Constructing Porous Energetic Spherulites via Solvation-Growth Coupling for Enhanced Combustion.

The fabrication of materials with hierarchical structures has garnered great interest, owing to the potential for significantly enhancing their functions. Herein, a strategy of coupling molecular solvation and crystal growth is presented to fabricate porous spherulites of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20), an important energetic material. With the addition of polyvinylpyrrolidone in the antisolvent crystallization, the metastable solvate of CL-20 is formed and grows spherulitically, and spontaneously desolvates to obtain the porous spherulite when filtration, in which the characteristic peak of the nitro group of CL-20 shifts detected by the in situ micro-confocal Raman spectroscopy. The effect of polyvinylpyrrolidone is thought to induce the solvation of CL-20, confirmed by density functional theory calculations, meanwhile acting on the (020) face of CL-20 to trigger spherulitic growth, demonstrated through infrared spectroscopy and Rietveld refinement of powder X-ray diffraction. Moreover, compared to common CL-20 crystals, porous spherulites exhibit enhanced combustion with increases of 6.24% in peak pressure, 40.21% in pressurization rate, and 9.63% in pressure duration effect, indicating the capability of hierarchical structures to boost the energy release of energetic crystals. This work demonstrates a new route via solvation-growth coupling to construct hierarchical structures for organic crystals and provides insight into the structure-property relations for material design.

Kruppel-like factor 1-GATA1 fusion protein improves the sickle cell disease phenotype in mice both in vitro and in vivo.

Sickle cell disease (SCD) and ß-thalassemia are among the most common genetic disorders worldwide, affecting global health and mortality. Hemoglobin A2 (HbA2, α2δ2) is expressed at a low level in adult blood due to the lack of the Kruppel-like factor 1 (KLF1) binding motif in the δ-globin promoter region. However, HbA2 is fully functional as an oxygen transporter, and could be a valid antisickling agent in SCD, as well as a substitute for hemoglobin A in ß-thalassemia. We have previously demonstrated that KLF1-GATA1 fusion protein could interact with the δ-globin promoter and increase δ-globin expression in human primary CD34+ cells. We report the effects of 2 KLF1-GATA1 fusion proteins on hemoglobin expression, as well as SCD phenotypic correction in vitro and in vivo. Forced expression of KLF1-GATA1 fusion protein enhanced δ-globin gene and HbA2 expression, as well as reduced hypoxia-related sickling, in erythroid cells cultured from both human sickle CD34+ cells and SCD mouse hematopoietic stem cells (HSCs). The fusion proteins had no impact on erythroid cell differentiation, proliferation, and enucleation. Transplantation of highly purified SCD mouse HSCs expressing KLF1-GATA1 fusion protein into SCD mice lessened the severity of the anemia, reduced the sickling of red blood cells, improved SCD-related pathological alterations in spleen, kidney, and liver, and restored urine-concentrating ability in recipient mice. Taken together, these results indicate that the use of KLF1-GATA1 fusion constructs may represent a new gene therapy approach for hemoglobinopathies.

Reproductive outcomes of dual trigger therapy with GnRH agonist and hCG versus hCG trigger in women with diminished ovarian reserve: a retrospective study.

