Expression of Concern: One-pot synthesis of acid-degradable polyphosphazene prodrugs for efficient tumor chemotherapy.

Expression of Concern for 'One-pot synthesis of acid-degradable polyphosphazene prodrugs for efficient tumor chemotherapy' by Na Zhou et al., J. Mater. Chem. B, 2020, 8, 10540-10548, https://doi.org/10.1039/D0TB01992E.

Corticotropin-releasing hormone neurons control trigeminal neuralgia-induced anxiodepression via a hippocampus-to-prefrontal circuit.

Anxiety and depression are frequently observed in patients suffering from trigeminal neuralgia (TN), but neural circuits and mechanisms underlying this association are poorly understood. Here, we identified a dedicated neural circuit from the ventral hippocampus (vHPC) to the medial prefrontal cortex (mPFC) that mediates TN-related anxiodepression. We found that TN caused an increase in excitatory synaptic transmission from vHPCCaMK2A neurons to mPFC inhibitory neurons marked by the expression of corticotropin-releasing hormone (CRH). Activation of CRH+ neurons subsequently led to feed-forward inhibition of layer V pyramidal neurons in the mPFC via activation of the CRH receptor 1 (CRHR1). Inhibition of the vHPCCaMK2A-mPFCCRH circuit ameliorated TN-induced anxiodepression, whereas activating this pathway sufficiently produced anxiodepressive-like behaviors. Thus, our studies identified a neural pathway driving pain-related anxiodepression and a molecular target for treating pain-related psychiatric disorders.

Weaning difficulty after severe pneumonia in adult-onset mitochondrial myopathy with A3243G mutation in the mitochondrial tRNA gene: A case report.

Background: Mitochondrial myopathy is a group of diseases caused by abnormal mitochondrial structure or function. The mitochondrial myopathy impacts muscles of the whole body and exhibits variable symptoms. Respiratory muscle deficits deteriorate pulmonary function in patients with severe pneumonia. Case presentation: We report the case of a male patient with severe pneumonia-induced respiratory failure. He was abnormally dependent invasive ventilator-assisted ventilation after his condition had improved. Then we found abnormal ventilator waveform and a decline in muscle strength of him. Mitochondrial myopathy was ultimately confirmed by muscle pathological biopsy and body fluid genetic testing. Vitamin B complex, coenzyme Q10, Neprinol AFD, l-arginine, and MITO-TONIC were used to improve mitochondrial function and muscle metabolism. After treatment, discomfort associated with chest tightness, fatigue, cough, and sputum disappeared, and the patient was discharged. Conclusion: This case presented an uncommon cause of difficult weaning and extubation-acute onset of mitochondrial myopathy. Muscle biopsy and genetic testing of body fluid are essential for diagnosing mitochondrial myopathy. The A3243G mutation in the MT-TL1 gene of mitochondrial DNA contributes to pathogenesis of this case.

Analysis of factors of willingness to adopt intelligent construction technology in highway construction enterprises.

This study aims to investigate the factors that influence the willingness of highway construction enterprises in China to adopt intelligent construction technology. Based on the existing literature, a TOSE framework was proposed, and four dimensions and 15 hypothesized influencing factors were identified through expert interviews. By using a combination of PLS-SEM and ANN, 513 survey data were analyzed to determine the linear and non-linear relationships of the influencing factors on the willingness to adopt. The results showed that all 14 hypothesized factors had varying degrees of positive or negative effects on the willingness to adopt, except for organizational culture, which was found to have no significant impact. Specifically, technology cost was found to be the most influential negative factor, while market demand and organizational structure were the most influential positive factors. The findings of this study have important reference value for decision makers and participants in highway construction enterprises, as well as other construction companies when considering the adoption of smart construction technologies. The originality of this research lies in the novel application of the TOSE framework to investigate smart construction technology adoption, and the combined use of PLS-SEM and ANN to examine both linear and nonlinear relationships between variables for the first time.

