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Although weighted total least-squares (WTLS) adjustment within the errors-in-variables (EIV) model is a rigorous method developed for parameter estimation, its exact solution is complicated since the matrix operations are extremely time-consuming in the whole repeated iteration process, especially when dealing with large data sets. This paper rewrites the EIV model to a similar Gauss–Markov model by taking the random error of the design matrix and observations into account, and reformulates it as an iterative weighted least-squares (IWLS) method without complicated theoretical derivation. IWLS approximates the “exact solution” of the general WTLS and provides a good balance between computational efficiency and estimation accuracy. Because weighted LS (WLS) method has a natural advantage in solving the EIV model, we also investigate whether WLS can directly replace IWLS and WTLS to implement the EIV model when the parameters in the EIV model are small. The results of numerical experiments confirmed that IWLS can obtain almost the same solution as the general WTLS solution of Jazaeri [21] and WLS can achieve the same accuracy as the general WTLS when the parameters are small.

Supplementary Materials and Methods Supplementary References Tables S1 to S3 and legends Figures S1 to S4 and legends

Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non–small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC.Significance:These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-a-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo.

Conditional overexpression of histone reader Tripartite motif containing protein 24 (TRIM24) in mouse mammary epithelia (Trim24COE) drives spontaneous development of mammary carcinosarcoma tumors, lacking ER, PR and HER2. Human carcinosarcomas or metaplastic breast cancers (MpBC) are a rare, chemorefractory subclass of triple-negative breast cancers (TNBC). Comparison of Trim24COE metaplastic carcinosarcoma morphology, TRIM24 protein levels and a derived Trim24COE gene signature reveals strong correlation with human MpBC tumors and MpBC patient-derived xenograft (PDX) models. Global and single-cell tumor profiling reveal Met as a direct oncogenic target of TRIM24, leading to aberrant PI3K/mTOR activation. Here, we find that pharmacological inhibition of these pathways in primary Trim24COE tumor cells and TRIM24-PROTAC treatment of MpBC TNBC PDX tumorspheres decreased cellular viability, suggesting potential in therapeutically targeting TRIM24 and its regulated pathways in TRIM24-expressing TNBC.

Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We have previously identified a subset of cancers harbouring homozygous deletion of the glycolytic enzyme enolase (ENO1) that have exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. Here, we show that a small-molecule enolase inhibitor, POMHEX, can selectively kill ENO1-deleted glioma cells at low-nanomolar concentrations and eradicate intracranial orthotopic ENO1-deleted tumours in mice at doses well-tolerated in non-human primates. Our data provide an in vivo proof of principle of the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential use across a range of therapeutic settings.

A high pulse energy and high beam quality Nd:YAG laser system with extremely high brightness of 105 PW/sr $\cdot $ cm2 is reported. The system is based on a master oscillator power amplifier scheme containing a Nd:YVO4 mode-locked oscillator, laser diode end-pumped Nd:YAG regenerative amplifier, O6.35-mm double-pass amplifier, and two O15-mm double-pass amplifiers. Laser pulses with energy of 363 mJ and pulse duration of 63 ps were obtained at a repetition rate of 100 Hz, corresponding to a peak power of ~5.76 GW. A near-Gaussian beam with $M^{2} and a narrow bandwidth with 0.17 nm were achieved, which make this laser system an attractive light source for ultra-remote laser ranging.

Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal

Inhibition of glutaminase-1 (GLS-1) hampers the proliferation of tumor cells reliant on glutamine. Known glutaminase inhibitors have potential limitations, and in vivo exposures are potentially limited due to poor physicochemical properties. We initiated a GLS-1 inhibitor discovery program focused on optimizing physicochemical and pharmacokinetic properties, and have developed a new selective inhibitor, compound 27 (IPN60090), which is currently in phase 1 clinical trials. Compound 27 attains high oral exposures in preclinical species, with strong in vivo target engagement, and should robustly inhibit glutaminase in humans.

Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non–small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC. Significance: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.

Electronic expansion valve (EEV) takes advantages of its fast response, wide working range and accurate control and is been widely used in CO2 heat pump and air-conditioning system while the CO2 mass flow characteristics is the most crucial parameter for EEV. Different from other refrigerants, at the inlet of EEV, CO2 maintains at supercritical state. In this study, the effects of inlet pressure, inlet temperature, outlet pressure, EEV flowing area and EEV geometries on CO2 mass flowing through EEVs have been investigated under a wide operation range for three different EEVs. Meanwhile, a new empirical correlation has been developed to predict the mass flow rate of CO2 flowing through EEVs based on the experimental data. The proposed dimensionless correlation shows a good agreement with the test data. Approximately 91.8% of the experimental data within a relative deviation of ±5% for all EEVs. The average deviation and standard deviation of the predictions are 0.36% and 1.93% respectively.

