MyD88-Dependent Signaling Is Required for HOIP Deficiency-Induced Autoinflammation.

The linear ubiquitin chain assembly complex (LUBAC) plays pivotal roles in regulating lymphocyte activation, inflammation, and cell death. This is highlighted by the fact that patients with mutations in LUBAC catalytic subunit HOIP suffer from autoinflammation combined with immunodeficiency. Although defective development of T and B cells resulting from HOIP deficiency in adaptive immunity can explain immunodeficiency, the pathogenesis of autoinflammation is not clear. In this study, we found that dendritic cell (DC)-specific deletion of HOIP resulted in spontaneous inflammation, indicating the essential role of HOIP in maintaining DC homeostasis. Although HOIP deficiency in DCs did not affect TNF-α-induced NF-κB activation, it enhanced TNF-α-induced apoptosis and necroptosis. However, crossing HoipDC KO mice with TNFR1-knockout mice surprisingly could not rescue the systematic inflammation, suggesting that the autoinflammation is not due to the effect of HOIP on TNF-α signaling. In contrast, treatment of HoipDC KO mice with antibiotics reduced the inflammation, implying that TLR signaling may contribute to the inflammatory phenotype found in HoipDC KO mice. Consistently, we found that LPS induced more cell death and significantly higher levels of IL-1α and IL-1ß in HoipDC KO cells. Importantly, MyD88 deficiency rescued the inflammatory phenotype in HoipDC KO mice. Together, these findings reveal the indispensable function of HOIP in maintaining DC homeostasis, and MyD88-dependent proinflammatory signal plays a substantial role in the pathogenesis of human autoinflammation associated with HOIP mutations.

Identification of competing endogenous RNA network in laryngeal squamous cell carcinoma.

OBJECTIVE: This study was conducted to investigate key long noncoding RNAs (lncRNAs) involved in competitive endogenous RNA (ceRNA) network associated with laryngeal squamous cell carcinoma (LSCC). MATERIALS AND METHODS: Three mRNA datasets, two miRNA datasets, and one lncRNA dataset of LSCC were downloaded from GEO database. Following the identification of differentially expressed mRNAs (DEmRNAs), (microRNAs) miRNAs (DEmiRNAs), and lncRNAs (DElncRNAs) in LSCC compared with adjacent tissues, functional enrichment of DEmRNAs was performed. Then, construction of the ceRNA (DElncRNA-DEmiRNA-DEmRNA) regulatory network and functional analyses of all DEmRNAs in ceRNA regulatory network were conducted. Quantitative real-time polymerase chain reactions (qRT-PCR) were used to detect the expression levels of selected DEmRNAs, DEmiRNAs, and DElncRNAs. RESULTS: A total of 3449 DEmRNAs, 40 DEmiRNAs, and 100 DElncRNAs were identified in LSCC. The ceRNA networks, which contained 132 DElncRNA-DEmiRNA pairs and 287 DEmiRNA-DEmRNA pairs, involving 44 lncRNAs, 3 miRNAs, and 271 mRNAs, were obtained. DEmRNAs in ceRNA regulatory networks were significantly enriched in pathways in cancer, prostate cancer, and aldosterone-regulated sodium reabsorption. Except for HCG22 and hsa-miR-1246, expressions of the others in the qRT-PCR results played the same pattern with that in our integrated analysis, generally. CONCLUSIONS: We concluded that HCG22/EGOT-hsa-miR-1275-FAM107A and HCG22/EGOT-hsa-miR-1246-Glycerol-3-phosphate dehydrogenase 1 like interaction pairs may play a central role in LSCC.

Structure-based screening and biological validation of the anti-thrombotic drug-dicoumarol as a novel and potent PPARγ-modulating ligand.

