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Here we present analysis of a novel reactive material system that employs dinitrogen tetroxide (N2O4) as a liquid oxidizer with metal powder fuels. The oxidizer was added to micron scale aluminum and zirconium powders by a remote injection system. When ignited with a high voltage spark, the mixtures were observed to possess reactivity comparable to nanocomposite reactive materials, with open-tube flame expansion velocities from 500 to 1400 m/s depending on fuel/oxidizer ratio and tube diameter. Temperatures were observed to range from 3000 to 3500 K as measured with gray body fits to 16-channel time-resolved pyrometer and time-integrated spectrometer data. These values were significantly below calculated adiabatic flame temperatures, which we attribute to local deviations from stoichiometry and kinetic/energetic limitations similar to those observed in studies of particles burning in high pressures gaseous oxidizers. Al/N2O4 reactivity was found to be most likely limited by the vaporization of the metal from the particle surface and Zr/N2O4 was limited by slower burning and complex interactions involving the solubility of nitrogen and oxygen in the molten Zr. We also discuss the potential for these materials to be used to create an “on/off” reactive material, since N2O4 can be added remotely and driven to evaporate via vacuum or purge of inert gases to return it to a safe condition.

Spin crossover complexes are known to undergo bond length, volume, and enthalpy changes during spin transition. In an explosive spin crossover complex, these changes could affect the mechanical and...

Spin crossover complexes are known to undergo bond length, volume, and enthalpy changes during spin transition. In an explosive spin crossover complex, these changes could affect the mechanical and initiation sensitivity of the explosive and lead to the development of a new class of sensitivity switchable materials. To explore this relationship, the well-known spin crossover compound [Fe(Htrz)

The sensitivity of explosives is controlled by factors that span from intrinsic chemical reactivity to mesoscale structure, and has been a topic of extensive study for over 50 years., The sensitivity of explosives is controlled by factors that span from intrinsic chemical reactivity and chemical intramolecular effects to mesoscale structure and defects, and has been a topic of extensive study for over 50 years. Due to these complex competing chemical and physical elements, a unifying relationship between molecular framework, crystal structure, and sensitivity has yet to be developed. In order to move towards this goal, ideally experimental studies should be performed on systems with small, systematic structural modifications, with modeling utilized to interpret experimental results. Pentaerythritol tetranitrate (PETN) is a common nitrate ester explosive that has been widely studied due to its use in military and commercial explosives. We have synthesized PETN derivatives with modified sensitivity characteristics by substituting one –CCH2ONO2 moiety with other substituents, including –CH, –CNH2, –CNH3X, –CCH3, and –PO. We relate the handling sensitivity properties of each PETN derivative to its structural properties, and discuss the potential roles of thermodynamic properties such as heat capacity and heat of formation, thermal stability, crystal structure, compressibility, and inter- and intramolecular hydrogen bonding on impact sensitivity. Reactive molecular dynamics (MD) simulations of the C/H/N/O-based PETN-derivatives have been performed under cook-off conditions that mimic those accessed in impact tests. These simulations infer how changes in chemistry affect the subsequent decomposition pathways.

We report the nitration of tris(hydroxymethyl)aminomethane to tris(nitromethyl)-aminomethane (2) and its corresponding hydrogen chloride (3) and hydrogen bromide (4) salts. While both 3 and 4 conglomerate into tetramers, there are significant differences in the packing of those tetrameric units. In both 3 and 4 the tetrameric units arrange in a hexagonal pattern, but in 3 the units adopt alternating orientations leading to severe interlocking of the alkyl nitrate groups. This ultimately leads to a 2-fold decrease in the mechanical sensitivity of 4 relative to 3 and suggests that utilizing anion size may lead to more efficient packing arrangements and reduced mechanical sensitivity in energetic salts.

A triazolotriazine carbonitrile (1) was formed by diazotization of 3-amino-5-cyano-1,2,4-triazole followed by treatment with nitroacetonitrile. Cyclization of the C≡N bond with sodium azide results in a tetrazolyl triazolotriazine (2). Formation of the sodium salt of 2, followed by metathesis with [PPN][Cl] resulted in the organic salt 3. Compounds 1, 2, and 3 were characterized by elemental analysis and infrared, 1H, and 13C{1H} NMR spectroscopy and 1 and 3 were characterized by single-crystal X-ray diffraction. Compound 2 has a density of 1.819 g cm−1, is thermally stable up to 305 °C, and is insensitive to impact, friction, and electrical discharge. The detonation pressure and velocity of 2 are calculated to be 27.04 GPa and 8.312 km s−1, respectively, making this a 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) replacement candidate.

The synthesis and characterization of new 1,2,4-triazolyl and 4-nitro-pyrazolyl substituted tetrazine ligands has been achieved. The strongly electron deficient 1,2,4-triazolyl substituted ligands did not coordinate Fe(II) metal centers, while the mildly electron deficient 4-nitro-pyrazolyl substituted ligands did coordinate Fe(II) metal centers in a 2:1 ratio of ligand to metal. The thermal stability and mechanical sensitivity characteristics of the complexes are similar to the conventional explosive pentaerythritol tetranitrate. The complexes had strong absorption in the visible region of the spectrum that extended into the near-infrared. In spite of having improved oxygen balances, increased mechanical sensitivity, and similar absorption of NIR light to recently reported Fe(II) tetrazine complexes, these newly synthesized explosives were more difficult to initiate with Nd:YAG pulsed laser light. Specifically, the complexes required lower densities (0.9 g/cm3) to initiate at the same threshold utilized ...

