The effects of HLA-identical sibling donor (ISD) hematopoietic stem cell transplantation (HSCT) on adults with intermediate- or high-risk acute myeloid leukemia (AML) in the first complete remission ...(CR1) are well established. Previous single-center studies have demonstrated similar survival after unmanipulated haploidentical donor (HID) vs ISD HSCT for hematologic malignancies. To test the hypothesis that haploidentical HSCT would be a valid option as postremission therapy for AML patients in CR1 lacking a matched donor, we designed a disease-specific, prospective, multicenter study. Between July 2010 and November 2013, 450 patients were assigned to undergo HID (231 patients) or ISD HSCT (219 patients) according to donor availability. Among HID and ISD recipients, the 3-year disease-free survival rate was 74% and 78% (P = .34), respectively; the overall survival rate was 79% and 82% (P = .36), respectively; cumulative incidences of relapse were 15% and 15% (P = .98); and those of the nonrelapse-mortality were 13% and 8% (P = .13), respectively. In conclusion, unmanipulated haploidentical HSCT achieves outcomes similar to those of ISD HSCT for AML patients in CR1. Such transplantation was demonstrated to be a valid alternative as postremission treatment of intermediate- or high-risk AML patients in CR1 lacking an identical donor. This trial was registered at www.chictr.org as #ChiCTR-OCH-10000940.
•Haploidentical transplant achieves outcomes similar to those of identical-sibling transplant for AML patients in first remission.•Haploidentical transplant is a valid postremission treatment of intermediate- or high-risk AML patients lacking an identical donor.
To accelerate the application of the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/ CRISPR-associated protein 9) system to a variety of plant species, a toolkit with ...additional plant selectable markers, more gRNA modules, and easier methods for the assembly of one or more gRNA expression cassettes is required.
We developed a CRISPR/Cas9 binary vector set based on the pGreen or pCAMBIA backbone, as well as a gRNA (guide RNA) module vector set, as a toolkit for multiplex genome editing in plants. This toolkit requires no restriction enzymes besides BsaI to generate final constructs harboring maize-codon optimized Cas9 and one or more gRNAs with high efficiency in as little as one cloning step. The toolkit was validated using maize protoplasts, transgenic maize lines, and transgenic Arabidopsis lines and was shown to exhibit high efficiency and specificity. More importantly, using this toolkit, targeted mutations of three Arabidopsis genes were detected in transgenic seedlings of the T1 generation. Moreover, the multiple-gene mutations could be inherited by the next generation.
We developed a toolkit that facilitates transient or stable expression of the CRISPR/Cas9 system in a variety of plant species, which will facilitate plant research, as it enables high efficiency generation of mutants bearing multiple gene mutations.
Arabidopsis mutants produced by constitutive overexpression of the CRISPR/Cas9 genome editing system are usually mosaics in the T1 generation. In this study, we used egg cell-specific promoters to ...drive the expression of Cas9 and obtained non-mosaic T1 mutants for multiple target genes with high efficiency. Comparisons of 12 combinations of eight promoters and two terminators found that the efficiency of the egg cell-specific promoter-controlled CRISPR/Cas9 system depended on the presence of a suitable terminator, and the composite promoter generated by fusing two egg cell-specific promoters resulted in much higher efficiency of mutation in the T1 generation compared with the single promoters.
Simple steps, complex result: Consecutive organo‐catalyzed reactions of 3‐indolylmethanol compounds with aldehydes and N‐protected indoles lead to the formation of structurally complex ...cyclopentabindoles (see scheme, Bn=benzyl). These one‐pot multistep reactions have a broad substrate scope and give the products in high yields, and with excellent diastereoselectivities and enantioselectivities.
Bariatric surgery is recommended for patients with obesity and type 2 diabetes. Recent evidence suggested a strong connection between gut microbiota and bariatric surgery.
Systematic review.
The ...PubMed and OVID EMBASE were used, and articles concerning bariatric surgery and gut microbiota were screened. The main outcome measures were alterations of gut microbiota after bariatric surgery and correlations between gut microbiota and host metabolism. We applied the system of evidence level to evaluate the alteration of microbiota. Modulation of short-chain fatty acid and gut genetic content was also investigated.
Totally 12 animal experiments and 9 clinical studies were included. Based on strong evidence, 4 phyla (Bacteroidetes, Fusobacteria, Verrucomicrobia and Proteobacteria) increased after surgery; within the phylum Firmicutes, Lactobacillales and Enterococcus increased; and within the phylum Proteobacteria, Gammaproteobacteria, Enterobacteriales Enterobacteriaceae and several genera and species increased. Decreased microbial groups were Firmicutes, Clostridiales, Clostridiaceae, Blautia and Dorea. However, the change in microbial diversity is still under debate. Faecalibacterium prausnitzii, Lactobacillus and Coprococcus comes are implicated in many of the outcomes, including body composition and glucose homeostasis.
There is strong evidence to support a considerable alteration of the gut microbiome after bariatric surgery. Deeper investigations are required to confirm the mechanisms that link the gut microbiome and metabolic alterations in human metabolism.
•The short-term subsidy strategy for new users (strategy S) of ride-hailing platform is studied.•Impacts of user base and expected benefit on platform’s decision on adopting strategy S are ...considered.•The platform’s optimal subsidies for new users are obtained.•Impacts of strategy S on ride-hailing platform’s profit and social welfare are examined.•Useful managerial insights for ride-hailing platform and government are given.