PPARγ full agonists, thiazolidinediones (TZDs), have been known as a class of most effective drugs for the treatment of type 2 diabetes mellitus (T2DM). However, recently their therapeutic benefits have been compromised by several undesirable side effects. In this study, a host-based repurposing strategy and in combination with comprehensive biological evaluations were synergistically employed to seek for potent PPARγ ligands, which led to the identification of an anti-thrombotic drug, dicoumarol (Dic), as the novel and safer selectively PPARγ modulator (SPPARγM) with advantages over current TZD drugs. The results in vitro showed that Dic had a potent binding affinity and weakly agonistic activity for PPARγ and its downstream key genes. Moreover, in diabetic model, it significantly reduced blood glucose without leading to the weight gain of both body and main organ tissues. Further mechanistic investigations revealed that Dic possessed such desired pharmacological properties mainly through effectively inhibiting the phosphorylation of PPARγ-Ser273 and selectively regulating the expressions of insulin-sensitive and resistance genes. Finally, the docking studies on the analysis of the potent binding mode of Dic with PPARγ revealed a remarkable difference on interaction region compared with other developed PPARγ agonists, which not only gave a proof of concept for the abovementioned mechanism but also provided the molecular basis for the discrimination of Dic from other PPARγ ligands, especially TZD drugs. Taken together, our findings suggested that Dic could serve as a new and promising candidate with good therapeutic index for treating T2DM, especially for those T2DM patients with thrombosis.

Circ_0007331 knock-down suppresses the progression of endometriosis via miR-200c-3p/HiF-1α axis.

Endometriosis is considered a benign gynaecological disease with cancer-like characterizations, which has a high incidence among women of reproductive age. However, this disease has so far lacked timely diagnosis and effective treatment owing to its unclear aetiology. In this study, we identified aberrant high expression of circ_0007331 in ectopic endometrial cells by comparing the endometrial samples from patients with and without endometriosis. Further functional experiments revealed that circ_0007331 knock-down effectively suppressed the viability, proliferation and invasive capacity of ectopic endometrial cells. Additionally, we attempted to define the molecular mechanism of circ_0007331 in the initiation and progression of endometriosis. Circ_0007331 acted as a miRNA sponge for miR-200c-3p to indirectly regulate the function of HIF-1α, which plays a key role in the local angiogenesis and hypoxic mechanisms of ectopic endometrium. A final in vivo experiment confirmed that circ_0007331 knock-down could suppress the development of endometriosis through down-regulating the expression of HIF-1α. Collectively, we preliminarily characterized the role and possible insights of circ_0007331/miR-200c-3p/HIF-1α axis in the proliferation and invasion of ectopic endometrial cells. We hope that by exploring the potential function and molecular mechanism of circ_0007331, we can increase our biological insight into the pathogenesis of endometriosis, which will bring the new ways for the diagnosis and therapy of this disease.

Targeting of mTORC1/2 by dihydroevocarpine induces cytotoxicity in acute myeloid leukemia.

Interactions between the tumor cells and bone marrow (BM) microenvironment promote survival, growth, and chemoresistance of acute myeloid leukemia (AML). The mTOR pathway plays a key role in mediating the AML-BM microenvironment interactions. Here, we report the anti-AML activity of a natural monomer extracted from the Chinese medicinal herb Evodia rutaecarpa, dihydroevocarpine. Our results showed that dihydroevocarpine-induced cytotoxicity, apoptosis, and G0/G1 arrest in AML cells, and inhibited the tumor growth in an AML xenograft model. Importantly, our study revealed that the dihydroevocarpine treatment inhibited the mTOR pathway via suppressing the mTORC1/2 activity, and thus overcame the protective effect of the BM microenvironment on AML cells. Taken together, our findings suggest that dihydroevocarpine could be used as a potential anti-AML agent alone or a therapeutic adjunct in AML therapy, particularly in the presence of the BM microenvironment.

Compound K Induces Endoplasmic Reticulum Stress and Apoptosis in Human Liver Cancer Cells by Regulating STAT3.

