Publications by authors named "Mingzhi Zhang"

395 Publications

Hydroa vacciniforme-like lymphoproliferative disorder: A clinicopathological, immunohistochemical, and prognostic study of 24 cases in China.

J Dermatol 2021 May 13. Epub 2021 May 13.

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a rare cutaneous disease associated with Epstein-Barr virus infection. We retrospectively analyzed the clinical presentation, histopathological characteristics, and prognostic study of HV-LPD in 24 Chinese patients. All patients presented with recurrent papulovesicular and necrotic eruptions on the face, neck, and extremities, with 11 showing systemic symptoms. Twenty patients were diagnosed with HV-LPD in childhood (age < 18 years) and four in adulthood (age ≥ 18 years). The median age at diagnosis was 8.5 years old (range, 2-50). Histopathology revealed variably dense lymphocyte infiltration throughout the dermis. All cases were strongly positive for CD3 and Epstein-Barr encoding region based on in situ hybridization. Of 18 cases with a T-cell phenotype, 15 harbored monoclonal rearrangements in T-cell receptor (TCR) genes. Four cases with a natural killer cell phenotype carried polyclonal rearrangements in TCR genes. Among 24 patients, eight (33.3%) received chemotherapy, two (8.3%) allogeneic hematopoietic stem cell transplantation, and both are currently alive without disease. The median follow-up period was 24 months (range, 7-120) and 23 patients were available: 15 (62.5%) were alive, and eight (33.3%) had died. Fourteen cases had a relapse of disease and three developed lymphoma within 24 months of diagnosis. The mean survival time of childhood-onset patients was longer than that of adult-onset patients (36.4 vs. 20.8 months). In summary, the wide clinical course and representative presentation of cases in our center reflect the pedigree characteristics of HV-LPD. Allogeneic hematopoietic stem cell transplantation should be a preferred choice for relapse and refractory patients due to the poor effect of chemotherapy. Adult-onset and high serum EBV DNA loads may indicate an increased risk of aggressive disease in patients with HV-LPD.
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http://dx.doi.org/10.1111/1346-8138.15944DOI Listing
May 2021

Determinants of peripapillary retinal nerve fiber layer's grayscale value in normal eyes by spectral domain optical coherence tomography.

Sci Rep 2021 May 5;11(1):9577. Epub 2021 May 5.

Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou University Medical College, Shantou, 515000, Guangdong, China.

To determine and evaluate the distribution, variation, and determinants of peripapillary retinal nerve fiber layer (pRNFL) grayscale value with spectral-domain optical coherence tomography (SD-OCT) in normal eyes. In this cross-sectional study, three hundred ninety-seven normal eyes from 397 healthy Chinese adults aged 18-80 were consecutively recruited from a tertiary eye care center. An SD-OCT instrument took pRNFL imaging. We used a customized software to measure pRNFL parameters, including thickness and grayscale value. Univariable and multiple linear regression analyses were performed to examine the relationship between pRNFL grayscale value with ocular (e.g., axial length [A.L.], spherical equivalent [S.E.], intraocular pressure [IOP]), and systemic (e.g., age, sex) factors. A total of 397 eyes from 397 healthy subjects were included in the final analysis with mean (± SD) age 44.63 ± 16.43 years (range 18-80 years) and 196 (49.4%) males. The mean average of pRNFL grayscale value and thickness 164.82 ± 5.69 and 106.68 ± 8.89 μm, respectively. pRNFL grayscale value in nasal sectors (163.26 ± 9.31) was significantly lower comparing those in all other five sectors (all with p < 0.001)]. In multivariable analysis, average pRNFL grayscale value was independently correlated to older age (β = - 0.053, p = 0.002), longer axial length (β = - 0.664, p = 0.003), lower RPE grayscale value (β = 0.372, p < 0.001) and lower ImageQ (β = 0.658, p < 0.001). In this study, we provided normative SD-OCT data on the pRNFL grayscale value profile in nonglaucomatous eyes. Lower average pRNFL grayscale value was independently correlated to older age, longer axial length, lower RPE grayscale value, and lower ImageQ. These determinants should be considered when interpreting pRNFL grayscale value in glaucoma assessment.
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http://dx.doi.org/10.1038/s41598-021-88604-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100177PMC
May 2021

Automated Explainable Multidimensional Deep Learning Platform of Retinal Images for Retinopathy of Prematurity Screening.

JAMA Netw Open 2021 May 3;4(5):e218758. Epub 2021 May 3.

Joint Shantou International Eye Center of Shantou University, the Chinese University of Hong Kong, Shantou, Guangdong, China.

Importance: A retinopathy of prematurity (ROP) diagnosis currently relies on indirect ophthalmoscopy assessed by experienced ophthalmologists. A deep learning algorithm based on retinal images may facilitate early detection and timely treatment of ROP to improve visual outcomes.

Objective: To develop a retinal image-based, multidimensional, automated, deep learning platform for ROP screening and validate its performance accuracy.

Design, Setting, And Participants: A total of 14 108 eyes of 8652 preterm infants who received ROP screening from 4 centers from November 4, 2010, to November 14, 2019, were included, and a total of 52 249 retinal images were randomly split into training, validation, and test sets. Four main dimensional independent classifiers were developed, including image quality, any stage of ROP, intraocular hemorrhage, and preplus/plus disease. Referral-warranted ROP was automatically generated by integrating the results of 4 classifiers at the image, eye, and patient levels. DeepSHAP, a method based on DeepLIFT and Shapley values (solution concepts in cooperative game theory), was adopted as the heat map technology to explain the predictions. The performance of the platform was further validated as compared with that of the experienced ROP experts. Data were analyzed from February 12, 2020, to June 24, 2020.

Exposure: A deep learning algorithm.

Main Outcomes And Measures: The performance of each classifier included true negative, false positive, false negative, true positive, F1 score, sensitivity, specificity, receiver operating characteristic, area under curve (AUC), and Cohen unweighted κ.

Results: A total of 14 108 eyes of 8652 preterm infants (mean [SD] gestational age, 32.9 [3.1] weeks; 4818 boys [60.4%] of 7973 with known sex) received ROP screening. The performance of all classifiers achieved an F1 score of 0.718 to 0.981, a sensitivity of 0.918 to 0.982, a specificity of 0.949 to 0.992, and an AUC of 0.983 to 0.998, whereas that of the referral system achieved an F1 score of 0.898 to 0.956, a sensitivity of 0.981 to 0.986, a specificity of 0.939 to 0.974, and an AUC of 0.9901 to 0.9956. Fine-grained and class-discriminative heat maps were generated by DeepSHAP in real time. The platform achieved a Cohen unweighted κ of 0.86 to 0.98 compared with a Cohen κ of 0.93 to 0.98 by the ROP experts.

Conclusions And Relevance: In this diagnostic study, an automated ROP screening platform was able to identify and classify multidimensional pathologic lesions in the retinal images. This platform may be able to assist routine ROP screening in general and children hospitals.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.8758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100867PMC
May 2021

Ibrutinib combined with venetoclax for the treatment of relapsed/refractory diffuse large B cell lymphoma.

