Proteomic and metabolomic analyses illustrate the mechanisms of expression of the O6 -methylguanine-DNA methyltransferase gene in glioblastoma.

AIM: Glioblastoma (GBM) has been reported to be the most common high-grade primary malignant brain tumor in clinical practice and has a poor prognosis. O6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation has been related to prolonged overall survival (OS) in GBM patients after temozolomide treatment. METHODS: Proteomics and metabolomics were combined to explore the dysregulated metabolites and possible protein expression alterations in white matter (control group), MGMT promoter unmethylated GBM (GBM group) or MGMT promoter methylation positive GBM (MGMT group). RESULTS: In total, 2745 upregulated and 969 downregulated proteins were identified in the GBM group compared to the control group, and 131 upregulated and 299 downregulated proteins were identified in the MGMT group compared to the GBM group. Furthermore, 131 upregulated and 299 downregulated metabolites were identified in the GBM group compared to the control group, and 187 upregulated and 147 downregulated metabolites were identified in the MGMT group compared to the GBM group. The results showed that 94 upregulated and 19 downregulated proteins and 20 upregulated and 16 downregulated metabolites in the MGMT group were associated with DNA repair. KEGG pathway enrichment analysis illustrated that the dysregulated proteins and metabolites were involved in multiple metabolic pathways, including the synthesis and degradation of ketone bodies, amino sugar and nucleotide sugar metabolism. Moreover, integrated metabolomics and proteomics analysis was performed, and six key proteins were identified in the MGMT group and GBM group. Three key pathways were recognized as potential biomarkers for recognizing MGMT promoter unmethylated GBM and MGMT promoter methylation positive GBM from GBM patient samples, with areas under the curve of 0.7895, 0.7326 and 0.7026, respectively. CONCLUSION: This study provides novel mechanisms to understand methylation in GBM and identifies some biomarkers for the prognosis of two different GBM types, MGMT promoter unmethylated or methylated GBM, by using metabolomics and proteomics analyses.

Deep-Learning-Enabled Microwave-Induced Thermoacoustic Tomography Based on ResAttU-Net for Transcranial Brain Hemorrhage Detection.

OBJECTIVE: Hemorrhagic stroke is a leading threat to human's health. The fast-developing microwave-induced thermoacoustic tomography (MITAT) technique holds potential to do brain imaging. However, transcranial brain imaging based on MITAT is still challenging due to the involved huge heterogeneity in speed of sound and acoustic attenuation of human skull. This work aims to address the adverse effect of the acoustic heterogeneity using a deep-learning-based MITAT (DL-MITAT) approach for transcranial brain hemorrhage detection. METHODS: We establish a new network structure, a residual attention U-Net (ResAttU-Net), for the proposed DL-MITAT technique, which exhibits improved performance as compared to some traditionally used networks. We use simulation method to build training sets and take images obtained by traditional imaging algorithms as the input of the network. RESULTS: We present ex-vivo transcranial brain hemorrhage detection as a proof-of-concept validation. By using an 8.1-mm thick bovine skull and porcine brain tissues to perform ex-vivo experiments, we demonstrate that the trained ResAttU-Net is capable of efficiently eliminating image artifacts and accurately restoring the hemorrhage spot. It is proved that the DL-MITAT method can reliably suppress false positive rate and detect a hemorrhage spot as small as 3 mm. We also study effects of several factors of the DL-MITAT technique to further reveal its robustness and limitations. CONCLUSION: The proposed ResAttU-Net-based DL-MITAT method is promising for mitigating the acoustic inhomogeneity issue and performing transcranial brain hemorrhage detection. SIGNIFICANCE: This work provides a novel ResAttU-Net-based DL-MITAT paradigm and paves a compelling route for transcranial brain hemorrhage detection as well as other transcranial brain imaging applications.

Recent Advances in Ferroelectric-Enhanced Low-Dimensional Optoelectronic Devices.

