Bridging Molecules Research Articles

Bone: a key aspect to understand phenomena in clinical hematology.

The bone marrow (BM) is located inside the bone. Now, it appears that bone tissue functionally communicates with the BM hematopoietic system. Osteoblast lineage cells serve as a part of the microenvironment for immature hematopoietic (stem/progenitor) cells. In contrast, mature hematopoietic cells such as neutrophils and macrophages play a critical role to regulate osteoblast activity. A progressive distortion of this precise inter-organ communication between hematopoietic and skeletal systems may lead to hematologic disorders. Recent studies have revealed that vitamin D receptor is a pivotal bridging molecule for this network and for the pathogenesis of myelofibrosis.

BIRC5/Survivin is a novel ATG12–ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells

ABSTRACT BIRC5/Survivin is known as a dual cellular functions protein that directly regulates both apoptosis and mitosis in embryonic cells during embryogenesis and in cancer cells during tumorigenesis and tumor metastasis. However, BIRC5 has seldom been demonstrated as a direct macroautophagy/autophagy regulator in cells. ATG7 expression and ATG12–ATG5-ATG16L1 complex formation are crucial for the phagophore elongation during autophagy in mammalian cells. In this study, we observed that the protein expression levels of BIRC5 and ATG7 were inversely correlated, whereas the expression levels of BIRC5 and SQSTM1/p62 were positively correlated in normal breast tissues and tumor tissues. Mechanistically, we found that BIRC5 negatively modulates the protein stability of ATG7 and physically binds to the ATG12–ATG5 conjugate, preventing the formation of the ATG12–ATG5-ATG16L1 protein complex in human cancer (MDA-MB-231, MCF7, and A549) and mouse embryonic fibroblast (MEF) cells. We also observed a concurrent physical dissociation between BIRC5 and ATG12–ATG5 (but not CASP3/caspase-3) and upregulation of autophagy in MDA-MB-231 and A549 cells under serum-deprived conditions. Importantly, despite the fact that upregulation of autophagy is widely thought to promote DNA repair in cells under genotoxic stress, we found that BIRC5 maintains DNA integrity through autophagy negative-modulations in both human cancer and MEF cells under non-stressed conditions. In conclusion, our study reveals a novel role of BIRC5 in cancer cells as a direct regulator of autophagy. BIRC5 may act as a “bridging molecule”, which regulates the interplay between mitosis, apoptosis, and autophagy in embryonic and cancer cells. Abbreviations ACTA1: actin; ATG: autophagy related; BIRC: baculoviral inhibitor of apoptosis repeat-containing; BAF: bafilomycin A1; CQ: chloroquine; CASP3: caspase 3; HSPB1/Hsp27: heat shock protein family B (small) member 1/heat shock protein 27; IAPs: inhibitors of apoptosis proteins; IP: immunoprecipitation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PLA: proximity ligation assay; SQSTM1/p62: sequestosome 1; siRNA: small interfering RNA

Measuring Apoptotic Cell Engulfment (Efferocytosis) Efficiency.

Efferocytosis is the process of recognizing and removing dead and dying cells, performed by a variety of phagocytic cells including macrophages. It has recently been shown that liver X receptor (LXR) signaling in macrophages regulates the expression of important efferocytosis receptors, bridging and signaling molecules. Here we describe a sensitive yet robust efferocytosis assay, optimized to measure bone marrow-derived macrophage (BMDM) apoptotic cell engulfment capability. This assay can be applied to genetically or pharmacologically altered BMDMs.

Identification of TIM-3/Gal-9 Autocrine Loop As a Novel Wnt-Ligands Independent Machinery for the Constitutive Activation of Canonical Wnt Pathway in AML-LSCs