Time-dependent density functional theory was used to investigate optical absorption of novel Fe(II) coordination complexes with tetrazine ligands. These octahedral compounds absorb near-infrared (NIR) light and can be applied as secondary explosives with low laser-initiation thresholds compared to pentaerythritol tetranitrate. Herein, numerous ligand architectures are studied to determine relationships between molecular structure and optical absorption in order to tune the low-energy charge transfer (CT) band. Geometrical structures and vertical excitation energies calculated with the TPSSh density functional and 6-311G basis set are in excellent agreement with experiment, with a maximum deviation from UV–vis spectra of 0.10 eV. By altering molecular substituents of the ligand scaffold, the CT band can be tuned between 500 and 1100 nm. Additional conjugation in the ligand scaffold pushes the CT band into the NIR region of the spectrum. Triazolo-tetrazine ligands shift the CT band by approximately 0.70 eV ...

We have prepared energetic nitrate ester derivatives of 1,2,4,5-tetrazine and 1,2,4-triazolo[4,3-b]-[1,2,4,5]-tetrazine ring systems as model compounds to study the electrochemical behavior of tetrazines in the presence of explosive groups. The model compounds showed lower thermal stabilities relative to PETN (pentaerythritol tetranitrate), but slightly improved mechanical sensitivities. The presence of electron-rich amine donors leads to a cathodic shift of the tetrazine redox potentials relative to those of previously reported tetrazine explosives. At these potentials, electron-rich tetrazines with either covalently bound or co-dissolved nitrate ester groups are irreversibly reduced. Effectively, changes in the electronic structure of tetrazines affect their electrochemical response to the presence of nitrate ester groups. Thus, it may be possible to develop tetrazine-based electrochemical sensors for the detection of specific explosives and electrocatalysts for their disposal.

The synthesis and characterization of explosive coordination complexes of CuII with nitrogen-rich tetrazine ligands and nitrate counter-anions have been achieved. The complexes adopt a variety of coordination geometries including monomeric and dimeric architectures with five and six coordinate CuII centers. The thermal stabilities of the complexes correlate to the strength of the Cu–nitrate interaction such that more strongly bound nitrates exhibit higher thermal stability. Exchanging amine groups on the coordinating ligands with 3,3′-dinitroazetidine groups led to changes in the solid-state structures and increases to the impact sensitivity of the resulting complexes relative to the corresponding amine derivatives.

The synthesis and characterization of air stable Fe(II) coordination complexes with tetrazine and triazolo-tetrazine ligands and perchlorate counteranions have been achieved. Time-dependent density functional theory (TD-DFT) was used to model the structural, electrochemical, and optical properties of these materials. These compounds are secondary explosives that can be initiated with Nd:YAG laser light at lower energy thresholds than those of PETN. Furthermore, these Fe(II) tetrazine complexes have significantly lower sensitivity than PETN toward mechanical stimuli such as impact and friction. The lower threshold for laser initiation was achieved by altering the electronic properties of the ligand scaffold to tune the metal ligand charge transfer (MLCT) bands of these materials from the visible into the near-infrared region of the electromagnetic spectrum. Unprecedented decrease in both the laser initiation threshold and the mechanical sensitivity makes these materials the first explosives that are both safer to handle and easier to initiate than PETN with NIR lasers.

Proton relays are known to increase reaction rates for H2 evolution and lower overpotentials in electrocatalytic reactions. In this report we describe two electrocatalysts, [Fe4N(CO)11(PPh3)]− (1−) which has no proton relay, and hydroxyl-containing [Fe4N(CO)11(Ph2P(CH2)2OH)]− (2−). Solid state structures indicate that these phosphine-substituted clusters are direct analogs of [Fe4N(CO)12]− where one CO ligand has been replaced by a phosphine. We show that the proton relay changes the selectivity of reactions: CO2 is reduced selectively to formate by 1− in the absence of a relay, and protons are reduced to H2 under a CO2 atmosphere by 2−. These results implicate a hydride intermediate in the mechanism of the reactions and demonstrate the importance of controlling proton delivery to control product selectivity. Thermochemical measurements performed using infrared spectroelectrochemistry provided pKa and hydricity values for [HFe4N(CO)11(PPh3)]−, which are 23.7, and 45.5 kcal mol−1, respectively. The pKa of the hydroxyl group in 2− was determined to fall between 29 and 41, and this suggests that the proximity of the proton relay to the active catalytic site plays a significant role in the product selectivity observed, since the acidity alone does not account for the observed results. More generally, this work emphasizes the importance of substrate delivery kinetics in determining the selectivity of CO2 reduction reactions that proceed through metal–hydride intermediates.

