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Several preclinical and clinical studies have attempted to elucidate the pathophysiological mechanism associated with spinal cord injury. However, investigations have been unable to define the precise related mechanisms, and this has led to the lack of effective therapeutic agents for the condition. Neuroinflammation is one of the predominant processes that hinder spinal cord injury recovery. Resveratrol is a compound that has several biological features, such as antioxidation, antibacterial, and antiinflammation. Herein, we reviewed preclinical and clinical studies to delineate the role of toll-like receptors, nod-like receptors, and astrocytes in neuroinflammation. In particular, the alteration of astrocytes in SCI causes glial scar formation that impedes spinal cord injury recovery. Therefore, to improve injury recovery would be to prevent the occurrence of this process. Resveratrol is safe and effective in the significant modulation of neuroinflammatory factors, particularly those mediated by astrocytes. Thus, its potential ability to enhance the injury recovery process and ameliorate spinal cord injury.

Spinal cord injury (SCI) is a high incident rate of central nervous system disease that usually causes paralysis below the injured level. The occurrence of chronic inflammation with the axonal regeneration difficulties are the underlying barriers for the recovery of SCI patients. Current studies have paid attention to controlling the instigative and developmental process of neuro-inflammation. Ethyl pyruvate, as a derivative of pyruvate, has strong anti-inflammatory and neuroprotective functions. Herein, we reviewed the recent studies of ethyl pyruvate and high mobility group box-1 (HMGB1). We think HMGB1 that is one of the main nuclear protein mediators to cause an inflammatory response. This protein induces astrocytic activation, and promotes glial scar formation. Interestingly, ethyl pyruvate has potent inhibitory effects on HMGB1 protein, as it inhibits chronic inflammatory response by modulating the HMGB1/TLR4/NF-κB signaling pathway. This paper discusses the potential mechanism of ethyl pyruvate in inhibiting chronic inflammation after SCI. Ethyl pyruvate can be a prospective therapeutic agent for SCI.

The complexity of central nervous system diseases together with their intricate pathogenesis complicate the establishment of effective treatment strategies. Presently, the superiority of adipose-derived mesenchymal stem cells (ADSCs) on neuronal injuries has attracted significant attention. Similarly, extracellular vesicles (EVs) are potential interventional agents that could identify and treat nerve injuries. Herein, we reviewed the potential effects of ADSCs and EVs on amyotrophic lateral sclerosis (ALS) injured nerves, and expound on their practical application in the clinic setting. This article predominantly focused on the therapeutic role of ADSCs concerning the pathogenesis of ALS, the protective and reparative effects of EVs on nerve injury, as well as the impact following the combined usage of ADSCs and EVs in ALS.

Traumatic brain injury (TBI) has both high morbidity and mortality rates and can negatively influence physical and mental health, while also causing extreme burden to both individual and society. Hitherto, there is no effective treatment for TBI because of the complexity of the brain anatomy and physiology. Currently, management strategies mainly focus on controlling inflammation after TBI. Tumor necrotizing factor alpha (TNF-α) plays a crucial role in neuroinflammation post-TBI. TNF-α acts as the initiator of downstream inflammatory signaling pathways, and its activation can trigger a series of inflammatory reactions. Infliximab is a monoclonal anti-TNF-α antibody that reduces inflammation. Herein, we review the latest findings pertaining to the role of TNF-α and infliximab in TBI. We seek to present a comprehensive clinical application prospect of infliximab in TBI and, thus, discuss potential strategies of infliximab in treating TBI.

Acute myeloid leukemia (AML) is prone to relapse. Targeted therapy with a specific inhibitor of the anti-apoptotic protein Bcl-2 ABT-199 is an effective method for relapsed and refractory patients, but drug resistance is likely, which is primarily related to high Mcl-1 and S100A8 expression. All-trans retinoic acid (ATRA) can inhibit Bcl-2 and Mcl-1 expression. The study purpose was to determine whether ATRA can enhance the antileukemia effect of ABT-199 on AML cells. Our data showed that ATRA combined with ABT-199 exerts a synergistic antileukemic effect by inducing apoptosis and cell cycle arrest in AML. In vivo, combination therapy prolonged the survival of AML xenograft mice. The possible mechanism involves promoting apoptosis through downregulation of S100A8 expression by inhibiting the PI3K/AKT signaling pathway. This study provides a potential treatment strategy and theoretical support for overcoming the clinical ABT-199 resistance problem in AML patients.

Zircon is a critical mineral for the extraction of zirconium, uranium and hafnium. Physical separation techniques like gravity and electrical separation have been widely used to obtain a commercial-grade zircon. Flotation, as a supplementary approach, can be used to separate fine zircon from heavy minerals (i.e. rutile, cassiterite). However, it is challenging to selectively recover iron/aluminosilicate contaminated zircon, due to its low floatability. In this study, two zircon samples containing high and low amounts of impurities were selected in order to determine the influence of surface composition on flotation. Scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), speciation diagrams, and zeta-potentials demonstrated that pretreatment methods can improve the surface purity of zircon via the removal of coated impurities (iron-oxides and aluminosilicates) as well as increasing the exposure of the ZrO2 and ZrSiO4 phases. SEM, XPS, zeta-potential and flotation studies performed with sodium oleate (NaOL) as an environmentally benign collector show that the pretreated zircon samples display better flotation performance than the untreated zircon. First-principle calculations revealed that the chemical bond between NaOL and zircon is ionic in nature; NaOL can be both chemically and physically adsorbed onto zircon surfaces. Adsorption is mainly affected by electrostatic attractions reflected by changes in the zeta-potential. Surface pretreatment can thus substantially improve the flotation performance of zircon. Refereed/Peer-reviewed

