Publications by authors named "Qun He"

266 Publications

Integrated genomic and transcriptomic analysis suggests mutation and are key genetic alterations related to the prognosis between astrocytoma and glioblastoma.

Ann Transl Med 2021 Apr;9(8):713

Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Background: Astrocytoma and glioblastoma (GBM) are the two main subtypes of glioma, with the 2016 World Health Organization Classification of Tumors of the Central Nervous System (CNS WHO) classifying them into different grades. GBM is the most malignant among all CNS tumors with a 5-year survival rate of less than 5%. Although the prognosis of patients with astrocytoma is better than that of GBM in general, patients with anaplastic astrocytoma (AA) and isocitrate dehydrogenase () wild type have a similar prognosis as GBM and entail a high risk of progression. Exploring the molecular driving force behind the malignant phenotype of astrocytoma and GBM will help explain the diversity of glioma and discover new drug targets.

Methods: We enrolled 12 patients with astrocytoma and 12 patients with GBM and performed whole-exome sequencing (WES) and RNA sequencing analysis on tumor samples from the patients.

Results: We found that the somatic mutation of , which is associated with cell apoptosis and adhesion by interacting with receptor 1-associated protein (TRADD) and pinin, was significantly enriched in astrocytoma, but rare in GBM. Copy number loss of , which is closely related to a poor prognosis of glioma, was found to be significantly enriched in GBM. In addition, different somatic copy number alteration (SCNA), gene expression, and immune cell infiltration patterns between astrocytoma and GBM were found.

Conclusions: This study revealed the distinct characteristics of astrocytoma and GBM at the DNA and RNA level. Somatic mutation of and copy number loss of , two key genetic alterative genes in astrocytoma and GBM, have the potential to become therapeutic targets in glioma.
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http://dx.doi.org/10.21037/atm-21-1317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106028PMC
April 2021

Noninvasive evaluation of tumor immune microenvironment in patients with clear cell renal cell carcinoma using metabolic parameter from preoperative 2-[F]FDG PET/CT.

Eur J Nucl Med Mol Imaging 2021 May 12. Epub 2021 May 12.

Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China.

Purpose: Nowadays, it is necessary to explore effective biomarkers associated with tumor immune microenvironment (TIME) noninvasively. Here, we investigated whether the metabolic parameter from preoperative 2-[F]FDG PET/CT could provide information related to TIME in patients with clear cell renal cell carcinoma (ccRCC).

Methods: Ninety patients with newly diagnosed ccRCC who underwent 2-[F]FDG PET/CT prior to surgery were retrospectively reviewed. The immunological features included tumor-infiltrating lymphocytes (TILs) density, programmed death-ligand 1 (PD-L1) expression, and tumor immune microenvironment types (TIMTs). TIMTs were classified as TIMT I (positive PD-L1 and high TILs), TIMT II (negative PD-L1 and low TILs), TIMT III (positive PD-L1 and low TILs), and TIMT IV (negative PD-L1 and high TILs). The relationship between maximum standardized uptake value (SUVmax) in the primary lesion from 2-[F]FDG PET/CT and immunological features was analyzed. Cox proportional hazards analyses were performed to identify the prognostic factors for disease-free survival (DFS) after nephrectomy.

Results: Tumors with high TILs infiltration showed remarkable correlation with elevated SUVmax and aggressive clinicopathological characteristics, such as high World Health Organization/International Society of Urological Pathology (WHO/ISUP) grade. PD-L1 expression on tumor cells was positively associated with WHO/ISUP grade and negatively correlated with body mass index (BMI). However, no correlation was observed between SUVmax and PD-L1 expression, regardless of its spatial tissue distribution. SUVmax of TIMT I and IV was higher than that of TIMT II, but there was remarkable difference merely between TIMT II and IV. In multivariate analysis, SUVmax (P = 0.022, HR 3.120, 95% CI 1.175-8.284) and WHO/ISUP grade (P = 0.046, HR 2.613, 95% CI 1.017-6.710) were the significant prognostic factors for DFS. Six cases (16.2%) with normal SUVmax showed disease progression, while 25 cases (71.4%) with elevated SUVmax experienced disease progression. Conversely, the immunological features held no prognostic value.

Conclusions: Our findings demonstrated that 2-[F]FDG PET/CT could provide metabolic information of TIME for ccRCC patients and develop image-guided therapeutic strategies accordingly. Patients with elevated preoperative SUVmax should be seriously considered, and perioperative immunotherapy might be beneficial for them.
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http://dx.doi.org/10.1007/s00259-021-05399-9DOI Listing
May 2021

Pilot Demonstration of Reclaiming Municipal Wastewater for Irrigation Using Electrodialysis Reversal: Effect of Operational Parameters on Water Quality.

Membranes (Basel) 2021 Apr 30;11(5). Epub 2021 Apr 30.

Department of Civil Engineering, New Mexico State University, Las Cruces, NM 88003, USA.

The modification of ion composition is important to meet product water quality requirements, such as adjusting the sodium adsorption ratio of reclaimed water for irrigation. Bench- and pilot-scale experiments were conducted using an electrodialysis reversal (EDR) system with Ionics normal grade ion-exchange membranes (CR67 and AR204) to treat the reclaimed water in the Scottsdale Water Campus, Arizona. The goal is to investigate the impact of operating conditions on improving reclaimed water quality for irrigation and stream flow augmentation. The desalting efficiency, expressed as electrical conductivity (EC) reduction, was highly comparable at the same current density between the bench- and pilot-scale EDR systems, proportional to the ratio of residence time in the electrodialysis stack. The salt flux was primarily affected by the current density independent of flow rate, which is associated with linear velocity, boundary layer condition, and residence time. Monovalent-selectivity in terms of equivalent removal of divalent ions (Ca, Mg, and SO) over monovalent ions (Na, Cl) was dominantly affected by both current density and water recovery. The techno-economic modeling indicated that EDR treatment of reclaimed water is more cost-effective than the existing ultrafiltration/reverse osmosis (UF/RO) process in terms of unit operation and maintenance cost and total life cycle cost. The EDR system could achieve 92-93% overall water recovery compared to 88% water recovery of the UF/RO system. In summary, electrodialysis is demonstrated as a technically feasible and cost viable alternative to treat reclaimed water for irrigation and streamflow augmentation.
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http://dx.doi.org/10.3390/membranes11050333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147136PMC
April 2021

Laparoscopic versus open radical cystectomy in 607 patients with bladder cancer: Comparative survival analysis.

Int J Urol 2021 Jun 13;28(6):673-680. Epub 2021 Mar 13.

Department of Urology, Peking University First Hospital, Beijing, China.

