Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199.

Adhesion molecules play essential roles in the homeostatic regulation and malignant transformation of hematopoietic cells. The dysregulated expression of adhesion molecules in leukemic cells accelerates disease progression and the development of drug resistance. Thus, targeting adhesion molecules represents an attractive anti-leukemic therapeutic strategy. In this study, we investigated the prognostic role and functional significance of cytohesin-1 (CYTH1) in acute myeloid leukemia (AML). Analysis of AML patient data from the GEPIA and BloodSpot databases revealed that CYTH1 was significantly overexpressed in AML and independently correlated with prognosis. Functional assays using AML cell lines and an AML xenograft mouse model confirmed that CYTH1 depletion significantly inhibited the adhesion, migration, homing, and engraftment of leukemic cells, delaying disease progression and prolonging animal survival. The CYTH1 inhibitor SecinH3 exerted in vitro and in vivo anti-leukemic effects by disrupting leukemic adhesion and survival programs. In line with the CYTH1 knockdown results, targeting CYTH1 by SecinH3 suppressed integrin-associated adhesion signaling by reducing ITGB2 expression. SecinH3 treatment efficiently induced the apoptosis and inhibited the growth of a panel of AML cell lines (MOLM-13, MV4-11 and THP-1) with mixed-lineage leukemia gene rearrangement, partly by reducing the expression of the anti-apoptotic protein MCL1. Moreover, we showed that SecinH3 synergized with the BCL2-selective inhibitor ABT-199 (venetoclax) to inhibit the proliferation and promote the apoptosis of ABT-199-resistant leukemic cells. Taken together, our results not only shed light on the role of CYTH1 in cell-adhesion-mediated leukemogenesis but also propose a novel combination treatment strategy for AML.

Optimal transplantation strategy using human induced pluripotent stem cell-derived cardiomyocytes for acute myocardial infarction in nonhuman primates.

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) have the potential to be a therapeutic option for myocardium restoration. However, hiPSC-CMs of varying maturation and transplantation routes exhibit different reactivity and therapeutic effects. We previously demonstrated that the saponin+ compound induces more mature hiPSC-CMs. The safety and efficacy of multi-route transplantation of saponin+ compound-induced hiPSC-CMs in a nonhuman primate with myocardial infarction will be investigated for the first time in this study. Our findings indicate that optimized hiPSC-CMs transplanted via intramyocardial and intravenous routes may affect myocardial functions by homing or mitochondrial transfer to the damaged myocardium to play a direct therapeutic role as well as indirect beneficial roles via anti-apoptotic and pro-angiogenesis mechanisms mediated by different paracrine growth factors. Due to significant mural thrombosis, higher mortality, and unilateral renal shrinkage, intracoronary transplantation of hiPSC-CMs requires closer attention to anticoagulation and caution in clinical use. Collectively, our data strongly indicated that intramyocardial transplantation of hiPSC-CMs is the ideal technique for clinical application; multiple cell transfers are recommended to achieve steady and protracted efficacy because intravenous transplantation's potency fluctuates. Thus, our study offers a rationale for choosing a therapeutic cell therapy and the best transplantation strategy for optimally induced hiPSC-CMs.

The transplantation of rapamycin-treated senescent human mesenchymal stem cells with enhanced proangiogenic activity promotes neovascularization and ischemic limb salvage in mice.

Few therapies can reverse the proangiogenic activity of senescent mesenchymal stromal/stem cells (MSCs). In this study, we investigated the effects of rapamycin on the proangiogenic ability of senescent human umbilical cord MSCs (UCMSCs). An in vitro replicative senescent cell model was established in cultured UCMSCs. We found that late passage (P25 or later) UCMSCs (LP-UCMSCs) exhibited impaired proangiogenic abilities. Treatment of P25 UCMSCs with rapamycin (900 nM) reversed the senescent phenotype and notably enhanced the proangiogenic activity of senescent UCMSCs. In a nude mouse model of hindlimb ischemia, intramuscular injection of rapamycin-treated P25 UCMSCs into the ischemic limb significantly promoted neovascularization and ischemic limb salvage. We further analyzed the changes in the expression of angiogenesis-associated genes in rapamycin-primed MSCs and found higher expression of several genes related to angiogenesis, such as VEGFR2 and CTGF/CCN2, in primed cells than in unprimed MSCs. Taken together, our data demonstrate that rapamycin is a potential drug to restore the proangiogenic activity of senescent MSCs, which is of importance in treating ischemic diseases and tissue engineering.

Bloodletting Puncture at Hand Twelve Jing-Well Points Improves Neurological Recovery by Ameliorating Acute Traumatic Brain Injury-Induced Coagulopathy in Mice.