We present laser-driven shock Hugoniot measurements of single-crystal (SC) 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) between 15 and 83 GPa, spanning pressures below and well above the Chapman–Jouguet pressure of ∼28 GPa for TATB formulations (TATB grains mixed with plastic binders at 5–10 wt. %). The new SC data are generally ∼3% more compressible than previously published data on neat and formulated TATB measured in gas-gun and explosive-driven experiments. An exception is at compressions in the density of ∼1.5 ( ∼30–40 GPa), where our new SC data exhibit significantly lower pressures than previous results on overdriven TATB formulations, suggesting that our SC samples remain largely unreacted below 35 GPa over the short nanosecond-time scales inherent to our laser-driven experiments. These novel equation-of-state measurements are a critical step toward understanding TATB in its most fundamental form and improving predictive modeling of TATB-based explosives.

Photoactive explosives show promise to be relatively insensitive to impact and friction compared to pentaerythritol tetranitrate (PETN) and other detonator materials, but can be more easily initiated with laser light. Metal-ligand charge transfer (MLCT) complexes have been previously shown to have tunable explosive properties and absorption profiles, making them strong candidates for laser detonator materials. Here, we provide a summary of the synthesis and characterization of multiple iron-based MLCT complexes, as well as results from recent efforts to initiate detonation in a high-density PETN output pellet. Paths forward will be discussed.

Understanding the factors that influence sensitivity is critical for the design and screening of new energetic molecules and materials, but it is often difficult to isolate a single variable to analyze its effect. Pentaerythritol tetranitrate (PETN) is a very common nitrate ester explosive that has been widely studied due to its use in military and commercial explosives. We have developed PETN derivatives with modified sensitivity characteristics by substituting the -CCH2ONO2 moiety with other substituents, including -CH, -CNH2, -CNH3X, -CCH3, or -PO. We relate the handling sensitivity properties of each PETN derivative to its structure, and discuss the potential roles of the central atom, oxygen balance, thermal stability, heat capacity, crystal structure, and inter- and intramolecular hydrogen bonding on impact sensitivity. Reactive molecular dynamics (MD) simulations of the C, H, N, O-based PETN-derivatives have been performed under cook-off conditions that provide insights into how the substituents change the initial chemistry and decomposition paths.

The synthesis of pentaerythritol trinitrate persubstituted 1,2,4,5-tetrazine and 1,3,5-triazine is reported. These materials were characterized with respect to their chemical and energetic materials properties. X-ray crystallographic analyses were also performed. The UV/Vis, Raman, and cyclic voltammetry data were collected and are reported.

The synthesis of 1,2,4,5-tetrazinylamino-1,2,4,5-tetrazines is reported, including the preparation of compounds containing three tetrazine heterocycles in a single compound. These materials were compared to phenylamine derivatives, also synthesized in this study. The UV/Vis and cyclic voltammetry data were collected and are reported, along with the crystal structure of one of the tritetrazine compounds.

Herein, we report that molecular aluminium complexes of the bis(imino)pyridine ligand, (PhI2P2−)Al(THF)X, X = H (1), CH3 (2), promote selective dehydrogenation of formic acid to H2 and CO2 with an initial turnover frequency of 5200 turnovers per hour. Low-temperature reactions show that reaction of 1 with HCOOH affords a complex that is protonated three times: twice on the PhI2P2− ligand and once to liberate H2 or CH4 from the Al-hydride or Al-methyl, respectively. We demonstrate that in the absence of protons, insertion of CO2 into the Al-hydride bond of 1 is facile and produces an Al-formate. Upon addition of protons, liberation of CO2 from the Al-formate complex affords an Al-hydride. Deuterium labelling studies and the solvent dependence of the reaction indicate that outer sphere β-hydride abstraction supported by metal–ligand cooperative hydrogen bonding is a likely mechanism for the C–H bond cleavage.

Summary A comprehensive and coherent approach to spatial patterning in human posture and movement is visible on the horizon. Advances in the study of fascia, neural plasticity, and epigenetics allow an overarching theory to unite all who work in human movement from osteopaths to personal trainers. Trainers, rehab specialists, manual therapists and physical educators are joining to embrace and develop this unifying construct to help our growing children meet the demands of the 21st century electronic environment.

The control of radical reactions to afford selective carbon–carbon bond formation is a significant synthetic challenge with applications ranging from small-molecule activation to natural product synthesis. Oxidation of (IP–)2Al(CH3) (1, IP = iminopyridine) with TrBPh4 (Tr = trityl) afforded the C–C coupled product [(IP)(Tr-IP)Al(CH3)][BPh4] (2) in which the trityl radical and the IP– radical have undergone C–C bond formation. In contrast, oxidation of 1 with TrBArF24 {BArF24 = tetrakis[(3,5-trifluoromethyl)phenyl]borate} or TrB(C6F5)4 affords cationic [(IP)(IP–)Al(CH3)][BArF24] (3a) or [(IP)(IP–)Al(CH3)][B(C6F5)4] (3b), respectively . The different reaction outcomes provided by the different counteranions of Tr+ imply that a difference in stability of the products or of the intermediate mixed-valent [(IP)(IP-)Al(CH3)]+ state exists. We speculate that the most likely factor is the difference in solubility afforded by the different anions of the products that are formed. We also show that the formation of stable, cationic biradical complexes is possible and that these complexes do not undergo C–C radical coupling at the IP ligand. Cationic [(IP–)2Al(OEt2)][BArF24] (4) was obtained by protonolysis of 1 with H(OEt2)2BArF24, and two-electron oxidation of [(IP2–)2Al]– (5) afforded [(IP–)2Al(thf)][BArF24] (6).