ANP32B suppresses B-cell acute lymphoblastic leukemia through activation of PU.1 in mice.

ANP32B, a member of the acidic leucine-rich nuclear phosphoprotein 32 kDa (ANP32) family of proteins, is critical for normal development because its constitutive knockout mice are perinatal lethal. It is also shown that ANP32B acts as a tumor-promoting gene in some kinds of cancer such as breast cancer and chronic myelogenous leukemia. Herein, we observe that ANP32B is lowly expressed in B-cell acute lymphoblastic leukemia (B-ALL) patients, which correlates with poor prognosis. Furthermore, we utilized the N-myc or BCR-ABLp190 -induced B-ALL mouse model to investigate the role of ANP32B in B-ALL development. Intriguingly, conditional deletion of Anp32b in hematopoietic cells significantly promotes leukemogenesis in two B-ALL mouse models. Mechanistically, ANP32B interacts with purine rich box-1 (PU.1) and enhances the transcriptional activity of PU.1 in B-ALL cells. Overexpression of PU.1 dramatically suppresses B-ALL progression, and highly expressed PU.1 significantly reverses the accelerated leukemogenesis in Anp32b-deficient mice. Collectively, our findings identify ANP32B as a suppressor gene and provide novel insight into B-ALL pathogenesis.

FBXO22 promotes leukemogenesis by targeting BACH1 in MLL-rearranged acute myeloid leukemia.

BACKGROUND: Selectively targeting leukemia stem cells (LSCs) is a promising approach in treating acute myeloid leukemia (AML), for which identification of such therapeutic targets is critical. Increasing lines of evidence indicate that FBXO22 plays a critical role in solid tumor development and therapy response. However, its potential roles in leukemogenesis remain largely unknown. METHODS: We established a mixed lineage leukemia (MLL)-AF9-induced AML model with hematopoietic cell-specific FBXO22 knockout mice to elucidate the role of FBXO22 in AML progression and LSCs regulation, including self-renewal, cell cycle, apoptosis and survival analysis. Immunoprecipitation combined with liquid chromatography-tandem mass spectrometry analysis, Western blotting and rescue experiments were performed to study the mechanisms underlying the oncogenic role of FBXO22. RESULTS: FBXO22 was highly expressed in AML, especially in MLL-rearranged (MLLr) AML. Upon FBXO22 knockdown, human MLLr leukemia cells presented markedly increased apoptosis. Although conditional deletion of Fbxo22 in hematopoietic cells did not significantly affect the function of hematopoietic stem cells, MLL-AF9-induced leukemogenesis was dramatically abrogated upon Fbxo22 deletion, together with remarkably reduced LSCs after serial transplantations. Mechanistically, FBXO22 promoted degradation of BACH1 in MLLr AML cells, and overexpression of BACH1 suppressed MLLr AML progression. In line with this, heterozygous deletion of BACH1 significantly reversed delayed leukemogenesis in Fbxo22-deficient mice. CONCLUSIONS: FBXO22 promotes MLLr AML progression by targeting BACH1 and targeting FBXO22 might be an ideal strategy to eradicate LSCs without influencing normal hematopoiesis.

Non-canonical phosphorylation of Bmf by p38 MAPK promotes its apoptotic activity in anoikis.

Bmf contributes to the onset of anoikis by translocating from cytoskeleton to mitochondria when cells lose attachment to the extracellular matrix. However, the structural details of Bmf cytoskeleton tethering and the control of Bmf release upon loss of anchorage remained unknown. Here we showed that cell detachment induced rapid and sustained activation of p38 MAPK in mammary epithelial cell lines. Inhibition of p38 signaling or Bmf knockdown rescued anoikis. Activated p38 MAPK could directly phosphorylate Bmf at multiple sites including a non-proline-directed site threonine 72 (T72). Crystallographic studies revealed that Bmf T72 directly participated in DLC2 binding and its phosphorylation would block Bmf/DLC2 interaction through steric hindrance. Finally, we showed that phosphomimetic mutation of T72 enhanced Bmf apoptotic activity in vitro and in a knock-in mouse model. This work unraveled a novel regulatory mechanism of Bmf activity during anoikis and provided structural basis for Bmf cytoskeleton tethering and dissociation.

