A new tau dephosphorylation-targeting chimera for the treatment of tauopathies.

Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.

High incidence of EDNRB gene mutation in seven southern Chinese familial cases with Hirschsprung's disease.

PURPOSE: Hirschsprung's disease (HSCR) is the leading cause of neonatal functional intestinal obstruction, which has been identified in many familial cases. HSCR, a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. We present a genetic investigation of familial HSCR to clarify the genotype-phenotype relationship. METHODS: We performed whole exome sequencing (WES) on Illumina HiSeq X Ten platform to investigate genetic backgrounds of core family members, and identified the possibly harmful mutation genes. Mutation carriers and pedigree relatives were validated by Sanger sequencing for evaluating the gene penetrance. RESULTS: Four familial cases showed potential disease-relative variants in EDNRB and RET gene, accounting for all detection rate of 57.1%. Three familial cases exhibited strong pathogenic variants as frameshift or missense mutations in EDNRB gene. A novel c.367delinsTT mutation of EDNRB was identified in one family member. The other two EDNRB mutations, c.553G>A in family 2 and c.877delinsTT in family 5, have been reported in previous literatures. The penetrance of EDNRB variants was 33-50% according mutation carries. In family 6, the RET c.1858T>C (C620R) point mutation has previously been reported to cause HSCR, with 28.5% penetrance. CONCLUSION: We identified a novel EDNRB (deleted C and inserted TT) mutation in this study using WES. Heterozygote variations in EDNRB gene were significantly enriched in three families and RET mutations were identified in one family. EDNRB variants showed an overall higher incidence and penetrance than RET in southern Chinese families cases.

Design, Synthesis, and Anti-Hepatocellular Carcinoma Evaluation of Sesquiterpene Lactone Epimers Trilobolide-6-O-isobutyrate Analogs.

Hepatocellular carcinoma (HCC), one of the most common malignant cancers with a low 5-year survival rate, is the third leading cause of cancer-related deaths worldwide. The finding of novel agents and strategies for the treatment of HCC is an urgent need. Sesquiterpene lactones (SLs) have attracted extensive attention because of their potent antitumor activity. In this study, a new series of SL derivatives (3-18) were synthesized using epimers 1 and 2 as parent molecules, isolated from Sphagneticola trilobata, and evaluated for their anti-HCC activity. Furthermore, the structures of 4, 6, and 14 were confirmed by X-ray single-crystal diffraction analyses. The cytotoxic activities of 3-18 on two HCC cell lines, including HepG2 and Huh7, were evaluated using the CCK-8 assay. Among them, compound 10 exhibited the best activity against the HepG2 and Huh7 cell lines. Further studies showed that 10 induced cell apoptosis, arrested the cell cycle at the S phase, and induced the inhibition of cell proliferation and migration in HepG2 and Huh7. In addition, absorption, distribution, metabolism, and excretion (ADME) properties prediction showed that 10 may possess the properties to be a drug candidate. Thus, 10 may be a promising lead compound for the treatment of HCC.

Synthetic viability induces resistance to immune checkpoint inhibitors in cancer cells.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized the treatment for multiple cancers. However, most of patients encounter resistance. Synthetic viability (SV) between genes could induce resistance. In this study, we established SV signature to predict the efficacy of ICI treatment for melanoma. METHODS: We collected features and predicted SV gene pairs by random forest classifier. This work prioritized SV gene pairs based on CRISPR/Cas9 screens. SV gene pairs signature were constructed to predict the response to ICI for melanoma patients. RESULTS: This study predicted robust SV gene pairs based on 14 features. Filtered by CRISPR/Cas9 screens, we identified 1,861 SV gene pairs, which were also related with prognosis across multiple cancer types. Next, we constructed the six SV pairs signature to predict resistance to ICI for melanoma patients. This study applied the six SV pairs signature to divide melanoma patients into high-risk and low-risk. High-risk melanoma patients were associated with worse response after ICI treatment. Immune landscape analysis revealed that high-risk melanoma patients had lower natural killer cells and CD8+ T cells infiltration. CONCLUSIONS: In summary, the 14 features classifier accurately predicted robust SV gene pairs for cancer. The six SV pairs signature could predict resistance to ICI.