Time-dependent density functional theory (TD-DFT) was used to investigate the relationship between molecular structure and the one- and two-photon absorption (OPA and TPA, respectively) properties of novel and recently synthesized conjugated energetic molecules (CEMs). The molecular structures of CEMs can be strategically altered to influence the heat of formation and oxygen balance, two factors that can contribute to the sensitivity and strength of an explosive material. OPA and TPA are sensitive to changes in molecular structure as well, influencing the optical range of excitation. We found calculated vertical excitation energies to be in good agreement with experiment for most molecules. Peak TPA intensities were found to be significant and on the order of 10(2) GM. Natural transition orbitals for essential electronic states defining TPA peaks of relatively large intensity were used to examine the character of relevant transitions. Modification of molecular substituents, such as additional oxygen or other functional groups, produces significant changes in electronic structure, OPA, and TPA and improves oxygen balance. The results show that certain molecules are apt to undergo nonlinear absorption, opening the possibility for controlled, direct optical initiation of CEMs through photochemical pathways.

The synthesis of two four-coordinate and square planar (SP) complexes of aluminum(III) is presented. Reaction of a phenyl-substituted bis(imino)pyridine ligand that is reduced by two electrons, Na2((Ph)I2P(2-)), with AlCl3 afforded five-coordinate [((Ph)I2P(2-))Al(THF)Cl] (1). Square-planar [((Ph)I2P(2-))AlCl] (2) was obtained by performing the same reaction in diethyl ether followed by lyphilization of 2 from benzene. The four-coordinate geometry index for 2, τ4, is 0.22, where 0 would be a perfectly square-planar molecule. The analogous aluminum hydride complex, [((Ph)I2P(2-))AlH] (3), is also square-planar, and was characterized crystallographically and has τ4=0.13. Both 2 and 3 are Lewis acidic and bind 2,6-lutidine.

Background: Triple-negative breast cancer (TNBC) lacks the receptor targets ER, PR, and HER2 and thus it does not respond to receptor-targeted treatments such as hormonal therapy and trastuzumab, leaving chemotherapy as the mainstay of treatment. TNBC also has higher recurrence, metastasis, and mortality rates than other receptor subtypes. The MAPK (RAS/MEK/ERK) pathway plays a crucial role in cancer cell survival, invasion, and metastasis and critically contributes to aggressive features of TNBC, as demonstrated by our novel therapeutic synergy identification screening of RNA interference. Two BRAF inhibitors (vemurafenib and dabrafenib) and two MEK inhibitors (trametinib and cobimetinib) have received U.S. Food and Drug Administration approval for treatment of melanoma, clinically validating the potential of MAPK pathway inhibition to meaningfully benefit patients with TNBC. However, the rapidly emerging resistance of TNBC to current standard treatments and disease progression remain clinical challenges for these pathway-targeted agents. E6201 is a novel MEK1 inhibitor being evaluated in phase 1 clinical trials in patients with advanced solid tumors (NCT00794781) and with melanoma metastasized to the central nervous system (NCT03332589). In the preclinical study described herein, we determined the in vitro anti-tumor efficacy and in vivo anti-metastatic efficacy of E6201 in TNBC to prepare for further development of E6201 in the clinic. Methods: The anti-tumor effects of E6201 were examined using cell proliferation and anchorage-independent colony-formation assays. To evaluate the anti-metastatic activity of E6201 in vitro and in vivo, a migration/invasion assay and an experimental/spontaneous metastasis assay were performed, respectively. Results: In vitro cell proliferation data demonstrated that E6201 inhibited growth more effectively (half maximal inhibitory concentration [IC50] range: 0.05-5 µM) than did other MEK inhibitors (selumetinib, pimasertib, and trametinib). E6201 inhibited TNBC cell-colony formation in a dose-dependent manner (P = 0.0001). Also, E6201 suppressed the migration and invasion of MDA-MB-231 (IC50: 1 µM) and SUM149 (IC50: 0.25 µM) cells in a dose-dependent manner (P = 0.001). In vivo experimental and spontaneous metastasis assays demonstrated that E6201 inhibited lung metastases of the SUM149 and MDA-MB-231-LM2 cell lines (P = 0.0001). Immunohistochemical staining demonstrated that E6201 decreased the metastatic burden in the lung (P = 0.011) and decreased phosphorylated ERK expression in a dose-dependent manner. Conclusion: Taken together, these data demonstrate that E6201 is an effective inhibitor targeting the MAPK pathway in TNBC, showing anti-tumor efficacy in vitro and anti-metastatic efficacy in vivo. Our data provide a rationale for further clinical development of E6201 as MEK-targeted therapy for treatment of TNBC. Citation Format: Jangsoon Lee, Bora LIM, Kuicheon Choi, Troy Pearson, Linda Paradiso, Thomas Myers, Debu Tripathy, Naoto T. Ueno. E6201, a novel MEK1 inhibitor, suppresses the metastatic capability of triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5780.

Summary Shoulder dysfunctions are frequently accompanied by a pattern of retraction in key myofascial components. Soft-tissue release techniques for three pivotal myofascial ‘tethers’ in the shoulder complex—subclavius, pectoralis minor, and teres minor—are described in terms of assessment, palpation, and treatment.

