SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma.

Burkitt lymphoma (BL) is an aggressive lymphoma type that is currently treated by intensive chemoimmunotherapy. Despite the favorable clinical outcome for most patients with BL, chemotherapy-related toxicity and disease relapse remain major clinical challenges, emphasizing the need for innovative therapies. Using genome-scale CRISPR-Cas9 screens, we identified B-cell receptor (BCR) signaling, specific transcriptional regulators, and one-carbon metabolism as vulnerabilities in BL. We focused on serine hydroxymethyltransferase 2 (SHMT2), a key enzyme in one-carbon metabolism. Inhibition of SHMT2 by either knockdown or pharmacological compounds induced anti-BL effects in vitro and in vivo. Mechanistically, SHMT2 inhibition led to a significant reduction of intracellular glycine and formate levels, which inhibited the mTOR pathway and thereby triggered autophagic degradation of the oncogenic transcription factor TCF3. Consequently, this led to a collapse of tonic BCR signaling, which is controlled by TCF3 and is essential for BL cell survival. In terms of clinical translation, we also identified drugs such as methotrexate that synergized with SHMT inhibitors. Overall, our study has uncovered the dependency landscape in BL, identified and validated SHMT2 as a drug target, and revealed a mechanistic link between SHMT2 and the transcriptional master regulator TCF3, opening up new perspectives for innovative therapies.

Effects of implant placement timing and type of soft-tissue grafting on histological and histomorphometric outcomes in a preclinical canine model.

AIM: To determine the effects of implant timing and type of soft-tissue grafting on histological and histomorphometric outcomes in a preclinical model. MATERIALS AND METHODS: Four implant placement protocols were randomly applied at the mesial root sites of the third and fourth mandibular premolars in 10 mongrel dogs: immediate placement (group IP), early placement (group EP), delayed placement with/without alveolar ridge preservation (groups ARP and DP, respectively). A connective-tissue graft (CTG) or porcine-derived volume-stable collagen matrix (VCMX) was applied to enhance the ridge profile (simultaneously with implant placement in group IP and staged for others), resulting in five sites for each combination. All dogs were sacrificed 3 months after soft-tissue grafting. Histological and histomorphometric analyses were performed, and the data were analysed descriptively. RESULTS: CTG and VCMX were difficult to differentiate from the augmented area. The median total tissue thickness on the buccal aspect of the implant was largest in group IP/CTG (between 2.78 and 3.87 mm). The soft-tissue thickness was generally favourable with CTG at all implant placement timings. Within the DP groups, CTG yielded statistically significantly larger total and soft-tissue thickness than VCMX (p < .05). Among the groups with VCMX, group EP/VCMX showed the largest soft-tissue thickness at apical levels to the implant shoulder. CONCLUSIONS: CTG generally led to greater tissue thickness than VCMX.

The protein landscape of chronic lymphocytic leukemia.

Many functional consequences of mutations on tumor phenotypes in chronic lymphocytic leukemia (CLL) are unknown. This may be in part due to a scarcity of information on the proteome of CLL. We profiled the proteome of 117 CLL patient samples with data-independent acquisition mass spectrometry and integrated the results with genomic, transcriptomic, ex vivo drug response, and clinical outcome data. We found trisomy 12, IGHV mutational status, mutated SF3B1, trisomy 19, del(17)(p13), del(11)(q22.3), mutated DDX3X and MED12 to influence protein expression (false discovery rate [FDR] = 5%). Trisomy 12 and IGHV status were the major determinants of protein expression variation in CLL as shown by principal-component analysis (1055 and 542 differentially expressed proteins, FDR = 5%). Gene set enrichment analyses of CLL with trisomy 12 implicated B-cell receptor (BCR)/phosphatidylinositol 3-kinase (PI3K)/AKT signaling as a tumor driver. These findings were supported by analyses of protein abundance buffering and protein complex formation, which identified limited protein abundance buffering and an upregulated protein complex involved in BCR, AKT, MAPK, and PI3K signaling in trisomy 12 CLL. A survey of proteins associated with trisomy 12/IGHV-independent drug response linked STAT2 protein expression with response to kinase inhibitors, including Bruton tyrosine kinase and mitogen-activated protein kinase kinase (MEK) inhibitors. STAT2 was upregulated in unmutated IGHV CLL and trisomy 12 CLL and required for chemokine/cytokine signaling (interferon response). This study highlights the importance of protein abundance data as a nonredundant layer of information in tumor biology and provides a protein expression reference map for CLL.

Dimensional ridge changes in conjunction with four implant timing protocols and two types of soft tissue grafts: A pilot pre-clinical study.

AIM: To determine the effect of (1) implant placement timing and (2) the type of soft tissue graft in terms of ridge profile changes. MATERIALS AND METHODS: Four implant treatment modalities were applied in the mesial root areas of the third and fourth mandibular premolars of 10 mongrel dogs alongside connective-tissue graft (CTG) and volume-stable cross-linked collagen matrix (VCMX): immediate, early, and delayed placement (DP), and DP following alveolar ridge preservation (ARP). All dogs were sacrificed 3 months after soft tissue augmentation. Standard Tessellation Language files from designated time points were analysed. RESULTS: Compared with the pre-extraction situation, the median width of the ridge demontstrated a linear increase only in group ARP/CTG (0.07 mm at the 2-mm level), whereas all other groups showed a reduction (between -1.87 and -0.09 mm, p > .05). Groups ARP/CTG (0.17 mm) and DP/CTG (0.05 mm) exhibited a profilometric tissue gain in a set region of interest (p > .05). The net effect of CTG and VCMX ranged from 0.14 to 0.79 mm. CONCLUSIONS: Dimensional ridge changes varied between treatment protocols. ARP with CTG led to the smallest difference in ridge profile between the pre-extraction and the study end time point. Both CTG and VCMX enhanced the ridge contour.