Management of autoimmune retinopathy treated with intravitreal dexamethasone implant.

PURPOSE: The purpose of this study is to evaluate clinical outcomes of autoimmune retinopathy (AIR) in the patients treated with intravitreal dexamethasone implant (IDI). METHOD: Twenty-one eyes of 11 AIR patients treated with at least 1 injection of IDI were retrospectively reviewed. Clinical outcomes before and after treatment, including best corrected visual acuity (BCVA), optic coherence tomography (OCT), fundus autofluorescence (FAF), full-field electroretinography (ff-ERG), and visual field (VF) at last visit within 6 and/or 12 months, were recorded. RESULTS: Among all the patients, 3 had cancer-associated retinopathy (CAR) and 8 had non-paraneoplastic-AIR (npAIR) with mean followed up of 8.52 ± 3.03 months (range 4-12 months). All patients achieved improved or stable BCVA within 6 and/or 12 months after the treatment. Cystoid macular edema (CME) in 2 eyes and significant retinal inflammation in 4 eyes were markedly resolved after single injection. Central retinal thickness (CFT) in all eyes without CME, ellipsoid zone (EZ) on OCT in 71.4% of eyes, ERG response in 55% of eyes, and VF in 50% of eyes were stable or improved within 6 months after treatment. At last visit within 12 months, both BCVA and CFT remained stable in the eyes treated with either single or repeated IDI; however, progression of EZ loss and damage of ERG response occurred in some patients with single IDI. CONCLUSION: Clinical outcomes, including BCVA and parameters of OCT, ERG, and VF, were stable or improved after IDI in a majority of AIR patients. Local treatment of AIR with IDI was a good option to initiate the management or an alternative for the patients' refractory to the systemic therapy but with limited side effect.

Serum antiretinal antibodies and cytokine profiling in autoimmune retinopathy and their association with clinical outcomes.

PURPOSE: Autoimmune retinopathy (AIR) is a group of autoimmune retinal diseases that can cause blindness. The purpose of this study is to investigate the profiles of serum antiretinal antibodies (ARAs) and cytokines and their association with disease diagnosis as well as clinical features in AIR. METHODS: The patients with presumed para (p) and non-paraneoplastic (np) AIR diagnosis, the patients with retinitis pigmentosa and bilateral uveitis as disease controls, and healthy subjects were prospectively enrolled. Western blotting and Luminex multiple cytokine assay/enzyme linked immunosorbent assay were used to determine the presence of serum ARAs and the concentration of cytokines, respectively. Kruskal-Wallis or chi square test was applied to compare the profiles of ARA and cytokines among various groups. The multilevel mixed-effect regression was used to investigate the association of ARA or cytokines with clinical features. RESULTS: No significant difference in the band number and subtypes of serum ARAs was found between AIR patients and their controls. AIR patients had higher concentration of serum IFN-ɤ, CXCL9, or CXCL10 than non-AIR controls. A positive correlation was found between increased number of ARAs and elevated TNF-α in np-AIR patients. Elevated pro-inflammatory cytokines or ARA subtypes (antibody against recoverin and α-enolase) were associated with worse retinal functions or anatomy, including visual acuity, visual field, ERG parameters, and central retinal thickness. CONCLUSIONS: The data of our study demonstrate that detection of serum ARAs has limited value in the diagnosis of AIR. Th1-type cytokines/chemokines or specific ARA subtypes are associated with pathogenesis and disease severity of the AIR.

Cytotoxic Indole Diterpenoids from a Sphagneticola trilobata-Derived Fungus Aspergillus sp. PQJ-1.

