Blockade of the Phagocytic Receptor MerTK on Tumor-Associated Macrophages Enhances P2X7R-Dependent STING Activation by Tumor-Derived cGAMP.

Clearance of apoptotic cells by macrophages prevents excessive inflammation and supports immune tolerance. Here, we examined the effect of blocking apoptotic cell clearance on anti-tumor immune response. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulation of apoptotic cells within tumors and triggered a type I interferon response. Treatment of tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergized with anti-PD-1 or anti-PD-L1 therapy. The anti-tumor effect induced by anti-MerTK treatment was lost in Stinggt/gt mice, but not in Cgas-/- mice. Abolishing cGAMP production in Cgas-/- tumor cells, depletion of extracellular ATP, or inactivation of the ATP-gated P2X7R channel also compromised the effects of MerTK blockade. Mechanistically, extracellular ATP acted via P2X7R to enhance the transport of extracellular cGAMP into macrophages and subsequent STING activation. Thus, MerTK blockade increases tumor immunogenicity and potentiates anti-tumor immunity, which has implications for cancer immunotherapy.

Terahertz parametric amplification as a reporter of exciton condensate dynamics.

Condensates are a hallmark of emergence in quantum materials such as superconductors and charge density waves. Excitonic insulators are an intriguing addition to this library, exhibiting spontaneous condensation of electron-hole pairs. However, condensate observables can be obscured through parasitic coupling to the lattice. Here we employ nonlinear terahertz spectroscopy to disentangle such obscurants through measurement of the quantum dynamics. We target Ta2NiSe5, a putative room-temperature excitonic insulator in which electron-lattice coupling dominates the structural transition (Tc = 326 K), hindering identification of excitonic correlations. A pronounced increase in the terahertz reflectivity manifests following photoexcitation and exhibits a Bose-Einstein condensation-like temperature dependence well below the Tc, suggesting an approach to monitor the exciton condensate dynamics. Nonetheless, dynamic condensate-phonon coupling remains as evidenced by peaks in the enhanced reflectivity spectrum at select infrared-active phonon frequencies, indicating that parametric reflectivity enhancement arises from phonon squeezing. Our results highlight that coherent dynamics can drive parametric stimulated emission.

13-Oxyingenol-dodecanoate inhibits the growth of non-small cell lung cancer cells by targeting ULK1.

Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. Euphorbia kansui yielded 13-oxyingenol-dodecanoate (13OD), an ingenane-type diterpenoid, which had a strong cytotoxic effect on NSCLC cells. The underlying mechanism and potential target, however, remained unknown. The study found that 13OD effectively inhibited the cell proliferation and colony formation of NSCLC cells (A549 and H460 cells), with less toxicity in normal human lung epithelial BEAS-2B cells. Moreover, 13OD can cause mitochondrial dysfunction, and apoptosis in NSCLC cells. Mechanistically, the transcriptomics results showed that differential genes were mainly enriched in the mTOR and AMPK signaling pathways, which are closely related to cellular autophagy, the related indicators were subsequently validated. Additionally, bafilomycin A1 (Baf A1), an autophagy inhibitor, reversed the mitochondrial damage caused by 13OD. Furthermore, the Omics and Text-based Target Enrichment and Ranking (OTTER) method predicted ULK1 as a potential target of 13OD against NSCLC cells. This hypothesis was further confirmed using molecular docking, the cellular thermal shift assay (CETSA), and Western blot analysis. Remarkably, ULK1 siRNA inhibited 13OD's toxic activity in NSCLC cells. In line with these findings, 13OD was potent and non-toxic in the tumor xenograft model. Our findings suggested a possible mechanism for 13OD's role as a tumor suppressor and laid the groundwork for identifying targets for ingenane-type diterpenoids.

The classical D1 dopamine receptor antagonist SCH23390 is a functional sigma-1 receptor allosteric modulator.

