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In massive multiple-input multiple-output (MIMO) systems, the large number of high-resolution analog-to-digital converters (ADCs) lead to high hardware cost and power consumption. In this work, the uplink achievable rates of massive MIMO systems with low-resolution ADCs are studied with consideration of both “Uniform-ADC” that uses ADCs with the same number of quantization bits and “Mixed-ADC” that allows the use of ADCs with different resolutions. By leveraging an additive quantization noise model (AQNM), the asymptotic achievable rates are obtained for maximum ratio combining (MRC), zero-forcing (ZF), and linear minimum mean squared error (LMMSE) receivers in very simple forms. Taking advantages of the theoretical results, we propose two criteria for allocation of quantization bits. It is found that the optimal quantization bits allocation for LMMSE is Mixed-ADCs with number of quantization bits that are polarized, while Uniform-ADC is optimal for MRC and ZF. When there is a constraint on the total ADC power consumption, the proposed quantization-bit allocation scheme for LMMSE becomes Uniform-ADC when the transmit signal-to-noise ratio (SNR) is below a threshold, which is related to the system scale and the ADC power consumption. The theoretical results are verified by Monte-Carlo simulations.

Most of the existing acoustic imaging studies in reverberant field ignore the influence of signal-to-noise ratio. As a result, commonly used beamforming algorithms in reverberant backgrounds have poor imaging accuracy for low signal-to-noise ratio sound sources. In response to that problem, an improved adaptive beamforming algorithm called SC-DAMAS is put forward in this paper. The algorithm replaces the free-field Green's function with the impulse response function, making the algorithm more suitable for acoustic imaging of low signal-to-noise ratio in a reverberant environment. Besides, the comparative simulation results with the conventional beamforming method and orthogonal matching pursuit algorithm-based DAMAS, as well as sound source acoustic imaging experiments are carried out to analyze its effectiveness. It is indicated that, in the reverberation field, the SC-DAMAS has no obvious sidelobes and achieves higher positioning accuracy for acoustic imaging of low signal-to-noise ratio sound source than the abovementioned counterparts, and its imaging test result is consistent with the actual situation, which verifies the effectiveness of the algorithm.

Event detection (ED) aims to identify events of interest described in the text. With the current explosive growth of text data on the internet, ED is increasingly practical and has gained many researchers’ attention. The existing works usually design ED as a token-level multi-class classification task. In this setting, given a sentence, ED models’ prediction for each token is relatively independent and thus cannot fully utilize sentence-level information and the association relations between multiple events in this sentence. To handle these situations, this paper proposes a multi-task learning based event detection model, which introduces an event type oriented text classification as an auxiliary task to improve the model’s understanding of sentence-level information. In addition, this model utilizes a Conditional Random Field (CRF) to explore the correlations between various event types and constrain the model’s output space. Experimental comparisons with state-of-the-art baselines on DuEE dataset demonstrate the model’s effectiveness.

Objective We reviewed the benefits of an all-single-room intensive care unit in the prevention of hospital-acquired infection. Method The intensive care medicine department of the First Affiliated Hospital of Bengbu Medical College commenced single-room management in 2019. This study reviewed the prevalence of pathogenic bacterial infection and altered drug resistance of major pathogens in patients hospitalized from January 2016 to December 2020. Results of bacterial resistance and changes in bacterial numbers were analyzed separately and the two time periods compared. Results In 2016, 320 strains of pathogenic bacteria were identified compared with 601 in 2020. At both times, bacteria were predominantly gram-negative. The ratio of the number of pathogenic bacteria to the number of beds revealed a decreasing trend each year from 2016–2020: 22.86, 17.57, 28.36, 14.33, and 15.41 respectively (P Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Burkholderia cepacia. The source of bacteria was mainly sputum, followed by blood, and the site of infection was predominantly the respiratory tract. Staphylococcus aureus resistant to ciprofloxacin, levofloxacin and erythromycin had decreased significantly (P Klebsiella pneumoniae and penicillin-resistant Pseudomonas aeruginosa decreased after the introduction of single-room wards (P = 0.025, P = 0.002 respectively). Conclusion Introduction of a single-room ward directly or indirectly reduced the possibility of cross-infection. The establishment of single-room wards has no adverse effects and was beneficial to patients, the department and the hospital.