BACKGROUND: Diminished ovarian reserve (DOR) is one of the obstacles affecting the reproductive outcomes of patients receiving assisted reproductive therapy. The purpose of this study was to investigate whether dual trigger, including gonadotropin-releasing hormone agonist (GnRHa) and human chorionic gonadotropin (hCG), can improve pregnancy outcomes in patients with DOR undergoing in vitro fertilization (IVF) cycles using mild stimulation protocols. METHODS: A total of 734 patients with DOR were included in this retrospective study. Patients were divided into a recombinant hCG trigger group and a dual trigger group (hCG combined with GnRHa) according to the different trigger drugs used. The main outcome measures included the number of oocytes retrieved, the fertilization rate, the number of transferable embryos, the implantation rate, the clinical pregnancy rate, the miscarriage rate, the live birth rate (LBR), and the cumulative live birth rate (CLBR). Generalized linear model and logistic regression analyses were performed for confounding factors. RESULTS: There were 337 cycles with a single hCG trigger and 397 cycles with dual trigger. The dual trigger group demonstrated significantly higher numbers of retrieved oocytes [3.60 vs. 2.39, adjusted ß = 0.538 (0.221-0.855)], fertilized oocytes [2.55 vs. 1.94, adjusted ß = 0.277 (0.031-0.523)] and transferable embryos [1.22 vs. 0.95, adjusted ß = 0.162 (-0.005-0.329)] than did the hCG trigger group, whereas no significant difference in the fertilization rate was observed between the two groups. Moreover, the embryo transfer cancellation rate (35.5% vs. 43.9%) was obviously lower in the dual trigger group. Among the fresh embryo transfer cycles, the implantation rate, clinical pregnancy rate, miscarriage rate and live birth rate were similar between the two groups. After controlling for potential confounding variables, the trigger method was identified as an independent factor affecting the number of oocytes retrieved but had no significant impact on the CLBR. CONCLUSIONS: Dual triggering of final oocyte maturation with hCG combined with GnRHa can significantly increase the number of oocytes retrieved in patients with DOR but has no improvement effect on the implantation rate, clinical pregnancy rate or LBR of fresh cycles or on the CLBR.

Obstetric and perinatal outcomes following frozen and fresh embryo transfer in patients with endometrial hyperplasia and carcinoma: a retrospective study in a high-volume reproductive center.

BACKGROUND: There is ongoing debate regarding which embryo transfer procedure can achieve a higher live birth rate. Research has suggested that frozen ET might be beneficial for certain populations, such as hyper-responders. This study aimed to compare outcomes of pregnancies between frozen and fresh embryo transfer cycles in patients with endometrial hyperplasia and carcinoma. METHODS: This retrospective cohort study was conducted at a high-volume reproductive center from January 2010 to January 2022. Patients who were diagnosed with endometrial hyperplasia with atypia and endometrial carcinoma were included. They all underwent in vitro fertilization after conservative treatment. The primary outcome was live birth after frozen and fresh embryo transfer cycles, and secondary outcomes included perinatal complications and other pregnancy outcomes. RESULTS: Overall, 259 ET cycles (130 fresh and 129 frozen) were included. The rate of live births per embryo transfer cycle of the whole cohort was 20.8% (54/259), and no significant between-group difference was found after adjusting for potential confounding factors (23.8% vs. 17.8%; adjusted OR, 0.47; 95% CI, 0.21-1.06; p=0.068). Compared to fresh embryo transfer group, the incidence of total maternal complications in the frozen embryo transfer group was significantly higher (30.4% vs. 6.5%, p=0.019). Analyzing each complication as a separate entity, patients in the frozen embryo transfer group had a higher incidence of hypertensive disorders of pregnancy (p=0.028). Multiple logistic regression analysis showed that frozen embryo transfer was related with an increased occurrence of maternal complications (OR, 6.68, 95% CI, 1.01-44.19, p=0.040). CONCLUSIONS: Among patients with endometrial hyperplasia and carcinoma, the rate of live births was comparable between both embryo transfer procedures, while frozen embryo transfer might be associated with a higher risk of maternal complications compared to that with fresh embryo transfer.

MIFNN: Molecular Information Feature Extraction and Fusion Deep Neural Network for Screening Potential Drugs.

Molecular property prediction is essential for drug screening and reducing the cost of drug discovery. Current approaches combined with deep learning for drug prediction have proven their viability. Based on the previous deep learning networks, we propose the Molecular Information Fusion Neural Network (MIFNN). The features of MIFNN are as follows: (1) we extracted directed molecular information using 1D-CNN and the Morgan fingerprint using 2D-CNN to obtain more comprehensive feature information; (2) we fused two molecular features from one-dimensional and two-dimensional space, and we used the directed message-passing method to reduce the repeated collection of information and improve efficiency; (3) we used a bidirectional long short-term memory and attention module to adjust the molecular feature information and improve classification accuracy; (4) we used the particle swarm optimization algorithm to improve the traditional support vector machine. We tested the performance of the model on eight publicly available datasets. In addition to comparing the overall classification capability with the baseline model, we conducted a series of ablation experiments to verify the optimization of different modules in the model. Compared with the baseline model, our model achieved a maximum improvement of 14% on the ToxCast dataset. The performance was very stable on most datasets. On the basis of the current experimental results, MIFNN performed better than previous models on the datasets applied in this paper.

AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53.

BACKGROUND & AIMS: Promoted by pancreatitis, oncogenic KrasG12D triggers acinar cells' neoplastic transformation through acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia. Anterior gradient 2 (Agr2), a known inhibitor of p53, is detected at early stage of pancreatic ductal adenocarcinoma (PDAC) development. RNA polymerase II (RNAPII) is a key nuclear enzyme; regulation of its nuclear localization in mammalian cells represents a potential therapeutic target. METHODS: A mouse model of inflammation-accelerated KrasG12D-driven ADM and pancreatic intraepithelial neoplasia development was used. Pancreas-specific Agr2 ablation was performed to access its role in pancreatic carcinogenesis. Hydrophobic hexapeptides loaded in liposomes were developed to disrupt Agr2-RNAPII complex. RESULTS: We found that Agr2 is up-regulated in ADM-to-pancreatic intraepithelial neoplasia transition in inflammation and KrasG12D-driven early pancreatic carcinogenesis. Genetic ablation of Agr2 specifically blocks this metaplastic-to-neoplastic process. Mechanistically, Agr2 directs the nuclear import of RNAPII via its C-terminal nuclear localization signal, undermining the ATR-dependent p53 activation in ADM lesions. Because Agr2 binds to the largest subunit of RNAPII in a peptide motif-dependent manner, we developed a hexapeptide to interfere with the nuclear import of RNAPII by competitively disrupting the Agr2-RNAPII complex. This novel hexapeptide leads to dysfunction of RNAPII with concomitant activation of DNA damage response in early neoplastic lesions; hence, it dramatically compromises PDAC initiation in vivo. Moreover, the hexapeptide sensitizes PDAC cells and patient-derived organoids harboring wild-type p53 to RNAPII inhibitors and first-line chemotherapeutic agents in vivo. Of note, this therapeutic effect is efficient across various cancer types. CONCLUSIONS: Agr2 is identified as a novel adaptor protein for nuclear import of RNAPII in mammalian cells. Also, we provide genetic evidence defining Agr2-dependent nuclear import of RNAPII as a pharmaceutically accessible target for prevention and treatment in PDAC in the context of wild-type p53.

Pressure effects on the thermal decomposition of the LLM-105 crystal.

Thermal mechanical responses under high temperature and high pressure are basic information to understand the performance of energetic materials. In this work, the pressure effects on the thermal decay of 2,6-diamino-3,5-dinitropyrazine-1-oxide (LLM-105) are explored. Up to the initial pressure of 4.6 GPa, the pressure dependent decomposition boundary is built and no phase transition occurs until the decomposition of the LLM-105 crystal. The decomposition temperature is significantly lifted via a weak loading pressure. The experimental measurement confirms the decomposition products, including NO2, CO2 and NH3, which are predicted by the density functional tight-binding molecular dynamics method. The calculation described the details of thermal decay in the initial stages under high pressure. The sudden drop in the shifts of the Raman modes associated with hydrogen bonds under high pressure indicates the strengthening of the intermolecular hydrogen bonds and the occurrence of intermolecular hydrogen transfer prior to crystal decomposition. The simulation supported the existence of intermolecular hydrogen transfer and provided the transfer path and decomposition mechanism. All of these jobs not only contribute significantly to the understanding of thermal decomposition of energetic materials as a function of pressure, but also contribute to the understanding of sensitivity mechanisms and safety issues.

Analysis of IVF/ICSI outcomes in infertile women with early-stage endometrial cancer and atypical endometrial hyperplasia after conservative treatment.

