Recent progress in chimeric antigen receptor-modified T-cell (CAR-T cell) technology in cancer therapy is extremely promising, especially in the treatment of patients with B-cell acute lymphoblastic ...leukemia. In contrast, due to the hostile immunosuppressive microenvironment of a solid tumor, CAR T-cell accessibility and survival continue to pose a considerable challenge, which leads to their limited therapeutic efficacy. In this study, we constructed two anti-MUC1 CAR-T cell lines. One set of CAR-T cells contained SM3 single chain variable fragment (scFv) sequence specifically targeting the MUC1 antigen and co-expressing interleukin (IL) 12 (named SM3-CAR). The other CAR-T cell line carried the SM3 scFv sequence modified to improve its binding to MUC1 antigen (named pSM3-CAR) but did not co-express IL-12. When those two types of CAR-T cells were injected intratumorally into two independent metastatic lesions of the same MUC1
+
seminal vesicle cancer patient as part of an interventional treatment strategy, the initial results indicated no side-effects of the MUC1 targeting CAR-T cell approach, and patient serum cytokines responses were positive. Further evaluation showed that pSM3-CAR effectively caused tumor necrosis, providing new options for improved CAR-T therapy in solid tumors.
•Livestock depredation by highly endangered Amur tigers is a major source of human-tiger conflict in Northeast China.•We model ungulate density and the spatial risk of depredation.•Lower overall prey ...densities and depredation risk were associated inter alia with proximity to snares.•Compensation payments for depredation within the protected area provide an incentive to use it as grazing land.•Eliminating cattle and snaring from the protected area may be essential to reduce conflict.
Livestock depredation by highly endangered Amur tigers is a major source of human-tiger conflict in Northeast China. We model livestock depredation risk to understand factors shaping the spatial distribution of depredation conflicts using Hunchun, China as a case study. Ungulate occupancy survey data, presence of ungulate snares and other landscape covariates (such as elevation, slope and tree cover) were first used to model ungulate prey densities using generalised least squares. Predicted densities were then incorporated together with landscape covariates as predictors for actual livestock depredation incidents in a zero-inflated negative binomial model for depredation risk. Lower overall prey densities were associated with proximity to snares, and other anthropogenic-related covariates like distances to villages and roads were also important predictors of prey densities. Depredation conflicts were associated with closer proximity to snares and rivers, greater distances from roads, greater tree cover, and deciduous forest habitats. High-risk areas were found to be concentrated in community-management zones in Hunchun National Nature Reserve (HNR). The results suggest that compensation payments for depredations within HNR provide an unwanted incentive for local people to continue to use the protected area (especially in community co-managed zones) as grazing lands, leading to increased conflict. Eliminating cattle and snaring from HNR and other tiger recovery zones within Northeast China may be essential to reduce conflicts and minimise detrimental impacts on tiger populations.
Historical records can provide important evidence of changes in distributions of wildlife species. Here we discuss the distribution of the tiger (Panthera tigris Linnaeus, 1758) over the past 2000 ...years in China based on 2635 historical records. We also compare tiger distributions outlined in these records with ecosystem type maps. Throughout this time period, tigers maintained a broad distribution across 7 biomes (from forests to deserts). However, in recent decades the range has been significantly condensed. Today, only 2 populations remain, neither of which is independently viable. Tigers have completely disappeared from the temperate broadleaf and mixed forests of central China, a region that was traditionally their most important biome in China. The continued presence of wild tigers in China is highly dependent on significant conservation measures.
Background
Both submucosal tunneling endoscopic resection (STER) and endoscopic full-thickness resection (EFTR) are effective method for treating gastric gastrointestinal stromal tumors (GISTs); ...however, little is known about the comparison between STER and EFTR. The aim of the study was to compare the safety and efficacy of STER and EFTR for treating gastric GIST.
Methods
We retrospectively collected the clinical data about patients with gastric GISTs who received STER or EFTR at our hospital from April 2011 to June 2016. Epidemiological data (gender, age), tumor size, procedure-related parameters, complications, length of stay, cost and follow-up data were compared between STER and EFTR.
