Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study.

BACKGROUND: Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. PATIENTS AND METHODS: Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. CONCLUSION: In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.

Low-dose CT of paediatric paranasal sinus using an ultra-low tube voltage (70 kVp) combined with the flash technique.

AIM: To evaluate the radiation dose and diagnostic image quality of low-dose computed tomography (CT) of the paranasal sinus in children, with acquisition at an ultra-low tube voltage (70 kVp) combined with the Flash technique. MATERIALS AND METHODS: Eighty paediatric patients underwent CT of the paranasal sinus and were divided into two groups according to different protocols (group A: 80 kVp protocol with conventional spiral mode [n=40] and group B: 70 kVp protocol with Flash scan mode [n=40]). For each examination, the CT dose index (CTDIvol), dose-length product (DLP), and effective dose (ED) were estimated. The image noise, signal-to-noise ratio (SNR), and overall subjective diagnostic image quality were also evaluated. RESULTS: For radiation dose, the CTDIvol (mGy), DLP (mGy·cm), and ED (mSv) values of the 70 kVp protocol were significantly lower than those of the 80 kVp protocol (CTDIvol: 1.57±0.009 versus 0.39±0.004 mGy, p<0.001; DLP: 19.88±2.01 versus 6.31±0.52 mGy·cm, p<0.001; ED: 0.079±0.016 versus 0.024±0.005 mSv, p<0.001). Compared with those of the 80-kVp protocol, the image noise increased by 40.7% (p=0.113), the SNRsoft-tissue decreased by 48.9%, and the SNRbone increased by 10.1% with the 70-kVp protocol (p=0.176 and 0.227, respectively). There was no significant difference in the overall subjective image quality grades between these two groups (p=0.15). CONCLUSION: When imaging the paranasal sinus in children, an ultra-low tube voltage (70 kVp) combined with the Flash CT technique can reduce the radiation dose significantly while maintaining diagnostic image quality with clinically acceptable image noise.

LncRNA FOXC2-AS1 stimulates proliferation of melanoma via silencing p15 by recruiting EZH2.

OBJECTIVE: The aim of this study was to elucidate the role of FOXC2-AS1 in promoting the proliferative ability and inhibiting apoptosis of melanoma by silencing p15, thereafter regulating the progression of melanoma. PATIENTS AND METHODS: FOXC2-AS1 levels in melanoma patients with or without metastasis and those with the tumor in different stages were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Regulatory effects of FOXC2-AS1 on viability and apoptosis in melanoma cells were assessed, and subcellular distribution of FOXC2-AS1 was analyzed. Subsequently, the interactions of FOXC2-AS1 with EZH2 and SUZ12 were explored by RNA-Binding Protein Immunoprecipitation (RNA-RIP) assay. Through chromatin immunoprecipitation (ChIP) assay, the role of FOXC2-AS1 to regulate p15 transcription by recruiting EZH2 was verified. At last, regulatory effects of FOXC2-AS1/p15 axis on viability and apoptosis in melanoma cells were investigated. RESULTS: It was found that FOXC2-AS1 was upregulated in melanoma tissues, especially those with metastasis or stage II-IV. Melanoma patients expressing high level of FOXC2-AS1 showed worse survival than those with low level. Knockdown of FOXC2-AS1 inhibited viability, and stimulated apoptosis in A375 and sk-mel-110 cells. Besides, P15 level was upregulated in melanoma cells transfected with si-FOXC2-AS1, and FOXC2-AS1 was mainly distributed in cytoplasm. RNA-RIP assay confirmed that FOXC2-AS1 was mainly enriched in anti-EZH2 and aniti-SUZ12. Knockdown of EZH2 could markedly upregulate protein level of p15 in melanoma cells. Furthermore, it was verified that FOXC2-AS1 inhibited p15 transcription via recruiting EZH2, and the knockdown of p15 could partially reverse the regulatory effects of FOXC2-AS1 on viability and apoptosis in melanoma. CONCLUSIONS: FOXC2-AS1 stimulates proliferative ability in melanoma via silencing p15.

Band Dependent Interlayer f-Electron Hybridization in CeRhIn_{5}.