PURPOSE: To investigate the in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) outcomes and identify factors that might affect live births in patients with early-stage endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH). METHODS: This retrospective study was performed in a tertiary hospital. Patients (n = 123) with EEC or AEH, who underwent IVF/ICSI treatment between January 2010 and December 2019, were divided into a live birth group and a non-live birth group. Clinical characteristics and IVF/ICSI outcomes were assessed. RESULTS: A total of 123 patients (28 with EEC and 95 with AEH) underwent 215 ovarian stimulation cycles, resulting in 121 fresh embryo transfer (ET) and 108 frozen-thawed ET. Among 229 ET cycles, 91 (23.7%) of 384 embryos were implanted and 86 pregnancies were achieved, including five ectopic pregnancies (5.8%), 28 miscarriages (32.6%), and 53 live births (61.6%). The clinical pregnancy and live birth rates in each ET cycle were 37.6% and 23.1%, respectively. Fifty-one patients gave birth to 57 live neonates, and the cumulative live birth rate was 41.46%. Multiple logistic regression analysis showed that maternal age, histological type, thin endometrium, and time after complete remission (CR) to IVF cycle started were significantly associated with live births. CONCLUSIONS: The live birth rate after IVF/ICSI is promising in infertile patients with EEC and AEH. A shorter interval between CR and IVF/ICSI treatment might be a positive factor, while age > 35 years, endometrial thickness < 8 mm on the day of ET, and degree of endometrial lesion progressing into carcinoma can negatively influence IVF/ICSI outcomes.

Combined analysis of human chorionic gonadotrophin concentrations at different time points after frozen-thawed blastocyst transfer can improve our ability to predict the pregnancy outcomes of single gestations.

In this study, we conducted a retrospective single-centre study of 1664 singleton pregnancies derived from frozen-thawed blastocyst transfer between January 2017 and December 2018. Analysis showed that there were 596 early pregnancy losses and 1068 ongoing pregnancies. We compared serum HCG (human chorionic gonadotophin) concentrations on days 12, 14, 19, and 21, between the pregnancy loss group and the ongoing pregnancy group. The cut-off level of HCG at each time point was calculated to predict pregnancy outcome. Joint analysis of two single HCG levels taken one week apart was carried out to improve predictive accuracy. The levels of HCG at four time points were significantly lower in the early pregnancy loss group than in the ongoing pregnancy group. According to the area under ROC (receiver operating characteristic curve) curves, all levels of HCG taken at four time points showed good ability to predict the outcome of pregnancy. The joint analysis of two single HCG levels taken one week apart further improved the accuracy of prediction.Impact statementWhat is already known on this subject? Multiple studies have shown that the maternal level of serum HCG is the best parameter for predicting the course of pregnancy.What do the results of this study add? The levels of HCG on days 12, 14, 19 and 21 were significantly lower in the early pregnancy loss group than in the group of ongoing pregnancies. According to the area under ROC curves, all levels of HCG taken at four time points showed a good ability to predict the outcome of pregnancy.What are the implications of these findings for clinical practice and/or further research? The joint analysis of two single HCG levels, taken one week apart, further improved the accuracy of prediction.

Development of a nomogram predicting metastatic disease and the assessment of NCCN, AUA and EAU guideline recommendations for bone imaging in prostate cancer patients.

PURPOSE: We identified the risk predictors related to prostate cancer (PCa) metastasis using contemporary data in a community setting. Then, we assessed the performance of indications for bone imaging recommended from the NCCN, AUA and EAU guidelines. METHODS: Using the Surveillance, Epidemiology, and End Results database (2010-2015), we collected clinicopathological information from PCa patients. The associated risk factors found by multivariate analyses were used to establish forest plots and nomograms for distant metastasis (DM) and bone(s)-only metastasis (BM). We next evaluated the NCCN, AUA and EAU guidelines indications for the discovery of certain subgroups of patients who should receive bone imaging. RESULTS: A total of 120,136 patients were eligible for analysis, of which 96.7% had no metastasis. The odds ratios of positive DM and BM results were 13.90 times and 15.87 times higher in patients with a histologic grade group (GG) 5 than in the reference group. The concordance index of the nomograms based on race, age, T/N stage, PSA, GG, percentage of positive scores for predicting DM and BM was 0.942 and 0.928, respectively. Performance of the NCCN, AUA and EAU guidelines was high and relatively similar in terms of sensitivity (93.2-96.9%) and negative predictive value (99.8-99.9%). NCCN guidelines had the highest accuracy, specificity and positive likelihood ratio, while negative likelihood ratio was lowest in AUA guideline. CONCLUSION: Histologic GG 5 was the foremost factor for DM and BM. NCCN-based recommendations may be more rational in clinical practice. Nomograms predicting metastasis demonstrate high accuracy.