SCH23390 is a widely used D1 dopamine receptor (D1R) antagonist that also elicits some D1R-independent effects. We previously found that the benzazepine, SKF83959, an analog of SCH23390, produces positive allosteric modulation of the Sigma-1 receptor (Sig1R). SCH23390 does not bind to the orthodoxic site of Sig1R but enhances the binding of 3H (+)-pentazocine to Sig1R. In this study, we investigated whether SCH23390 functions as an allosteric modulator of Sig1R. We detected increased Sig1R dissociation from binding immunoglobulin protein (BiP) and translocation of Sig1R to the plasma membrane in response to SCH23390 in transfected HEK293T and SH-SY5Y cells, respectively. Activation of Sig1R by SCH23390 was further confirmed by inhibition of GSK3ß activity in a time- and dose-dependent manner; this effect was blocked by pretreatment with the Sig1R antagonist, BD1047, and by knockdown of Sig1R. SCH23390 also inhibited GSK3ß in wild-type mice but not in Sig1R knockout mice. Finally, we showed that SCH23390 allosterically modulated the effect of the Sig1R agonist SKF10047 on inhibition of GSK3ß. This positive allosteric effect of SCH23390 was further confirmed via promotion of neuronal protection afforded by SKF10047 in primary cortical neurons challenged with MPP+. These results provide the first evidence that SCH23390 elicits functional allosteric modulation of Sig1R. Our findings not only reveal novel pharmacological effects of SCH23390 but also indicate a potential mechanism for SCH23390-mediated D1R-independent effects. Therefore, attention should be paid to these Sig1R-mediated effects when explaining pharmacological responses to SCH23390.

GMMAD: a comprehensive database of human gut microbial metabolite associations with diseases.

BACKGROUND: The natural products, metabolites, of gut microbes are crucial effect factors on diseases. Comprehensive identification and annotation of relationships among disease, metabolites, and microbes can provide efficient and targeted solutions towards understanding the mechanism of complex disease and development of new markers and drugs. RESULTS: We developed Gut Microbial Metabolite Association with Disease (GMMAD), a manually curated database of associations among human diseases, gut microbes, and metabolites of gut microbes. Here, this initial release (i) contains 3,836 disease-microbe associations and 879,263 microbe-metabolite associations, which were extracted from literatures and available resources and then experienced our manual curation; (ii) defines an association strength score and a confidence score. With these two scores, GMMAD predicted 220,690 disease-metabolite associations, where the metabolites all belong to the gut microbes. We think that the positive effective (with both scores higher than suggested thresholds) associations will help identify disease marker and understand the pathogenic mechanism from the sense of gut microbes. The negative effective associations would be taken as biomarkers and have the potential as drug candidates. Literature proofs supported our proposal with experimental consistence; (iii) provides a user-friendly web interface that allows users to browse, search, and download information on associations among diseases, metabolites, and microbes. The resource is freely available at http://guolab.whu.edu.cn/GMMAD . CONCLUSIONS: As the online-available unique resource for gut microbial metabolite-disease associations, GMMAD is helpful for researchers to explore mechanisms of disease- metabolite-microbe and screen the drug and marker candidates for different diseases.

Treatment outcomes and prognosis of patients with primary and acquired BRAF-mutated non-small cell lung cancer: A multicenter retrospective study.

The incidence of primary and acquired BRAF mutations is low in non-small cell lung cancer (NSCLC), with limited demographic and treatment outcome data available for this patient population. We evaluated lung cancer samples with programmed cell death ligand 1 (PD-L1) information extracted from 12 051 cases (cohort A) of lung cancer from OncoPanscan™-based sequencing of tissue (Genetron Health) and conducted retrospective multicenter data analysis using the database of Zhejiang Cancer Hospital and four other centers (cohort B, including 73 primary BRAF mutation and 14 acquired BRAF mutation cases) to compare treatment outcomes of patient groups with primary and acquired BRAF mutations. In cohort A, after propensity score analysis, 165 samples of NSCLC with BRAF mutations were screened along with 165 paired non-BRAF mutation samples. We observed no significant differences in the proportion of samples with ≥1% PD-L1 between BRAF and non-BRAF mutant groups. The median progression-free survival (mPFS) period in 13 patients with primary BRAF mutations receiving BRAF tyrosine kinase inhibitors (BRAF-TKIs) was 7.0 months. The group with primary BRAF mutations receiving immune checkpoint inhibitor (ICI) combination chemotherapy had better PFS than those administered ICI monotherapy (14.77 months vs. 5.0 months, p = 0.025) and similar results were obtained for OS (unreached vs. 20.3 months, p = 0.013). For acquired BRAF mutations, mPFS of BRAF-TKI, ICI-based, and chemotherapy-based regimens were 3.8, 1.5, and 1.9 months, respectively. Therefore, for patients with the primary BRAF V600E mutation, targeted therapy or immunochemotherapy could serve as effective treatment choices, while for those with acquired BRAF V600E, targeted drug therapy may remain the preferred solution in China.