We originally identified T-cell immunoglobulin mucin-3 (TIM-3) as a leukemic stem cells (LSCs)-specific surface molecule and a useful marker for discriminating LSCs from hematopoietic stem cells (HSCs). Furthermore, we recently identified an unique autocrine loop composed of TIM-3 and its ligand galectin-9 (Gal-9). This TIM-3/Gal-9 autocrine loop enhances self-renewal capacity of AML-LSCs and contributes to leukemia progression(Kikushige et al., Cell Stem Cell 2015).To clarify the molecular mechanism how TIM-3 signaling enhances stem cell properties of AML-LSCs, we performed shRNA-mediated knock-down(KD) of TIM-3 in KASUMI-3 (TIM-3+ AML cell line). As a result, TIM-3-KD significantly reduce the proliferation of KASUMI-3. To investigate how TIM-3-KD attenuated leukemia propagation, we compared gene expression profile of scramble-infected control and TIM-3-KD KASUMI-3 cells. Gene Set Enrichment Analysis (GSEA) revealed TIM-3-KD resulted in the significaltly attenuated expression of HSCs and LSCs-related genes (Eppert et al., Nature Med 2011) and canonical Wnt pathway-related genes (BioCarta). Since canonical Wnt pathway is known to regulate stem cell properties via inducing the nucleus accumulation ofβ-catenin in many types of stem cells including HSCs, we next examined the β-catenin level in TIM-3-KD-KASUMI-3 cells. Array scan analysis revealed that KD of TIM-3 significantly impaired the the nucleus accumulation of β-catenin in KASUMI-3 cells. In various types of cancers, the constitutive activation of β-catenin is one of the most common oncogenic signatures, and it is mainly driven by somatic mutations in the genes related to the canonical Wnt pathway. However, such mutations are rarely detected in AML.We, therefore, hypothesized that TIM-3/Gal-9 autocrine loop signaling might be a novel mutation-independent machinery for the constitutive activation of canonical Wnt pathway in primary AML.To test this hypothethis, we first evaluated the phosphorylation status of LDL receptor-related protein 6 (LRP6), because LRP6 phosphorylation is a crucial step for canonical Wnt pathway activation. Surprisingly, Gal-9 stimulation induced phosphorylation of LRP6 and subsequent β-catenin accumulation in primary TIM-3+ AML cells even in the absence of Wnt ligand. On the other hand, LRP6 phosphorylation induced by Gal-9 stimulation was canceled by the blocking antibody to TIM-3 (F38-2E2). These results indicate that Gal-9 stimulation should induce canonical Wnt pathway activation via TIM-3 dependent manner in primary AML cells. Since Gal-9 ligation to TIM-3 is known to induce phosphorylation of tyrosine residues of TIM-3 cytoplasmic tail, leading to the recruitment and activation of several Src family kinases (SFKs) for downstream signal transduction. We found that TIM-3/Gal-9 interaction recruited hematopoietic cell kinase (HCK), a member of SFKs, to TIM-3 and activated HCK by phosphorylation of the SH1 domain (Y410 in HCK) in TIM-3+ AML cells. Furthermore, we confirmed a specific HCK inhibitor A-419259 efficiently blocked the LRP6 phosphorylation and subsequent β-catenin accumulation induced by TIM-3/Gal-9 interaction in primary AML cells. These results suggest that the canonical Wnt pathway activation induced by Gal-9 ligation to TIM-3 is mainly mediated by HCK in primary AML cells.We next focused on p120-catenin as a bridging molecule between HCK activation and LRP6 phosphorylation because, as previously reported, this molecule can be directly activated by SFKs and the activation of this molecule is an initial step for canonical Wnt pathway activation preceding LRP6 phosphorylation. We found that Gal-9 ligation to TIM-3 immediately induced the direct association of HCK and p120-catenin, leading to the activation of p120-catenin in TIM-3+ AML cells. We also confirmed that specific inhibition of HCK completely abrogated the activation of p120-catenin and subsequent canonical Wnt pathway activation in primary TIM-3+ AML cells, indicating that the activation of p120-catenin mediated by HCK is a bridging moleculer machinery for connecting TIM-3 signaling and previously identified canonical Wnt pathway. Since TIM-3 as well as HCK is specifically expressed in LSCs but not in HSCs, we conclude that TIM-3/Gal-9 autocrine loop is a novel Wnt-ligands independent machinery for the constitutive activation of canonical Wnt pathway specific for AML-LSCs. (summarized in figure) [Display omitted] DisclosuresAkashi:Celgene: Research Funding, Speakers Bureau; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Taiho Pharmaceutical: Research Funding; MSD: Research Funding; Asahi-kasei: Research Funding; Chugai Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Otsuka Pharmaceutical: Research Funding; Eli Lilly Japan: Research Funding; Novartis pharma: Research Funding; Eisai: Research Funding; sanofi: Research Funding; Astellas Pharma: Research Funding.