To explore the clinical characteristics and prognostic values of TP53 gene variant in patients with acute leukemia(AL).The clinical data of 44 newly diagnosed AL patients with TP53 variant detected by next generation sequencing (NGS) were analyzed retrospectively. Targeted sequencing technique containing 108 leukemia-related genes was used for variant analysis, and conventional R-banding technique was used for karyotype analysis. The clinical features, cytogenetics, gene variant, curative effect and survival of AL patients with TP53 gene variant were analyzed.The median age of AML patients with TP53 gene variant (46 years) was higher than that of ALL patients (17.5 years), and the median number of bone marrow blasts (40.5%) was lower than the latter (89.2%), the differences were statistically significant (P0.01). A total of 28 cases of abnormal karyotype were detected, of which 25 cases were complex karyotype, 16 cases were monomeric karyotype, 14 cases had -17/17p-. The detection rates of TP53 in complex karyotype, monomeric karyotype and -17/17p- were 59.5%, 38.1% and 33.3%, respectively. Subgroup analysis showed that the detection rate of TP53 gene abnormalities in AML and ALL complex karyotypes was 73.1% and 40% respectively, the difference was statistically significant. A total of 41 TP53 gene variant types were found, and the median variant frequency was 43.58%. 75.6% variant was located in the DNA binding domain. The concomitant variant genes were mainly TET2 and IKZF1. Among 18 AML and 17 ALL patients who could be evaluated the curative effect, the CR rate of one course of treatment was 22.2% and 94.12% respectively, and the difference was statistically significant. The median RFS of 4 cases of AML with CR and 16 cases of ALL with CR were 174 and 246 days respectively, the difference was statistically insignificant. The median OS of AML and ALL was 20 and 375 days respectively, the difference was statistically significant.The TP53 gene variant is associated with the complex karyotype of AML, but has no significant effect on ALL. The variant site of TP53 gene was mainly distributed in the DNA binding domain. The remission rate of AML with TP53 gene variant was lower than that of ALL. The prognosis of AL patients with TP53 gene variant is poor, so allogeneic hematopoietic stem cell transplantation should be performed as soon as possible to prolong the survival of the patients.

BackgroundDrug-resistance is a major obstacle to the treatment of breast cancer. Circular RNA (circRNA) circ-MMP11 has been reported to be promoting the progression of breast cancer. This study is designed to explore the role and mechanism of circ-MMP11 in lapatinib resistance in breast cancer.MethodsCirc-MMP11, microRNA-153-3p (miR-153-3p), and Anillin (ANLN) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, number of colonies, apoptosis, migration, and invasion were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation, flow cytometry, and transwell assays, respectively. Exosomes were exerted and detected by differential centrifugation and a transmission electron microscope. The protein levels of CD63, CD9, and ANLN were assessed by western blot assay. The binding relationship between miR-153-3p and circ-MMP11 or ANLN was predicted by circinteractome or starbase, and then verified by a dual-luciferase reporter assay and RNA pull-down assay. The biological role of circ-MMP11 on breast cancer tumor growth and drug resistance was detected by the xenograft tumor model in vivo.ResultsCirc-MMP11 and ANLN were highly expressed, and miR-153-3p was decreased in LR breast cancer tissues and cells. Circ-MMP11 could be transported by exosomes. Furthermore, circ-MMP11 knockdown promoted lapatinib sensitivity by repressing cell viability, colony number, migration, invasion, and boosting apoptosis in LR breast cancer cells. Circ-MMP11 deficiency improved the drug sensitivity of breast cancer in vivo. Mechanically, circ-MMP11 could regulate ANLN expression through sponging miR-153-3p.ConclusionCirc-MMP11 could be transferred by exosomes in breast cancer cells. And circ-MMP11 functioned as a sponge of miR-153-3p to regulate ANLN expression, thereby promoting lapatinib resistance in breast cancer cells, providing therapeutic targets for the treatment of breast cancer.

Random measurements have been shown to induce a phase transition in an extended quantum system evolving under chaotic unitary dynamics, when the strength of measurements exceeds a threshold value. Below this threshold, a steady state with a sub-thermal volume law entanglement emerges, which is resistant to the disentangling action of measurements, suggesting a connection to quantum error-correcting codes. Here we quantify these notions by identifying a universal, subleading logarithmic contribution to the volume law entanglement entropy: $S^{(2)}(A)=\kappa L_A+\frac{3}{2}\log L_A$ which bounds the mutual information between a qudit inside region $A$ and the rest of the system. Specifically, we find the power law decay of the mutual information $I(\{x\}:\bar{A})\propto x^{-3/2}$ with distance $x$ from the region's boundary, which implies that measuring a qudit deep inside $A$ will have negligible effect on the entanglement of $A$. We obtain these results by mapping the entanglement dynamics to the imaginary time evolution of an Ising model, to which we can apply field-theoretic and matrix-product-state techniques. Finally, exploiting the error-correction viewpoint, we assume that the volume-law state is an encoding of a Page state in a quantum error-correcting code to obtain a bound on the critical measurement strength $p_{c}$ as a function of the qudit dimension $d$: $p_{c}\log[(d^{2}-1)({p_{c}^{-1}-1})]\le \log[(1-p_{c})d]$. The bound is saturated at $p_c(d\rightarrow\infty)=1/2$ and provides a reasonable estimate for the qubit transition: $p_c(d=2) \le 0.1893$., Comment: 26 pages, 10 figures

This article has been withdrawn at the request of the author for the following reason. Recently, we found an experimental error in this study. The results of dual-luciferase reporter assay in Fig. 5G and 5F may be incorrect. We conducted the experiment again, and found that the luciferase activity didn’t reduced by miR-149-5p in FGF5-wt group. The results were showed as below. So whether miR-149-5p directly targets FGF5 is uncertain. Therefore, we decide to withdraw the manuscript. We are very sorry for the trouble. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal

Parkinson's disease is a common progressive neurodegenerative disease, and presently has no curative agent. Curcumin, as one of the natural polyphenols, has great potential in neurodegenerative diseases and other different pathological settings. The brain-derived neurotrophic factor (BDNF) and phosphatidylinositol 3 kinase (PI3k)/protein kinase B (Akt) signaling pathways are significantly involved nerve regeneration and anti-apoptotic activities. Currently, relevant studies have confirmed that curcumin has an optimistic impact on neuroprotection via regulating BDNF and PI3k/Akt signaling pathways in neurodegenerative disease. Here, we summarized the relationship between BDNF and PI3k/Akt signaling pathway, the main biological functions and neuroprotective effects of curcumin via activating BDNF and PI3k/Akt signaling pathways in Parkinson's disease. This paper illustrates that curcumin, as a neuroprotective agent, can delay the progression of Parkinson's disease by protecting nerve cells.