Clinical validation of a 90-gene expression test for tumor tissue of origin diagnosis: a large-scale multicenter study of 1417 patients.

BACKGROUND: Once malignancy tumors were diagnosed, the determination of tissue origin and tumor type is critical for clinical management. Although the significant advance in imaging techniques and histopathological approaches, the diagnosis remains challenging in patients with metastatic and poorly differentiated or undifferentiated tumors. Gene expression profiling has been demonstrated the ability to classify multiple tumor types. The present study aims to assess the performance of a 90-gene expression test for tumor classification (i.e. the determination of tumor tissue of origin) in real clinical settings. METHODS: Formalin-fixed paraffin-embedded samples and associated clinicopathologic information were collected from three cancer centers between January 2016 and January 2021. A total of 1417 specimens that met quality control criteria (RNA quality, tumor cell content ≥ 60% and so on) were analyzed by the 90-gene expression test to identify the tumor tissue of origin. The performance was evaluated by comparing the test results with histopathological diagnosis. RESULTS: The 1417 samples represent 21 main tumor types classified by common tissue origins and anatomic sites. Overall, the 90-gene expression test reached an accuracy of 94.4% (1338/1417, 95% CI: 0.93 to 0.96). Among different tumor types, sensitivities were ranged from 74.2% (head&neck tumor) to 100% (adrenal carcinoma, mesothelioma, and prostate cancer). Sensitivities for the most prevalent cancers of lung, breast, colorectum, and gastroesophagus are 95.0%, 98.4%, 93.9%, and 90.6%, respectively. Moreover, specificities for all 21 tumor types are greater than 99%. CONCLUSIONS: These findings showed robust performance of the 90-gene expression test for identifying the tumor tissue of origin and support the use of molecular testing as an adjunct to tumor classification, especially to those poorly differentiated or undifferentiated tumors in clinical practice.

PEGylation of anti-MerTK Antibody Modulates Ocular Biodistribution.

Here, we explore whether PEGylation of antibodies can modulate their biodistribution to the eye, an organ once thought to be immune privileged but has recently been shown to be accessible to IV-administered large molecules, such as antibodies. We chose to PEGylate an anti-MerTK antibody, a target with known potential for ocular toxicity, to minimize biodistribution to retinal pigment epithelial cells (RPEs) in the eye by increasing the hydrodynamic volume of the antibody. We used site-specific conjugation to an engineered cysteine on anti-MerTK antibody to chemically attach 40-kDa branched or linear PEG polymers. Despite reduced binding to MerTK on cells, site-specifically PEGylated anti-MerTK retained similar potency in inhibiting MerTK-mediated macrophage efferocytosis of apoptotic cells. Importantly, we found that PEGylation of anti-MerTK significantly reduced MerTK receptor occupancy in RPE cells in both naïve mice and MC-38 tumor-bearing mice, with the branched PEG exhibiting a greater effect than linear PEG. Furthermore, similar to unconjugated anti-MerTK, PEGylated anti-MerTK antibody triggered type I IFN response and exhibited antitumor effect in syngeneic mouse tumor studies. Our results demonstrate the potential of PEGylation to control ocular biodistribution of antibodies.

Universal Conductance Scaling of Andreev Reflections Using a Dissipative Probe.

The Majorana search is caught up in an extensive debate about the false-positive signals from nontopological Andreev bound states. We introduce a remedy using the dissipative probe to generate electron-boson interaction. We theoretically show that the interaction-induced renormalization leads to significantly distinct universal zero-bias conductance behaviors, i.e., distinct characteristic power law in temperature, for different types of Andreev reflections, that show a sharp contrast to that of a Majorana zero mode. Various specific cases have been studied, including the cases in which two charges involved in an Andreev reflection process maintain or lose coherence, and the cases for multiple Andreev bound states with or without a Majorana. A transparent list of conductance features in each case is provided to help distinguish the observed subgap states in experiments, which also promotes the identification of Majorana zero modes.