Olfactomedin 4 downregulation is associated with tumor initiation, growth and progression in human prostate cancer.

The olfactomedin 4 (OLFM4) gene has been analyzed as a tumor-suppressor gene and a putative biomarker in many cancers. In our study, we analyzed the relationship of OLFM4 expression with clinicopathological features and with CpG site methylation in the OLFM4 gene promoter region in human primary prostate adenocarcinoma. OLFM4 protein expression was significantly reduced in prostate cancer tissue compared to adjacent normal tissue and was further significantly reduced in more advanced cancers. Bioinformatic studies with clinical datasets revealed that primary prostate adenocarcinoma patients with reduced OLFM4 mRNA expression exhibited higher Gleason scores and higher preoperative serum prostate-specific antigen levels, as well as lower recurrence-free survival. Three of the eight CpG sites in the OLFM4 gene promoter region were hypermethylated in cancerous prostate cells compared to adjacent normal cells, and reduced methylation of eight CpG sites was associated with increased OLFM4 mRNA expression in RWPE1 and PC-3 cells. Furthermore, knockdown of OLFM4 gene expression was associated with enhanced epithelial-mesenchymal transition (EMT)-marker expression in RWPE immortalized normal prostate cells. In contrast, restoration of OLFM4 expression in PC-3 and DU145 prostate cancer cells lacking OLFM4 significantly inhibited both EMT-marker expression and tumor cell growth in in vitro and in vivo models, indicating that OLFM4 may play a tumor-suppressor role in inhibiting the EMT program, as well as tumor initiation and growth, in prostate cells. Taken together, these findings suggest that OLFM4 plays an important tumor-suppressor role in prostate cancer progression and might be useful as a novel candidate biomarker for prostate cancer.

In vivo characterization of RC28-E, a fusion protein targeting VEGF and bFGF: Pharmacokinetics and ocular distribution in primates.

Administration of RC28-E, a VEGF/bFGF dual decoy receptor (IgG1 Fc-fusion protein), have shown relative therapeutic value in ocular in vivo models, including laser-induced choroidal neovascularization (CNV) in monkeys and streptozotocin (STZ)-induced diabetic retinopathy (DR) in rats. In the present study, we have elucidated the pharmacokinetics profiles of RC28-E at the systemic, vitreous and aqueous humor after administration in a primate model (Macaca fascicularis). Moreover, here we tease out the ocular tissue distribution of RC28-E after intravitreal administration, and we also determine the systemic bioavailability after both intravitreal and intravenous administration. Our results show that RC28-E is rapidly and well-distributed into ocular tissues after intravitreal administration. Drug exposure in choroid and retina was approximately one-quarter and one-twelfth of that in vitreous humor, while its half-life in vitreous and aqueous humor were well-sustained (3.3 and 3.0 days). Remarkably, RC28-E could cross the blood-ocular barrier, and the systemic bioavailability of RC28-E was ~25%. No drug accumulation after multiple administration was noticed, but low titers of antibody produce against RC28-E were detected. Overall, RC28-E exhibited high clinical value due to adequate pharmacokinetic profiling, safety and efficacy.

A mechanism for two-step thermal decomposition of 2,6-diamino-3,5-dinitropyrazine-1-oxide (LLM-105).