Objectives: To compare perioperative and oncologic survival outcomes between laparoscopic radical cystectomy and open radical cystectomy.

Methods: A total of 607 patients underwent open radical cystectomy (n = 412) or laparoscopic radical cystectomy (n = 195) at a single academic institution from January 2006 to April 2017. Their medical records were retrospectively analyzed. One-to-one propensity score matching was carried out to reduce selection bias. Estimated blood loss and complications were compared. Overall survival, cancer-specific survival and progression-free survival estimates for all patients and patients with locally advanced bladder cancer were analyzed using the Kaplan-Meier method.

Results: Either before or after matching, the laparoscopic radical cystectomy group had less estimated blood loss (P < 0.001 and P < 0.001) and fewer complications (P < 0.001 and P = 0.008). There was no difference in the overall survival (P = 0.216 and P = 0.961) and progression-free survival (P = 0.826 and P = 0.462) for all the patients having either laparoscopic radical cystectomy or open radical cystectomy. However, the 5-year progression-free survival of open radical cystectomy was higher than that of laparoscopic radical cystectomy (P = 0.019 and P = 0.021) for patients with locally advanced bladder cancer.

Conclusions: Laparoscopic radical cystectomy is superior to open radical cystectomy in terms of perioperative outcomes, and similar to open radical cystectomy in terms of oncologic outcomes for patients with early stage bladder cancer. However, for patients with locally advanced bladder cancer, laparoscopic radical cystectomy seems to be associated with shorter progression-free survival than open radical cystectomy.
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http://dx.doi.org/10.1111/iju.14537DOI Listing
June 2021

HMGCS1 drives drug-resistance in acute myeloid leukemia through endoplasmic reticulum-UPR-mitochondria axis.

Biomed Pharmacother 2021 May 15;137:111378. Epub 2021 Feb 15.

Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, China. Electronic address:

Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is a key enzyme in the mevalonate pathway of cholesterol synthesis. Dysregulation of HMGCS1 expression is a common occurrence in many solid tumors. It was also found to be overexpressed in newly diagnosed (ND) and relapsed/refractory (RR) acute myeloid leukemia (AML) patients. Previous study proved that HMGCS1 could induce drug-resistance in AML cells. However, the underlying mechanism how HMGCS1 contributed to chemoresistance remains elusive. Here, we confirmed that HMGCS1 inhibitor Hymeglusin enhanced cytarabine/Adriamycin (Ara-c/ADR) chemo-sensitivity in AML cells lines. Moreover, Ara-c-resistant HL-60 cells (HL-60/Ara-c) and ADR-resistant HL-60 cells (HL-60/ADR) were more sensitive to HMGCS1 inhibition than HL-60 cells. In addition, we demonstrated that the transcription factor GATA1 was the upstream regulator of HMGCS1 and could directly bind to the HMGCS1 promoter. After treatment of Tunicamycin (Tm), the number of mitochondria was increased and the damage of endoplasmic reticulum (ER) was reduced in bone marrow cells from AML-RR patients, compared to cells from AML-CR group. HMGCS1 protected mitochondria and ER under ER stress and up-regulated unfold protein response (UPR) downstream molecules in AML cells. In summary, we proved that HMGCS1 could upregulate UPR downstream components, protect mitochondria and ER from damage in AML cells under stress, therefore conferring drug resistance. Therefore, HMGCS1 could serve as a novel target for treatment of patients with intolerant chemotherapy and AML-RR patients.
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http://dx.doi.org/10.1016/j.biopha.2021.111378DOI Listing
May 2021

Clinical and Pathological Features of Prostatic Stromal Tumor of Uncertain Malignant Potential: A Retrospective Study of 23 Chinese Cases.

Urol Int 2021 20;105(3-4):206-214. Epub 2020 Nov 20.

Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Research Center for Genitourinary Oncology, Beijing, China.

Introduction: Prostatic stromal tumor of uncertain malignant potential (STUMP) is a rare disease that may coexist with prostate stromal sarcoma (PSS). We aimed to analyze the histological and clinical features of STUMP.

Methods: Twenty-three patients diagnosed with STUMP from 2008 to 2019 were included. Clinicopathological and follow-up information was collected. In the subgroup analysis, we divided the patients into a pure STUMP group (N = 18) and a mixed STUMP (STUMP coexisting with PSS) group (N = 5). Student's t test was used to compare the 2 groups.

Results: Patients had a mean age of 55.5 ± 19.4 years and an average follow-up time of 42.3 months. The mean prostate volume was 109.2 ± 73.5 cm3, and the mean prostate-specific antigen was 8.03 ± 10.5 ng/mL. In the subgroup analysis, 16.7% (2/12) of pure STUMP patients had disease progression, while 100% (3/3) of mixed STUMP patients suffered from recurrence. Compared with the pure STUMP group, the mixed STUMP group was younger (37.2 vs. 60.6 years, p = 0.013) and had lower expression of estrogen receptor and progesterone receptor (p = 0.004 and p < 0.001, respectively).

Conclusion: STUMP is a rare disease with a relatively good prognosis. However, there is still a possibility of disease progression or coexistence with stromal sarcoma. Timely diagnosis and regular monitoring may be helpful in improving treatment outcomes.
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http://dx.doi.org/10.1159/000508763DOI Listing
November 2020

Static Ultrasound Guidance VS. Anatomical Landmarks for Subclavian Vein Puncture in the Intensive Care Unit: A Pilot Randomized Controlled Study.

J Emerg Med 2020 Dec 22;59(6):918-926. Epub 2020 Sep 22.

Department of Intensive Care Unit, Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.

Background: Subclavian vein puncture is commonly used in the intensive care unit (ICU) but is associated with complications.

Objective: Our aim was to compare the efficacy and safety of static ultrasound-guided subclavian vein puncture with traditional anatomical landmark-guided subclavian vein puncture in critically ill patients in the ICU.

Methods: This pilot randomized controlled trial enrolled patients admitted to the ICU and requiring subclavian vein puncture between November 2017 and September 2018. The patients were randomized to ultrasound-guided puncture or anatomical landmark-guided puncture. The primary outcome measure was the puncture success rate. The secondary outcome measures included the number of punctures, rate of success at the first attempt, puncture time (i.e., procedure duration) and incidence of complications.

Results: A total of 194 patients were included in the analyses. Compared with the anatomical landmarks group, the ultrasound group had a higher puncture success rate (91.7% vs. 77.6%; p = 0.007), lower rate of complications (7.3% vs. 20.4%; p = 0.008), and lower incidence of mispuncture of an artery (2.1% vs. 14.3%; p = 0.002). There were no significant differences in the number of punctures and puncture time between the two groups (both, p > 0.05).