Ann Hematol 2021 Jun 26;100(6):1509-1516. Epub 2021 Apr 26.

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.1 Jianshe East Road, Zhengzhou, China.

Treatment outcomes of relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) are far from satisfactory. Certain efficacy of ibrutinib has been observed in non-GCB subtype DLBCL patients. This study aimed to investigate the efficacy and safety of ibrutinib plus BCL2 inhibitor venetoclax in R/R DLBCL patients with non-GCB subtype and BCL2 overexpression. Combinational therapy (ibrutinib 560mg/day; venetoclax started 1 week later, oral dose increased from 100 to 400mg/day in 3 weeks) was conducted, and one cycle was 4 weeks. Both drugs were stopped when disease progress or serious adverse reactions appear. The primary end-point was overall response rate (ORR) at two cycles. From December 2018 to July 2020, a total of 13 patients were treated with the combined therapy. Among them, eleven (84.6%) patients previously received at least two treatment regimens, eight (61.5%) patients were C-myc and BCL2 double expression. The ORR at two cycles was 61.5%, with 3 (23.1%) patients achieved complete remission (CR) and 5 (38.4%) patients achieved partial remission (PR). The ORR at four cycles and six cycles was 53.8% and 46.2%, respectively. The median duration of response was 11 months (range, 1.5-13.6 months). The median progression-free survival and overall survival were 5.6 months (range, 0.4-15.6) and 11.3 months (range, 2.8-17.2), respectively. The most common adverse event was grade 1/2 neutropenia (53.8%), and nonhematologic toxicities included Grade1/2 diarrhea (46.2%) and elevated liver enzymes (30.8%). Combined therapy of ibrutinib and venetoclax showed promising efficacy and synergistic effects in R/R DLBCL patients with non-GCB subtype and BCL2 overexpression, and the toxicities were well-tolerated.
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http://dx.doi.org/10.1007/s00277-021-04535-7DOI Listing
June 2021

Altered Gut Microbiota Taxonomic Compositions of Patients With Sepsis in a Pediatric Intensive Care Unit.

Front Pediatr 2021 7;9:645060. Epub 2021 Apr 7.

Pediatric Intensive Care Unit, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.

The gut is thought to play an important role in the pathogenesis of sepsis. Changes in the gut microbiota are closely related to the occurrence and development of human diseases, but few studies have focused on taxonomic composition of gut microbiota in septic patients. Knowledge of changes in the gut microbiota is a key issue in intensive care. Clinicians must understand how an altered gut microbiota affects the susceptibility and prognosis of septic patients. In the single-center case control study, 20 septic patients and 20 healthy children were recruited. The taxonomic composition of gut microbiota was determined 16S rRNA gene sequencing. Gut microbiota diversity in children with sepsis was significantly reduced compared with that in healthy children. The taxonomic composition of gut microbiota can effectively distinguish children with sepsis from healthy children. Thirteen taxa of gut microbiota were significantly increased in the guts of children with sepsis compared with those of healthy children. The increased abundances of Enterococcaceae, , and in gut of septic patients were significantly positively correlated with blood inflammation indicators CRP and WBC. The abundances of seven bacteria were significantly decreased in the guts of septic children compared with those of healthy children. The decreased abundance of Bifidobacteriales in gut of septic patients is significantly negatively correlated with blood inflammation index WBC. A machine-learning classifier was built for distinguishing sepsis and achieved the AUC value of 81.25%. It shows that the composition of gut microbiota has certain potential for diagnosis of sepsis. Gut microbiota alterations in septic patients exhibit proliferation of opportunistic pathogenic bacteria, the massive reduction of the commensal flora, and the significant decrease in the diversity of the gut microbiota. Dysbiosis may also account for some changes in the inflammation indexes.
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http://dx.doi.org/10.3389/fped.2021.645060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058355PMC
April 2021

Identification of low-dose radiation-induced exosomal circ-METRN and miR-4709-3p/GRB14/PDGFRα pathway as a key regulatory mechanism in Glioblastoma progression and radioresistance: Functional validation and clinical theranostic significance.

Int J Biol Sci 2021 2;17(4):1061-1078. Epub 2021 Mar 2.

Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People's Republic of China.

Glioblastoma is a central nervous malignancy with a very poor prognosis. This study attempted to explore the role of exosomes induced by low-dose radiation-induced (ldrEXOs) and ldrEXOs-derived circ-METRN in glioblastoma progression and radioresistance at the molecular, cellular, animal, and clinical levels. Results in the present study revealed that low-dose radiation stimulated the secretion of ldrEXOs which delivered high levels of circ-METRN. And circ-METRN-abundant ldrEXOs increased the expression of γ-H2AX, indicating an efficient DNA damage-repair process in glioblastoma cells. The ldrEXOs-derived circ-METRN enhanced the glioblastoma progression and radioresistance via miR-4709-3p/GRB14/PDGFRα pathway. Up-regulating PDGFRα can rescue the tumor-promoting function of ldrEXOs in groups previously treated with inhibition of GRB14. Additionally, in-vivo experiments revealed that treatments with ldrEXOs promoted the growth of xenografted tumors and shortened the survival period. Furthermore, clinical researches indicated that circ-METRN may be transported into the bloodstream by exosomes in the early stages of fractionated radiotherapy. It has important clinical values to detect the serum exosomal circ-METRN in the early stage of radiotherapy, which is not only conducive to predict radioresistance and prognosis but also to assist MRI diagnosis in detecting the very early recurrence of glioblastoma. In summary, this study reveals for the first time that low-dose radiation-induced exosomal circ-METRN plays an oncogenic role in glioblastoma progression and radioresistance through miR-4709-3p/GRB14/PDGFRα pathway, providing mechanistic insights into the roles of circRNAs and a valuable marker for therapeutic targets in glioblastoma.
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http://dx.doi.org/10.7150/ijbs.57168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040305PMC
March 2021

CircANKRD52 Promotes the Tumorigenesis of Hepatocellular Carcinoma by Sponging miR-497-5p and Upregulating BIRC5 Expression.

Cell Transplant 2021 Jan-Dec;30:9636897211008874

Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China.

CircRNAs participate in the pathogenesis of a variety of cancers. Previous studies showed that baculoviral IAP repeat containing 5 (BIRC5) can promote tumor progression. But, the mechanisms by which circRNAs regulate BIRC5 expression in hepatocellular carcinoma (HCC) remain unknown. The clinical prognosis of BIRC5 or miR-497-5p expression in patients with HCC was assessed by TCGA RNA-seq dataset. hsa_circ_0026939 (circANKRD52) or BIRC5 was identified to bind with miR-497-5p by luciferase gene report, RIP and circRIP assays. MTT, colony formation, Transwell assays and a xenograft tumor model were used to estimate the role of miR-497-5p or circANKRD52 in HCC cells. As a result, we found that elevated expression of BIRC5 or decreased expression of miR-497-5p was linked to poor survival in HCC. Restored expression of miR-497-5p repressed cell proliferation, colony formation and invasiveness by targeting BIRC5, but its inhibitor showed the opposite results. Furthermore, circANKRD52 possessed a tumor-promoting effect by acting as a sponge of miR-497-5p and thereby upregulated BIRC5 in HCC cells. In conclusion, our findings demonstrated that circANKRD52 enhances the tumorigenesis of HCC by sponging miR-497-5p and upregulating BIRC5 expression.
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http://dx.doi.org/10.1177/09636897211008874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058805PMC
April 2021

LncRNA MEG3 regulates breast cancer proliferation and apoptosis through miR-141-3p/RBMS3 axis.

