筛选条件 共查询到29条结果
排序方式
Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models

第一作者:Song, YF

期刊: NATURE MEDICINE, 2019; 25 (10)

The essential product of the Duchenne muscular dystrophy (DMD) gene is dystrophin(1), a rod-like protein(2) that protects striated myocytes from contraction-induced injury(3,4). Dystrophin-related protein (or utrophin) retains most of the structural and protein binding elements of dystrophin(5). Importantly, normal thymic expression in DMD patients(6) should protect utrophin by central immunologic tolerance. We designed a codon-optimized, synthetic transgene encoding a miniaturized utrophin (mu Utro), deliverable by adeno-associated virus (AAV) vectors. Here, we show that mu Utro is a highly functional, non-immunogenic substitute for dystrophin, preventing the most deleterious histological and physiological aspects of muscular dystrophy in small and large animal models. Following systemic administration of an AAV-mu Utro to neonatal dystrophin-deficient mdx mice, histological and biochemical markers of myonecrosis and regeneration are completely suppressed throughout growth to adult weight. In the dystrophin-deficient golden retriever model, mu Utro non-toxically prevented myonecrosis, even in the most powerful muscles. In a stringent test of immunogenicity, focal expression of mu Utro in the deletional-null German shorthaired pointer model produced no evidence of cell-mediated immunity, in contrast to the robust T cell response against similarly constructed mu Dystrophin (mu Dystro). These findings support a model in which utrophin-derived therapies might be used to treat clinical dystrophin deficiency, with a favorable immunologic profile and preserved function in the face of extreme miniaturization.

IF:30.64

The practical implementation of artificial intelligence technologies in medicine

第一作者:He, JX

期刊: NATURE MEDICINE, 2019; 25 (1)

The development of artificial intelligence (AI)-based technologies in medicine is advancing rapidly, but real-world clinical implementation has not yet become a reality. Here we review some of the key practical issues surrounding the implementation of AI into existing clinical workflows, including data sharing and privacy, transparency of algorithms, data standardization, and interoperability across multiple platforms, and concern for patient safety. We summarize the current regulatory environment in the United States and highlight comparisons with other regions in the world, notably Europe and China.

IF:30.64

Cannabinoid CB1 receptors in the amygdalar cholecystokinin glutamatergic afferents to nucleus accumbens modulate depressive-like behavior

第一作者:Shen, CJ

期刊: NATURE MEDICINE, 2019; 25 (2)

Major depressive disorder is a devastating psychiatric disease that afflicts up to 17% of the world's population. Postmortem brain analyses and imaging studies of patients with depression have implicated basal lateral amygdala (BLA) dysfunction in the pathophysiology of depression. However, the circuit and molecular mechanisms through which BLA neurons modulate depressive behavior are largely uncharacterized. Here, in mice, we identified that BLA cholecystokinin (CCK) glutamatergic neurons mediated negative reinforcement via D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and that chronic social defeat selectively potentiated excitatory transmission of the CCKBLA-D2(NAc) circuit in susceptible mice via reduction of presynaptic cannabinoid type-1 receptor (CB1R). Knockdown of CB1R in the CCKBLA-D2(NAc) circuit elevated synaptic activity and promoted stress susceptibility. Notably, selective inhibition of the CCKBLA-D2(NAc) circuit or administration of synthetic cannabinoids in the NAc was sufficient to produce antidepressant-like effects. Overall, our studies reveal the circuit and molecular mechanisms of depression.

IF:30.64

Tumor-educated B cells selectively promote breast cancer lymph node metastasis by HSPA4-targeting IgG

第一作者:Gu, Y

期刊: NATURE MEDICINE, 2019; 25 (2)

Primary tumors may create the premetastatic niche in secondary organs for subsequent metastasis. Humoral immunity contributes to the progression of certain cancers, but the roles of B cells and their derived antibodies in premetastatic niche formation are poorly defined. Using a mouse model of spontaneous lymph node metastasis of breast cancer, we show that primary tumors induced B cell accumulation in draining lymph nodes. These B cells selectively promoted lymph node metastasis by producing pathogenic IgG that targeted glycosylated membrane protein HSPA4, and activated the HSPA4-binding protein ITGB5 and the downstream Src/NF-kappa B pathway in tumor cells for CXCR4/SDF1 alpha-axis-mediated metastasis. High serum anti-HSPA4 IgG was correlated with high tumor HSPA4 expression and poor prognosis of breast cancer subjects. Our findings identify a key role for tumor-educated B cells and their derived antibodies in lymph node premetastatic niche formation, providing potential targets for cancer intervention.