Conclusions: Static ultrasound-guided subclavian vein puncture is superior to the traditional landmark-guided approach for critically ill patients in the ICU. It is suggested that static ultrasound-guided puncture techniques should be considered for subclavian vein puncture in the ICU.

Trial Registration: ChiCTR1900024051.
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http://dx.doi.org/10.1016/j.jemermed.2020.07.039DOI Listing
December 2020

How Many Targeted Biopsy Cores are Needed for Clinically Significant Prostate Cancer Detection during Transperineal Magnetic Resonance Imaging Ultrasound Fusion Biopsy?

J Urol 2020 12 27;204(6):1202-1208. Epub 2020 Jul 27.

Department of Urology, Peking University First Hospital, Beijing, China.

Purpose: In this study we determined the optimal number of transperineal magnetic resonance imaging ultrasound fusion targeted biopsy cores per lesion needed for the detection of clinically significant prostate cancer.

Materials And Methods: A total of 101 patients with at least 1 lesion with a PI-RADS® (Prostate Imaging Reporting and Data System) score of 3 or greater were recruited prospectively. At least 4 transperineal magnetic resonance imaging ultrasound fusion targeted biopsy cores per lesion were performed, followed by systematic biopsy. The Kappa test was used to evaluate the consistency of the clinically significant prostate cancer detection rate between different targeted biopsy cores and 4 or more cores, which was regarded as reference standard.

Results: In the total cohort of 101 patients 49 (48.5%), 55 (54.5%) and 57 (56.4%) were diagnosed with clinically significant prostate cancer by systematic biopsy, targeted biopsy or targeted biopsy plus systematic biopsy, respectively. As for the total of 161 lesions, the clinically significant prostate cancer detection rate based on 1, 2, 3, or 4 or more targeted biopsy cores was made in 27.3%, 32.9%, 37.3% and 39.1%, respectively. Three cores showed great consistency with 4 or more cores in clinically significant prostate cancer detection rate (Kappa coefficient of 0.961, p <0.001) with a sensitivity of 95.2% (95% CI 85.8-98.8), and only missed 3 lesions harboring clinically significant prostate cancer. Similar results were obtained in cases with PI-RADS 3 or 4 or maximal diameter of less than 1.5 cm.

Conclusions: Three targeted biopsies per lesion were suitable during transperineal magnetic resonance imaging ultrasound fusion biopsy, especially for lesions of PI-RADS 3 or 4, or small lesions (maximal diameter less than 1.5 cm), which may help to tailor targeted prostate biopsy procedures.
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http://dx.doi.org/10.1097/JU.0000000000001302DOI Listing
December 2020

Normal Patterns of Histone H3K27 Methylation Require the Histone Variant H2A.Z in .

Genetics 2020 09 10;216(1):51-66. Epub 2020 Jul 10.

Department of Microbiology, University of Georgia, Athens, Georgia 30602

contains a minimal Polycomb repression system, which provides rich opportunities to explore Polycomb-mediated repression across eukaryotes and enables genetic studies that can be difficult in plant and animal systems. Polycomb Repressive Complex 2 is a multi-subunit complex that deposits mono-, di-, and trimethyl groups on lysine 27 of histone H3, and trimethyl H3K27 is a molecular marker of transcriptionally repressed facultative heterochromatin. In mouse embryonic stem cells and multiple plant species, H2A.Z has been found to be colocalized with H3K27 methylation. H2A.Z is required for normal H3K27 methylation in these experimental systems, though the regulatory mechanisms are not well understood. We report here that mutants lacking H2A.Z or SWR-1, the ATP-dependent histone variant exchanger, exhibit a striking reduction in levels of H3K27 methylation. RNA-sequencing revealed downregulation of , encoding a subunit of PRC2, in an mutant compared to wild type, and overexpression of EED in a Δ;Δ background restored most H3K27 methylation. Reduced expression leads to region-specific losses of H3K27 methylation, suggesting that differential dependence on EED concentration is critical for normal H3K27 methylation at certain regions in the genome.
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http://dx.doi.org/10.1534/genetics.120.303442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463285PMC
September 2020

NC2 complex is a key factor for the activation of catalase-3 transcription by regulating H2A.Z deposition.

Nucleic Acids Res 2020 09;48(15):8332-8348

State Key Laboratory of Agrobiotechnology and MOA Key Laboratory of Soil Microbiology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.

Negative cofactor 2 (NC2), including two subunits NC2α and NC2β, is a conserved positive/negative regulator of class II gene transcription in eukaryotes. It is known that NC2 functions by regulating the assembly of the transcription preinitiation complex. However, the exact role of NC2 in transcriptional regulation is still unclear. Here, we reveal that, in Neurospora crassa, NC2 activates catalase-3 (cat-3) gene transcription in the form of heterodimer mediated by histone fold (HF) domains of two subunits. Deletion of HF domain in either of two subunits disrupts the NC2α-NC2β interaction and the binding of intact NC2 heterodimer to cat-3 locus. Loss of NC2 dramatically increases histone variant H2A.Z deposition at cat-3 locus. Further studies show that NC2 recruits chromatin remodeling complex INO80C to remove H2A.Z from the nucleosomes around cat-3 locus, resulting in transcriptional activation of cat-3. Besides HF domains of two subunits, interestingly, C-terminal repression domain of NC2β is required not only for NC2 binding to cat-3 locus, but also for the recruitment of INO80C to cat-3 locus and removal of H2A.Z from the nucleosomes. Collectively, our findings reveal a novel mechanism of NC2 in transcription activation through recruiting INO80C to remove H2A.Z from special H2A.Z-containing nucleosomes.
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http://dx.doi.org/10.1093/nar/gkaa552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470962PMC
September 2020

Expression and prognostic value of PD-L1 in non-schistosoma-associated urinary bladder squamous cell carcinoma.

Transl Androl Urol 2020 Apr;9(2):428-436

Department of Urology, Peking University First Hospital and Institute of Urology, National Research Center for Genitourinary Oncology, Beijing 100034, China.

Background: Non-schistosoma-associated urinary bladder squamous cell carcinoma (SqCC) has low incidence and is associated with chronic inflammation. Due to its unique etiology and pathology, expression of programmed cell death ligand 1 (PD-L1) in SqCC could be different from that of urothelial carcinoma, which may contribute to different responses to immunotherapy. In this study, we intended to explore the expression profile and prognostic value of PD-L1 in non-schistosoma-associated urinary bladder SqCC under the consideration of tumor-infiltrating lymphocytes' (TILs) density.