The electron-rich Ru sites are isolated in body-centered cubic RuGa intermetallic compounds, which reduces the energy barrier of the rate-limiting step in the HER process, thus promoting the high-current-density HER activity.

Recently, with increasing awareness of health issues, non-alcoholic fatty liver disease (NAFLD) has become an epidemic attracting global attention. As a serious chronic disease, NAFLD is clinically managed with pharmacological interventions that are usually associated with poor long-term efficacy and adverse effects. In this scenario, traditional Chinese medicine (TCM) characterized by "multiple ingredients-multiple targets-multiple pathways" shows promise as a potential option to treat NAFLD. Zexie decoction (ZXD) is a classical TCM formula that possesses favorable lipid-lowering and anti-inflammatory activities. Accumulating evidence indicates that ZXD displays robust efficacy in treating NAFLD. The effectiveness of ZXD against NAFLD has been evaluated in our previous studies. This study further examines its probable mechanism of action in an in-depth manner using multi-omic analysis based on the gut-liver axis and sheds light on the potential relationship among genes, hepatic lipid metabolites, and gut microbiotas. Totally, 71 differentially expressed genes (34 upregulated and 37 downregulated genes), 31 differential lipid molecules (8 upregulated and 23 downregulated), and 56 differential gut microbiotas (37 upregulated and 19 downregulated) were identified in the ZXD-treated group rats compared with the negative control group rats. Of these, owing to their key role in the association analysis, g_Blautia, g_Romboutsia, and g_Lactobacillus were hypothesized to be crucial gut microbiotas in the ZXD-mediated treatment of NAFLD. These microbiotas were found to synergize with key genes, such as AKR1B8, CCN1, and TNKS2, and hepatic lipid metabolites, such as glycerophospholipid and sphingomyelin, which might play a therapeutic role by regulating fatty acid synthesis, correcting lipid metabolism disorder, or reducing the inflammatory response. Overall, the present study provides fresh insights into the ZXD-mediated treatment of NAFLD, which, in turn, is expected to give a push to the modernization of TCM.

Gold nanoparticles (AuNPs) were synthesized by one-step reduction of chloroauric acid using pomelo leaf polyphenol extract as reducing and protective agent. The AuNPs were characterized by UV-Vis absorption spectroscopy. Compared with AuNPs prepared with sodium citrate as reducing agent, AuNPs prepared with pomelo leaf polyphenol extract had better stability. The antioxidant properties of green-synthesized AuNPs were investigated by Bland-Williams method. The antibacterial activity of the green synthesized AuNPs was investigated by the transparent inhibition zone method and the minimum inhibitory concentration method. The results showed that the AuNPs prepared with pomelo leaf polyphenol extract as biological template had good antioxidant activity. The scavenging rate of 1, 1-diphenyl-2-trinitrophenylhydrazide free radical (DPPH•) was 95.65% when the 1.0 g/L AuNPs solution was used. The antibacterial activity of AuNPs synthesized from pomelo leaf polyphenol extract against Staphylococcus aureus was higher than that of AuNPs synthesized chemically. The minimum inhibitory concentration of green synthesized AuNPs was 0.85 g/L, while the minimum inhibitory concentration of chemically synthesized AuNPs was 1.58 g/L.

Belinostat (PXD101), a new histone deacetylase inhibitor, has shown good performance in various cancer treatments and has been approved by the FDA for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in patients with drugs. PXD101 is considered to have certain anti-allergic and anti-inflammatory properties, but its beneficial effects in UVB-induced skin photoaging have not been reported. In a recent study, HacaT cells and C57BL6 mice were used to study the impact of PXD101 on UVB-induced cellular senescence and skin photoaging and to explore their potential mechanisms of action. Studies have shown that PXD101 inhibits UVB-induced HacaT cell senescence, which appears to be achieved by inhibiting activation of the UVB-induced NF-κB/p65 signaling pathway. At the same time, PXD101 inhibits the expression of MMPs. In addition, PXD101 alleviated skin damage on the dorsal skin of mice, reduced skin aging and inflammation, increased collagen fiber synthesis, and restored UVB-induced epidermal thickening. In short, we believe that PXD101 effectively inhibits cellular senescence and skin photoaging caused by UVB exposure, a potential method for developing clinical prevention and treatment of skin aging.