Results
A total of 52 patients were enrolled, and 20 of them received STER, while the other 32 cases received EFTR. There was no significant difference between the two groups in terms of gender, age, concomitant diseases, tumor size, en bloc resection rate, operation time, complications, pathohistological grade of GIST, hospital stay and cost (
P
> 0.05). However, patients who received EFTR had a longer suture time and needed more clips to close the gastric-wall defect (STER vs EFTR, 291.5 ± 68.7 vs 380.6 ± 96.9s and 6.0 ± 1.2 vs 7.6 ± 1.6,
P
< 0.05). No recurrence was noted in the STER and EFTR groups during a mean follow-up of 10.9 and 23.8 months, respectively.
Conclusions
The treatment efficacy between STER and EFTR for treating gastric GISTs was comparable, and a large-scale, randomized study is necessary for a more confirmed conclusion.
We carried out a genome-wide association study among Chinese women to identify risk variants for breast cancer. After analyzing 607,728 SNPs in 1,505 cases and 1,522 controls, we selected 29 SNPs for ...a fast-track replication in an independent set of 1,554 cases and 1,576 controls. We further investigated four replicated loci in a third set of samples comprising 3,472 cases and 900 controls. SNP rs2046210 at 6q25.1, located upstream of the gene encoding estrogen receptor α (ESR1), showed strong and consistent association with breast cancer across all three stages. Adjusted odds ratio (95% CI) were 1.36 (1.24-1.49) and 1.59 (1.40-1.82), respectively, for genotypes A/G and A/A versus G/G (P for trend 2.0 × 10−15) in the pooled analysis of samples from all three stages. We also found a similar, albeit weaker, association in an independent study comprising 1,591 cases and 1,466 controls of European ancestry (Ptrend = 0.01). These results strongly implicate 6q25.1 as a susceptibility locus for breast cancer.
Little is known about the molecular mechanism of the R2R3-MYB transcriptional repressors involved in plant phenylpropanoid metabolism. Here, we describe one R2R3-type MYB repressor, FtMYB11 from ...Fagopyrum tataricum. It contains the SID-like motif GGDFNFDL and it is regulated by both the importin protein ‘Sensitive to ABA and Drought 2’ (SAD2) and the jasmonates signalling cascade repressor JAZ protein.
Yeast two hybrid and bimolecular fluorescence complementation assays demonstrated that FtMYB11 interacts with SAD2 and FtJAZ1. Protoplast transactivation assays demonstrated that FtMYB11 acts synergistically with FtSAD2 or FtJAZ1 and directly represses its target genes via the MYB-core element AATAGTT.
Changing the Asp122 residue to Asn in the SID-like motif results in cytoplasmic localization of FtMYB11 because of loss of interaction with SAD2, while changing the Asp126 residue to Asn results in the loss of interaction with FtJAZ1. Overexpression of FtMYB11 or FtMYB11
D126N in F. tataricum hairy roots resulted in reduced accumulation of rutin, while overexpression of FtMYB11
D122N in hairy roots did not lead to such a change.
The results indicate that FtMYB11 acts as a regulator via interacting with FtSAD2 or FtJAZ1 to repress phenylpropanoid biosynthesis, and this repression depends on two conserved Asp residues of its SID-like motif.
Genome-wide association studies (GWASs) have identified multiple genetic susceptibility loci for breast cancer. However, these loci explain only a small fraction of the heritability. Very few studies ...have evaluated copy number variation (CNV), another important source of human genetic variation, in relation to breast cancer risk.
We conducted a CNV GWAS in 2623 breast cancer patients and 1946 control subjects using data from Affymetrix SNP Array 6.0 (stage 1). We then replicated the most promising CNV using real-time quantitative polymerase chain reaction (qPCR) in an independent set of 4254 case patients and 4387 control subjects (stage 2). All subjects were recruited from population-based studies conducted among Chinese women in Shanghai.
Of the 268 common CNVs (minor allele frequency ≥ 5%) investigated in stage 1, the strongest association was found for a common deletion in the APOBEC3 genes (P = 1.1×10(-4)) and was replicated in stage 2 (odds ratio =1.35, 95% confidence interval CI = 1.27 to 1.44; P = 9.6×10(-22)). Analyses of all samples from both stages using qPCR data produced odds ratios of 1.31 (95% CI = 1.21 to 1.42) for a one-copy deletion and 1.76 (95% CI = 1.57 to 1.97) for a two-copy deletion (P = 2.0×10(-24)).