Ferroelectric (FE) materials, including BiFeO3 , P(VDF-TrFE), and CuInP2 S6 , are a type of dielectric material with a unique, spontaneous electric polarization that can be reversed by applying an external electric field. The combination of FE and low-dimensional materials produces synergies, sparking significant research interest in solar cells, photodetectors (PDs), nonvolatile memory, and so on. The fundamental aspects of FE materials, including the origin of FE polarization, extrinsic FE materials, and FE polarization quantification are first discussed. Next, the state-of-the-art of FE-based optoelectronic devices is focused. How FE materials affect the energy band of channel materials and how device structures influence PD performance are also summarized. Finally, the future directions of this rapidly growing field are discussed.

Improved detectivity and response speed of MoS2 phototransistors based on the negative-capacitance effect and defect engineering.

Due to the unique crystal structure, outstanding optoelectronic properties and a tunable band gap from 1.2-1.8 eV, two-dimensional molybdenum disulfide (MoS2) has attracted extensive attention as a promising candidate for future photodetectors. In this work, a negative-capacitance (NC) MoS2 phototransistor is fabricated by using H f 0.5 Z r 0.5 O 2 (HZO) as ferroelectric layer and Al2O3 as matching layer, and a low subthreshold swing (SS) of 39 mV/dec and an ultrahigh detectivity of 3.736×1014 cmHz1/2W-1 are achieved at room temperature due to the NC effect of the ferroelectric HZO. Moreover, after sulfur (S) treatment on MoS2, the transistor obtained a lower SS of 33 mV/dec, a detectivity of 1.329×1014 cmHz1/2W-1 and specially a faster response time of 3-4 ms at room temperature, attributed to the modulation of photogating effect induced by S-vacancy passivation in MoS2 by the S treatment. Therefore, the combination of the defect engineering on MoS2 and the NC effect from ferroelectric thin film could provide an effective solution for high-sensitivity phototransistors based on two-dimensional materials in the future.

Identification of ubiquitin-specific protease 32 as an oncogene in glioblastoma and the underlying mechanisms.

Glioblastoma (GBM) patients present poor prognosis. Deubiquitination by deubiquitinating enzymes (DUBs) is a critical process in cancer progression. Ubiquitin-specific proteases (USPs) constitute the largest sub-family of DUBs. Evaluate the role of USP32 in GBM progression and provide a potential target for GBM treatment. Clinical significance of USP32 was investigated using Gene Expression Omnibus databases. Effects of USP32 on cell growth and metastasis were studied in vitro and in vivo. Differentially expressive genes between USP32-knockdown U-87 MG cells and negative control cells were detected using RNA sequencing and used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomic pathway enrichment analyses. Finally, RT-qPCR was used to validate the divergent expression of genes involved in the enriched pathways. USP32 was upregulated in GBM patients, being correlated to poor prognosis. USP32 downregulation inhibited cell growth and metastasis in vitro. Furthermore, USP32 knockdown inhibited tumorigenesis in vivo. In addition, UPS32 was identified as a crucial regulator in different pathways including cell cycle, cellular senescence, DNA replication, base excision repair, and mismatch repair pathways. USP32 acts as an oncogene in GBM through regulating several biological processes/pathways. It could be a potential target for GBM treatment.

Awake craniotomy for removal of gliomas in eloquent areas: An analysis of 21 cases.

OBJECTIVE: To discuss the techniques and methods in respective operation of brain gliomas located in eloquent brain region under awake anesthesia state METHODS: 21 patients admitted into Department of Neurosurgery of the First Affiliated Hospital of Xiamen University were chosen as subject. Diagnosed with brain gliomas, they received operation with neuronavigation, intraoperative ultrasonography for locating the lesion and intraoperative direct electric stimulation for functional mapping of the eloquent brain region after receiving awake anesthesia. All patients were followed up from post-surgical 3 months to 18 months. RESULTS: Applied with MRI scanning during post-surgical 60-90d, resection results shows that 5 cases (23.8%) received total resection of lesions, 10 cases (47.6%) received subtotal resection while 6 cases (28.6%) received partial resection. Post-surgical performance shows 8 cases (38.1%) of transitory postoperative aphasia, 5 cases(23.8%) of transitory postoperative dyskinesia and 1 case(4.8%) of permanent dyskinesia. Recovery was achieved in the patients except for the 1 case of permanent dyskinesia. CONCLUSIONS: Comprehensive application of awake anesthesia, neuronavigation, intraoperative ultrasonography and intraoperative direct electrical stimulation facilitates recognition of clear position relationship between gliomas and eloquent brain region, and maximum safe resection of gliomas in eloquent brain region with maximal protection of brain function.