Short-term subsidy strategy for new passengers and drivers (hereafter strategy S) has been frequently adopted by ride-hailing platforms. However, how to set the suitable subsidy is still unclear. This paper examines the strategy S of ride-hailing platform(s) in the monopoly and duopoly markets, respectively. The results show that adopting strategy S is profitable for the ride-hailing platform when the user base of either passengers or drivers is small in the monopoly market. In the duopoly market, adopting strategy S is profitable for the ride-hailing platform when the user bases of both passengers and drivers are small. Moreover, in the monopoly and duopoly markets, adopting strategy S cannot effectively increase social welfare when the user bases of both passengers and drivers are large.
In South China (Gejiu City, Yunnan Province), lung cancer incidence and associated mortality rate is the most prevalent and observed forms of cancer. Lung cancer in this area is called Gejiu squamous ...cell lung carcinoma (GSQCLC). Research has demonstrated that overexpression of miR-21 occurs in many cancers. However, the unique relationship between miR-21 and its target genes in GSQCLC has never been investigated. The molecular mechanism involved in GSQCLC must be compared to other non-small cell lung cancers in order to establish a relation and identify potential therapeutic targets.
In the current study, we initially found overexpression of miR-21 occurring in non-small cell lung cancer (NSCLC) cell lines when compared to the immortalized lung epithelial cell line BEAS-2B. We also demonstrated that high expression of miR-21 could increase tumor cell proliferation, invasion, viability, and migration in GSQCLC cell line (YTMLC-90) and NSCLC cell line (NCI-H157). Additionally, our results revealed that miR-21 could suppress YTMLC-90 and NCI-H157 cell apoptosis through arresting cell-cycle at G2/M phase. Furthermore, we demonstrated that PTEN, RECK and Bcl-2 are common target genes of miR-21 in NSCLC. Finally, our studies showed that down-regulation of miR-21 could lead to a significant increase in PTEN and RECK and decrease in Bcl-2 at the mRNA and protein level in YTMLC-90 and NCI-H157 cell lines. However, we have not observed any remarkable difference in the levels of miR-21 and its targets in YTMLC-90 cells when compared with NCI-H157 cells.
miR-21 simultaneously regulates multiple programs that enhance cell proliferation, apoptosis and tumor invasiveness by targeting PTEN, RECK and Bcl-2 in GSQCLC. Our results demonstrated that miR-21 may play a vital role in tumorigenesis and progression of lung squamous cell carcinoma and suppression of miR-21 may be a novel approach for the treatment of lung squamous cell carcinoma.
Summary
We retrospectively investigated outcomes of haploidentical donor (HID) transplant for adults with standard‐risk acute lymphoblastic leukaemia (ALL) in first complete remission (CR1) compared ...with human leucocyte antigen (HLA)‐matched sibling donor (MSD) and HLA‐matched unrelated donor (MUD) transplants. A total of 348 adult patients were enrolled, including 127 HID, 144 MSD and 77 MUD recipients. The cumulative incidence of grade II–IV acute graft‐versus‐host disease (aGVHD) was 39·5%, 24·0% and 40·3% for HID, MSD and MUD, respectively (P = 0·020). However, there was no difference in grade III–IV aGVHD (11·4%, 7·7%, 13·5%, respectively, P = 0·468). The 5‐year cumulative transplant‐related mortality was 16·4%, 11·6% and 19·6% (P = 0·162), the 5‐year relapse rate post‐transplantation was 14·8%, 21·1% and 16·7% (P = 0·231), the 5‐year overall survival was 70·1%, 73·7% and 69·8% (P = 0·525), and the 5‐year disease‐free survival was 68·7%, 67·3% and 63·7%, respectively (P = 0·606). Furthermore, the 3‐year GVHD‐free, relapse‐free survival was not different (50·8%, 54·9% and 52·2%, respectively, P = 0·847). Our results indicate that the outcomes of HID transplants are equivalent to those of MSD and MUD, and that HID transplantation is a valid alternative for standard‐risk adults with ALL in CR1 who lack matched donors.
Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of ...Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous SmoD99N/D99N (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo−/− mice. Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway-related cancers by targeting SMO cholesterylation.
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•SMO is covalently modified by cholesterol on the Asp95 (D95) residue•Cholesterol modification of SMO is inhibited by Ptch1 and enhanced by Hh•SMO cholesterylation is essential for Hh signaling and embryonic development
Xiao et al. identify that SMO is covalently modified by cholesterol. This modification is regulated by Ptch1 and Hh and is essential for Hh signaling. It suggests that Hh signaling transduces to SMO through modulating its cholesterylation and that targeting SMO cholesterylation may provide a therapeutic approach to treat Hh-pathway-related cancers.
The effects of different initial microstructures of Mg–9Al–1Zn alloy on microstructure and mechanical properties after rolled were investigated in this study. Three original Mg–9Al–1Zn alloys ...involving as-cast, cast-rolling and as-extruded conditions present different initial grain sizes and initial textures. After a rolling process, all the corresponding rolled sheets show a fine-grained recrystallized microstructure (2.7–3.6μm) and a strong basal (0002) texture. The tensile tests of the three rolled sheets show that the as-extruded alloy after rolled exhibits the highest yield strength (~248MPa) and the highest tensile strength (~382MPa) at room temperature, and has the greatest ultimate elongation (~697%) at 300°C. Therefore, the Mg–9Al–1Zn alloy sheet via a combination of extrusion and rolling possesses the best integrated performance in service at room temperature and presents the most excellent superplastic capacity at elevated temperature among all the three sheets. The results in this study would be of high industrial or scientific interest in industrial applications and superplastic preprocessing on magnesium alloys.
•Effects of initial microstructures on the rolled microstructures and mechanical properties of AZ91 sheets were investigated.•All three rolled AZ91 sheets present a fine-grained recrystallized microstructure and a strong basal (0002) texture.•The extrusion-rolling AZ91 sheet possesses relatively excellent mechanical properties.
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