LncRNA SAMMSON Mediates Adaptive Resistance to RAF Inhibition in BRAF-Mutant Melanoma Cells.

The long noncoding RNA (lncRNA) SAMMSON is required for human melanoma cell growth and survival. However, whether SAMMSON regulates the response of mutant BRAF melanoma cells to RAF inhibitors remains unknown. In this work, we showed that SAMMSON is rapidly induced upon inhibition of ERK signaling, and SAMMSON overexpression conferred resistance to vemurafenib-induced cytotoxicity in melanoma cells. SOX10 mediated transcriptional induction of SAMMSON by vemurafenib, and SOX10 sumoylation at K55 was essential for this function. In addition, depletion of SAMMSON activated p53 signaling, which is dependent on the SAMMSON-interacting protein CARF. Depletion of SAMMSON sensitized mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo, while CARF knockdown reversed the enhanced sensitivity. In summary, these findings suggest that SAMMSON may function as a new mediator of adaptive resistance to RAF inhibitors in melanoma by modulating CARF-p53 signaling. SIGNIFICANCE: This study highlights the role of a SAMMSON/CARF/p53 signaling axis in modulating the adaptive resistance of mutant BRAF melanoma to RAF inhibitors.

Facile preparation of pH/redox dual-responsive biodegradable polyphosphazene prodrugs for effective cancer chemotherapy.

In order to maximize the therapeutic effect and and minimize the systemtic side effect of the small molecule anticancer drugs, biodegradable drug delivery systems (DDSs) that respond to tumor microenvironment (TME) have attracted significant attention. Herein, a novel redox/pH dual-responsive and biodegradable polyphosphazene (PPZ) nano-prodrugs have been prepared via one-pot crosslinking of vanillin modified DOX (VMD, acid-sensitive) and 4,4'-dihydroxydiphenyl disulfide (HPS, GSH-responsive) with hexachlorocyclotriphosphazene (HCCP). The phenol groups of the as-synthesized VMD and HPS have high nucleophilic substitution activity towards HCCP under base catalyst and afforded PPZ nano-prodrugs, denoted as HCCP-VMD-HPS, with a high drug loading ratio of up to 56.4 %. As expected, the skeleton of the PPZ consisting of imine bonds in VMD and the disulfide bonds in HPS and cyclotriphosphazenes inclined to be decomposed in low pH conditions and high level of GSH environments. The antitumor drug DOX was found to be controlled released in TME conditions (extracellular, pH∼6.8 and endosomes, lysosomes pH∼5.0 with ∼10 mM GSH), rather than neutral physiological conditions (pH 7.4 with ∼20 µM GSH). Moreover, the resulting HCCP-VMD-HPS nano-prodrug have obvious cytotoxicity to cancer cells while a negligible side effect to normal cells. We therefore believe that the prepared redox/pH dual-responsive and biodegradable PPZ DDSs have great potential in various field.

One-pot synthesis of acid-degradable polyphosphazene prodrugs for efficient tumor chemotherapy.