Methods: We conducted a retrospective study to review 604 bladder cancer patients who received radical cystectomy (RC) from 2009 to 2013 in Peking University First Hospital. We enrolled 67 bladder SqCC patients in total, including pure SqCC (n=19) and mixed SqCC (n=48, with urothelial carcinoma). PD-L1 protein expression and TILs density were evaluated by immunohistochemistry.

Results: Nine female and 58 male patients (median age 67.4 years) were enrolled in the present study. There were 15 stage T1-2 patients and 52 stage T3-4 patients. 27 patients had N1-2 lymph node metastasis. Overall, 61.2% cases were PD-L1-positive. Dense TILs coincided with higher PD-L1 expression rate. Median survival time of PD-L1 positive cases was significantly higher than negative cases (P=0.026). During multivariate analysis, positive PD-L1 expression and dense TILs were independent protective factors affecting overall survival (OS, PD-L1: P=0.022; TILs: P=0.010) and progression free survival (PFS, PD-L1: P=0.018; TILs: P=0.009).

Conclusions: PD-L1 expression and dense TILs were frequently detected in urinary bladder SqCC tumors. Positive PD-L1 expression and dense TILs were correlated with better survival outcomes in non-schistosoma-associated urinary bladder SqCC. The immunotherapy targeting PD-L1 might be helpful to bladder SqCC patients.
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http://dx.doi.org/10.21037/tau.2020.02.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215043PMC
April 2020

Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma.

Theranostics 2020 4;10(10):4323-4333. Epub 2020 Mar 4.

Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.

: Dietary exposure to aristolochic acids and similar compounds (collectively, AA) is a significant risk factor for nephropathy and subsequent upper tract urothelial carcinoma (UTUC). East Asian populations, who have a high prevalence of UTUC, have an unusual genome-wide AA-induced mutational pattern (COSMIC signature 22). Integrating mutational signature analysis with clinicopathological information may demonstrate great potential for risk ranking this UTUC subtype. : We performed whole-genome sequencing (WGS) on 90 UTUC Chinese patients to extract mutational signatures. Genome sequencing data for urinary cell-free DNA from 26 UTUC patients were utilized to noninvasively identify the mutational signatures. Genome sequencing for primary tumors on 8 out of 26 patients was also performed. Metastasis-free survival (MFS) and cancer-specific survival (CSS) were measured using Kaplan-Meier methods. : Data analysis showed that a substantial proportion of patients harbored the AA mutational signature and were associated with AA-containing herbal drug intake, female gender, poor renal function, and multifocality. Field cancerization was found to partially contribute to multifocality. Nevertheless, AA Sig subtype UTUC patients exhibited favorable outcomes of CSS and MFS compared to the No-AA Sig subtype. Additionally, AA Sig subtype patients showed a higher tumor mutation burden, higher numbers of predicted neoantigens, and infiltrating lymphocytes, suggesting the potential for immunotherapy. We also confirmed the AA signature in AA-treated human renal tubular HK-2 cells. Notably, the AA subtype could be ascertained using a clinically applicable sequencing strategy (low coverage) in both primary tumors and urinary cell-free DNA as a basis for therapy selection. : The AA mutational signature as a screening tool defines low-risk UTUC with therapeutic relevance. The AA mutational signature, as a molecular prognostic marker using either ureteroscopy and/or urinary cell-free DNA, is especially useful for diagnostic uncertainty when kidney-sparing treatment and/or immune checkpoint inhibitor therapy were considered.
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http://dx.doi.org/10.7150/thno.43251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150494PMC
February 2021

Two dominant selectable markers for genetic manipulation in Neurospora crassa.

Curr Genet 2020 Aug 9;66(4):835-847. Epub 2020 Mar 9.

State Key Laboratory of Agrobiotechnology and MOA Key Laboratory of Soil Microbiology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.

Neurospora crassa is an excellent model fungus for studies on molecular genetics, biochemistry, physiology, and molecular cell biology. Along with the rapid progress of Neurospora research, new tools facilitating more efficient and accurate genetic analysis are in high demand. Here, we tested whether the dominant selective makers widely used in yeasts are applicable in N. crassa. Among them, we found that the strains of N. crassa are sensitive to the aminoglycoside antibiotics, G418 and nourseothricin. 1000 μg/mL of G418 or 50 μg/mL of nourseothricin is sufficient to inhibit Neurospora growth completely. When the neomycin phosphotransferase gene (neo) used in mammalian cells is expressed, N. crassa shows potent resistance to G418. This establishes G418-resistant marker as a dominant selectable marker to use in N. crassa. Similarly, when the nourseothricin acetyltransferase gene (nat) from Streptomyces noursei is induced by qa-2 promoter in the presence of quinic acid (QA), N. crassa shows potent resistance to nourseothricin. When nat is constitutively expressed by full-length or truncated versions of the promoter from the N. crassa cfp gene (NCU02193), or by the trpC promoter of Aspergillus nidulans, the growth of N. crassa in the presence of nourseothricin is proportional to the expression levels of Nat. Finally, these two markers are used to knock-out wc-2 or al-1 gene from the N. crassa genome. The successful development of these two markers in this study expands the toolbox for N. crassa and very likely for other filamentous fungi as well.
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http://dx.doi.org/10.1007/s00294-020-01063-1DOI Listing
August 2020

Effects of Trough Concentration and Solute Carrier Polymorphisms on Imatinib Efficacy in Chinese Patients with Chronic Myeloid Leukemia.

J Pharm Pharm Sci 2020 ;23(1):1-9

Department of Pharmacy, the Second Xiangya Hospital, Central South University; Institute of Clinical Pharmacy, Central South University.

Purpose: We investigated the relationship between imatinib trough concentrations and genetic polymorphisms with efficacy of imatinib in Chinese patients with chronic myeloid leukemia (CML).

Methods: There were 171 eligible patients. Peripheral blood samples were collected from 171 eligible patients between 21 and 27 hours after the last imatinib administration. Complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR) were used as metrics for efficacy. Nine single nucleotide polymorphisms in 5 genes, SLC22A4 (917 T>C, -248 C>G and -538 C>G), SLC22A5 (-945 T>G and -1889 T>C), SLCO1A2 (-361 G>A), SLCO1B3 (334 T>G and 699 G>A) and ABCG2 (421C>A) were selected for genotyping.