Plateau Regions for Zero-Bias Peaks within 5% of the Quantized Conductance Value 2e

Probing an isolated Majorana zero mode is predicted to reveal a tunneling conductance quantized at 2e^{2}/h at zero temperature. Experimentally, a zero-bias peak (ZBP) is expected and its height should remain robust against relevant parameter tuning, forming a quantized plateau. Here, we report the observation of large ZBPs in a thin InAs-Al hybrid nanowire device. The ZBP height can stick close to 2e^{2}/h, mostly within 5% tolerance, by sweeping gate voltages and magnetic field. We further map out the phase diagram and identify two plateau regions in the phase space. Despite the presence of disorder and quantum dots, our result constitutes a step forward toward establishing Majorana zero modes.

Suppressing Andreev Bound State Zero Bias Peaks Using a Strongly Dissipative Lead.

Hybrid semiconductor-superconductor nanowires are predicted to host Majorana zero modes that induce zero-bias peaks (ZBPs) in tunneling conductance. ZBPs alone, however, are not sufficient evidence due to the ubiquitous presence of Andreev bound states. Here, we implement a strongly resistive normal lead in InAs-Al nanowire devices and show that most of the expected Andreev bound state-induced ZBPs can be suppressed, a phenomenon known as environmental Coulomb blockade. Our result is the first experimental demonstration of this dissipative interaction effect on Andreev bound states and can serve as a possible filter to narrow down the ZBP phase diagram in future Majorana searches.

Diffusion kurtosis imaging as an imaging biomarker for predicting prognosis in chronic kidney disease patients.

BACKGROUND: Renal fibrosis is the strongest prognostic predictor of end-stage renal disease (ESRD) in chronic kidney disease (CKD). Diffusion kurtosis imaging (DKI) is a promising method of magnetic resonance imaging successfully used to assess renal fibrosis in immunoglobulin A nephropathy. This study aimed to be the first to evaluate the long-term prognostic value of DKI in CKD patients. METHODS: Forty-two patients with CKD were prospectively enrolled, and underwent DKI on a clinical 3T MR scanner. We excluded patients with comorbidities that could affect the volume or the components of the kidney. DKI parameters, including mean Kurtosis (K), mean diffusivity and apparent diffusion coefficient (ADC) of kidney cortex were obtained by region-of-interest measurement. We followed up these patients for a median of 43 months and investigated the correlations between each DKI parameter and overall renal prognosis. RESULTS: Both K and ADC values were correlated well with the estimated glomerular filtration rate (eGFR) on recruitment and the eGFR of the last visit in follow-up (P ˂ 0.001). K and ADC values were also well associated with the eGFR slopes in CKD patients, both with the first-last time point slope (P = 0.011 and P ˂ 0.001, respectively) and with the regression slope (P = 0.010 and P ˂ 0.001, respectively). Cox proportional hazard regression indicated that lower eGFR and ADC values independently predicted eGFR loss of ˃30% and ESRD. The receiver operating characteristic analysis showed that K and ADC values were predictable for renal prognosis, and ADC displayed better capabilities for both ESRD [area under the curve (AUC) 0.936, sensitivity 92.31%, specificity 82.76%] and the composite endpoint (eGFR loss ˃30% or ESRD) (AUC 0.881, sensitivity 66.67%, specificity 96.3%). CONCLUSIONS: Renal ADC values obtained from DKI showed significant predictive value for the prognosis of CKD patients, which could be a promising noninvasive technique in follow-up.

[Research Progress of Magnetic Resonance Imaging-based Radiomics in Prostate Cancer].

Radiomics can extract high-throughput and quantitative image features from medical images and mine the information related to the pathophysiology of tumors,which can help clinical decision-making and improve the diagnostic and predictive performance.Radiomics has been widely used in the study of prostate cancer (PCa),demonstrating application values in the diagnosis and differential diagnosis,pathology classification,invasion assessment,efficacy prediction,and prognosis analysis of PCa.Here we reviewed the recent research progress of magnetic resonance imaging-based radiomics in PCa.