In order to improve the therapeutic efficacy and reduce the side effects of anticancer drugs, stimuli-responsive and biodegradable drug-delivery systems have attracted significant attention in the past three decades. Herein, we report acid-responsive and degradable polyphosphazene nano-prodrugs synthesized via a one-pot cross-linking reaction of 4-hydroxybenzhydrazide-modified doxorubicin (BMD) with hexachlorocyclotriphosphazene (HCCP). The phenol groups in the as-synthesized BMD exhibited a high reactivity towards HCCP and in the presence of a basic catalyst the determined drug loading ratio of the nanoparticles, denoted as HCCP-BMD, was up to 85.64%. Interestingly, the hydrazone bonds in BMD and the skeleton of polyphosphazene tended to break down in acidic environments, and the antitumor active drug DOX was found to be released in an acidic tumor microenvironment (pH ∼ 6.8 for extracellular, and pH ∼ 5.0 for endosomes and lysosomes). The resulting HCCP-BMD prodrug exhibited high cytotoxicity to HeLa cells and could effectively suppress tumor growth, with negligible damage to normal tissues. We therefore believe that this acid- degradable polyphosphazene prodrug may offer great potential in various biomedical fields.

CIC Is a Mediator of the ERK1/2-DUSP6 Negative Feedback Loop.

DUSP6 functions as an important negative feedback component of the MAPK/ERK signaling pathway. Although DUSP6 expression is tightly regulated by ERK1/2 signaling, the molecular mechanism of this regulation remains partially understood. In this work, we show that the transcriptional repressor CIC functions downstream of the ERK1/2 signaling to negatively regulate DUSP6 expression. CIC directly represses DUSP6 transcription by binding to three cis-regulatory elements (CREs) in DUSP6 promoter. p90RSK, a downstream target of ERK1/2, phosphorylates CIC at S173 and S301 sites, which creates a 14-3-3 recognition motif, resulting in 14-3-3-mediated nuclear export of CIC and derepression of DUSP6. Finally, we demonstrate that the oncogenic CIC-DUX4 fusion protein acts as a transcriptional activator of DUSP6 and its nuclear/cytoplasmic distribution remains regulated by ERK1/2 signaling. These results complete an ERK1/2/p90RSK/CIC/DUSP6 negative feedback circuit and elucidate the molecular mechanism of how RTK/MAPK signaling harnesses the transcriptional repressor activity of CIC in mammalian cells.

Iron overload as a risk factor for poor graft function following allogeneic hematopoietic stem cell transplantation.

Hematological malignancies are increasingly treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, iron overload is a frequent adverse effect of allo-HSCT and is associated with poor prognosis. In the present study, we investigated hematopoiesis in iron-overloaded mice and elucidated the effects of iron overload on the bone marrow (BM) microenvironment. Iron-overloaded BALB/C mice were generated by injecting 20 mg/mL saccharated iron oxide intraperitoneally. Hematoxylin-eosin staining was performed to evaluate the effects of an iron overload in mice. BM cells obtained from C57BL/6 mice were transplanted into irradiated BALB/C mice (whole-body irradiation of 4 Gy, twice with a 4-hours interval) by tail vein injection. Two weeks after allo-HSCT, the hematopoietic reconstitution capacity was evaluated in recipients by colony-forming assays. Histopathological examinations showed brown-stained granular deposits, irregularly arranged lymphocytes in the liver tissues, and blue-stained blocks in the BM collected from mice received injections of high-dose saccharated iron oxide (20 mg/mL). Iron-overloaded mice showed more platelets, higher-hemoglobin (HGB) concentration, fewer granulocyte-macrophage colony-forming units (CFU-GM), erythrocyte colony-forming units (CFU-E), and mixed granulocyte/erythrocyte/monocyte/megakaryocyte colony-forming units (CFU-mix) than healthy mice. Iron-overloaded recipients presented with reduced erythrocytes and HGB concentration in peripheral blood, along with decreased marrow stroma cells, CFU-GM, CFU-E, and CFU-mix relative to healthy recipients. Taken together, our findings demonstrate that iron overload might alter the number of red blood cells after transplantation in mice by destroying the BM microenvironment, thereby affecting the recovery of BM hematopoietic function.

150-200 V Split-Gate Trench Power MOSFETs with Multiple Epitaxial Layers.

