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Symmetry plays a central role in conventional and topological phases of matter, making the ability to optically drive symmetry changes a critical step in developing future technologies that rely on such control. Topological materials, like topological semimetals, are particularly sensitive to a breaking or restoring of time-reversal and crystalline symmetries, which affect both bulk and surface electronic states. While previous studies have focused on controlling symmetry via coupling to the crystal lattice, we demonstrate here an all-electronic mechanism based on photocurrent generation. Using second harmonic generation spectroscopy as a sensitive probe of symmetry changes, we observe an ultrafast breaking of time-reversal and spatial symmetries following femtosecond optical excitation in the prototypical type-I Weyl semimetal TaAs. Our results show that optically driven photocurrents can be tailored to explicitly break electronic symmetry in a generic fashion, opening up the possibility of driving phase transitions between symmetry-protected states on ultrafast timescales.
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Using femtosecond time-resolved x-ray diffraction, we investigated optically excited coherent acoustic phonons in the Weyl semimetal TaAs. The low symmetry of the (112) surface probed in our experiment enables the simultaneous excitation of longitudinal and shear acoustic modes, whose dispersion closely matches our simulations. We observed an asymmetry in the spectral line shape of the longitudinal mode that is notably absent from the shear mode, suggesting a time-dependent frequency chirp that is likely driven by photoinduced carrier diffusion. We argue on the basis of symmetry that these acoustic deformations can transiently alter the electronic structure near the Weyl points and support this with model calculations. Our study underscores the benefit of using off-axis crystal orientations when optically exciting acoustic deformations in topological semimetals, allowing one to transiently change their crystal and electronic structures.
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This retrospective analysis was conducted on clinical obtained DCE-MR images of 198 patients, age from 21 to 79 years(45.5±13.7). The CBAM-ResNet model was developed to perform the classification automatically at the image-level based on deep learning method using the pathological examination as the reference standard,then the classification result of each individual patient was obtained by ensemble learning. The proposed method can have an accuracy of 82.69% for correctly distinguishing between benign and malignant breast tumors at the slice-level based on CBAM-ResNet model and with a sensitivity of 85.67%.. After the voting mechanism is applied, the classification accuracy can reach up to 88.24% at the patient-level with a sensitivity of 87.50%. Our experimental results demonstrated the proposed approach have a high classification accuracy.
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Inteligencia Artificial , Neoplasias de la Mama , Adulto , Anciano , Neoplasias de la Mama/diagnóstico por imagen , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Objective: To evaluate the medium-and long-term outcomes of cardiac assist devices after coronary artery bypass grafting (CABG) in patients with left ventricular dysfunction. Methods: From January 2012 to May 2018, a total of 127 patients with low left ventricular ejection fraction (LVEF) value (≤40%) undergoing CABG in the Department of Cardiovascular Surgery of the First Affiliated Hospital of Zhengzhou University were selected. Meanwhile, another 2 454 cases with LVEF>55% were also enrolled as controls. Clinical data of intra-aortic balloon pump (IABP) and extracorporeal membrane oxygenation (ECMO) application were compared and analyzed. All patients were followed up at the Outpatient Clinic at different time points (3 and 6 months after surgery, then every year). Results: Compared to the control group, IABP usage (10.2% vs 0.8%), ECMO usage (6.3% vs 0.3%) and the mortality (4.7% vs 0.7%) were higher (all P<0.05) in the left ventricular dysfunction group. Additionally, Intensive Care Unit stay [(50±12) h vs (33±10) h] and the hospital stay after surgery [(15±3) d vs (11±4) d] was longer in the left ventricular dysfunction group (all P<0.05). In the left ventricular dysfunction group, LVEF at 3, 6 month and 1 year was (48±8)%, (51±9)%, and (55±9)%, respectively, and then maintained stable. Conclusions: Patients with left ventricular dysfunction who received coronary artery bypass grafting had a high rate of cardiac assist devicesuse, however, optimal perioperative management can save the lives of some patients, whose medium-and long-term outcome are good. Therefore, it is worthy of being recommended in clinical practice.