Two new indole diterpene derivatives, 5S-hydroxy-ß-aflatrem (1) and 14R-hydroxy-ß-aflatrem (2), along with one known analogue, 14-(N,N-dimethl-L-valyloxy)paspalinine (3), were isolated from the fermentation broth of the fungus Aspergillus sp. PQJ-1 derived from Sphagneticola trilobata. The structures of the new compounds were elucidated from spectroscopic data and ECD spectroscopic analyses. All the compounds (1-3) were evaluated for their cytotoxicity against A549, Hela, Hep G2, and MCF-7 cell lines. Compounds 1 and 2 exhibited selective inhibition against Hela cells. Further studies showed that 1 significantly induced apoptosis and suppressed migration and invasion in Hela cells. Moreover, 1 could up-regulate pro-apoptotic genes BAX and Caspase-3 and down-regulate anti-apoptotic genes Bcl-xL and XIXP.

Four Undescribed Pyranones from the Scutellaria formosana-Derived Endophytic Fungi Ascomycota sp. FAE17.

Four undescribed pyranone derivatives, named ascomycopyrones A-D (1-4), as well as one known analogue simplicilopyrone (5) (this is the first study to report the absolute configuration), were isolated from the endophytic fungus Ascomycota sp. FAE17 derived from the flowers of Scutellaria formosa. The structures of these pyranones were identified by comprehensive spectroscopic and MS analyses, and the absolute configurations were determined by their experimental and quantum chemical electronic circular dichroism (ECD) calculations. All isolated compounds were tested for various bioactivities, including antibacterial, cytotoxic activity, and NO inhibitory activity. Unfortunately, none of the compounds showed significant bioactivities.

[Advances in pharmacological effects of jujuboside B].

Ziziphi Spinosae Semen(ZSS) is an edible TCM derived from the dried ripe seeds of Ziziphus jujube Mill. var. spinosa(Bunge)Hu ex H. F. Chou(Rhamnaceae), which has the effects of nourishing the heart, tonifying the liver, calming the heart, tranquilizing the mind, arresting sweating, and promoting fluid production, and is widely used in the treatment and health care of diseases related to cardiovascular, nervous, and immune systems. Jujuboside B(JuB), one of the main active ingredients of ZSS, possesses various pharmacological effects with application values. This paper reviewed the chemical structure and pharmacological effects of JuB. JuB has sedative, hypnotic, antitumor, anti-platelet, anti-inflammatory, and other biological activities, which shows the potential thera-peutic effects on insomnia, tumors, coronary artery disease, airway inflammation, and liver injury. However, there are some limitations to the results of current studies. More comprehensive studies, including basic research and clinical trials, need to be carried out to provide more reliable evidence.

A novel approach for relapsed/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv/NKG2D-CAR T cells and gilteritinib.

BACKGROUND: Patients with relapsed/refractory acute myeloid leukaemia (AML) with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) have limited treatment options and poor prognosis. Therefore, novel treatment modalities are needed. Since high expression of natural killer group 2 member D ligands (NKG2DLs) can be induced by FLT3 inhibitors, we constructed dual-target FLT3 single-chain fragment variable (scFv)/NKG2D-chimeric antigen receptor (CAR) T cells, and explored whether FLT3 inhibitors combined with FLT3scFv/NKG2D-CAR T cells could have synergistic anti-leukaemia effects. METHODS: FLT3scFv and NKG2D expression in CAR T cells, FLT3 and NKG2DL expression in AML cells, and the in vitro cytotoxicity of combining CAR T cells with gilteritinib were assessed by flow cytometry. The therapeutic effect was evaluated in a xenograft mouse model established by injection of MOLM-13 cells. Mechanisms underlying the gilteritinib-induced NKG2DL upregulation were investigated using siRNA, ChIP-QPCR and luciferase assays. RESULTS: The FLT3scFv/NKG2D-CAR T cells specifically lysed AML cells both in vitro and in the xenograft mouse model. The efficacy of FLT3scFv/NKG2D-CAR T cells was improved by gilteritinib-pretreatment. The noncanonical NF-κB2/Rel B signalling pathway was found to mediate gilteritinib-induced NKG2DL upregulation in AML cells. CONCLUSIONS: Bispecific FLT3scFv/NKG2D-CAR T cells can effectively eradicate AML cells. The FLT3 inhibitor gilteritinib can synergistically improve this effect by upregulating NF-κB2-dependent NKG2DL expression in AML cells.