Background: To explore the diagnostic value of combination of exfoliative cytology with detection of tumor markers carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), neuron specific enolase (NSE), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) and CA15-3 for lung cancer. Methods: A total of 256 patients were enrolled, including 164 males and 92 females aged (64.51±22.68) years old. Among them, 189 patients (100 males and 89 females) were randomly selected as Tumor group, and the remaining 67 patients were used for validation. Another 514 healthy people receiving physical examination in our hospital during the same period were selected, from which 397 cases (266 males and 131 females) were randomly selected as No Tumor group, and the remaining 117 cases were used for validation. The biochemical criteria were detected in all subjects. The diagnostic value of each index for lung cancer was analyzed using receiver operating characteristic (ROC) curves. Results: The results of ROC curve analysis revealed that in Tumor group, the area under curve (AUC) of exfoliative cytology, CA125, CYFRA21-1, CA15-3, CEA and NSE was ≥0.7, while that of CA72-4, CA19-9, TSGF, AFP, CA242, SCCAg and CA50 was Conclusions: The lung cancer prediction model balances sensitivity and specificity without reducing the diagnostic efficiency.

Massive multiple-input multiple-output (MIMO) systems based on millimeter-wave (mmWave) technology commonly utilize a combination of hybrid analog and digital signal processing to reduce the number of radiofrequency (RF) chains, cutting down the hardware costs and power consumption. The subconnected structure is one of the architectures that realize hybrid analog and digital processing, in which each RF chain is connected to a subset of antennas through phase shifters so as to reduce the implementation complexity. In this paper, we investigate the best subconnected structure design for mmWave massive MIMO systems. First, we formulate the optimization problem based on a simplified connection model. Next, we derive a suboptimal solution in closed form by leveraging the mmWave channel characteristics and discuss the impact of different connection parameters on the spectral efficiency. The spectral efficiency is closely related to the structure of the analog processing and the interantenna spacing. When the interantenna spacing is an even a multiple of half wavelength, the localized structure, i.e., i = 1 achieves the maximum spectral efficiency. When the interantenna spacing is an odd multiple of half wavelength and the analog processing is accomplished by i = 2 interleaved structure, the best performance is obtained. Numerical results demonstrate the correctness of the theoretical analysis.

Marimastat is one of the potent inhibitors of MMP (MMPIs) with few side effects. The impact of marimastat on cellular senescence remains unexplored. Our study evaluated the marimastate effect on oxidative stress-induced cell senescence using NIH3T3 cells. Marimastate administration was found to suppress senescence-β-galactosidase (SA-β-gal) activity and development linked with aging. Furthermore, we observed that this effect of marimastat was closely linked with the recovery of autophagy dysfunction and mTOR suppression in H

Orchitis accounts for a high proportion of male animal reproductive disorders. Hence, it is urgent to identify drugs for the prevention and treatment of orchitis. Antimicrobial peptides (AMPs) are currently recognized as one of the most promising alternatives to antibiotics. However, the protective effects of AMPs on lipopolysaccharide (LPS)-induced orchitis have not been reported. In this study, we developed an LPS-induced orchitis model in which primary bovine Sertoli cells were used as model cells. MPX was indicated to effectively reduce the inflammatory response of Sertoli cells. MPX attenuated the gene expression of the proinflammatory cytokines TNF-α, IL-6 and IL-1β by suppressing the MAPK pathway, especially the phosphorylation of p38 and ERK. MPX also decreased the oxidative stress response caused by LPS and upregulated Occludin and Claudin-1 expression, thereby maintaining the integrity of the blood-testis barrier. Moreover, we found that MPX inhibited apoptosis in Sertoli cells. In a mouse model, we found that MPX significantly inhibited the disruptive effects of LPS, reducing seminiferous epithelium damage, vacuolations, hyperplasia, and apoptosis in spermatogenic cells and rescuing spermatogenesis. In addition, the expression of inflammatory factors such as IL-1β, IL-18, IL-6 and TNF-α was decreased after MPX treatment in the mouse testes. MPX had no effect on other organs in mice, indicating its safety. This study was undertaken to investigate how MPX regulates the inflammatory response in Sertoli cells and provide a reference for the clinical prevention and treatment of male animal orchitis.