Complete Freund's adjuvant-induced protein dysregulation correlated with mirror image pain as assessed by quantitative proteomics of the mouse spinal cord.

Inflammation or trauma occurring on one side of the body can cause pathological pain on the contralateral noninjured side in a phenomenon called mirror-image pain (MIP). Although some potential mechanisms involved in MIP have been reported, including those involving the immune system and glial cells as well as neural mechanisms, the molecular mechanisms are not well understood. In this study, we aimed to understand the molecular mechanisms in MIP using quantitative proteomics and whole-cell patch clamp recordings. Behavioral test results showed that complete Freund's adjuvant could induce MIP in the mice. The results of isobaric tags for relative and absolute quantification (iTRAQ) quantitative proteomics showed that 108 proteins were dysregulated, and these proteins may represent potential targets. Furthermore, bioinformatics analysis was applied to explore the potential molecular mechanisms during MIP after complete Freund's adjuvant (CFA) treatment. Parallel reaction monitoring (PRM) results showed that PKCδ and seven other dysregulated proteins were related to MIP after CFA treatment. Patch clamp recording results showed that CFA treatment could increase intrinsic excitability and spontaneous firing in spinal cord neurons during MIP. In summary, we found that CFA could induce MIP. The results of proteomic research on the spinal cord after CFA treatment could provide new insight into the molecular mechanisms of MIP. Moreover, the neuronal activity of spinal cord neurons was upregulated during MIP after CFA treatment. In summary, the results of the spinal cord proteomic profile provide a potential molecular mechanism for understanding MIP.

Organocatalytic ß,γ-Selective Activation of Deconjugated Butenolides Access to Chiral Tricyclic Chroman-butyrolactones.

A highly efficient method for the ß,γ-selective activation of deconjugated butenolides has been developed through an organocatalytic asymmetric vinylogous cascade reaction. This protocol enables the construction of a broad range of substituted tricyclic chroman-butyrolactones by vinylogous Michael/oxa-Michael pathways in good yield (up to 89%) with good to high enantioselectivity (up to 97:3 er) and excellent diastereoselectivity. The ring-opening esterification of butyrolactones was also demonstrated.

Intensity-dependent angular distribution of low-energy electrons generated by intense high-frequency laser pulse.

By solving the three-dimensional time-dependent Schrödinger equation, we investigate the angular distributions of the low-energy electrons when an intense high-frequency laser pulse is applied to the hydrogen atom. Our numerical results show that the angular distributions of the low-energy electrons which generated by the nonadiabatic transitions sensitively depend on the laser intensity. The angular distributions evolve from a two-lobe to a four-lobe structure as the laser intensity increases. By analyzing nonadiabatic process in the Kramers-Henneberger frame, we illustrate that this phenomenon is attributed to the intensity-dependent adiabatic evolution of the ground state wavefunction. When the laser intensity further increases, the pathway of nonadiabatic transition from the ground state to the excited state and then to the continuum states is non-negligible, which results in the ring-like structure in the photoelectron momentum distribution. The angular distributions of the low-energy electrons provide a way to monitor the evolution of the electron wavefunction in the intense high frequency laser fields.

