Hypoxia-induced factor-1 alpha upregulates vascular endothelial growth factor C to promote lymphangiogenesis and angiogenesis in breast cancer patients

Hypoxia-induced factor-1 alpha （HIF-1α） affects many effector molecules and regulates tumor lymphangio- genesis and angiogenesis during hypoxia. The aim of this study was to investigate the role of HIF-1α in the regu- lation of vascular endothelial growth factor C （VEGF-C） expression and its effect on lymphangiogenesis and an- giogenesis in breast cancer. Lymphatic vessel density （LVD）, microvessel density （MVD） and the expressions of HIF-1α and VEGF-C proteins were evaluated by immunohistochemistry in 75 breast cancer samples. There was a significant correlation between HIF-1α and VEGF-C （P = 0.014, r = 0.273, Spearman＇s coefficient of correlation）. HIF-1α and VEGF-C overexpression was significantly correlated with higher LVD （P = 0.003 and P = 0.017, re- spectively）, regional lymph nodal involvement （P = 0.002 and P = 0.004, respectively） and advanced tumor, node, metastasis （TNM） classification （P = 0.001 and P = 0.01, respectively）. Higher MVD was observed in the group expressing higher levels of HIF-1α and VEGF-C （P = 0.033 and P = 0.037, respectively）. Univariate analysis showed shorter survival time in patients expressing higher levels of HIF-1α and VEGF-C. HIF-1α was also found to be an independent prognostic factor of overall survival in multivariate analysis. The results suggest that HIF-1α may affect VEGF-C expression, thus acting as a crucial regulator of lymphangiogenesis and angiogenesis in breast cancer. This study highlights promising potential of HIF- 1α as a therapeutic target against tumor lymph node me- tastasis.

STAT3 mediates resistance of CD44^+CD24^(-/low) breast cancer stem cells to tamoxifen in vitro

We sought to determine whether STAT3 mediated tamoxifen resistance of breast cancer stem cells in vitro.The capacities for mammosphere formation and STAT3 expression of CD44＋CD24-/low MCF-7 and MCF-7 were observed.The CD44＋CD24-/low subpopulation ratio and its sensitivity to adriamycin were analyzed in MCF-7 and TAM resistant（TAM-R） cells.Cell cycle,apoptosis,STAT3 and phospho-STAT3 changes were observed af-ter treatment with tamoxifen.Small interference RNA-mediated knockdown of STAT3 in TAM-R cells was also performed.CD44＋CD24-/low MCF-7 showed higher capacities for mammosphere formation and STAT3 expression than total MCF-7.The CD44＋CD24-/low subpopulation was also upregulated in TAM-R cells with less sensitivity to adriamycin than MCF-7.Cell cycle changes,anti-apoptotic effects and STAT3 changes were also found.Mean-while,the knock-down of STAT3 in TAM-R resulted in an increase in sensitivity to tamoxifen.It is concluded that STAT3 plays an essential role in breast cancer stem cells,which correlated with tamoxifen resistance.

Treatment patterns for adjuvant docetaxel-based chemotherapy in early-stage breast cancer in China：A pooled retrospective analysis of four observational studies