Although the weighted total least squares (WTLS) adjustment is a rigorous method for estimating parameters in errors-in-variables (EIV) models, its solution is unreliable if the design matrix and/or observations contain multiple outliers. Existing methods are not capable of fully eliminating the influence of multiple outliers on the parameters. First, we reformulate an EIV model as a correction model by taking the outliers of the design matrix and observations into account, and we introduce the concept of total outliers to simplify the problem of detecting multiple outliers in EIV models. Then, based on the effect of the outliers on the estimated posteriori variance, we develop a full search algorithm to form a location matrix that can describe the location of the total outliers. Next, we derive a set of formulae to numerically estimate the unknown model parameters and total outliers simultaneously. Finally, the results of three numerical experiments show that the proposed method can effectively eliminate the influence of the outliers and obtain reliable parameters.

A high gain, low thermal-induced wavefront distortion, laser diode-pumped Nd: YAG slab amplifier is demonstrated with its active media dimensions of 7 mm × 35 mm × 138.2 mm. Under the 200 Hz, 1440 W pulse pumping condition while no seed light to amplify, the thermal induced wavefront aberration of a He-Ne probe passing through the gain meUdium is 0.165 λ @633 nm (RMS). The amplifier shows stable aberration character with two major low-order terms, defocus and 0° astigmatism. The fluorescence distribution, stored energy, and small-signal gain of the amplifier are measured and have a good agreement with the calculated results. In the amplifier, the fluorescence is uniformly distributed and the maximum stored energy of 3.2 J can be achieved with a plane-concave cavity at 200 Hz pump repetition frequency. For a repetition frequency of 200 Hz, 25 μ J injection polarized seed-light and 1440 W pump power, the small signal gain reaches 9.45. The amplifier has been successfully employed in a 200 Hz, 5 J, MOPA system with 1.7 times diffraction limited output.

A diode-double-face-pumped Nd:YAG ceramic slab laser amplifier with uniform gain distribution and low depolarization loss was presented. Energy storage of 2.6 J was achieved at 1064 nm with a repetition rate of 200 Hz and a pulse width of 200 us from a 140 mm × 40 mm × 7 mm ceramic slab at a total pump power of 1215 W, corresponding to an optical-to-optical efficiency of 42.8%. An average small signal gain of 5.45 was achieved with a standard deviation of only 0.09 in the cross section, which shown good concentration uniformity. An average depolarization loss of 2.6% at different positions of the slab was obtained due to small thermal gradient of the zigzag configuration.

A full-aperture gain measurement obtained with the intensity ratio is presented for a diode-pumped ceramic slab laser amplifier. The small-signal gain profile of the amplifier is calculated by the ratio of pump-on and pump-off intensities. The distribution of absorbed pumping power, fluorescence distribution and gain in the width direction of the slab amplifier are simulated and measured, respectively. A gain homogeneity presented by standard deviation (σ) of 0.17 at a pump power of 1800 W is obtained in the experiment.

Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.

In this paper, an experiment is designed to research the properties of the stimulated Brillouin scattering phase conjugation mirror (SBS-PCM) working under joule-level pump energy and 200 Hz repetition rate. The nonlinear medium FC-770 is chosen as the SBS medium working in high-power condition. Due to the excellent preparation process and ultra-filtration technology for SBS-PCM, there is no optical breakdown phenomenon under the reflectivity maintained at 98% under 200 Hz and pump energy from 500 mJ to 1100 mJ. Under 800 mJ pump energy, the diffraction fringes of the near-field pattern are reduced and the beam quality of the laser beam has been improved to 1.42 times diffraction limited after the double-pass amplification from the single-pass 2.01 times diffraction limited. The incident and reflected pulse width are becoming wider with pump energy increasing. When the pump energy reaches a certain extent, the reflected pulse width will become nearly approximate to the incident pulse width. When the pump energy is 800 mJ, the pump pulse width is 40.3 ns and the output pulse width is 38.8 ns.

We demonstrate a laser-diode-pumped Nd:YAG slab amplifier with dimensions of 7×35×138.2 mm. The fluorescence is homogeneously distributed in the Nd:YAG amplifier, and a stored energy of 3.2 J can be achieved at 1,500 W pump power. For a repetition frequency of 200 Hz, 25 μJ injection polarized seed light, and 1,500 W pump power, the small signal gain reaches 12.66. At the same repetition frequency, 0.4 mJ with 27 ns bandwidth of injected seed-light energy and a 6×26 mm aperture, the output energy reaches 1.071 J. The extraction efficiency is 33.46% after four-pass amplification. An energy amplification from millijoules to joules is realized for the injected laser beam.