This study aimed to explore the prevalence and distribution of mental disorders in the elderly population 5 years after the Lushan earthquake in Ya'an, China.A multi-stage, group-matching random sampling method was adopted with 2579 elderly participants (≥ 60 years old) who were interviewed from January to May 2019. Preliminary screening was conducted using the scale by trained psychiatric nurses, followed by a diagnostic interview during the second stage using Chinese Version of the 5th edition of the Diagnostic and Statistical Manual of Mental Disorder by trained psychiatrists.A total of 2561 participants were included in this study with complete data. The weighted lifetime prevalence of all mental disorders in the elderly was 16.2% (95% CI 15.3-17.1), and the weighted 12-month prevalence was 15.2% (95% CI 13.4-17.0). Depressive disorders, anxiety disorders, substance-related and addictive disorders were the most common mental disorders. The 12-month prevalence of all mental disorders were significantly higher in the elderly living alone, with chronic somatic disease, and being poor (P 0.05). The 12-month prevalence of posttraumatic stress disorder (PTSD) was significantly higher in the elderly in extremely severely earthquake-affected areas (P 0.001).The results of this study show that mental health status of the elderly in Ya'an area differ by socio-economic development, geographical location, and natural disasters. The social and economic development characteristics, the impact of major natural disasters (e.g., earthquakes), and population characteristics should be combined to formulate strategies and interventions to promote the mental health of the elderly.

Type 2 diabetes mellitus (DM) accounts for more and more individuals worldwide. D-dimer has been demonstrated to be associated with cardiovascular diseases. The aim is to study the potential impact of D-dimer on the long-term prognosis of acute coronary syndrome (ACS) in the special population with type 2 DM.A total of 2265 consecutive patients with DM and ACS were eligible in the study. Patients were divided into four groups according to quartiles of D-dimer concentration. Univariate and multivariate Cox regression analysis were conducted to explore the prognostic value of D-dimer for future outcomes. Patients with higher level of D-dimer presented with higher percentage of major adverse cardiovascular events (MACEs) (23.7%), all-cause death (18.3%) and cardiovascular (CV) death (9.4%) in Quartile 4. In multivariate Cox regression analysis, D-dimer was demonstrated to be independently associated with MACEs, all-cause death and CV death. The prognostic value of D-dimer is still significant in subgroups of HbA1C7% and ≥7%. In Kaplan-Meier analysis, higher D-dimer showed poorer prognosis in MACEs, all-cause death and CV death (all log rank p 0.001). The area under the curve (AUC) by receiver operating characteristic (ROC) curve analysis is 0.609 for MACEs, 0.708 for all-cause death, 0.747 for CV death (p 0.001).The present study demonstrated the independent predictive value of D-dimer for outcomes in DM patients with ACS. In addition, for the first time, we explored the prognostic value in different glucose control status.

The superiorities of renewable energy, such as wind and solar energy, have promoted the development of microgrids (MGs) and multi-microgrids (MMGs). However, how to coordinate the scheduling and transactions of MMGs with multi-timescale is still an important issue. This paper presents a scheduling and trading strategy of MMGs with two time-scales: day-ahead and intra-day. In the day-ahead scheduling stage, a MMG system with peer-to-peer connection is considered. Based on the idea of distributed updating parameters and adaptive selecting values in Alternating Direction Method of Multipliers (ADMM), an accelerated ADMM algorithm named improved adaptive accelerated ADMM (IAA-ADMM) is proposed, which is modeled and solved in a distributed manner. In the intra-day scheduling stage, based on the day-ahead scheduling, this paper utilizes stochastic model predictive control (SMPC) to optimize the intra-day model, which helps address the uncertainties of wind, solar, and load forecasting. The effectiveness of the proposed approach is validated using numerical examples. The results show that the IAA-ADMM provides higher stability and faster convergence and facilitates easier implementation. The SMPC shows higher economic performance and has a higher application potential.