We provide convincing evidence for a novel breast cancer locus at the APOBEC3 genes. This CNV is one of the strongest common genetic risk variants identified so far for breast cancer.
Autonomous agents have long been a research focus in academic and industry communities. Previous research often focuses on training agents with limited knowledge within isolated environments, which ...diverges significantly from human learning processes, and makes the agents hard to achieve human-like decisions. Recently, through the acquisition of vast amounts of Web knowledge, large language models (LLMs) have shown potential in human-level intelligence, leading to a surge in research on LLM-based autonomous agents. In this paper, we present a comprehensive survey of these studies, delivering a systematic review of LLM-based autonomous agents from a holistic perspective. We first discuss the construction of LLM-based autonomous agents, proposing a unified framework that encompasses much of previous work. Then, we present a overview of the diverse applications of LLM-based autonomous agents in social science, natural science, and engineering. Finally, we delve into the evaluation strategies commonly used for LLM-based autonomous agents. Based on the previous studies, we also present several challenges and future directions in this field.
The cytoskeletal architecture of osteoclasts (OCs) and bone resorption activity must be appropriately controlled for proper bone remodeling, which is associated with osteoporosis. The RhoA protein of ...GTPase plays a regulatory role in cytoskeletal components and contributes to osteoclast adhesion, podosome positioning, and differentiation. Although osteoclast investigations have traditionally been performed by in vitro analysis, however, the results have been inconsistent, and the significance of RhoA in bone physiology and pathology is still unknown.
We generated RhoA knockout mice by specifically deleting RhoA in the osteoclast lineage to understand more about RhoA's involvement in bone remodeling. The function of RhoA in osteoclast differentiation and bone resorption and the mechanisms were assessed using bone marrow macrophages (BMMs) in vitro. The ovariectomized (OVX) mouse model was adopted to examine the pathological effect of RhoA in bone loss.
Conditional deletion of RhoA in the osteoclast lineage causes a severe osteopetrosis phenotype, which is attributable to a bone resorption suppression. Further mechanistic studies suggest that RhoA deficiency suppresses Akt-mTOR-NFATc1 signaling during osteoclast differentiation. Additionally, RhoA activation is consistently related to the significant enhancement the osteoclast activity, which culminates in the development of an osteoporotic bone phenotype. Furthermore, in mice, the absence of RhoA in osteoclast precursors prevented occurring OVX-induced bone loss.
RhoA promoted osteoclast development via the Akt-mTOR-NFATc1 signaling pathway, resulting a osteoporosis phenotype, and that manipulating RhoA activity might be a therapeutic strategy for osteoporotic bone loss.
Lowering the isoelectric point (pI) through engineering the variable region or framework of an IgG can improve its exposure and half-life via a reduction in clearance mediated through non-specific ...interactions. As such, net charge is a potentially important property to consider in developing therapeutic IgG molecules having favorable pharmaceutical characteristics. Frequently, it may not be possible to shift the pI of monoclonal antibodies (mAbs) dramatically without the introduction of other liabilities such as increased off-target interactions or reduced on-target binding properties. In this report, we explored the influence of more subtle modifications of molecular charge on the in vivo properties of an IgG1 and IgG4 monoclonal antibody. Molecular surface modeling was used to direct residue substitutions in the complementarity-determining regions (CDRs) to disrupt positive charge patch regions, resulting in a reduction in net positive charge without affecting the overall pI of the mAbs. The effect of balancing the net positive charge on non-specific binding was more significant for the IgG4 versus the IgG1 molecule that we examined. This differential effect was connected to the degree of influence on cellular degradation in vitro and in vivo clearance, distribution and metabolism in mice. In the more extreme case of the IgG4, balancing the charge yielded an ∼7-fold improvement in peripheral exposure, as well as significantly reduced tissue catabolism and subsequent excretion of proteolyzed products in urine. Balancing charge on the IgG1 molecule had a more subtle influence on non-specific binding and yielded only a modest alteration in clearance, distribution and elimination. These results suggest that balancing CDR charge without affecting the pI can lead to improved mAb pharmacokinetics, the magnitude of which is likely dependent on the relative influence of charge imbalance and other factors affecting the molecule's disposition.
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