Genomics 2021 Apr 9;113(4):1689-1704. Epub 2021 Apr 9.

Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China. Electronic address:

Maternally expressed 3 (MEG3) and RNA binding motif single stranded interacting protein 3 (RBMS3) are abnormally expressed in breast cancer susceptibility genes (BRCA), but the mechanism of the two in breast cancer (BC) is unclear. By performing in vivo and in vitro experiments, we found that MEG3 and RBMS3 were low-expressed, negatively correlated with high-expressed miR-141-3p, were positively correlated with each other in BC. MEG3 targeted miR-141-3p, and miR-141-3p targeted RBMS3. MEG3, which was mainly distributed in BC cytoplasm, could down-regulate miR-141-3p and up-regulate RBMS3, and reverse effect of miR-141-3p on related gene expressions and on promoting cancer development. Overexpressed MEG3 inhibited growth of xenografts, promoted cell apoptosis via regulating apoptosis related factors, and up-regulated RBMS3 expression but down-regulated miR-141-3p. The findings of this study showed that MEG3 inhibited proliferation and promoted apoptosis of BC cells through the miR-141-3p/RBMS3 axis, and MEG3 inhibited growth of xenografts through miR-141-3p.
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http://dx.doi.org/10.1016/j.ygeno.2021.04.015DOI Listing
April 2021

RAI14 Regulated by circNFATC3/miR-23b-3p axis Facilitates Cell Growth and Invasion in Gastric Cancer.

Cell Transplant 2021 Jan-Dec;30:9636897211007055

Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China.

Circular RNAs (circRNAs) have been proved to act crucial roles in multiple malignancies including gastric cancer (GC). Retinoic acid induced 14 (RAI14) acts as an oncogene in human cancers, but the underlying mechanisms by which RAI14 is regulated by circRNA/miRNA axis remain elusive. The clinical value of RAI14, miR-23b-3p and circNFATC3 was estimated by The Cancer Genome Atlas and fluorescence in situ hybridization. The interplay between miR-23b-3p and RAI14 or circNFATC3 was determined by qRT-PCR, Western blot, luciferase gene report and RIP assays. Biological function assays and a subcutaneous xenograft model were executed to unveil the role of circNFATC3/miR-23b-3p/RAI14 axis in GC cells. As a consequence, upregulation of RAI14 and circNFATC3 or downregulation of miR-23b-3p was associated with poor prognosis in patients with GC. Restored miR-23b-3p depressed cell proliferation, colony formation, and cell invasion by targeting RAI14, whereas RAI14 facilitated cell progression and reversed the anti-tumor effects of miR-23b-3p in GC cells. Then, circNFATC3 had a co-localization with miR-23b-3p in the cytoplasm in GC tissue cells and could act as a sponge of miR-23b-3p in GC cell line. Silencing of circNFATC3 inhibited cell growth and in vivo tumorigenesis by upregulating miR-23b-3p and downregulating RAI14. In conclusion, our findings indicated that RAI14 facilitated cell growth and invasion and was regulated by circNFATC3/miR-23b-3p axis in GC.
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http://dx.doi.org/10.1177/09636897211007055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044574PMC
April 2021

Feedback activation of NF-KB signaling leads to adaptive resistance to EZH2 inhibitors in prostate cancer cells.

Cancer Cell Int 2021 Apr 1;21(1):191. Epub 2021 Apr 1.

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.

Background: Prostate cancer (PCa) is the most common malignant tumor in developed countries, which has seriously threatened men's lifestyle and quality of life. The up-regulation of EZH2 is associated with advanced PCa and poor prognosis, making it a promising therapeutic target. However, the EZH2 inhibitors-based treatment is basically ineffective against PCa, which limits its clinical application.

Methods: Microarray data (GSE107779) from LNCaP cells treated with either siRNA against EZH2 or a EZH2 inhibitor EPZ6438 was analyzed by Limma R package. Western blot, real-time PCR and luciferase reporter assays were used to determine the EZH2-SOX9-TNFRSF11A axis and the activity of NF-κB signaling in PCa cells. CCK-8 assay was used to determine the viability of PCa cells following various treatments.

Results: Genetic ablation or pharmacological inhibition of EZH2 leads to feedback activation of NF-κB signaling in PCa cells. EZH2-dependent SOX9 expression regulates the activation of NF-κB signaling. TNFRSF11A, also known as receptor activator of NF-κB (RANK), is a downstream target of SOX9 in PCa cells. SOX9 recognizes two putative SOX9 response elements in the promoter region of TNFRSF11A gene to drive TNFRSF11A expression and downstream NF-κB signaling activation. Suppression of the NF-κB signaling by either TNFRSF11A silencing or BAY11-7082 treatment rendered PCa cells to EZH2 inhibitors.

Conclusion: Collectively, our finding reveals a EZH2-SOX9-TNFRSF11A axis in the regulation of activity of NF-κB signaling in PCa cells and suggests that a combination of EZH2 inhibitors and BAY11-7082 would be an effective approach for the treatment of PCa patients in the future.
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http://dx.doi.org/10.1186/s12935-021-01897-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017762PMC
April 2021

Asymptomatic Hyperuricemia and Metabolically Unhealthy Obesity: A Cross-Sectional Analysis in the Tianning Cohort.

Diabetes Metab Syndr Obes 2021 25;14:1367-1374. Epub 2021 Mar 25.

Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, People's Republic of China.

Objective: The relationship between obesity and hyperuricemia has been demonstrated by many studies. However, whether or to what extent metabolic condition influents the association between obesity and hyperuricemia was not clear. Here, we aimed to examine the association between obese-metabolic phenotype and hyperuricemia in a large sample of Chinese adults.

Methods: According to BMI and metabolic syndrome, obese-metabolic phenotype was defined as metabolically unhealthy obesity (MUO), metabolically healthy obesity (MHO), metabolically unhealthy non-obesity (MUNO) and metabolically healthy non-obesity (MHNO)in the Tianning cohort (N=5072). We conducted a cross-sectional analysis between obese-metabolic phenotype and hyperuricemia, followed by a Mendelian Randomization analysis using GWAS summary data to confirm the causality between uric acid and BMI.

Results: The average level of serum UA showed 41.87-higher μmol/L in participants with MHO (β=41.87, <0.001) and 63.18-higher μmol/L in participants with MUO (β=63.18, <0.001), compared to those with MHNO. Compared to participants with MHNO, those with MUO had the highest likelihood to have hyperuricemia (OR=4.56, <0.001), followed by those with MHO (OR=3.32, <0.001). Mendelian randomization analysis indicated that uric acid was more likely to be a consequence of BMI (β=0.059, =6.54×10).