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Disfunción Ventricular Izquierda , Función Ventricular Izquierda , Puente de Arteria Coronaria , Humanos , Contrapulsador Intraaórtico , Estudios Retrospectivos , Volumen Sistólico , Resultado del TratamientoRESUMEN
We investigate polarization-dependent ultrafast photocurrents in the Weyl semimetal TaAs using terahertz (THz) emission spectroscopy. Our results reveal that highly directional, transient photocurrents are generated along the noncentrosymmetric c axis regardless of incident light polarization, while helicity-dependent photocurrents are excited within the ab plane. This is consistent with earlier static photocurrent experiments, and demonstrates on the basis of both the physical constraints imposed by symmetry and the temporal dynamics intrinsic to current generation and decay that optically induced photocurrents in TaAs are inherent to the underlying crystal symmetry of the transition metal monopnictide family of Weyl semimetals.
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We present an infrared spectroscopy study of ZrTe_{5}, which confirms a recent theoretical proposal that this material exhibits a temperature-driven topological quantum phase transition from a weak to a strong topological insulating state with an intermediate Dirac semimetal state around T_{p}≃138 K. Our study details the temperature evolution of the energy gap in the bulk electronic structure. We found that the energy gap closes around T_{p}, where the optical response exhibits characteristic signatures of a Dirac semimetal state, i.e., a linear frequency-dependent optical conductivity extrapolating to the origin (after subtracting a weak Drude response). This finding allows us to reconcile previous diverging reports about the topological nature of ZrTe_{5} in terms of a variation of T_{p} that depends on the crystal growth condition.
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We discover a pair of spin-polarized surface bands on the (111) face of grey arsenic by using angle-resolved photoemission spectroscopy (ARPES). In the occupied side, the pair resembles typical nearly-free-electron Shockley states observed on noble-metal surfaces. However, pump-probe ARPES reveals that the spin-polarized pair traverses the bulk band gap and that the crossing of the pair at Γ[over ¯] is topologically unavoidable. First-principles calculations well reproduce the bands and their nontrivial topology; the calculations also support that the surface states are of Shockley type because they arise from a band inversion caused by crystal field. The results provide compelling evidence that topological Shockley states are realized on As(111).
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We demonstrate a TE/TM polarization-independent plasmonic subtractive color filtering scheme employing ultrathin two-dimensional Ag nanodisks. These TE/TM polarization-independent subtractive color filters exhibit small feature sizes (below 200 nm) and high transmission up to 70% in the visible spectral region, superior to previously reported plasmonic color filters. Simulated optical transmission spectra and colors are in good agreement with experimental results. The color-filtering behaviors strongly depend on thickness and period of nanodisks. Underlying mechanisms are also discussed in detail.
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OBJECTIVE: To study the expression of ALK protein in pulmonary adenocarcinoma as detected by Ventana immunohistochemistry, with correlation of clinicopathologic features. METHODS: Immunohistochemical study for ALK protein using Ventana ALK (D5F3) kit was carried in 7 371 pulmonary adenocarcinoma samples. The clinicopathologic features were subsequently analyzed. RESULTS: ALK fusion protein was detected in 446 of the 7 371 lung adenocarcinoma samples studied (6.05%). The ALK positivity rate in small biopsy samples was higher than that in surgical specimens [9.02% (153/1 696) versus 5.16% (293/5 675); P<0.01]. ALK fusion protein expression correlated with patient age, sample type and smoking history. ALK positivity rate in each age group increased with younger patient age. ALK positivity rate was 45.45% (10/22) in patients younger than 30 years old. The positivity rate of ALK fusion protein in adenocarcinoma in-situ, minimally invasive adenocarcinoma and invasive adenocarcinoma was 0, 0.48% (2/418) and 5.63% (291/5 165), respectively. The differences of ALK positivity rate amongst different subtypes had statistical significance (P<0.01). Invasive mucinous adenocarcinoma had highest ALK positivity rate, followed by invasive adenocarcinoma with predominantly solid pattern. CONCLUSIONS: ALK fusion protein is more often found in young patients with pulmonary adenocarcinoma, especially in those younger than 30 years old. ALK fusion protein is rarely expressed in early-stage pulmonary adenocarcinoma. Invasive mucinous adenocarcinoma and invasive adenocarcinoma with solid pattern have higher ALK positivity rate than other adenocarcinoma subtypes.