Results: Patients with CCyR achieve higher trough concentrations than those without CCyR (1478.18±659.83 vs 984.89±454.06 ng mL-1, p<0.001). Patients with MMR and CMR achieve higher trough concentrations than those without MMR and CMR, respectively (1486.40±703.38 vs 1121.17±527.14 ng mL-1, p=0.007; 1528.00±709.98 vs 1112.67±518.35 ng mL-1, p=0.003, respectively). Carriers of A allele in SLCO1A2 -361G>A achieve higher CCyR and MMR rates (p=0.047, OR=4.320, 95% CI: 0.924-20.206; p=0.042, OR=2.825, 95% CI: 1.016-7.853, respectively). Both trough concentrations and SLCO1A2 -361G>A genotypes are independent factors affecting imatinib efficacy. The positive and negative predictive values for CCyR are 71.01% and 68.75%, respectively. The positive and negative predictive values for MMR are 62.86% and 69.70%, respectively.

Conclusion: Imatinib trough concentrations and SLCO1A2 -361G>A genotypes are associated with imatinib efficacy in Chinese patients with CML.
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http://dx.doi.org/10.18433/jpps30559DOI Listing
April 2021

A proper PiCAT2 level is critical for sporulation, sporangium function, and pathogenicity of Phytophthora infestans.

Mol Plant Pathol 2020 04 29;21(4):460-474. Epub 2020 Jan 29.

College of Plant Protection and Key Lab of Pest Monitoring and Green Management, MOA, China Agricultural University, Beijing, China.

Catalase is present in prokaryotic and eukaryotic organisms and is important for the protective effects of the antioxidant system against free radicals. Many studies have confirmed that catalase is required for the growth, development, and pathogenesis of bacteria, plants, animals, and fungi. However, there has been relatively little research on the catalases in oomycetes, which form an important group of fungus-like eukaryotes that produce zoosporangia. In this study, we detected two Phytophthora infestans genes encoding catalases, but only PiCAT2 exhibited catalase activity in the sporulation stage and was highly produced during asexual reproduction and in the late infection stage. Compared with the wild-type strain, the PiCAT2-silenced P. infestans transformants were more sensitive to abiotic stress, were less pathogenic, and had a lower colony expansion rate and lower PiMPK7, PiVPS1, and PiGPG1 expression levels. In contrast, the PiCAT2-overexpressed transformants were slightly less sensitive to abiotic stress. Interestingly, increasing and decreasing PiCAT2 expression from the normal level inhibited sporulation, germination, and infectivity, and down-regulated PiCdc14 expression, but up-regulated PiSDA1 expression. These results suggest that PiCAT2 is required for P. infestans mycelial growth, asexual reproduction, abiotic stress tolerance, and pathogenicity. However, a proper PiCAT2 level is critical for the formation and normal function of sporangia. Furthermore, PiCAT2 affects P. infestans sporangial formation and function, pathogenicity, and abiotic stress tolerance by regulating the expression of cell cycle-related genes (PiCdc14 and PiSDA1) and MAPK pathway genes. Our findings provide new insights into catalase functions in eukaryotic pathogens.
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http://dx.doi.org/10.1111/mpp.12907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060140PMC
April 2020

Achieving Efficient Alkaline Hydrogen Evolution Reaction over a Ni P Catalyst Incorporating Single-Atomic Ru Sites.

Adv Mater 2020 Mar 27;32(11):e1906972. Epub 2020 Jan 27.

National Synchrotron Radiation Laboratory, Hefei National Laboratory for Physical Sciences at the Microscale, CAS Center for Excellence in Nanoscience, University of Science and Technology of China, Hefei, Anhui, 230029, China.

Developing efficient electrocatalysts for alkaline water electrolysis is central to substantial progress of alkaline hydrogen production. Herein, a Ni P electrocatalyst incorporating single-atom Ru (Ni P -Ru) is synthesized through the filling of Ru species into the metal vacancies of nickel hydroxides and subsequent phosphorization treatment. Electron paramagnetic resonance spectroscopy, X-ray-based measurements, and electron microscopy observations confirm the strong interaction between the nickel-vacancy defect and Ru cation, resulting in more than 3.83 wt% single-atom Ru incorporation in the obtained Ni P -Ru. The Ni P -Ru as an alkaline hydrogen evolution reaction catalyst achieves low onset potential of 17 mV and an overpotential of 54 mV at a current density of 10 mA cm together with a small Tafel slope of 52.0 mV decade and long-term stability. Further spectroscopy analyses combined with density functional theory calculations reveal that the doped Ru sites can cause localized structure polarization, which brings the low energy barrier for water dissociation on Ru site and the optimized hydrogen adsorption free energy on the interstitial site, well rationalizing the experimental reactivity.
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http://dx.doi.org/10.1002/adma.201906972DOI Listing
March 2020

Author Correction: FRQ-CK1 interaction determines the period of circadian rhythms in Neurospora.

Nat Commun 2020 Jan 14;11(1):346. Epub 2020 Jan 14.

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390-9040, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-13862-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959297PMC
January 2020

Carbon Microtube Aerogel Derived from Kapok Fiber: An Efficient and Recyclable Sorbent for Oils and Organic Solvents.

ACS Nano 2020 Jan 7;14(1):595-602. Epub 2020 Jan 7.

School of Materials Science & Engineering , Nanyang Technological University , Singapore 639798.

A carbon microtube aerogel (CMA) with hydrophobicity, strong adsorption capacity, and superb recyclability was obtained by a feasible approach with economical raw material, such as kapok fiber. The CMA possesses a great adsorption capacity of 78-348 times its weight. Attributed to its outstanding thermal stability and excellent mechanical properties, the CMA can be used for many cycles of distillation, squeezing, and combustion without degradation, which suggests a potential practical application in oil-water separation. In addition, the adsorption capacity still retained 98% by distillation, 97% by squeezing, and 90% by combustion after 10 cycles. Therefore, the obtained CMA has a broad prospect as an economical, efficient, and environmentally friendly adsorbent.
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http://dx.doi.org/10.1021/acsnano.9b07063DOI Listing
January 2020

Exogenous indole acetic acid alleviates Cd toxicity in tea (Camellia sinensis).

Ecotoxicol Environ Saf 2020 Mar 23;190:110090. Epub 2019 Dec 23.