Wind power, as an eco-friendly renewable energy, has been widely integrated into modern power systems. The prediction accuracy of wind power is crucial to the secure operation of power systems. To improve the prediction accuracy, a hybrid hour-ahead wind power prediction method is presented in this paper. First, the variational mode decomposition (VMD) is used to decompose the original wind power sequences into a set of intrinsic mode functions (IMFs) with different frequencies. Then, the prediction model is formulated by using the long short-term memory (LSTM) network for each IMF. To enhance the LSTM, a bio-inspired algorithm named Harris Hawks optimization (HHO) is blended to optimize the parameters of each LSTM prediction model. The final prediction output power is thus obtained by integrating all prediction results from these individual IMFs, so that the novel VMD–HHO–LSTM prediction strategy is developed. Finally, case studies based on the real historical dataset are performed, demonstrating that the proposed hybrid hour-ahead wind power prediction model named VMD–HHO–LSTM has better prediction performance and higher applicability to multiple dataset scenarios.

Since 2007, the Yellow Sea has undergone a large-scale outbreak of green tide for 15 years. The large biomass of green tide has caused great economic losses to Shandong and Jiangsu Province. The monitoring data in the recent years indicated that the dominant algae in the Southern Yellow Sea (SYS) was a special ecological type of Ulva species (Ulva prolifera). In order to make rational use of green tide algae and avoid the waste of biological resources, the achievements in the research and technical development on the resource utilization of green tide algae were systematically introduced. Moreover, the utilization and development of U. prolifera, such as food, beauty products, feed or feed additives, fertilizer, energy and papermaking engineering, were summarized. In addition, solutions to reduce the losses caused by the outbreak of green tide algae were also proposed.

Trifluridine, a key component of trifluridine/tipiracil, is a potential anti-cancer drug that can act effectively on refractory metastatic colorectal cancer. Chemotherapy is important for cancer treatment, but its adverse effects limit its use. Long-term side-effects caused by the drug used during chemotherapy are closely related to the accumulation of cellular senescence. However, the relationship between trifluridine and normal cell aging remains unclear. The purpose of this study is to evaluate whether trifluridine can induce the senescence of human umbilical vein endothelial cells and to explore the possible mechanism. Human umbilical vein endothelial cells were treated with trifluridine, senescence levels were measured via senescence-related acidic β-galactosidase staining and senescence-associated secretory phenotype levels respectively. Autophagy was assessed by the protein levels of LC3II/LC3I and p62, and LC3 fusion was detected by fluorescence microscopy. Chloroquine diphosphate salt and rapamycin were used to detect the effect of trifluridine on autophagy flux and mTOR signaling pathway. Trifluridine increased the expression of senescence-associated acidic β-galactosidase and senescence-related secretory phenotype mRNA levels in cells. In addition, also trifluridine induced cellular senescence by inhibiting autophagy and was closely related to the activation of the mTOR signaling pathway, therefore, we believe that trifluridine may be an effective mTOR activator. The findings also provide a new strategy for establishing autophagy or aging models, as well as a new theoretical basis for the use of trifluridine in clinical treatment.

Five new polycyclic polyprenylated acylphloroglucinols (1-5), ascyrones A-E, and four known compounds (6-9) were isolated from the aerial parts of Hypericum ascyron. All of the isolates containing a bicyclo[3.3.1]nonane-2,4,9-trione core and a benzoyl group, belonged to type B bicyclic polyprenylated acylphloroglucinols (BPAPs). Their structures and absolute configurations were established based on spectroscopic analyses and calculated electronic circular dichroism (ECD) data. The anti-inflammatory, neuroprotective and cytotoxicity activities of compounds 1-4 and 6-9 were evaluated. Compound 6 exhibited obvious anti-inflammatory activity in lipopolysaccharide (LPS)-induced RAW264.7 cells. Compounds 1 and 9 exhibited slight cytotoxicity against Hep3B cells. Meanwhile, compound 1 showed mild neuroprotective activity against corticosterone (CORT)-induced PC12 cell damage at 10 μmol·L