A proton shuttle in the second coordination sphere of [Fe4N(CO)12]– promotes H2 evolution over formate formation from CO2., Proton relays are known to increase reaction rates for H2 evolution and lower overpotentials in electrocatalytic reactions. In this report we describe two electrocatalysts, [Fe4N(CO)11(PPh3)]– (1 –) which has no proton relay, and hydroxyl-containing [Fe4N(CO)11(Ph2P(CH2)2OH)]– (2 –). Solid state structures indicate that these phosphine-substituted clusters are direct analogs of [Fe4N(CO)12]– where one CO ligand has been replaced by a phosphine. We show that the proton relay changes the selectivity of reactions: CO2 is reduced selectively to formate by 1 – in the absence of a relay, and protons are reduced to H2 under a CO2 atmosphere by 2 –. These results implicate a hydride intermediate in the mechanism of the reactions and demonstrate the importance of controlling proton delivery to control product selectivity. Thermochemical measurements performed using infrared spectroelectrochemistry provided pK a and hydricity values for [HFe4N(CO)11(PPh3)]–, which are 23.7, and 45.5 kcal mol–1, respectively. The pK a of the hydroxyl group in 2 – was determined to fall between 29 and 41, and this suggests that the proximity of the proton relay to the active catalytic site plays a significant role in the product selectivity observed, since the acidity alone does not account for the observed results. More generally, this work emphasizes the importance of substrate delivery kinetics in determining the selectivity of CO2 reduction reactions that proceed through metal–hydride intermediates.

Complexes of 3-amino-6-(3,5-dimethylpyrazole)tetrazine) (NH2TzDMP, 1) and 3-(3,3'-dinitroazetidine)-6-(3,5-dimethylpyrazole)tetrazine) (DNAZTzDMP, 2) with first row transition metal centers were synthesized. Reactions of Fe(II)(H2O)6(BF4)2 and Fe(NO3)3·9H2O with 1 and 2 both led to complexes of the form [(RTzDMP)3Fe]X2 (X = BF4, R = NH2 (3), DNAZ (4); X = NO3, R = NH2 (5), DNAZ (6)), which showed intense MLCT bands in the visible region of the spectrum. Ligands 1 and 2 also reacted with Cu(II)(NO3)2·5/2H2O to form [(RTzDMP)2Cu(NO3)][NO3] (R = NH2 (7), DNAZ (8)) in addition to reacting with Cu(I)(CH3CN)4(PF6) to form [(RTzDMP)2Cu][PF6] (R = NH2 (9), DNAZ (10)). Lastly reactions of 1 and 2 with Co(NO3)2·6H2O and Ni(NO3)2·6H2O led to [(NH2TzDMP)2Co(H2O) (NO3)][NO3] (11), [(DNAZTzDMP)2Co(H2O)2][NO3]2 (12), [(NH2TzDMP)3Ni][NO3]2 (13), and [(DNAZTzDMP)2Ni(H2O)2][NO3]2 (14). The complexes display rich electrochemical and photophysical properties that are unaffected by derivation with explosive groups.

The engineering of high-performance enzymes for future sequencing and PCR technologies as well as the development of many anticancer drugs requires a detailed analysis of DNA/RNA synthesis processes. However, due to the complex molecular interplay involved, real-time methodologies have not been available to obtain comprehensive information on both binding parameters and enzymatic activities. Here we introduce a chip-based method to investigate polymerases and their interactions with nucleic acids, which employs an electrical actuation of DNA templates on microelectrodes. Two measurement modes track both the dynamics of the induced switching process and the DNA extension simultaneously to quantitate binding kinetics, dissociation constants and thermodynamic energies. The high sensitivity of the method reveals previously unidentified tight binding states for Taq and Pol I (KF) DNA polymerases. Furthermore, the incorporation of label-free nucleotides can be followed in real-time and changes in the DNA polymerase conformation (finger closing) during enzymatic activity are observable.

The synthesis of accurate, full-length cDNA from low-abundance RNA and the subsequent PCR amplification under conditions which provide amplicon that contains minimal mutations remain a difficult molecular biological process. Many of the challenges associated with performing sensitive, long RT/PCR have been alleviated by using a mixture of DNA polymerases. These mixtures have typically contained a DNA polymerase devoid of 3'-5' exonuclease, or "proofreading", activity blended with a small amount of an Archaea DNA polymerase possessing 3'-5' exonuclease activity, since reverse transcriptases lack 3'-5' exonuclease activity and generally have low fidelity. To create a DNA polymerase with efficient reverse transcriptase and 3'-5' exonuclease activity, a family of mutant DNA polymerases with a range of attenuated 3'-5' exonuclease activities was constructed from a chimeric DNA polymerase derived from Thermus species Z05 and Thermotoga maritima DNA polymerases. These "designer" DNA polymerases were fashioned using structure-based tools to identify amino acid residues involved in the substrate-binding site of the exonuclease domain of a thermostable DNA polymerase. Mutation of some of these residues resulted in proteins in which DNA polymerase activity was unaffected, while proofreading activity ranged from 60% of the wild-type level to undetectable levels. Kinetic characterization of the exonuclease activity indicated that the mutations affected catalysis much more than binding. On the basis of their specificity constants (kcat/KM), the mutant enzymes have a 5-15-fold stronger preference for a double-stranded mismatched substrate over a single-stranded substrate than the wild-type DNA polymerase, a desirable attribute for RT/PCR. The utility of these enzymes was evaluated in a RT/PCR assay to generate a 1.7 kb amplicon from HIV-1 RNA.

