Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial ...omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo-electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and G
or G
trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120.
In this paper, a novel electrochemiluminescence resonance energy transfer (ECL-RET) system from O2/S2O8(2-) to a kind of amino-terminated perylene derivative (PTC-NH2) was demonstrated for the first ...time, which was then applied to construct a ratiometric aptasensor for lead ion (Pb(2+)) detection. First, gold-nanoparticles-functionalized fullerene nanocomposites (AuNPs@nano-C60) were coated on a glassy carbon electrode (GCE), and then thiol-modified assistant probes (APs) were attached on AuNPs@nano-C60/GCE. Then the resultant electrode was hybridized with capture probes (the aptamer of the Pb(2+), abbreviated as CPs) to generate DNA duplexes, which could induce PTC-NH2 to be intercalated into the dsDNA grooves by the electrostatic adsorption. Herein, ECL dual peaks at -0.7 V (vs Ag/AgCl) and -2.0 V (vs Ag/AgCl) were obtained when the prepared aptasensor was detected in air-saturated S2O8(2-) solution, which could be attributed to the emission of excited dimmers (π-excimers) ((1)(NH2-PTC)2*) and (1)(O2)2*, respectively. In the presence of Pb(2+), the dsDNA was unwound, and Pb(2+) G-quadruplex structure was generated because of the highly specific affinity between Pb(2+) and CPs, which made the PTC-NH2 release from the electrode surface. As a result, the ECL signal at -0.7 V was decreased, and the ECL signal around -2.0 V was increased. By measuring the ratio of ECL intensities at two excitation potentials, the developed aptasensor exhibited the linear response range from 1.0 × 10(-12) M to 1.0 × 10(-7) M with a detection limit of 3.5 × 10(-13) M (S/N = 3) for Pb(2+), which could offer an alternative analytical method with excellent properties of high selectivity, accuracy, and sensitivity.
Summary
To explore the type, prevalence and outcomes in chronic myeloid leukaemia (CML) patients with uncommon BCR‐ABL1 transcripts in the era of tyrosine kinase inhibitors (TKIs), uncommon BCR‐ABL1 ...transcripts were screened in 4750 patients by multiplex polymerase chain reaction (PCR), and type‐specific real‐time quantitative PCR was regularly performed for molecular monitoring. A total of 19 uncommon transcripts, including e1a2, e1a3, e6a2, e8a2, e12a2, unusual e13a2, e13a3, unusual e14a2, e14a3 and e19a2 were identified in 83 (1·7%) patients. The three most frequent types were e19a2, e13a3/e14a3 and e1a2. Compared with the 571 newly diagnosed CML patients in chronic phase with common e13a2/e14a2 transcripts receiving frontline imatinib therapy, patients with the e19a2 (n = 16) and e1a2 (n = 11) transcripts had significantly reduced probabilities of 1‐year complete cytogenetic response (CCyR, P = 0·0004 and 0·016) and major molecular response (MMR, P = 0·0018 and 0·0035), and patients with the e13a3/e14a3 transcript (n = 10) had significantly increased probabilities of 1‐year CCyR (P = 0·0072) and MMR (P = 0·0073). Patients with the e19a2 transcript had low probabilities of 2‐year event‐free survival (EFS, P = 0·0004) and progression‐free survival (P = 0·0067), and patients with the e1a2 transcript had low probability of 2‐year EFS (P < 0·0001). Therefore, uncommon BCR‐ABL1 fusion transcripts are rare and diverse in patients with CML and may be relevant for TKI therapy outcomes.
Recent studies highlighted that CD8+ T cells are necessary for restraining reservoir in HIV-1-infected individuals who undergo antiretroviral therapy (ART), whereas the underlying cellular and ...molecular mechanisms remain largely unknown. Here, we enrolled 60 virologically suppressed HIV-1-infected individuals, to assess the correlations of the effector molecules and phenotypic subsets of CD8+ T cells with HIV-1 DNA and cell-associated unspliced RNA (CA usRNA). We found that the levels of HIV-1 DNA and usRNA correlated positively with the percentage of CCL4+CCL5- CD8+ central memory cells (T
CM
) while negatively with CCL4-CCL5+ CD8+ terminally differentiated effector memory cells (T
EMRA
). Moreover, a virtual memory CD8+ T cell (T
VM
) subset was enriched in CCL4-CCL5+ T
EMRA
cells and phenotypically distinctive from CCL4+ T
CM
subset, supported by single-cell RNA-Seq data. Specifically, T
VM
cells showed superior cytotoxicity potentially driven by T-bet and RUNX3, while CCL4+ T
CM
subset displayed a suppressive phenotype dominated by JUNB and CREM. In viral inhibition assays, T
VM
cells inhibited HIV-1 reactivation more effectively than non-T
VM
CD8+ T cells, which was dependent on CCL5 secretion. Our study highlights CCL5-secreting T
VM
cells subset as a potential determinant of HIV-1 reservoir size. This might be helpful to design CD8+ T cell-based therapeutic strategies for cure of the disease.