Role of I2 Molecules and Weak Interactions in Supramolecular Assembling of Pseudo-Three-Dimensional Hybrid Bismuth Polyiodides: Synthesis, Structure, and Optical Properties of Phenylenediammonium Polyiodobismuthate(III)

Phenylenediammonium polyiodobismuthate(III), [PDA(BiI4)2·I2] (PDA = phenylenediammonium, [NH3C6H4NH3]2+), represents a new hybrid halometallate synthesized in a form of black well-shaped crystals by a facile reaction in aqueous solution of HI containing dissolved I2. It crystallizes in triclinic space group P1 with the unit cell parameters a = 7.761(1) A, b = 9.259(1) A, c = 9.689(1) A, α = 95.68(3)°, β = 103.19(3)°, γ = 93.56(3)°, and Z = 1. Its crystal structure comprises three levels of organization discriminated by a type of chemical bonding. The first level is provided by covalently bonded [BiI6] octahedra linked into [BiI4]∞– one-dimensional anionic chains; the second level features secondary bonds between the chains and I2 bridging molecules, whereas the third level is specified by the weak hydrogen N–H···I bonds involving a diammonium cation and I···I intermolecular interactions that additionally link anionic chains. Altogether, these three interaction types ensure the formation of a complex pseu...

Coordination polymers based on zinc(ii) and manganese(ii) with 1,4-cyclohexanedicarboxylic acid

Three new metal-organic coordination polymers were obtained namely, [Mn3(chdc)3-(NMP)2(DMF)2] (1, chdc2– is trans-1,4-cyclohexanedicarboxylate, NMP is N-methylpyrrolidone, DMF is N,N-dimethylformamide), [Zn3(chdc)3(NMP)2]•2NMP (2), and [Zn3(chdc)3(ur)-(DMF)0.5]•DMF (3, ur is the urotropine). The crystal structures of polymers 1, 2, and 3 were determined by single-crystal X-ray crystallography. All three compounds were found to contain a trinuclear secondary building unit {M3(OOC)6}. Coordination polymers 1 and 2 have a layered structure, while polymer 3 has a three-dimensional coordination framework with isolated pores formed due to the presence of urotropine bridging molecules. Compounds 1 and 3 were characterized by IR spectroscopy, thermogravimetric and elemental analysis data, powder X-ray diffraction. Compound 3 was also characterized by UV-Vis diffuse reflectance spectrum.

Pyridyl and triazole ligands directing the assembling of zinc(II) into coordination polymers with different dimensionality through azides

Five coordination polymers catena-[(3-Hampy)2[Zn7(N3)16(3-ampy)4]·3H2O] (1), catena-[Zn2(μ2-4-HO-py)(μ1,1-N3)4]·H2O (2), catena-[Zn2(μ2-4-amtz)(μ1,1-N3)4] (3), catena-[Zn(5-Et-2-Me-py)(μ1,1-N3)2] (4) and catena-[Zn(μ2-2-O-py-N-oxide)(μ1,1-N3)] (5), where 3-ampy=3-aminopyridine, 4-HOpy=4-hydroxypyridine, 4-amtz=4-amino-4H-1,2,4-triazole, 5-Et-2-Mepy=5-ethyl-2-methylpyridine and 2-HO-py-N-oxide=2-hydroxypyridine-N-oxide were synthesized and structurally characterized by single crystal X-ray crystallography. The complexes display different dimensionality depending on the nature of the coligand. The anionic polymer in complex 1 consists of 1D system of defective dicubanes with two different azido-bridging μ1,1-N3 and μ1,1,1-N3 modes. Complexes 2 and 3 are isostructural and both exhibit 2D networks with μ(O,O)-pyridinone bridging molecule in 2 or μ(N,N′)-bridging 4-amtz in 3, and μ1,1,-azide bridging. Complex 4 reveals a zigzag chains of 1D polyhedral through a doubly bridged μ1,1-N3 bonding mode, whereas in complex 5 a 1D polymeric chain is generated via singly bridged μ1,1-N3 bonding and hydrogen bonding results in the formation of supramolecular 2D system. The emission spectral properties of the parent free ligands and their corresponding Zn(II) complexes were investigated where enhancement luminescence emissions with strong red shifts were observed in complexes 2, 4 and 5.