Objective：Adjuvant docetaxel-based chemotherapy is frequently used for operable early breast cancer（EBC）.This study investigated patterns of use of docetaxel（T）in real-life clinical practice in China.Methods：This was a retrospective pooled analysis of the Asia-Pacific Breast Initiatives（APBI）Ⅰ（2006–2008）and Ⅱ（2009–2011）registries,and two Chinese observational studies;BC STATE（2011–2014）and BC Local Registry（2007–2010）.Female Chinese adults（≥18 years）with operable breast cancer treated with docetaxel-based adjuvant chemotherapy were included in the analysis.Patients with metastatic disease were excluded.The primary endpoint was assessment of treatment patterns and patient profiles.A logistic regression analysis was conducted to identify factors associated with choice of adjuvant chemotherapy regimen.Results：Data from 3,020 patients were included.The most frequently used adjuvant regimen was docetaxel/anthracycline combination[n=1,421（47.1%）;of whom 52.0%received T/epirubicin（E）/cyclophosphamide（C）],followed by docetaxel/other[n=705（23.3%）;of whom 72.8%received TC],docetaxel/anthracycline sequential[n=447（14.8%）;of whom 40.9%and 39.6%received 5-Fu/EC-T and EC-T,respectively],and＂other＂[n=447（14.8%）;of whom 91.5%received T].A significant association was found between adjuvant therapy with docetaxel/anthracycline combination and patient weight,menopausal status and estrogen receptor status.Conclusions：Real-world data revealed that docetaxel/anthracycline combination is the most commonly used category of docetaxel-based adjuvant therapy for patients with operable breast cancer in China;of which TEC is the most frequently used regimen.

Diagnostic performance of contrast-enhanced ultrasound and enhanced magnetic resonance for breast nodules

In the current study, we sought to evaluate the diagnostic efficacies of conventional ultrasound（US）, contrastenhanced US（CEUS）, combined US and CEUS and magnetic resonance imaging（MRI） in detecting focal solid breast lesions. Totally 117 patients with 120 BI-RADS category 4A-5 breast lesions were evaluated by conventional US and CEUS, and MRI, respectively. SonoVue was used as contrast agent in CEUS and injected as an intravenous bolus; nodule scan was performed 4 minutes after bolus injection. A specific sonographic quantification software was used to obtain color-coded maps of perfusion parameters for the investigated lesion, namely the time-intensity curve.The pattern of contrast enhancement and related indexes regarding the time-intensity curve were used to describe the lesions, comparatively with pathological results. Histopathologic examination revealed 46 benign and 74 malignant lesions. Sensitivity, specificity, and accuracy of US in detecting malignant breast lesions were 90.14%, 95.92%, and 92.52%, respectively. Meanwhile, CE-MRI showed sensitivity, specificity, and accuracy of 88.73%, 95.92%, and91.67%, respectively. The area under the ROC curve for combined US and CEUS in discriminating benign from malignant breast lesions was 0.936, while that of MRI was 0.923, with no significant difference between them, as well as among groups. The time-intensity curve of malignant hypervascular fibroadenoma and papillary lesions mostly showed a fast-in/fast-out pattern, with no good correlation between them（kappa 〈0.20）. In conclusion, the combined use of conventional US and CEUS displays good agreement with MRI in differentiating benign from malignant breast lesions.

Influence of coronal holes on CMEs in causing SEP events

The issue of the influence of coronal holes （CHs） on coronal mass ejections （CMEs） in causing solar energetic particle （SEP） events is revisited. It is a continuation and extension of our previous work, in which no evident effects of CHs on CMEs in generating SEPs were found by statistically investigating 56 CME events. This result is consistent with the conclusion obtained by Kahler in 2004. We extrapolate the coronal magnetic field, define CHs as the regions consisting of only open magnetic field lines and perform a similar analysis on this issue for 76 events in total by extending the study interval to the end of 2008. Three key parameters, CH proximity, CH area and CH relative position, are involved in the analysis. The new result confirms the previous conclusion that CHs did not show any evident effect on CMEs in causing SEP events.

Exohiss wave enhancement following substorm electron injection in the dayside magnetosphere

Exohiss is a low-frequency structureless whistler-mode emission potentially contributing to the precipitation loss of radiation belt electrons outside the plasmasphere. Exohiss is usually considered the plasmaspheric hiss leaked out of the dayside plasmapause.However, the evolution of exohiss after the leakage has not been fully understood. Here we report the prompt enhancements of exohiss waves following substorm injections observed by Van Allen Probes. Within several minutes, the energetic electron fluxes around 100 keV were enhanced by up to 5 times, accompanied by an up to 10-time increase of the exohiss wave power. These substorm-injected electrons are shown to produce a new peak of linear growth rate in the exohiss band(< 0.1 f_(ce)). The corresponding path-integrated growth rate of wave power within 10° latitude of the magnetic equatorial plane can reach 13.4, approximately explaining the observed enhancement of exohiss waves. These observations and simulations suggest that the substorm-injected energetic electrons could amplify the preexisting exohiss waves.