We studied the impact of risk stratification–directed interventions for minimal residual disease (MRD) on relapse and disease-free survival (DFS) prospectively in 814 subjects with standard-risk ...acute leukemia receiving allotransplantation in first or second complete remission. A total of 709 subjects were MRD− after transplantation (Group A); 105 subjects were MRD+, 49 received low-dose IL-2 (Group B), and 56 received modified donor lymphocyte infusion (DLI) with or without low-dose IL-2 (Group C). Posttransplantation immune suppression for GVHD was also modified based on MRD state. The cumulative risk of relapse was significantly less and DFS was significantly better in subjects in Group C than in subjects in Group B (P = .001 and P = .002, respectively), but was not different from subjects in Group A (P = .269 and P = .688, respectively). Multivariate analyses confirmed that MRD state and modified DLI were significantly correlated with relapse (P = .000, odds ratio OR = 0.255 and P = .000, OR = 0.269) and DFS (P = .001, OR = 0.511 and P = .006, OR = 0.436, respectively). These data suggest that risk stratification–directed interventions with modified DLI in patients with standard-risk acute leukemia who are MRD+ after transplantation may improve transplantation outcomes.
Summary
There is an urgent need for an oral, efficient and safe regimen for high‐risk APL under the pandemic of COVID‐19. We retrospectively analysed 60 high‐risk APL patients. For induction therapy ...(IT), in addition to all‐trans retinoic acid (ATRA) and oral arsenic (RIF), 22 patients received oral etoposide (VP16) as cytotoxic chemotherapy (CC), and 38 patients received intravenous CC as historical control group. The median dose of oral VP16 was 1000 mg interquartile rage (IQR), 650–1250. One patient died during IT in the control group, 59 evaluable patients (100%) achieved complete haematological remission (CHR) after IT and complete molecular remission (CMR) after consolidation therapy. The median time to CHR and CMR was 36 days (33.8–44) versus 35 days (32–42; p = 0.75) and 3 months (0.8–3.5) versus 3.3 months (2.4–3.7; p = 0.58) in the oral VP16 group and in the control group. Two (9.1%) and 3 (7.9%) patients experienced molecular relapse in different group respectively. The 2‐year estimated overall survival and event‐free survival were 100% versus 94.7% (p = 0.37) and 90.9% versus 89.5% (p = 0.97) respectively. A completely oral, efficient and safe induction regimen including oral VP16 as cytoreductive chemotherapy combined with ATRA and RIF is more convenient to administer for patients with high‐risk APL.
Under the pandemic of COVID‐19, an oral, efficient and safe regimen for high‐risk acute promyelocytic leukaemia (APL) induction therapy is an urgent need. For induction therapy, in addition to all‐trans retinoic acid (ATRA) and oral arsenic (RIF), high‐risk APL was retrospectively analysed by dividing into two cytoreductive groups: the oral etoposide group (the completely oral group) and the intravenous cytoreductive group. The rate of complete haematological remission (CHR), complete molecular remission (CMR) and molecular relapse did not differ between the two groups. The 2‐year overall survival (OS) and 2‐year event‐free survival (EFS) were comparable. Moreover, the completely oral group manifested the same safety as intravenous cytoreductive group.
Introduction
Immune microenvironment plays an important role in the occurrence and development of acute myeloid leukemia (AML). Studies assessing the prognostic significance of bone marrow (BM) ...lymphocyte subsets' frequencies at diagnosis in patients with AML were limited.
Methods
Fresh BM samples collected from 97 adult AML patients at diagnosis were tested for lymphocyte, T, CD4+T, CD8+T, γδT, NK, and B cell frequencies using multi‐parameter flow cytometry.
Results
Low frequencies of lymphocytes, T, CD4+T, and CD8+T cells were associated with significantly lower rates of one‐course complete remission (CR) (all p < 0.05). Moreover, the frequency of CD4+T cells independently predicted one‐course CR achievement (p = 0.021). Low frequencies of T and CD8+T cells were significantly associated with lower relapse‐free survival (RFS) rates (p = 0.032; 0.034), respectively, and a low frequency of CD8+T cells was associated with a significantly lower overall survival (OS) rate (p = 0.028). Combination of frequency of CD8+T cells and ELN risk stratification showed that patients with ELN‐intermediate/adverse risk + high CD8+T cell frequency had a similar RFS rate to those with ELN‐favorable risk + high CD8+T cell frequency and those with ELN‐favorable risk + low CD8+T cell frequency (p = 0.88; 0.76), respectively. The RFS rate of patients with ELN intermediate/adverse risk + low CD8+T cell frequency was significantly lower than that of all aforementioned patients (p = 0.021; 0.0007; 0.028), respectively.
Conclusion
The frequencies of BM lymphocyte subsets at diagnosis predicted clinical outcomes and could help improve risk stratification in AML.
Studies suggest that the scaffolding protein, postsynaptic density protein-95 (PSD-95), is involved in multiple neurological dysfunctions. However, the role of PSD-95 in the anterior cingulate cortex ...(ACC) in neuropathic pain (NP) has not been investigated. The current study addressed the role of PSD-95 in the ACC in NP and its modulating profile with NMDA receptor subunit 2B (NR2B). The NP model was established by chronic constriction injury (CCI) of the sciatic nerve, and mechanical and thermal tests were used to evaluate behavioral hyperalgesia. Protein expression and distribution were evaluated using immunohistochemistry and western blotting. The results showed that PSD-95 and NR2B were co-localized in neurons in the ACC. After CCI, both PSD-95 and NR2B were upregulated in the ACC. Inhibiting NR2B with Ro 25-6981 attenuated pain hypersensitivity and decreased the over-expression of PSD-95 induced by CCI. Furthermore, intra-ACC administration of PSD-95 antisense oligonucleotide not only attenuated pain hypersensitivity but also downregulated the NR2B level and the phosphorylation of cyclic AMP response element-binding protein. These results demonstrated that PSD-95 in the ACC contributes to NP by interdependent activation of NR2B.
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