Synthesis of the Molybdenum Precursor for Slurry-Phase Hydrocracking of Heavy Oil.

In this study, Molybdenum precursors were synthesized with butanoic acid, hexanoic acid, nonanoic acid, decanoic acid, and undecanoic acid. In order to determine chemical structure of Synthesized molybdenum precursors, 1H(13C)-NMR, EA and ICP were used pyrolysis properties were measured TGA. The molybdenum precursors was used for Hydrocracking of Vacuum R1esidue (VR). It was shown that molybdenum nonanoate(3) was shown the lowerst Toluene Insoluble and Gas Product about 2.1 and 5.0 percent.

Al-Ti-Containing Lightweight High-Entropy Alloys for Intermediate Temperature Applications.

In this study, new high-entropy alloys (HEAs), which contain lightweight elements, namely Al and Ti, have been designed for intermediate temperature applications. Cr, Mo, and V were selected as the elements for the Al-Ti-containing HEAs by elemental screening using their binary phase diagrams. AlCrMoTi and AlCrMoTiV HEAs are confirmed as solid solutions with minor ordered B2 phases and have superb specific hardness when compared to that of commercial alloys. The present work demonstrates the desirable possibility for substitution of traditional materials that are applied at intermediate temperature to Al-Ti-containing lightweight HEAs.

Multi-omic and functional analysis for classification and treatment of sarcomas with FUS-TFCP2 or EWSR1-TFCP2 fusions.

Linking clinical multi-omics with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in ALK variants that are oncogenic and sensitive to ALK inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a rationale for PRMT5-targeted therapies. Functional studies show that FUS-TFCP2 blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair. Unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibit genomic instability and signs of defective homologous recombination. DNA methylation profiling demonstrates a close relationship with undifferentiated sarcomas. In two patients, sarcoma was preceded by benign lesions carrying FUS-TFCP2, indicating stepwise sarcomagenesis. This study illustrates the potential of linking precision oncology with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers.

Directly patternable, highly conducting polymers for broad applications in organic electronics.

Postdeposition solvent annealing of water-dispersible conducting polymers induces dramatic structural rearrangement and improves electrical conductivities by more than two orders of magnitude. We attain electrical conductivities in excess of 50 S/cm when polyaniline films are exposed to dichloroacetic acid. Subjecting commercially available poly(ethylene dioxythiophene) to the same treatment yields a conductivity as high as 250 S/cm. This process has enabled the wide incorporation of conducting polymers in organic electronics; conducting polymers that are not typically processable can now be deposited from solution and their conductivities subsequently enhanced to practical levels via a simple and straightforward solvent annealing process. The treated conducting polymers are thus promising alternatives for metals as source and drain electrodes in organic thin-film transistors as well as for transparent metal oxide conductors as anodes in organic solar cells and light-emitting diodes.

Design of an Intermediate Die for the Multi-Pass Shape Drawing Process.

The multi-pass shape drawing process is mainly used in metal forming processes to manufacture long components with constant arbitrary cross-sectional shapes along their lengths. The cross-roller guide is a typical component that is manufactured by a multi-pass shape drawing process. The cross-roller guide is mostly used in optical measurement equipment where high-precision movement is required. Therefore, the dimensional accuracy of the cross-roller guide is very important since it can influence precision linear motion. However, the unfilled defects can occur in a case where the product has a complex cross-sectional shape. In this study, a new design method for an intermediate die is suggested by using an equal-radial-velocity variation method in order to reduce the unfilled defects. The proposed design method can reduce the unfilled defects by minimizing the radial velocity variation in the deformation zone of the drawing die. The intermediate die was designed by geometrical information of the final product without prior finite element (FE) analysis. The suggested method was applied to design the multi-pass shape drawing process for manufacturing the cross-roller guide. FE analysis was performed to validate the effectiveness of the proposed method in comparison to the conventional design method that uses equipotential lines in the multi-pass shape drawing process. Finally, a shape drawing experiment was performed to compare the target shape and the FE analysis with the experimental data.

Drug-perturbation-based stratification of blood cancer.

As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non-BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.

Novel strip-cast Mg/Al clad sheets with excellent tensile and interfacial bonding properties.

In order to broaden industrial applications of Mg alloys, as lightest-weight metal alloys in practical uses, many efforts have been dedicated to manufacture various clad sheets which can complement inherent shortcomings of Mg alloys. Here, we present a new fabrication method of Mg/Al clad sheets by bonding thin Al alloy sheet on to Mg alloy melt during strip casting. In the as-strip-cast Mg/Al clad sheet, homogeneously distributed equi-axed dendrites existed in the Mg alloy side, and two types of thin reaction layers, i.e., γ (Mg17Al12) and ß (Mg2Al3) phases, were formed along the Mg/Al interface. After post-treatments (homogenization, warm rolling, and annealing), the interfacial layers were deformed in a sawtooth shape by forming deformation bands in the Mg alloy and interfacial layers, which favorably led to dramatic improvement in tensile and interfacial bonding properties. This work presents new applications to multi-functional lightweight alloy sheets requiring excellent formability, surface quality, and corrosion resistance as well as tensile and interfacial bonding properties.