The Efficacy and Safety of Programmed Death-1 and Programmed Death Ligand 1 Inhibitors for the Treatment of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage where only systemic treatment can be offered. The emergence of immune checkpoint inhibitors (ICIs) provides hope for the treatment of HCC. In this study, we performed a meta-analysis to provide evidence for the efficacy and safety of ICIs in the treatment of HCC. METHODS: The following databases and websites were searched: Embase, PubMed, Cochrane Library and ClinicalTrials.gov. The primary endpoints were response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). RESULTS: Finally, twelve studies were included in this meta-analysis. When the corresponding outcome indicators and their 95% confidence intervals (CIs) were pooled directly, the overall RR, DCR, PFS and OS were 0.17 (0.15-0.19, I2 = 56.2%, P=0.009), 0.58 (0.55-0.61, I2 = 75.9%, P<0.001), 3.27 months (2.99-3.55, I2 = 73.0%, P=0.001), 11.73 months (10.79-12.67, I2 = 90.3%, P<0.001). Compared to the control group, treatment with ICIs significantly improved RR, PFS and OS, the OR and HRs were 3.11 (2.17-4.44, P<0.001), 0.852 (0.745-0.974, P=0.019) and 0.790 (0.685-0.911, P=0.001), respectively. However, no significant improvement in DCR was found in ICIs treatment in this meta-analysis. CONCLUSION: HCC patients would benefit from ICIs treatment, however, more studies are needed in the future to provide more useful evidence for the treatment of HCC by programmed death-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors.

Two-Electron Interference in Strong-Field Ionization of He by a Short Intense Extreme Ultraviolet Laser Pulse.

Double ionization of helium by a single intense (above 10^{18} W/cm^{2}) linearly polarized extreme ultraviolet laser pulse is studied by numerically solving the full-dimensional time-dependent Schrödinger equation. For the laser intensities well beyond the perturbative limit, novel gridlike interference fringes are found in the correlated energy spectrum of the two photoelectrons. The interference can be traced to the multitude of two-electron wave packets emitted at different ionization times. A semianalytical model for the dressed two-photon double ionization is shown to qualitatively account for the interference patterns in the joint energy spectrum. Similar signatures of interferences between transient induced time-delayed ionization bursts are expected for other atomic and molecular multielectron systems.

Photon Momentum Transfer in Single-Photon Double Ionization of Helium.

We theoretically and experimentally investigate the photon momentum transfer in single-photon double ionization of helium at various large photon energies. We find that the forward shifts of the momenta along the light propagation of the two photoelectrons are roughly proportional to their fraction of the excess energy. The mean value of the forward momentum is about 8/5 of the electron energy divided by the speed of light. This holds for fast and slow electrons despite the fact that the energy sharing is highly asymmetric and the slow electron is known to be ejected by secondary processes of shake off and knockout rather than directly taking its energy from the photon. The biggest deviations from this rule are found for the region of equal energy sharing where the quasifree mechanism dominates double ionization.

Low-energy photoelectron interference structure in attosecond streaking.

By numerically solving the time-dependent Schrödinger equation, we theoretically investigate the dynamics of the low-energy photoelectrons ionized by a single attosecond pulse in the presence of an infrared laser field. The obtained photoelectron momentum distributions exhibit complicated interference structures. With the semiclassical model, the originations for the different types of the interference structures are unambiguously identified. Moreover, by changing the time delay between the attosecond pulse and the infrared laser field, these interferences could be selectively enhanced or suppressed. This enables us to extract information about the ionization dynamics encoded in the interference structures. As an example, we show that the phase of the electron wave-packets ionized by the linearly and circularly polarized attosecond pulses can be extracted from the interference structures of the direct and the near-forward rescattering electrons.

Dynamic interference as signature of atomic stabilization.

We study the ionization of atoms by very intense linearly polarized pulse with moderately high frequency by numerically solving the time-dependent Schrödinger equation (TDSE). In this regime, the photon energy exceeds the ionization potential allowing for one-photon ionization which is, however, strongly influenced by strong nonlinear photon-atom interactions. We find that the onset of atomic stabilization can be monitored by the appearance of a dynamic interference pattern in the photoelectron spectrum.

Efficient Split-Lanczos propagator for strong-field ionization of atoms.

High angular momentum partial waves are indispensable in the numerical calculations of the time-dependent Schrödinger equation (TDSE) for the interaction between atoms and strong long-wavelength laser pulses. In these cases, the widely-applied Lanczos propagator, used to solve the TDSE, requires an extremely small time step to be convergent. By splitting out the centrifugal potential from the whole Hamiltonian, we demonstrate that the stiffness of the TDSE can be reduced and a rather large time step is allowed for the present Split-Lanczos propagator. Compared with the ordinary Lanczos propagator, the efficiency of the propagation can be improved by more than 100 times for large angular momentum in present tests.

miR-455-5p functions as a potential oncogene by targeting galectin-9 in colon cancer.