In this work, we study non-equilibrium dynamics in Floquet conformal field theories (CFTs) in 1+1D, in which the driving Hamiltonian involves the energy-momentum density spatially modulated by an arbitrary smooth function. This generalizes earlier work which was restricted to the sine-square deformed type of Floquet Hamiltonians, operating within a $\mathfrak{sl}_2$ sub-algebra. Here we show remarkably that the problem remains soluble in this generalized case which involves the full Virasoro algebra, based on a geometrical approach. It is found that the phase diagram is determined by the stroboscopic trajectories of operator evolution. The presence/absence of spatial fixed points in the operator evolution indicates that the driven CFT is in a heating/non-heating phase, in which the entanglement entropy grows/oscillates in time. Additionally, the heating regime is further subdivided into a multitude of phases, with different entanglement patterns and spatial distribution of energy-momentum density, which are characterized by the number of spatial fixed points. Phase transitions between these different heating phases can be achieved simply by changing the duration of application of the driving Hamiltonian. We demonstrate the general features with concrete CFT examples and compare the results to lattice calculations and find remarkable agreement., 36 pages, 11 figures

In this paper and its sequel, we study non-equilibrium dynamics in driven 1+1D conformal field theories (CFTs) with periodic, quasi-periodic, and random driving. We study a soluble family of drives in which the Hamiltonian only involves the energy-momentum density spatially modulated at a single wavelength. The resulting time evolution is then captured by a M\"obius coordinate transformation. In this Part I, we establish the general framework and focus on the first two classes. In periodically driven CFTs, we generalize earlier work and study the generic features of entanglement/energy evolution in different phases, i.e. the heating, non-heating phases and the phase transition between them. In quasi-periodically driven CFTs, we mainly focus on the case of driving with a Fibonacci sequence. We find that (i) the non-heating phases form a Cantor set of measure zero; (ii) in the heating phase, the Lyapunov exponents (which characterize the growth rate of the entanglement entropy and energy) exhibit self-similarity, and can be arbitrarily small; (iii) the heating phase exhibits periodicity in the location of spatial structures at the Fibonacci times; (iv) one can find exactly the non-heating fixed point, where the entanglement entropy/energy oscillate at the Fibonacci numbers, but grow logarithmically/polynomially at the non-Fibonacci numbers; (v) for certain choices of driving Hamiltonians, the non-heating phases of the Fibonacci driving CFT can be mapped to the energy spectrum of electrons propagating in a Fibonacci quasi-crystal. In addition, another quasi-periodically driven CFT with an Aubry-Andr\'e like sequence is also studied. We compare the CFT results to lattice calculations and find remarkable agreement., Comment: 82 pages, many figures; reference added

Thalidomide was first marketed in 1957 but soon withdrawn because of its notorious teratogenicity. Studies on the mechanism of action of thalidomide revealed the pleiotropic properties of this class of drugs, including their anti-inflammatory, antiangiogenic and immunomodulatory activities. Based on their notable activities, thalidomide and its analogues, lenalidomide and pomalidomide, have been repurposed to treat erythema nodosum leprosum, multiple myeloma and other haematological malignancies. Thalidomide analogues were recently found to hijack CRL4CRBN ubiquitin ligase to target a number of cellular proteins for ubiquitination and proteasomal degradation. Thalidomide-mediated degradation of SALL4 and p63, transcription factors essential for embryonic development, very likely plays a critical role in thalidomide embryopathy. In this review, we provide a brief retrospective summary of thalidomide-induced teratogenesis, the mechanism of thalidomide activity, and the latest advances in the molecular mechanism of thalidomide-induced birth malformations.

Background/Aims: Resistance to trastuzumab remains a common challenge to HER-2 positive breast cancer. Up until now, the underlying mechanism of trastuzumab resistance is still unclear. tRNA-derived small non-coding RNAs, a new class of small non-coding RNA (sncRNAs), have been observed to play an important role in cancer progression. However, the relationship between tRNA-derived fragments and trastuzumab resistance is still unknown. Methods: We detected the levels of tRNA-derived fragments expression in normal breast epithelial cell lines, trastuzumab-sensitive and -resistant breast cancer cell lines using high-throughput sequencing. qRT-PCR was conducted to validate the differentially expressed fragments in serums from trastuzumab-sensitive and -resistant patients. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the power of specific tRNA-derived fragments. Progression-free survival (PFS) was analyzed using Cox-regression. Results: Our sequence results showed that tRNA-derived fragments were differentially expressed in the HBL-100, SKBR3, and JIMT-1 cell lines. tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN were found significantly upregulated in trastuzumab-resistant patients compared to sensitive individuals, and the ROC analysis showed that tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN were correlated with trastuzumab resistance. In a multivariate analysis, higher levels of tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN expression were associated with significantly shorter PFS in patients with metastatic HER-2 positive breast cancer. Conclusion: Our results suggest that tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN play important roles in trastuzumab resistance. Patients with high levels of tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN expression benefitted less from trastuzumab-based therapy than those that express lower-levels of these molecules. tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN may be potential biomarkers and intervention targets in the clinical treatment of trastuzumab-resistant breast cancer.