[Trans-Douglas Retzius' space-sparing robot-assisted simple prostatectomy for large-volume benign prostate hyperplasia].

OBJECTIVE: To report the safety and efficacy of trans-Douglas Retzius' space-sparing robot-assisted simple prostatectomy (RSS-RASP) in the treatment of large-volume BPH. METHODS: This retrospective study included 24 cases of large-volume (>80 ml) BPH treated by trans-Douglas RSS-RASP from August 2019 to June 2021. The patients ranged in age from 55 to 80 (mean 68.5) years, with an average body mass index of 25.1 (20.5－34.9) kg/m2 , median prostate volume of 132.4 (85.6－235.7) ml, and preoperative tPSA of 10.8 (0.5－37.9) ng/ml, IPSS of 25 (3－35) and quality of life (QOL) score of 5 (3－8). Before surgery, 12 of the patients received catheterization for urinary retention, 1 underwent cystostomy, 2 were complicated with hydronephrosis, 1 had stones and diverticulum in the bladder, and 14 were excluded from the cases of PCa by prostatic biopsy. The operation time, intraoperative blood loss, hemoglobin level on the first day after surgery, blood transfusion, and intra- and postoperative complications were recorded. The patients were followed up for 3 to 21 months postoperatively. Comparisons were made before and after operation in the IPSS, maximum urinary flow rate (Qmax), postvoid residual volume (PVR), QOL score, IIEF score and Male Sexual Health Questionnaire (MSHQ) score. RESULTS: Trans-Douglas RSS-RASP was successfully completed in all the 24 cases, with a mean operation time of 175 (100－285) min, intraoperative blood loss of 200 (50－800) ml, hemoglobin decrease of 25 (4－57) g/L on the first day after surgery, postoperative drainage tube indwelling of 3 (2－7) d, and urinary catheterization of 12 (4－18) d. Six (25%) of the patients received intraoperative blood transfusion, 1 underwent transurethral electrocoagulation hemostasis 1 month after surgery because of postoperative bleeding, and 1 received transurethral resection of the cicatrical adhesive tissue of the bladder neck 12 months after surgery. No other complications occurred postoperatively. The IPSS (3 ［1－7］), Qmax (19.6 ［9.9－32.1］ ml/s), PVR (0 ［0－34.9］ ml) and QOL score (2 ［0－3］) of the patients were significantly improved after surgery (P < 0.05), but no statistically significant differences were observed in the IIEF (20 ［19－24］) and MSHQ scores (14 ［13－14］) as compared with the baseline (P > 0.05). CONCLUSION: Trans-Douglas RSS-RASP is a safe and effective minimally invasive method for the treatment of large-volume (>80 ml) BPH, which can improve the urinary function of the patient after operation.

New perspectives on the laser initiation for metal tetrazine complexes: a theoretical study.

In order to understand the relationship between laser initiation and charge transfer of metal tetrazine complexes (MTCs), several sets of MTCs with different metals and ligands were designed and their charge transfer (CT) characters were examined using a time-dependent density functional theory method (TD-DFT) in combination with UV-vis spectra, hole-electron distribution, interfragment charge transition, and transition density matrix analyses. Results show that Fe(II), Mn(II), and Cu(II) are suitable divalent transition metal cores in constructing the optical initiation tetrazine complexes. By replacing the divalent metal cores with a monovalent center, new sets of complexes are proved to possess metal-to-ligand charge transfer (MLCT) character and stronger absorption intensity in the near-infrared (NIR) region, which implies that monovalent MTCs are more in favor of low-energy laser initiation than divalent MTCs. Reasonable tuning of the structure of pyrazole substituent can expect to enhance the explosive performance while preserving the optical characteristics, which is an important design principle. This work thoroughly depicts the photoactive states for MTCs and gives a train of thought to explore new desirable laser initiation explosives.

Radiomics Based on MRI as a Biomarker to Guide Therapy by Predicting Upgrading of Prostate Cancer From Biopsy to Radical Prostatectomy.

