Worldwide, lung cancer is the most common cause of cancer-related deaths. Molecular targeted therapies and immunotherapies for non-small-cell lung cancer (NSCLC) have improved outcomes markedly over ...the past two decades. However, the vast majority of advanced NSCLCs become resistant to current treatments and eventually progress. In this Perspective, we discuss some of the recent breakthrough therapies developed for NSCLC, focusing on immunotherapies and targeted therapies. We highlight our current understanding of mechanisms of resistance and the importance of incorporating genomic analyses into clinical studies to decipher these further. We underscore the future role of neoadjuvant and maintenance combination therapy approaches to potentially cure early disease. A major challenge to successful development of rational combination therapies will be the application of robust predictive biomarkers for clear-cut patient stratification, and we provide our views on clinical research areas that could influence how NSCLC will be managed over the coming decade.
CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased antigen presentation, maturation ...(licensing) of dendritic cells, and activation of CD8+ T cells. Here we analyzed gene expression data from The Cancer Genome Atlas in melanoma, renal cell carcinoma, and pancreatic adenocarcinoma and found correlations between CD40 and several genes involved in antigen presentation and T cell function, supporting further exploration of CD40 agonists to treat cancer. Agonist CD40 antibodies have induced anti-tumor effects in several tumor models and the effect has been more pronounced when used in combination with other treatments (immune checkpoint inhibition, chemotherapy, and colony-stimulating factor 1 receptor inhibition). The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies.
Constituting approximately 10% of flowering plant species, orchids (Orchidaceae) display unique flower morphologies, possess an extraordinary diversity in lifestyle, and have successfully colonized ...almost every habitat on Earth. Here we report the draft genome sequence of Apostasia shenzhenica, a representative of one of two genera that form a sister lineage to the rest of the Orchidaceae, providing a reference for inferring the genome content and structure of the most recent common ancestor of all extant orchids and improving our understanding of their origins and evolution. In addition, we present transcriptome data for representatives of Vanilloideae, Cypripedioideae and Orchidoideae, and novel third-generation genome data for two species of Epidendroideae, covering all five orchid subfamilies. A. shenzhenica shows clear evidence of a whole-genome duplication, which is shared by all orchids and occurred shortly before their divergence. Comparisons between A. shenzhenica and other orchids and angiosperms also permitted the reconstruction of an ancestral orchid gene toolkit. We identify new gene families, gene family expansions and contractions, and changes within MADS-box gene classes, which control a diverse suite of developmental processes, during orchid evolution. This study sheds new light on the genetic mechanisms underpinning key orchid innovations, including the development of the labellum and gynostemium, pollinia, and seeds without endosperm, as well as the evolution of epiphytism; reveals relationships between the Orchidaceae subfamilies; and helps clarify the evolutionary history of orchids within the angiosperms.
Many plants of
genus are precious traditional herbs with high commercial value and excellent medicinal effects. They are perennial aerophytes or epiphytes of terrestrial orchids growing on cliffs and ...tree trunks covered with mosses in forests throughout the tropical and subtropical Asia and eastern Australia. The stem contains a variety of bioactive components, including polysaccharides and alkaloids, with strong antioxidant, neuroprotective, and immunomodulatory effects. Great attention has been drawn to the
genus regarding its medicinal effectiveness, and the related researches have been accumulating rapidly in recent years. The bioactive components are mainly the intermediates or final products produced in specialized metabolite biosynthesis. Thus far, the activity, molecular structure, and composition of major medicinal ingredients have been partially elucidated, and the sequencing of several transcriptomes has been starting to shed new light on the biosynthesis regulation mechanism. This paper reviewed the advances of researches concerning the biosynthetic pathways of medicinal specialized metabolites from
, especially the large number of related genes, with the hope of further promoting the development and utilization of those components and correspondingly protecting the
resources in more effective ways.
Osteoarthritis (OA) is a degenerative joint disease affecting a large population of people. The mechanism of this highly prevalent disease is not fully understood. Currently there is no effective ...disease-modifying treatment for OA. The purpose of this study was two-fold: 1) to investigate the role of MMP13 in the development of OA; and 2) to evaluate the efficacy of the MMP13 inhibitor CL82198 as a pharmacologic treatment for preventing OA progression.
To investigate the role of the endogenous Mmp13 gene in OA development, tamoxifen was administered to two-week-old Col2CreER;Mmp13fx/fx (Mmp13Col2ER) and Cre-negative control mice for five days. OA was induced by meniscal-ligamentous injury (MLI) when the mice were 10 weeks old and MLI or sham-operated joints were harvested 4, 8, 12, or 16 weeks after surgery. To evaluate the efficacy of CL82198, MLI surgery was performed on 10-week-old wild type mice. CL82198 or saline was administered to the mice daily beginning immediately after the surgery for up to 16 weeks. The joint tissues collected from both experiments were evaluated by cartilage grading, histology/histomorphometry, immunohistochemistry (IHC), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The ability of CL82198 to inhibit MMP13 activity in vitro was confirmed by ELISA.