The aim of this study was assessing the mechanism of HIF-1α gene carried with albumin nanoparticles in regulating the tumor angiogenesis in HPV through induction of PI3K/AKT signal pathway. 40 of Wistar rats were divided into blank set, HIF-1α set, agonist set and inhibitor set randomly. There were 10 rats in every set. The gene expression of HIF-1α, presentation rate of CD31 and SMA, protein expression of VEGF and TSP-1, and presentation of factors related with PI3K/AKT signal pathway were all studied. HIF-1α gene carried with albumin nanoparticles was prepared successfully, and the gene expression of HIF-1α in HIF-1α set was highest. The second highest expression was in the inhibitor set, while the lowest was in the blank and agonist sets. There were notably-visible tan particles in the tumor tissue from the blank, HIF-1α and agonist sets, and they were reduced notably in the inhibitor set. The presentation rates for CD31 and SMA in the tumor tissues from the blank, HIF-1α and agonist sets were highest, while the rate was reduced in the inhibitor set. The action on VEGF protein expression was similar, and there was positive correlation between abnormal activation of HIF-1α and tumor angiogenesis in HPV. The PI3k/AKT signal transduction pathway was activated by HIF-1α and PI3k and AKI were phosphorylated. The HIF-1α was prompted to enter into cell nucleus and interact with element with low oxygen effect so as to increase the presentation of VEGF, CD31 and SMA. The angiogenesis in the HPV was also prompted, but the action was eliminated by inhibitor from the PI3K/AKT pathway.

The primary processed product of Panax ginseng C.A. Meyer (P. ginseng) is red ginseng. As technology advances, new products of red ginseng have arisen. Red ginseng products, e.g., traditional red ginseng, sun ginseng, black ginseng, fermented red ginseng, and puffed red ginseng, are commonly used in herbal medicine. Ginsenosides are the major secondary metabolites of P. ginseng. The constituents of P. ginseng are significantly changed during processing, and several pharmacological activities of red ginseng products are dramatically increased compared to white ginseng. In this paper, we aimed to review the ginsenosides and pharmacological activities of various red ginseng products, the transformation law of ginsenosides in processing, and some clinical trials of red ginseng products. This article will help to highlight the diverse pharmacological properties of red ginseng products and aid in the future development of red ginseng industrialization.

As a copper (Cu) transport ATPase, ATP7B plays an important role in maintaining Cu homeostasis in the body and its dysfunction is associated with retinal disease. How ATP7B dysfunction and the subsequent Cu overload induce retinal damage, however, are unknown. Here, we show that atp7b−/− homozygous zebrafish larvae are insensitive to light stimulation, with a reduction in retinal cells but normal like morphological phenotypes. Additionally, a series of differentially expressed genes are unveiled in atp7b−/− mutated larvae, which enrich in photo-transduction, structural constituent of eye lens, sensory perception of light stimulus, oxidative phosphorylation, and ATPase activity. Moreover, we show the Cu accumulation in retinal cells in atp7b−/− mutated larvae, which results in endoplasmic reticulum (ER) stress and retinal cell apoptosis and subsequent retinal defects. The integral data in this study demonstrate that atp7b mutation leads to Cu accumulation in zebrafish retinal cells and the consequence ER stress and retinal cell death. These data may give some possible hints to explain retinal disease occurred in the Cu dysregulation syndromes Wilson’s disease with ATP7B mutation.

Improving energy efficiency is an effective way to achieve carbon neutrality in the context of growing advocacy for a green economy in both academia and government. In this study, we analyzed the impact mechanism of the manufacturing agglomeration on total factor energy efficiency. Based on this work, we identified 30 provinces (autonomous regions and municipalities) in China using 2002 to 2017 panel data. We used the data envelopment analysis game cross-efficiency model to calculate the interprovincial current state of energy efficiency. We constructed a spatial Durbin model and used an adjacent space weight matrix, geographic distance weight matrix, and economic distance weight matrix to study the impact of manufacturing agglomeration on total factor energy efficiency. The results showed that under different spatial weights, the interprovincial total factor energy efficiency had a significant spatial dependence; under the three spatial weights, we identified a U-shaped relationship between manufacturing agglomeration and total factor energy efficiency. Industrial agglomeration had obvious spatial spillover effects on total factor energy efficiency, and the spillover effects under the weight of geographic distance were higher than other spatial weights. During the sample period, the direct, indirect, and total effects of the manufacturing industry had an impact on energy efficiency. It all had a negative number indicating that there was a crowding effect in manufacturing agglomeration, and it had an inhibitory effect on energy efficiency.