A rating voltage of 150 and 200 V split-gate trench (SGT) power metal-oxide- semiconductor field-effect transistor (Power MOSFET) with different epitaxial layers was proposed and studied. In order to reduce the specific on-resistance (Ron,sp) of a 150 and 200 V SGT power MOSFET, we used a multiple epitaxies (EPIs) structure to design it and compared other single-EPI and double-EPIs devices based on the same fabrication process. We found that the bottom epitaxial (EPI) layer of a double-EPIs structure can be designed to support the breakdown voltage, and the top one can be adjusted to reduce the Ron,sp. Therefore, the double-EPIs device has more flexibility to achieve a lower Ron,sp than the single-EPI one. When the required voltage is over 100 V, the on-state resistance (Ron) of double-EPIs device is no longer satisfying our expectations. A triple-EPIs structure was designed and studied, to reduce its Ron, without sacrificing the breakdown voltage. We used an Integrated System Engineering-Technology Computer-Aided Design (ISE-TCAD) simulator to investigate and study the 150 V SGT power MOSFETs with different EPI structures, by modulating the thickness and resistivity of each EPI layer. The simulated Ron,sp of a 150 V triple-EPIs device is only 62% and 18.3% of that for the double-EPIs and single-EPI structure, respectively.

Acid-Responsive and Biologically Degradable Polyphosphazene Nanodrugs for Efficient Drug Delivery.

To enhance the therapeutic effects and reduce the damage to normal tissues in cancer chemotherapy, it is indispensable to develop drug delivery carriers with controllable release and good biocompatibility. In this work, acid-responsive and degradable polyphosphazene (PPZ) nanoparticles were synthesized by the reaction of hexachlorotripolyphosphonitrile (HCCP) with 4-hydroxy-benzoic acid (4-hydroxy-benzylidene)-hydrazide (HBHBH) and anticancer drug doxorubicin (DOX). The controlled release of DOX could be realized based on the acid responsiveness of acylhydrazone in HBHBH. Experimental results showed that polyphosphazene nanoparticles remained stable in the body's normal fluids (pH ∼ 7.4), while they were degraded and controllable release of DOX in an acidic environment such as tumors (pH ∼ 6.8) and lysosome and endosome (∼5.0) in cancer cells In particular, the doxorubicin (DOX)-loading ratio was fair high and could be tuned from 10.6 to 52.6% by changing the dosing ratio of DOX to HBHBH. Meanwhile, the polyphosphazene nanodrugs showed excellent toxicity to tumor cells and reduced the side effect to normal cells both in vitro and in vivo due to their enhanced permeability and retention (EPR) effect and pH-sensitive degradation properties. Therefore, the constructed pH-sensitive drug delivery system has great potential for cancer chemotherapy.

pH/redox dual-stimuli-responsive cross-linked polyphosphazene nanoparticles for multimodal imaging-guided chemo-photodynamic therapy.

Multifunctional nanodrugs with the integration of precise diagnostic and effective therapeutic functions have shown great promise in improving the efficacy of cancer therapy. We report herein a simple and effective approach to directly assemble an anticancer drug (curcumin), a photodynamic agent (Ce6) and tumor environment-sensitive molecules into cross-linked polyphosphazene and coat on superparamagnetic Fe3O4 nanoclusters to form discrete nanoparticles (termed as FHCPCe NPs). FHCPCe NPs have high physiological stability and good biocompatibility, and can enhance accumulation in tumor tissue via the enhanced permeability and retention effect. Meanwhile, the FHCPCe NPs exhibit an effective performance of dual-modality magnetic resonance imaging (MRI) due to the Fe3O4 cores and fluorescence imaging (FL) in the xenografted HeLa tumor because of the fluorescence of Ce6. Importantly, under the conditions of supernormal glutathione levels and acidic microenvironment in tumor tissue, curcumin and Ce6 can be effectively released by the degradation of FHCPCe NPs. Therefore, excellent anti-tumor effects both in vitro and in vivo have been achieved by synergistic chemotherapy/photodynamic therapy (CT/PDT) using multifunctional NPs. Our study highlights the promise of developing multifunctional nanomaterials for accurate multimodal imaging-guided highly sensitive therapy of cancer.