Key Laboratory of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan, 410128, China; National Research Center of Engineering Technology for Utilization of Functional Ingredients from Botanicals, Collaborative Innovation Centre of Utilization of Functional Ingredients from Botanicals, Hunan Agricultural University, Changsha, Hunan, 410128, China. Electronic address:

Cadmium (Cd), a toxic heavy metal, restrains the growth and development of plants and threatens global food safety. Many studies on the alleviation of heavy metal toxicity by exogenous phytohormones have emerged, but reports on tea (Camellia sinensis) are still scarce. In this study, the effects of indole acetic acid (IAA) (2 μM and 10 μM) on Cd uptake and on the physiological and biochemical characteristics of the 'Xiangfeicui' tea cultivar were investigated for the first time. The order of Cd accumulation in tea seedlings was root > stem > mature leaf > tender leaf. Under Cd stress (30 mg kg), photosynthetic pigment levels, antioxidant enzyme activity, root vigor, root IAA content, and the levels of most metabolites (including caffeine, soluble sugar, total amino acids, some amino acid components, and most catechins) were significantly reduced, while levels of malondialdehyde, proline, epicatechin, and some amino acids increased. We therefore propose that by reducing Cd accumulation, exogenous IAA can lessen the adverse effects of Cd on the physiology and biochemistry of tea seedlings, promoting the growth of healthier tea plants.
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http://dx.doi.org/10.1016/j.ecoenv.2019.110090DOI Listing
March 2020

Electrochemical Conversion of CO to Syngas with Controllable CO/H Ratios over Co and Ni Single-Atom Catalysts.

Angew Chem Int Ed Engl 2020 Feb 9;59(8):3033-3037. Epub 2020 Jan 9.

Department of Chemical Engineering, Columbia University, New York, NY, 10027, USA.

The electrochemical CO reduction reaction (CO RR) to yield synthesis gas (syngas, CO and H ) has been considered as a promising method to realize the net reduction in CO emission. However, it is challenging to balance the CO RR activity and the CO/H ratio. To address this issue, nitrogen-doped carbon supported single-atom catalysts are designed as electrocatalysts to produce syngas from CO RR. While Co and Ni single-atom catalysts are selective in producing H and CO, respectively, electrocatalysts containing both Co and Ni show a high syngas evolution (total current >74 mA cm ) with CO/H ratios (0.23-2.26) that are suitable for typical downstream thermochemical reactions. Density functional theory calculations provide insights into the key intermediates on Co and Ni single-atom configurations for the H and CO evolution. The results present a useful case on how non-precious transition metal species can maintain high CO RR activity with tunable CO/H ratios.
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http://dx.doi.org/10.1002/anie.201912719DOI Listing
February 2020

The atypical cadherin flamingo determines the competence of neurons for activity-dependent fine-scale topography.

Mol Brain 2019 12 10;12(1):109. Epub 2019 Dec 10.

School of Medicine, Dalian University, Dalian, 116622, Liaoning, China.

The topographic projection of afferent terminals into two-dimensional maps is essential for sensory systems to encode the locations of sensory stimuli. In vertebrates, guidance cues are critical for establishing a coarse topographic map, while neuronal activity directs fine-scale topography between adjacent afferent terminals. However, the molecular mechanism underlying activity-dependent fine-scale topography is not well known. Studies in the Drosophila visual system have demonstrated that cell-adhesion molecules direct fine-scale topography, but whether or not these molecules are involved in activity-dependent fine-scale topography remains to be determined. We previously reported that the nociceptors in Drosophila larvae form an activity-dependent fine-scale topographic system. The establishment of this system is instructed by the level of neuronal activity in individual nociceptors. Here, we show that the atypical cadherin Flamingo (Fmi) is required for establishing the nociceptor topographic map. We found that the topographic defect caused by loss of fmi was epistatic to the inhibition of neuronal activity and the overexpression of the activity-regulated gene Trim9. These results suggest that Fmi and neuronal activity interact to regulate fine-scale topography. This study provides a link between neuronal activity and the cell-adhesion molecule in the establishment of fine-scale topography.
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http://dx.doi.org/10.1186/s13041-019-0531-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905094PMC
December 2019

Urothelial Carcinoma Detection Based on Copy Number Profiles of Urinary Cell-Free DNA by Shallow Whole-Genome Sequencing.

Clin Chem 2020 01;66(1):188-198

Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.

Background: Current noninvasive assays for urothelial carcinoma (UC) lack clinical sensitivity and specificity. Given the utility of plasma cell-free DNA (cfDNA) biomarkers, the development of urinary cfDNA biomarkers may improve the diagnostic sensitivity.

Methods: We assessed copy number alterations (CNAs) by shallow genome-wide sequencing of urinary cfDNA in 95 cancer-free individuals and 65 patients with UC, 58 with kidney cancer, and 45 with prostate cancer. We used a support vector machine to develop a diagnostic classifier based on CNA profiles to detect UC (UCdetector). The model was further validated in an independent cohort (52 patients). Genome sequencing data of tumor specimens from 90 upper tract urothelial cancers (UTUCs) and CNA data for 410 urothelial carcinomas of bladder (UCBs) from The Cancer Genome Atlas were used to validate the classifier. Genome sequencing data for urine sediment from 32 patients with UC were compared with cfDNA. To monitor the treatment efficacy, we collected cfDNA from 7 posttreatment patients.

Results: Urinary cfDNA was a more sensitive alternative to urinary sediment. The UCdetector could detect UC at a median clinical sensitivity of 86.5% and specificity of 94.7%. UCdetector performed well in an independent validation data set. Notably, the CNA features selected by UCdetector were specific markers for both UTUC and UCB. Moreover, CNA changes in cfDNA were consistent with the treatment effects. Meanwhile, the same strategy could localize genitourinary cancers to tissue of origin in 70.1% of patients.

Conclusions: Our findings underscore the potential utility of urinary cfDNA CNA profiles as a basis for noninvasive UC detection and surveillance.
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http://dx.doi.org/10.1373/clinchem.2019.309633DOI Listing
January 2020

Improving cellulases production by Myceliophthora thermophila through disruption of protease genes.

Biotechnol Lett 2020 Feb 4;42(2):219-229. Epub 2019 Dec 4.

Key Laboratory of Systems Microbial Biotechnology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China.

Objective: To identify main protease genes for the proteolytic degradation of cellulases in M. thermophila and generate a lower-proteases fungal host that can be used for further metabolic engineering to increase cellulase production and heterologous protein expression.

Results: Systematic transcriptomic analysis were conducted on the expression of proteases genes in M. thermophila genome and five highly expressed genes encoding extracellular proteases were selected for mutation analyses. A series of single- and multi-gene mutants of these five selected genes was constructed using the CRISPR-Cas9 technique. Compared with WT, the ΔMtalp1 and the quintuple mutant showed significantly lower protease activity (decreased 52.7% and 58.4%, respectively) and at least double enhanced cellulase production.

Conclusions: The results indicated that Mtalp1 is a critical protease gene in cellulase degradation in M. thermophila and disruption of protease genes showed significantly decreased protease activity and obviously enhanced cellulase production in the fermentation broth of ΔMtalp1 and the quintuple mutant.
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http://dx.doi.org/10.1007/s10529-019-02777-0DOI Listing
February 2020

STK-12 acts as a transcriptional brake to control the expression of cellulase-encoding genes in Neurospora crassa.