Rapid Derivatization of Phenolic and Oxime Hydroxyl with Isonicotinoyl Chloride under Aqueous Conditions and Its Application in LC-MS/MS Profiling Multiclass Steroids.

Quantification of steroids possesses a crucial clinical value in early diagnosis and prognosis evaluation of various endocrine diseases. However, it is still challenging to realize feasible analysis of estrogens, androgens, progestogens, and corticoids within one single workflow. In this study, two derivatization reactions were newly designed for improvement: (1) acylation of phenolic hydroxyl on estrogens with isonicotinoyl chloride (INC) under the catalysis of 4-dimethylaminopyridine and (2) post-modification of oxime hydroxyl on hydroxylamine-pretreated ketosteroids with INC. Both reactions could conduct instantaneously at room temperature under aqueous conditions. Moreover, the resulting phenolic-INC and oxime-INC esters exhibited favorable MS responses. Through integrating these derivatization strategies with cold-induced phase separation technology, a feasible LC-MS/MS method was developed for simultaneous quantification of 15 multiclass steroids with proper sample consumption (50 µL serum), satisfying sensitivity (lower limit of quantitation at 0.01-5.00 ng/mL) and high throughput (40 min for sample-preparation). The practical applicability was tested by detecting 30 real samples from pregnant and non-pregnant women. The obtained results showed a good agreement with a previous validated methodology.

Risk factors and treatment of rectal stenosis after transanal endoscopic microsurgery.

AIM: Rectal stenosis is a relatively rare complication after transanal endoscopic microsurgery (TEM). This study aims to identify the predictive parameters for stenosis and the application of TEM in the treatment. METHOD: The clinical data of patients who underwent TEM for rectal adenoma and early cancer from 2008 to 2019 were retrospectively reviewed. We compared the clinicopathological characteristics of patients with stenosis and those without stenosis and analysed the risk factors for stenosis. Treatment outcomes of stenosis with TEM were evaluated. RESULTS: A total of 230 patients were enrolled in this study. Overall, the postoperative complication rate was 11.7% (27/230), including eight (3.5%) patients with stenosis. Patients with stenosis exhibited a higher rate of tumour showing a laterally spreading morphology (P = 0.048), a wider circumferential extent of mucosal defect (P < 0.001), a shorter distance of the tumour from the anal verge (P = 0.001) and a wider longitudinal extent of mucosal defect (P = 0.027). A circumferential extent of mucosal defect >3/4 (OR 94.945, 95% CI 3.611-2496.41, P = 0.006) was identified as the only independent risk factor for stenosis. The four patients with both stenosis and clinical symptoms were treated by incising the stenosis ring using the TEM platform; the stenosis was cured, and symptoms disappeared after one to four courses of treatment. CONCLUSIONS: Circumferential extent of mucosal defect ≥3/4 was an independent risk factor for stenosis in treating rectal adenoma and early cancer with TEM. Incision of the stenosis ring using the TEM platform is an effective strategy for treating stenosis.