Spontaneous growth of the reconnection electric field during magnetic reconnection with a guide field:A theoretical model and particle-in-cell simulations

Reconnection electric field is a key element of magnetic reconnection.It quantifies the change of magnetic topology and the dissipation of magnetic energy.In this work,two-dimensional(2D)particle-in-cell(PIC)simulations are performed to study the growth of the reconnection electric field in the electron diffusion region(EDR)during magnetic reconnection with a guide field.At first,a seed electric field is produced due to the excitation of the tearing-mode instability.Then,the reconnection electric field in the EDR,which is dominated by the electron pressure tensor term,suffers a spontaneous growth stage and grows exponentially until it saturates.A theoretical model is also proposed to explain such a kind of growth.The reconnection electric field in the EDR is found to be directly proportional to the electron outflow speed.The time derivative of electron outflow speed is proportional to the reconnection electric field in the EDR because the outflow is formed after the inflow electrons are accelerated by the reconnection electric field in the EDR and then directed away along the outflow direction.This kind of reinforcing process at last leads to the exponential growth of the reconnection electric field in the EDR.

Study on electron stochastic motions in the magnetosonic wave field: Test particle simulations

Using the test particle simulation method, we investigate the stochastic motion of electrons with energy of 300 keV in a monochromatic magnetosonic(MS) wave field. This study is motivated by the violation of the quasi-linear theory assumption, when strong MS waves(amplitude up to ~1 nT) are present in the Earth's magnetosphere. First, electron motion can become stochastic when the wave amplitude exceeds a certain threshold. If an electron initially resonates with the MS wave via bounce resonance, as the bounce resonance order increases, the amplitude threshold of electron stochastic motion increases until it reaches the peak at about the 11 th order in our study, then the amplitude threshold slowly declines. Further, we find that the coexistence of bounce and Landau resonances between electrons and MS waves will significantly reduce the amplitude threshold. In some cases, the electron motion can become stochastic in the field of an MS wave with amplitudes below 1 nT. Regardless, if neither the bounce nor Landau resonance condition is satisfied initially, then the amplitude threshold of stochastic motion shows an increasing trend for lower frequencies and a decreasing trend for higher frequencies, even though the amplitude threshold is always very large(> 5 nT). Our study suggests that electron stochastic motion should also be considered when modeling electron dynamics regulated by intense MS waves in the Earth's magnetosphere.

Locating the source field lines of Jovian decametric radio emissions

Decametric(DAM) radio emissions are one of the main windows through which one can reveal and understand the Jovian magnetospheric dynamics and its interaction with the moons. DAMs are generated by energetic electrons through cyclotron-maser instability. For Io(the most active moon) related DAMs, the energetic electrons are sourced from Io volcanic activities, and quickly trapped by neighboring Jovian magnetic field. To properly interpret the physical processes behind DAMs, it is important to precisely locate the source field lines from which DAMs are emitted. Following the work by Hess et al.(2008, 2010), we develop a method to locate the source region as well as the associated field lines for any given DAM emission recorded in a radio dynamic spectrum by, e.g.,Wind/WAVES or STEREO/WAVES. The field lines are calculated by the state-of-art analytical model, called JRM09(Connerney et al., 2018).By using this method, we may also derive the emission cone angle and the energy of associated electrons. If multiple radio instruments at different perspectives observe the same DAM event, the evolution of its source region and associated field lines is able to be revealed. We apply the method to an Io-DAM event, and find that the method is valid and reliable. Some physical processes behind the DAM event are also discussed.