We present a compact sub-nanosecond diode-end-pumped Nd:YVO 4 laser system running at 1 kHz. A maximum output energy of 65.4 mJ without significant stimulated Raman scattering (SRS) process was obtained with a pulse duration of 600 ps, corresponding to a pulse peak power of 109 MW. Laser pulses from this system had good beam quality, where M 2 &lt, 1.6, and the excellent signal to noise ratio was more than 42 dB. By frequency doubling with an LBO crystal, 532 nm green light with an average power of 40.5 W and a power stability of 0.28% was achieved. The diode-end-pumped pump power limitation on a high peak power amplifier caused by the SRS process and thermal fracture in bulk Nd:YVO 4 crystal is also analyzed.

Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We recently demonstrated that SF2312, a natural product phosphonate antibiotic, is a potent inhibitor of the glycolytic enzyme Enolase with potential utility for the collateral lethality-based treatment of Enolase-deficient glioblastoma (GBM). However, phosphonates are anionic at physiological pH, limiting cell and tissue permeability. Here, we show that addition of pivaloyloxymethyl (POM) groups to SF2312 (POMSF) dramatically increases potency, leading to inhibition of glycolysis and killing of ENO1-deleted glioma cells in the low nM range. But the utility of POMSF in vivo is dose-limited by severe hemolytic anemia. A derivative, POMHEX, shows equipotency to POMSF without inducing hemolytic anemia. POMHEX can eradicate intracranial orthotopic ENO1-deleted tumors, despite sub-optimal pharmacokinetic properties. Taken together, our data provide in vivo proof-of-principal for collateral lethality in precision oncology and showcase POMHEX as a useful molecule for the study of glycolysis in cancer metabolism.

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.

Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (30) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound 30 demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of N-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (Cav,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of 30 at or above targeted efficacious plasma levels for ...

In case of shallow buried depth and high hydraulic pressure, it was very difficult to control excavation face stability during shield tunneling, frequently followed by catastrophic results (e.g., significant subsidence due to collapse of tunneling face). Based on three-dimensional (3D) numerical parametric analyses validated by centrifuge model test results, this study investigates the effect of supporting pressure on tunneling face stability, in terms of deformation of tunneling face and ground settlement and so on. To simulate the cases featuring high groundwater level, complete fluid-solid coupling calculation was taken into account in the numerical analyses. This was achieved by assuming that shield was in a shutdown state; meanwhile, by reducing excavation pressure gradually and setting the seepage time, the relationship between the stress-strain of the strata surrounding shield and supporting pressure of tunneling were explored.

We report a stable optical fiber pumped Nd:YVO4 all solid state regenerative amplifier with all fiber picosecond laser as seed source. 888 nm Yb optical fiber lasers was chosen as pump source to reduce quantum defect for improved thermal performance. At the repetition rate of 99.6 kHz, maximum power of 19.63 W with 36 ps pulse duration were achieved when seeded by a 150 mW picosecond oscillator. The wavelength delivered was 1064.07 nm with spectral width of 0.14 nm.

In this Letter, we present an adaptive aberration correction system to simultaneously compensate for aberrations and reshaping the beams. A low-order aberration corrector is adapted. In this corrector, four lenses are mounted on a motorized rail, whose positions can be obtained using a ray tracing method based on the beam parameters detected by a wavefront sensor. After automatic correction, the PV value of the wavefront is reduced from 26.47 to 1.91 μm, and the beam quality β is improved from 18.42 to 2.86 times that of the diffraction limit. After further correction with a deformable mirror, the PV value of the wavefront is less than 0.45 μm, and the beam quality is 1.64 times that of the diffraction limit. To the best of our knowledge, this is the highest performance from such a high-power, high-pulse repetition rate Nd:YAG solid-state laser ever built.

In a certain amplification system, signal laser can be amplified from 1 nJ to 5 J. To realize a high quality imaging transfer, meet beam diameter expansion requirement, and get good filtering effects, three spatial filters are designed and assembled. Lenses in these spatial filters can be assembled and adjusted by their reflection spots to meet wave-front requirements. In this letter, we analyze precision of the assembling, and make a ray-tracing simulation to discuss the relation between assembling precision and lenses parameters. On the optimized distance of 1000 mm, adjusting precision of lens tilt can reach 5 mrad.