PLoS Genet 2019 11 25;15(11):e1008510. Epub 2019 Nov 25.

Key Laboratory of Systems Microbial Biotechnology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.

Cellulolytic fungi have evolved a complex regulatory network to maintain the precise balance of nutrients required for growth and hydrolytic enzyme production. When fungi are exposed to cellulose, the transcript levels of cellulase genes rapidly increase and then decline. However, the mechanisms underlying this bell-shaped expression pattern are unclear. We systematically screened a protein kinase deletion set in the filamentous fungus Neurospora crassa to search for mutants exhibiting aberrant expression patterns of cellulase genes. We observed that the loss of stk-12 (NCU07378) caused a dramatic increase in cellulase production and an extended period of high transcript abundance of major cellulase genes. These results suggested that stk-12 plays a critical role as a brake to turn down the transcription of cellulase genes to repress the overexpression of hydrolytic enzymes and prevent energy wastage. Transcriptional profiling analyses revealed that cellulase gene expression levels were maintained at high levels for 56 h in the Δstk-12 mutant, compared to only 8 h in the wild-type (WT) strain. After growth on cellulose for 3 days, the transcript levels of cellulase genes in the Δstk-12 mutant were 3.3-fold over WT, and clr-2 (encoding a transcriptional activator) was up-regulated in Δstk-12 while res-1 and rca-1 (encoding two cellulase repressors) were down-regulated. Consequently, total cellulase production in the Δstk-12 mutant was 7-fold higher than in the WT. These results strongly suggest that stk-12 deletion results in dysregulation of the cellulase expression machinery. Further analyses showed that STK-12 directly targets IGO-1 to regulate cellulase production. The TORC1 pathway promoted cellulase production, at least partly, by inhibiting STK-12 function, and STK-12 and CRE-1 functioned in parallel pathways to repress cellulase gene expression. Our results clarify how cellulase genes are repressed at the transcriptional level during cellulose induction, and highlight a new strategy to improve industrial fungal strains.
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http://dx.doi.org/10.1371/journal.pgen.1008510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901240PMC
November 2019

Increased Expression Of SOX2 Predicts A Poor Prognosis And Promotes Malignant Phenotypes In Upper Tract Urothelial Carcinoma.

Cancer Manag Res 2019 24;11:9095-9106. Epub 2019 Oct 24.

Department of Urology, Peking University First Hospital, Beijing, People's Republic of China.

Background: The transcription factor SRY-related HMG-box 2 (SOX2) plays important regulatory roles in diverse biological processes (cell proliferation, migration, invasion and tumorigenicity). However, the relationship between SOX2 and upper tract urothelial carcinoma (UTUC) have not been intensively investigated. This study aims to analyze the expression of SOX2 in UTUC as well as the predictive value for prognosis and the effect on tumor aggressiveness of SOX2.

Methods: Formalin-fixed, paraffin-embedded blocks containing samples from 341 patients with UTUC who underwent radical nephroureterectomy (RNU) at our institute were analyzed for SOX2 expression by immunohistochemistry (IHC). Associations between the SOX2 expression level and clinicopathological characteristics, disease-free survival (DFS) and cancer-specific survival (CSS) were analyzed. SOX2 expression in a normal urothelial cell line, urothelial carcinoma cell lines, 16 UTUC tissues and their pair-matched adjacent normal tissues was evaluated by RT-qPCR. Using RNA interference in vitro, the effects of SOX2 inhibition on cell proliferation, migration, invasion and tumorigenicity were determined.

Results: SOX2 expression was significantly upregulated in UTUC tissue samples compared with paired-adjacent nontumorous tissue samples. SOX2 expression was correlated with important clinicopathological features, including tumor stage, tumor grade, tumor architecture and the presence of glandular or sarcoma differentiation, and was an independent predictor of poor DFS and CSS. Further experiments indicated that SOX2 expression was higher in UTUC cell lines than in a normal urothelial cell line. Knocking down SOX2 expression could inhibit malignant phenotypes (cell proliferation, stemness, migration, invasion and tumorigenicity) in UTUC cells.

Conclusion: SOX2 is an independent prognostic marker of poor DFS and CSS in UTUC patients who have undergone RNU. Moreover, these data suggest that SOX2 may be a promising therapeutic target in UTUC.
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http://dx.doi.org/10.2147/CMAR.S219568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817346PMC
October 2019

Prognostic Significance of Murine Double Minute 2 Expression in Tumor Cells in Upper Tract Urothelial Carcinoma: An Analysis of 341 Cases in a Large Chinese Center.

Genet Test Mol Biomarkers 2019 Nov;23(11):797-806

Department of Urology, Peking University First Hospital, Beijing, China.

The prognostic significance of murine double minute 2 (MDM2) expression remains unknown in patients with upper tract urothelial carcinoma (UTUC). This study was designed to evaluate MDM2 expression and its association with clinicopathological characteristics and tumor outcomes in UTUC patients. Expression levels of MDM2 and p53 were determined by immunohistochemistry in a cohort of 341 UTUC patients. Associations of MDM2 and p53 expression levels with clinicopathological characteristics, disease-free survival (DFS), cancer-specific survival (CSS), and intravesical recurrence-free survival (IVRFS) were analyzed. Nuclear expression of MDM2 and p53 were detected in the tumor cells of 129 (37.8%) and 203 (59.5%) patients, respectively. Decreased p53 expression was associated with positive MDM2 staining in tumor cells ( = 0.002). MDM2 expression was correlated with the exposure to aristolochic acids ( = 0.020), better preoperative renal function ( = 0.016), ureter location ( = 0.002), higher pathological T stage ( = 0.006), high tumor grade ( < 0.001), presence of glandular differentiation ( = 0.036), and sarcoma differentiation ( = 0.020). Kaplan-Meier analysis showed that positive MDM2 staining was associated with shorter CSS ( < 0.001), DFS ( < 0.001), and IVRFS ( = 0.020); MDM2+/p53- was associated with shorter CSS ( < 0.001) and DFS ( < 0.001), but not IVRFS ( = 0.145); while CSS, DFS, and IVRFS did not differ significantly between the p53+ and p53- patients ( = 0.307, 0.089, and 0.198, respectively). Multivariate analyses revealed that MDM2 expression in tumor cells independently predicted shorter CSS ( < 0.001; hazard ratio [HR] = 2.600; 95% confidence interval [CI]: 1.625-4.161) and DFS ( < 0.001; HR = 1.863; 95% CI: 1.314-2.641), excepting IVRFS ( = 0.092; HR = 1.590; 95% CI: 0.928-2.726). UTUC patients with elevated MDM2 expression may exhibit more aggressive biological features of the tumor and tend to have shorter CSS and DFS.
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http://dx.doi.org/10.1089/gtmb.2019.0126DOI Listing
November 2019

[Influence of Oridonin on the Icilling Acitivity of NK-92 MI Cells Targeting Cell THP1 and Its Mechanism].