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Adenocarcinoma Mucinoso/enzimología , Adenocarcinoma/enzimología , Neoplasias Pulmonares/enzimología , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Adenocarcinoma Mucinoso/patología , Adulto , Quinasa de Linfoma Anaplásico , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana EdadRESUMEN
We have investigated the spin texture of surface Fermi arcs in the recently discovered Weyl semimetal TaAs using spin- and angle-resolved photoemission spectroscopy. The experimental results demonstrate that the Fermi arcs are spin polarized. The measured spin texture fulfills the requirement of mirror and time-reversal symmetries and is well reproduced by our first-principles calculations, which gives strong evidence for the topologically nontrivial Weyl semimetal state in TaAs. The consistency between the experimental and calculated results further confirms the distribution of chirality of the Weyl nodes determined by first-principles calculations.
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OBJECTIVE: Perioperative anxiety and depression syndrome (PADS) is a common clinical concern among women with systemic tumors. Esketamine has been considered for its potential to alleviate anxiety and depressive symptoms. However, its specific application and effectiveness in PADS among women with systemic tumors remain unclear. This study aimed to analyze the utility of Machine Learning (ML) algorithms based on electroencephalogram (EEG) signals in evaluating perioperative anxiety and depression in women with systemic tumors treated with Esketamine, utilizing a large-scale medical data background. PATIENTS AND METHODS: A single-center, randomized, placebo-controlled (SC-RPC) trial design was adopted. A total of 112 female patients with systemic tumors and PADS who received Esketamine treatment were included as study participants. A moderate dose (0.7 mg/kg) of Esketamine was administered through intravenous infusion over a duration of 60 minutes. EEG signals were collected from all patients, and the EEG signal features of individuals with depression were compared to those without depression. In this study, a Support Vector Machine (SVM)-K-Nearest Neighbour (KNN) hybrid classifier was constructed based on SVM and KNN algorithms. Using the EEG signals, the classifier was utilized to assess the anxiety and depression status of the patients. The predictive performance of the classifier was evaluated using accuracy, sensitivity, and specificity measures. RESULTS: The C2 correntropy feature of the delta rhythm in the left-brain EEG signal was significantly higher in individuals with depression compared to those without depression (p<0.05). Moreover, the C2 correntropy feature of the Alpha, Beta, and Gamma rhythms in the left-brain EEG signal was significantly lower in individuals with depression compared to those without depression (p<0.05). In the right brain EEG signal, the C2 correntropy feature of the delta rhythm was significantly higher in individuals with depression (p<0.05), while the C2 correntropy feature of the alpha and gamma rhythms was significantly lower in individuals with depression compared to those without depression (p<0.05). Additionally, the C1 correntropy feature of the Gamma rhythm in the right brain EEG signal was significantly higher in individuals with depression compared to those without depression (p<0.05). The SVM classifier achieved accuracy, sensitivity, and specificity of 98.23%, 98.10%, and 98.56%, respectively, in recognizing the left-brain EEG signals, with a correlation coefficient of 0.95. In recognizing the right brain EEG signals, the SVM classifier achieved accuracy, sensitivity, and specificity of 98.74%, 98.43%, and 99.03%, respectively, with a correlation coefficient of 0.96. The improved SVM-KNN approach yielded an accuracy, recall, precision, F-score, area over the curve (AOC), and Receiver Operation Characteristics (ROC) of 0.829, 0.811, 0.791, 0.853, 0.787, and 0.877, respectively, in predicting anxiety. For predicting depression, the accuracy, recall, precision, F-score, AOC, and ROC were 0.869, 0.842, 0.831, 0.893, 0.827, and 0.917, respectively. CONCLUSIONS: Significant differences were observed in the brain EEG signals between individuals with depression and those without depression. The improved SVM-KNN algorithm developed in this study demonstrates good predictive capability for anxiety and depression.