In this paper we first compute the out-of-time-order correlators (OTOC) for both a phenomenological model and a random-field XXZ model in the many-body localized phase. We show that the OTOC decreases in power law in a many-body localized system at the scrambling time. We also find that the OTOC can also be used to distinguish a many-body localized phase from an Anderson localized phase, while a normal correlator cannot. Furthermore, we prove an exact theorem that relates the growth of the second R\'enyi entropy in the quench dynamics to the decay of the OTOC in equilibrium. This theorem works for a generic quantum system. We discuss various implications of this theorem., Comment: 6 pages, 3 figures, published version

We study the energy and entanglement dynamics of $(1+1)$D conformal field theories (CFTs) under a Floquet drive with the sine-square deformed (SSD) Hamiltonian. Previous work has shown this model supports both a non-heating and a heating phase. Here we analytically establish several robust and `super-universal' features of the heating phase which rely on conformal invariance but not on the details of the CFT involved. First, we show the energy density is concentrated in two peaks in real space, a chiral and anti-chiral peak, which leads to an exponential growth in the total energy. The peak locations are set by fixed points of the M\"obius transformation. Second, all of the quantum entanglement is shared between these two peaks. In each driving period, a number of Bell pairs are generated, with one member pumped to the chiral peak, and the other member pumped to the anti-chiral peak. These Bell pairs are localized and accumulate at these two peaks, and can serve as a source of quantum entanglement. Third, in both the heating and non-heating phases we find that the total energy is related to the half system entanglement entropy by a simple relation $E(t)\propto c \exp \left( \frac{6}{c}S(t) \right)$ with $c$ being the central charge. In addition, we show that the non-heating phase, in which the energy and entanglement oscillate in time, is unstable to small fluctuations of the driving frequency in contrast to the heating phase. Finally, we point out an analogy to the periodically driven harmonic oscillator which allows us to understand global features of the phases, and introduce a quasiparticle picture to explain the spatial structure, which can be generalized to setups beyond the SSD construction., Comment: 41 pages, 19 figures

To explore the effect of preoperative infusion chemotherapy combined with hyperthermia on the expressions of sPD-L1 and CEA in elderly patients undergoing radical surgery for lung cancer, and their prognosis.136 elderly patients undergoing radical resection of lung cancer in our hospital from October 2012 to October 2014 were studied. Patients were randomly divided into two groups, namely the combination group and the individual treatment group, with 68 patients in each group. Patients in the individual treatment group received only preoperative chemotherapy, whereas those in combination group received preoperative infusion chemotherapy and preoperative and postoperative hyperthermia. The treatment efficacy, levels of sPD-L1 tumor marker CEA (carcino-embryonic antigen), and T-lymphocyte subsets (CD4+, CD3+, CD8+, CD29+) were compared between the two groups. Three-year follow-up data were collected to compare the overall survival (OS) of the two groups.The effective rates in the combination group and individual treatment group were 87.5 and 67.5%, respectively (p0.05). After treatment, lower serum levels of CEA and sPD-L1 were seen in the combination group vs the individual treatment group (p=0.036, p=0.008, respectively). Levels of T-lymphocyte subsets CD4+, CD3+, and CD29+ in both groups increased, and were higher in the combination group vs the individual treatment group (p0.05). Follow-up data demonstrated that OS in the combination group and the individual treatment group was 61.7 and 48.5%, respectively. Significant difference in OS between the two groups was confirmed by Log-rank test (p=0.043).Preoperative infusion chemotherapy combined with hyperthermia for elderly patients with lung cancer can improve patient immunity, inhibit tumor growth and lengthen overall survival by improving T-lymphocyte subset levels and reducing the circulating tumor cell content.

Objective: Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic system in which arrested maturation, excessive proliferation and inhibition of apoptosis have been observed in the process of hematopoietic stem cell differentiation. Some patients, especially elderly patients, do not tolerate cytotoxic chemotherapy, and some patients are resistant to chemotherapeutic drugs, consequently molecular targeting therapy has brought new hope for AML treatment. Venetoclax (ABT-199) is a selective inhibitor of the antiapoptotic protein Bcl-2. Increased expression of Bcl-2 is an important factor in the inhibition of apoptosis in leukemia cells. The use of a single drug is often limited because of resistance, and a better curative effect can be obtained in combination with other drugs. All-trans retinoic acid (all-trans-retinoic acid, ATRA) was first used by Chinese doctor to treat acute promyelocytic leukemia (APL). Many studies have shown that ATRA can inhibit the expression of Bcl-2 in AML cells and promote apoptosis. We aimed to test for the first time whether the combination of ATRA and venetoclax would produce a stronger anti-AML effect. Methods: The effects of ATRA and ABT-199 on the ABT-199-resistant AML cell lines OCI-AML3 and THP-1 and the sensitive cell lines MV-4-11 and MOLM-13 were observed in vitro. The following methods were used in this study. 1. CCK8 assay was used to detect cell proliferation. 2. Annexin V/FITC and PI double staining were used to detect apoptosis rate by flow cytometry. 3. Flow cytometry was used to detect the expression of CD11b. 4. PI single staining and flow cytometry were used to study the cell cycle. 5. Western blotting was used to detect the expression of Bcl-2, Bax, Mcl-1, PARP, caspase3, GSK-3β and Cyclin-D1 proteins in OCI-AML3 cells. Results:1. Compared with the control group and the ATRA or ABT-199 single drug group, cell proliferation was significantly inhibited in the combined drug group, the apoptosis rate was significantly increased, and the cell cycle was blocked in G1 phase. 2. The expression of CD11b in the ATRA or ABT-199 group and combination group was significantly higher than that in the control group. 3. In OCI-AML3 cells, compared with the ABT-199 drug group, the expression of Bcl-2, Mcl-1 and Cyclin-D1 decreased, and the expression of Bax, cleaved-PARP, cleaved caspase3 and p-GSK-3β expression increased in the combined treatment group. Conclusion: All-trans retinoic acid (ATRA) can enhance the anti-leukemia effect of ABT-199 on AML cell lines by inhibiting cell proliferation as seen by the cell cycle arrest of AML cells in G1 phase, promoting apoptosis and inducing differentiation. ATRA can reverse the drug resistance of AML cells to ABT-199 by inhibiting the expression of Bcl-2 and Mcl-1. Our observations may provide new strategies and theoretical support for the clinical treatment of AML. Key Wor ds :AML, Venetoclax, ATRA, Apoptosis Disclosures No relevant conflicts of interest to declare.