Based on field data, this study investigates responses of six pre-existing buildings to an adjacent 24.8–25.2 m deep subway station excavated by the covered semi-top-down method. During excavation of 1 m wide and 50.2–50.5 m deep slurry trenches for diaphragm wall panels (i.e., diaphragm walling), buildings on both shallow and deep foundations developed noticeable settlements up to 15 mm. Subsequent excavation of the upper 15.9–17.7 m thick soils inside the pit only incurred limited building settlements less than 10 mm, which contrasted sharply with remarkable displacements of the diaphragm wall and ground nearby. As excavation continued to the final level, buildings on strip footing, stiffened raft foundation, strip footing atop long piles, and short piled raft foundation settled dramatically up to 40 mm, but those on long piled raft foundation still were hardly displaced. Like diaphragm wall and ground, all buildings developed significant postexcavation settlements up to 34.5 mm. Eventually, int...

Chronic liver disease is one of the most common diseases that threaten human health. Effective treatment is still lacking in western medicine.Semen Persicae(Taoren) andFlos Carthami(Honghua) are known to relieve acute hepatic injury and inflammation, improve microcirculation, and reduce tissue fiber. The aim of our study is to investigate the potential mechanisms of Taoren-Honghua Herb Pair (THHP) in murine model of chronic liver disease caused by Carbon Tetrachloride (CCl4). Mice were randomly divided into seven groups: (1) blank, (2) model, (3) control (colchicine, 0.1 mg/kg), (4) THHP (5.53, 2.67, and 1.33 g/kg), and (5) Tao Hong Siwu Decoction (THSWD) (8.50 g/kg). Histological change and microvessels density were examined by microscopy. Hepatic function, serum fibrosis related factors, and hepatic vascular endothelial growth factor (VEGF) were measured with ELISA. VEGF, kinase insert domain-containing receptor (KDR), Flt-1, and Akt mRNA expression in hepatic tissue were determined with PCR. Tissues of Akt, pAkt, KDR, and Flt-1 were measured with western blotting. Data from this study showed that THHP improved hepatic function and restrained the hepatic inflammation and fibrosis. Its role in inhibiting pathological angiogenesis and hepatic fibrogenesis may be through affecting the angiogenesis-associated VEGF and its upstream and downstream signaling pathways.

Utilizing structure-based virtual library design and scoring, a novel chimeric series of phosphodiesterase 10A (PDE10A) inhibitors was discovered by synergizing binding site interactions and ADME properties of two chemotypes. Virtual libraries were docked and scored for potential binding ability, followed by visual inspection to prioritize analogs for parallel and directed synthesis. The process yielded highly potent and selective compounds such as 16. New X-ray cocrystal structures enabled rational design of substituents that resulted in the successful optimization of physical properties to produce in vivo activity and to modulate microsomal clearance and permeability.

Over the past few years we and others reported that specific populations of tumor cells including AML, subsets of lymphoma, glioblastoma, triple negative breast cancer (TNBC), melanoma and pancreatic ductal adenocarcinoma (PDAC) are highly dependent upon oxidative phosphorylation (OXPHOS) to meet their energy and biomass needs. Inhibition of OXPHOS in the context of these dependent tumor populations represents therefore an exciting therapeutic opportunity. Through an extensive medicinal chemistry campaign we discovered IACS-010759, a potent, selective small molecule inhibitor of complex I of the mitochondria electron transport chain that possesses excellent pharmacokinetic (PK) and pharmacologic properties, making it suitable for clinical development. We advanced IACS-010759 through IND studies and have recently initiated Phase I studies in patients with relapsed/refractory acute myeloid leukemia (AML) and advanced solid tumors and lymphomas (NCT02882321 and NCT03291938). In this presentation we will describe the identification of a novel series of Complex I inhibitors and their optimization into the clinical candidate compound IACS-010759. Several challenges were successfully overcome, including the optimization of the pharmacokinetic profile and the identification of inhibitors with minimal activity shift across preclinical species, thus enabling a thorough evaluation of the efficacy and toxicology profile. Aspects of the extensive translational research conducted to elucidate the mechanism of action of IACS-010759 and to position it into the clinic will be discussed, including the compelling pharmacological response observed in multiple PDX models of primary AML, and PDX xenograft models of lymphoma, TNBC, glioblastoma, melanoma and PDAC. The observed response was associated with robust pharmacodynamic read-out as assessed by modulation of oxygen consumption rate (OCR), aspartate and specific transcriptional changes. The presentation will also cover the preclinical development activities which resulted in IACS-010759 advancing into on-going phase 1 evaluation in AML and solid tumors. Citation Format: Maria Emilia Di Francesco, Joseph R. Marszalek, Timothy McAfoos, Christopher L. Carroll, Zhijun Kang, Gang Liu, Jay P. Theroff, Jennifer P. Bardenhager, Madhavi L. Bandi, Jennifer R. Molina, Sonal Gera, Marina Protopopova, Yuting Sun, Mary K. Geck Do, Ningping Feng, Jason P. Gay, Florian Muller, Marina Konopleva, Funda Meric-Bernstam, Carlo Toniatti, Timothy P. Heffernan, Giulio F. Draetta, Philip Jones. Discovery and development of IACS-010759, a novel inhibitor of Complex I currently in phase I studies to exploit oxidative phosphorylation dependency in acute myeloid leukemia and solid tumors [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 1655.