Effects of electron trapping on nonlinear electron-acoustic waves excited by an electron beam via particle-in-cell simulations

By performing one-dimensional particle-in-cell simulations, the nonlinear effects of electronacoustic(EA) waves are investigated in a multispecies plasma, whose constituents are hot electrons, cold electrons, and beam electrons with immobile neutralized positive ions. Numerical analyses have identified that EA waves with a sufficiently large amplitude tend to trap cold electrons. Because EA waves are dispersive, where the wave modes with different wavenumbers have different phase velocities, the trapping may lead to the mixing of cold electrons. The cold electrons finally get thermalized or heated. The investigation also shows that the excited EA waves give rise to a broad range of wave frequencies, which may be helpful for understanding the broadband-electrostatic-noise spectrum in the Earth’s auroral region.

Reply to Comment by Lamy et al. on “Locating the source field lines of Jovian decametric radio emissions”

Locating the source of decametric(DAM)radio emissions is a key step in the use of remote radio observations to understand the Jovian magnetospheric dynamics and their interaction with the planet’s moons.Wang YM et al.(2020)presented a method by which recorded arc-shaped DAM emissions in the radio dynamic spectra can be used to locate the source of a DAM.An Io-related DAM event on March 14,2014 was used to demonstrate the method.A key parameter in the method is whether the DAM is emitted in the northern or the southern hemisphere;the hemisphere of origin can be determined definitively from the polarization of the emission.Unfortunately,polarization information for the emission on March 14,2014 event was not recorded.Our analysis assumed the source to be in the northern hemisphere.Lamy et al.(2022)argue convincingly that the source was probably in the southern hemisphere.We appreciate the helpful contribution of Lamy et al.(2022)to this discussion and have updated our analysis,this time assuming that the DAM source was in the southern hemisphere.We also explore the sensitivity of our method to another parameter-the height at which the value of fce,max,which is the maximal electron cyclotron frequency reached along the active magnetic flux tube,is adopted.Finally,we introduce our recent statistical study of 68 DAM events,which lays a more solid basis for testing the reliability of our method,which we continue to suggest is a promising tool by which remote radio observations can be used to locate the emission source of Jovian DAMs.

Damped large amplitude oscillations in a solar prominence and a bundle of coronal loops

We investigate the evolutions of two prominences （P1, P2） and two bundles of coronal loops （L1, L2）, observed with SDO/AIA near the east solar limb on 2012 September 22. It is found that there were large-amplitude oscillations in P1 and L1 but no detectable motions in P2 and L2. These transverse oscillations were triggered by a large-scale coronal wave, originating from a large flare in a remote active region behind the solar limb. By carefully comparing the locations and heights of these oscillating and non-oscillating structures, we conclude that the propagating height of the wave is between 50 Mm and 130 Mm. The wave energy deposited in the oscillating prominence and coronal loops is at least of the order of 10-8 erg. Furthermore, local magnetic field strength and Alfv6n speeds are derived from the oscillating periods and damping time scales, which are extracted from the time series of the oscillations. It is demon- strated that oscillations can be used in not only coronal seismology, but also to reveal the properties of the wave.

The regulatory mechanism of rapid lignification for timely anther dehiscence

Anther dehiscence is a crucial event in plant reproduction,tightly regulated and dependent on the lignification of the anther endothecium.In this study,we investigated the rapid lignification process that ensures timely anther dehiscence in Arabidopsis.Our findings reveal that endothecium lignification can be divided into two distinct phases.During Phase Ⅰ,lignin precursors are synthesized without polymerization,while Phase Ⅱ involves simultaneous synthesis of lignin precursors and polymerization.The transcription factors MYB26,NST1/2,and ARF17 specifically regulate the pathway responsible for the synthesis and polymerization of lignin monomers in Phase Ⅱ.MYB26-NST1/2 is the key regulatory pathway responsible for endothecium lignification,while ARF17 facilitates this process by interacting with MYB26.Interestingly,our results demonstrate that the lignification of the endothecium,which occurs within approximately 26 h,is much faster than that of the vascular tissue.These findings provide valuable insights into the regulation mechanism of rapid lignification in the endothecium,which enables timely anther dehiscence and successful pollen release during plant reproduction.