Traumatic brain injury (TBI) contributes to hypocoagulopathy associated with prolonged bleeding and hemorrhagic progression. Bloodletting puncture therapy at hand twelve Jing-well points (BL-HTWP) has been applied as a first aid measure in various emergent neurological diseases, but the detailed mechanisms of the modulation between the central nervous system and systemic circulation after acute TBI in rodents remain unclear. To investigate whether BL-HTWP stimulation modulates hypocoagulable state and exerts neuroprotective effect, experimental TBI model of mice was produced by the controlled cortical impactor (CCI), and treatment with BL-HTWP was immediately made after CCI. Then, the effects of BL-HTWP on the neurological function, cerebral perfusion state, coagulable state, and cerebrovascular histopathology post-acute TBI were determined, respectively. Results showed that BL-HTWP treatment attenuated cerebral hypoperfusion and improve neurological recovery post-acute TBI. Furthermore, BL-HTWP stimulation reversed acute TBI-induced hypocoagulable state, reduced vasogenic edema and cytotoxic edema by regulating multiple hallmarks of coagulopathy in TBI. Therefore, we conclude for the first time that hypocoagulopathic state occurs after acute experimental TBI, and the neuroprotective effect of BL-HTWP relies on, at least in part, the modulation of hypocoagulable state. BL-HTWP therapy may be a promising strategy for acute severe TBI in the future.

Surgical treatment of thoracolumbar fracture with incomplete lower limb paralysis in a patient with COVID-19.

Since December 2019, COVID-19, an acute infectious disease, has gradually become a global threat. We report a case of thoracolumbar fractures (T12 and L1) and incomplete lower limb paralysis in a patient with COVID-19. After a series of conservative treatment which did not work at all, posterior open reduction and pedicle screw internal fixation of the thoracolumbar fracture were performed in Wuhan Union Hospital. Three weeks later, the patient could stand up and the pneumonia is almost cured. We successfully performed a surgery in a COVID-19 patient, and to our knowledge it is the first operation for a COVID-19 patient ever reported.

LKB1 suppresses glioma cell invasion via NF-κB/Snail signaling repression.

BACKGROUND: Liver kinase B1 (LKB1) is involved in various human diseases. Aberrant expression of LKB1 expression is involved in glioma progression and associated with prognosis, however, the specific mechanism involving NF-κB/Snail signaling pathways remain unknown. MATERIALS AND METHODS: In the present study, quantitative real-time PCR analysis was used to investigate the expression of LKB1 tumor tissue samples and cell lines. In glioma cell lines, CCK-8 assay, transwell invasion and migration assays were used to investigate the effects of LKB1on proliferation and invasion. RESULTS: We observed that LKB1 knockdown promoted glioma cell proliferation, migration and invasion. This effect was induced through NF-κB/Snail signaling activation. Also, LKB1 overexpression suppressed proliferation, migration, and invasion, which could be rescued by Snail overexpression. CONCLUSION: Taken together, our results show that LKB1 knockdown promotes remarkably glioma cell proliferation, migration and invasion by regulating Snail protein expression through activating the NF-κB signaling. This may serve as a potential prognostic marker and therapeutic target for glioma.

Brain connectomic associations with traditional Chinese medicine diagnostic classification of major depressive disorder: a diffusion tensor imaging study.

BACKGROUND: Major depressive disorder (MDD) is highly heterogeneous in pathogenesis and manifestations. Further classification may help characterize its heterogeneity. We previously have shown differential metabolomic profiles of traditional Chinese medicine (TCM) diagnostic subtypes of MDD. We further determined brain connectomic associations with TCM subtypes of MDD. METHODS: In this naturalistic study, 44 medication-free patients with a recurrent depressive episode were classified into liver qi stagnation (LQS, n = 26) and Heart and Spleen Deficiency (HSD, n = 18) subtypes according to TCM diagnosis. Healthy subjects (n = 28) were included as controls. Whole-brain white matter connectivity was analyzed on diffusion tensor imaging. RESULTS: The LQS subtype showed significant differences in multiple network metrics of the angular gyrus, middle occipital gyrus, calcarine sulcus, and Heschl's gyrus compared to the other two groups. The HSD subtype had markedly greater regional connectivity of the insula, parahippocampal gyrus, and posterior cingulate gyrus than the other two groups, and microstructural abnormalities of the frontal medial orbital gyrus and middle temporal pole. The insular betweenness centrality was strongly inversely correlated with the severity of depression and dichotomized the two subtypes at the optimal cutoff value with acceptable sensitivity and specificity. CONCLUSIONS: The LQS subtype is mainly characterized by aberrant connectivity of the audiovisual perception-related temporal-occipital network, whereas the HSD subtype is more closely associated with hyperconnectivity and microstructural abnormalities of the limbic-paralimbic network. Insular connectivity may serve a biomarker for TCM-based classification of depression.Trial registration Registered at http://www.clinicaltrials.gov (NCT02346682) on January 27, 2015.

Burr hole drainage and burr hole drainage with irrigation to treat chronic subdural hematoma: A systematic review and meta-analysis.