BACKGROUND: Biopsy Gleason score (GS) is crucial for prostate cancer (PCa) treatment decision-making. Upgrading in GS from biopsy to radical prostatectomy (RP) puts a proportion of patients at risk of undertreatment. PURPOSE: To develop and validate a radiomics model based on multiparametric magnetic resonance imaging (mp-MRI) to predict PCa upgrading. STUDY TYPE: Retrospective, radiomics. POPULATION: A total of 166 RP-confirmed PCa patients (training cohort, n = 116; validation cohort, n = 50) were included. FIELD STRENGTH/SEQUENCE: 3.0T/T2 -weighted (T2 W), apparent diffusion coefficient (ADC), and dynamic contrast enhancement (DCE) sequences. ASSESSMENT: PI-RADSv2 score for each tumor was recorded. Radiomic features were extracted from T2 W, ADC, and DCE sequences and Mutual Information Maximization criterion was used to identify the optimal features on each sequence. Multivariate logistic regression analysis was used to develop predictive models and a radiomics nomogram and their performance was evaluated. STATISTICAL TESTS: Student's t or chi-square were used to assess the differences in clinicopathologic data between the training and validation cohorts. Receiver operating characteristic (ROC) curve analysis was performed and the area under the curve (AUC) was calculated. RESULTS: In PI-RADSv2 assessment, 67 lesions scored 5, 70 lesions scored 4, and 29 lesions scored 3. For each sequence, 4404 features were extracted and the top 20 best features were selected. The radiomics model incorporating signatures from the three sequences achieved better performance than any single sequence (AUC: radiomics model 0.868, T2 W 0.700, ADC 0.759, DCE 0.726). The combined mode incorporating radiomics signature, clinical stage, and time from biopsy to RP outperformed the clinical model and radiomics model (AUC: combined model 0.910, clinical model 0.646, radiomics model 0.868). The nomogram showed good performance (AUC 0.910) and calibration (P-values: training cohort 0.624, validation cohort 0.294). DATA CONCLUSION: Radiomics based on mp-MRI has potential to predict upgrading of PCa from biopsy to RP. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 5 J. Magn. Reson. Imaging 2020;52:1239-1248.

Analysis of the Gynaephora qinghaiensis pupae immune transcriptome in response to parasitization by Thektogaster sp.

As a pest on the Qinghai-Tibet Plateau, Gynaephora qinghaiensis causes severe damage to grassland vegetation and its pupae are also natural hosts of Thektogaster sp. To successfully parasitize, endoparasitoids generally introduce or secrete multiple parasitic factors into the host body during the spawning stage to suppress the host immune response. To study the parasitic effects of Thektogaster sp. on G. qinghaiensis, a transcriptome analysis of immune-related genes in parasitized and nonparasitized G. qinghaiensis pupae was performed. A total of 371,260,704 clean reads were assembled into 118,144 unigenes with an average length of 884.33 base pairs. Of these, 23,660 unigenes were annotated in at least one database and 94,484 unigenes were not annotated in any databases. These findings indicated that the majority of the genetic resources (79.97% of all unigenes) in Gynaephora should be further explored. Parasitization significantly affected the transcriptional profile of G. qinghaiensis pupae. The present study identified 12,322 differentially expressed genes and 57 immune-related genes were identified in parasitized G. qinghaiensis pupae. Most immune-related genes were downregulated, potentially resulting from the inhibitory effect of Thektogaster sp. on G. qinghaiensis pupae after parasitization. Overall, the transcriptome analysis sheds valuable light on the molecular mechanisms of G. qinghaiensis parasitization by Thektogaster sp. and promotes the development of novel biocontrol strategies for Gynaephora based on immune defense.

Investigation of the AQP Family in Soybean and the Promoter Activity of TIP2;6 in Heat Stress and Hormone Responses.