We present a high-repetition-rate, high-pulse-energy, high-beam-quality, and high-average-power laser system using an ultraclean closed-type stimulated-Brillouin-scattering phase-conjugate mirror (SBS-PCM). By controlling microparticles of SBS-PCM down to 40 nm, thermal load capacity of such closed-type SBS-PCM was greatly improved, which presented the best reported cleanliness. The closed-type SBS-PCM, lacking scanning wedge plates, achieved reflectivity as high as 92% and showed no optical breakdown phenomena or obvious thermal effects at a 500 Hz pulse-repetition frequency (PRF). Operation at 550 W output power, approximately 1.1 J pulse energy, and beam quality M2 of approximately 2 represents, to our knowledge, the best reported performance. Thermal phase distortion was compensated, and the maximum-output-power pulse-width compression improved from 30 ns to approximately 10 ns.

Utilizing structure-based drug design, a 4-aminoimidazole heterocyclic core was synthesized as a replacement for a 2-aminothiazole due to potential metabolically mediated toxicity. The synthetic route utilized allowed for ready synthesis of 1-substituted-4-aminoimidazoles. SAR exploration resulted in the identification of a novel cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E.

Because greenfields available for new developments in congested urban areas are scarce in China, more and more excavations for building basements or other underground facilities (e.g., new metro lines, underground shopping malls, parking garages) have to be carried out in the close proximity of existing metro lines. To ensure project safety, it is essential to know potential adverse effects of excavations on adjacent metro lines in service. Until now, many studies have contributed to the cases of excavations overlying existing tunnels. In contrast, only a few were known for excavations parallel to adjacent existing tunnels. With regard to the responses of existing metro stations to adjacent excavations, few case studies were reported in the literature. Through an extensive field instrumentation program in combination of numerical simulations, this study examines the performance of an oversized deep excavation in stiff clayey deposits and the corresponding responses of the adjacent metro station an...

High-throughput screening with cyclin-dependent kinase 5 (cdk5)/p25 led to the discovery of N-(5-isopropyl-thiazol-2-yl)isobutyramide (1). This compound is an equipotent inhibitor of cdk5 and cyclin-dependent kinase 2 (cdk2)/cyclin E (IC50 = ca. 320 nM). Parallel and directed synthesis techniques were utilized to explore the SAR of this series. Up to 60-fold improvements in potency at cdk5 and 12-fold selectivity over cdk2 were achieved.

We are sorry about omitting Yanzhong Chen and Jianguo He in the list of authors of the paper Experimental Study of a Diode-Pumped Nd:YAG Slab Laser Amplifier.