Conclusion: MUO, in comparison with MHO, was significantly associated with hyperuricemia in Chinese adults.
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http://dx.doi.org/10.2147/DMSO.S301363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006809PMC
March 2021

CXCL5/CXCR2 modulates inflammation-mediated neural repair after optic nerve injury.

Exp Neurol 2021 Mar 27;341:113711. Epub 2021 Mar 27.

Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, Guangdong, China. Electronic address:

Background: Previous studies reported that mild inflammation promotes retinal ganglion cell (RGC) survival and axonal regeneration after optic nerve (ON) injury with involvement of infiltrating macrophages and neutrophils. Here we aimed to evaluate the involvement and regulation of the main inflammatory chemokine pathway CXCL5/CXCR2 in the inflammation-mediated RGC survival and axonal regeneration in mice after ON injury.

Methods: The expressions and cellular locations of CXCL5 and CXCR2 were confirmed in mouse retina. Treatment effects of recombinant CXCL5 and CXCR2 antagonist SB225002 were studied in the explant culture and the ON injury model with or without lens injury. The number of RGCs, regenerating axons, and inflammatory cells were determined, and the activation of Akt andSTAT3 signaling pathways were evaluated.

Results: Cxcr2 and Cxcl5 expressions were increased after ON and lens injury. Addition of recombinant CXCL5 promoted RGC survival and neurite outgrowth in retinal explant culture with increase in the number of activated microglia, which was inhibited by SB225002 or clodronate liposomes. Recombinant CXCL5 also alleviated RGC death and promoted axonal regeneration in mice after ON injury, and promoted the lens injury-induced RGC protection with increase in the number of activated CD68 cells. SB225002 inhibited lens injury-induced cell infiltration and activation, and attenuated the promotion effect on RGC survival and axonal regeneration through reduction of lens injury-induced Akt activation.

Conclusions: CXCL5 promotes RGC survival and axonal regeneration after ON injury and further enhances RGC protection induced by lens injury with CD68 cell activation, which is attenuated by CXCR2 antagonist. CXCL5/CXCR2 could be a potential therapeutic target for RGC survival promotion after ON injury.
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http://dx.doi.org/10.1016/j.expneurol.2021.113711DOI Listing
March 2021

Comparison of corneal aberrations and refractive outcomes after small-incision lenticule extraction and femtosecond-assisted laser-assisted in situ keratomileusis.

Int Ophthalmol 2021 Mar 30. Epub 2021 Mar 30.

Joint Shantou International Eye Center of Shantou University, The Chinese University of Hong Kong, Shantou, 515041, China.

Purposes: To retrospectively compare the short-term refractive outcomes and corneal aberrations after small-incision lenticule extraction (SMILE) and femtosecond-assisted laser-assisted in situ keratomileusis (FS-LASIK) combined with smart pulse technology (SPT) in patients with compound myopic astigmatism.

Methods: A total of 91 eyes (91 patients) were included, 43eyes in FS-LASIK group and 48 eyes in the SMILE group. Uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), refractive results and corneal topography were evaluated 1 and 3 months postoperatively. Corneal aberrations of anterior corneal surface were calculated from the topography data over 6 mm-diameter.

Results: There was no significant difference in UCVA, BCVA, and refractive results between the two groups. There were no statistical difference in TIA (target induced astigmatism), SIA (surgery induced astigmatism), DV (difference vector), ME (magnitude of error), AE (angle of error), AE (absolute value) and CI (correction index) between both groups at 1 and 3 months. Coma and spherical aberration improved in all the patients in both groups at 1 and 3 months postoperatively. The amount of induced spherical aberrations was higher in FS-LASIK group compared to SMILE group.

Conclusions: Both FS-LASIK and SMILE achieved similar refractive outcomes in patients with myopia and compound myopic astigmatism. FS-LASIK combined with SPT resulted in higher spherical aberration than SMILE in early postoperative period.
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http://dx.doi.org/10.1007/s10792-021-01810-4DOI Listing
March 2021

Interleukin-6 reverses Adriamycin resistance in nasal NK/T-cell lymphoma via downregulation of ABCC4 and inactivation of the JAK2/STAT3/NF-κB/P65 pathway.

Environ Toxicol Pharmacol 2021 Mar 23;85:103639. Epub 2021 Mar 23.

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China. Electronic address:

Chemotherapy is generally effective for extranodal natural killer (NK)/T-cell lymphoma (ENKTCL), nasal type. Nevertheless, multidrug resistance (MDR) remains a key challenge in treating nasal NK/T-cell lymphoma. Interleukin-6 (IL-6) is reportedly an important regulator of MDR in many cancers, implicating a role of IL-6 in the chemotherapy response. However, the effects and mechanism of IL-6 in nasal NK/T-cell lymphoma remain unclear. Herein, we demonstrated that the IL-6 serum level was decreased in nasal NK/T-cell lymphoma patients compared to chronic rhinitis patients. Lower serum levels of IL-6 were closely correlated with Ki67 expression and patient survival. ATP-binding cassette (ABC) drug transporter ABCC4 in patients was abnormally upregulated. IL-6 significantly inhibited resistance to Adriamycin (ADM) in ADM-resistant SNK-6 cells (SNK-6/ADM). Moreover, IL-6 resulted in cell cycle arrest and led to apoptosis in SNK-6/ADM cells. Furthermore, IL-6 decreased ABCC4, p-JAK2, p-STAT3, and phospho-NF-κB p65 expression in SNK-6/ADM cells. IL-6 in combination with ADM inhibited tumor growth and increased the survival of SNK-6/ADM xenograft mice. In conclusion, our findings suggest that IL-6 can inhibit the upregulation of ABCC4 and inactivate the JAK2/STAT3/NF-κB/P65 pathway to sensitize NK/T-cell lymphoma to ADM, indicating that combination therapy with IL-6 and other chemotherapeutic drugs may be effective in reversing acquired resistance in nasal NK/T-cell lymphoma.
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http://dx.doi.org/10.1016/j.etap.2021.103639DOI Listing
March 2021

Efficacy and Safety of the Biosimilar IBI301 Plus Standard CHOP (I-CHOP) in Comparison With Rituximab Plus CHOP (R-CHOP) in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A Randomized, Double-Blind, Parallel-Group, Phase 3 Trial.

Adv Ther 2021 04 9;38(4):1889-1903. Epub 2021 Mar 9.

Hematology Department, Qilu Hospital of Shandong University, Jinan, China.

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) have limited access to rituximab. IBI301 is a recombinant chimeric murine/human anti-CD20 monoclonal antibody and is a candidate biosimilar to rituximab. This study aimed to assess the therapeutic equivalence of IBI301 and rituximab in previously untreated patients with diffuse large B-cell lymphoma (DLBCL).

Methods: This multicenter, randomized, double-blind, parallel-group, phase 3 trial compared IBI301 and rituximab, both plus the chemotherapy of doxorubicin, cyclophosphamide, vindesine, and prednisone (CHOP), was conducted in 68 centers across China. Eligible patients with untreated CD20 positive (CD20) DLBCL randomly received IBI301 (375 mg/m) plus the standard CHOP or rituximab (375 mg/m) plus the standard CHOP for six cycles of a 21-day cycle. The primary end point was the overall remission rate (ORR). Efficacy equivalence was defined if 95% CIs for the ORR difference between the two groups were within a ± 12.0% margin.