Metal–Organic Frameworks Precipitated by Reactive Crystallization in Supercritical CO2

Fine chemical and pharmaceutical companies often employ reactive crystallization or precipitation to make crystalline intermediates and finished products. In this work, the supercritical reactive crystallization route is used for the precipitation of diverse metal–organic frameworks (MOFs). 1D and 2D MOFs were obtained by reacting either bypyridil (two linking positions) or triazine (three linking positions)-based bridging molecules, respectively, with supercritical CO2 soluble M(hfacac)2 (where M = Zn2+ or Cu2+ and hfacac– stands for hexafluoroacetylacetonate). Additionally, miscellaneous reactions were designed for the crystallization of 3D MOFs in scCO2, embracing the precipitation of MIL-88B(Fe), ZIF-8, and a new Zn2+–curcumin coordination polymer. Obtained crystals in each case were analyzed from a morphological point of view by scanning electron microscopy analysis to elucidate potential formation mechanisms. The focus was on the obtained crystal habits at different reaction points, linked to the pr...

Selective and Quantitative Detection of Trace Amounts of Mercury(II) Ion (Hg²⁺) and Copper(II) Ion (Cu²⁺) Using Surface-Enhanced Raman Scattering (SERS).

We report the development of a surface-enhanced Raman scattering (SERS)-based heavy metal ion sensor targeting the detection of mercury(II) ion (Hg(2+)) and copper(II) ion (Cu(2+)) with high sensitivity and selectivity. To achieve the detection of vibrational-spectroscopically silent heavy metal ions, the SERS substrate composed of gold nanorod (AuNR)-polycaprolactone (PCL) nanocomposite fibers was first functionalized using metal ion-binding ligands. Specifically, 2,5-dimercapto-1,3,4-thiadiazole dimer (di-DMT) and trimercaptotriazine (TMT) were attached to the SERS substrates serving as bridging molecules to capture Hg(2+) and Cu(2+), respectively, from solution. Upon heavy metal ion coordination, changes in the vibrational spectra of the bridging molecules, including variations in the peak-intensity ratios and peak shifts were observed and taken as indicators of the capture of the target ions. With rigorous spectral analysis, the coordination mechanism between the heavy metal ion and the corresponding bridging molecule was investigated. Mercury(II) ion primarily interacts with di-DMT through the cleavage of the disulfide bond, whereas Cu(2+) preferentially interacts with the heterocyclic N atoms in TMT. The specificity of the coordination chemistry provided both di-DMT and TMT with excellent selectivity for the detection of Hg(2+) and Cu(2+) in the presence of other interfering metal ion species. In addition, quantitative analysis of the concentration of the heavy metal ions was achieved through the construction of internal calibration curves using the peak-intensity ratios of 287/387 cm(-1) for Hg(2+) and 1234/973 cm(-1) for Cu(2+).

A direct method of quantification of maximal chemisorption of 3-aminopropylsilyl groups on silica gel using DRIFT spectroscopy

3-Aminopropylsilyl (APS) modified silica gel plays an important role as a precursor for further modifications, where APS acts as a spacer or bridging molecule. A monolayer of APS which is most suitable for this purpose was obtained in anhydrous conditions. The properties of the APS-modified silica gel depend on the amount of molecules chemisorbed on the surface. A direct quantitative method using Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy was proposed. The obtained results were further supported by elemental analysis. The conclusion was that the proposed methodology can be used for the quantification of APS groups chemisorbed on silica gel when the grafting chemical reaction was mainly irreversible.

Coordination Chemistry of Mercury-Containing Anticrowns. Complexation of Perfluoro-o,o′-biphenylenemercury with o-Xylene and Acetonitrile and the First X-ray Diffraction Evidence for Its Trimeric Structure

The paper reports the first X-ray diffraction data evidencing the cyclic trimeric structure of the earlier synthesized octafluoro-o,o′-biphenylenemercury (8), being of considerable interest as a potential anticrown. The conclusion on the trimeric (o,o′-C6F4C6F4Hg)3 structure of this mercuracycle is based on an X-ray structural analysis of its o-xylene and acetonitrile complexes {[(o,o′-C6F4C6F4Hg)3](o-Me2C6H4)2} (9) and {[(o,o′-C6F4C6F4Hg)3](MeCN)3} (10), which were obtained from 8 in an analytically pure state and fully characterized. Complex 9 contains two o-xylene species per one molecule of 8 and forms in the crystal infinite chains consisting of alternating mercuramacrocycle units and bridging o-xylene ligands. One more o-xylene molecule in each macrocyclic fragment of the chain serves as a terminal ligand. Both bridging and terminal molecules of o-xylene are coordinated in all cases with only one Hg site of the corresponding mercuracycle. The back transformation of complex 9 into 8 and o-xylene occu...

