Publications by authors named "Na Qiao"

58 Publications

Long-term copper exposure promotes apoptosis and autophagy by inducing oxidative stress in pig testis.

Environ Sci Pollut Res Int 2021 Jun 15. Epub 2021 Jun 15.

College of Veterinary, South China Agricultural University, Guangzhou, 510642, China.

Copper (Cu) is a heavy metal which is being used widely in the industry and agriculture. However, the overuse of Cu makes it a common environmental pollutant. In order to investigate the testicular toxicity of Cu, the pigs were divided into three groups and were given Cu at 10 (control), 125, and 250 mg/kg body weight, respectively. The feeding period was 80 days. Serum hormone results showed that Cu exposure decreased the concentrations of follicular stimulating hormone (FSH) and luteinizing hormone (LH) and increased the concentration of thyroxine (T4). Meanwhile, Cu exposure upregulated the expression of Cu transporter mRNA (Slc31a1, ATP7A, and ATP7B) in the testis, leading to increase in testicular Cu and led to spermatogenesis disorder. The Cu exposure led to an increased expression of antioxidant-related mRNA (Gpx4, TRX, HO-1, SOD1, SOD2, SOD3, CAT), along with increase in the MDA concentration in the testis. In LG group, the ROS in the testis was significantly increased. Furthermore, the apoptotic-related mRNA (Caspase3, Caspase8, Caspase9, Bax, Cytc, Bak1, APAF1, p53) and protein (Active Caspase3) and the autophagy-related mRNA (Beclin1, ATG5, LC3, and LC3B) expression increased after Cu exposure. The mitochondrial membrane potential in the testicular tissue decreased, while the number of apoptotic cells increased, as a result of oxidative stress. Overall, our study indicated that the Cu exposure promotes testicular apoptosis and autophagy by mediating oxidative stress, which is considered as the key mechanism causing testicular degeneration as well as dysfunction.
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http://dx.doi.org/10.1007/s11356-021-14853-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203493PMC
June 2021

Metabolomics and transcriptomics indicated the molecular targets of copper to the pig kidney.

Ecotoxicol Environ Saf 2021 May 1;218:112284. Epub 2021 May 1.

College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China. Electronic address:

Copper poses huge environmental and public health concerns due to its widespread and persistent use in the past several decades. Although it is well established that at higher levels copper causes nephrotoxicity, the exact mechanisms of its toxicity is not fully understood. Therefore, this experimental study for the first time investigates the potential molecular mechanisms including transcriptomics, metabolomics, serum biochemical, histopathological, cell apoptosis and autophagy in copper-induced renal toxicity in pigs. A total of 14 piglets were randomly assigned to two group (7 piglets per group) and treated with a standard diet (11 mg CuSO per kg of feed) and a high copper diet (250 mg CuSO per kg of feed). The results of serum biochemical tests and renal histopathology suggested that 250 mg/kg CuSO in the diet significantly increased serum creatinine (CREA) and induced renal tubular epithelial cell swelling. Results on transcriptomics and metabolomics showed alteration in 804 genes and 53 metabolites in kidneys of treated pigs, respectively. Combined analysis of transcriptomics and metabolomics indicated that different genes and metabolism pathways in kidneys of treated pigs were involved in glycerophospholipids metabolism and glycosphingolipid metabolism. Furthermore, copper induced mitochondrial apoptosis characterized by increased bax, bak, caspase 3, caspase 8 and caspase 9 expressions while decreased bcl-xl and bcl2/bax expression. Exposure to copper decreased the autophagic flux in terms of increased number of autophagosomes, beclin1 and LC3b/LC3a expression and p62 accumulation. These results indicated that the imbalance of glycosphingolipid metabolism, the impairment of autophagy and increase mitochondrial apoptosis play an important role in copper induced renal damage and are useful mechanisms to understand the mechanisms of copper nephrotoxicity.
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http://dx.doi.org/10.1016/j.ecoenv.2021.112284DOI Listing
May 2021

Effects of 25(OH)D supplementation during late gestation on the serum biochemistry and reproductive performance of aged sows and newborn piglets.

J Anim Physiol Anim Nutr (Berl) 2021 Mar 13. Epub 2021 Mar 13.

College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.

The purpose of this study was to investigate the effects of diet type (normal or low Ca and P diets) and 25(OH)D supplementation (with or with not 2000 IU/kg 25(OH)D ) during late gestation on the serum biochemistry and reproductive performance of aged sows and newborn piglets. A total of 40 sows, which are at their 7th parity, were divided into four groups: control group (standard diet), low Ca group, 25(OH)D group and low Ca plus 25(OH)D group respectively (10 in each group). The blood of sows on day 100 and 114 of gestation and newborn piglets was collected for serum biochemical analyses. Results showed that the reproductive performance of sows was not influenced by diet type or 25(OH)D supplementation (p > 0.05). And the addition of 25(OH)D to diet low Ca group caused that the content of serum TG in sows on day 100 of gestation was not different from that of the control group (p > 0.05). The addition of 25(OH)D significantly decreases the content of serum TG in sows on day 114 of gestation (p < 0.05). The addition of 25(OH)D significantly increased the content of serum UREA and CREA in newborn piglets (p < 0.05). Overall, feeding 2000 IU/kg 25(OH)D to aged sows at late gestation had no effects on reproductive performance, but partly contributed to keeping serum TG balance in sows and may indicate increased pressure on kidneys in newborn piglets.
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http://dx.doi.org/10.1111/jpn.13530DOI Listing
March 2021

Acetyl-L-Carnitine Induces Autophagy to Promote Mouse Spermatogonia Cell Recovery after Heat Stress Damage.

Biomed Res Int 2021 18;2021:8871328. Epub 2021 Jan 18.

College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.