Results: Between August 22, 2016, and September 5, 2018, 419 patients were randomly allocated into the IBI301 group (N = 209) and rituximab group (N = 210). In the full analysis set, the ORR was 89.9% and 93.8% in the IBI301 and rituximab groups, respectively, and the ORR difference was -3.9% (95% CI - 9.1%-1.3%), falling within a ± 12.0% margin. The occurrences of treatment-emergent adverse events (TEAEs) (100% vs. 99.0%) and AEs of grade ≥ 3 (87.1% vs. 83.3%) were similar in the two groups (P > 0.05).

Conclusions: IBI301 had a non-inferiority efficacy and a comparable safety compared with rituximab. IBI301 plus CHOP could be suggested as a candidate treatment regimen for untreated patients with CD20 DLBCL.

Trial Registration: This trial is registered on ClinicalTrials.gov (NCT02867566).
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http://dx.doi.org/10.1007/s12325-020-01603-8DOI Listing
April 2021

Myeloablative Haploidentical Transplant as an Alternative to Matched Sibling Transplant for Peripheral T-Cell Lymphomas.

Cell Transplant 2021 Jan-Dec;30:963689721999615

Department of Hematology, Chinese PLA General Hospital, Beijing, China.

The number of HLA-haploidentical allogeneic hematopoietic stem-cell transplantation (Haplo-HSCT) is increasing. Comparative studies about Haplo-HSCT versus allo-HSCT with HLA-matched sibling donors (MSD-HSCT) have been tried in leukemias and B-cell lymphomas. Few studies were reported in Peripheral T-cell lymphomas (PTCLs). We performed a multicenter retrospective study about 52 patients with PTCLs undergoing Haplo-HSCT ( = 20) or MSD-HSCT ( = 32). All Haplo-HSCT recipients received antithymocyte globulin (ATG) based graft versus host disease (GVHD) prophylaxis. The median follow-up for all survivors was 38 months. The 100-day cumulative incidence of grade II to IV acute GVHD was similar (19% in the MSD-HSCT group versus 28% in the Haplo-HSCT group, 0.52). The 2-year cumulative incidence of chronic GVHD (limited and extensive) after Haplo-HSCT (30%) was also similar with that in the MSD-HSCT group (50%, 0.15). The 3-year relapse rates (33% vs 27%, 0.84) and non-relapse mortality (21% vs 22%, 0.78) did not differ between these two groups. There were also no differences in 3-year overall survival (OS) (48% vs 50%, 0.78) and progression-free survival (47% vs 51%, 0.95) between these two groups. On multivariate analysis, prognostic index for T-cell lymphoma (PIT) score (higher than 1: hazard ratio [HR], 4.0; 0.003) and disease status (stable or progression disease before HSCT: HR, 2.8; 0.03) were independent variables associated with worse OS. We concluded that ATG-based haplo-HSCT platform could work as an alternative to MSD-HSCT for patients with PTCLs.
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http://dx.doi.org/10.1177/0963689721999615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989122PMC
March 2021

Comparison of Continuous Subcutaneous Insulin Infusion and Multiple Daily Injections in Pediatric Type 1 Diabetes: A Meta-Analysis and Prospective Cohort Study.

Front Endocrinol (Lausanne) 2021 2;12:608232. Epub 2021 Mar 2.

Department of Endocrinology, Children's Hospital of Nanjing Medical University, Nanjing, China.

Background: The incidence of pediatric type 1 diabetes (T1D) is increasing worldwide, and the appropriate choice of therapy regimens is important for children, especially in developing countries with inadequate resources.

Methods: We conducted a design combining meta-analysis and prospective cohort study. In meta-analysis, 14 studies involving 69,085 TID cases reported glycosylated hemoglobin (HbA) levels, including 48,363 multiple daily insulin injections therapy (MIT) and 20,722 continuous subcutaneous insulin infusion (CSII). In our prospective cohort study, TID cases were recruited from a tertiary children's hospital, and randomly divided into Group MIT and Group CSII. After the 4-year follow-up, the effects of MDI (n = 112) and CSII (n = 76) therapy on glycemic control, long-term complications, as well as the growth and pubertal development were explored.

Results: Compared to CSII in TID, HbA levels in MDI (WMD = 0.21, 95% CI: 0.20 to 0.23) were increased significantly in meta-analysis. Among 188 clinical cases, mean age at recruitment was 7.55 (SD 2.91) years. Duration of TID was 4.23 (SD 2.61) years. 50.53% (n = 95) of them were boys. The 4-year follow-up showed that children's HbA was 0.67 (95% CI -1.28, -0.05) % lower in children with CSII compared to children with MDI in multivariable regression models with adjustment for potential confounders (children's age at follow-up, duration of TID, gender, birthweight, parity, and delivery method). CSII was associated with 2.31 kg higher in children's weight (95% CI 0.59, 4.04) in the adjusted model. No difference was found in peripheral nerve and fundus consequences as well as the status of obesity and thin and pubertal development between CSII and MIT.

Conclusion: CSII might be associated with better glycemic control and better effect for children growth development. No higher risks of long-term complications and delayed pubertal development were observed in CSII. Our findings provided evidence for a better therapy regimen for T1D in children, nevertheless, they need to be validated by a larger sample size study.
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http://dx.doi.org/10.3389/fendo.2021.608232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961074PMC
March 2021

Molecular and genetic biomarkers implemented from next-generation sequencing provide treatment insights in clinical practice for Waldenström macroglobulinemia.

Neoplasia 2021 04 15;23(4):361-374. Epub 2021 Mar 15.

Division of Hematopathology, Department of Pathology, Duke University Medical Center, Durham, NC, USA; Duke University Medical Center and Duke Cancer Institute, Durham, NC, USA. Electronic address:

Waldenström macroglobulinemia (WM) is a distinct type of indolent lymphoplasmacytic lymphoma (LPL) with a high frequency of MYD88 mutation. Treatment for WM/LPL is highly variable in clinic and ibrutinib (a Bruton tyrosine kinase inhibitor, BTKi) has become a new treatment option for WM. To investigate the clinical impact of genetic alterations in WM, we assembled a large cohort of 219 WMs and 12 LPLs dividing into two subcohorts: a training cohort, patients sequenced by a same targeted 29-gene next-generation sequencing (NGS) panel, and a validation cohort, patients sequenced by allele specific-PCR or other targeted NGS panels. In both training and validation subcohorts, MYD88 and TP53 mutations showed favorable and adverse prognostic effects, respectively. CXCR4 nonsense/missense mutations (CXCR4), cytogenetic complex karyotypes, and a family history of lymphoma/leukemia in first-degree relatives were associated with significantly worse clinical outcomes only or more in the validation subcohort. We further investigated the efficacy of various treatments and interaction with genetic factors in the entire cohort. Upfront dexamethasone usage was associated with poorer clinical outcomes in patients who received non-proteasome-containing chemotherapy as first-line treatment independent of genetic factors. Maintenance rituximab was associated with better survival. Ibrutinib/BTKi showed potential benefit in relapsed/refractory patients and patients without CXCR4 including those with TP53 mutations. In conclusion, genetic testing for MYD88, TP53, and CXCR4 mutations and cytogenetic analysis provide important information for prognosis prediction and therapy selection. The findings in these study are valuable for improving treatment decisions on therapies available for WM/LPL patients with integration of NGS in clinic.
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http://dx.doi.org/10.1016/j.neo.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985670PMC
April 2021

Updating targets for natural killer/T-cell lymphoma immunotherapy.