IF:30.64

RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling

第一作者:Yao, Z

期刊: NATURE MEDICINE, 2019; 25 (2)

Activating BRAF mutants and fusions signal as RAS-independent constitutively active dimers with the exception of BRAF V600 mutant alleles which can function as active monomers(1). Current RAF inhibitors are monomer selective, they potently inhibit BRAF V600 monomers but their inhibition of RAF dimers is limited by induction of negative cooperativity when bound to one site in the dimer(1-3). Moreover, acquired resistance to these drugs is usually due to molecular lesions that cause V600 mutants to dimerize(4-8). We show here that PLX8394, a new RAF inhibitor(9), inhibits ERK signaling by specifically disrupting BRAF-containing dimers, including BRAF homodimers and BRAF-CRAF heterodimers, but not CRAF homodimers or ARAF-containing dimers. Differences in the amino acid residues in the amino (N)-terminal portion of the kinase domain of RAF isoforms are responsible for this differential vulnerability. As a BRAF-specific dimer breaker, PLX8394 selectively inhibits ERK signaling in tumors driven by dimeric BRAF mutants, including BRAF fusions and splice variants as well as BRAF V600 monomers, but spares RAF function in normal cells in which CRAF homodimers can drive signaling. Our work suggests that drugs with these properties will be safe and useful for treating tumors driven by activating BRAF mutants or fusions.

IF:30.64

IL1R1 is required for celastrol's leptin-sensitization and antiobesity effects

第一作者:Feng, XD

期刊: NATURE MEDICINE, 2019; 25 (4)

Celastrol, a pentacyclic triterpene, is the most potent antiobesity agent that has been reported thus far(1). The mechanism of celastrol's leptin-sensitizing and antiobesity effects has not yet been elucidated. In this study, we identified interleukin-1 receptor 1 (IL1R1) as a mediator of celastrol's action by using temporally resolved analysis of the hypothalamic transcriptome in celastrol-treated DIO, lean, and db/db mice. We demonstrate that IL1R1-deficient mice are completely resistant to the effects of celastrol in leptin sensitization and treatment of obesity, diabetes, and nonalcoholic steatohepatitis. Thus, we conclude that IL1R1 is a gatekeeper for celastrol's metabolic actions.

IF:30.64

Prospective virome analyses in young children at increased genetic risk for type 1 diabetes

第一作者:Vehik, K

期刊: NATURE MEDICINE, 2019; 25 (12)

Viruses are implicated in autoimmune destruction of pancreatic islet beta cells, which results in insulin deficiency and type 1 diabetes (T1D)(1-4). Certain enteroviruses can infect beta cells in vitro(5), have been detected in the pancreatic islets of patients with T1D(6) and have shown an association with T1D in meta-analyses(4). However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses(7) and the selection of variants with altered pathogenicity and ability to spread in populations. beta cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection(8). Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to beta cells between serotypes and within the same serotype(9,10). In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.