Tumor cells depend on both glycolysis and oxidative phosphorylation (OXPHOS) for energy and biomass production to support cell proliferation. Recent data has demonstrated a dependence of various tumor types on mitochondrial OXPHOS, which represents an exciting therapeutic opportunity. Through an extensive medicinal chemistry campaign, IACS-010759 was identified as a potent, selective inhibitor of complex I of the electron transport chain, which is orally bioavailable and has excellent PK and physicochemical properties in preclinical species. Our group and others have demonstrated that AML, plus subsets of glioblastoma, neuroblastoma, lymphoma, melanoma, triple negative breast cancer (TNBC) and pancreatic cancer (PDAC) are highly dependent on OXPHOS to meet energy and biomass demands. Treatment of multiple cell lines and patient derived xenograft (PDX) models in several cancer types with IACS-010759 led to a robust decrease in cell viability and often an increase in apoptosis with EC50 values between 1 nM - 50 nM across multiple lines. Through a series of mechanistic studies we established that IACS-10759 blocks complex I of the electron transport at the quinone binding site. Mechanistically, response to IACS-010759 was associated with induction of a metabolic imbalances that negatively impacted energy homeostasis, aspartate biosynthesis, and NTP production due to reduced conversion of NADH to NAD+ by complex I, decreased ATP production, TCA cycle flux and nucleotide biosynthesis. Tumor growth inhibition and regression have been observed in molecularly defined subsets of TNBC and PDAC PDX xenograft models treated with IACS-010759, indicating that subsets of these indications are dependent on OXPHOS. Furthermore, treating TNBC or PDAC PDX models post-chemotherapy with IACS-010759 extends progression free survival, consistent with IACS-010759 targeting recently described metabolically adapted residual tumor cells. In orthotopic xenograft models of primary AML cells, daily oral treatment with 1-7.5 mg/kg IACS-010759 extended the median survival. Efficacy was paralleled by robust modulation of OCR, aspartate, and a gene signature levels. Therefore, these readouts (OCR, aspartate and a nanostring geneset) have been validated for use as exploratory clinical biology of response endpoints. In parallel, completion of preclinical chemistry, manufacturing and control (CMC) as well as GLP safety and tolerability studies with IACS-010759 in multiple species have enabled the selection of a clinical entry dose. As a result of the robust response in multiple cell lines, primary patient samples, and efficacy in PDX models, a Phase I clinical trial in relapsed, refractory AML was initiated in October 2016, with a parallel trial in solid tumors expected to initiate in early 2017. Initial results from the on-going AML trial will be disclosed. Citation Format: Jennifer Molina, Madhavi Bandi, Jennifer Bardenhagen, Christopher Bristow, Christopher Carroll, Edward Chang, Jason Cross, Naval Daver, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Jing Han, Judy Hirst, Sha Huang, Yongying Jiang, Zhijun Kang, Marina Konopleva, Gang Liu, Helen Ma, Polina Matre, Timothy McAfoos, Funda Meric-Bernstam, Pietro Morlacchi, Florian Muller, Marina Protopopova, Melinda Smith, Sonal Sonal, Yuting Sun, Jay Theroff, Andrea Viale, Quanyun Xu, Carlo Toniatti, Giulio Draetta, Philip Jones, M. Emilia Di Francesco, Joseph R. Marszalek. IACS-010759, a novel inhibitor of complex I in Phase I clinical development to target OXPHOS dependent 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 4971. doi:10.1158/1538-7445.AM2017-4971

A non-pulse-leakage optical fiber pumped 100-kHz level high beam quality Nd:YVO4 picosecond amplifier has been developed. An 80 MHz, 11.5 ps mode-locked picosecond laser is used as the seed with single pulse energy of 1 nJ. By harnessing the double β-BaB2O4 (BBO) crystal Pockels cells in both the pulse picker and regenerative amplifier, the seed pulse leakage of the output is suppressed effectively with an adjustable repetition rate from 200 to 500 kHz. Through one stage traveling-wave amplifier, a maximum output power of 24.5 W is generated corresponding to the injected regenerative amplified power of 9.73 W at 500 kHz. The output pulse duration is 16.9 ps, and the beam quality factor M2 is measured to be 1.25 with near-field roundness higher than 99% at the full output power.