Zhongguo Shi Yan Xue Ye Xue Za Zhi 2019 Oct;27(5):1374-1379

Department of Hematology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China,E-mail:

Objective: To investigate the influence of oridonin on the killing activity of NK-92 MI cells targeting THP1 and the related mechanism.

Methods: The killing activity of NK-92 MI to THP1 before and after oridonin treatment was detected by LDH release assay; the expression of natural killer cell ligands activating receptor D (NKG2D, including MICA, MICB, ULBP1, ULBP2 and ULBP3) was detected by real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot respectively; the expression of cytokine TNF-α, TNF-β and IFN-γ in the co-culture supernatant of NK-92 MI cells and THP1 cells were measured by ELISA.

Results: The killing efficiency after oridonin treatment at different effector-target ratio (1:1, 5:1, 10:1) was all significantly up-regulated in comparison with that before oridonin treatment (P<0.05). QRT-PCR and Western blot showed that the expressions of mRNA and protein levels of MICB, ULBP1, ULBP2 increased to varying degree (P<0.05), but the expression levels of MICA and ULBP3 were not statistically significant between experimental group and control group (P>0.05). ELISA results indicated that IFN-γ and TNF-β release were significantly increased after oridonin treatment (P<0.05), however, the TNF-α release was not statistically different in comparison with control group (P>0.05).

Conclusion: Oridonin can significantly improve killing efficiency of NK-92 MI on THP1, that might be related with up-regulation of MICB, ULBP1 and ULBP2 expression and promotion of IFN-γ and TNF-β release.
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http://dx.doi.org/10.19746/j.cnki.issn.1009-2137.2019.05.004DOI Listing
October 2019

The Neurospora RNA polymerase II kinase CTK negatively regulates catalase expression in a chromatin context-dependent manner.

Environ Microbiol 2020 01 21;22(1):76-90. Epub 2019 Oct 21.

State Key Laboratory of Agrobiotechnology and MOA Key Laboratory of Soil Microbiology, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.

Clearance and adaptation to reactive oxygen species (ROS) are crucial for cell survival. As in other eukaryotes, the Neurospora catalases are the main enzymes responsible for ROS clearance and their expression are tightly regulated by the growth and environmental conditions. The RNA polymerase II carboxyl terminal domain (RNAPII CTD) kinase complex (CTK complex) is known as a positive elongation factor for many inducible genes by releasing paused RNAPII near the transcription start site and promoting transcription elongation. However, here we show that deletion of CTK complex components in Neurospora led to high CAT-3 expression level and resistance to H O -induced ROS stress. The catalytic activity of CTK-1 is required for such a response. On the other hand, CTK-1 overexpression led to decreased expression of CAT-3. ChIP assays shows that CTK-1 phosphorylates the RNAPII CTD at Ser2 residues in the cat-3 ORF region during transcription elongation and deletion of CTK-1 led to dramatic decreases of SET-2 recruitment and H3K36me3 modification. As a result, histones at the cat-3 locus become hyperacetylated to promote its transcription. Together, these results demonstrate that the CTK complex is negative regulator of cat-3 expression by affecting its chromatin structure.
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http://dx.doi.org/10.1111/1462-2920.14821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216558PMC
January 2020

FRQ-CK1 interaction determines the period of circadian rhythms in Neurospora.

Nat Commun 2019 09 25;10(1):4352. Epub 2019 Sep 25.

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390-9040, USA.

Circadian clock mechanisms have been extensively investigated but the main rate-limiting step that determines circadian period remains unclear. Formation of a stable complex between clock proteins and CK1 is a conserved feature in eukaryotic circadian mechanisms. Here we show that the FRQ-CK1 interaction, but not FRQ stability, correlates with circadian period in Neurospora circadian clock mutants. Mutations that specifically affect the FRQ-CK1 interaction lead to severe alterations in circadian period. The FRQ-CK1 interaction has two roles in the circadian negative feedback loop. First, it determines the FRQ phosphorylation profile, which regulates FRQ stability and also feeds back to either promote or reduce the interaction itself. Second, it determines the efficiency of circadian negative feedback process by mediating FRQ-dependent WC phosphorylation. Our conclusions are further supported by mathematical modeling and in silico experiments. Together, these results suggest that the FRQ-CK1 interaction is a major rate-limiting step in circadian period determination.
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http://dx.doi.org/10.1038/s41467-019-12239-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761100PMC
September 2019

Expression of programmed cell death-ligand 1 in primary testicular diffuse large B cell lymphoma: A retrospective study.

Oncol Lett 2019 Sep 9;18(3):2670-2676. Epub 2019 Jul 9.

Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing 100034, P.R. China.

The present study evaluated programmed cell death-ligand 1 (PD-L1) expression in tumor cells and in the tumor microenvironment (TME) and its association with clinical data in primary testicular diffuse large B cell lymphoma (DLBCL). PD-L1 was determined by immunohistochemistry in 30 patients with primary testicular DLBCL and assessed for associations with clinical characteristics, progression-free survival (PFS) and overall survival (OS). The mean patient age was 62.2 years. Overall, 10 (33.3%) patients had advanced-stage (stage III/IV) disease and 14 (46.7%) patients had an International Prognostic Index (IPI) of ≥3. The median follow-up time following orchiectomy was 23.5 months. During this time, 10 (33.3%) patients experienced disease progression and 11 (36.7%) patients succumbed. PD-L1 expression in tumor cells and in the TME was detected in 20 (66.7%) and 13 (43.3%) patients, respectively. PD-L1 expression on tumor cells and in the TME was higher in those at an early stage compared with patients with an advanced stage of disease (P=0.045 and 0.017, respectively). In addition, PD-L1 expression in tumor cells was higher in patients with a low IPI compared with those with a high IPI (P=0.019). A Kaplan-Meier analysis identified no association of PD-L1 expression on tumor cells with PFS (P=0.763) or OS (P=0.531), or of PD-L1 expression in the TME with PFS (P=0.572) or OS (P=0.934). The present study demonstrated that PD-L1 expression in tumor cells and in the TME was higher in patients at an early stage of disease compared with those at an advanced stage, and that PD-L1 expression on tumor cells was higher in patients with a low IPI than in those with a high IPI. Furthermore, PD-L1 expression in tumor cells and in the TME was not associated with PFS or OS.
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http://dx.doi.org/10.3892/ol.2019.10595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676532PMC
September 2019