Addition of the O–H bonds in water across the aluminum–nitrogen bond of a molecular aluminum–amido complex affords an alumoxane. The reaction of (PhI2P2–)AlH (1) with water forms dimeric [(PhHI2P–)AlH](μ-O) (2) under mild conditions. Upon reaction of 2 with excess water [(PhHI2P–)Al(OH)](μ-O) (3) is formed with liberation of H2.

Redox-active Group 13 molecules possess the unusual combination of concomitant redox and acid-base reactivity. These combined properties enable regeneration of a metal hydroxide complex in a cycle for conversion of CO2 into carbonate salts. Reaction of (IP(-))2Al(OH) (M = Al, Ga) with 1 atm of CO2 affords [(IP(-))2Al]2(μ(2)κ(1):κ(2)-OCO2). Subsequent reduction affords MgCO3 or CaCO3 and two equivalents of [(IP(2-))2Al](-), which can be reoxidized to (IP(-))2Al(OH) to close a cycle.

Structural Integration (SI), known popularly as ‘rolfing', 1 1Capital R ‘Rolfing ® ' and ‘Rolfer ® ' are registered service marks of the Rolf Institute ® , one of more than a dozen schools of Structural Integration. Therefore, ‘Structural Integration', Dr. Rolf's original name for her work, is becoming the generic designation for this type of manipulative approach. The word ‘rolfing'—a nickname for her work which came from her time in the Esalen Institute in California, and a name she herself disliked and only reluctantly accepted—remains, for the time being, the more publicly known term for this type of work. is a systematic programme of connective tissue manipulation. Parts 1 and 2 of this series defined the scope of SI practice, and presented a general outline of Dr. Rolf's multi-session protocol of the SI ‘Recipe'. In this final part we present an alternate version based on longitudinal myofascial continuities.

Structural Integration (SI), known popularly as ‘rolfing', 1 1In the inevitable fractures and resultant legal battles which followed Dr. Rolf's death, the terms ‘Rolfing ® ' and ‘Rolfer ® ' became registered service marks of the Rolf Institute, which is now one of perhaps a dozen schools of Structural Integration. Therefore, ‘Structural Integration', Dr. Rolf's original name for her work, is becoming the generic designation for this type of manipulative approach. The word ‘rolfing'—a nickname for her work which came from her time in the Esalen Institute in California, and a name she herself disliked and only reluctantly accepted—remains, for the time being, the more publicly known term for this type of work. is a systematic programme of postural repatterning via connective tissue manipulation that has gained increased attention and application during the current Renaissance of natural therapies. SI has also been the object of jokes and misconceptions, as in "Rolfing—isn't that the one where they flay your muscles off the bone and make you scream about your mother?" (Rolfing, Healing Arts Press, Rochester, VT, 1977; Feitis, Ida Rolf Talks. Rolf Institute, Boulder, CO, USA, 1978.) The intent of this series is to allay some of these misconceptions by briefly defining the scope of SI practice, and presenting a general outline of Dr. Rolf's central contribution, the multi-session protocol of the SI ‘Recipe' and the somatic balance it is designed to evoke. The variations among various current SI programs will be explored, and an alternate version of the SI protocol based on longitudinal myofascial continuities is also presented. 2 2The author would like to emphasize that the views expressed in this article are his and his alone. While every attempt has been made to get the facts straight, there is much debate within the Structural Integration community as to which key concepts are primary, the exact intent of Ida Rolf when contradictory statements appear in the record, as well as to the actual application and scope of practice of SI. The author does not speak for the Rolf Institute, or any other SI school or organization. The author hopes for and welcomes other contributions to debatable issues from within and without the larger SI community. In Part 1, we explored the history and scope of SI, and argued that the ‘recipe' that Dr. Rolf developed was the central contribution of her approach, rather than the collective library of techniques. Here in Part 2, we explore the internal logic of Dr. Rolf's SI ‘recipe', before going on to detail variations in its current presentation.

Structural integration (SI), known popularly as ‘rolfing', 1 1In the inevitable fractures and resultant legal battles which followed Dr. Rolf's death, the terms ‘Rolfing ® ' and ‘Rolfer ® ' became registered service marks of the Rolf Institute, which is now one of perhaps a dozen schools of Structural Integration. Therefore, 'Structural Integration', Dr. Rolf's original name for her work, is becoming the generic designation for this type of manipulative approach. The word ‘rolfing'—a nickname for her work which came from her time in the Esalen Institute in California, and a name she herself disliked and only reluctantly accepted —remains, for the time being, the more publicly known term for this type of work. is a systematic program of postural repatterning via connective tissue manipulation that has gained increased attention and application during the current Renaissance of natural therapies. SI has also been the object of jokes and misconceptions, as in "Rolfing—isn't that the one where they flay your muscles off the bone and make you scream about your mother?" The intent of this series is to allay some of these misconceptions by briefly defining the scope of SI practice, and presenting a general outline of Dr. Rolf's central contribution, the multi-session protocol of the Structural Integration ‘Recipe' and the somatic balance it is designed to evoke. The variations among various current Structural Integration programs will be explored, and an alternate version of the SI protocol based on longitudinal myofascial continuities is also presented. 2 2The author would like to emphasize from the outset that the views expressed in this article are his and his alone. While every attempt has been made to get the facts straight, there is much debate within the Structural Integration community as to which key concepts are primary, the exact intent of Ida Rolf when contradictory statements appear in the record, as well as to the actual application and scope of practice of SI. The author does not speak for the Rolf Institute, or any other SI school or organization. The author hopes for and welcomes other contributions to debatable issues from within and without the larger SI community.