Acetyl-L-carnitine (ALC) is an effective substrate for mitochondrial energy metabolism and is known to prevent neurodegeneration and attenuate heavy metal-induced injury. In this study, we investigated the function of ALC in the recovery of mouse spermatogonia cells (GC-1 cells) after heat stress (HS). The cells were randomly divided into three groups: control group, HS group (incubated at 42°C for 90 min), and HS + ALC group (treatment of 150 M ALC after incubated at 42°C for 90 min). After heat stress, all of the cells were recovered at 37°C for 6 h. In this study, the content of intracellular lactate dehydrogenase (LDH) in the cell supernatant and the malondialdehyde (MDA) levels, catalase (CAT) levels, and total antioxidant capacity (T-AOC) were significantly increased in the HS group compared to the CON group. In addition, the mitochondrial membrane potential (MMP) was markedly decreased, while the apoptosis rate and the expression of apoptosis-related genes (Bcl-2, Bax, and caspase3) were significantly increased in the HS group compared to the CON group. Furthermore, the number of autophagosomes and the expression of autophagy-related genes (Atg5, Beclin1, and LC3II) and protein levels of p62 were increased, but the expression of LAMP1 was decreased in the HS group compared to the CON group. However, treatment with ALC remarkably improved cell survival and decreased cell oxidative stress. It was unexpected that levels of autophagy were markedly increased in the HS + ALC group compared to the HS group. Taken together, our present study evidenced that ALC could alleviate oxidative stress and improve the level of autophagy to accelerate the recovery of GC-1 cells after heat stress.
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http://dx.doi.org/10.1155/2021/8871328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837762PMC
May 2021

Cu-induced mitochondrial dysfunction is mediated by abnormal mitochondrial fission through oxidative stress in primary chicken embryo hepatocytes.

J Trace Elem Med Biol 2021 May 23;65:126721. Epub 2021 Jan 23.

College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China. Electronic address:

Background: Excess copper (Cu) is an oxidative stress factor which associates with a variety of diseases. The aim of this study was to evaluate the effect of Cu in primary chicken embryo hepatocytes (CEHs).

Methods: CEHs were isolated from 13 days old chicken embryos and followed by different concentration Cu (0, 10, 100, 200 μM) and/or ALC treatment (0.3 mg/mL) for 12 or 24 h. The effects of Cu exposure in CEHs were determined by detecting reactive oxygen species (ROS), malondialdehyde (MDA), mitochondrial membrane potential (MMP), and ATP levels. The expression of mitochondrial dynamics-related genes and proteins were also detected.

Results: Results showed that Cu treatment (100 or 200 μM) significantly decreased CEHs viability, MMP and ATP levels, increased ROS and MDA levels in 12 or 24 h. The up-regulated mitochondrial fission genes and protein in 100 and 200 μM Cu groups suggested Cu promoted mitochondrial division but not fusion. However, the co-treatment of ALC and Cu alleviated those changes compared with the 100 or 200 μM Cu groups.

Conclusion: In conclusion, we speculated that Cu increased the oxidative stress and induced mitochondria dysfunction via disturbing mitochondrial dynamic balance in CEHs, and this process was not completely reversible.
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http://dx.doi.org/10.1016/j.jtemb.2021.126721DOI Listing
May 2021

Subgroup analysis of nelipepimut-S plus GM-CSF combined with trastuzumab versus trastuzumab alone to prevent recurrences in patients with high-risk, HER2 low-expressing breast cancer.

Clin Immunol 2021 04 22;225:108679. Epub 2021 Jan 22.

Cancer Vaccine Development Program, 1422 E. Grayson, 3rd Floor, San Antonio, TX 78208, USA.

HER2-targeted therapy has not benefited patients with low levels of HER2 expression; however, combination therapy may be effective. Primary analysis of a phase IIb trial investigating the HER2-derived vaccine nelipepimut-S (NPS) did not benefit the intention-to-treat population, but subset analysis showed a benefit in triple-negative breast cancer (TNBC) patients. The subset analysis of this multicenter, randomized, single-blind, phase IIb trial identified significant improvement in 36-month disease-free survival (DFS) between NPS (n = 55) and placebo (n = 44) in TNBC (HR 0.25, p = 0.01) and those who express HLA-A24 (HR 0.41, p = 0.05). The TNBC cohort demonstrated improved 36-month DFS in those with HER2 1+ expression (HR 0.17, p = 0.01), HLA-A24 positivity (HR 0.08, p < 0.01), or in those who received neoadjuvant chemotherapy (HR 0.21, p < 0.01). NPS vaccination with trastuzumab was associated with improved 36-month DFS among patients with TNBC. The observed benefit to this high-risk subgroup warrants confirmation in a phase III trial.
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http://dx.doi.org/10.1016/j.clim.2021.108679DOI Listing
April 2021

The hepatotoxicity of altrazine exposure in mice involves the intestinal microbiota.

Chemosphere 2021 Jun 11;272:129572. Epub 2021 Jan 11.

College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China. Electronic address:

Atrazine (ATR), a bio accumulative herbicide is frequently used in agriculture to control unwanted weeds. Due to continuous application, atrazine persists in the environment and causes deleterious impacts including neurotoxicity, hepatotoxicity, and gut microbiota disorders. Therefore, this study for the first time reports the variation in the gut microbiota, induction of process of apoptosis and autophagy in mice induced by ATR. Results indicated that TUNEL-positive hepatocytes suggestive of apoptosis were increased in livers of different experimental mice. Results on metabolic analysis in liver tissues indicated an overall change in seventy-six metabolites particularly Uridine 5'-diphosphate, Propenoylcarnitine and Chinenoside V resulting in generation of energy-related metabolic disorders and imbalance of oxidation/autoxidation status. Results on gut microbiome inquisition showed that ATR changed the richness and diversity of gut microbiota of mice and number of Firmicutes. Moreover, results also revealed that ATR induced apoptosis via disruption of apoptotic (Bax, Bcl2, and Casp3) and autophagy (LC3/Map1lc3a, Beclin 1/Becn1 and P62/Sqstm1) genes. Results of our experimental study confirmed that changes in gut microbiota play a significant role in process of gut immune regulation and inflammation via different metabolites. In conclusion, the findings of our study provide a new idea for the involvement of mechanisms of detoxification in liver and inquisition of gut microbiota plays crucial role in regulation of physiological activities through liver-gut axis to mitigate toxic effects in animals.
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http://dx.doi.org/10.1016/j.chemosphere.2021.129572DOI Listing
June 2021

Exposure to copper induces mitochondria-mediated apoptosis by inhibiting mitophagy and the PINK1/parkin pathway in chicken (Gallus gallus) livers.