The ginsenoside compound K (20-O-ß-d-glucopyranosyl-20(S)-protopanaxadiol; CK) is an intestinal bacterial metabolite of ginseng protopanaxadiol saponin that has been reported to induce apoptosis in many cancer cells; however, the precise mechanisms of its activity in human hepatocellular carcinoma (HCC) cells remain unclear. Herein, we demonstrated that CK inhibited the growth and colony formation of HepG2 and SMMC-7721 cells, phenotypes that were mediated by inducing apoptosis. Meanwhile, CK showed lower toxicity in normal hepatoma cells. After treating HepG2 and SMMC-7721 cells with CK, p-STAT3 levels decreased, the three branches of the unfolded protein response were activated, and levels of endoplasmic reticulum stress (ERS)-related proteins were increased. We also revealed that CK decreased the DNA-binding capacity of STAT3. Moreover, silencing STAT3 with CRISPR/Cas9 technology enhanced CK-induced ERS and apoptosis. Finally, we showed that CK inhibited the growth of liver cancer xenografts with little toxicity. Mice bearing human HCC xenografts that were treated with CK showed increased GRP78 expression and decreased p-STAT3 levels. Taken together, these data showed that CK induced ERS and apoptosis by inhibiting p-STAT3 in human liver cancer cells; thus, CK might be a potential therapeutic candidate for human HCC.

Influence of storage time on vitrified human cleavage-stage embryos froze in open system.

BACKGROUND: During in vitro fertilization, rapid growth of vitrification and liquid nitrogen storage of embryos have been well characterized. However, the effect of storage time on vitrified cleavage-stage embryos in an open system is poorly understood. AIMS: To investigate the influence of storage time on the survival and pregnancy outcomes of vitrified human cleavage-stage embryos froze and stored in an open system. METHODS: A retrospective study of 786 vitrified-warmed cycles of 735 patients was performed from January 2013 to October 2013. The cycles were divided into five groups according to storage time: 1-3 months, 4-6 months, 7-12 months, 13-24 and 25-60 months. The clinical outcomes of cycles with different storage time were analyzed. RESULTS: There were no significant differences of the survival rate, clinical pregnancy outcomes, birth rate, gestational weeks and singleton birthweights at various storage times. CONCLUSION: For vitrified embryos froze and stored in an open system, the storage time would not influence the survival rate and pregnancy outcomes by storage time up to 5 years.

Effect of normal sperm morphology rate (NSMR) on clinical outcomes and fertilization methods selection in the ultra-short-term GnRH-a protocol.

PURPOSE: To investigate whether intracytoplasmic sperm injection (ICSI) can improve the clinical outcomes of the male patients with teratozoospermia in the ultra-short term GnRH-a protocol. METHODS: Based on different normal sperm morphology rate (NSMR), the patients were divided into three groups as follows: NSMR = 0% group, 1% ≤NSMR <4% group and NSMR ≥4% group. Each group was compared with two fertilization type of in-vitro fertilization (IVF) and ICSI separately. Main outcomes compared were normal fertilization, high-quality embryo, transferrable embryo, implantation, pregnancy and abortion rate. RESULTS: We observed that the total clinical pregnancy rate in single cleavage-stage embryo transfer (SET) group was significantly lower compared with double cleavage-stage embryo transfer (DET) group (23.87% versus 40.08%; p < 0.001). There was no significant difference in the aspects of female age, endometrial thickness, infertility duration and the number of retrieved oocytes among three groups (p > 0.05). The normal fertilization, high-quality embryo, transferrable embryo, implantation, pregnancy and abortion rate of IVF and ICSI showed no significant difference among three groups (p > 0.05). CONCLUSION: ICSI cannot improve clinical outcomes of the patients with teratozoospermia in the ultra-short term GnRH-a protocol.

Effects of three pro-nuclei (3PN) proportion incidence on clinical outcomes of patients with lower retrieved oocytes in the fresh cleavage-stage embryo transfer (ET) cycles.