Use of SiCl4 as an organometallic reagent can be complicated by access to Si3+, Si2+, and unwanted sigmatropic rearrangements. Herein we report a mild reduction route, using (IP–)2Mg(THF) (1) and M...

Background: CDH3 gene overexpression of P-cadherin correlates with increased tumor cell invasiveness and is observed in breast, colon, lung, and pancreatic tumors. FF-21101 is a human-mouse chimeric monoclonal antibody directed against P-cadherin, conjugated with 111In for dosimetry and 90Y for therapy. This first-in-human study assesses dosimetry (biodistribution) and therapeutic outcome of FF-21101(90Y). Methods: For dosimetry, patients (pts) received 5 mCi/5mg FF-21101(111In) 1 week before the FF-21101(90Y) therapeutic dose to assess biodistribution and ensure 90Y radiation dose estimates did not exceed the recommended allowable limit for each organ. Single therapeutic dose cohorts were planned for FF-21101(90Y) (8 mCi/mg) at 5, 10, 15, 20 or 25 mCi/m2 (3+3 dose escalation schema), with repeat doses allowed every 4 cycles. Disease assessments were based on RECIST V1.1. Pre-treatment tumor samples were assessed for P-cadherin expression by immunohistochemistry (IHC). Pharmacokinetics (PK) of FF-21101 also were assessed. Results: Seven pts (3M, 4F) with advanced primary solid tumors and loco-regional metastases were treated with FF-21101(90Y) in the first 3 dose cohorts. Median (range) values: age 55 years (31 – 69), number of prior treatments, including surgery, radiation and/or chemotherapy 5 (2 – 8); tumor types: ovarian carcinoma (CA) (2 pts), vaginal CA, pancreatic neuroendocrine tumor (PNET), desmoplastic small round cell (DSRC) tumor, colorectal CA (CRC), recurrent liposarcoma (1 pt each). Primary and/or metastatic tumors from 4 of 7 pts (57.1%) demonstrated positive uptake of FF-21101(111In). Highest uptake was seen in epithelial tumors, consistent with P-cadherin targeting. Median (range) time on study following the FF-21101(90Y) dose was 8 (4 – 40) weeks. The vaginal CA pt demonstrated an 18.5% decrease as best response through 16 weeks following a single therapeutic dose. A viable pre-study tumor sample was not available for IHC staining. Pre-treatment tumor samples available from 6 of 7 patients demonstrated high H scores (≥ 100) in 3 pts (50%); 2 ovarian and 1 PNET; all remain on study through 4, 12 and 40 weeks, respectively, thus demonstrating the potential predictive utility of pre-treatment tumor P-cadherin expression. FF-21101(90Y) has been well-tolerated. Drug-related adverse events (AEs) include Gr 1 rash (1 pt) and increased AST (Gr 1/2, 2 pts) at 5 mCi/m2, and lymphopenia (1 Gr 3 in 3 pts at 10 mCi/m2), all reversible. There have been no drug-related serious AEs. Mean FF-21101 Cmax and AUC0-t increased with dose, suggesting linear PK. Conclusions: Tumor P-cadherin overexpression provides an attractive target for radioimmunotherapy. FF-21101(111In/90Y) exhibits favorable dosimetry, good tolerability and preliminary evidence of reduction in tumor burden. Pre-treatment tumor P-cadherin expression may be an important biomarker for patient selection. Citation Format: Vivek Subbiah, William Erwin, Osama Mawlawi, Carlos Gonzalez Lepera, Masahiko Tokura, Masayuki Kawakami, Holly Liu, Shubham Pant, Michele Rosner, Mary Johansen, Louis De Palatis, Thomas Myers, Linda Paradiso, Elmer Santos, Gregory Ravizzini. Phase 1 study of FF-21101(90Y), a radioimmunotherapeutic targeting P-cadherin, in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT097. doi:10.1158/1538-7445.AM2017-CT097