J Hazard Mater 2021 04 19;408:124888. Epub 2020 Dec 19.

College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, Guangdong, PR China. Electronic address:

Copper (Cu), a transition metal with essential cellular functions, exerts toxic effects when present in excess by inducing oxidative stress. However, the Cu-induced crosstalk between mitophagy and apoptosis and the underlying mechanisms are unknown. Here, the mechanism of Cu-induced hepatotoxicity mediated by mitophagy and apoptosis was explored in vivo and in vitro. In in vivo experiments, chickens were fed a diet with various levels of Cu (11, 110, 220, and 330 mg/kg) for 7 weeks, which led to ultrastructural damage, mitophagy, and apoptosis in liver tissue. In vitro experiments on primary chicken hepatocytes showed that Cu treatment for 24 h increased the numbers of mitophagosomes and upregulated PINK1, parkin, and p62 mRNA levels and parkin and p62 protein levels, inducing mitophagy. Moreover, treatment with 3- methyladenine (3-MA) aggravated Cu-induced S-phase arrest in cell cycle; increased the apoptotic rate; increased p53, Bak1, Bax, Cyt C, and Caspase3/cleaved-caspase3 mRNA and protein levels; and decreased Bcl2 mRNA and protein levels. However, rapamycin (Rapa) had the opposite effects on the above factors. In general, the results reveal that Cu exposure can cause mitophagy through the PINK1/Parkin pathway in chicken livers, and that mitophagy might attenuate Cu-induced mitochondrial apoptosis.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124888DOI Listing
April 2021

Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers.

Nat Commun 2020 10 21;11(1):5332. Epub 2020 Oct 21.

Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA.

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types.
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http://dx.doi.org/10.1038/s41467-020-19141-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577998PMC
October 2020

Copper induces energy metabolic dysfunction and AMPK-mTOR pathway-mediated autophagy in kidney of broiler chickens.

Ecotoxicol Environ Saf 2020 Dec 30;206:111366. Epub 2020 Sep 30.

College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China. Electronic address:

To explore the effects of copper (Cu) on energy metabolism and AMPK-mTOR pathway-mediated autophagy in kidney, a total of 240 one-day-old broiler chickens were randomized into four equal groups and fed on the diets with different levels of Cu (11, 110, 220, and 330 mg/kg) for 49 d. Results showed that excess Cu could induce vacuolar degeneration and increase the number of autophagosomes in kidney, and the adenosine triphosphate (ATP) level and mRNA levels of energy metabolism-related genes were decreased with the increasing dietary Cu level. Moreover, immunohistochemistry and immunofluorescence showed that the positive expressions of Beclin1 and LC3-II were mainly located in cytoplasm of renal tubular epithelial cells and increased significantly with the increasing levels of Cu. The mRNA levels of Beclin1, Atg5, LC3-I, LC3-II, Dynein and the protein levels of Beclin1, Atg5, LC3-II/LC3-I and p-AMPKα1/AMPKα1 were markedly elevated in treated groups compared with control group (11 mg/kg Cu). However, the mRNA and protein levels of p62 and p-mTOR/mTOR were significantly decreased with the increasing levels of Cu. These results suggest that impaired energy metabolism induced by Cu may lead to autophagy via AMPK-mTOR pathway in kidney of broiler chickens.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111366DOI Listing
December 2020

Integration of transcriptomic and metabolomic data reveals metabolic pathway alteration in mouse spermatogonia with the effect of copper exposure.

Chemosphere 2020 Oct 10;256:126974. Epub 2020 May 10.

College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China. Electronic address:

Copper is a widespread heavy metal in environment and has toxic effects when exposed. However, study of copper-induced male reproductive toxicity is still insufficient to report, and the underlying mechanisms are unknown. Keeping in view, RNA-Seq and metabolomic were performed to identify metabolic pathways that were distressed in mouse spermatogonia with the effect of copper sulfate, and the integrated analysis of the mechanism of copper administered GC-1 cells from metabolomic and transcriptomic data. Our results demonstrated that many genes and metabolites were regulated in the copper sulfate-treated cells. The differential metabolites analysis showed that 49 and 127 metabolites were significantly different in ESI+ and ESI- mode, respectively. Meanwhile, a total of 2813 genes were up-regulated and 2488 genes were down-regulated in the treatment groups compared to those in the control groups. Interestingly, ophthalmic acid and gamma glutamylleucine were markedly increased by copper treatment in two modes. By integrating with transcriptomic and metabolomic data, we revealed that 37 and 22 most related pathways were over-enriched in ESI+ and ESI- mode, respectively. Whereas, amino acid biosynthesis and metabolism play essential role in the potential relationship between DEGs and metabolites, which suggests that amino acid biosynthesis and metabolism may be the major metabolic pathways disturbed by copper in GC-1 cells. This study provides important clues and evidence for understanding the mechanisms responsible for copper-induced male spermatogenesis toxicity, and useful biomarkers indicative of copper exposure could be discovered from present study.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126974DOI Listing
October 2020

Copper induces oxidative stress with triggered NF-κB pathway leading to inflammatory responses in immune organs of chicken.

Ecotoxicol Environ Saf 2020 Sep 22;200:110715. Epub 2020 May 22.

College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, Guangdong, PR China. Electronic address:

Copper (Cu) is a necessary trace mineral due to its biological activity. Excessive Cu can induce inflammatory response in humans and animals, but the underlying mechanism is still unknown. Here, 240 broilers were used to study the effects of excessive Cu on oxidative stress and NF-κB-mediated inflammatory responses in immune organs. Chickens were fed with diet containing different concentrations of Cu (11, 110, 220, and 330 mg of Cu/kg dry matter). The experiment lasted for 49 days. Spleen, thymus, and bursa of Fabricius (BF) on day 49 were collected for histopathological observation and assessment of oxidative stress status. Additionally, the mRNA and protein levels of NF-κB and inflammatory cytokines were also analyzed. The results indicated that excess Cu could increase the number and area of splenic corpuscle as well as the ratio of cortex and medulla in thymus and BF. Furthermore, excessive Cu intake could decrease activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px); but increase contents of malondialdehyde (MDA), TNF-α, IL-1, IL-1β; up-regulate mRNA levels of TNF-α, IFN-γ, IL-1, IL-1β, IL-2, iNOS, COX-2, NF-κB and protein levels of TNF-α, IFN-γ, NF-κB, p-NF-κB in immune organs. In conclusion, excessive Cu could cause pathologic changes and induce oxidative stress with triggered NF-κB pathway, and might further regulate the inflammatory response in immune organs of chicken.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110715DOI Listing
September 2020

Evaluating the impacts of water resources technology progress on development and economic growth over the Northwest, China.