Cancer Biol Med 2021 Feb;18(1):52-62

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Lymphoma Diagnosis and Treatment Center of Henan, Zhengzhou 450052, China.

Natural killer/T-cell lymphoma (NKTCL) is a highly invasive subtype of non-Hodgkin lymphoma, typically positive for cytoplasmic CD3, CD56, cytotoxic markers, including granzyme B and TIA1, and Epstein-Barr virus (EBV). The current treatment methods for NKTCL are associated with several drawbacks. For example, chemotherapy can lead to drug resistance, while treatment with radiotherapy alone is inadequate and results in frequent relapses. Moreover, hematopoietic stem cell transplantation exhibits limited efficacy and is not well recognized by domestic and foreign experts. In recent years, immunotherapy has shown good clinical results and has become a hot spot in cancer research. Clinical activity of targeted antibodies, such as daratumumab (anti-CD38 antibody) and brentuximab vedotin (anti-CD30 antibody), have been reported in NKTCL. Additionally, dacetuzumab and Campath-1H have demonstrated promising results. Further encouraging data have been obtained using checkpoint inhibitors. The success of these immunotherapy agents is attributed to high expression levels of programmed death-ligand 1 in NKTCL. Furthermore, anti-CCR4 monoclonal antibodies (mAbs) exert cytotoxic actions on both CCR4+ tumor cells and regulatory T cells. Depletion of these cells and the long half-life of anti-CCR4 mAbs result in enhanced induction of antitumor effector T cells. The role of IL10 in NKTCL has also been investigated. It has been proposed that exploitation of this cytokine might provide potential novel therapeutic strategies. Cellular immunotherapy with engineered cytotoxic T lymphocytes targeted against LMP1 and LMP2 has shown promising results and sustained remission. Cellular immunotherapy may be used either as maintenance therapy following initial induction chemotherapy or in cases of relapsed/refractory disease. The present review outlines the known immunotherapy targets for the treatment of NKTCL.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877170PMC
February 2021

Corrigendum: CDC27 Promotes Tumor Progression and Affects PD-L1 Expression in T-Cell Lymphoblastic Lymphoma.

Front Oncol 2020 27;10:583698. Epub 2021 Jan 27.

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

[This corrects the article DOI: 10.3389/fonc.2020.00488.].
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http://dx.doi.org/10.3389/fonc.2020.583698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875015PMC
January 2021

Association between dietary sodium, potassium intake and lung cancer risk: evidence from the prostate, lung, colorectal and ovarian cancer screening trial and the Women's Health Initiative.

Transl Lung Cancer Res 2021 Jan;10(1):45-56

Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.

Background: Epidemiological studies have reported that dietary mineral intake plays an important role on lung cancer risk, but the association of sodium, potassium intake is still unclear.

Methods: We determined the association between dietary sodium, potassium intake and lung cancer risk based on the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial and the Women's Health Initiative (WHI). Totally 165,409 participants who completed the baseline questionnaire (BQ) and diet history questionnaire (DHQ) were included into the analytical dataset, including 92,984 (44,959 men and 48,025 women) from the PLCO trial and 72,425 (women only) from the WHI cohort. Multivariable Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident lung cancer associated with dietary potassium and sodium intake. The dose-response relationship was also described using the spline smoothed curve after adjusting covariates.

Results: After the median follow-up of 8.55 and 18.56 years, 1,278 and 1,631 new cases of lung cancer were identified in the PLCO trial and WHI cohort, respectively. Intake of sodium was significantly associated with the incidence of lung cancer in the PLCO trial after multivariate adjustment for men (HR: 1.19, 95% CI: 1.05-1.35; P for linear trend =0.044). There was a suggestion that lung cancer risk had a quadratic curve correlation with the increase of potassium intake for women (third vs. lowest quintile: HR: 0.72, 95% CI: 0.54-0.96; P for quadratic trend =0.042). The similar results showing an inverse association between potassium intake and lung cancer risk were also observed in the WHI cohort for women (highest vs. lowest quintile: HR: 0.82, 95% CI: 0.70-0.97; P for linear trend =0.009).

Conclusions: Appropriate intake of potassium has a protective effect against lung cancer, while high consumption of sodium is associated with an increased risk of lung cancer.
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http://dx.doi.org/10.21037/tlcr-20-870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867772PMC
January 2021

Efficacy and safety of geptanolimab (GB226) for relapsed or refractory peripheral T cell lymphoma: an open-label phase 2 study (Gxplore-002).

J Hematol Oncol 2021 01 12;14(1):12. Epub 2021 Jan 12.

Department of Hematology, The First Hospital of Lanzhou University, Lanzhou, China.

Background: Peripheral T cell lymphoma (PTCL) is a rare disease and recent approved drugs for relapsed/refractory (r/r) PTCL provided limited clinical benefit. We conducted this study to evaluate the efficacy and safety of geptanolimab (GB226), an anti-PD-1 antibody, in r/r PTCL patients.

Methods: We did this single-arm, multicenter phase 2 study across 41 sites in China. Eligible patients with r/r PTCL received geptanolimab 3 mg/kg intravenously every 2 weeks until disease progression or intolerable toxicity. All patients who received at least one dose of geptanolimab and histological confirmed PTCL entered full analysis set (FAS). The primary endpoint was objective response rate (ORR) in FAS assessed by the independent radiological review committee (IRRC) per Lugano 2014 criteria.

Results: Between July 12, 2018, and August 15, 2019, 102 patients were enrolled and received at least one dose of geptanolimab. At the data cutoff date (August 15, 2020), the median follow-up was 4.06 (range 0.30-22.9) months. For 89 patients in FAS, 36 achieved objective response (40.4%, 95% CI 30.2-51.4), of which 13 (14.6%) were complete response and 23 (25.8%) had partial response assessed by IRRC. The median duration of response (DOR) was 11.4 (95% CI 4.8 to not reached) months per IRRC. Patients with PD-L1 expression ≥ 50% derived more benefit from geptanolimab treatment compared to < 50% ones (ORR, 53.3% vs. 25.0%, p = 0.013; median PFS 6.2 vs. 1.5 months, p = 0.002). Grade ≥ 3 treatment-related adverse events occurred in 26 (25.5%) patients, and the most commonly observed were lymphocyte count decreased (n = 4) and platelet count decreased (n = 3). Serious adverse events were observed in 45 (44.1%) patients and 19 (18.6%) were treatment related.

Conclusions: In this study, geptanolimab showed promising activity and manageable safety profile in patients with r/r PTCL. Anti-PD-1 antibody could be a new treatment approach for this patient population.