Publisher Correction: ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma.

In the original version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include the following: The National Basic Research Program (2015CB553602 to J.L.), the National Natural Science Foundation of China (31570777, 91649106, 31770917 to J.L.) and Tianjin Applied Basic and Frontier Tech Major Project (12JCZDJC34400 to J.L.) and Tianjin Higher Education Sci-Tech Development Project (20112D05 to J.L.).

Multifunctional Nanoflowers for Simultaneous Multimodal Imaging and High-Sensitivity Chemo-Photothermal Treatment.

Liver cancer is currently among the most challenging cancers to diagnose and treat. It is of prime importance to minimize the side effects on healthy tissues and reduce drug resistance for precise diagnoses and effective treatment of liver cancer. Herein, we report a facile but high-yield approach to fabricate a multifunctional nanomaterial through the loading of chitosan and metformin on Mn-doped Fe3O4@MoS2 nanoflowers. Mn-doped Fe3O4 cores are used as simultaneous T1/T2 magnetic resonance imaging (MRI) agents for sensitive and accurate cancer diagnosis, while MoS2 nanosheets are used as effective near-infrared photothermal conversion agents for potential photothermal therapy. The surface-functionalized chitosan was able not only to improve the dispersibility of Mn-doped Fe3O4@MoS2 nanoflowers in biofluids and increase their biocompatibility, but also to significantly enhance the photothermal effect. Furthermore, metformin loading led to high suppression and eradication of hepatoma cells when photothermally sensitized, but exhibited negligible effects on normal liver cells. Due to its excellent combination of T1/T2 MRI properties with sensitive chemotherapeutic and photothermal effects, our study highlights the promise of developing multifunctional nanomaterials for accurate multimodal imaging-guided, and highly sensitive therapy of liver cancer.

ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma.

In human mutant BRAF melanoma cells, the stemness transcription factor FOXD3 is rapidly induced by inhibition of ERK1/2 signaling and mediates adaptive resistance to RAF inhibitors. However, the mechanism underlying ERK signaling control of FOXD3 expression remains unknown. Here we show that SOX10 is both necessary and sufficient for RAF inhibitor-induced expression of FOXD3 in mutant BRAF melanoma cells. SOX10 activates the transcription of FOXD3 by binding to a regulatory element in FOXD3 promoter. Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity. Finally, depletion of SOX10 sensitizes mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo. Thus, our work discovers a novel phosphorylation-dependent regulatory mechanism of SOX10 transcription activity and completes an ERK1/2/SOX10/FOXD3/ERBB3 axis that mediates adaptive resistance to RAF inhibitors in mutant BRAF melanoma cells.

In vitro effects of reprogramming factors on the expressions of pluripotent genes and CD34 gene in human acute promyelocytic leukemia HL-60 cells.

OBJECTIVE: Our study aims to explore the in vitro effects of reprogramming factors on the expressions of pluripotent genes and CD34 gene in HL-60 cells. METHODS: According to the construction of lentiviral vector LV-OSCK of reprogramming factors (Oct-4, Sox2, Klf4, c-Myc), 293T cells were transfected to detect virus titer. The endogenous pluripotent genes (Oct4, SOX2, c-Myc and Klf4) and CD34 mRNA and protein expressions were detected by AP staining, immunofluorescence staining, qRT-PCR and flow cytometry. RESULTS: Expressions of Oct4, SOX2, c-Myc and Klf4 were 0.220±0.013, 0.186±0.009, 0.287±0.015 and 0.153±0.007. These levels were significantly higher in the experimental group than the control and blank groups. CD34 protein expression in the experimental group was also discovered to be significantly higher than the other two groups. CONCLUSION: The reprogramming factors could increase the expressions of pluripotent genes and CD34 gene in HL-60 cells.