A key issue in heavy fermion research is how subtle changes in the hybridization between the 4f (5f) and conduction electrons can result in fundamentally different ground states. CeRhIn_{5} stands out as a particularly notable example: when replacing Rh with either Co or Ir, antiferromagnetism gives way to superconductivity. In this photoemission study of CeRhIn_{5}, we demonstrate that the use of resonant angle-resolved photoemission spectroscopy with polarized light allows us to extract detailed information on the 4f crystal field states and details on the 4f and conduction electron hybridization, which together determine the ground state. We directly observe weakly dispersive Kondo resonances of f electrons and identify two of the three Ce 4f_{5/2}^{1} crystal-electric-field levels and band-dependent hybridization, which signals that the hybridization occurs primarily between the Ce 4f states in the CeIn_{3} layer and two more three-dimensional bands composed of the Rh 4d and In 5p orbitals in the RhIn_{2} layer. Our results allow us to connect the properties observed at elevated temperatures with the unusual low-temperature properties of this enigmatic heavy fermion compound.

Long noncoding RNA RUSC1-AS-N indicates poor prognosis and increases cell viability in hepatocellular carcinoma.

OBJECTIVE: This study aimed at exploring the expression and prognostic values of a novel long noncoding RNA RUSC1-AS-N in hepatocellular carcinoma (HCC), and to investigate the biological roles of RUSC1-AS-N in HCC cells. PATIENTS AND METHODS: RUSC1-AS-N expression in public available microarray data was analyzed. The expression of RUSC1-AS-N in our cohort containing 66 HCC tissues and paired adjacent non-cancerous hepatic tissues was measured by qRT-PCR. The correlation between RUSC1-AS-N expression and clinicopathological characteristics was evaluated by Pearson χ2-test. The prognostic value of RUSC1-AS-N was analyzed by Kaplan-Meier survival analysis. The biological roles of RUSC1-AS-N on HCC cell viability were evaluated by Glo cell viability assays and Ethynyl deoxyuridine incorporation assays. The effects of RUSC1-AS-N on HCC cell cycle were evaluated by fluorescence-activated cell sorting (FACS) analyses of propidium-iodide (PI) stained cells. The effects of RUSC1-AS-N on HCC cell apoptosis were evaluated by TdT-mediated dUTP nick end-labeling (TUNEL) assays. RESULTS: RUSC1-AS-N is upregulated in HCC tissues and associated with poor prognosis of HCC patients from GSE54238 and GSE40144. In our cohort, we further confirmed the upregulation of RUSC1-AS-N in HCC tissues. High expression of RUSC1-AS-N associates with large tumor size, vein invasion, encapsulation incompletion, advanced BCLC stage, and poor recurrence-free survival and overall survival. Functional assays revealed that RUSC1-AS-N knockdown markedly decreases cell viability, induces cell-cycle arrest and apoptosis of HCC cells. CONCLUSIONS: RUSC1-AS-N is upregulated and acts as an oncogene in HCC. RUSC1-AS-N may be a promising prognostic biomarker and therapeutic target for HCC.

Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects.

Several preclinical studies have reported the rapid antidepressant effects of N-methyl-D-aspartate receptor (NMDAR) antagonists, although the underlying mechanisms are still unclear. Death-associated protein kinase 1 (DAPK1) couples GluN2B subunits at extrasynaptic sites to regulate NMDAR channel conductance. In the present study, we found that chronic unpredictable stress (CUS) induced extracellular glutamate accumulation, accompanied by an increase in the DAPK1-NMDAR interaction, the high expression of DAPK1 and phosphorylated GluN2B at Ser1303, a decrease in phosphorylated DAPK1 at Ser308 and synaptic protein deficits in the rat medial prefrontal cortex (mPFC). CUS also enhanced GluN2B-mediated NMDA currents and extrasynaptic responses that were induced by bursts of high-frequency stimulation, which may be associated with the loss of astrocytes and low expression of glutamate transporter-1 (GLT-1). The blockade of GLT-1 in the mPFC was sufficient to induce depressive-like behavior and cause similar molecular changes. Selective GluN2B antagonist, DAPK1 knockdown by adeno-associated virus-mediated short-hairpin RNA or a pharmacological inhibitor, and the uncoupling of DAPK1 from the NMDAR GluN2B subunit produced rapid antidepressant-like effects and reversed CUS-induced alterations in the mPFC. The inhibition of DAPK1 and its interaction with GluN2B subunit in the mPFC also rescued CUS-induced depressive-like behavior 7 days after treatment. A selective GluN2B antagonist did not have rewarding effects in the conditioned place preference paradigm. Altogether, our findings suggest that the DAPK1 interaction with the NMDAR GluN2B subunit acts as a critical component in the pathophysiology of depression and is a potential target for new antidepressant treatments.

Highly Anisotropic and Twofold Symmetric Superconducting Gap in Nematically Ordered FeSe_{0.93}S_{0.07}.