PLoS One 2020 12;15(3):e0229571. Epub 2020 Mar 12.

Northwest Institute of Historical Environment and Socio-Economic Development, Shaanxi Normal University, Xi'an, Shaanxi, China.

Water technologies have become new solutions to water scarcity and could play an increasingly crucial role in the future. However, theoretic and empirical studies on the economic effect of water technologies which incorporate water resources into a sustainable economic growth model remain scarce in northwest China. This article attempts to build a water technology endogenous model based on "learning by doing" theory to identify the mechanisms of water technologies affect economic growth due to changing water consumption. Considering the case of Northwest China in this empirical research, we apply the stochastic production frontier model by using panel data from 1996 to 2017. The results shows that progress in water technologies has indeed increased GDP growth and the current level of water technologies is not a key factor in eliminating the constraints of water resources. In addition, water scarcity still constrains economic growth in Northwest China and progress in water science and technology is the main power of all water technologies. Finally, the speed of water science and technology slows as the amount of water consumption increase and the impact of water technical efficiency on economic growth depends on water institutions of different areas. This study may enhance the policy relevance of water technological governance and economic growth transformation, which were beneficial for informing policies towards sustainable water resource utilization in northwest China.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229571PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067393PMC
June 2020

Results of a Randomized Phase IIb Trial of Nelipepimut-S + Trastuzumab versus Trastuzumab to Prevent Recurrences in Patients with High-Risk HER2 Low-Expressing Breast Cancer.

Clin Cancer Res 2020 06 18;26(11):2515-2523. Epub 2020 Feb 18.

Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Preclinical data provide evidence for synergism between HER2-targeted peptide vaccines and trastuzumab. The efficacy of this combination was evaluated in patients with HER2 low-expressing breast cancer in the adjuvant setting.

Patients And Methods: A phase IIb, multicenter, randomized, single-blinded, controlled trial enrolled disease-free patients after standard therapy completion (NCT01570036). Eligible patients were HLA-A2, A3, A24, and/or A26+, and had HER2 IHC 1+/2+, FISH nonamplified breast cancer, that was node positive and/or hormone receptor-negative [triple-negative breast cancer (TNBC)]. Patients received trastuzumab for 1 year and were randomized to placebo (GM-CSF, control) or nelipepimut-S (NPS) with GM-CSF. Primary outcome was 24-month disease-free survival (DFS). Secondary outcomes were 36-month DFS, safety, and immunologic response.

Results: Overall, 275 patients were randomized; 136 received NPS with GM-CSF, and 139 received placebo with GM-CSF. There were no clinicopathologic differences between groups. Concurrent trastuzumab and NPS with GM-CSF was safe with no additional overall or cardiac toxicity compared with control. At median follow-up of 25.7 (interquartile range, 18.4-32.7) months, estimated DFS did not significantly differ between NPS and control [HR, 0.62; 95% confidence interval (CI), 0.31-1.25; = 0.18]. In a planned exploratory analysis of patients with TNBC, DFS was improved for NPS versus control (HR, 0.26; 95% CI, 0.08-0.81, = 0.01).

Conclusions: The combination of NPS with trastuzumab is safe. In HER2 low-expressing breast cancer, no significant difference in DFS was seen in the intention-to-treat analysis; however, significant clinical benefit was seen in patients with TNBC. These findings warrant further investigation in a phase III randomized trial.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2741DOI Listing
June 2020

The effect of combined scalp acupuncture and cognitive training in patients with stroke on cognitive and motor functions.

NeuroRehabilitation 2020 ;46(1):75-82

Department of Physical Medicine and Rehabilitation, Zhongnan Hospital of Wuhan University, Wuhan, China.

Objective: To investigate the effect of combined scalp acupuncture and cognitive training on cognitive and motor functioning in patients with stroke during the recovery stage.

Methods: Seventy patients with post-stroke cognitive impairment were randomly divided into an experimental group and a control group. Patients in the experimental group additionally received scalp acupuncture and cognitive training, while the control group received sham scalp acupuncture and cognitive training. The cognitive and motor functioning of all patients were assessed using MMSE, LOTCA, and FMA, before and 12 weeks after treatment. In addition, the plasma BDNF and NGF levels were measured from peripheral blood samples using ELISA kits.

Results: After 12 weeks, the MMSE, LOTCA and FMA scores were significantly higher in the experimental group than in the control group. In the experimental group, there was an improvement in the total MMSE score, orientation, spatial executive function, the total LOTCA score, and the score of command of language orientation post-treatment. Significant improvements of BDNF and NGF were found in the experimental group after treatment, while only significant improvements of NGF was found in the control group after treatment. Both BDNF and NGF in the experiment group were higher than those in the control group at the last day of treatment.

Conclusions: Combined scalp acupuncture and cognitive training can efficiently enhance cognitive and motor functions in patients with stroke during the recovery stage, which may be a more effective rehabilitation treatment after stroke than routine therapy and rehabilitation training alone.
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http://dx.doi.org/10.3233/NRE-192942DOI Listing
July 2020

Two unique HLA-A*0201 restricted peptides derived from cyclin E as immunotherapeutic targets in leukemia.

Leukemia 2020 06 6;34(6):1626-1636. Epub 2020 Jan 6.

Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.