Although there is evidence that galectin-9 is a critical factor in health and disease, the upstream regulatory microRNA (miRNA or miR) of the protein remains poorly defined. miR-455-5p is characterized as a tumor-associated miRNA in cancer research. However, the actual role of miR-455-5p with respect to inhibiting or promoting tumorigenesis in colon cancer is unclear. The present study aimed to investigate the expression, role and target regulation association of galectin-9 and miR-455-5p in colon cancer. Western blot analysis and reverse transcription-quantitative polymerase chain reaction were used for the detection of the expression levels of galectin-9 and miRNAs. Cell Counting kit-8 test was used for the evaluation of cell proliferation, while flow cytometry was used for cell apoptosis analysis. A potential interaction between galectin-9 and miR-455-5p was predicted by target prediction programs and confirmed by luciferase assay and transfection with miRNA mimics. The present study revealed that elevated expression of galectin-9 and miR-455-5p in colon cancer was associated with HT29 cell proliferation and apoptosis. Furthermore, the present study demonstrated that miR-455-5p reduced galectin-9 expression by directly targeting its 3'-untranslated region. These data suggest that miR-455-5p functions as a potential oncogene in colon cancer by targeting galectin-9.

Association between FOXP3 gene polymorphisms and risk of differentiated thyroid cancer in Chinese Han population.

BACKGROUND: Foxp3 plays important roles in autoimmune and inflammatory diseases as well as human malignancies. This study aimed to investigate the association between Foxp3 gene polymorphisms and the susceptibility to differentiated thyroid cancers (DTC). METHODS: Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 350 DTC patients and 306 healthy controls. FOXP3 relative expression was measured by real-time quantitative PCR (qRT-PCR). RESULTS: AA/AC genotype of Foxp3-rs3761548 was associated with a higher risk of DTC. The frequency of Foxp3-rs2280883 CC/CT genotype was lower in DTC patients. Besides, the AA/AC genotype of rs3761548 was more frequent in female DTC than male DTC. The association between two single nucleotide polymorphisms (SNPs) and clinical characteristics of DTC was further analyzed. We found that rs3761548 AA/AC genotype was more frequent in severe DTC patients (tumor diameter >1 cm) compared with the relative tender DTC patients (tumor diameter <1 cm). On the contrast, the frequency of rs2280883 CC/CT genotype was lower in severe DTC patients. In addition, the Foxp3 relative expression in DTC with AA/AC genotype of rs3761548 was higher than that of DTC with CC genotype. CONCLUSION: Our findings suggested that Foxp3 polymorphisms were associated with the risk of DTC in Chinese Han population.

Role of PALB2 Polymorphisms with Regard to Susceptibility to Female Breast Cancer Risk in the Chinese Population.

AIMS: PALB2 (partner and localizer of BRCA2) is a nuclear partner of BRCA2 and promotes its localization and stability in the nucleus, allowing it to function in DNA repair and at the S-phase checkpoint. It has been hypothesized that polymorphisms in the PALB2 gene may be associated with tumorigenesis, particularly with respect to susceptibility to breast cancer. METHODS: To assess the association of polymorphisms in the PALB2 gene with breast cancer risk in a Chinese female population a total of 351 female breast cancer patients and 360 age-, gender-matched tumor-free individuals were enrolled in this case-control study. The genotypes of five PALB2 gene polymorphic sites (rs120963, rs16940342, rs249954, rs447529, and rs249935) were characterized by using the Sequenom MassARRAY platform. RESULTS: The data showed that the genotypes rs249954 CT (adjusted odds ratio [OR] = 1.52; 95% confidence interval [95% CI], 1.10-2.09), TT (adjusted OR = 2.36; 95% CI, 1.39-4.02), and CT/TT (adjusted OR = 1.65; 95% CI, 1.22-2.24) were associated with increased risk of breast cancer, respectively, relative to the CC genotype. Similarly, the rs120963 TC (adjusted OR = 1.89; 95% CI, 1.38-2.59), CC (adjusted OR = 3.88; 95% CI, 1.75-8.60), and TC/CC (adjusted OR = 2.05; 95% CI, 1.51-2.78) genotypes were associated with increased risk of breast cancer, respectively, relative to the TT genotype. Additionally, a weakly significant association was observed between G allele (AG/GG genotype) carriers of the rs249935 SNP in the sub-group of T1-2 (Adjusted OR = 1.43; 95% CI, 1.03-10.84) and negative lymphatic involvement (Adjusted OR = 3.23; 95% CI, 0.97-10.84) and risk of breast cancer. CONCLUSIONS: This case-control study provided evidence that rs120963 and rs249954 of the PALB2 gene are associated with increased breast cancer risk, and that the association of rs249935 with breast cancer risk may be modified by the tumor pathological characteristics.