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Macrodatos , Ketamina , Neoplasias , Femenino , Humanos , Depresión/diagnóstico , Depresión/tratamiento farmacológico , Ritmo Gamma , Ansiedad/diagnóstico , Ansiedad/tratamiento farmacológico , SíndromeRESUMEN
Genomic imprinting and DNA methylation play an important role in mammalian development. Many cloned animals showed heterogeneous DNA methylation profiles. However, there are fewer reports in cloned lambs because of a lack of genomic imprinting information. In this study, we investigated DNA methylation patterns in CpG islands and differentially methylated regions of putative imprinted gene Peg10 and imprinted genes Dlk1, Igf2R and H19 in cloned lambs. Five organs from two cloned lambs died shortly after birth and two normal controls were investigated. We observed normal DNA methylation profiles in cloned lambs. The imprinted genes Dlk1, Igf2R and H19 in livers, kidneys, hearts, muscles and lungs of the two cloned lambs exhibited relatively normal DNA methylation, except for Peg10 showing some differences between controls and cloned lambs. Our results indicate that somatic cell nuclear transfer-produced sheep exhibited relatively normal DNA methylation pattern and experienced normal DNA methylation reprogramming at imprinted loci.
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Clonación de Organismos/veterinaria , Metilación de ADN/fisiología , Ovinos/genética , Ovinos/fisiología , Animales , Secuencia de Bases , Islas de CpG , Impresión Genómica , Datos de Secuencia Molecular , Técnicas de Transferencia Nuclear , Reacción en Cadena de la PolimerasaRESUMEN
OBJECTIVE: Proliferative vitreoretinopathy (PVR) is a complex ocular disease that leads to detached retinas and irreversible vision loss. The epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells plays a critical role in PVR occurrence. However, the core targets driven by the EMT process that lead to the pathogenesis of PVR remain unclear. In our study, the relationship between embryonic stem cell-expressed Ras (ERas) and EMT in RPE cells was investigated. PATIENTS AND METHODS: The subretinal and epiretinal membrane specimens of human PVR were examined for ERas and hallmarks of autophagy and EMT using Western blotting and immunofluorescence. EMT was induced by transforming growth factor (TGF)-ß1 or epidermal growth factor (EGF) in ARPE-19 cells. Autophagy was inhibited by U0126 or bafilomycin A1 in ARPE-19 cells. RESULTS: ERas was decreased and the classical autophagy biomarker microtubule associated protein 1 light chain 3 alpha (LC3) was upregulated in the subretinal and epiretinal membranes of PVR patients in vivo. Moreover, ERas was downregulated and autophagy was activated in RPE ARPE-19 cells in response to transforming growth factor (TGF)-ß1 and epidermal growth factor (EGF) induction. Finally, overexpression of ERas in RPE cells inhibited autophagy via impaired formation of autophagosomes and lysosomes. CONCLUSIONS: Our study revealed the role of ERas in the pathogenesis of PVR through EMT and provided a novel therapeutic target for PVR prevention and treatment.
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Proliferación Celular/fisiología , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Proteína Oncogénica p21(ras)/metabolismo , Pigmentos Retinianos/metabolismo , Vitreorretinopatía Proliferativa/metabolismo , Adulto , Anciano , Autofagia/fisiología , Células Cultivadas , Células Epiteliales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína Oncogénica p21(ras)/antagonistas & inhibidores , Vitreorretinopatía Proliferativa/patologíaRESUMEN
OBJECTIVE: The purpose of this study was to illustrate the role of NAA10 in aggravating the malignant progression of renal cell carcinoma (RCC) by upregulating UPK1B. PATIENTS AND METHODS: NAA10 levels in RCC tissues and paracancerous tissues were detected. Thereafter, the potential relationship between NAA10 level and clinical parameters of RCC patients was analyzed. After knockdown of NAA10, changes in proliferative potential of 786-O and Caki-1 cells were examined by cell counting kit-8 (CCK-8), colony formation and 5-Ethynyl-2'-deoxyuridine (EdU) assay. Finally, the regulatory role of NAA10 in the downstream gene UPK1B and the involvement of UPK1B in the development of RCC were determined via rescue experiments. RESULTS: NAA10 was upregulated in RCC tissues than paracancerous tissues. Tumor staging was much worse in RCC patients expressing a higher level of NAA10. Knockdown of NAA10 inhibited proliferative potential and downregulated UPK1B in RCC cells. Besides, NAA10 level was identified to be positively linked to UPK1B level in RCC tissues. At last, overexpression of UPK1B was able to abolish the inhibitory effect of silenced NAA10 on RCC proliferation. CONCLUSIONS: NAA10 level is closely linked to tumor staging and poor prognosis in RCC patients. NAA10 aggravates the malignant progression of RCC by upregulating UPK1B and may be a specific biomarker in RCC.