Background Acute myeloid leukaemia (AML) is a malignancy derived from haematopoietic stem cells in which maturation and apoptosis are blocked and proliferation is uncontrolled during differentiation. With the optimization of chemotherapy regimens, the emergence of new drugs and the development of haematopoietic stem cell transplantation technology, the complete remission (CR) rate and long-term survival of AML patients have significantly improved, but 20-40% of patients still have difficulty achieving a CR. Furthermore, approximately 60% of patients eventually relapse after a CR. Patients who are unable to obtain a CR and who relapse after remission are more likely to develop refractory AML. For patients with refractory/relapsed AML, there is no standard rescue therapy, and general chemotherapy drugs have limited efficacy. It is of great significance to explore new salvage treatment options. Venetoclax (ABT-199) is an effective oral inhibitor of Bcl-2. ABT-199 has been used to treat various in vitro and in vivo tumour models, including AML models, and these experiments have shown its effectiveness as a single agent. However, its efficacy is very limited in refractory/relapsed AML, Mcl-1 play important roles in ABT-199 resistance. As an ancient pro-apoptotic drug, arsenic trioxide (ATO) has been shown to induce apoptosis in vivo and in vitro. ATO can downregulate the expression of Mcl-1, thereby inducing apoptosis. objective To explore not only the synergistic pro-apoptotic effects of the Bcl-2 inhibitor ABT-199 and ATO on AML cell lines and AML primary cells, but also the clinical effects on refractory/relapsing AML patients. Methods 1. Bcl-2 and Mcl-1 mRNA and protein levels in AML cell lines (MOLM13, MV4-11, THP-1, OCI-AML3, U937) were detected by real-time PCR and Western blot, respectively; 2.Apoptosis rates of AML cell lines after treatment with different concentrations of ABT-199 or ATO alone or in combination were measured by flow cytometry; 3. The transcriptomes of THP-1 and OCI-AML3 cells before and after treatment with ABT-199 or ATO alone or in combination were analysed; 4. Western blot, co-immunoprecipitation, cell cycle assay ABT-199, ATO effect on oci-AML3 cells; 5. ABT-199 combined with ATO in the treatment of patients with relapsed and refractory AML, the specific program is: ABT-199 100mg d1, 200mg d2, 400mg d3-28, oral 30 minutes after breakfast, ATO 6mg/m2, d1-28, daily intravenous infusion for 6 hours, review the effect of bone marrow aspiration on the 28th day. Results 1.MOLM13, MV4-11, THP-1, OCI-AML3 and U937 cells expressed both Bcl-2 and Mcl-1. The sensitivity of AML cell lines to ABT-199 was positively correlated with the Bcl-2 protein expression level; 2.In AML cell lines whether ABT-sensitive or ABT-resistant and primary AML cells, ABT-199 and ATO synergistically promoted apoptosis in a time- and concentration-dependent manner; 3. ABT-199 up-regulated the expression of Mcl-1 in ABT-resistant OCI-AML3 cells, ATO down-regulated the expression of p-AKT, p-GSK3β, and Mcl-1, and the expression of Mcl-1 decreased after the combination of the two drugs. Bim and Mcl-1 protein binding decreased after treatment OCI-AML3 cells with the combination of the two drugs for 24h; 4. ATO promotes DNA damage, and the effect is further enhanced when combinated with ABT-199; 5. A total of 7 patients with relapse were treated with ABT-ATO combined regimen. Four of the 7 patients had multiple relapses and 3 patients had short-term recurrence after remission, with an average age of 49 years. On the 28th day, the bone marrow was reviewed. Two of them achieved CRi, one case with Leukemia-free state (MLFS), two cases with PR, one case with SD, and one case with PD. Conclusion We demenstrated ATO could reverse AML resistance to ABT-199 and the synergistic effects of the combination of ATO and ABT-199, which may provide a new and probably more effective treatment strategy for refractory/relapsed AML . Key Words Bcl-2 inhibitor; ABT-199; arsenic trioxide; Mcl-1; AKT; apoptosis Disclosures No relevant conflicts of interest to declare.

Table S1. Information of primers for RT-PCR of SH2D1A gene. (DOCX 16Â kb)

Cpf1, an RNA-guided DNA endonuclease that belongs to a new class II CRISPR system, has recently been harnessed for genome editing. Herein, we report an RNase-resistant caged truncated pre-tRNA-like crRNA (catRNA) that confers precise and efficient gene editing with the Lachnospiraceae bacterium Cpf1 (LbCpf1) and enables the reprogramming of catalytically dead LbCpf1 (dCpf1) lacking DNA endonuclease activity into a transcriptional modulator. Specific gene knock-outs and knock-ins were increased 3.2-fold and 4.3-fold, respectively, with catRNA compared to that induced by conventional crRNA. A much higher augmentation of gene disruption (up to 37-fold) was observed when electroporation was used. We report herein that catRNA enables efficient gene activation with dCpf1 activators. Our study reveals the potential of catRNA and a versatile application of the CRISPR/Cpf1 system, establishing a simple approach for selective gene perturbation in mammalian cells.

Background X-linked lymphoproliferative syndrome type 1 (XLP1) is an X-linked recessive genetic disorder with a strong resemblance to hemophagocytic lymphohistiocytosis (HLH). Causative mutations for XLP1 have been identified in SH2D1A, located on chromosome Xq25. Case presentation We report a case of an 18-month-old male with a novel nonsense mutation in SH2D1A. The patient presented the typical phenotype of HLH, including splenomegaly and hemophagocytosis in the bone marrow. Thus, he was initially diagnosed with HLH based on HLH-2004 guidelines. High-throughput amplicon sequencing was performed to detect mutations in the most commonly reported causative genes of HLH, i.e., PRF1, UNC13D, STX11, STXBP2, SH2D1A, and XIAP. A likely pathogenic nonsense mutation was detected in SH2D1A (NM_002351.4:c.300T>A). The mutation was inherited from the patient’s mother, and an X-linked recessive mode of inheritance was confirmed by a two-generation pedigree analysis based on Sanger sequencing results. Conclusions The nonsense mutation in SH2D1A (NM_002351.4:c.300T>A) was reported for the first time in a case of XLP1 and was considered to be likely pathogenic based on the truncation of the mRNA sequence. This finding expands the spectrum of known XLP-related mutations in Chinese patients and indicates the utility of amplicon sequencing for XLP and HLH diagnosis. Electronic supplementary material The online version of this article (10.1186/s12881-018-0576-y) contains supplementary material, which is available to authorized users.