Postsynthetic Paddle-Wheel Cross-Linking and Functionalization of 1,3-Phenylenebis(azanetriyl)tetrabenzoate-Based MOFs

A new metal–organic framework, Cu2(mpbatb)(H2O)2 (DUT-71; DUT, Dresden University of Technology) (mpbatb, 4,4′,4″,4‴-(1,3-phenylenebis(azanetriyl)tetrabenzoate)), was prepared by a solvothermal reaction in a mixture of DMF and EtOH. Postsynthetic modification of DUT-71 using different neutral nitrogen-containing bridging molecules in a single-crystal to single-crystal transformation fashion results in a series of porous compounds (DUT-72, DUT-73a, DUT-73b, DUT-74, DUT-90, DUT-91, and DUT-95) with apparent BET surface area up to 2700 m2 g–1. Interestingly, the Cu–Cu distances between paddle wheels during the transformation are adapted to the bridging ligands, demonstrating the flexible character of DUT-71. After solvent removal and resolvation, a drastic color change from green to dark blue and vice versa was observed. This observation was studied in detail in situ by monitoring the adsorption of ethanol in the low-concentration region by UV/vis analysis. The correlation between the ethanol adsorption upta...

Incomplete clearance of apoptotic cells in systemic lupus erythematosus: pathogenic role and potential biomarker.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with repeated inflammation against multiple organs. Although its pathophysiology is not yet unveiled, uncleared apoptotic cells and their accumulation in tissue contribute to the autoimmune disturbance in SLE. Apoptosis is a programmed cell death process, which maintains tissue homeostasis and inhibits the development of any further immune response against apoptotic remnants. Earlier studies revealed that various 'eat-me' signals on apoptotic cells, bridging molecules and their receptors on phagocytes play a role in such a complicated process. Tyro3-Axl-Mer receptors, their bridging molecules, milk fat globulin epidermal growth factor-8, T-cell immunoglobulin mucin domain protein family, scavenger receptors, C1q, and pentraxins were found to be abnormal in SLE. In this review, apoptosis and clearance of its remnants are summarized, and the molecules involved in the incomplete clearance of apoptotic cells in SLE are discussed.

Stat3 controls cell death during mammary gland involution by regulating uptake of milk fat globules and lysosomal membrane permeabilization.

We have previously demonstrated that Stat3 regulates lysosomal mediated-programmed cell death (LM-PCD) during mouse mammary gland involution in vivo. However, the mechanism that controls the release of lysosomal cathepsins to initiate cell death in this context has not been elucidated. We show here that Stat3 regulates the formation of large lysosomal vacuoles that contain triglyceride. Furthermore, we demonstrate that milk fat globules (MFGs) are toxic to epithelial cells and that, when applied to purified lysosomes, the MFG hydrolysate oleic acid potently induces lysosomal leakiness. Additionally, uptake of secreted MFGs coated in butyrophilin 1A1 is diminished in Stat3 ablated mammary glands while loss of the phagocytosis bridging molecule MFG-E8 results in reduced leakage of cathepsins in vivo. We propose that Stat3 regulates LM-PCD in mouse mammary gland by switching cellular function from secretion to uptake of MFGs. Thereafter, perturbation of lysosomal vesicle membranes by high levels of free fatty acids results in controlled leakage of cathepsins culminating in cell death.

Detection and classification of host–guest interactions using β-cyclodextrin-decorated carbon nanotube-based chemiresistors

Carbon nanotubes (CNTs) in a chemiresistor setup have been widely explored in bio/chemical sensing. Detection of certain molecules with environmental and health related importance such as 9-anthracenecarboxylic acid, diclofenac sodium, and curcumin using electrochemical methods/unfunctionalized CNTs suffer from lack of response, high limit of detection (LOD) and poor selectivity. The key to overcome these issues is to decorate CNTs with host (receptor) molecules like β-cyclodextrin (β-CD) that interact with guest (target) molecules by host–guest complex formation. To improve guest recognition, and consequently, the sensor performance, effective immobilization of β-CD on the CNT surface using a non-covalent bridging molecule such as 3, 4, 9, 10-perylene tetracarboxylic acid (PTCA) is required. Furthermore, the selectivity can be assessed using the conductance correlation patterns of different host–guest systems in conjunction with a pattern classification tool. Our results indicate that PTCA linked β-CD-decorated CNT chemiresistors showed a good linear detection range (∼100 pM–100 nM), sensitivity (∼3 × 10−3–9 × 10−2 nM−1) and LOD (∼62 pM–101 nM), compared to devices without PTCA, in the detection of the guest molecules. The distinction in correlation patterns of different host–guest systems was corroborated by pattern classification yielding a classification accuracy, sensitivity, and specificity of ∼91.83%, ∼90.13%, and ∼85.39%, respectively.

