfully
manipulate the TLR signaling, thus hijacking the defensive strategies of the host. Despite the presence
of lipophosphoglycan, a TLR2 ligand capable of eliciting host-defensive cytokine response, on the
surface of Leishmania, the strategies adopted by the parasite to silence the TLR2-mediated
proinflammatory response is not understood. In this study, we showed that Leishmania donovani
modulates the TLR2-mediated pathway in macrophages through inhibition of the IKK-NF-κB
cascade and suppression of IL-12 and TNF-α production. This may be due to impairment of
the association of TRAF6 with the TAK-TAB complex, thus inhibiting the recruitment of TRAF6 in
TLR2 signaling. L. donovani infection drastically reduced Lys 63-linked ubiquitination of TRAF6, and
the deubiquitinating enzyme A20 was found to be significantly upregulated in infected macrophages.
Small interfering RNA-mediated silencing of A20 restored the Lys 63-linked ubiquitination of TRAF6
as well as IL-12 and TNF-α
levels with a concomitant decrease in IL-10 and TGF-ß synthesis in infected macrophages.
Knockdown of A20 led to lower parasite survival within macrophages. Moreover, in vivo silencing of
A20 by short hairpin RNA in BALB/c mice led to increased NF-κB DNA binding and
host-protective proinflammatory cytokine response resulting in effective parasite clearance. These
results suggest that L. donovani might exploit host A20 to inhibit the TLR2-mediated proinflammatory
gene expression, thus escaping the immune responses of the host
Uncoupling Protein 2 Negatively Regulates Mitochondrial Reactive Oxygen Species Generation and Induces Phosphatase-Mediated Anti-Inflammatory Response in Experimental Visceral Leishmaniasis
To reside and multiply successfully within the host macrophages, Leishmania parasites impair the generation of reactive oxygen
species (ROS), which are a major host defense mechanism against any invading pathogen. Mitochondrial uncoupling proteins are
associated with mitochondrial ROS generation, which is the major contributor of total cellular ROS generation. In the present
study we have demonstrated that Leishmania donovani infection is associated with strong upregulation of uncoupling protein 2
(UCP2), a negative regulator of mitochondrial ROS generation located at the inner membrane of mitochondria. Functional
knockdown of macrophage UCP2 by small interfering RNA-mediated silencing was associated with increased mitochondrial
ROS generation, lower parasite survival, and induction of marked proinflammatory cytokine response. Induction of proinflammatory
cytokine response in UCP2 knocked-down cells was a direct consequence of p38 and ERK1/2 MAPK activation, which
resulted from ROS-mediated inhibition of protein tyrosine phosphatases (PTPs). Administration of ROS quencher, N-acetyl-Lcysteine,
abrogated PTP inhibition in UCP2 knocked-down infected cells, implying a role of ROS in inactivating PTP. Short
hairpin RNA-mediated in vivo silencing of UCP2 resulted in decreased Src homology 2 domain-containing tyrosine phosphatase 1
and PTP-1B activity and host-protective proinflammatory cytokine response resulting in effective parasite clearance. To our
knowledge, this study, for the first time, reveals the induction of host UCP2 expression during Leishmania infection to downregulate
mitochondrial ROS generation, thereby possibly preventing ROS-mediated PTP inactivation to suppress macrophage
defense mechanisms
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A Conserved Acidic Residue in the C-Terminal Flexible Loop of HIV-1 Nef Contributes to the Activity of SERINC5 and CD4 Downregulation
The host transmembrane protein SERINC5 is incorporated into retrovirus particles and inhibits HIV-1 infectivity. The lentiviral Nef protein counteracts SERINC5 by downregulating it from the cell surface and preventing its incorporation into virions. The ability of Nef to antagonize the host factor varies in magnitude between different HIV-1 isolates. After having identified a subtype H nef allele unable to promote HIV-1 infectivity in the presence of SERINC5, we investigated the molecular determinants responsible for the defective counteraction of the host factor. Chimeric molecules with a subtype C Nef highly active against SERINC5 were constructed to locate Nef residues crucial for the activity against SERINC5. An Asn at the base of the C-terminal loop of the defective nef allele was found in place of a highly conserved acidic residue (D/E 150). The conversion of Asn to Asp restored the ability of the defective Nef to downregulate SERINC5 and promote HIV-1 infectivity. The substitution was also found to be crucial for the ability of Nef to downregulate CD4, but not for Nef activities that do not rely on the internalization of receptors from the cell surface, suggesting a general implication in promoting clathrin-mediated endocytosis. Accordingly, bimolecular fluorescence complementation revealed that the conserved acidic residue contributes to the recruitment of AP2 by Nef. Altogether, our results confirm that Nef downregulates SERINC5 and CD4 by engaging a similar machinery and indicates that, in addition to the di-leucine motif, other residues in the C-terminal flexible loop are important for the ability of the protein to sustain clathrin-mediated endocytosis