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Carcinoma de Células Renales/metabolismo , Neoplasias Renales/metabolismo , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/metabolismo , Uroplaquina Ib/metabolismo , Carcinoma de Células Renales/patología , Proliferación Celular , Células Cultivadas , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa E N-Terminal/genética , Uroplaquina Ib/genéticaRESUMEN
OBJECTIVE: Lung cancer is the leading cause of cancer death in the world and microRNAs (miRNA) have been found to be involved in the initiation and development of cancer by acting as potential oncogenes or tumor suppressor genes. PATIENTS AND METHODS: In this study, we investigated the expression of miR-34b in non-small cell lung cancer (NSCLC) patients and discussed the molecular mechanism of miR-34b in the invasion and migration of A549 cells in vitro. RESULTS: Our results showed that miR-34b was significantly down-regulated in primary cancer tissues when compared with the normal lung tissues. The over-expression of miR-34b inhibited migration and invasion, and promoted apoptosis of A549 lung cancer cells. Furthermore, Luciferase reporter assay validated YY1-associated factor 2 (YAF2) as a direct target of miR-34b and YAF2 expression was significantly increased in clinical NSCLC tissue samples. In addition, the over-expression of miR-34b inhibited YAF2, p-Jak2, p-STAT3 and MMP2 protein expression and promoted caspase 3 protein expression in cancer cells. CONCLUSIONS: Our results suggest that miR-34b may inhibit migration and invasion of NSCLC cells by targeting YAF2. Thus, our findings provide new insight into the molecular mechanisms of lung cancer metastasis and miR-34b may serve as a potential target in the treatment of human lung cancer.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , MicroARNs/genética , Proteínas Musculares/genética , Proteínas Represoras/genética , Células A549 , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Janus Quinasa 2/metabolismo , Neoplasias Pulmonares/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
Objective: To evaluate the effect of different insertion angles on the osseointegration of loaded microscrews in beagle jaws. Methods: Forty-eight microscrews were inserted at four different angles (30°, 50°, 70° and 90°) into the interradicular zones between the mandibular first molar and third premolar in twelve beagles and the microscrews had been loaded with a force of 2 N immediately for 8 weeks. After microscrew-bone specimens fixed, the maximum output value (Fmax) of pull-out test was recorded and the histomorphological changes of hard tissue were observed. The bone-implant contact (BIC%) was quantitatively analyzed and the osseointegration of microscrew-bone interface was comprehensively evaluated. Results: Both Fmax and BIC% values of microscrews were influenced by the insertion angles. The maximum value of Fmax was (385±23) N in the group with 50° angle, and the minimum value was (198±16) N in the group with 30° angle(P <0.05). The maximum value of BIC% was (59.1±6.0)% in the group with 70° angle, and the minimum value was (30.2±3.2)% in the group with 30° angle (P <0.05). Histomorphology observation revealed that in peri-screws region, the various degree of bone remodeling was found in different angle samples. Conclusions: The insertion angles (50°and 70°) were favorable to the stability of the microscrew.