The OA progression was decelerated in Mmp13Col2ER mice 8, 12, and 16 weeks post-surgery. Cartilage grading by blinded observers confirmed decreased articular cartilage degeneration in Mmp13Col2ER mice at 8, 12 and 16 weeks compared to Cre-negative mice. Histomorphometric analysis demonstrated that Mmp13Col2ER mice had a higher articular cartilage area and thickness at 12 and 16 weeks post-surgery compared to the control mice. Results of IHC revealed greater type II collagen and proteoglycan expression in Mmp13Col2ER mice. Chondrocyte apoptosis, as determined by TUNEL staining, was higher in control mice compared to Mmp13Col2ER mice. CL82198 inhibited MMP13 activity in conditioned media from vehicle (>85%) or bone morphogenetic protein 2 (BMP2)-treated (>90%) primary murine sternal chondrocytes. Intraperitoneal injection of CL82198 decelerated MLI-induced OA progression, increased type II collagen and proteoglycan levels, and inhibited chondrocyte apoptosis compared to saline treatment as determined by OA grading, histology, histomorphometry, IHC, and TUNEL staining, respectively.
Mmp13 is critical for OA progression and pharmacologic inhibition of MMP13 is an effective strategy to decelerate articular cartilage loss in a murine model of injury-induced knee OA.
This research focuses on the “Improved Product R&D Project” of Sichuan Chaochen Electric Co., Ltd, analyzing its market status from the life style of its main consumer groups, namely users of the ...secondary and tertiary markets. Through field observation and in-depth interview methods, the user's daily habits and demands for washing machines are closely looked into. Then the research comes up with some design elements aiming at the low-end markets, and also offers the corresponding specific design proposal. On this basis, it provides new ideas and fresh design methods for the appearance improvements of the secondary and tertiary market washing machines, from angels of external morphology, human-computer interaction and concept trends etc, thus in hopes of being referential to the actual product improvements of the mid-and-low-end washing machine markets.
Abstract
Background
Dendrobium catenatum
/
D. officinale
(here after
D. catenatum
), a well-known economically important traditional medicinal herb, produces a variety of bioactive metabolites ...including polysaccharides, alkaloids, and flavonoids with excellent pharmacological and clinical values. Although many genes associated with the biosynthesis of medicinal components have been cloned and characterized, the biosynthetic pathway, especially the downstream and regulatory pathway of major medicinal components in the herb, is far from clear. β-glucosidases (BGLUs) comprise a diverse group of enzymes that widely exist in plants and play essential functions in cell wall modification, defense response, phytohormone signaling, secondary metabolism, herbivore resistance, and scent release by hydrolyzing β-D-glycosidic bond from a carbohydrate moiety. The recent release of the chromosome-level reference genome of
D. catenatum
enables the characterization of gene families. Although the genome-wide analysis of the
BGLU
gene family has been successfully conducted in various plants, no systematic analysis is available for the
D. catenatum
. We previously isolated
DcBGLU2
in the
BGLU
family as a key regulator for polysaccharide biosynthesis in
D. catenatum
. Yet, the exact number of
DcBGLU
s in the
D. catenatum
genome and their possible roles in bioactive compound production deserve more attention.
Results
To investigate the role of
BGLU
s in active metabolites production, 22
BGLU
s (
DcBGLU1
-
22
) of the glycoside hydrolase family 1 (GH1) were identified from
D. catenatum
genome. Protein prediction showed that most of the DcBGLUs were acidic and phylogenetic analysis classified the family into four distinct clusters. The sequence alignments revealed several conserved motifs among the DcBGLU proteins and analyses of the putative signal peptides and N-glycosylation site revealed that the majority of DcBGLU members dually targeted to the vacuole and/or chloroplast. Organ-specific expression profiles and specific responses to MeJA and
MF23
were also determined. Furthermore, four
DcBGLU
s were selected to test their involvement in metabolism regulation. Overexpression of
DcBGLU2
,
6
,
8
, and
13
significantly increased contents of flavonoid, reducing-polysaccharide, alkaloid and soluble-polysaccharide, respectively.
Conclusion
The genome-wide systematic analysis identified candidate
DcBGLU
genes with possible roles in medicinal metabolites production and laid a theoretical foundation for further functional characterization and molecular breeding of
D. catenatum
.
Recent studies on co-transformation of the growth regulator, TaGRF4-GIF1 chimera (Growth Regulating Factor 4-GRF Interacting Factor 1), in cultivated wheat varieties (Triticum aestivum), showed ...improved regeneration efficiency, marking a significant breakthrough. Here, a simple and reproducible protocol using the GRF4-GIF1 chimera was established and tested in the medicinal orchid Dendrobium catenatum, a monocot orchid species. TaGRF4-GIF1 from T. aestivum and DcGRF4-GIF1 from D. catenatum were reconstructed, with the chimeras significantly enhancing the regeneration efficiency of D. catenatum through in planta transformation. Further, mutating the microRNA396 (miR396) target sites in TaGRF4 and DcGRF4 improved regeneration efficiency. The target mimicry version of miR396 (MIM396) not only boosted shoot regeneration but also enhanced plant growth. Our methods revealed a powerful tool for the enhanced regeneration and genetic transformation of D. catenatum.
Osteoarthritis (OA) is a highly prevalent disease affecting more than 20% of American adults. Predispositions include joint injury, heredity, obesity, and aging. Biomechanical alterations are ...commonly involved. However, the molecular mechanisms of this disease are complex, and there is currently no effective disease‐modifying treatment. The initiation and progression of OA subtypes is a complex process that at the molecular level probably involves many cell types, signaling pathways, and changes in extracellular matrix. Ex vivo studies with tissue derived from OA patients and in vivo studies with mutant mice have suggested that pathways involving receptor ligands such as TGF‐β1, WNT3a, and Indian hedgehog; signaling molecules such as Smads, β‐catenin, and HIF‐2a; and peptidases such as MMP13 and ADAMTS4/5 are probably involved to some degree. This review focuses on molecular mechanisms of OA development related to recent findings.
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