Trial Registration: This clinical trial was registered at the ClinicalTrials.gov (NCT03502629) on April 18, 2018.
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http://dx.doi.org/10.1186/s13045-021-01033-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802130PMC
January 2021

Relmacabtagene autoleucel (relma-cel) CD19 CAR-T therapy for adults with heavily pretreated relapsed/refractory large B-cell lymphoma in China.

Cancer Med 2021 02 31;10(3):999-1011. Epub 2020 Dec 31.

Department of Lymphoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China.

Background: Despite numerous chimeric antigen receptor T-cell (CAR-T) trials conducted in China, no CAR-T has been registered in the country. Furthermore, China law and regulations restrict the export of patient material for CAR-T manufacture abroad. Relma-cel (JWCAR029), an anti-CD19 product produced with a commercial-ready process in China, was evaluated in the first prospective, single-arm, multicenter, pivotal study of CAR-T therapy conducted under Chinese IND to support an NMPA-accepted BLA submission in relapsed/refractory (r/r) LBCL (NCT04089215).

Methods: Patients were randomized to receive either 100 × 10 (low dose, n = 27) or 150 × 10 (high dose, n = 32) CAR+ T-cells as a single infusion following lymphodepleting chemotherapy (fludarabine 25 mg/m and cyclophosphamide 250 mg/m daily × 3), and then, monitored for efficacy and safety outcomes and pharmacokinetics. The primary endpoint was ORR at 3 months, as assessed by the investigators. Secondary endpoints included DOR, PFS, OS, and adverse event frequency/severity and cell expansion kinetics.

Results: As of the data cutoff on 17 June 2020, 68 patients were enrolled, and 59 were treated. Among the 58 efficacy-evaluable patients, the primary endpoint of 3 month ORR was 60.3% (95% CI, 46.6-73.0), excluding the null hypothesis rate of 20%. Any grade and severe grade CRS occurred in 47.5% and 5.1%, respectively, and any grade and severe grade neurotoxicity events occurred in 20.3% and 5.1%.

Conclusions: Relma-cel met the primary endpoint analysis and demonstrated a high rate of durable responses and low rate of CAR-T-associated toxicities in patients with r/r LBCL in a multicenter trial supporting regulatory submission in China.
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http://dx.doi.org/10.1002/cam4.3686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897944PMC
February 2021

Selection of new immunotherapy targets for NK/T cell lymphoma.

Am J Transl Res 2020 15;12(11):7034-7047. Epub 2020 Nov 15.

Department of Oncology, Zhengzhou University First Affiliated Hospital, Lymphoma Diagnosis and Treatment Center of Henan Province No. 1 Jianshe East Road, Zhengzhou, Henan, China.

Extranodal NK/T cell lymphoma, nasal type, is a rare type of non-Hodgkin's lymphoma (NHL), and the aetiology is not fully understood. Although the clinical outcome of anthracycline-based chemotherapy was dismal because of multidrug resistance (MDR). Novel therapeutic strategies including L-asparaginase-containing regimens, radiotherapy, sequential chemotherapy and radiotherapy, and concurrent chemoradiotherapy (CCRT) have remarkably improved outcomes. However, the overall survival (OS) rate of advanced stage patients is not satisfactory compared with patients with non-advanced-stage disease. Immunotherapy is a promising treatment for ENKTCL. Indeed, it has been proven that targeted therapies such as anti-CD30 antibodies and naked anti-CD38 antibodies are effective. In addition to these therapies that target cell surface antigens, therapies targeting intracellular signalling pathways and the microenvironment are considerably beneficial. EBV-driven overexpression of latent membrane proteins [LMP1 and LMP2] activates the pro-proliferation NF-κB/MAPK signalling pathway and leads to high PD-L1 expression. Binding of PD-L1 to PD-1 expressing cytotoxic T cells causes apoptosis and inactivation of T lymphocytes, achieving immune escape. On the basis of this mechanism, a variety of small molecular inhibitors, such as anti-PD-1 antibodies, NF-κB inhibitors, EBV antigens, and LMP1 and LMP2 antigens, can be applied. Via another signalling pathway the JAK/STAT pathway, upregulation and activation and mutation of genes promotes proliferation and ENKTCL lymphomagenesis, and JAK inhibitors have thus been applied. This article reviews recent advances in ENKTCL immunotherapy as a promising treatment for this fatal disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724344PMC
November 2020

Baseline Total Metabolic Tumor Volume and Total Lesion Glycolysis Measured on 18F-FDG PET-CT Predict Outcomes in T-Cell Lymphoblastic Lymphoma.

Cancer Res Treat 2020 Dec 2. Epub 2020 Dec 2.

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Purpose: There is no optimal prognostic model for T-cell lymphoblastic lymphoma (T-LBL). Here, we discussed the predictive value of total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) measured on 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) in T-LBL.

Materials And Methods: Thirty-seven treatment naïve T-LBL patients with PET-CT scans were enrolled. TMTV was obtained using the 41% maximum standardized uptake value (SUVmax) threshold method, and TLG was measured as MTV multiplied by the mean SUV. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier curves and compared by the log-rank test.

Results: The optimal cutoff values for SUVmax, TMTV, and TLG were 12.7, 302 cm3, and 890, respectively. A high SUVmax, TMTV, and TLG indicated a shorten PFS and OS. On multivariable analysis, TMTV ≥ 302 cm3, and central nervous system (CNS) involvement predicted inferior PFS, while high SUVmax, TLG and CNS involvement were associated with worse OS. Subsequently, we generated a risk model comprising high SUVmax, TMTV or TLG and CNS involvement, which stratified the population into three risk groups, which had significantly different median PFS of not reached, 14 months, and 7 months for low-risk group, mediate-risk group, and high-risk group, respectively (p < 0.001). Median OS were not reached, 27 months, and 13 months, respectively (p < 0.001).

Conclusion: Baseline SUVmax, TMTV, and TLG measured on PET-CT are strong predictors of worse outcome in T-LBL. A risk model integrating these three parameters with CNS involvement identifies patients at high risk of disease progression.
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http://dx.doi.org/10.4143/crt.2020.123DOI Listing
December 2020

Peritoneal macrophages attenuate retinal ganglion cell survival and neurite outgrowth.

Neural Regen Res 2021 Jun;16(6):1121-1126

Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong Province, China.

Inflammation is a critical pathophysiological process that modulates neuronal survival in the central nervous system after disease or injury. However, the effects and mechanisms of macrophage activation on neuronal survival remain unclear. In the present study, we co-cultured adult Fischer rat retinas with primary peritoneal macrophages or zymosan-treated peritoneal macrophages for 7 days. Immunofluorescence analysis revealed that peritoneal macrophages reduced retinal ganglion cell survival and neurite outgrowth in the retinal explant compared with the control group. The addition of zymosan to peritoneal macrophages attenuated the survival and neurite outgrowth of retinal ganglion cells. Conditioned media from peritoneal macrophages also reduced retinal ganglion cell survival and neurite outgrowth. This result suggests that secretions from peritoneal macrophages mediate the inhibitory effects of these macrophages. In addition, increased inflammation- and oxidation-related gene expression may be related to the enhanced retinal ganglion cell degeneration caused by zymosan activation. In summary, this study revealed that primary rat peritoneal macrophages attenuated retinal ganglion cell survival and neurite outgrowth, and that macrophage activation further aggravated retinal ganglion cell degeneration. This study was approved by the Animal Ethics Committee of the Joint Shantou International Eye Center of Shantou University and the Chinese University of Hong Kong, Shantou, Guangdong Province, China, on March 11, 2014 (approval no. EC20140311(2)-P01).
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http://dx.doi.org/10.4103/1673-5374.300462DOI Listing
June 2021

Epigenetic alterations and advancement of treatment in peripheral T-cell lymphoma.