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Diente Premolar , Tornillos Óseos , Diente Molar , Oseointegración , Animales , Remodelación Ósea , Implantes Dentales , Humanos , MaxilaresRESUMEN
Strong coupling between discrete phonon and continuous electron-hole pair excitations can induce a pronounced asymmetry in the phonon line shape, known as the Fano resonance. This effect has been observed in various systems. Here we reveal explicit evidence for strong coupling between an infrared-active phonon and electronic transitions near the Weyl points through the observation of a Fano resonance in the Weyl semimetal TaAs. The resulting asymmetry in the phonon line shape, conspicuous at low temperatures, diminishes continuously with increasing temperature. This behaviour originates from the suppression of electronic transitions near the Weyl points due to the decreasing occupation of electronic states below the Fermi level (EF) with increasing temperature, as well as Pauli blocking caused by thermally excited electrons above EF. Our findings not only elucidate the mechanism governing the tunable Fano resonance but also open a route for exploring exotic physical phenomena through phonon properties in Weyl semimetals.
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Recently, theoretical studies show that layered HfTe5 is at the boundary of weak &strong topological insulator (TI) and might crossover to a Dirac semimetal state by changing lattice parameters. The topological properties of 3D stacked HfTe5 are expected hence to be sensitive to pressures tuning. Here, we report pressure induced phase evolution in both electronic &crystal structures for HfTe5 with a culmination of pressure induced superconductivity. Our experiments indicated that the temperature for anomaly resistance peak (Tp) due to Lifshitz transition decreases first before climbs up to a maximum with pressure while the Tp minimum corresponds to the transition from a weak TI to strong TI. The HfTe5 crystal becomes superconductive above ~5.5 GPa where the Tp reaches maximum. The highest superconducting transition temperature (Tc) around 5 K was achieved at 20 GPa. Crystal structure studies indicate that HfTe5 transforms from a Cmcm phase across a monoclinic C2/m phase then to a P-1 phase with increasing pressure. Based on transport, structure studies a comprehensive phase diagram of HfTe5 is constructed as function of pressure. The work provides valuable experimental insights into the evolution on how to proceed from a weak TI precursor across a strong TI to superconductors.
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OBJECTIVE: In this study, we analyzed features of 256-slice spiral CT bronchial artery imaging in common pathological types of central-type lung cancer to provide a reference for clinical diagnosis. PATIENTS AND METHODS: 74 patients diagnosed as central-type lung cancer were selected. They included 34 cases of squamous carcinoma and 40 cases of non-squamous carcinoma. 256-slice spiral CT bronchial artery imaging examination was performed for patients in the two groups. The 3D reconstruction technique was used in a stand-alone workstation, using different rotation axis to observe space anatomical details of the bronchial artery and to compare development ratio of the bronchial artery, artery diameter, diameter of tumor and developing condition of the pulmonary artery. RESULTS: It was found that left side, right side and both sides developing ratios of a bronchial artery in the squamous carcinoma group were higher than the other group. Moreover, the average diameter of the artery and diameter of the tumor was significantly higher than non-squamous carcinoma group. The occurrence rates of compression and narrowing on the pulmonary arterial branch at tumor side were significantly increased (p<0.05). CONCLUSIONS: There were different 256-slice spiral CT bronchial artery imaging results for different pathological types of central-type lung cancer, which has a certain reference value for clinical diagnosis.
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Arterias Bronquiales , Neoplasias Pulmonares , Carcinoma de Células Escamosas , Humanos , Arteria Pulmonar , Tomografía Computarizada EspiralRESUMEN
We report a comparative polarized Raman study of Weyl semimetals TaAs, NbAs, TaP and NbP. The evolution of the phonon frequencies with the sample composition allows us to determine experimentally which atoms are mainly involved for each vibration mode. Our results confirm previous first-principles calculations indicating that the A1, B1(2), E(2) and E(3) modes involve mainly the As(P) atoms, the B1(1) mode is mainly related to Ta(Nb) atoms, and the E(1) mode involves both kinds of atoms. By comparing the energy of the different modes, we establish that the B1(1), B1(2), E(2) and E(3) become harder with increasing chemical pressure. This behaviour differs from our observation on the A1 mode, which decreases in energy, in contrast to its behaviour under external pressure.