Immunotherapy targeting leukemia-associated antigens has shown promising results. Because of the heterogeneity of leukemia, vaccines with a single peptide have elicited only a limited immune response. Targeting several peptides together elicited peptide-specific cytotoxic T lymphocytes (CTLs) in leukemia patients, and this was associated with clinical responses. Thus, the discovery of novel antigens is essential. In the current study, we investigated cyclin E as a novel target for immunotherapy. Cyclin E1 and cyclin E2 were found to be highly expressed in hematologic malignancies, according to reverse transcription polymerase chain reaction and western blot analysis. We identified two HLA-A*0201 binding nonameric peptides, CCNE1 from cyclin E1 and CCNE2 from cyclin E2, which both elicited the peptide-specific CTLs. The peptide-specific CTLs specifically kill leukemia cells. Furthermore, CCNE1 and CCNE2 CTLs were increased in leukemia patients who underwent allogeneic hematopoietic stem cell transplantation, and this was associated with desired clinical outcomes. Our findings suggest that cyclin E1 and cyclin E2 are potential targets for immunotherapy in leukemia.
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http://dx.doi.org/10.1038/s41375-019-0698-zDOI Listing
June 2020

Toxic effects of arsenic trioxide on spermatogonia are associated with oxidative stress, mitochondrial dysfunction, autophagy and metabolomic alterations.

Ecotoxicol Environ Saf 2020 Mar 14;190:110063. Epub 2019 Dec 14.

College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China. Electronic address:

Arsenic is a toxic metalloid that can cause male reproductive malfunctions and is widely distributed in the environment. The aim of this study was to investigate the cytotoxicity of arsenic trioxide (ATO) induced GC-1 spermatogonial (spg) cells. Our results found that ATO increased the levels of catalase (CAT) and malonaldehyde (MDA) and reactive oxygen species (ROS), while decreasing glutathione (GSH) and the total antioxidant capacity (T-AOC). Therefore, ATO triggered oxidative stress in GC-1 spg cells. In addition, ATO also caused severe mitochondrial dysfunction that included an increase in residual oxygen consumption (ROX), and decreased the routine respiration, maximal and ATP-linked respiration (ATP-L-R), as well as spare respiratory capacity (SRC), and respiratory control rate (RCR); ATO also damaged the mitochondrial structure, including mitochondrial cristae disordered and dissolved, mitochondrial vacuolar degeneration. Moreover, degradation of p62, LC3 conversion, increasing the number of acidic vesicle organelles (AVOs) and autophagosomes and autolysosomes are demonstrated that the cytotoxicity of ATO may be associated with autophagy. Meanwhile, the metabolomics analysis results showed that 20 metabolites (10 increased and 10 decreased) were significantly altered with the ATO exposure, suggesting that maybe there are the perturbations in amino acid metabolism, lipid metabolism, glycan biosynthesis and metabolism, metabolism of cofactors and vitamins. We concluded that ATO was toxic to GC-1 spg cells via inducing oxidative stress, mitochondrial dysfunction and autophagy as well as the disruption of normal metabolism. This study will aid our understanding of the mechanisms behind ATO-induced spermatogenic toxicity.
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http://dx.doi.org/10.1016/j.ecoenv.2019.110063DOI Listing
March 2020

Speeding up in Vitro Discovery of Structure-Switching Aptamers via Magnetic Cross-Linking Precipitation.

Anal Chem 2019 11 16;91(21):13383-13389. Epub 2019 Oct 16.

Department of Chemistry , Capital Normal University , Xisanhuan North Road. 105 , Beijing 100048 , China.

We report here a modified aptamer selection method, magnetic cross-linking precipitation (MCP)-SELEX, for highly efficient library enrichment and aptamer isolation. MCP-SELEX isolates bound aptamers via highly efficient chemical cross-linking between amino groups of target proteins and activated carboxylic acid groups on magnetic beads (>90% coupling efficiency). Importantly, MCP-SELEX avoids surface interferences in conventional target-fixed methods and substantially minimizes nonspecific binding. The enrichment efficiencies of MCP-SELEX for various proteins (PD-L1, ubiquitin, thrombin, and HSA) were all greatly higher than those of the conventional target-bound magnetic bead based-SELEX (MB-SELEX). Antithrombin aptamer with K of 33 nM was successfully isolated by four rounds of MCP-SELEX. MCP-SELEX also enabled the efficient aptamer isolation by coupling with MB-SELEX or falling-off-SELEX. We identified structure-switching aptamers (SSAs) that specifically bind to HSA with low nanomolar dissociation constant via three rounds of MCP-SELEX and 1 round of falling-off-SELEX. Our HSA SSAs also have ∼3-fold higher specificity against streptavidin relative to thrombin SSAs discovered through falling-off-SELEX only. The enriched library has ∼78-fold higher signal-to-noise ratio (the number of DNAs eluted by 50 nM HSA divided by the number of DNAs self-dissociated in blank buffer) than that obtained by 4 rounds of direct falling-off-SELEX. We finally demonstrated the application of the selected SSA in fluorescent detection of HSA in urine with diagnostic required sensitivity and dynamic range. We expect that MCP-SELEX may be coupled with other selection methods to substantially accelerate aptamer discovery.
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http://dx.doi.org/10.1021/acs.analchem.9b00081DOI Listing
November 2019

Copper-induced apoptosis and autophagy through oxidative stress-mediated mitochondrial dysfunction in male germ cells.

Toxicol In Vitro 2019 Dec 3;61:104639. Epub 2019 Sep 3.

College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, People's Republic of China. Electronic address:

Excess copper reduces sperm number and motility but the causes are unclear. We investigated the toxic effects of copper exposure on the immortalized male germ cell line GC-1. Copper addition to cells altered viability and morphology in a dose-dependent manner. Copper addition resulted in increased levels of reactive oxygen species (ROS), malonaldehyde (MDA) and lactate dehydrogenase (LDH) while catalase (CAT) activity and glutathione (GSH) declined. The mitochondrial transmembrane potential and ATP levels decreased in response to copper as did mitochondria fission that led to mitochondrial dysfunction. The apoptosis rate was also proportional to the level of copper in the growth medium. Copper also down-regulated Bcl2 and up-regulated Bax, Casp8 and Casp3 linking the effects of copper to increased apoptosis. The levels of mRNA for the autophagy-related genes (Atg3, Atg5, p62, Lc3b/Lc3a) and proteins (Lc3b/Lc3a, BECN1, Atg5, p62) all increased in copper-treated cells as were levels Lc3 determined by fluorescence microscopy. These results indicated that copper induces apoptosis and autophagy through oxidative stress-mediated mitochondrial dysfunction.
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http://dx.doi.org/10.1016/j.tiv.2019.104639DOI Listing
December 2019

Chronic Copper Exposure Induces Hypospermatogenesis in Mice by Increasing Apoptosis Without Affecting Testosterone Secretion.