PURPOSE: To analyze the three pro-nuclei (3PN) incidence on clinical outcomes of patients with lower retrieved oocytes in the fresh cleavage-stage embryo transfer (ET) cycles. METHODS: This study included 1200 fresh cleavage-stage ET cycles from January 2013 to June 2015. The patients were divided into 3PN = 0% (773 cycles) and 3PN > 0% (427 cycles) group. Main outcomes compared were fertilization, cleavage, normal fertilization, good quality embryo, implantation, clinical pregnancy, and early abortion rate. RESULTS: We observed that there was no significant difference in female's age, the number of retrieved oocytes, the number of transferred embryos, the number of good quality embryos, endometrial thickness, infertile time, basal serum follicle-stimulating hormone, and E2 value between two groups (p > 0.05). The fertilization (89.43 versus 83.90%, p < 0.001) and cleavage (98.34 versus 97.19%, p = 0.048) rates were significantly higher in 3PN > 0% than 3PN = 0% group. However, the normal fertilization (70.05 versus 50.67%, p < 0.001), good quality embryos (37.11 versus 26.47%, p < 0.001), and clinical pregnancy (49.81 versus 43.79%, p = 0.046) rates were significantly higher in 3PN = 0% than 3PN > 0% group. The implantation (35.88 versus 33.78%, p = 0.333) and early abortion (8.83 versus 10.70%, p = 0.474) rates were not significantly different between two groups. CONCLUSION: 3PN incidence might make a negative effect on clinical outcomes for patients with lower retrieved oocytes in the fresh cleavage-stage ET cycles.

[The rate of morphologically normal sperm does not affect the clinical outcomes of conventional IVF in patients with one retrieved oocyte].

OBJECTIVE: To investigate the influence of the rate of morphologically normal sperm (MNS) on the clinical outcomes of conventional in vitro fertilization (IVF) in patients with one retrieved oocyte. METHODS: From January 2013 to January 2015, a total of 256 couples with one retrieved oocyte underwent conventional IVF in our center. According to the rate of MNS, the patients were divided into two groups: MNS < 4% (134 cycles) and MNS ≥ 4% (122 cycles). We compared the rates of no transferrable embryo cycles, fertilization, cleavage, normal fertilization, abnormal fertilization, high-quality embryo and transferrable embryo between the two groups. A total of 75 fresh embryo transfer cycles were performed, 43 in the MNS < 4% group and the other 32 in the MNS ≥ 4% group. We also compared the rates of implantation, clinical pregnancy and abortion between the two groups. RESULTS: There were no statistically significant differences between the two groups in the rates of no transferrable embryo cycles, fertilization, cleavage, normal fertilization, abnormal fertilization, high-quality embryo and transferrable embryo (P > 0.05). The rates of implantation, clinical pregnancy and abortion exhibited no remarkable differences either in the fresh embryo transfer cycles between the two groups (P > 0.05). CONCLUSION: The rate of MNS does not affect the clinical outcomes of conventional IVF in patients with one retrieved oocyte.

Effects of triploidy incidence on clinical outcomes for IVF-ET cycles in different ovarian stimulation protocols.

