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Transcription factors are important drivers of cancer but the development of therapeutics against these factors has had limited success. We developed a stringent high-throughput chemical genetic screening platform to identify compounds that target oncogenic transcription factor SALL4 dependency in liver cancer. The platform comprises SALL4 low- and high-expressing endogenous and engineered isogenic liver cancer cell lines. Unexpectedly, from screening 21,575 natural product extracts, the top hits were four oxidative phosphorylation inhibitors that selectively reduced SALL4-dependent cell viability. The ATP synthase inhibitor oligomycin suppressed SALL4-expressing cancer in lung and liver cancer cell culture models, and in patient-derived xenograft models of liver cancer. Oligomycin also synergized with sorafenib, the standard-of-care targeted therapy in liver cancer, to effectively suppress SALL4-driven tumorigenesis in vivo. When aberrantly expressed in cancer, SALL4 binds ~50% of mitochondrial genes, including many oxidative phosphorylation genes, to predominantly upregulate their expression. SALL4 upregulation also alters the levels of oxidative phosphorylation-related metabolites and functionally increases oxidative phosphorylation activity. Application of our endogenous/isogenic transcription factor-screening platform revealed a therapeutically actionable oxidative phosphorylation vulnerability in SALL4-expressing cancers. Citation Format: Justin L. Tan, Feng Li, Joanna Z. Yeo, Kol Jia Yong, Mahmoud A. Bassal, Guo Hao Ng, May Yin Lee, Chung Yan Leong, Hong Kee Tan, Chan-Shuo Wu, Bee Hui Liu, Hon Man Chan, Zi Hui Tan, Yun Shen Chan, Siyu Wang, Zhi Han Lim, Tan Boon Toh, Lissa Hooi, Kia Ngee Low, Siming Ma, Nikki R. Kong, Alicia J. Stein, Yue Wu, Matan T. Thangavelu, Atsushi Suzuki, Giridharan Periyasamy, John M. Asara, Yock Young Dan, Glenn K. Bonney, Edward K. Chow, Guo-Dong Lu, Huck Hui Ng, Yoganathan Kanagasundaram, Siew Bee Ng, Wai Leong Tam, Li Chai, Daniel G. Tenen. A high-throughput chemical genetic screen reveals SALL4-induced metabolic vulnerabilities in cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1788.

Recent product development has focussed on developing a range of higher strength structural grades, covering the strip thickness range 0.9-1.5 mm, utilising Nb microalloying. A wide range of Nb levels have been successfully strip cast by the CASTRIP® process. Niobium was found to retard austenite grain refinement and substantially enhanced hardenability, which produced significant microstructural hardening and higher strength hot band. Niobium was retained in solid solution enabling further significant strengthening to be achieved from an age hardening heat treatment. Strength levels ranging from 400 MPa to in excess of 550 MPa, in combination with high ductility, were achieved in the age hardened and hot dip galvanised condition, utilising the annealing furnaces of a conventional hot dip galvanising line. The effect of microalloying content and processing conditions on the microstructure and final mechanical properties of Nb microalloyed UCS products produced by the CASTRIP process are described.

The effects of pressurized compressive chip and low dosage sulphite pretreatments were evaluated for production of thermomechanical pulp in mill scale trials using Norway spruce (Picea abies) at the Braviken paper mill (Holmen Paper AB, Sweden). The aim of the study was to provide knowledge leading to the improvement of energy efficiency during the production of mechanical pulps suitable for news and improved new grade papers. Pulps produced in the mill trials were characterized using conventional pulp and paper testing and by advanced methods including image analysis, FTIR with multivariate analysis, Simons staining with statistical analysis, spectral imaging and HCL fibre cleavage. Sulphite pre-treatment gave a linear dose response in tensile index and light scattering with addition of sulphite (≥ 1.2% Na2SO3). The maximum in tensile index and light scattering at a sulphur content of 0.2% (as Na2SO3) reported previously was not found in this mill study. Low dosage sulphite pre-treatment increased delamination/internal fibrillation of fibres indicating increased fibre flexibility. These fibres produced denser sheets with higher tensile index and slightly reduced light scattering at certain specific energy consumption. The specific energy consumption needed to produce pulp at a certain tensile index was reduced by 320 kWh/BDT (15%) for chips pre-treated with ~1.2% Na2SO3 compared with untreated chips. This gave a reduction in light scattering for sulphite pre-treated pulps when compared at equal tensile index. Image analysis of fibre cross-sections provided information of the composition of the total fibre population, fibre cross-sectional compactness as well as effects of sulphite treatment. Results showed a fairly constant fibre population (40% early-/60% latewood) existing in all samples and for higher energy to cause greater fibre splitting of untreated fibres particularly of latewood fibres. Increasing the amount of sulphite reduced fibre splitting with less severe fibre delamination for pulps refined at 1820 and 1850 KWh/ADT. Sulphite treatment seemed in general to induce more refining of early- than latewood fibres. SEM observation on fibres revealed high degree of deformation along the fibre axis that could also be seen on the fibre crosssections analyzed. FTIR analyses indicated that the highest degree of sulphonation (10 kg/BDT) gave rise to different fibre separation mechanisms during refining compared with the reference unsulphonated pulps providing a different fibre surface and thereby mechanical properties. Multivariate analysis of FTIR spectra suggested the exposed fibre surface to be richer in hemicellulose for sulphonated pulped fibres. This could provide for a better binding surface and higher strength for paper. However, no clear pattern of differences in the distribution images and therefore the microdistribution of xylan were determined. Statistical analysis of the Simons´ staining of fibres indicated that both the energy input and chip pre-treatment significantly induced wall delamination and internal fibrillation (D/IF) of pulp fibres. It was shown that the fibre development of pulp 10(1580) (with lowest SEC) gained via improved wall D/IF was almost similar to that shown for pulp 00(1850) (with highest SEC). This indicates that an energy efficient refining can be obtained with 10 kg/BDT sulfite pre-treatment prior to refining and will produce the most flexible fibres. Spectral imaging showed sulphite treatment of impressarefiner chips to improve the optical properties of pulps with a clear dose-response shown at both higher and lower SEC levels, the former having the largest effect on whiteness. Photochemical effects of sulfonation using reflectance intensities showed complex results regarding lignocellulosic autofluorescence. Unlike wood, impressarefiner chips and pulp fibres showed a clear blue-shifted fluorescence maximum characteristic for a shortened conjugated system indicating that both the chipping and Impressafiner pretreatment induced a minor degradation of the lignocellulosic matrix that can be measured using spectral imaging. Refining however, increased the red edge fluorescence of the sulfonated whole long fibre fraction with a similar effect on the lignin fluorescence of wood. Using the HCL method of fibre analysis no significant trend for the effect of sulphite treatment was noted and only minor differences in fibre length were detected.