Biol Trace Elem Res 2020 Jun 23;195(2):472-480. Epub 2019 Aug 23.

College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.

Chronic copper exposure impaired spermatogenesis in adult male mice. The aim of this study was to determine whether chronic copper exposure can induce apoptosis of testicular cell and hypospermatogenesis via disturbing testosterone synthesis in adult male mice. In the present study, sixty CD-1 male mice were randomly divided into four groups, and were continuously administered for 8 weeks by oral gavage with copper sulfate at a dose of 0, 25, 100, and 150 mg/kg/day, respectively. We determined the content of serum and testicular copper, testicular coefficient, testicular histopathology, sperm count and motility, the mRNA and protein levels of Caspase-3, Bax, and Bcl-2, Leydig cell count, testosterone content, testosterone synthetase, and testosterone synthesis-related genes. The results showed that the copper levels in serum increased in a dose-dependent manner, and the copper levels in testes were significantly related to serum copper levels. Male mice given copper sulfate 100 and 150 dosage groups showed significant decreased in sperm motility and sperm number as well as increased in testes damage, and there was no significant change in testicular coefficient in the four groups. The mRNA levels of Bcl-2 decreased and Caspase-3 increased in 150 dosage group, and Bax increased in two higher dosage groups. Meanwhile, Caspase-3 and Bax proteins increased in 150 dosage group, and Bcl-2 protein decreased in three copper treatment groups. Nevertheless, there were no differences on the levels of testosterone content and testosterone synthetase of 3β-HSD, 17β-HSD, 17α-Hyd, and 20α-Hyd, mRNA levels of Cyp11a1, Cyp17a1, and Star, and quantity of Leydig cells in four groups. Overall, these data showed that chronic copper exposure led to copper residues in the testes, and the doses of 100 and 150 mg/kg/day copper sulfate may induce hypospermatogenesis by increasing apoptosis without affecting testosterone secretion.
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http://dx.doi.org/10.1007/s12011-019-01852-xDOI Listing
June 2020

Effect of a background Ca entry pathway mediated by TRPC1 on myocardial damage of broilers with induced ascites syndrome.

Avian Pathol 2019 Oct 19;48(5):429-436. Epub 2019 Jul 19.

College of Veterinary Medicine, South China Agricultural University , Guangzhou , P. R. People's Republic of China.

Ascites syndrome (AS) in chickens is associated with profound vascular remodelling and increased pulmonary artery pressure as well as right ventricular hypertrophy. Classical transient receptor potential cation channels (TRPCs) are key regulators of cardiac hypertrophy that act regulation of calcium influx in mammals. We investigated whether classical transient receptor potential channels in chickens with right ventricular hypertrophy still possess this mechanism for regulating Ca flux. Intravenous injection of cellulose particles was successfully used to induce AS in chickens, and tissues were examined 22 days after treatment. The chickens in the test group showed cardiac hypertrophy with oedema of the cardiac muscle and disruption of myofilaments. The right-to-total ventricle weight ratio (RV/TV), the levels of serum aspartate aminotransferase (AST) and creatine kinase (CK) of the test group were significantly higher than in the control group. Intracellular calcium levels were significantly increased in cardiomyocytes from chickens in the test group. Gene expression of TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7 in heart tissues from the test group showed no significant differences compared with controls. However, TRPC1 protein levels, as well as mRNA levels, were down-regulated in the heart muscle of AS chickens ( < 0.05). Although we observed an increase in calcium concentration, the expression of TRPC1 decreased in cardiac cells. We hypothesized that an increase in intracellular free calcium concentration could inversely regulate calcium channel expression. Intracellular Ca levels were increased in the myocardium of AS broilers. Expression of TRPC1, which mediates calcium influx, was decreased in the myocardium of AS broilers. The relationship between intracellular Ca levels and expression of TRPC1 requires further study.
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http://dx.doi.org/10.1080/03079457.2019.1617834DOI Listing
October 2019

Fucosylation Enhances the Efficacy of Adoptively Transferred Antigen-Specific Cytotoxic T Lymphocytes.

Clin Cancer Res 2019 04 15;25(8):2610-2620. Epub 2019 Jan 15.

Department of Surgical Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.

Purpose: Inefficient homing of adoptively transferred cytotoxic T lymphocytes (CTLs) to tumors is a major limitation to the efficacy of adoptive cellular therapy (ACT) for cancer. However, through fucosylation, a process whereby fucosyltransferases (FT) add fucose groups to cell surface glycoproteins, this challenge may be overcome. Endogenously fucosylated CTLs and fucosylated cord blood stem cells and regulatory T cells were shown to preferentially home to inflamed tissues and marrow. Here, we show a novel approach to enhance CTL homing to leukemic marrow and tumor tissue.

Experimental Design: Using the enzyme FT-VII, we fucosylated CTLs that target the HLA-A2-restricted leukemia antigens CG1 and PR1, the HER2-derived breast cancer antigen E75, and the melanoma antigen gp-100. We performed homing assays to study the effects of fucosylation on CTL homing and target killing. We used mouse models to demonstrate the effects of fucosylation on CTL antitumor activities against leukemia, breast cancer, and melanoma.

Results: Our data show that fucosylation increases homing and cytotoxicity of antigen-specific CTLs. Furthermore, fucosylation enhances CTL homing to leukemic bone marrow, breast cancer, and melanoma tissue in NOD/SCID gamma (NSG) and immunocompetent mice, ultimately boosting the antitumor activity of the antigen-specific CTLs. Importantly, our work demonstrates that fucosylation does not interfere with CTL specificity.

Conclusions: Together, our data establish CTL fucosylation as a novel approach to improving the efficacy of ACT, which may be of great value for the future of ACT for cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467811PMC
April 2019

Copper induces oxidative stress and apoptosis through mitochondria-mediated pathway in chicken hepatocytes.