PURPOSE: To discuss the relationship between triploidy incidence and clinical outcomes of embryos derived from normally fertilized oocytes from the same cohort for in vitro fertilization-embryo transfer (IVF-ET) cycles in different ovarian stimulation protocol. METHODS: This study included 2070 in vitro fertilization (IVF) cycles with long-term protocol, 802 IVF cycles with ultra short-term protocol and 508 IVF-D (in vitro fertilization by donor semen) cycles with long-term protocol from January 2013 to September 2014. According to the different 3PN rate, patients were divided into three groups as follows: Group 1 included patients with 0% 3PN zygotes, Group 2 included patients with 1-25% 3PN zygotes and Group 3 included patients with >25% 3PN zygotes. MAIN OUTCOME MEASURE: female age, no. of retrieved oocytes, normal fertilization rate, day-3 grade I + II embryos rate, day-3 grade I + II + III embryos rate, implantation rate, pregnancy rate and early abortion rate. RESULTS: Triploidy cycle incidence rate in IVF and IVF-D cycles with long-term protocol were significantly higher than in IVF cycles with ultra short-term protocol (p < 0.001). Triploidy fertilization rate found no significant difference between the three groups (p > 0.05). In three protocols, normal fertilization rate in 3PN = 0% and 3PN = 1-25% groups were significantly higher compared to 3PN > 25% group (p < 0.001). In IVF cycles with long-term protocol, the day-3 grade I + II embryos, implantation and pregnancy rate in 3PN > 25% group were significantly lower than other two groups (p < 0.05). The day-3 grade I + II + III embryos and early abortion rate found no significant difference between the three groups (p > 0.05). In IVF cycles with ultra short-term protocol, there were no significant differences found in day-3 grade I + II embryos, day-3 grade I + II + III embryos, implantation, pregnancy and early abortion rate (p > 0.05). In IVF-D cycles with long-term protocol, the day-3 grade I + II embryos, day-3 grade I + II + III embryos and implantation rate in 3PN > 25% group were significantly lower than other two groups (p < 0.05). The pregnancy and early abortion rates found no significant difference in the three groups (p > 0.05). CONCLUSION: We observed that high proportion of triploid zygotes made a negative effect on clinical outcomes for IVF-ET cycles with long-term protocol.

Efficacy of swim-up versus density gradient centrifugation in improving sperm deformity rate and DNA fragmentation index in semen samples from teratozoospermic patients.

PURPOSE: To compare the efficacy of swim-up and DGC in improving sperm deformity and DNA fragmentation and to determine which method is better in teratozoospermic patients requiring artificial reproduction. METHODS: The present study compared the effects of swim-up and density gradient centrifugation (DGC), the two most commonly used semen preparation methods, on sperm deformity rate and DNA fragmentation index (DFI) in semen samples from teratozoospermic patients. RESULTS: The results demonstrated that both swim-up and DGC yielded a significantly lower sperm deformity rate and DFI in comparison to unprocessed whole semen, with DGC having more favorable results. Sperm deformity rate in unprocessed whole semen samples was significantly lower in the 20-29 age group than in the 40-49 age group, but no significant difference was observed in DFI between different age groups. There was no significant correlation between sperm deformity rate and DFI. CONCLUSIONS: Our findings suggest that enrichment of sperm with normal morphology and intact DNA in teratozoospermic patients could be achieved by both DGC and swim-up procedures, and that DGC is a better method.

Mask and Release Strategy-Enabled Diversity-Oriented Synthesis for DNA-Encoded Library.

An ideal DNA-encoded library (DEL) selection requires the library to consist of diverse core skeletons and cover chemical space as much as possible. However, the lack of efficient on-DNA synthetic approaches toward core skeletons has greatly restricted the diversity of DEL. To mitigate this issue, this work disclosed a "Mask & Release" strategy to streamline the challenging on-DNA core skeleton synthesis. N-phenoxyacetamide is used as a masked phenol and versatile directing group to mediate diversified DNA-compatible C-H functionalization, introducing the 1st-dimensional diversity at a defined site, and simultaneously releasing the phenol functionality, which can facilitate the introduction of the 2nd diversity. This work not only provides a set of efficient syntheses toward DNA-conjugated drug-like core skeletons such as ortho-alkenyl/sulfiliminyl/cyclopropyl phenol, benzofuran, dihydrobenzofuran but also provides a paradigm for on-DNA core skeleton synthetic method development.

Factors related to clinical pregnancy after vitrified-warmed embryo transfer: a retrospective and multivariate logistic regression analysis of 2313 transfer cycles.