ICAM5 as a Novel Target for Treating Cognitive Impairment in Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, resulted from the silencing of the Fmr1 gene and the subsequent loss of fragile X mental retardation protein (FMRP). Spine dysgenesis and cognitive impairment have been extensively characterized in FXS; however, the underlying mechanism remains poorly understood. As an important regulator of spine maturation, intercellular adhesion molecule 5 (ICAM5) mRNA may be one of the targets of FMRP and involved in cognitive impairment in FXS. Here we show that in Fmr1 KO male mice, ICAM5 was excessively expressed during the late developmental stage, and its expression was negatively correlated with the expression of FMRP and positively related with the morphological abnormalities of dendritic spines. While in vitro reduction of ICAM5 normalized dendritic spine abnormalities in Fmr1 KO neurons, and in vivo knockdown of ICAM5 in the dentate gyrus rescued the impaired spatial and fear memory and anxiety-like behaviors in Fmr1 KO mice, through both granule cell and mossy cell with a relative rate of 1.32 ± 0.15. Furthermore, biochemical analyses showed direct binding of FMRP with ICAM5 mRNA, to the coding sequence of ICAM5 mRNA. Together, our study suggests that ICAM5 is one of the targets of FMRP and is implicated in the molecular pathogenesis of FXS. ICAM5 could be a therapeutic target for treating cognitive impairment in FXS.SIGNIFICANCE STATEMENT Fragile X syndrome (FXS) is characterized by dendritic spine dysgenesis and cognitive dysfunctions, while one of the FMRP latent targets, ICAM5, is well established for contributing both spine maturation and learning performance. In this study, we examined the potential link between ICAM5 mRNA and FMRP in FXS, and further investigated the molecular details and pathological consequences of ICAM5 overexpression. Our results indicate a critical role of ICAM5 in spine maturation and cognitive impairment in FXS and suggest that ICAM5 is a potential molecular target for the development of medication against FXS.

Laparoscopic versus open resection for elderly patients with gastric cancer: a double-center study with propensity score matching method.

PURPOSE: The applicability of laparoscopic-assisted radical gastrectomy for elderly patients with gastric cancer is still not well clarified. The aim of this double-center study was to explore the feasibility and effectiveness of laparoscopic-assisted radical gastrectomy on elderly patients with gastric cancer. METHODS: We prospectively collected data of patients who underwent gastrectomy for cancer in two centers from June 2016 to December 2019. Propensity score matching was performed at a ratio of 1:1 to compare the laparoscopic-assisted radical gastrectomy group and open radical gastrectomy group. Univariate analyses and multivariate logistic regression analyses evaluating the risk factors for total, surgical, and medical complications were performed. RESULTS: A total of 481 patients with gastric cancer met the inclusion criteria and were included in this study. After propensity score analysis, 258 patients were matched each other (laparoscopic-assisted radical gastrectomy (LAG) group, n = 129; open radical gastrectomy (OG) group, n = 129). LAG group had lower rate of surgical complications (P = 0.009), lower rate of severe complications (P = 0.046), shorter postoperative hospital stay (P = 0.001), and lower readmission rate (P = 0.039). Multivariate analyses revealed that anemia, Charlson comorbidity index, and combined resection were independent risk factors in the LAG group, whereas body mass index and American Society of Anesthesiology grade in the OG group. CONCLUSION: Laparoscopic-assisted radical gastrectomy was relative safe even effective in elderly gastric cancer patients. We should pay attention to the different risk factors when performing different surgical procedures for gastric cancer in elderly patients.

Trilobolide-6-O-isobutyrate suppresses hepatocellular carcinoma tumorigenesis through inhibition of IL-6/STAT3 signaling pathway.

Currently available therapies for hepatocellular carcinoma (HCC), with a high morbidity and high mortality, are only marginally effective and with sharp adverse side effects, which makes it compulsory to explore novel and more effective anticancer molecules. Chinese medicinal herbs exhibited prominent anticancer effects and were applied to supplement clinical cancer treatment. Here, we reported a compound, trilobolide-6-O-isobutyrate (TBB), isolated from the flowers of Wedelia trilobata with a markedly cytotoxic effect on HCC cells. We found that TBB time- and dose-dependently inhibited HCC cells' growth and colony formation in vitro. Moreover, TBB induced cell cycle arrest at the G2/M phase, mitochondrial caspase-dependent apoptosis, and suppressed migration and invasion, as well as the glycolysis of HCC cells. Mechanistically, our data indicated that TBB inhibited the STAT3 pathway activation by directly interacting with the TYR 640/657 sites of the STAT3 protein and decreasing the level of p-STAT3. TBB also regulated the expression of PCNA, Ki67, Cyclin B1, Cyclin E, Bax, Bcl2, MMP2/9, and PGK1 through the inhibition of the IL-6/STAT3 signaling pathway. Lastly, we confirmed that TBB effectively eliminated tumor growth without causing overt toxicity to healthy tissues in the xenograft tumor model. The exploration of anticancer activity and the underlying mechanism of TBB suggested its usage as a promising chemotherapeutic agent for HCC.