Serum miR-21, miR-26a and miR-101 as potential biomarkers of hepatocellular carcinoma.

AIM: This study aimed to investigate the expressions of serum miR-21, miR-26a and miR-101 in hepatocellular carcinoma (HCC) and their diagnostic value. METHODS: Serum levels of miR-21, miR-26a and miR-101 were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in 52 HCC patients, 42 chronic hepatitis (CH) patients and 43 healthy controls. ROC curve analysis was performed to evaluate the diagnostic value. Clinical parameters were collected. RESULTS: Serum level of miR-21 was higher while miR-26a and miR-101 were significantly lower in HCC patients than those in healthy controls (P<0.05, P<0.001 and P<0.05, respectively). Serum levels of miR-26a and miR-101 were significantly lower in HCC patients than those in CH patients (P<0.001 and P<0.05). ROC curve analyses revealed that miR-21, miR-26a and miR-101 could differentiate HCC patients from healthy controls, the area under ROC curve (AUC) were 0.621 (67.4% sensitivity and 55.8% specificity), 0.754 (51.9% sensitivity and 95.2% specificity) and 0.631 (47.1% sensitivity and 81% specificity), respectively. Combination of miRNAs and alpha-fetoprotein (AFP) yielded an AUC of 0.914 with 87.0% sensitivity and 78.0% specificity. miR-26a and miR-101 had diagnostic potential for differentiating HCC from CH with AUC of 0.762 (75% sensitivity and 70% specificity) and 0.623 (54.9% sensitivity and 76.9% specificity). Combination of miR-26a, miR-101 and AFP yielded an improved AUC than AFP alone (0.854 vs. 0.683). Notably, miR-26a could differentiate small tumors HCC (≤3cm) from CH with an AUC of 0.753 (80% sensitivity and 62.5% specificity). CONCLUSIONS: Serum miR-21, miR-26a and miR-101 are deregulated in HCC and can serve as potential biomarkers. Combination of these miRNAs and AFP provide a better detection than AFP alone. Serum miR-26a is a promising biomarker for early detection of HCC.

Virtual Sequential Picture for Nonsequential Two-Photon Double Ionization of Helium.

By using a model based on the second-order time-dependent perturbation theory, we show that the nonsequential two-photon double ionization of He can be understood in a virtual sequential picture: to excite the final double continuum state |k_{1},k_{2}⟩ by absorbing two photons from the ground state |1s^{2},^{1}S_{0}⟩, the single continuum states |1s,k_{1}⟩ and |1s,k_{2}⟩ serve as the dominant intermediate states. This virtual sequential picture is verified by the perfect agreement of the total ionization cross section, respectively, calculated by this model and by the sophisticated numerical solution to the full-dimensional time-dependent Schrödinger equation. This model, without the consideration of the electron correlation in the final double continuum state, works well for a wide range of laser parameters extending from the nonsequential to the sequential regime. The present Letter demonstrates that the electron correlation in the final double continuum state is not important in evaluating the total cross section, while it is indispensable for an accurate computation of a triply differential cross section. In addition, the virtual sequential picture bridges the sequential and nonsequential two-photon double ionization and reveals connections and distinctions between them.