儿童期代谢指标异常及其聚集性与颈动脉内中膜厚度的关联研究

目的探讨儿童期代谢指标异常与颈动脉内中膜厚度(cIMT)的关系。方法采用方便整群抽样的方法,以山东省淄博市桓台县某小学为调查点,于2017年11月至2018年1月进行调查,选取了该学校年龄为6~11岁的所有儿童,所有体测指标、问卷调查和血生化指标变量均完整者共计1 240名。采用协方差分析比较不同代谢指标异常组以及其不同聚集性组之间的cIMT的水平,采用多元线性回归模型分析代谢指标聚集性与cIMT的关系。结果 1 240名调查对象年龄为(8.9±1.5)岁,其中男生657名(53.0%)。异常代谢指标中,腹型肥胖检出率最高,男生和女生中检出率分别为30.9%(203/657)和29.7%(173/583);男、女生cIMT分别为(0.49±0.08)和(0.45±0.07)mm。调整性别、年龄、蔬菜水果、碳酸饮料、睡眠时间、视屏时间和体力活动等因素后,腹型肥胖、血压、甘油三酯和空腹血糖偏高等代谢指标异常与cIMT相关(P值均<0.001)。携带0、1、2和≥3个代谢指标异常儿童的cIMT分别为(0.45±0.07)、(0.48±0.08)、(0.50±0.09)和(0.53±0.08)mm,即cIMT随着代谢指标异常项数的增加而升高(P趋势<0.001)。结论腹型肥胖、血压偏高、甘油三酯偏高和空腹血糖偏高及其聚集性与cIMT相关。

高血压儿童青少年代谢异常指标聚集性与左心室肥厚的关系

目的探讨儿童青少年代谢异常指标与左心室肥厚(LVH)之间的关系,为预防儿童青少年心脏结构损害提供参考依据。方法资料来源于2012年9月至2014年9月开展的国家"十二五"科技支撑计划课题项目"儿童心血管疾病的预警、诊治技术研究"分课题济南调查点,共纳入261名6~17岁高血压中小学生。采用协方差分析探讨代谢异常指标的聚集性对左心室质量指数(LVMI)水平的影响,采用多元Logistic回归模型探讨代谢异常指标聚集性对LVH的影响。结果调整性别、年龄和血压,携带0,1和≥2个代谢异常指标儿童青少年的平均LVMI分别为(33.21±1.85)(38.57±1.19)和(43.00±1.63)g/m^2.7;随着代谢异常指标数量的增加,LVMI水平逐渐增加(P<0.01)。与携带0个代谢异常指标的儿童青少年相比,携带1和≥2个代谢异常指标者罹患LVH的风险增加,OR值及95%CI分别为2.41(1.11~5.23)和4.69(2.05~10.74)。结论代谢异常指标聚集性增加儿童青少年的LVMI水平和罹患LVH的风险。需综合防控相关代谢异常指标,降低儿童青少年早期心脏结构的损害。

Microwave ablation of primary breast cancer inhibits metastatic progression in model mice via activation of natural killer cells

Surgery is essential for controlling the symptoms and complications of stage IV breast cancer.However,locoregional treatment of primary tumors often results in distant progression,including lung metastasis,the most common type of visceral metastasis.As a minimally invasive thermal therapy,microwave ablation(MWA)has been attempted in the treatment of breast cancer,but the innate immune response after MWA has not yet been reported.Using two murine models of stage IV breast cancer,we found that MWA of primary breast cancer inhibited the progression of lung metastasis and improved survival.NK cells were activated after MWA of the primary tumor and exhibited enhanced cytotoxic functions,and the cytotoxic pathways of NK cells were activated.Depletion experiments showed that NK cells but not CD4+or CD8+T cells played a pivotal role in prolonging survival.Then,we found that compared with surgery or control treatment,MWA of the primary tumor induced completely different NK-cell-related cytokine profiles.Macrophages were activated after MWA of the primary tumor and produced IL-15 that activated NK cells to inhibit the progression of metastasis.In addition,MWA of human breast cancer stimulated an autologous NK-cell response.These results demonstrate that MWA of the primary tumor in metastatic breast cancer inhibits metastatic progression via the macrophage/IL-15/NK-cell axis.MWA of the primary tumor may be a promising treatment strategy for de novo stage IV breast cancer,although further substantiation is essential for clinical testing.

