Low doses of IFN-γ maintain self-renewal of leukemia stem cells in acute myeloid leukemia.

Conventional therapies for acute myeloid leukemia (AML) often fail to eliminate the disease-initiating leukemia stem cell (LSC) population, leading to disease relapse. Interferon-γ (IFN-γ) is a known inflammatory cytokine that promotes antitumor responses. Here, we found that low serum IFN-γ levels correlated with a higher percentage of LSCs and greater relapse incidence in AML patients. Furthermore, IFNGR1 was overexpressed in relapsed patients with AML and associated with a poor prognosis. We showed that high doses (5-10 µg/day) of IFN-γ exerted an anti-AML effect, while low doses (0.01-0.05 µg/day) of IFN-γ accelerated AML development and supported LSC self-renewal in patient-derived AML-LSCs and in an LSC-enriched MLL-AF9-driven mouse model. Importantly, targeting the IFN-γ receptor IFNGR1 by using lentiviral shRNAs or neutralizing antibodies induced AML differentiation and delayed leukemogenesis in vitro and in mice. Overall, we uncovered essential roles for IFN-γ and IFNGR1 in AML stemness and showed that targeting IFNGR1 is a strategy to decrease stemness and increase differentiation in relapsed AML patients.

Abemaciclib drives the therapeutic differentiation of acute myeloid leukaemia stem cells.

Self-renewal and differentiation arrest are two features of leukaemia stem cells (LSCs) responsible for the high relapse rate of acute myeloid leukaemia (AML). To screen drugs to overcome differentiation blockade for AML, we conducted screening of 2040 small molecules from a library of United States Food and Drug Administration-approved drugs and found that the cyclin-dependent kinase (CDK)4/6 inhibitor, abemaciclib, exerts high anti-leukaemic activity. Abemaciclib significantly suppressed proliferation and promoted the differentiation of LSCs in vitro. Abemaciclib also efficiently induced differentiation and impaired self-renewal of LSCs, thus reducing the leukaemic cell burden and improving survival in various preclinical animal models, including patient-derived xenografts. Importantly, abemaciclib strongly enhanced anti-tumour effects in combination with venetoclax, a B-cell lymphoma 2 (Bcl-2) inhibitor. This treatment combination led to a marked decrease in LSC-enriched populations and resulted in a synergistic anti-leukaemic effect. Target screening revealed that in addition to CDK4/6, abemaciclib bound to and inhibited CDK9, consequently attenuating the protein levels of global p-Ser2 RNA Polymerase II (Pol II) carboxy terminal domain (CTD), Myc, Bcl-2, and myeloid cell leukaemia-1 (Mcl-1), which was important for the anti-AML effect of abemaciclib. Collectively, these data provide a strong rationale for the clinical evaluation of abemaciclib to induce LSC differentiation and treat highly aggressive AML as well as other advanced haematological malignancies.

Tough, Healable, and Sensitive Strain Sensor Based on Multiphysically Cross-Linked Hydrogel for Ionic Skin.

Ion conductive hydrogels (ICHs) have attracted great interest in the application of ionic skin because of their superior characteristics. However, it remains a challenge for ICHs to achieve balanced properties of high strength, large fracture strain, self-healing and freezing tolerance. In this study, a strong, stretchable, self-healing and antifreezing ICH was demonstrated by rationally designing a multiphysically cross-linked network structure consisting of the hydrophobic association, metal-ion coordination and chain entanglement among poly(acrylic acid) (PAA) polymer chains. The deliberately designed Brij S 100 acrylate (Brij-100A) micelle cross-linker can effectively dissipate energy and endow hydrogels with desirable stretchability. The self-healing ability of hydrogels originates from the reversible hydrophobic association in micelles and Fe3+-COO- coordination. After the addition of NaCl, the chain-entangled physical network caused by the salting-out effect can both enhance mechanical strength and promote electron transport. With the synergy of hydrophobic association, mental-ligand coordination and chain entanglement, the PAA/Brij-100A/Fe3+/NaCl (PAA/BA/Fe3+/NaCl) hydrogels exhibited a high tensile strain of 1140%, a tensile strength of 0.93 MPa and a toughness of 3.48 MJ m-3. Besides, the PAA/BA/Fe3+/NaCl hydrogels exhibited a high conductivity of 0.43 S m-1 and good freezing resistance. The ionic skin based on the PAA/BA/Fe3+/NaCl hydrogels showed high sensitivity (GF = 5.29), wide strain range (0-950%), fast response time (220 ms) and good stability. Also, the self-healing ability of the ionic skin can significantly prolong its service time, and the antifreezing property can broaden its applicable temperature. This study offers new insight into the design of multifunctional ionic skin for wearable electronics.