STUDY QUESTION: What factors does multivariate logistic regression show to be significantly associated with the likelihood of clinical pregnancy in vitrified-warmed embryo transfer (VET) cycles? SUMMARY ANSWER: Assisted hatching (AH) and if the reason to freeze embryos was to avoid the risk of ovarian hyperstimulation syndrome (OHSS) were significantly positively associated with a greater likelihood of clinical pregnancy. WHAT IS KNOWN ALREADY: Single factor analysis has shown AH, number of embryos transferred and the reason of freezing for OHSS to be positively and damaged blastomere to be negatively significantly associated with the chance of clinical pregnancy after VET. It remains unclear what factors would be significant after multivariate analysis. STUDY DESIGN, SIZE, DURATION: The study was a retrospective analysis of 2313 VET cycles from 1481 patients performed between January 2008 and April 2012. A multivariate logistic regression analysis was performed to identify the factors to affect clinical pregnancy outcome of VET. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 22 candidate variables selected based on clinical experiences and the literature. With the thresholds of α entry = α removal= 0.05 for both variable entry and variable removal, eight variables were chosen to contribute the multivariable model by the bootstrap stepwise variable selection algorithm (n = 1000). Eight variables were age at controlled ovarian hyperstimulation (COH), reason for freezing, AH, endometrial thickness, damaged blastomere, number of embryos transferred, number of good-quality embryos, and blood presence on transfer catheter. A descriptive comparison of the relative importance was accomplished by the proportion of explained variation (PEV). MAIN RESULTS AND THE ROLE OF CHANCE: Among the reasons for freezing, the OHSS group showed a higher OR than the surplus embryo group when compared with other reasons for VET groups (OHSS versus Other, OR: 2.145; CI: 1.4-3.286; Surplus embryos versus Other, OR: 1.152; CI: 0.761-1.743) and high PEV (marginal 2.77%, P = 0.2911; partial 1.68%; CI of area under receptor operator characteristic curve (ROC): 0.5576-0.6000). AH also showed a high OR (OR: 2.105, CI: 1.554-2.85) and high PEV (marginal 1.97%; partial 1.02%; CI of area under ROC: 0.5344-0.5647). The number of good-quality embryos showed the highest marginal PEV and partial PEV (marginal 3.91%, partial 2.28%; CI of area under ROC: 0.5886-0.6343). LIMITATIONS, REASONS FOR CAUTION: This was a retrospective multivariate analysis of the data obtained in 5 years from a single IVF center. Repeated cycles in the same woman were treated as independent observations, which could introduce bias. Results are based on clinical pregnancy and not live births. Prospective analysis of a larger data set from a multicenter study based on live births is necessary to confirm the findings. WIDER IMPLICATIONS OF THE FINDINGS: Paying attention to the quality of embryos, the number of good embryos, AH and the reasons for freezing that are associated with clinical pregnancy after VET will assist the improvement of success rates.

Nomogram for predicting the prognosis of sudden sensorineural hearing loss patients based on clinical characteristics: a retrospective cohort study.