Background Fusion genes generated from chromosomal translocation play an important role in hematological malignancies. Detection of fusion genes currently employ use of either conventional RT-PCR methods or fluorescent in situ hybridization (FISH), where both methods involve tedious methodologies and require prior characterization of chromosomal translocation events as determined by cytogenetic analysis. In this study, we describe a real-time quantitative reverse transcription PCR (qRT-PCR)-based multi-fusion gene screening method with the capacity to detect 22 fusion genes commonly found in leukemia. This method does not require pre-characterization of gene translocation events, thereby facilitating immediate diagnosis and therapeutic management. Methods We performed fluorescent qRT-PCR (F-qRT-PCR) using a commercially-available multi-fusion gene detection kit on a patient cohort of 345 individuals comprising 108 cases diagnosed with acute myeloid leukemia (AML) for initial evaluation; remaining patients within the cohort were assayed for confirmatory diagnosis. Results obtained by F-qRT-PCR were compared alongside patient analysis by cytogenetic characterization. Results Gene translocations detected by F-qRT-PCR in AML cases were diagnosed in 69.4% of the patient cohort, which was comparatively similar to 68.5% as diagnosed by cytogenetic analysis, thereby demonstrating 99.1% concordance. Overall gene fusion was detected in 53.7% of the overall patient population by F-qRT-PCR, 52.9% by cytogenetic prediction in leukemia, and 9.1% in non-leukemia patients by both methods. The overall concordance rate was calculated to be 99.0%. Fusion genes were detected by F-qRT-PCR in 97.3% of patients with CML, followed by 69.4% with AML, 33.3% with acute lymphoblastic leukemia (ALL), 9.1% with myelodysplastic syndromes (MDS), and 0% with chronic lymphocytic leukemia (CLL). Conclusions We describe the use of a F-qRT-PCR-based multi-fusion gene screening method as an efficient one-step diagnostic procedure as an effective alternative to lengthy conventional diagnostic procedures requiring both cytogenetic analysis followed by targeted quantitative reverse transcription (qRT-PCR) methods, thus allowing timely patient management.

The Sachdev-Ye-Kitaev (SYK) model is a concrete solvable model to study non-Fermi liquid properties, holographic duality and maximally chaotic behavior. In this work, we consider a generalization of the SYK model that contains two SYK models with different number of Majorana modes coupled by quadratic terms. This model is also solvable, and the solution shows a zero-temperature quantum phase transition between two non-Fermi liquid chaotic phases. This phase transition is driven by tuning the ratio of two mode numbers, and a Fermi liquid non-chaotic phase sits at the critical point with equal mode number. At finite temperature, the Fermi liquid phase expands to a finite regime. More intriguingly, a different non-Fermi liquid phase emerges at finite temperature. We characterize the phase diagram in term of the spectral function, the Lyapunov exponent and the entropy. Our results illustrate a concrete example of quantum phase transition and critical regime between two non-Fermi liquid phases., 5 pages, 3 figures

Background Long noncoding RNAs (lncRNAs) have emerged as critical regulators in a variety of human cancers, including gastric cancer (GC). However, the function and mechanisms responsible for these molecules in GC are not fully understood. In our previous study, we found that GC associated lncRNA HOXA11-AS is significantly upregulated in GC tissues. Over-expressed HOXA11-AS promotes GC cells proliferation and invasion through scaffolding the chromatin modification factors PRC2, LSD1 and DNMT1. Methods HOXA11-AS expression levels in GC cells was detected by quantitative real-time PCR (qPCR). HOXA11-AS siRNAs and overexpression vector were transfected into GC cells to down-regulate or up-regulate HOXA11-AS expression. In vitro and in vivo assays were performed to investigate the functional role of HOXA11-AS in GC cells cell cycle progression, invasion and metastasis. RIP and ChIP assays were used to determine the mechanism of HOXA11-AS’s regulation of underlying targets. Results We found that knockdown of HOXA11-AS induced GC cells G0/G1 phase arrest and suppressed GC cells migration, invasion and metastasis in vivo. Moreover, mechanistic investigation showed that HOXA11-AS could interact with WDR5 and promote β-catenin transcription, bind with EZH2 and repress P21 transcription, and induce KLF2 mRNA degradation via interacting with STAU1. Conclusions Taken together, these findings show that HOXA11-AS not only could promote GC cells migration and invasion in vitro, but also promotes GC cells metastasis in vivo, at least in part, by regulating β-catenin and KLF2. Electronic supplementary material The online version of this article (doi:10.1186/s12943-017-0651-6) contains supplementary material, which is available to authorized users.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) which originated from peptidergic neurons of the digestive tract and neuroendocrine cells constitute a rare and heterogeneous group of tumors with varied biology. Because of the concealment of symptoms in mostly nonfunctional GEP-NENs, the difficult early diagnosis challenging reduced the chances of curative surgery, and decreased patients’ survival. This study analyzed 73 patients diagnosed with nonfunctional GEP-NENs between July 2004 and May 2015, including the clinical characteristics, treatment outcome and survival of patients, which aimed to prepare a practical guide to be used in common clinical practice. SPSS 17.0 was use to analyze the statistical significance. The median age of the 73 patients was 58 years, 50 were men. 5 patients were classified as NEN G1 (n=5; 6.8%), 6 were G2 (n=6; 8.2%), 43 were neuroendocrine carcinoma (NEC) (n=43; 58.9%), and 19 were MANEC (n=19; 26.0%). Most cases were diagnosed with III-IV tumors at presentation (n=42; 57.5%), although the majority of well-differentiated GEP-NENs (G1 and G2) were diagnosed with earlier stage I and II (n=7; 70%). Operation based on comprehensive treatment were performed in most patients (n=64; 87.7%), while the other 9 cases underwent radiotherapy or chemotherapy simply. The median follow-up period was 37 months. The overall 3-year and 5-year survival were 76.9% and 40.5%. In the univariate analysis, higher stage according to the AJCC/UICC classification (P

