Simultaneous evaluation of treatment efficacy and toxicity for bispecific T-cell engager therapeutics in a humanized mouse model.

Immuno-oncology (IO)-based therapies such as checkpoint inhibitors, bi-specific antibodies, and CAR-T-cell therapies have shown significant success in the treatment of several cancer indications. However, these therapies can result in the development of severe adverse events, including cytokine release syndrome (CRS). Currently, there is a paucity of in vivo models that can evaluate dose-response relationships for both tumor control and CRS-related safety issues.

Solving the regulation puzzle of periderm development using advances in fruit skin.

Periderm protects enlarged organs of most dicots and gymnosperms as a barrier to water loss and disease invasion during their secondary growth. Its development undergoes a complex process with genetically controlled and environmental stress-induced characters. Different development of periderm makes the full and partial russet of fruit skin, which diverges in inheritance with qualitative and quantitative characters, respectively, in pear pome.

An ARF1-binding factor triggering programmed cell death and periderm development in pear russet fruit skin.

Plants have a cuticular membrane (CM) and periderm membrane (PM), which act as barriers to terrestrial stresses. The CM covers primary organs with a continuous hydrophobic layer of waxes embedded in cutin, while the PM stacks with suberized cells outermost to the secondary tissues. The formation of native periderm is regulated by a postembryonic meristem phellogen that produces suberized phellem (cork) outwardly.

Proteome and transcriptome profile analysis reveals regulatory and stress-responsive networks in the russet fruit skin of sand pear.

The epidermal tissues of the cuticular membrane (CM) and periderm membrane (PM) confer first-line protection from environmental stresses in terrestrial plants. Although PM protection is essentially ubiquitous in plants, the protective mechanism, the function of many transcription factors and enzymes, and the genetic control of metabolic signaling pathways are poorly understood. Different microphenotypes and cellular components in russet (PM-covered) and green (CM-covered) fruit skins of pear were revealed by scanning and transmission electron microscopy.

Characterization of the Selective Indoleamine 2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy.

Tumors use indoleamine 2,3-dioxygenase-1 (IDO1) as a major mechanism to induce an immunosuppressive microenvironment. IDO1 expression is upregulated in many cancers and considered to be a resistance mechanism to immune checkpoint therapies. IDO1 is induced in response to inflammatory stimuli such as IFNγ and promotes immune tolerance by depleting tryptophan and producing tryptophan catabolites, including kynurenine, in the tumor microenvironment.

Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy.

Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg- PrkdcIL2rg/Sz (null; NSG) mice were transplanted with human (h)CD34 hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)].

Primitive Genepools of Asian Pears and Their Complex Hybrid Origins Inferred from Fluorescent Sequence-Specific Amplification Polymorphism (SSAP) Markers Based on LTR Retrotransposons.

Recent evidence indicated that interspecific hybridization was the major mode of evolution in Pyrus. The genetic relationships and origins of the Asian pear are still unclear because of frequent hybrid events, fast radial evolution, and lack of informative data. Here, we developed fluorescent sequence-specific amplification polymorphism (SSAP) markers with lots of informative sites and high polymorphism to analyze the population structure among 93 pear accessions, including nearly all species native to Asia.

Isolation and characterization of putative functional long terminal repeat retrotransposons in the Pyrus genome.

Background: Long terminal repeat (LTR)-retrotransposons constitute 42.4 % of the genome of the 'Suli' pear (Pyrus pyrifolia white pear group), implying that retrotransposons have played important roles in Pyrus evolution. Therefore, further analysis of retrotransposons will enhance our understanding of the evolutionary history of Pyrus.

Dormancy-associated MADS-box genes and microRNAs jointly control dormancy transition in pear (Pyrus pyrifolia white pear group) flower bud.

Bud dormancy in perennial plants is indispensable to survival over winter and to regrowth and development in the following year. However, the molecular pathways of endo-dormancy induction, maintenance, and release are still unclear, especially in fruit crops. To identify genes with roles in regulating endo-dormancy, 30 MIKC(C)-type MADS-box genes were identified in the pear genome and characterized.

Prediction of retrotransposons and assessment of genetic variability based on developed retrotransposon-based insertion polymorphism (RBIP) markers in Pyrus L.

Interspecific hybridization has been considered the major mode of evolution in Pyrus (pear), and thus, the genetic relationships within this genus have not been well documented. Retrotransposons are ubiquitous components of plant genomes and 42.4 % of the pear genome was reported to be long terminal repeat (LTR) retrotransposons, implying that retrotransposons might be significant in the evolution of Pyrus.

Phylogeny and evolutionary histories of Pyrus L. revealed by phylogenetic trees and networks based on data from multiple DNA sequences.

Reconstructing the phylogeny of Pyrus has been difficult due to the wide distribution of the genus and lack of informative data. In this study, we collected 110 accessions representing 25 Pyrus species and constructed both phylogenetic trees and phylogenetic networks based on multiple DNA sequence datasets. Phylogenetic trees based on both cpDNA and nuclear LFY2int2-N (LN) data resulted in poor resolution, especially, only five primary species were monophyletic in the LN tree.

Development of genic SSR markers from transcriptome sequencing of pear buds.

A total of 8375 genic simple sequence repeat (SSR) loci were discovered from a unigene set assembled from 116282 transcriptomic unigenes in this study. Dinucleotide repeat motifs were the most common with a frequency of 65.11%, followed by trinucleotide (32.

Single copy nuclear gene analysis of polyploidy in wild potatoes (Solanum section Petota).

Background: Recent genomic studies have drastically altered our knowledge of polyploid evolution. Wild potatoes (Solanum section Petota) are a highly diverse and economically important group of about 100 species widely distributed throughout the Americas. Thirty-six percent of the species in section Petota are polyploid or with diploid and polyploid cytotypes.

Asymmetric single-strand conformation polymorphism: an accurate and cost-effective method to amplify and sequence allelic variants.

Premise Of The Study: An efficient alternative strategy to conventional cloning was needed to generate high-quality DNA sequences from a variety of nuclear orthologs for phylogenetic studies. This method would facilitate studies and minimize technical problems typically encountered in cloning methodologies.

Methods: We tested a variety of single-strand conformation polymorphism (SSCP) protocols including purified and unpurified symmetric and asymmetric PCR, loading buffers, and electrophoresis conditions (buffers, matrix, running time, temperature).

Non-concerted ITS evolution, early origin and phylogenetic utility of ITS pseudogenes in Pyrus.

Molecular studies of 19 species of the genus Pyrus L. revealed different degrees of intra-individual polymorphism of the internal transcribed spacer (ITS 1, 5.8S rDNA and ITS 2) region due to the existence of putative non-functional copies (pseudogenes), putative recombinants and non-concerted evolution among functional copies.

Novel cyclooxygenase-1 inhibitors discovered using affinity fingerprints.

We used protein affinity fingerprints to discover structurally novel inhibitors of cyclooxygenase-1 (COX-1) by screening a selected number of compounds, thus providing an alternative to extensive screening. From the affinity fingerprints of 19 known COX-1 inhibitors, a computational model for COX-1 inhibition was constructed and used to select candidate inhibitors from our compound library to be tested in the COX-1 assay. Subsequent refinement of the model by including affinity fingerprints of inactive compounds identified three molecules that were more potent than ibuprofen, a commonly used COX-1 inhibitor.

Discovery of substrate for type I signal peptidase SpsB from Staphylococcus aureus.

Based on the kinetic model of substrate phage proteolysis, we have formulated a strategy for best manipulating the conditions in screening phage display libraries for protease substrates (Sharkov, N. A., Davis, R.