2,6-Diamino-3,5-dinitropyrazine-1-oxide (LLM-105) is a representative of the new generation of low-sensitivity energetic materials and has been applied extensively in formulations as an insensitive high-energetic ingredient. Although the initial thermal decomposition mechanism of LLM-105 has been studied based on quantum chemical calculations, the internal mechanism of the two-step thermal decomposition still lacks experimental research. Thus, this study involves a detailed experimental study to reveal the mechanism of the two-step thermal decomposition of LLM-105. The results showed that LLM-105 decay was a consecutive reaction. The first-step reaction dominated the early stage of the LLM-105 decomposition, and its products participated in the reaction of the second step. The cleavage of NO2 and NH2 groups of LLM-105 mainly occurred in the first step, while gaseous products NO and C2N2 were released during the second reaction step. The first-step reaction had a higher oxygen consumption rate and a lower carbon consumption rate, producing more heat due to more extensive oxidation of the carbon backbone. The difference in the oxidative ability and reaction rate between the two steps resulted in a two-step exothermic and mass loss behavior. This study provides further insights into the entire reaction process of LLM-105 and would be helpful for its better application and for the design of new explosives.

Pattern and risk factors of local recurrence after nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: This study aims to identify predictive local recurrence risk factors and site-specific local recurrence pattern of upper tract urothelial carcinoma (UTUC) with different primary tumor locations. METHODS: Three hundred and eighty-nine UTUC patients with radical nephroureterectomy were included in this study. Univariate and multivariate Cox proportional hazards regressions were performed to measure the risk of local recurrence. We also mapped the position of local recurrence sites stratified by primary tumor locations. RESULTS: A total of 73 patients (18.7%) developed local recurrence within a median follow-up of 41 months (range, 3-80 months). For patients with local recurrence, the median interval of local recurrence was 9 months. Ureter tumor, multifocality, T stage, G grade, lymph node metastasis (LNM), lymph node dissection (LND), and lymph vascular invasion (LVI) were all significantly associated with increased local recurrence by univariable analyses (P < 0.05). Only multifocality, T3-4, G3, and LNM remained independent predictors of increased local recurrence by multivariable analyses. Adjuvant radiotherapy could reduce the local recurrence (HR = 0.177; 95% CI 0.064-0.493, P = 0.001). Patients with local recurrence had poorer cancer-specific survival (4-year cancer-specific survival rate 36 ± 7.5% vs 88.4 ± 2.2%, P = 0.000). We evaluated local recurrence pattern stratified by tumor locations. Para-aortic lymph node region was the most common recurrence area for all the patients. Left-sided UTUC had more than 70% recurrent lymph nodes in the left para-aortic region (LPA). For right-sided UTUC patients, recurrent para-aortic lymph nodes distributed in the LPA (33.3%), aortocaval (AC) (41.5%), and right paracaval (RPC) (25.2%) regions. Recurrence in the internal and external iliac regions was only found in the distal ureter group (P < 0.05). Renal pelvic fossa recurrence was only found in renal pelvic tumor (22.2%, P = 0.007). The ureter tumor bed recurrence rate was higher for ureter patients (P = 0.001). CONCLUSIONS: Multifocality, T3-4, G3, and LNM are predictors of higher local recurrence rate of UTUC. Adjuvant radiotherapy can reduce local recurrence rate. Local recurrence patterns are different according to primary tumor locations.

Olfactomedin 4 contributes to hydrogen peroxide-induced NADPH oxidase activation and apoptosis in mouse neutrophils.

Neutrophils increase production of reactive oxygen species, including superoxide, hydrogen peroxide (H2O2), and hydroxyl radical, to destroy invading microorganisms under pathological conditions. Conversely, oxidative stress conditions, such as the presence of H2O2, induce neutrophil apoptosis, which helps to remove neutrophils after inflammation. However, the detailed molecular mechanisms that are involved in the latter process have not been elucidated. In this study, we investigated the potential role of olfactomedin 4 (Olfm4) in H2O2-induced superoxide production and apoptosis in mouse neutrophils. We have demonstrated that Olfm4 is not required for maximal-dosage PMA- and Escherichia coli bacteria-induced superoxide production, but Olfm4 contributes to suboptimal-dosage PMA- and H2O2-induced superoxide production. Using an NADPH oxidase inhibitor and gp91phox-deficient mouse neutrophils, we found that NAPDH oxidase was required for PMA-stimulated superoxide production and that Olfm4 mediated H2O2-induced superoxide production through NADPH oxidase, in mouse neutrophils. We have shown that neutrophils from Olfm4-deficient mice exhibited reduced H2O2-induced apoptosis compared with neutrophils from wild-type mice. We also demonstrated that neutrophils from Olfm4-deficient mice exhibited reduced H2O2-stimulated mitochondrial damage and membrane permeability, and as well as reduced caspase-3 and caspase-9 activity, compared with neutrophils from wild-type mice. Moreover, the cytoplasmic translocation of the proapoptotic mitochondrial proteins Omi/HtrA2 and Smac/DIABLO in response to H2O2 was reduced in neutrophils from Olfm4-deficient mice compared with neutrophils from wild-type mice. Our study demonstrates that Olfm4 contributes to H2O2-induced NADPH oxidase activation and apoptosis in mouse neutrophils. Olfactomedin 4 might prove to be a potential target for future studies on inflammatory neutrophil biology and for inflammatory disease treatment.