Background: FF10502-01 is a synthetic pyrimidine nucleoside analogue that is structurally similar to gemcitabine with a substitution of sulfur for oxygen in the pentose ring. FF-10502-01 showed potent anti-tumor activity in preclinical studies. In Capan-1 and SUIT-2 pancreatic ca xenograft models, FF-502-01 achieved superior tumor growth suppression and survival, respectively, compared to gemcitabine (gem), with less toxicity at clinically relevant doses. In gem-resistant pancreatic PDX models, FF-10502-01, alone and in combination with nab-paclitaxel (nab-pac), had higher efficacy and tolerability than gem/gem+nab-pac. Methods: We conducted a standard 3+3, dose-escalation phase 1 trial with FF-10502-01 to determine safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) i.e. FF-10502 incorporation into peripheral blood cellular DNA, and preliminary antitumor activity. Eligibility criteria included age >18 years, solid tumors refractory to standard treatment and adequate organ function. FF-10502-01 was administered IV over 60 minutes on days 1, 8, and 15 every 4 weeks. Planned dosing cohorts included 8, 12, 18, 27, 40, 60, 90, 135 and 200 mg/m2. Supportive medications such as anti-nausea prophylaxis were allowed. Results: 22 patients (pts) have been treated in 6 dose cohorts of 8-60 mg/m2. The median number of cycles received was 2 (range 1 to >12). Pts with the following cancers were enrolled: pancreatic (5 pts); ovarian and cholangiocarcinoma (3 each); parotid gland, prostate, and sarcoma (2 each); and endometrial, squamous cell carcinoma of the head and neck, anal, colon-neuroendocrine, and unknown primary (1 pt each). 11 pts were male and 11 female, median age 63 years (range 21-80), average number of prior cytotoxic therapies 3 (range 1-7) and 9 pts with prior gemcitabine therapy. Common related adverse events were Gr 1/2 nausea (43%), rash (38%), fever (29%), fatigue (19%), and vomiting despite prophylactic ondansetron and dexamethasone (14%). One pt had Gr 3 nausea (a DLT). Cytopenias have been minimal: 2 pts with Gr 1 and 2 anemia; with no neutropenia or thrombocytopenia. No pts have required dose reduction for toxicity. To date, an MTD has not been identified and enrollment continues. A pt with chondroblastic osteogenic sarcoma (18 mg/m2) achieved an unconfirmed partial response (73% decrease) in a maxillary mass but developed progressive disease at another site. 3 currently active patients (1 each of acinar pancreatic, prostate, parotid gland), demonstrated durable stable disease for > 48, 40 and 28 weeks, respectively, at doses ranging from 8 to 27 mg/m2. FF-10502 plasma concentrations increased with dose. Additional PK and PD data will be presented. Conclusions: The pyrimidine nucleoside antimetabolite FF-10502-01 is well tolerated with prophylactic anti-emetics and demonstrated preliminary antitumor activity in heavily pretreated patients. Citation Format: Gerald Steven Falchook, Lindsay Bramwell, Lori Hannan, Deeksha Vishwamitra, Takayuki Yamada, Michele Rosner, David Wages, Thomas Myers, Linda Paradiso, Filip Janku. First-in-human phase 1 trial of pyrimidine anti-metabolite FF-10502-01 in patients with advanced cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT100. doi:10.1158/1538-7445.AM2017-CT100

Summary The author welcomes comment on this initial attempt to set an agenda on applying manual therapeutic principles to Physical Education. New skills, tools, and insights (as well as revived ancient techniques) have developed within this field that have wide educational application. Furthermore, these tools are particularly adapted to the needs of the coming century. Opportunities abound for applying these insights educationally to more general populations than have been reached so far by individual practitioners doing one-on-one work in middle-to-upper class venues. As ‘Kinesthetic Dystonia’ comes to be recognized as a societal misapplication of education, a synthesis of diverse bodywork and movement approaches will be applied to combat it. All the work we have done to date is valuable empirical research; may we make the most of this opportunity for its wider application.

Myofascial continuities are key to global pattern assessment in bodywork and movement treatments. Five major lines are traced and their clinical implications discussed.

Myofascial continuities are key to global pattern assessment in bodywork and movement treatments. Five major lines are traced and their clinical implications discussed.

Molecular profiling of tumor tissue to detect alterations, such as oncogenic mutations, plays a vital role in determining treatment options in oncology. Hence, there is an increasing need for a robust and high-throughput technology to detect oncogenic hotspot mutations. Although commercial assays are available to detect genetic alterations in single genes, only a limited amount of tissue is often available from patients, requiring multiplexing to allow for simultaneous detection of mutations in many genes using low DNA input. Even though next-generation sequencing (NGS) platforms provide powerful tools for this purpose, they face challenges such as high cost, large DNA input requirement, complex data analysis, and long turnaround times, limiting their use in clinical settings. We report the development of the next generation mutation multi-analyte panel (MUT-MAP), a high-throughput microfluidic, panel for detecting 120 somatic mutations across eleven genes of therapeutic interest (AKT1, BRAF, EGFR, FGFR3, FLT3, HRAS, KIT, KRAS, MET, NRAS, and PIK3CA) using allele-specific PCR (AS-PCR) and Taqman technology. This mutation panel requires as little as 2 ng of high quality DNA from fresh frozen or 100 ng of DNA from formalin-fixed paraffin-embedded (FFPE) tissues. Mutation calls, including an automated data analysis process, have been implemented to run 88 samples per day. Validation of this platform using plasmids showed robust signal and low cross-reactivity in all of the newly added assays and mutation calls in cell line samples were found to be consistent with the Catalogue of Somatic Mutations in Cancer (COSMIC) database allowing for direct comparison of our platform to Sanger sequencing. High correlation with NGS when compared to the SuraSeq500 panel run on the Ion Torrent platform in a FFPE dilution experiment showed assay sensitivity down to 0.45%. This multiplexed mutation panel is a valuable tool for high-throughput biomarker discovery in personalized medicine and cancer drug development.