Influence of the Auxiliary Acceptor on the Absorption Response and Photovoltaic Performance of Dye-Sensitized Solar Cells

Three new dyes with a 2-(1,1-dicyanomethylene)rhodanine (IDR-I, -II, -III) electron acceptor as anchor were synthesized and applied to dye-sensitized solar cells. We varied the bridging molecule to fine tune the electronic and optical properties of the dyes. It was demonstrated that incorporation of auxiliary acceptors effectively increased the molar extinction coefficient and extended the absorption spectra to the near-infrared (NIR) region. Introduction of 2,1,3-benzothiadiazole (BTD) improved the performance by nearly 50 %. The best performance of the dye-sensitized solar cells (DSSCs) based on IDR-II reached 8.53 % (short-circuit current density (Jsc)=16.73 mA cm(-2), open-circuit voltage (Voc)=0.71 V, fill factor (FF)=71.26 %) at AM 1.5 simulated sunlight. However, substitution of BTD with a group that featured the more strongly electron-withdrawing thiadiazolo[3,4-c]pyridine (PT) had a negative effect on the photovoltaic performance, in which IDR-III-based DSSCs showed the lowest efficiency of 4.02 %. We speculate that the stronger auxiliary acceptor acts as an electron trap, which might result in fast combination or hamper the electron transfer from donor to acceptor. This inference was confirmed by electrical impedance analysis and theoretical computations. Theoretical analysis indicates that the LUMO of IDR-III is mainly localized at the central acceptor group owing to its strong electron-withdrawing character, which might in turn trap the electron or hamper the electron transfer from donor to acceptor, thereby finally decreasing the efficiency of electron injection into a TiO2 semiconductor. This result inspired us to select moderated auxiliary acceptors to improve the performance in our further study.

186P - Palb2 Mrna Expression As a Predictive and Prognostic Marker in Advanced Non-Small-Cell Lung Cancer (Nsclc) Patients (P) Treated with Cisplatin- Docetaxel Chemotherapy

ABSTRACT Aim: The Spanish Lung Cancer Group (SLCG) undertook an industry-independent, two biomarker-directed, randomized trial in advanced NSCLC p. The study (NCT00617656/GECP-BREC) compared non-selected cisplatin-based chemotherapy with therapy customized according to BRCA1/RAP80 mRNA levels. The trial was closed prematurely due to a detrimental effect in the biomarker-directed arm. Further genetic analysis defined PALB2, the bridging molecule that connects BRCA1 and BRCA2, as a promising biomarker to elucidate DNA repair mechanisms. Methods: We assessed mRNA levels of PALB2, RIF1, 53BP1, RNF8 and ATM (as biomarkers with critical roles in homologous recombination [HR]) in tissue from 177 cisplatin plus docetaxel-treated NSCLC p in the BREC trial. We correlated our findings with PFS, OS and response. Results: Median age 62; 79.1% male; 51.4% adenocarcinoma. Results of PALB2 mRNA expression were intriguing. PFS was 5.6 months (m) for p with high/intermediate (H-I) PALB2 and 4.1 m for p with low (L) PALB2 (p = 0.0018). OS was 13.2 m for p with H-I PALB2 compared to 9.9 for p with L PALB2 (p = 0.0377). In the univariate analysis, H-I PALB2 was a marker of longer PFS (HR = 0.56, 95% CI, 0.38, 0.80; p = 0.002) and OS (HR = 0.64, 95% CI, 0.41, 0.98; p = 0.0394). In the multivariate analysis, only H-I PALB2 was associated with longer PFS (here HR = 0.56 and p = 0.0022) and OS (HR = 0.61 and p = 0.0343). Among 143 p with data for response and PALB2 expression, 49.5% of p with H-I PALB2 were responders, compared to only 28% with L PALB2 (p = 0.0131). No significant differences were found for PFS, OS or response according to expression status of the other 4 biomarkers. Conclusions: Our findings reveal PALB2 to be a predictive and prognostic biomarker in advanced NSCLC p treated with docetaxel plus cisplatin. The BRCA1-PALB2-BRCA2 network is a critical determinant of responsiveness to DNA interstrand cross-linking agents and antimicrotubule agents. In our study, BRCA1 had no effect on treatment outcome of this population. PALB2 was found to be a strong marker to predict sensitivity to antimicrotubule agents, without affecting sensitivity to DNA damage-based chemotherapy. Disclosure: All authors have declared no conflicts of interest.