Clin Epigenetics 2020 11 7;12(1):169. Epub 2020 Nov 7.

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, 450052, Henan Province, China.

Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of clinically aggressive diseases associated with poor prognosis. Except for ALK + anaplastic large-cell lymphoma (ALCL), most peripheral T-cell lymphomas are highly malignant and have an aggressive disease course and poor clinical outcomes, with a poor remission rate and frequent relapse after first-line treatment. Aberrant epigenetic alterations play an important role in the pathogenesis and development of specific types of peripheral T-cell lymphoma, including the regulation of the expression of genes and signal transduction. The most common epigenetic alterations are DNA methylation and histone modification. Histone modification alters the level of gene expression by regulating the acetylation status of lysine residues on the promoter surrounding histones, often leading to the silencing of tumour suppressor genes or the overexpression of proto-oncogenes in lymphoma. DNA methylation refers to CpG islands, generally leading to tumour suppressor gene transcriptional silencing. Genetic studies have also shown that some recurrent mutations in genes involved in the epigenetic machinery, including TET2, IDH2-R172, DNMT3A, RHOA, CD28, IDH2, TET2, MLL2, KMT2A, KDM6A, CREBBP, and EP300, have been observed in cases of PTCL. The aberrant expression of miRNAs has also gradually become a diagnostic biomarker. These provide a reasonable molecular mechanism for epigenetic modifying drugs in the treatment of PTCL. As epigenetic drugs implicated in lymphoma have been continually reported in recent years, many new ideas for the diagnosis, treatment, and prognosis of PTCL originate from epigenetics in recent years. Novel epigenetic-targeted drugs have shown good tolerance and therapeutic effects in the treatment of peripheral T-cell lymphoma as monotherapy or combination therapy. NCCN Clinical Practice Guidelines also recommended epigenetic drugs for PTCL subtypes as second-line therapy. Epigenetic mechanisms provide new directions and therapeutic strategies for the research and treatment of peripheral T-cell lymphoma. Therefore, this paper mainly reviews the epigenetic changes in the pathogenesis of peripheral T-cell lymphoma and the advancement of epigenetic-targeted drugs in the treatment of peripheral T-cell lymphoma (PTCL).
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http://dx.doi.org/10.1186/s13148-020-00962-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648940PMC
November 2020

Research on the midterm efficacy and prognosis of patients with diffuse large B-cell lymphoma by different evaluation methods in interim PET/CT.

Eur J Radiol 2020 Dec 24;133:109301. Epub 2020 Sep 24.

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China. Electronic address:

Purpose: To investigate the midterm efficacy and prognostic evaluation of patients with diffuse large B-cell lymphoma (DLBCL) by three image analysis methods: International Harmonization Project (IHP), Deauville 5-Point Scale (5-PS) and Δ SUVmax criteria in F-FDG PET/CT.

Methods: This was a retrospective analysis of 141 patients with DLBCL. All patients were given 3-4 cycles of chemotherapy and F-FDG PET/CT. According to three criteria, the patients were divided into negative and positive groups, respectively. Statistical methods were used to assess the midterm efficacy and prognosis factors.

Results: During the midterm follow-up, a total of 109 people achieved CR. Three methods showed statistically significant differences in OS and PFS for the interim PET/CT, and Δ SUVmax criterion was an independent risk factor for the prognosis of DLBCL patients.

Conclusion: In our research, IHP, 5-PS and Δ SUVmax criteria all had a significant predictive value, while Δ SUVmax criterion had more advantages in evaluating the midterm efficacy and predicting prognosis for patients with DLBCL in interim PET/CT. But it should be noticed that Δ SUVmax criterion needs more strict guidelines in multicenter trials. The optimal cutoff value of Δ SUVmax% we recommended was 81.54%, which helped to judge the midterm efficacy.
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http://dx.doi.org/10.1016/j.ejrad.2020.109301DOI Listing
December 2020

XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53.

J Hematol Oncol 2020 11 4;13(1):148. Epub 2020 Nov 4.

Division of Hematopathology, Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA.

The XPO1 inhibitor selinexor was recently approved in relapsed/refractory DLBCL patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL. High XPO1 expression (XPO1) showed significant adverse prognostic impact in 544 studied DLBCL patients, especially in those with BCL2 overexpression. Therapeutic study in 30 DLBCL cell lines with various molecular and genetic background found robust cytotoxicity of selinexor, especially in cells with BCL2-rearranged (BCL2-R) DLBCL or high-grade B-cell lymphoma with MYC/BCL2 double-hit (HGBCL-DH). However, expression of mutant (Mut) p53 significantly reduced the cytotoxicity of selinexor in overall cell lines and the BCL2-R and HGBCL-DH subsets, consistent with the favorable impact of XPO1 observed in Mut-p53-expressing patients. The therapeutic effect of selinexor in HGBCL-DH cells was significantly enhanced when combined with a BET inhibitor INCB057643, overcoming the drug resistance in Mut-p53-expressing cells. Collectively, these data suggest that XPO1 worsens the survival of DLBCL patients with unfavorable prognostic factors such as BCL2 overexpression and double-hit, in line with the higher efficacy of selinexor demonstrated in BCL2-R DLBCL and HGBCL-DH cell lines. Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.
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http://dx.doi.org/10.1186/s13045-020-00982-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641823PMC
November 2020

Potential strategies against resistance to CAR T-cell therapy in haematological malignancies.

Ther Adv Med Oncol 2020 13;12:1758835920962963. Epub 2020 Oct 13.

Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.

Chimeric antigen receptor (CAR) T-cell therapy is a rapidly developing method for adoptive immunotherapy of tumours in recent years. CAR T-cell therapies have demonstrated unprecedented efficacy in the treatment of patients with haematological malignancies. A 90% complete response (CR) rate has been reported in patients with advanced relapse or refractory acute lymphoblastic leukaemia, while >50% CR rates have been reported in cases of chronic lymphocytic leukaemia and partial B-cell lymphoma. Despite the high CR rates, a subset of the patients with complete remission still relapse. The mechanism of development of resistance is not clearly understood. Some patients have been reported to demonstrate antigen-positive relapse, whereas others show antigen-negative relapses. Patients who relapse following CAR T-cell therapy, have very poor prognosis and novel approaches to overcome resistance are required urgently. Herein, we have reviewed current literature and research that have investigated the strategies to overcome resistance to CAR T-cell therapy.
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http://dx.doi.org/10.1177/1758835920962963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576929PMC
October 2020