Recent Advances in Isolation, Synthesis and Biological Evaluation of Terrein.

Terrein is a small-molecule polyketide compound with a simple structure mainly isolated from fungi. Since its discovery in 1935, many scholars have conducted a series of research on its structure identification, isolation source, production increase, synthesis and biological activity. Studies have shown that terrein has a variety of biological activities, not only can inhibit melanin production and epidermal hyperplasia, but also has anti-cancer, anti-inflammatory, anti-angiopoietic secretion, antibacterial, insecticidal activities, and so on. It has potential application prospects in beauty, medicine, agriculture and other fields. This article reviews the process of structural identification of terrein since 1935, and summarizes the latest advances in its isolation, source, production increase, synthesis, and biological activity evaluation, with a view to providing a reference and helping for the in-depth research of terrein.

A case report of cervicothoracic penetrating injury with retention of foreign body.

BACKGROUND: Cervicothoracic penetrating injury, considered to be relatively rare, has a complicated mechanism that is difficult to treat. In this report, a special case of cervicothoracic injury caused by foreign body penetration was elucidated. In this case, the injury location and the involved foreign body were exceptionally particular, which induced a challenging process of diagnosis and treatment. CASE PRESENTATION: A male patient suffered from a serious injury caused by a thick branch that pierced through his neck in a traffic accident between an electric car and a tricycle carrying wood. There were also local injuries in the left scapular region. After an emergency multidisciplinary consultation, the patient was diagnosed and subsequently treated with vascular exploration and repair (common carotid artery), intrathoracic foreign body extraction, chest exploration, debridement, and suture. After surgery, he was transferred to the emergency intensive care unit for anticoagulation and anti-infection treatment. Finally, after the improvement of his physical condition, the patient was transferred to the general ward for further treatment and was successfully discharged from the hospital. Once discharged, the patient lived a normal life, free from sequelae or complications. CONCLUSION: It may be an extremely daunting task to cure cervicothoracic penetrating injury due to its rare occurrence in clinical practice. Different from the previous cervicothoracic traumas, the injury location in this case is exceedingly particular. In general, the common cervicothoracic trauma is associated with damage to the trachea, esophagus, throat, and other structures, easily resulting in dyspnea, which, however, does not occur in this case. The insertion position of foreign body is exceptionally particular as it does not pierce the common carotid artery but poses compression on it, which induces ischemia. It is essential for the successful treatment that the treatment plan is formulated via the detailed imaging examination and careful multidisciplinary consultation.

Dysregulation in nucleic acid-sensing pathway genes is associated with cancer patients' prognosis.

The innate immune system, the first line of defense against pathogens, is activated by nucleic acids from microbial invaders that are recognized by nucleic acid-sensing receptors. Recent evidence affirms the ability of these receptors to respond to nucleic acids released by damaged cancer cells. The innate immune system is also involved in cancer immunosurveillance, and could be modulated for devising effective antitumor therapies by targeting nucleic acid-sensing pathways. A systematic, comprehensive analysis of dysregulation in nucleic acid-sensing pathways in cancer is required to fully understand its role. Based on multidimensional data of The Cancer Genome Atlas pan-cancer cohort, we revealed that upregulation of cytosolic DNA-sensing genes like AIM2 and CGAS was common in tumor tissues. We used 15 genes in the nucleic acid-sensing pathway to cluster all tumor patients into 2 subgroups and found that the subgroup with higher expression of nucleic acid-sensing pathway genes was associated with poorer prognosis across cancer types. However, in homologous recombination deficient patients, the nucleic acid recognition activated subgroup was associated with better prognosis, which confirms the therapeutic effect of nucleic acid recognition. This study contributes to a better understanding of the functions and mechanisms of nucleic acid recognition in cancer, lays the foundation for new therapeutic strategies, and enlarges the scope of development of new drugs.