Theory of ultrafast photoinduced electron transfer from a bulk semiconductor to a quantum dot.

This paper describes analytical and numerical results from a model Hamiltonian method applied to electron transfer (ET) from a quasicontinuum (QC) of states to a set of discrete states, with and without a mediating bridge. Analysis of the factors that determine ET dynamics yields guidelines for achieving high-yield electron transfer in these systems, desired for instance for applications in heterogeneous catalysis. These include the choice of parameters of the laser pulse that excites the initial state into a continuum electronic wavepacket and the design of the coupling between the bridge molecule and the donor and acceptor. The vibrational mode on a bridging molecule between donor and acceptor has an influence on the yield of electron transfer via Franck-Condon factors, even in cases where excited vibrational states are only transiently populated. Laser-induced coherence of the initial state as well as energetic overlap is crucial in determining the ET yield from a QC to a discrete state, whereas the ET time is influenced by competing factors from the coupling strength and the coherence properties of the electronic wavepacket.

Ab Initio Study of the Adsorption of CO2 on Functionalized Benzenes

AbstractThe interaction of carbon dioxide with a series of functionalized aromatic molecules was studied by using quantum mechanical methods (MP2), to examine the effect of the substituent on the adsorption of CO2. Several different initial configurations of CO2 were taken into account for each functionalized benzene to locate the energetically most favorable configuration. To get a better estimation of the binding energies, we applied an extrapolation scheme to approach the complete basis set. CH2N3‐, COOH‐, and SO3H‐functionalized benzenes were found to have the strongest interaction with CO2, and the corresponding binding energies were calculated to be −3.62, −3.65, and −4.3 kcal mol−1, respectively. Electrostatic potential maps of the functionalized benzenes and electron redistribution density plots of the complexes were also created to get a better insight into the nature of the interaction of CO2 with the functionalized benzenes. The functional groups that were examined can be potentially incorporated in organic bridging molecules that connect the inorganic corners in MOF.

Surface code—biophysical signals for apoptotic cell clearance

Apoptotic cell death and the clearance of dying cells play an important and physiological role in embryonic development and normal tissue turnover. In contrast to necrosis, apoptosis proceeds in an anti-inflammatory manner. It is orchestrated by the timed release and/or exposure of so-called ‘find-me’, ‘eat me’ and ‘tolerate me’ signals. Mononuclear phagocytes are attracted by various ‘find-me’ signals, including proteins, nucleotides, and phospholipids released by the dying cell, whereas the involvement of granulocytes is prevented via ‘stay away’ signals. The exposure of anionic phospholipids like phosphatidylserine (PS) by apoptotic cells on the outer leaflet of the plasma membrane is one of the main ‘eat me’ signals. PS is recognized by a number of innate receptors as well as by soluble bridging molecules on the surface of phagocytes. Importantly, phagocytes are able to discriminate between viable and apoptotic cells both exposing PS. Due to cytoskeleton remodeling PS has a higher lateral mobility on the surfaces of apoptotic cells thereby promoting receptor clustering on the phagocyte. PS not only plays an important role in the engulfment process, but also acts as ‘tolerate me’ signal inducing the release of anti-inflammatory cytokines by phagocytes. An efficient and fast clearance of apoptotic cells is required to prevent secondary necrosis and leakage of intracellular danger signals into the surrounding tissue. Failure or prolongation of the clearance process leads to the release of intracellular antigens into the periphery provoking inflammation and development of systemic inflammatory autoimmune disease like systemic lupus erythematosus. Here we review the current findings concerning apoptosis-inducing pathways, important players of apoptotic cell recognition and clearance as well as the role of membrane remodeling in the engulfment of apoptotic cells by phagocytes.