Anther Endothecium-Derived Very-Long-Chain Fatty Acids Facilitate Pollen Hydration in Arabidopsis

Dear Editor,Pollen hydration is a prerequisite for pollen germination and sub- sequent pollen tube growth. As a result of two decades of biochemical studies and genetic identification of the eceriferum （cer） male-sterile mutants, the very-long-chain fatty acid （VLCFA） lipids in the pollen coat have been well known to play a critical role in pollen hydration （Preuss et al., 1993; Fiebig et al., 2000; Hiscock and Allen, 2008）.

A cellular mechanism underlying the restoration of thermo/photoperiod-sensitive genic male sterility

During anther development,the transformation of the microspore into mature pollen occurs under the pro-tection of first the tetrad wall and later the pollen wall.Mutations in genes involved in this wall transition often lead to microspore rupture and male sterility;some such mutants,such as the reversible male sterile(rvms)mutant,are thermo/photoperiod-sensitive genic male sterile(P/TGMS)lines.Previous studies have shown that slow development is a general mechanism of P/TGMS fertility restoration.In this study,we iden-tified restorer of rvms-2(res2),which is an allele of QUARTET3(QRT3)encoding a polygalacturonase that shows delayed degradation of the tetrad pectin wall.We found that MS188,a tapetum-specific transcrip-tion factor essential for pollen wall formation,can activate QRT3 expression for pectin wall degradation,indicating a non-cell-autonomous pathway involved in the regulation of the cell wall transition.Further as-says showed that a delay in degradation of the tetrad pectin wall is responsible for the fertility restoration of rvms and other P/TGMS lines,whereas early expression of QRT3 eliminates low temperature restoration of rvms-2 fertility.Taken together,these results suggest a likely cellular mechanism of fertility restoration in P/TGMS lines,that is,slow development during the cell wall transition of P/TGMS microspores may reduce the requirement for their wall protection and thus support their development into functional pollens,leading to restored fertility.

Delayed callose degradation restores the fertility of multiple P/TGMS lines in Arabidopsis

Photoperiod/temperature-sensitive genic male sterility(P/TGMS)is widely applied for improving crop production.Previous investigations using the reversible male sterile(rvms)mutant showed that slow development is a general mechanism for restoring fertility to P/TGMS lines in Arabidopsis.In this work,we isolated a restorer of rvms–2(res3),as the male sterility of rvms–2 was rescued by res3.Phenotype analysis and molecular cloning show that a point mutation in UPEX1 l in res3 leads to delayed secretion of callase A6 from the tapetum to the locule and tetrad callose wall degradation.Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis demonstrated that the tapetal transcription factor ABORTED MICROSPORES directly regulates UPEX1 expression,revealing a pathway for tapetum secretory function.Early degradation of the callose wall in the transgenic line eliminated the fertility restoration effect of res3.The fertility of multiple known P/TGMS lines with pollen wall defects was also restored by res3.We propose that the remnant callose wall may broadly compensate for the pollen wall defects of P/TGMS lines by providing protection for pollen formation.A cellular mechanism is proposed to explain how slow development restores the fertility of P/TGMS lines in Arabidopsis.

Unsteady magnetic reconnection in non-periodic multiple current sheets

The process of magnetic reconnection in non_periodic three_layer current sheets is studied numerically by using two_dimensional magnetohydrodynamic simulation. The results show that unlike periodic current sheets, it is complex unsteady magnetic reconnection. It may be important for solar flare and corona heating.