Comparison of effectiveness and safety outcomes of abiraterone versus enzalutamide in patients with metastatic castration-resistant prostate cancer: a systematic review and meta-analysis.

PURPOSE: To compare the effectiveness and safety between abiraterone and enzalutamide in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: We systematically searched for relevant articles from PubMed, Cochrane, Embase from their inception through November 4, 2019. Available articles from conferences were searched. The endpoints were prostate-specific antigen (PSA) response, overall survival (OS), progression-free survival (PFS), number of patients with any adverse event (AE). RESULTS: 15 cohort studies involving 3546 participants were included in this meta-analysis. Pooled result showed that PSA response rate in the enzalutamide group was significantly greater than that in the abiraterone group (867 patients, risk ratio (RR) 0.69, 95% confidence interval (CI) 0.61-0.79, p＜0.00001, I2=29%). There was no significant difference in the total incidence of AEs between two groups (730 patients, RR 0.42, 95% CI 0.14-1.31, p = 0.14, I2=84%). The common adverse events observed in the published articles were fatigue and perceived cognitive impairments. Patients who received enzalutamide had the higher risk to have the feeling of fatigue compared with abiraterone group (2555 patients, RR 0.45, 95% CI 0.24-0.85, p=0.01, I2=92%). And there was no statistical difference between two groups respect to the side effect of perceived cognitive impairments (1856 patients, RR 0.94, 95% CI 0.47-1.88, p=0.85, I2=15%). CONCLUSIONS: Our results demonstrated that enzalutamide was associated with higher PSA response rate compared to abiraterone in patients with mCRPC, and no significant difference was found between two groups in the overall AE. But enzalutamide use induced higher risk of the AE of fatigue.

The MAPK Kinase Kinase GmMEKK1 Regulates Cell Death and Defense Responses.

MAPK signaling pathways play critical roles in plant immunity. Here, we silenced multiple genes encoding MAPKs using virus-induced gene silencing mediated by Bean pod mottle virus to identify MAPK genes involved in soybean (Glycine max) immunity. Surprisingly, a strong hypersensitive response (HR) cell death was observed when soybean MAPK KINASE KINASE1 (GmMEKK1), a homolog of Arabidopsis (Arabidopsis thaliana) MEKK1, was silenced. The HR was accompanied by the overaccumulation of defense signaling molecules, salicylic acid (SA) and hydrogen peroxide. Genes involved in primary metabolism, translation/transcription, photosynthesis, and growth/development were down-regulated in GmMEKK1-silenced plants, while the expression of defense-related genes was activated. Accordingly, GmMEKK1-silenced plants were more resistant to downy mildew (Peronospora manshurica) and Soybean mosaic virus compared with control plants. Silencing GmMEKK1 reduced the activation of GmMPK6 but enhanced the activation of GmMPK3 in response to flg22 peptide. Unlike Arabidopsis MPK4, GmMPK4 was not activated by either flg22 or SA. Interestingly, transient overexpression of GmMEKK1 in Nicotiana benthamiana also induced HR. Our results indicate that GmMEKK1 plays both positive and negative roles in immunity and appears to differentially activate downstream MPKs by promoting GmMPK6 activation but suppressing GmMPK3 activation in response to flg22. The involvement of GmMPK4 kinase activity in cell death and in flg22- or SA-triggered defense responses in soybean requires further investigation.