Aquaporins (AQPs) are one diverse family of membrane channel proteins that play crucial regulatory roles in plant stress physiology. However, the heat stress responsiveness of AQP genes in soybean remains poorly understood. In this study, 75 non-redundant AQP encoding genes were identified in soybean. Multiple sequence alignments showed that all GmAQP proteins possessed the conserved regions, which contained 6 trans-membrane domains (TM1 to TM6). Different GmAQP members consisted of distinct Asn-Pro-Ala (NPA) motifs, aromatic/arginine (ar/R) selectivity filters and Froger's positions (FPs). Phylogenetic analyses distinguished five sub-families within these GmAQPs: 24 GmPIPs, 24 GmTIPs, 17 GmNIPs, 8 GmSIPs, and 2 GmXIPs. Promoter cis-acting elements analyses revealed that distinct number and composition of heat stress and hormone responsive elements existed in different promoter regions of GmAQPs. QRT-PCR assays demonstrated that 12 candidate GmAQPs with relatively extensive expression in various tissues or high expression levels in root or leaf exhibited different expression changes under heat stress and hormone cues (abscisic acid (ABA), l-aminocyclopropane-l-carboxylic acid (ACC), salicylic acid (SA) and methyl jasmonate (MeJA)). Furthermore, the promoter activity of one previously functionally unknown AQP gene-GmTIP2;6 was investigated in transgenic Arabidopsis plants. The beta-glucuronidase (GUS) activity driven by the promoter of GmTIP2;6 was strongly induced in the heat- and ACC-treated transgenic plants and tended to be accumulated in the hypocotyls, vascular bundles, and leaf trichomes. These results will contribute to uncovering the potential functions and molecular mechanisms of soybean GmAQPs in mediating heat stress and hormone signal responses.

[Nerve-sparing robot-assisted laparoscopic radical cystectomy: Clinical application and effect].

OBJECTIVE: To investigate the clinical feasibility and effect of nerve-sparing robot-assisted laparoscopic radical cystectomy (NSRA-LSRC). METHODS: We retrospectively reviewed the clinical data on 12 cases of NSRA-LSRC performed from March 2016 to May 2018. The patients were aged 45 to 65 years old and all potent before surgery, with a mean IIEF-5 score of >17. The surgical procedure involved excision of the bladder and prostate and dissection of the pelvic lymph nodes, with preservation of the bilateral neurovascular bundles, internal accessory pudendal artery and pubic bladder complex. All the patients were advised to take PDE5I postoperatively and followed up for the sexual function with the IIEF-5 scores. RESULTS: Surgical procedures were completed successfully, all with negative surgical margins. Postoperative pathology confirmed invasive high-grade urothelial carcinoma or carcinoma in situ in all the cases, including 11 cases in stage T2N0M0 or below and 1 case in stage T3aN0M0. There were no serious intraoperative or postoperative complications, nor recurrence or metastasis during the follow-up period of 12－36 (20.7 ± 8.0) months. The IIEF-5 scores of the patients at 3, 6 and 12 months after operation were 10.9 ± 6.9, 12.3 ± 6.9 and 14.1 ± 8.0, respectively. At 12 months, satisfactory sexual intercourse was achieved with the help of potency-enhancing medicine in 5 cases (41.7%), penile erection insufficient for sexual intercourse in 3 cases (25%), and no erection in 4 cases (33.3%). CONCLUSIONS: Nerve-sparing robot-assisted laparoscopic radical cystectomy can maximally preserve the sexual function of the patients with urinary bladder carcinoma.

Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Infants.

Ceftazidime, a third-generation cephalosporin, can be used for the treatment of adults and children with infections due to susceptible bacteria. To date, the pediatric pharmacokinetic data are limited in infants, and therefore we aimed to evaluate the population pharmacokinetics of ceftazidime in infants and to define the appropriate dose to optimize ceftazidime treatment. Blood samples were collected from children treated with ceftazidime, and concentrations of the drug were quantified by high-performance liquid chromatography with UV detection (HPLC-UV). A population pharmacokinetic analysis was performed using NONMEM software (version 7.2.0). Fifty-one infants (age range, 0.1 to 2.0 years) were included. Sparse pharmacokinetic samples (n = 90) were available for analysis. A one-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that body weight and creatinine clearance (CLCR) were significant covariates influencing ceftazidime clearance. Monte Carlo simulation demonstrated that the currently used dosing regimen of 50 mg/kg twice daily was associated with a high risk of underdosing in infants. In order to reach the target of 70% of the time that the free antimicrobial drug concentration exceeds the MIC (fT>MIC), 25 mg/kg every 8 h (q8h) and 50 mg/kg q8h were required for MICs of 4 and 8 mg/liter, respectively. The population pharmacokinetic characteristics of ceftazidime were evaluated in infants. An evidence-based dosing regimen was established based on simulation.