Labetuzumab govitecan (IMMU-130), an antibody–drug conjugate (ADC) with an average of 7.6 SN-38/IgG, was evaluated for its potential to enhance delivery of SN-38 to human colonic tumor xenografts. Mice bearing LS174T or GW-39 human colonic tumor xenografts were injected with irinotecan or IMMU-130 (SN-38 equivalents ∼500 or ∼16 μg, respectively). Serum and homogenates of tumors, liver, and small intestine were extracted, and SN-38, SN-38G (glucuronidated SN-38), and irinotecan concentrations determined by reversed-phase HPLC. Irinotecan cleared quickly from serum, with only 1% to 2% injected dose/mL after 5 minutes; overall, approximately 20% was converted to SN-38 and SN-38G. At 1 hour with IMMU-130, 45% to 63% injected dose/mL of the SN-38 was in the serum, with >90% bound to the ADC over 3 days, and with low levels of SN-38G. Total SN-38 levels decreased more quickly than the IgG, confirming a gradual SN-38 release from the ADC. AUC analysis found that SN-38 levels were approximately 11- and 16-fold higher in LS174T and GW-39 tumors, respectively, in IMMU-130–treated animals. This delivery advantage is amplified >30-fold when normalized to SN-38 equivalents injected for each product. Levels of SN-38 and SN-38G were appreciably lower in the liver and small intestinal contents in animals given IMMU-130. On the basis of the SN-38 equivalents administered, IMMU-130 potentially delivers >300-fold more SN-38 to CEA-producing tumors compared with irinotecan, while also reducing levels of SN-38 and SN-38G in normal tissues. These observations are consistent with preclinical and clinical data showing efficacy and improved safety. Mol Cancer Ther; 17(1); 196–203. ©2017 AACR.

Supplementary Table S1. Extraction efficiency for isolation of SN-38 in buffer with or without human serum albumin (HSA) or from the ADC with or without acid hydrolysis followed by extraction; Supplementary Figure S1. Schematic depiction of the conjugation of CL2A-SN-38 to mildly reduced IgG yielding site-specifically coupled SN-38 to 8 well-defined sites; Supplementary Figure S2. CL2A-SN38 amide capped with N-acetylcysteine; Supplementary Figure S3. SDS-Page gels comparing profiles for labetuzumab (unconjugated hMN-14 IgG) and labetuzumab govitecan (CL2A-SN-38 conjugated hMN-14 IgG; IMMU-130); Supplementary Figure S4. In vitro cell binding assay performed on LS174T cells, evaluating the binding of unconjugated hMN-14 IgG and SN-38-conjugated hMN-14 IgG (IMMU-130); Supplementary Figure S5. Stability of IMMU-130 in serum from different sources; Supplementary Figure S6. Evaluation of lactone ring stability of the CL2A-linked SN-38 compared to SN-38 at pH 7.4.

EAF1 and EAF2, the eleven-nineteen lysine-rich leukemia (ELL)-associated factors which can assemble to the super elongation complex (AFF1/4, AF9/ENL, ELL, and P-TEFb), are reported to participate in RNA polymerase II to actively regulate a variety of biological processes, including leukemia and embryogenesis, but whether and how EAF1/2 function in hematopoietic system related hypoxia tolerance during embryogenesis remains unclear. Here, we unveiled that deletion of EAF1/2 (eaf1−/− and eaf2−/−) caused reduction in hypoxia tolerance in zebrafish, leading to reduced erythropoiesis during hematopoietic processes. Meanwhile, eaf1−/− and eaf2−/− mutants showed significant reduction in the expression of key transcriptional regulators scl, lmo2, and gata1a in erythropoiesis at both 24 h post fertilization (hpf) and 72 hpf, with gata1a downregulated while scl and lmo2 upregulated at 14 hpf. Mechanistically, eaf1−/− and eaf2−/− mutants exhibited significant changes in the expression of epigenetic modified histones, with a significant increase in the binding enrichment of modified histone H3K27me3 in gata1a promoter rather than scl and lmo2 promoters. Additionally, eaf1−/− and eaf2−/− mutants exhibited a dynamic expression of canonical WNT/β-catenin signaling during erythropoiesis, with significant reduction in p-β-Catenin level and in the binding enrichment of both scl and lmo2 promoters with the WNT transcriptional factor TCF4 at 24 hpf. These findings demonstrate an important role of Eaf1/2 in erythropoiesis in zebrafish and may have shed some light on regeneration medicine for anemia and related diseases and on molecular basis for fish economic or productive traits, such as growth, disease resistance, hypoxia tolerance, and so on.

Figure S1. No significant change was observed in LVEF at baseline and after treatment (p=0.669, Kruskal-Wallis rank sum test).