IF:30.64

A fully human transgene switch to regulate therapeutic protein production by cooling sensation

第一作者:Bai, P

期刊: NATURE MEDICINE, 2019; 25 (8)

The ability to safely control transgene expression with simple synthetic gene switches is critical for effective gene-and cell-based therapies. In the present study, the signaling pathway controlled by human transient receptor potential (TRP) melastatin 8 (hTRPM8), a TRP channel family member(1), is harnessed to control transgene expression. Human TRPM8 signaling is stimulated by menthol, an innocuous, natural, cooling compound, or by exposure to a cool environment (15-18 degrees C). By functionally linking hTRPM8-induced signaling to a synthetic promoter containing elements that bind nuclear factor of activated T cells, a synthetic gene circuit was designed that can be adjusted by exposure to either a cool environment or menthol. It was shown that this gene switch is functional in various cell types and human primary cells, as well as in mice implanted with engineered cells. In response to transdermal delivery of menthol, microencapsulated cell implants harboring this gene circuit, coupled to expression of either of two therapeutic proteins, insulin or a modified, activin type IIB, receptor ligand trap protein (mActRIIB(ECD)-hFc), could alleviate hyperglycemia in alloxan-treated mice (a model of type 1 diabetes) or reverse muscle atrophy in dexamethasone-treated mice (a model of muscle wasting), respectively. This fully human-derived orthogonal transgene switch should be amenable to a wide range of clinical applications.

IF:30.64

Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome

第一作者:Qi, XY

期刊: NATURE MEDICINE, 2019; 25 (8)

Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries(1), and is often accompanied by insulin resistance(2). The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity(3,4). This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels. Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility. Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype. This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.

IF:30.64

Stress-glucocorticoid-TSC22D3 axis compromises therapy-induced antitumor immunity

第一作者:Yang, H

期刊: NATURE MEDICINE, 2019; 25 (9)

Psychological distress has long been suspected to influence cancer incidence and mortality. It remains largely unknown whether and how stress affects the efficacy of anticancer therapies. We observed that social defeat caused anxiety-like behaviors in mice and dampened therapeutic responses against carcinogen-induced neoplasias and transplantable tumors. Stress elevated plasma corticosterone and upregulated the expression of glucocorticoid-inducible factor Tsc22d3, which blocked type I interferon (IFN) responses in dendritic cell (DC) and IFN-gamma(+) T cell activation. Similarly, close correlations were discovered among plasma cortisol levels, TSC22D3 expression in circulating leukocytes and negative mood in patients with cancer. In murine models, exogenous glucocorticoid injection, or enforced expression of Tsc22d3 in DC was sufficient to abolish therapeutic control of tumors. Administration of a glucocorticoid receptor antagonist or DC-specific Tsc22d3 deletion reversed the negative impact of stress or glucocorticoid supplementation on therapeutic outcomes. Altogether, these results indicate that stress-induced glucocorticoid surge and Tsc22d3 upregulation can subvert therapy-induced anticancer immunosurveillance.

IF:30.64

Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells

第一作者:Zhao, LT

期刊: NATURE MEDICINE, 2018; 24 (10)

Impaired immunity in patients with late-stage cancer is not limited to antitumor responses, as demonstrated by poor vaccination protection and high susceptibility to infection(1-3). This has been largely attributed to chemotherapy-induced impairment of innate immunity, such as neutropenia(2), whereas systemic effects of tumors on hematopoiesis and adoptive immunity remain incompletely understood. Here we observed anemia associated with severe deficiency of CD8(+) T cell responses against pathogens in treatment-naive mice bearing large tumors. Specifically, we identify CD45(+) erythroid progenitor cells (CD71(+)TER119(+); EPCs) as robust immunosuppressors. CD45(+) EPCs, induced by tumor growth-associated extramedullary hematopoiesis, accumulate in the spleen to become a major population, outnumbering regulatory T cells (T(reg)s) and myeloid-derived suppressor cells (MDSCs). The CD45(+) EPC transcriptome closely resembles that of MDSCs, and, like MDSCs, reactive oxygen species production is a major mechanism underlying CD45(+) EPC-mediated immunosuppression. Similarly, an immunosuppressive CD45(+) EPC population was detected in patients with cancer who have anemia. These findings identify a major population of immunosuppressive cells that likely contributes to the impaired T cell responses commonly observed in patients with advanced cancer.