Tet methylcytosine dioxygenase 2 (TET2) mutations occur frequently in myelodysplastic syndromes (MDS), but its prognostic impact has not been fully assessed and was controversial. Therefore, we performed a meta-analysis to evaluate the prognostic significance of TET2 mutations in MDS. PubMed, EMBASE databases and Cochrane Library were searched for studies reporting TET2 mutations and overall survival in MDS. Hazard ratios (HR) with 95% confidence interval (CI) were determined using random-effect modeling. A total of 1494 patients from nine studies were subjected to meta-analysis. The frequency of TET2 mutations was 18.34% (274/1494) in the study. MDS with TET2 mutations had similar overall survival compared to patients without the mutations (hazard ratio 1.13, 95% CI: 0.81-1.5).Our findings suggest that TET2 mutations have no prognosis impact on OS of patients with MDS. Therefore, the status of TET2 mutations cannot be served as a prognostic marker in MDS.

Background BCR-ABL1 fusion proteins contain constitutively active tyrosine kinases that are potential candidates for targeted therapy with tyrosine kinase inhibitors such as imatinib in chronic myeloid leukemia (CML). However, uncharacterized BCR-ABL1 fusion genes can be missed by quantitative RT-PCR (qRT-PCR)-based routine screening methods, causing adverse effect on drug selection and treatment outcome. Case presentation In this study, we demonstrated that the next-generation sequencing (NGS) can be employed to overcome this obstacle. Through NGS, we identified a novel BCR-ABL1 fusion gene with breakpoints in the BCR intron 14 and the ABL1 intron 2, respectively, in a rare case of CML. Its mRNA with an e14a3 junction was then detected using customized RT-PCR followed by Sanger sequencing. Subsequently, the patient received targeted medicine imatinib initially at 400 mg/day, and later 300 mg/day due to intolerance reactions. With this personalized treatment, the patient’s condition was significantly improved. Interestingly, this novel fusion gene encodes a fusion protein containing a compromised SH3 domain, which is usually intact in the majority of CML cases, suggesting that dysfunctional SH3 domain may be associated with altered drug response and unique clinicopathological manifestations observed in this patient. Conclusion We identified a novel BCR-ABL1 fusion gene using NGS in a rare case of CML while routine laboratory procedures were challenged, demonstrating the power of NGS as a diagnostic tool for detecting novel genetic mutations. Moreover, our new finding regarding the novel fusion variant will provide useful insights to improve the spectrum of the genomic abnormalities recognizable by routine molecular screening.

The idea of the out-of-time-order correlator (OTOC) has recently emerged in the study of both condensed matter systems and gravitational systems. It not only plays a key role in investigating the holographic duality between a strongly interacting quantum system and a gravitational system, but also diagnoses the chaotic behavior of many-body quantum systems and characterizes the information scrambling. Based on the OTOCs, three different concepts -- quantum chaos, holographic duality, and information scrambling -- are found to be intimately related to each other. Despite of its theoretical importance, the experimental measurement of the OTOC is quite challenging and so far there is no experimental measurement of the OTOC for local operators. Here we report the measurement of OTOCs of local operators for an Ising spin chain on a nuclear magnetic resonance quantum simulator. We observe that the OTOC behaves differently in the integrable and non-integrable cases. Based on the recent discovered relationship between OTOCs and the growth of entanglement entropy in the many-body system, we extract the entanglement entropy from the measured OTOCs, which clearly shows that the information entropy oscillates in time for integrable models and scrambles for non-intgrable models. With the measured OTOCs, we also obtain the experimental result of the butterfly velocity, which measures the speed of correlation propagation. Our experiment paves a way for experimentally studying quantum chaos, holographic duality, and information scrambling in many-body quantum systems with quantum simulators.

This study aimed to identify the underlying therapeutic targets of angiotensin II (AngII)-induced hypertension, and screen the related drugs. The gene expression profiles of GSE93579 and GSE75815 were used to identify differentially expressed genes (DEGs) between AngII-induced hypertension and control samples based on meta-analysis. These DEGs were analyzed using Gene-Ontology (GO) function and pathway enrichment methods. Subsequently, the weighed gene coexpression network analysis (WGCNA)-based meta-analysis was applied to determine transcriptional signature with DEGs. Additionally, the functions of the modules were analyzed based on the network, and miRNAs were identified. Finally, small molecule drugs correlation with DEGs was identified. In total, 346 upregulated DEGs (e.g., Rgs7 bp) and 360 downregulated DEGs (e.g., Ebf3) were identified between AngII and control samples. In addition, a total of 150 DEGs in the brown, red, and yellow modules with higher correlation coefficient according to WGCNA, were used to construct the coexpression network, including Rgs7 bp and Ebf3, etc. in brown modules. Besides, 3 modules were obtained after the functions of the modules analysis. Moreover, 5 miRNAs were integrated in modules, including miR-124A, miR-524, miR-493, miR-323, and miR-203. Finally, anisomycin was the highest correlation with DEGs. MiR-124a might be involved in the pathogenesis of hypertension via targeting Ebf3 and Rgs7 bp, which possibly represent a novel and effective strategy for treatment of hypertension. Anisomycin might be performed to reduce blood pressure by blocking MAPK signaling pathway.