Hydroxyurea-inducible SAR1 gene acts through the Giα/JNK/Jun pathway to regulate γ-globin expression.

Hydroxyurea (HU) is effectively used in the management of ß-hemoglobinopathies by augmenting the production of fetal hemoglobin (HbF). However, the molecular mechanisms underlying HU-mediated HbF regulation remain unclear. We previously reported that overexpression of the HU-induced SAR1 gene closely mimics the known effects of HU on K562 and CD34(+) cells, including γ-globin induction and cell-cycle regulation. Here, we show that HU stimulated nuclear factor-κB interaction with its cognate-binding site on the SAR1 promoter to regulate transcriptional expression of SAR1 in K562 and CD34(+) cells. Silencing SAR1 expression not only significantly lowered both basal and HU-elicited HbF production in K562 and CD34(+) cells, but also significantly reduced HU-mediated S-phase cell-cycle arrest and apoptosis in K562 cells. Inhibition of c-Jun N-terminal kinase (JNK)/Jun phosphorylation and silencing of Giα expression in SAR1-transfected K562 and CD34(+) cells reduced both γ-globin expression and HbF level, indicating that activation of Giα/JNK/Jun proteins is required for SAR1-mediated HbF induction. Furthermore, reciprocal coimmunoprecipitation assays revealed an association between forcibly expressed SAR1 and Giα2 or Giα3 proteins in both K562 and nonerythroid cells. These results indicate that HU induces SAR1, which in turn activates γ-globin expression, predominantly through the Giα/JNK/Jun pathway. Our findings identify SAR1 as an alternative therapeutic target for ß-globin disorders.

Furazans with Azo Linkages: Stable CHNO Energetic Materials with High Densities, Highly Energetic Performance, and Low Impact and Friction Sensitivities.

Various highly energetic azofurazan derivatives were synthesized by simple and efficient chemical routes. These nitrogen-rich materials were fully characterized by FTIR spectroscopy, elemental analysis, multinuclear NMR spectroscopy, and high-resolution mass spectrometry. Four of them were further confirmed structurally by single-crystal X-ray diffraction. These compounds exhibit high densities, ranging from 1.62 g cm(-3) up to a remarkably high 2.12 g cm(-3) for nitramine-substituted azofurazan DDAzF (2), which is the highest yet reported for an azofurazan-based CHNO energetic compound and is a consequence of the formation of strong intermolecular hydrogen-bonding networks. From the heats of formation, calculated with Gaussian 09, and the experimentally determined densities, the energetic performances (detonation pressure and velocities) of the materials were ascertained with EXPLO5 v6.02. The results suggest that azofurazan derivatives exhibit excellent detonation properties (detonation pressures of 21.8-46.1 GPa and detonation velocities of 6602-10 114 m s(-1) ) and relatively low impact and friction sensitivities (6.0-80 J and 80-360 N, respectively). In particular, they have low electrostatic spark sensitivities (0.13-1.05 J). These properties, together with their high nitrogen contents, make them potential candidates as mechanically insensitive energetic materials with high-explosive performance.

A comparison among different methods of letrozole combined with gonadotropin in an antagonist protocol and high-dose gonadotropin ovarian stimulation antagonist protocol in poor ovarian responders undergoing in vitro fertilization.