Tumor cells normally depend on both glycolysis and oxidative phosphorylation (OXPHOS) to provide the energy and macromolecule building blocks needed to enable continued tumor cell growth. Genetic or epigenetic inactivation of one of these two redundant pathways represents a metabolic vulnerability that should be susceptible to an inhibitor of the other pathway. We have identified multiple contexts where all or a subset of these tumors demonstrate a dependence on mitochondrial OXPHOS, which represents an exciting therapeutic opportunity. Through an extensive medicinal chemistry campaign, IACS-10759 was identified as a potent inhibitor of complex I of oxidative phosphorylation. In isolated mitochondria or permeabilized cells, ATP production or oxygen consumption is inhibited at single digit nM concentrations in the presence of malate/glutamate, but not succinate. More directly, IACS-10759 inhibits the conversion of NADH to NAD+ in an immunoprecipitated complex I assay at low nM concentrations. Importantly, IACS-10759 is orally bioavailable with excellent pharmacokinetics properties in preclinical species, and has an overall profile suitable for clinical development. Our group and others have demonstrated that a variety of tumor types including: AML, plus subsets of lymphoma, breast, melanoma and PDAC are highly dependent on OXPHOS to meet energy and biomass demands. Treatment of multiple cell lines and patient derived xenograft (PDX) models in multiple cancer types with IACS-10759 led to decreased oxygen consumption rate (OCR). IACS-10759 treatment also led to a robust decrease in cell viability and often an increase in apoptosis with EC50 values between 1 nM - 50 nM across multiple lines. In multiple PDX models of primary AML IACS-10759 treatment extends the median survival. Efficacy was paralleled by robust modulation of OCR, aspartate, and p-AMPK levels. Additionally, tumor growth inhibition or regression was also observed in cell line and PDX xenograft models of lymphoma, triple negative breast, melanoma and PDAC treated with IACS-10759, indicating that subsets of several non-AML indications are also dependent on OXPHOS. Mechanistically, extensive metabolic profiling revealed that the response to IACS-10759 was associated with induction of a metabolic imbalances that negatively impacted energy homeostasis, amino acid biosynthesis, and NTP production due to reduced conversion of NADH to NAD+ by complex I, decreased ATP production, TCA cycle flux and nucleotide biosynthesis. As a result of the robust preclinical response in multiple model systems, IACS-10759 has been advanced through IND enabling studies. GLP safety and toxicology have been completed, clinical supplies manufactured, and a Phase I clinical trial in AML will be initiated during the second quarter of 2016. This abstract is also being presented as Poster B35. Citation Format: Philip Jones, M Emilia Di Francesco, Jennifer M. Molina, Marina Protopopova, Madhavi Bandi, Jennifer Bardenhagen, Christopher A. Bristow, Christopher L. Carroll, Ningping Feng, Jason P. Gay, Mary K. Geck Do, Jennifer M. Greer, Marina Konopleva, Zhijun Kang, Gang Liu, Timothy McAfoos, Pietro Morlacchi, Melinda G. Smith, Sonal Fnu, Jay P. Theroff, Giulio Draetta, Giulio Draetta, Carlo Toniatti, Joseph R. Marszalek. IACS-010759 a novel inhibitor of oxidative phosphorylation advancing into first-in-human studies to exploit metabolic vulnerabilities. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr PR01.

A broadband high-reflection (HR) coating was used to suppress the electric-field intensity (EFI) enhancement in artificial nodules with five different sizes. However, the finitie-difference time-domain simulations reflected that the nodules initiating from 1.0-μmSiO2 seeds showed abnormally stronger EFI enhancement, which is almost two times higher than the EFI enhancement of 1.0-μmSiO2 seeds in a quarter-wave HR coating. This was also confirmed by the laser-induced damage threshold measurement. Our previous model combining light focusing and light penetrating effects was carefully examined to check whether the hotspots in a nodule initiating from the 1.0-μmSiO2 seed were in the focal area or not. Although it was found that the focal length of the nodule decreased with reducing seed diameter, the hotspots in nodules initiating from a 1.0-μmSiO2 seed were still much shallower than the focal area. In the broadband HR coating, the standing-wave EFI profiles at different working angles were given, which showed that the standing-wave EFI at the hotspots region was not negligible. Some complex interference or diffraction may cause the light to arrive at the hotspots region in phase and result in strong EFI enhancement. More work is necessary to gain a deeper understanding of this phenomenon.

Tumor cells depend on both glycolysis and oxidative phosphorylation (OXPHOS) for energy and biomass production leading to robust cell proliferation. Recent data has demonstrated a dependence of various tumor types on mitochondrial OXPHOS, which represents an exciting therapeutic opportunity. Through an extensive medicinal chemistry campaign, IACS-10759 was identified as a potent, selective inhibitor of complex I of the electron transport chain, which is orally bioavailable and has excellent PK and physicochemical properties in preclinical species. Our group and others have demonstrated that a variety of tumor types including: AML, plus subsets of lymphoma, breast, melanoma and PDAC are highly dependent on OXPHOS to meet energy and biomass demands. Treatment of multiple cell lines and patient derived xenograft (PDX) models in multiple cancer types with IACS-10759 led to decreased oxygen consumption rate (OCR). IACS-10759 treatment also led to a robust decrease in cell viability and often an increase in apoptosis with EC50 values between 1 nM - 50 nM across multiple lines. Through a series of mechanistic studies we established that IACS-10759 blocks complex I of the electron transport at the quinone binding site. In an orthotopic xenograft model of primary AML cells derived from a patient who was refractory to standard of care and salvage therapies, 42 days of IACS-10759 treatment with 3 and 10 mg/kg orally using a 5 on/2 off schedule extended the median survival by greater than 2-fold. Efficacy was paralleled by robust modulation of OCR, aspartate, and p-AMPK levels. Additionally, tumor growth inhibition or regression was also observed in cell line and PDX xenograft models of lymphoma, triple negative breast, melanoma and PDAC treated with IACS-10759, indicating that subsets of several non-AML indications are also dependent on OXPHOS. Mechanistically, extensive metabolic profiling and flux analysis revealed that the response to IACS-10759 was associated with induction of a metabolic imbalance that negatively impacted energy homeostasis, amino acid biosynthesis, and NTP production due to reduced conversion of NADH to NAD+ by complex I, decreased ATP production, TCA cycle flux and nucleotide biosynthesis. As a result of the robust response in multiple cell lines, primary patient samples, and efficacy in PDX models, IACS-10759 has been advanced through IND enabling studies. GLP safety and toxicology have been completed, and we expect to file an IND at the end of 1Q2016 and initiate a Phase I clinical trial in AML during the second quarter of 2016. Citation Format: Jennifer R. Molina, Marina Protopopova, Madhavi Bandi, Jennifer Bardenhagen, Christopher Bristow, Christopher Carroll, Edward Chang, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Sha Huang, Yongying Jiang, Marina Konopleva, Polina Matre, Jing Han, Zhijun Kang, Gang Liu, Timothy McAfoos, Pietro Morlacchi, Melinda Smith, Sonal Gera, Jay Theroff, Quanyun Xu, Juliana Velez, Carlo Toniatti, Timothy Heffernan, Giulio Draetta, M. Emilia Di Francesco, Philip Jones, Joseph R. Marszalek. Title: IACS-010759 is a novel clinical candidate that targets AML cells by inducing a metabolic catastrophe through inhibition of oxidative phosphorylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 335.