IF:30.64

Regional variation limits applications of healthy gut microbiome reference ranges and disease models

第一作者:He, Y

期刊: NATURE MEDICINE, 2018; 24 (10)

Dysbiosis, departure of the gut microbiome from a healthy state, has been suggested to be a powerful biomarker of disease incidence and progression(1-3). Diagnostic applications have been proposed for inflammatory bowel disease diagnosis and prognosis(4), colorectal cancer prescreening(5) and therapeutic choices in melanoma(6). Noninvasive sampling could facilitate large-scale public health applications, including early diagnosis and risk assessment in metabolic(7) and cardiovascular diseases(8). To understand the generalizability of microbiota-based diagnostic models of metabolic disease, we characterized the gut microbiota of 7,009 individuals from 14 districts within 1 province in China. Among phenotypes, host location showed the strongest associations with microbiota variations. Microbiota-based metabolic disease models developed in one location failed when used elsewhere, suggesting that such models cannot be extrapolated. Interpolated models performed much better, especially in diseases with obvious microbiota-related characteristics. Interpolation efficiency decreased as geographic scale increased, indicating a need to build localized baseline and disease models to predict metabolic risks.

IF:30.64

The deubiquitinating enzyme TNFAIP3 mediates inactivation of hepatic ASK1 and ameliorates nonalcoholic steatohepatitis

第一作者:Zhang, P

期刊: NATURE MEDICINE, 2018; 24 (1)

Activation of apoptosis signal-regulating kinase 1 (ASK1) in hepatocytes is a key process in the progression of nonalcoholic steatohepatitis (NASH) and a promising target for treatment of the condition. However, the mechanism underlying ASK1 activation is still unclear, and thus the endogenous regulators of this kinase remain open to be exploited as potential therapeutic targets. In screening for proteins that interact with ASK1 in the context of NASH, we identified the deubiquitinase tumor necrosis factor alpha-induced protein 3 (TNFAIP3) as a key endogenous suppressor of ASK1 activation, and we found that TNFAIP3 directly interacts with and deubiquitinates ASK1 in hepatocytes. Hepatocyte-specific ablation of Tnfaip3 exacerbated nonalcoholic fatty liver disease-and NASH-related phenotypes in mice, including glucose metabolism disorders, lipid accumulation and enhanced inflammation, in an ASK1-dependent manner. In contrast, transgenic or adeno-associated virus-mediated TNFAIP3 gene delivery in the liver in both mouse and nonhuman primate models of NASH substantially blocked the onset and progression of the disease. These results implicate TNFAIP3 as a functionally important endogenous suppressor of ASK1 hyperactivation in the pathogenesis of NASH and identify it as a potential new molecular target for NASH therapy.

IF:30.64

An ALOX12-12-HETE-GPR31 signaling axis is a key mediator of hepatic ischemia-reperfusion injury

第一作者:Zhang, XJ

期刊: NATURE MEDICINE, 2018; 24 (1)

Hepatic ischemia-reperfusion (IR) injury is a common clinical issue lacking effective therapy and validated pharmacological targets. Here, using integrative 'omics' analysis, we identified an arachidonate 12-lipoxygenase (ALOX12)-12-hydroxyeicosatetraenoic acid (12-HETE)-G-protein-coupled receptor 31 (GPR31) signaling axis as a key determinant of the hepatic IR process. We found that ALOX12 was markedly upregulated in hepatocytes during ischemia to promote 12-HETE accumulation and that 12-HETE then directly binds to GPR31, triggering an inflammatory response that exacerbates liver damage. Notably, blocking 12-HETE production inhibits IR-induced liver dysfunction, inflammation and cell death in mice and pigs. Furthermore, we established a nonhuman primate hepatic IR model that closely recapitulates clinical liver dysfunction following liver resection. Most strikingly, blocking 12-HETE accumulation effectively attenuated all pathologies of hepatic IR in this model. Collectively, this study has revealed previously uncharacterized metabolic reprogramming involving an ALOX12-12-HETE- GPR31 axis that functionally determines hepatic IR procession. We have also provided proof of concept that blocking 12-HETE production is a promising strategy for preventing and treating IR-induced liver damage.

IF:30.64

共29条页码: 1/2页15条/页