FeSe exhibits a novel ground state in which superconductivity coexists with a nematic order in the absence of any long-range magnetic order. Here, we report on an angle-resolved photoemission study on the superconducting gap structure in the nematic state of FeSe_{0.93}S_{0.07}, without the complications caused by Fermi surface reconstruction induced by magnetic order. We find that the superconducting gap shows a pronounced twofold anisotropy around the elliptical hole pocket near Z (0, 0, π), with gap minima at the end points of its major axis, while no detectable gap is observed around Γ (0, 0, 0) and the zone corner (π, π, k_{z}). The large anisotropy and nodal gap distribution demonstrate the substantial effects of the nematicity on the superconductivity and thus put strong constraints on current theories.

[The effect of locally injected betamethasone on collagen deposition in benign central airway stenosis].

OBJECTIVE: To assess the effects of locally injected betamethasone on cicatricial tissue hyperplasia in patients with benign central airway stenosis. METHODS: A prospective study was conducted with 2 treatment modalities: conventional interventional(CI)therapy, and CI combined with local betamethasone injection(LBI). The average optical density value of TGF-ß1 and collagen density in the local airway tissues were compared before therapy and 7 d after the CI treatment and the LBI treatment, respectively. RESULTS: Six patients were recruited in this study from May 2013 to June 2015.The results showed significant statistical differences by paired t-test in TGF-ß1: 92±38 vs 164±47(t=-7.984, P=0.000)before and after the CI treatment, respectively; 128±45 vs 78±40 (t=10.055, P=0.000)before and after the LBI treatment, respectively. The collagen density was 91 932±59 520 vs 150 252±76 673(t=-8.105, P=0.000) before and after the CI treatment, respectively; 107 024±54 880 vs 114 038±50 772(t=-0.621, P=0.54) before and after the LBI treatment, respectively.Trend comparisons made before and after the treatments showed significant statistical differences in TGF-ß1(F=712.139, P=0.000) and in the collagen density (F=261.256, P=0.000)between the CI treatment and the LBI treatment groups. CONCLUSIONS: The CI treatment was shown to stimulate the production of TGF-ß1 and the deposition of collagen, while the LBI treatment was shown to reduce the production of TGF-ß1 and alleviate the deposition of collagen from the stimulation of the CI treatment.

G12V Kras mutations in cervical cancer under virtual microscope of molecular dynamics simulations.

Kras mutations and cancers are common and their role in the progression of cancer is well known and elucidated. The present work is searching for the most deleterious mutation of the four found at codon 12 and 13 of Kras in cervical cancers using prediction servers; different servers were used to look into different factors that govern the protein function. The in silico results predicted G12V to be the most devastating; this particular mutation was then subjected to molecular dynamics simulation (MDS) for further analysis. The authors' approach of MDSs helped them to place the native and mutant structure under virtual microscope and observe their dynamics over time. The results generated are enlightening the effect of G12V variation on the dynamics of Kras. The structural variation between the native and mutant Kras over 50 nanoseconds (ns) run varied at every parameter checked and the results are in excellent agreement with the available experimental data.

Signature of Strong Spin-Orbital Coupling in the Large Nonsaturating Magnetoresistance Material WTe2.

We report the detailed electronic structure of WTe2 by high resolution angle-resolved photoemission spectroscopy. We resolved a rather complicated Fermi surface of WTe2. Specifically, there are in total nine Fermi pockets, including one hole pocket at the Brillouin zone center Γ, and two hole pockets and two electron pockets on each side of Γ along the Γ-X direction. Remarkably, we have observed circular dichroism in our photoemission spectra, which suggests that the orbital angular momentum exhibits a rich texture at various sections of the Fermi surface. This is further confirmed by our density-functional-theory calculations, where the spin texture is qualitatively reproduced as the conjugate consequence of spin-orbital coupling. Since the spin texture would forbid backscatterings that are directly involved in the resistivity, our data suggest that the spin-orbit coupling and the related spin and orbital angular momentum textures may play an important role in the anomalously large magnetoresistance of WTe2. Furthermore, the large differences among spin textures calculated for magnetic fields along the in-plane and out-of-plane directions also provide a natural explanation of the large field-direction dependence on the magnetoresistance.

Xpert MTB/RIF Assay for Pulmonary Tuberculosis and Rifampicin Resistance in Children: a Meta-Analysis.