OBJECTIVE: Numerous studies have investigated different operative procedures for treating chronic subdural hematoma (CSDH); however, the results are controversial. This meta-analysis was performed to evaluate the efficacy of burr hole drainage without irrigation (BHD) and burr hole drainage with irrigation (BHDI) for CSDH. METHODS: We searched the following electronic databases to identify all studies from their inception to September 2017: Cochrane Library, Science Direct, MEDLINE, EMBASE, Scopus, Google Scholar, the China Biomedical Database (CBM), and the Chinese National Knowledge Infrastructure (CNKI). Randomized clinical trials (RCTs), prospective cohort studies, retrospective observational cohort studies, and case-control studies investigating BHD and BHDI for the treatment of CSDH were included. The Cochrane Collaboration's RevMan 5.3 software was used for meta-analysis. RESULTS: In total, 7 retrospective cohort studies and 2 RCTs involving 993 participants were included. Comprehensive analysis results of 9 studies indicated that the recurrence of the BHDI was similar to that in BHD (odds ratio [OR] = 1.27, 95% confidence interval [CI] = .61-2.63, P = .53). Moreover, analysis for comparing recurrence in the 2 RCTs was not significantly different (OR = 1.14, 95% CI = .16-8.24, P = .95).In addition, meta-analysis of pneumocephalus (OR = 5.91, 95% CI = .61-56.86, P = .12) and mortality (OR = 0.94, 95% CI 0.14-6.16, P = .95) was not significantly different. CONCLUSIONS: The results of this meta-analysis demonstrated that procedures with or without irrigation in the treatment of CSDH might have similar effect regarding recurrence and complications; therefore, irrigation might not be necessary. However, well-conducted RCTs and high-quality observational studies are still required to corroborate this issue.

Tunable band gaps and p-type transport properties of boron-doped graphenes by controllable ion doping using reactive microwave plasma.

We report tunable band gaps and transport properties of B-doped graphenes that were achieved via controllable doping through reaction with the ion atmosphere of trimethylboron decomposed by microwave plasma. Both electron energy loss spectroscopy and X-ray photoemission spectroscopy analyses of the graphene reacted with ion atmosphere showed that B atoms are substitutionally incorporated into graphenes without segregation of B domains. The B content was adjusted over a range of 0-13.85 atom % by controlling the ion reaction time, from which the doping effects on transport properties were quantitatively evaluated. Electrical measurements from graphene field-effect transistors show that the B-doped graphenes have a distinct p-type conductivity with a current on/off ratio higher than 10(2). Especially, the band gap of graphenes is tuned from 0 to ~0.54 eV with increasing B content, leading to a series of modulated transport properties. We believe the controllable doping for graphenes with predictable transport properties may pave a way for the development of graphene-based devices.

Tunable p-type conductivity and transport properties of AlN nanowires via Mg doping.

Arrays of well-aligned AlN nanowires (NWs) with tunable p-type conductivity were synthesized on Si(111) substrates using bis(cyclopentadienyl)magnesium (Cp(2)Mg) vapor as a doping source by chemical vapor deposition. The Mg-doped AlN NWs are single-crystalline and grow along the [001] direction. Gate-voltage-dependent transport measurements on field-effect transistors constructed from individual NWs revealed the transition from n-type conductivity in the undoped AlN NWs to p-type conductivity in the Mg-doped NWs. By adjusting the doping gas flow rate (0-10 sccm), the conductivity of AlN NWs can be tuned over 7 orders of magnitude from (3.8-8.5) × 10(-6) Ω(-1) cm(-1) for the undoped sample to 15.6-24.4 Ω(-1) cm(-1) for the Mg-doped AlN NWs. Hole concentration as high as 4.7 × 10(19) cm(-3) was achieved for the heaviest doping. In addition, the maximum hole mobility (∼6.4 cm(2)/V s) in p-type AlN NWs is much higher than that of Mg-doped AlN films (∼1.0 cm(2)/V s). (2) The realization of p-type AlN NWs with tunable electrical transport properties may open great potential in developing practical nanodevices such as deep-UV light-emitting diodes and photodetectors.

Incorporation of graphenes in nanostructured TiO(2) films via molecular grafting for dye-sensitized solar cell application.

This paper presents a systematic investigation on the incorporation of chemical exfoliation graphene sheets (GS) in TiO(2) nanoparticle films via a molecular grafting method for dye-sensitized solar cells (DSSCs). By controlling the oxidation time in the chemical exfoliation process, both high conductivity of reduced GS and good attachment of TiO(2) nanoparticles on the GS were achieved. Uniform GS/TiO(2) composite films with large areas on conductive glass were prepared by electrophoretic deposition, and the incorporation of GS significantly improved the conductivity of the TiO(2) nanoparticle film by more than 2 orders of magnitude. Moreover, the power conversion efficiency for DSSC based on GS/TiO(2) composite films is more than 5 times higher than that based on TiO(2) alone, indicating that the incorporation of GS is an efficient means for enhancing the photovoltaic (PV) performance. The better PV performance of GS/TiO(2) DSSC is also attributed to the better dye loading of GS/TiO(2) film than that of TiO(2) film. The effect of GS content on the PV performances was also investigated. It was found that the power conversion efficiency increased first and then decreased with the increasing of GS concentration due to the decrease in the transmittance at high GS content. Further improvements can be expected by fully optimizing fabrication conditions and device configuration, such as increasing dye loading via thicker films. The present synthetic strategy is expected to lead to a family of composites with designed properties.