Haploidentical donor stem cell transplantation had a lower incidence of bronchiolitis obliterans syndrome compared with HLA-matched sibling donor transplantation in patients with hematologic malignancies: Benefit from ATG?

Background: Haploidentical donor stem cell transplantation (HID-SCT) based on antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis had achieved a similar incidence of chronic graft-versus-host disease (cGVHD) with human leukocyte antigen (HLA)-matched sibling donor stem cell transplantation (MSD-SCT). However, bronchiolitis obliterans syndrome (BOS), which serves as pulmonary cGVHD, was rarely compared between HID and MSD transplantation. Methods: One thousand four hundred five patients with hematologic malignancies who underwent allogeneic SCT were enrolled in this retrospective study. Based on donor type, we divided the patients into three groups: HID, MSD, and match unrelated donor (MUD) groups. The cumulative incidences and risk factors of BOS were analyzed. Results: The 5-year cumulative incidence of BOS was 7.2% in the whole population. HID transplantation had a lower 5-year cumulative incidence of BOS than MSD transplantation (4.1% vs. 10.0%, p < 0.001) and a similar incidence with MUD transplantation (4.1% vs. 6.2%, p = 0.224). The 5-year cumulative incidence of BOS was lower in the ATG group than that in the non-ATG group in both the whole and MSD populations (4.6% vs. 11.2%, p < 0.001, and 4.1% vs. 11.2%, p = 0.042, respectively). The 5-year incidence of BOS in mixed grafts [peripheral blood stem cell (PBSC) plus bone marrow] group was also lower than that in the PBSC group (4.2% vs. 9.1, p = 0.001). Multivariate analysis showed that HID, ATG, and mixed grafts were protective factors for BOS [odds ratio (OR) 0.3, 95% CI 0.2-0.6, p < 0.001; OR 0.3, 95% CI 0.2-0.7, p = 0.001; OR 0.3, 95% CI 0.1-0.8, p = 0.013], and acute graft-versus-host disease (aGVHD) and cGVHD were independent risk factors for BOS (OR 2.1, 95% 1.1-4.3, p = 0.035; OR 10.1, 95% CI 4.0-25.0, p < 0.001). Conclusions: HID transplantation had a lower incidence of BOS than MSD transplantation, which might be associated with ATG and mixed grafts.

Organohydrogel based on cellulose-stabilized emulsion for electromagnetic shielding, flame retardant, and strain sensing.

In the past, electromagnetic interference (EMI) shielding materials have achieved great breakthroughs, however, they still suffer from high reflectivity and poor environmental stability, resulting in detrimental secondary pollution and weak adaptability. Herein, an organohydrogel-based EMI shielding material was prepared through cellulose nanofibril-based Pickering emulsion, composed of an MXene network for electron conduction, encapsulated paraffin wax microspheres with MXene-Fe3O4 shells for multiple scattering of the incident wave, and MXene-CNF-Fe3O4-polyacrylamide hybrid interfaces for dielectric polarization. The EMI shielding performance of our organohydrogel shows an absorption-dominated feature. It can effectively shield 99.625 % electromagnetic wave, satisfying the requirement of commercial EMI shielding materials. Moreover, the organohydrogel possesses excellent flame retardancy properties and long-time environment properties to improve safety and reliability; and it also demonstrates sensitive deformation responses as an on-skin sensor. Therefore, our organohydrogel can simultaneously detect human motion and protect human from EMI radiation and accidental burn.

LysM-positive neurons drive Tuberous Sclerosis Complex (TSC)-associated brain lesions.

Mutations of Tsc1 or Tsc2 can lead to excessive activation of mTORC1 and cause Tuberous Sclerosis Complex (TSC), which is an autosomal dominant genetic disease prominently characterized by seizures, mental retardation and multiorgan hamartoma. In TSC, pathological changes in the central nervous system are the leading cause of death and disability. In decades, series of rodent models have been established by mutating Tsc1 or Tsc2 genes in diverse neural cell lineages to investigate the underlying cellular and molecular mechanisms, however, the cellular origin triggering neural pathological changes in TSC is undetermined. In this study, we generated a novel mouse model involving conditional deletion of Tsc1 in lysozyme 2 (Lyz2)-positive cells which replicated several features of brain lesions including epileptic seizures, megalencephaly, highly enlarged pS6-positive neurons and astrogliosis. In addition, we confirmed that bone marrow-derived myeloid cells including microglia with Tsc1 deficiency are not the decisive lineage in the cerebral pathologies in TSC. These histological assays in our murine model indicate an essential contribution of Lyz2-positive neurons to TSC progression. The Lyz2-positive neural population-specific onset of Tsc1 loss in murine postnatal brain might be the key to pathological phenotypes. Our findings thus provided evidences supporting new insights into the role of Lyz2-positive neurons in TSC events.