To investigate the inhibitory effect of arsenic trioxide (As₂O₃) combined with tetradecanoylphorbol acetate (TPA) on the proliferation of Kasumi-1 cell line and its mechanism.Kasumi-1 cells were treated with 200 nmol/L TPA, different concentrations of As₂O₃ alone and combined with 200 nmol/L TPA. The proliferative inhibition rates were determined with CCK-8. Annexin V was adopted to detect apoptosis. Colony formation assay was used to determine the cloning efficiency. Flow cytometry was used to detect the cell differentiation and cell cycle changes. Western blot was employed to detect the expression of P38 and p-P38.The proliferation inhibition rates of Kasumi-1 cells by TPA combined with different concentrations of As₂O₃ (0.2, 2.0 and 20.0 mmol/L)for 48 h were (25.56 ± 7.29)%, (60.63 ± 6.64)%, and (73.37 ± 2.15)%, the apoptosis rates were (61.65 ± 2.62)%, (75.39 ± 1.04)%, and (89.95 ± 1.46)%, and the colony formation rates were (76.17 ± 2.06)%, (38.50 ± 1.87)%, and (18.53 ± 2.20)%, respectively, compared with the different concentrations of As₂O₃ alone groups, the difference was statistically significant (P0.05). Cells treated with both TPA and As₂O₃ expressed more CD11b antigens compared with the cells exposed to As₂O₃ alone. TPA treated Kasumi-1 cells were arrested at G1 phase compared with the control group, while As₂O₃ increased the percentage of Kasumi-1 cells in the G2 phase. Combination treatment increased the expression of p-P38 of Kasumi-1 cells compared with the cells exposed to As₂O₃ alone.TPA can enhance the effect of As₂O₃ on inducing apoptosis and regulating cell cycle, thereby enhancing its anti-leukemia effect.

Chromosomal aberrations are useful in assessing treatment options and clinical outcomes of acute myeloid leukemia (AML) patients. However, 40 ∼ 50% of the AML patients showed no chromosomal abnormalities, i.e., with normal cytogenetics aka the CN-AML patients. Testing of molecular aberrations such as FLT3 or NPM1 can help to define clinical outcomes in the CN-AML patients but with various successes. Goal of this study was to test the possibility of Wilms' tumor 1 (WT1) gene overexpression as an additional molecular biomarker. A total of 103 CN-AML patients, among which 28% had overexpressed WT1, were studied over a period of 38 months. Patient's response to induction chemotherapy as measured by the complete remission (CR) rate, disease-free survival (DFS) and overall survival (OS) were measured. Our data suggested that WT1 overexpression correlated negatively with the CR rate, DFS and OS. Consistent with previous reports, CN-AML patients can be divided into three different risk subgroups based on the status of known molecular abnormalities, i.e., the favorable (NPM1(mt)/no FLT3(ITD)), the unfavorable (FLT3(ITD)) and the intermediate risk subgroups. The WT1 overexpression significantly reduced the CR, DFS and OS in both the favorable and unfavorable groups. As the results, patients with normal WT1 gene expression in the favorable risk group showed the best clinical outcomes and all survived with complete remission and disease-free survival over the 37 month study period; in contrast, patients with WT1 overexpression in the unfavorable risk group displayed the worst clinical outcomes. WT1 overexpression by itself is an independent and negative indicator for predicting CR rate, DFS and OS of the CN-AML patients; moreover, it increases the statistical power of predicting the same clinical outcomes when it is combined with the NPM1(mt) or the FLT3(ITD) genotypes that are the good or poor prognostic markers of CN-AML.

Mitogen-activated protein kinase (MAPK) cascades play essential roles in the transduction of extracellular signals to cytoplasmic and nuclear effectors. The MAPK kinase kinase MEKK2 is essential for activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase 5 (ERK5). These pathways are important for expression of specific cytokine genes in mast cells following cross-linking of the high-affinity IgE receptor (FcepsilonRI). A consequence of ERK5 activation is activation of the transcriptional factor myocyte enhancing factor-2C (MEF2C), leading to increased c-Jun expression. We have investigated the role of MEF2C activation in mast cells and demonstrated that it requires sequential activation of the signaling cascade of MEKK2-MEK5-ERK5. Following phosphorylation of MEF2C, activated MEF2C regulates transcription of c-Jun but not TNF-alpha. Inhibition of ERK5, MEK5 activation or activation of MEKK2-deficient mast cells was associated with inhibition of MEF2C phosphorylation and a decrease in c-Jun expression. Thus, these data define an activation module, MEKK2-MEK5-ERK5-MEF2C in the transcriptional activation of c-Jun in mast cells following FcepsilonRI cross-linking. These results demonstrate the novel and important, MEKK2-dependent role of MEF2C in induction of c-Jun expression in mast cells activated through FcepsilonRI, a pathway distinct from that involving MEKK2-MEK5-ERK5 in the regulation of mast cell cytokine production.

Lad is an SH2 domain-containing adaptor protein that binds MEK kinase 2 (MEKK2), a mitogen-activated protein kinase (MAPK) kinase kinase for the extracellular signal-regulated kinase 5 (ERK5) and JNK pathways. Lad and MEKK2 are in a complex in resting cells. Antisense knockdown of Lad expression and targeted gene disruption of MEKK2 expression results in loss of epidermal growth factor (EGF) and stress stimuli-induced activation of ERK5. Activation of MEKK2 and the ERK5 pathway by EGF and stress stimuli is dependent on Src kinase activity. The Lad-binding motif is encoded within amino acids 228 to 282 in the N terminus of MEKK2, and expression of this motif blocks Lad-MEKK2 interaction, resulting in inhibition of Src-dependent activation of MEKK2 and ERK5. JNK activation by EGF is similarly inhibited by loss of Lad or MEKK2 expression and by blocking the interaction of MEKK2 and Lad. Our studies demonstrate that Src kinase activity is required for ERK5 activation in response to EGF, MEKK2 expression is required for ERK5 activation by Src, Lad and MEKK2 association is required for Src activation of ERK5, and EGF and Src stimulation of ERK5-regulated MEF2-dependent promoter activity requires a functional Lad-MEKK2 signaling complex.