BACKGROUND: The Xpert MTB/RIF assay has been recommended by WHO to replace conventional microscopy, culture, and drug resistance tests. It simultaneously detects both Mycobacterium tuberculosis infection (TB) and resistance to rifampicin (RIF) within two hours. The objective was to review the available research studies on the accuracy of the Xpert MTB/RIF assay for diagnosing pulmonary TB and RIF-resistance in children. METHODS: A comprehensive search of Pubmed and Embase was performed up to October 28, 2014. We identified published articles estimating the diagnostic accuracy of the Xpert MTB/RIF assay in children with or without HIV using culture or culture plus clinical TB as standard reference. QUADAS-2 tool was used to evaluate the quality of the studies. A summary estimation for sensitivity, specificity, diagnostic odds ratios (DOR), and the area under the summary ROC curve (AUC) was performed. Meta-analysis was used to establish the overall accuracy. RESULTS: 11 diagnostic studies with 3801 patients were included in the systematic review. The overall analysis revealed a moderate sensitivity and high specificity of 65% (95% CI: 61 - 69%) and 99% (95% CI: 98 - 99%), respectively, and a pooled diagnostic odds ratio of 164.09 (95% CI: 111.89 - 240.64). The AUC value was found to be 0.94. The pooled sensitivity and specificity for paediatric rifampicin resistance were 94.0% (95% CI: 80.0 - 93.0%) and 99.0% (95% CI: 95.0 - 98.0%), respectively. Hence, the Xpert MTB/RIF assay has good diagnostic and rifampicin performance for paediatric pulmonary tuberculosis. CONCLUSIONS: The Xpert MTB/RIF is sensitive and specific for diagnosing paediatric pulmonary TB. It is also effective in detecting rifamnicin resistance. It can, therefore, be used as an initial diagnostic tool.

Genetic diversity and pathogenicity differentiation of Sclerotinia sclerotiorum on rapeseed (Brassica napus L.) in Anhui Province, China.

The pathogenicity of 47 isolates of Sclerotinia sclerotiorum from oilseed rape (Brassica napus L.) in Anhui, China, was tested by detached leaf inoculation using the susceptible rape cultivar Wanyou-14. All isolates were pathogenic to the cultivar and could be grouped into 3 categories based on the lesion length on the leaves tested: weak pathogenicity type, intermediate pathogenicity type, and strong pathogenicity type. This suggested that there was differentiation in the pathogenicity among the strains tested of S. sclerotiorum. Additionally, the intraspecific DNA polymorphisms among 47 strains of S. sclerotiorum were investigated by screening 40 pairs of inter-simple sequence repeat (ISSR) primers. Unweighted pair-group method with arithmetic average cluster analysis of these ISSR data distinguished all strains from each other and revealed considerable genetic variability among them. These strains were classified into 7 clusters according to their branching in the dendrogram, and partial correlation was observed between the genetic polymorphisms and the pathogenicity of S. sclerotiorum strains.

Angle-resolved photoemission spectroscopy study on the surface states of the correlated topological insulator YbB6.

YbB6 is recently predicted to be a moderately correlated topological insulator, which provides a playground to explore the interplay between correlation and topological properties. With angle-resolved photoemission spectroscopy, we directly observed almost linearly dispersive bands around the time-reversal invariant momenta and with negligible kz dependence, consistent with odd number of surface states crossing the Fermi level in a Z2 topological insulator. Circular dichroism photoemission spectra suggest that these in-gap states possess chirality of orbital angular momentum, which is related to the chiral spin texture, further indicative of their topological nature. The observed insulating gap of YbB6 is about 100 meV, larger than that found by theoretical calculations. Our results present strong evidence that YbB6 is a correlated topological insulator and provide a foundation for further studies of this promising material.

Genetic diversity of Phytophthora capsici (Pythiaceae) isolates in Anhui Province of China based on ISSR-PCR markers.

Phytophthora capsici is a plant pathogenic oomycete that damages numerous crops worldwide. Consequently, interest in research on the genetic structure of this species has grown in recent decades. However, there is little information about P. capsici in eastern China. We investigated the genetic diversity of P. capsici isolates from three large regions of Anhui Province in eastern China based on ISSR-PCR technology. Thirteen random primers were screened and used to amplify DNA from 51 samples. We obtained 158 reproducible ISSR fragments, of which 90% were polymorphic, revealing a high degree of polymorphism among the isolates. Genetic similarity coefficients among all the isolates ranged from 0.56 to 0.94, with a mean of 0.84 based on the ISSR data, indicating a high level of genetic variation in these P. capsici isolates. Cluster analysis using UPGMA indicated that the Anhui isolates were divided into seven groups according to the DNA fingerprints, although there was no correlation between the ISSR group and geographic origin. Isolates from the same location showed no clustering based on the year of sampling. AMOVA partitioned variability among (13.6%) and within populations (86.4%). The gene flow among populations ranged from 2.804 to 4.937, with a mean of 3.545, indicating highly frequent gene exchange. Genetic distances and genetic differentiation were negatively correlated with geographic distances. These results lead us to suggest that this pathogen has considerable evolutionary potential, which will enable it to adapt to and overcome management strategies over time.