Toxicol In Vitro 2019 Feb 30;54:310-316. Epub 2018 Oct 30.

College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, Guangdong, PR China. Electronic address:

The aim of this study was to investigate the effects of excessive copper (Cu)-induced cytotoxicity on oxidative stress and mitochondrial apoptosis in chicken hepatocytes. Chicken hepatocytes were cultured in medium in the absence and presence of copper sulfate (CuSO) (10, 50, 100 μM), in N-acetyl-L-cysteine (NAC) (1 mM), and the combination of CuSO and NAC for 24 h. Morphologic observation and function, reactive oxygen species (ROS) level, antioxidant indices, nitric oxide (NO) content, mitochondrial membrane potential (MMP), and apoptosis-related mRNA and protein levels were determined. These results indicated that excessive Cu could induce release of intracellular lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT); increase levels of ROS, superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), lipid peroxidation (LPO), and NO; decrease glutathione (GSH) content and MMP; upregulated Bak1, Bax, CytC, and Caspase3 mRNA and protein expression, inhibited Bcl2 mRNA and protein expression, and induced cell apoptosis in a dose effect. The Cu-caused changes of all above factors were alleviated by treatment with NAC. These results suggested that excessive Cu could induce oxidative stress and apoptosis via mitochondrial pathway in chicken hepatocytes.
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http://dx.doi.org/10.1016/j.tiv.2018.10.017DOI Listing
February 2019

An efficient method to evaluate experimental factor influence on in vitro binding of aptamers.

Anal Biochem 2018 09 18;556:7-15. Epub 2018 Jun 18.

Department of Chemistry, Capital Normal University, Xisanhuan North Road. 105, Beijing, 100048, China. Electronic address:

Nucleic acid-based aptamers are promising alternative to antibodies, however, their selection process (SELEX) is challenging. A number of simulations and few experiments have been reported offering insights into experimental factors (EFs) that govern the effectiveness of the selection process. Though useful, these previous studied were either lack of experimental confirmation, or considered limited EFs. A more efficient experimental method is highly desired. In this study, we developed a fast method that is capable to quantitatively probe the influence of multiple EFs. Based on the fact that the aptamer enrichment efficiency is highly affected by background binding, the binding ratio between the numbers of specific aptamer binders and nonspecific (unselected library) binders per bead was used to quantitatively evaluate EF effects. Taking thrombin and streptavidin as models, three previously studied EFs (surface coverage, buffer composition, and DNA concentration) and four never-studied ones (surface chemistry, heat treatment, elution methodology and pool purity) were investigated. The EFs greatly affected binding ratio (ranging from 0.03 ± 0.03 to 14.60 ± 2.30). The results were in good agreement with the literature, suggesting the good feasibility of our method. Our study provides guidance for the choice of EFs not only for aptamer selection, but also for binding evaluation of aptamers.
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http://dx.doi.org/10.1016/j.ab.2018.06.015DOI Listing
September 2018

Targeting the Leukemia Antigen PR1 with Immunotherapy for the Treatment of Multiple Myeloma.

Clin Cancer Res 2018 07 16;24(14):3386-3396. Epub 2018 Apr 16.

Department of Stem Cell Transplantation and Cellular Therapy, Section of Transplant Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

PR1 is a human leukocyte antigen (HLA)-A2 nonameric peptide derived from neutrophil elastase (NE) and proteinase 3 (P3). We have previously shown that PR1 is cross-presented by solid tumors, leukemia, and antigen-presenting cells, including B cells. We have also shown that cross-presentation of PR1 by solid tumors renders them susceptible to killing by PR1-targeting immunotherapies. As multiple myeloma is derived from B cells, we investigated whether multiple myeloma is also capable of PR1 cross-presentation and subsequently capable of being targeted by using PR1 immunotherapies. We tested whether multiple myeloma is capable of cross-presenting PR1 and subsequently becomes susceptible to PR1-targeting immunotherapies, using multiple myeloma cell lines, a xenograft mouse model, and primary multiple myeloma patient samples. Here we show that multiple myeloma cells lack endogenous NE and P3, are able to take up exogenous NE and P3, and cross-present PR1 on HLA-A2. Cross-presentation by multiple myeloma utilizes the conventional antigen processing machinery, including the proteasome and Golgi, and is not affected by immunomodulating drugs (IMiD). Following PR1 cross-presentation, we are able to target multiple myeloma with PR1-CTL and anti-PR1/HLA-A2 antibody both and Collectively, our data demonstrate that PR1 is a novel tumor-associated antigen target in multiple myeloma and that multiple myeloma is susceptible to immunotherapies that target cross-presented antigens. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2626DOI Listing
July 2018

Phase Ib trial of folate binding protein (FBP)-derived peptide vaccines, E39 and an attenuated version, E39': An analysis of safety and immune response.

Clin Immunol 2018 07 21;192:6-13. Epub 2018 Mar 21.

Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1434, Houston, TX 77030, United States. Electronic address:

In this randomized phase Ib trial, we tested combining the E39 peptide vaccine with a vaccine created from E39', an attenuated version of E39. Patients with breast or ovarian cancer, who were disease-free after standard of care therapy, were enrolled and randomized to one of three arms. Arm EE received six E39 inoculations; arm EE' received three E39 inoculations followed by three E39'; and arm E'E received three E39' inoculations, followed by three E39. Within each arm, the first five patients received 500 μg of peptide and the remainder received 1000 μg. Patients were followed for toxicity, and immune responses were measured. This initial analysis after completion of the primary vaccination series has confirmed the safety of both vaccines. Immune analyses suggest incorporating the attenuated version of the peptide improves immune responses and that sequencing of E39 followed by E39' might produce the optimal immune response.

Trial Registration: NCT02019524.
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http://dx.doi.org/10.1016/j.clim.2018.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988975PMC
July 2018

Co-Upregulation of 14-3-3ζ and P-Akt is Associated with Oncogenesis and Recurrence of Hepatocellular Carcinoma.

Cell Physiol Biochem 2018 7;45(3):1097-1107. Epub 2018 Feb 7.

Department of Hepatobiliary Surgery, The General Hospital of Shenyang Military Area Command, Shenyang, China.