Tumor cells normally depend on both glycolysis and oxidative phosphorylation (OXPHOS) to provide the energy and macromolecule building blocks for rapid growth. Metabolic vulnerabilities caused by inactivation of glycolysis render tumor cells highly dependent on OXPHOS, and represent a therapeutic opportunity. Through an extensive medicinal chemistry campaign, we have identified IACS-10759 as a potent inhibitor of complex I of OXPHOS. IACS-10759 effectively inhibits ATP production and oxygen consumption in isolated mitochondria, and inhibits the conversion of NADH to NAD+ in immunoprecipitated complex I in low nM range. The exact subunit that IACS-10759 binds to is under investigation. Importantly, IACS-10759 is orally bioavailable with excellent physicochemical properties in preclinical species, and shows significant efficacy in multiple tumor indications both in vitro and in vivo. Specifically, in a glycolysis-deficient xenograft model, IACS-10759 causes robust tumor regression, but has no effect in the same model when glycolysis is restored. In addition, in AML where tumor cells have been shown to be highly OXPHOS-dependent, IACS-10759 robustly suppresses cell growth and induces apoptosis in both primary AML samples and cell lines in vitro, but not in normal patient-derived bone marrow cells. Significantly, IACS-10759 extends median survival by over 50 days in an AML orthotopic xenograft model. Furthermore, IACS-10759 also shows selective efficacy in other cell line panels including pancreatic cancer, non-small cell lung cancer and colorectal cancer, and has synergism with glycolysis inhibitors. In light of these results, we are currently performing IND enabling studies for IACS-10759, with first-in-human studies targeted for fourth quarter of 2015. Citation Format: Marina Protopopova, Madhavi Bandi, Yuting Sun, Jennifer Bardenhagen, Christopher Bristow, Christopher Carroll, Edward Chang, Ningping Feng, Jason Gay, Mary Geck Do, Jennifer Greer, Marina Konopleva, Polina Matre, Zhijun Kang, Gang Liu, Florian Muller, Timothy Lofton, Timothy McAfoos, Melinda Smith, Jay Theroff, Jing Han, Yuanqing Wu, Lynda Chin, Giulio Draetta, Philip Jones, Carlo Toniatti, M. Emilia Di Francesco, Joseph R. Marszalek. IACS-10759: A novel OXPHOS inhibitor that selectively kills tumors with metabolic vulnerabilities. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A65.

Phosphodiesterase 9A inhibitors have shown activity in preclinical models of cognition with potential application as novel therapies for treating Alzheimer's disease. Our clinical candidate, PF-04447943 (2), demonstrated acceptable CNS permeability in rats with modest asymmetry between central and peripheral compartments (free brain/free plasma = 0.32; CSF/free plasma = 0.19) yet had physicochemical properties outside the range associated with traditional CNS drugs. To address the potential risk of restricted CNS penetration with 2 in human clinical trials, we sought to identify a preclinical candidate with no asymmetry in rat brain penetration and that could advance into development. Merging the medicinal chemistry strategies of structure-based design with parallel chemistry, a novel series of PDE9A inhibitors was identified that showed improved selectivity over PDE1C. Optimization afforded preclinical candidate 19 that demonstrated free brain/free plasma ≥ 1 in rat and reduced microsomal clearance along with the ability to increase cyclic guanosine monophosphosphate levels in rat CSF.