Background: Based on the clinical characteristics of patients, a nomogram predicting the prognosis of patients suffering from sudden sensorineural hearing loss (SSNHL) was constructed, which could aid in personalized treatment. Methods: Data on the clinical characteristics of patients with SSNHL were collected and statistically analyzed. A nomogram for predicting the hearing prognosis of SSNHL patients were then constructed. Results: A total of 356 patients were included in this study, including 227 and 129 in the recovery group (63.76%) and non-recovery group (36.24%), respectively. Univariable logistic regression demonstrated that age, gender, body mass index (BMI), marital, Audiogram curve, vertigo, hearing loss degree, and time to initial treatment were associated with hearing outcomes. Multivariate logistic models showed that age [odds ratio (OR): 0.479, 95% confidence interval (CI): 0.301-0.748, P<0.001], descending (OR: 0.116, 95% CI: 0.047-0.275, P<0.001) and flat audiogram curves (OR: 0.397, 95% CI: 0.159-0.979, P=0.045), profound hearing loss (OR: 0.047, 95% CI: 0.013-0.152, P<0.001), and treatment initiation after 1 week (8-14 days: OR: 0.047, 95% CI: 0.013-0.152, P<0.001; >14 days: OR: 0.131, 95% CI: 0.039-0.413) were risk factors for the hearing recovery. Logistic regression analyses were conducted to construct the prognostic nomogram. As estimated by the area under the receiver operating characteristic curve (ROC), the model had an accuracy of 0.867 (95% CI: 0.709-0.747). The validation analysis confirmed the high accuracy of the nomogram, and the decision curve showed that the model has potential clinical application value. Conclusions: This study demonstrated that age, descending and flat audiogram curves, profound hearing loss, and initiating treatment after 1 week of SSNHL onset were independent risk factors associated with a worse hearing recovery prognosis. Using these factors, a nomogram with a high prediction accuracy was developed to predict the hearing recovery rate of SSNHL patients.

Emotion recognition from EEG based on multi-task learning with capsule network and attention mechanism.

Deep learning (DL) technologies have recently shown great potential in emotion recognition based on electroencephalography (EEG). However, existing DL-based EEG emotion recognition methods are built on single-task learning, i.e., learning arousal, valence, and dominance individually, which may ignore the complementary information of different tasks. In addition, single-task learning involves a new round of training every time a new task appears, which is time consuming. To this end, we propose a novel method for EEG-based emotion recognition based on multi-task learning with capsule network (CapsNet) and attention mechanism. First, multi-task learning can learn multiple tasks simultaneously while exploiting commonalities and differences across tasks, it can also obtain more data from different tasks, which can improve generalization and robustness. Second, the innovative structure of the CapsNet enables it to effectively characterize the intrinsic relationship among various EEG channels. Finally, the attention mechanism can change the weight of different channels to extract important information. In the DEAP dataset, the average accuracy reached 97.25%, 97.41%, and 98.35% on arousal, valence, and dominance, respectively. In the DREAMER dataset, average accuracy reached 94.96%, 95.54%, and 95.52% on arousal, valence, and dominance, respectively. Experimental results demonstrate the efficiency of the proposed method for EEG emotion recognition.

Naftopidil enantiomers suppress androgen accumulation and induce cell apoptosis via the UDP-glucuronosyltransferase 2B15 in benign prostate hyperplasia.

Accumulation of androgens mediate alterations in prostate growth and has emerged as an essential factor in benign prostate hyperplasia (BPH). Dihydrotestosterone (DHT), the most potent natural androgen, binds to androgen receptors (AR) and regulates the prostate growth. Many inhibitors of DHT synthesis have been developed to reduce DHT levels and used in the treatment of prostate diseases. However, therapies targeting the elimination of the DHT remain limited. The DHT in prostate is metabolized by UDP-glucuronosyltransferase 2B (UGT2B) and transforms into inactive products. In this study, we analyzed and demonstrated that two enantiomers of naftopidil (NAF), an α1D/1A-adrenoceptor blocker, induced expression and activity of UGT2B in BPH rat prostate models as well as UGT2B15 in human prostate cells, BPH-1. The NAF enantiomers reduced intraprostatic and intracellular DHT levels, thus promoting cell apoptosis. Besides, assays with siRNA UGT2B15 transfection showed that UGT2B15 played an essential role in mediating the effects of the NAF enantiomers. The UGT2B15 mediated the inhibition of AR and PSA expression by NAF enantiomers. The data showed that the mechanism of upregulating UGT2B15 by the NAF enantiomers might differ from that of AR antagonists and 5α-reductase inhibitors. Together, our results demonstrated that NAF enantiomers could be potential and novel UGT2B15 regulators, which accelerated the DHT elimination and promoted apoptosis of BPH-1 cells. This study could help expand the clinical application of NAF and support the development of new therapeutic strategies targeting the elimination of androgens for the treatment of BPH and other androgen-sensitive diseases.

Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global crisis, urgently necessitating the development of safe, efficacious, convenient-to-store, and low-cost vaccine options. A major challenge is that the receptor-binding domain (RBD)-only vaccine fails to trigger long-lasting protective immunity if used alone for vaccination. To enhance antigen processing and cross-presentation in draining lymph nodes (DLNs), we developed an interferon (IFN)-armed RBD dimerized by an immunoglobulin fragment (I-R-F). I-R-F efficiently directs immunity against RBD to DLNs. A low dose of I-R-F induces not only high titers of long-lasting neutralizing antibodies (NAbs) but also more comprehensive T cell responses than RBD. Notably, I-R-F provides comprehensive protection in the form of a one-dose vaccine without an adjuvant. Our study shows that the pan-epitope modified human I-R-F (I-P-R-F) vaccine provides rapid and complete protection throughout the upper and lower respiratory tracts against a high-dose SARS-CoV-2 challenge in rhesus macaques. Based on these promising results, we have initiated a randomized, placebo-controlled, phase I/II trial of the human I-P-R-F vaccine (V-01) in 180 healthy adults, and the vaccine appears safe and elicits strong antiviral immune responses. Due to its potency and safety, this engineered vaccine may become a next-generation vaccine candidate in the global effort to overcome COVID-19.

CRISPR-Cas9 genome editing for cancer immunotherapy: opportunities and challenges.

Cancer immunotherapy, consisting of antibodies, adoptive T-cell transfer, vaccines and cytokines, is a novel strategy for fighting cancer by artificially stimulating the immune system. It has developed rapidly in recent years, and its efficacy in hematological malignancies and solid tumors has been remarkable. It is regarded as one of the most promising methods for cancer therapy. The current trend in immunotherapy research seeks to improve its efficacy and to ensure the safety of cancer immunotherapy through the use of gene editing technologies. As it is an efficient and simple technology, the CRISPR-Cas9 system is highly anticipated to dramatically strengthen cancer immunotherapy. Intensive research on the CRISPR-Cas9 system has provided increasing confidence to clinicians that this system can be put into clinical use in the near future. This paper reviews the application and challenges of CRISPR-Cas9 in this field, based on various strategies including adaptive cell therapy and antibody therapy, and also highlights the function of CRISPR/Cas9 in the screening of new cancer targets.

Coordination Investigation of the Economic, Social and Environmental Benefits of Urban Public Transport Infrastructure in 13 Cities, Jiangsu Province, China.

This study proposed an investigation-based multiple-criteria coordinated model to evaluate the sustainable development of urban public transport (PT) infrastructure, based on economic, social and environmental data from 2009 to 2019. The main problem with the traditional approach for assessing urban PT development is that economic and social benefits are considered individually, but also attention to environmental factors and coordination among the three issues are nearly overlooked. This leads to the likelihood of inaccuracies in the handling/assessment of sustainable development or an imbalance among the attributes in different cities. An investigation-based coordinated model was introduced in which a survey of 35 sub-criteria was conducted to derive the criteria necessary for coupling/coordination. A case study involving 13 cities in Jiangsu Province, China, illustrated the problems in coordinating PT systems and verified the efficacy of the proposed approach. With employing the entropy method, this study validated coordination of the PT infrastructure development of various cities in a balanced manner and used panel regression formulas to analyse the theoretical gap and empirical bottlenecks existing among economic, social and environmental benefits. With the findings of the study, the data-based investigation from 13 cities enabled the city planners/managers (including ones from other cities with similar urban levels) to give the individual priority between the ternary benefits, advance technology, allow big data-based informatisation and implement near-future autonomous PT vehicles.