Plasma Exosomal miRNAs Associated With Metabolism as Early Predictor of Gestational Diabetes Mellitus.

To date, the miRNA expression profile of plasma exosomes in women whose pregnancy is complicated by gestational diabetes mellitus (GDM) has not been fully clarified. In this study, differentially expressed miRNAs in plasma exosomes were identified by high-throughput small-RNA sequencing in 12 pregnant women with GDM and 12 with normal glucose tolerance (NGT) and validated in 102 pregnant women with GDM and 101 with NGT. A total of 22 exosomal miRNAs were found, five of which were verified by real-time qPCR. Exosomal miR-423-5p was upregulated, whereas miR-122-5p, miR-148a-3p, miR-192-5p, and miR-99a-5p were downregulated in women whose pregnancy was complicated by GDM. IGF1R and GYS1 as target genes of miR-423-5p, and G6PC3 and FDFT1 as target genes of miR-122-5p were associated with insulin and AMPK signaling pathways and may participate in the regulation of metabolism in GDM. The five exosomal miRNAs had an area under the curve of 0.82 (95%CI, 0.73, ∼0.91) in early prediction of GDM. Our study demonstrates that dysregulated exosomal miRNAs in plasma from pregnant women with GDM might influence the insulin and AMPK signaling pathways and could contribute to the early prediction of GDM.

Continuous elevation of plasma asprosin in pregnant women complicated with gestational diabetes mellitus: A nested case-control study.

INTRODUCTION: To investigate the expression of asprosin, a novel insulin resistance-related factor, in plasma and placenta of pregnant women with and without gestational diabetes mellitus (GDM). METHODS: This is a nested case-control study within the prospective study named Early Diagnosis of Gestational Diabetes Mellitus (EDoGDM). Forty pregnant women with GDM and forty control cases with normal glucose tolerance (NGT) were recruited in the present study. Asprosin levels were tested by ELISA in maternal plasma at 18-20 and 24-28 gestational weeks and before delivery, as well as in umbilical plasma. Asprosin concentrations were compared between GDM and NGT groups, and the relationship between asprosin and other parameters were analyzed. Expression of asprosin in placenta was examined by Western blot and immunohistochemistry. RESULTS: Asprosin was elevated in plasma of GDM pregnant women and their offspring, after adjusted by maternal and neonatal clinical characteristics and lipid profiles. Asprosin was expressed in placenta from both GDM and NGT pregnant women. DISCUSSION: Protein asprosin is expressed in human placenta and is elevated in the plasma of pregnant women complicated with GDM and their offspring. As an insulin resistance-related factor increased before 20 gestational weeks, asprosin may play a role as a potential early biomarker of GDM.

[Brain regions for number involved in the processing of vocabulary of months in Chinese.].

The present study aimed to investigate the neuro-cognitive features in the processing of vocabularies of date in Chinese, using block-design functional magnetic resonance imaging (fMRI). Nineteen normal right-handed volunteers whose native language was Chinese performed judgments of vocabulary of month (JVM), the orientation of digit (JOD) and the meaning of words (JMW) respectively, while the fMRI data were recorded by Signa HDe 1.5T MR machine. All design of three tasks was adapted from previous studies with slight modification. The JOD and JWM were investigated as contrast conditions. JVM asked the subjects to determine whether the month belonged to the first half of the year. JOD was to tell whether the third digit had the same orientation (upright orientation or italic orientation) as the first two, and JMW was to determine whether the two-Chinese-character word was animate. The subjects responded according to the task instruction with a button pressing. Statistical parametric mapping (SPM2) was employed to process data and localize functional areas. We compared the average activation intensity of each activated brain regions in the same task against the rest and the activation intensity of the same regions in different tasks respectively. The activations in inferior parietal (BA40) and inferior occipital (BA18/19) were found in the JVM and JOD. The same areas in middle frontal (BA6), fusiform (BA18), posterior in right cerebellum areas were activated during the JVM and JMW. When the activation of the JMW was subtracted from the JVM, many areas concerning numerical processing, such as left anterior cingulate (BA32), post central (BA2), and the right superior temporal (BA39), superior parietal (BA7), as well as the inferior parietal (BA40), precuneus (BA7/19) of the bilateral hemispheres, were significantly activated. When the activation of the JOD was subtracted from the JVM, the left inferior occipital and the fusiform (BA18) of the bilateral hemispheres, which were also involved in the linguistic processing according to previous studies, were significantly activated. The above results prove that the processing of vocabulary of months in Chinese involves not only linguistic processing but also numerical processing; and these results further indicate that Chinese people might gain access to the cognitive experience of number during the process of acquisition of native language.