PURPOSE: This study aimed at comparing the effects of different methods of letrozole combined with gonadotropin (Gn) and high-dose Gn ovarian stimulation in antagonist protocol. METHODS: Retrospectively reviewed 220 poor responders from August 2012 to July 2014 at Peking University Third Hospital Reproductive Medical Center. Patients were divided into Group 1 (LZ 5 mg for 5 days sequentially overlapping with Gn cycles; n = 60), group 2 (LZ 7.5 mg for 3 days sequentially with Gn cycles; n = 60), and group 3 (high-dose Gn cycles; n = 100). We compared the basic status of patients and clinical outcomes of the three groups. RESULTS: Basic characteristics of patients were comparable among groups. Group 1 had significantly higher LH levels on day 7 and hCG than Group 2 and 3 (P < 0.05). Group 1 had significantly higher early LH elevation rate (>20 IU/L) on the hCG day than Groups 2 and 3 (11.7 vs. 6.7 and 2.0 %; P < 0.05). The amount of Gn used in LZ groups was significantly lower than Group 3 (P < 0.01). However, the clinical pregnancy rate and live birth rate were comparable among groups. CONCLUSION: In conclusion, the LZ/antagonist protocol is a cost-effective and patient friendly protocol, LZ 5 mg for 5 days sequentially overlapping with Gn protocol has comparable pregnancy outcomes, and LZ 7.5 mg for 3 days sequentially with the Gn protocol even has better clinical outcomes when compared with the standard GnRH antagonist protocol in poor responders. LZ 7.5 mg for 3 days sequentially with the Gn protocol appeared to have resulted in fewer improper LH surges and better outcomes than LZ 5 mg for 5 days sequentially overlapping with Gn in antagonist protocol.

Deletion of the olfactomedin 4 gene is associated with progression of human prostate cancer.

The olfactomedin 4 (OLFM4) gene is located on chromosome 13q14.3, which frequently is deleted in human prostate cancer. However, direct genetic evidence of OLFM4 gene alteration in human prostate cancer has not yet been obtained. In this study, we investigated the genetics, protein expression, and functions of the OLFM4 gene in human prostate cancer. We found overall 25% deletions within the OLFM4 gene in cancerous epithelial cells compared with adjacent normal epithelial cells that were microdissected from 31 prostate cancer specimens using laser-capture microdissection and genomic DNA sequencing. We found 28% to 45% hemizygous and 15% to 57% homozygous deletions of the OLFM4 gene via fluorescence in situ hybridization analysis from 44 different prostate cancer patient samples. Moreover, homozygous deletion of the OLFM4 gene significantly correlated with advanced prostate cancer. By using immunohistochemical analysis of 162 prostate cancer tissue array samples representing a range of Gleason scores, we found that OLFM4 protein expression correlated inversely with advanced prostate cancer, consistent with the genetic results. We also showed that a truncated mutant of OLFM4 that lacks the olfactomedin domain eliminated suppression of PC-3 prostate cancer cell growth. Together, our findings indicate that OLFM4 is a novel candidate tumor-suppressor gene for chromosome 13q and may shed new light on strategies that could be used for the diagnosis, prognosis, and treatment of prostate cancer patients.

Large-scale production of functional human serum albumin from transgenic rice seeds.

Human serum albumin (HSA) is widely used in clinical and cell culture applications. Conventional production of HSA from human blood is limited by the availability of blood donation and the high risk of viral transmission from donors. Here, we report the production of Oryza sativa recombinant HSA (OsrHSA) from transgenic rice seeds. The level of OsrHSA reached 10.58% of the total soluble protein of the rice grain. Large-scale production of OsrHSA generated protein with a purity >99% and a productivity rate of 2.75 g/kg brown rice. Physical and biochemical characterization of OsrHSA revealed it to be equivalent to plasma-derived HSA (pHSA). The efficiency of OsrHSA in promoting cell growth and treating liver cirrhosis in rats was similar to that of pHSA. Furthermore, OsrHSA displays similar in vitro and in vivo immunogenicity as pHSA. Our results suggest that a rice seed bioreactor produces cost-effective recombinant HSA that is safe and can help to satisfy an increasing worldwide demand for human serum albumin.