Background/aims: 14-3-3ζ is involved in the regulation of PI3K/Akt pathway which is closely associated with carcinogenesis. However, the clinical significance of combined detection of 14-3-3ζ and p-Akt in hepatocellular carcinoma (HCC) remains unclear.

Methods: Two-hundred pairs of HCC and adjacent liver specimens were subjected to tissue microarray. The association of 14-3-3ζ and p-Akt levels with the postoperative survival and recurrence in HCC patients was analyzed with univariate and multivariate methods. Moreover, the effects of 14-3-3ζ overexpression on the growth of HCC and the expressions of p-Akt and HIF-1α were assessed in a xenograft mouse model.

Results: Elevated levels of 14-3-3ζ and p-Akt were detected in HCC and a positive correlation between the levels of 14-3-3ζ and p-Akt was verified. HCC patients with satellite nodules, microvascular invasion, portal vein tumor thrombosis, poor tumor differentiation and an advanced tumor stage tended to have higher levels of 14-3-3ζ and p-Akt. In addition, the postoperative 3-, 5-, and 7-year overall survival rates in HCC patients with 14-3-3ζhigh and p-Akthigh were significantly lower compared with those with 14-3-3ζlow and p-Aktlow, and the cumulative recurrence rate in HCC patients with 14-3-3ζhigh and p-Akthigh was significantly higher than that in those with 14-3-3ζlow and p-Aktlow. The multivariate Cox proportional hazard analysis indicated that concomitant upregulation of 14-3-3ζ and p-Akt was an independent factor that predicted poor survival and high recurrence in HCC patients. Furthermore, animal experiment showed that overexpression of 14-3-3ζ accelerated the growth of HCC xenograft tumors and induced the expressions of p-Akt and HIF-1α in vivo.

Conclusion: Co-upregulation of 14-3-3ζ and p-Akt predicts poor prognosis in patients with HCC, and 14-3-3ζ-induced activation of the Akt signaling pathway contributes to HCC progression.
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http://dx.doi.org/10.1159/000487351DOI Listing
March 2018

Cathepsin G Is Expressed by Acute Lymphoblastic Leukemia and Is a Potential Immunotherapeutic Target.

Front Immunol 2017 25;8:1975. Epub 2018 Jan 25.

Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, United States.

Cathepsin G (CG) is a myeloid azurophil granule protease that is highly expressed by acute myeloid leukemia (AML) blasts and leukemia stem cells. We previously identified CG1 (FLLPTGAEA), a human leukocyte antigen-A2-restricted nonameric peptide derived from CG, as an immunogenic target in AML. In this report, we aimed to assess the level of CG expression in acute lymphoid leukemia (ALL) and its potential as an immunotherapeutic target in ALL. Using RT-PCR and western blots, we identified CG mRNA and protein, respectively, in B-ALL patient samples and cell lines. We also examined CG expression in a large cohort of 130 patients with ALL reverse-phase protein array (RPPA). Our data show that CG is widely expressed by ALL and is a poor prognosticator. In addition to endogenous expression, we also provide evidence that CG can be taken up by ALL cells. Finally, we demonstrate that patient ALL can be lysed by CG1-specific cytotoxic T lymphocytes . Together, these data show high expression of CG by ALL and implicate CG as a target for immunotherapy in ALL.
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http://dx.doi.org/10.3389/fimmu.2017.01975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790053PMC
January 2018

Trastuzumab Increases HER2 Uptake and Cross-Presentation by Dendritic Cells.

Cancer Res 2017 10 17;77(19):5374-5383. Epub 2017 Aug 17.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Early-phase clinical trials evaluating CD8 T cell-eliciting, HER2-derived peptide vaccines administered to HER2 breast cancer patients in the adjuvant setting suggest synergy between the vaccines and trastuzumab, the mAb targeting the HER2 protein. Among 60 patients enrolled in clinical trials evaluating the E75 + GM-CSF and GP2 + GM-CSF vaccines, there have been no recurrences in patients vaccinated after receiving trastuzumab as part of standard therapy in the per treatment analyses conducted after a median follow-up of greater than 34 months. Here, we describe a mechanism by which this synergy may occur. Flow cytometry showed that trastuzumab facilitated uptake of HER2 by dendritic cells (DC), which was mediated by the Fc receptor and was specific to trastuzumab. , increased HER2 uptake by DC increased cross-presentation of E75, the immunodominant epitope derived from the HER2 protein, an observation confirmed in two mouse models. This increased E75 cross-presentation, mediated by trastuzumab treatment, enabled more efficient expansion of E75-specific cytotoxic T cells (E75-CTL). These results demonstrate a mechanism by which trastuzumab links innate and adaptive immunity by facilitating activation of antigen-specific T cells. On the basis of these data, we conclude that HER2-positive breast cancer patients that have been treated with trastuzumab may experience a more robust antitumor immune response by restimulation of T cells with the E75 peptide vaccine, thereby accounting for the improved disease-free survival observed with combination therapy. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626640PMC
October 2017

Expression patterns and changes of the LCN2 gene in the testes of induced cryptorchidism and busulfan-treated mice.

Syst Biol Reprod Med 2017 Dec 3;63(6):364-369. Epub 2017 Aug 3.

a College of Veterinary Medicine , South China Agricultural University , Guangzhou , China.

Lipocalin-2 (LCN2) was known to play various roles in different type cells; however, little was known about the effect of LCN2 in male fertility. In this study, we aimed to explore the expression pattern of LCN2 with increasing age in mice, and to obtain insight into the role of LCN2 in mice testes by induced cryptorchidism and busulfan-treated infertility. In situ hybridization showed that LCN2 was localized primarily in Leydig cells, but was absent in Sertoli and germ cells. Its expression in testes exhibited an age-related increase from day 1 to 8 months, then reduced by the twelth month. The mRNA and protein levels of LCN2 in the testes of both infertile models increased as measured by real-time PCR and western blotting, respectively. LCN2 mRNA and protein levels were higher (p<0.05) in busulfan treated mice than that of cryptorchidism. These observations have shown that LCN2 is developmentally regulated and highly expressed in the Leydig cells of mouse testes.
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http://dx.doi.org/10.1080/19396368.2017.1355416DOI Listing
December 2017
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