TC10ß/CDC42 GTPase activating protein is required for the growth of cortical neuron dendrites.

Neuronal morphogenesis plays an important role in neuronal development. TC10ß/CDC42 GTPase-activating protein (TCGAP) is known to be a brain-enriched multiple domain protein, but its role in neuronal development process remains poorly understood. In the present study, we showed that TCGAP positively regulated dendritic outgrowth and spine formation in developing cortical neurons. Knocking down TCGAP by RNA interference led to a decrease in the overall length of dendrite arbors and the number of dendrite branches both in vitro and in vivo. Overexpressing TCGAP in cultured cortical neurons increased dendritic outgrowth and branching. Moreover, overexpressing TCGAP lead to an increase of spine density while knocking-down TCGAP decreased spine density in vivo. The defect by downregulating TCGAP could be rescued by expressing a knock-down resistant form of TCGAP both in vivo and in vitro. In contrast, neither downregulating nor overexpressing TCGAP had any effect on axonal morphogenesis in primary cortical neuron cultures. Together, our findings suggest that TCGAP regulates neuronal morphogenesis in developing cortical neurons at both early and late stage.

Distinguishing malignant from normal oral tissues using FTIR fiber-optic techniques.

Oral tissue samples were studied using mid-IR fiber-optic attenuated total reflectance spectroscopy and other spectral techniques. The 1745 cm(-1) band, which is assigned to the ester group (C==O) vibration of triglycerides, is a reliable marker that is present in normal tissues but absent or a weak band in malignant oral tissues. Other bands such as C--H stretching bands and the amide bands are also helpful in distinguishing malignant tissues from normal tissues. Subtraction spectra confirmed the above conclusion. In addition, Raman spectroscopic measurements were in agreement with the results observed from FTIR spectra.

[Energy transfer between electric polymer PVK and terbium complex and its transmission electronmicroscope (TME) study].

A chloroform-soluble terbium complex, which is confirmed to be Tb(aspirin)3 phen using element analysis and FT-IR spectroscopy, was synthesized. Photoluminescent investigation on the terbium complex and PVK-terbium complex composite was conducted. Förster energy transfer occurred between the terbium complex and the PVK matrix. There are no overlap between UV spectrum of the complex and the emission spectrum of PVK, however, overlap is observed between the excitation spectrum of the complex and the emission spectrum of PVK. Therefore, we suggest that the necessary condition of Förster energy transfer should be overlap between the excitation (not UV) spectrum of one complex and the emission spectrum of polymer matrix. Further investigation indicates that the emission of PVK can be suppressed at different extents by doping various amount of Tb(aspirin)3 phen into PVK films. The ratio of Tb(aspirin)3 phen: PVK = 1:2 (wt%) are regarded as an optimized ratio for limiting the emission of PVK. TEM images of PVK/Tb(aspirin)3 phen films reveal that nanoparticles of the Tb complex are dispersed in the PVK matrix. The size of the aggregated complex in PVK matrix is 20-30 nm. The film is not homogeneous as dark regions co-exist with light region in the TEM images. This phenomenon may be related to the short lifetime of electroluminescent devices.

Studies of the chlorpheniramine solid-state ion-selective electrode.

An Ag/AgCl solid-state electrode was prepared by using urea-formaldehyde resin as the frame material and KCl powder as the active material. Using the prepared Ag/AgCl solid-state electrode as substrate and chlorpheniramine tetraphenylborate ion-pair complex as the active component, a new type of solid-state chlorpheniramine ion-selective electrode was constructed. The properties of the electrode were studied in detail. The electrode shows a rather good stability and can be used in the potentiometric determination of chlorpheniramine.

[Studies on a new type of all-solid-state atropine ion-selective electrode].

Using urea-formaldehyde resin as frame material and KCl powder as active component, a Ag/AgCl solid state electrode was prepared. Then, using the prepared Ag/AgCl solid state electrode as substrate and atropine tetraphenylborate ion-pair complex as active component, a new type of all-solid-state atropine ion-selective electrode was constructed. The properties of this electrode were studied in detail. The results indicate that the electrode showed good stability and can be used for potentiometric determination of atropine in pharmaceutical preparations.